diff --git a/.DS_Store b/.DS_Store new file mode 100644 index 0000000000000000000000000000000000000000..716e79e1b3fee04a254d687c24178333a3304bf5 Binary files /dev/null and b/.DS_Store differ diff --git a/12136306.json b/12136306.json new file mode 100644 index 0000000000000000000000000000000000000000..2d6f89ea288e0d989c55e137a7107bddac25c354 --- /dev/null +++ b/12136306.json @@ -0,0 +1,8 @@ +{ + "id": "12136306", + "label": 0, + "article": { + "id": "12136306", + "text": "We report an infant with geleophysic dysplasia (MIM 231050) who developed multiple trigger fingers. The condition was progressive and distinct from trigger thumb, which is generally seen in infants without any underlying metabolic disease." + } +} \ No newline at end of file diff --git a/16105694.json b/16105694.json new file mode 100644 index 0000000000000000000000000000000000000000..b2344285a4d8b535472fe757a6f6a96b550fc418 --- /dev/null +++ b/16105694.json @@ -0,0 +1,8 @@ +{ + "id": "16105694", + "label": 0, + "article": { + "id": "16105694", + "text": "Clinical evaluation of children with skeletal dysplasias is often concentrated on morphologic and radiographic assessments, but many of these patients also have disease processes of the ear, nose, and throat. We report a case of an 11-month-old girl with an unknown short-limbed dwarfism, similar to acromicric dysplasia, with grade II subglottic stenosis. Laryngotracheoplasty with anterior autologous costal cartilage graft and posterior cricoid split was performed at age 13 months, with subsequent improvement of her airway status. In cases of children with skeletal dysplasias and obstructive airway symptoms, formal otolaryngologic evaluation is warranted for definitive diagnosis and treatment." + } +} \ No newline at end of file diff --git a/23027497.json b/23027497.json new file mode 100644 index 0000000000000000000000000000000000000000..8df2fbdaeeb7209192f618f80c1ceef91ff07b87 --- /dev/null +++ b/23027497.json @@ -0,0 +1,8 @@ +{ + "id": "23027497", + "label": 0, + "article": { + "id": "23027497", + "text": "Acromicric dysplasia is a skeletal dysplasia that is characterized by short stature, short hands and feet, typical facial dysmorphism, normal mental development, and characteristic hand radiology. Carpal tunnel syndrome may be seen in adults with acromicric dysplasia; however, to the authors' knowledge, it has not been reported in pediatric patients. This article describes a 9-year old boy with bilateral carpal tunnel syndrome and acromicric dysplasia treated operatively. No recurrences occurred during 1 year of postoperative follow-up.Carpal tunnel syndrome is a rare disease in childhood. The etiologic factors of carpal tunnel syndrome include trauma (especially distal radius epiphysealis), overuse, genetic or metabolic disorders, space-occupying lesions in the carpal tunnel, hemophilia, congenital anomalies, adverse effect of growth hormone replacement therapy, and idiopathic carpal tunnel syndrome. Acromicric dysplasia should be considered in the etiology of childhood carpal tunnel syndrome.The surgical outcome of carpal tunnel syndrome is good with early diagnosis and treatment. However, in the case of skeletal dysplasia, the diagnosis of carpal tunnel syndrome may be delayed due to anomalies of the hand and due to the child's difficulty in expressing symptoms. Because of the delay in diagnosis of carpal tunnel syndrome in patients with skeletal dysplasia, the treatment outcomes may not be promising. Electrophysiologic studies should be performed early when the clinical signs are positive." + } +} \ No newline at end of file diff --git a/23514648.json b/23514648.json new file mode 100644 index 0000000000000000000000000000000000000000..a9453cf275a0b8465bc6e430f8dbbdf12a91837d --- /dev/null +++ b/23514648.json @@ -0,0 +1,8 @@ +{ + "id": "23514648", + "label": 0, + "article": { + "id": "23514648", + "text": "In this case report, we present occurrence of bilateral angle closure glaucoma in a 9-year-old girl with geleophysic dysplasia. Bilateral YAG laser iridotomy was applied, but intraocular pressure (IOP) remained at high levels, necessitating bilateral trabeculectomy with mitomycin C. On her follow-up examinations for 3 years, IOP remained in the mid-20s with no need for further intervention or antiglaucoma medication. There are few reports describing the ocular findings of geleophysic dysplasia in literature. To our knowledge, this is the first case report describing an application of glaucoma surgery and its results at geleophysic dysplasia." + } +} \ No newline at end of file diff --git a/24339047.json b/24339047.json new file mode 100644 index 0000000000000000000000000000000000000000..3a56aff0ea383d284de26e01046281c7f083f280 --- /dev/null +++ b/24339047.json @@ -0,0 +1,8 @@ +{ + "id": "24339047", + "label": 0, + "article": { + "id": "24339047", + "text": "UNLABELLED:\nAcromicric dysplasia (AD) is an autosomal dominant disorder characterized by short stature, short extremities, stiff joint and skeleton features including brachymetacarpia, cone-shaped epiphyses, internal notch of the femoral head, and delayed bone age. Recently, we identified fibrillin 1 (FBN1) as the disease gene of AD. The aim of our study was to further describe the long-term follow up of AD patients with an emphasis on orthopedic management. Nine patients with FBN1 mutations were included in the study ranging in age from 5.5 to 64 years. For all, detailed clinical and radiological data were available.\n\nRESULTS:\nBirth parameters were always normal and patients progressively developed short stature \u003c-3 SD. Carpal tunnel syndrome was observed in four patients. We found discrepancy between the carpal bone age and the radius and ulna epiphysis bone ages, a variable severity of hip dysplasia with acetabular dysplasia, epiphyseal and metaphyseal femoral dysplasia resembling Legg-Perthes-Calvé disease and variable pelvic anteversion and hyperlordosis. Orthopedic surgery was required in two patients for hip dysplasia, in one for limb lengthening and in three for carpal tunnel syndrome. Our observations expand the AD phenotype and emphasize the importance of regular orthopedic survey." + } +} \ No newline at end of file diff --git a/25762570.json b/25762570.json new file mode 100644 index 0000000000000000000000000000000000000000..64821769dd4dfb1d40c1402091a7fc1add775734 --- /dev/null +++ b/25762570.json @@ -0,0 +1,8 @@ +{ + "id": "25762570", + "label": 0, + "article": { + "id": "25762570", + "text": "Mutations in the secreted glycoprotein ADAMTSL2 cause recessive geleophysic dysplasia (GD) in humans and Musladin-Lueke syndrome (MLS) in dogs. GD is a severe, often lethal, condition presenting with short stature, brachydactyly, stiff skin, joint contractures, tracheal-bronchial stenosis and cardiac valve anomalies, whereas MLS is non-lethal and characterized by short stature and severe skin fibrosis. Although most mutations in fibrillin-1 (FBN1) cause Marfan syndrome (MFS), a microfibril disorder leading to transforming growth factor-β (TGFβ) dysregulation, domain-specific FBN1 mutations result in dominant GD. ADAMTSL2 has been previously shown to bind FBN1 and latent TGFβ-binding protein-1 (LTBP1). Here, we investigated mice with targeted Adamtsl2 inactivation as a new model for GD (Adamtsl2(-/-) mice). An intragenic lacZ reporter in these mice showed that ADAMTSL2 was produced exclusively by bronchial smooth muscle cells during embryonic lung development. Adamtsl2(-/-) mice, which died at birth, had severe bronchial epithelial dysplasia with abnormal glycogen-rich inclusions in bronchial epithelium resembling the cellular anomalies described previously in GD. An increase in microfibrils in the bronchial wall was associated with increased FBN2 and microfibril-associated glycoprotein-1 (MAGP1) staining, whereas LTBP1 staining was increased in bronchial epithelium. ADAMTSL2 was shown to bind directly to FBN2 with an affinity comparable to FBN1. The observed extracellular matrix (ECM) alterations were associated with increased bronchial epithelial TGFβ signaling at 17.5 days of gestation; however, treatment with TGFβ-neutralizing antibody did not correct the epithelial dysplasia. These investigations reveal a new function of ADAMTSL2 in modulating microfibril formation, and a previously unsuspected association with FBN2. Our studies suggest that the bronchial epithelial dysplasia accompanying microfibril dysregulation in Adamtsl2(-/-) mice cannot be reversed by TGFβ neutralization, and thus might be mediated by other mechanisms." + } +} \ No newline at end of file diff --git a/27078247.json b/27078247.json new file mode 100644 index 0000000000000000000000000000000000000000..ca34112f3191a5db481d78d5ec180496e1e81f8c --- /dev/null +++ b/27078247.json @@ -0,0 +1,8 @@ +{ + "id": "27078247", + "label": 0, + "article": { + "id": "27078247", + "text": "HISTORY AND CLINICAL PRESENTATION:\nA 53-year old woman with recurrent polyarthralgias, negative test results in a recent rheumatologic work-up and an unmeasurably low uric acid serum concentration presented for suspected IgM paraproteinemia.\n\nINVESTIGATIONS:\nPhysical examination, abdominal ultrasound and routine laboratory test results were unremarkable. Repeat determination confirmed a markedly decreased uric acid (UA) serum concentration. Urinary xanthine and hypoxanthine concentrations were increased by 14-fold and 7.5-fold, respectively. Fractional urinary UA excretion was not increased and the allopurinol loading test was normal. Sequencing of the xanthine dehydrogenase (XDH) gene revealed the pathogenic deletion c.641delC in the homozygous state. Segregation analysis showed that the patient's mother and her two adult sons were carriers of the mutation but not a half-sister and a half-brother of her deceased father. There was no evidence of parental consanguinity. These results established xanthinuria type 1 as the cause of the patient's recurrent polyarthralgias due to a previously unreported homozygosity for the known mutation c.641delC of the XDH gene.\n\nTREATMENT AND COURSE:\nThe patient was advised to adhere to a low-purine diet and to ensure an increased daily fluid-intake of at least 2.5 l. She has since remained symptom free.\n\nCONCLUSION:\nMarkedly lowered serum uric acid concentrations are a hallmark of xanthinuria and of hereditary renal hypouricemia, and in the absence of severe hepatic failure or evidence of an untoward drug effect should raise suspicion of these diseases. A targeted diagnostic work-up should then be initiated and factitious hypouricemia due to IgM paraproteinemia considered only in the case of equivocal test results. Molecular-genetic characterization and segregation analysis will ultimately establish the underlying genotype." + } +} \ No newline at end of file diff --git a/27112522.json b/27112522.json new file mode 100644 index 0000000000000000000000000000000000000000..b783b4800af04a85873e357387b0f7c044fcb8e7 --- /dev/null +++ b/27112522.json @@ -0,0 +1,8 @@ +{ + "id": "27112522", + "label": 0, + "article": { + "id": "27112522", + "text": "OBJECTIVE:\nThe objective of this study was to describe the adverse effects of allopurinol on the urinary system during treatment of canine leishmaniasis.\n\nMETHODS:\nRetrospective case series of 42 dogs that developed xanthinuria while receiving allopurinol treatment for leishmaniasis.\n\nRESULTS:\nOf 320 dogs diagnosed with leishmaniasis, 42 (13%) developed adverse urinary effects. Thirteen (of 42) dogs (31%) developed xanthinuria, renal mineralisation and urolithiasis; 11 (26·2%) showed xanthinuria with renal mineralisation; 9 (21·4%) had xanthinuria with urolithiasis and 9 (21·4%) developed xanthinuria alone. Urinary clinical signs developed in 19 dogs (45·2%).\n\nCLINICAL SIGNIFICANCE:\nThis study demonstrates that urolithiasis and renal mineralisation can occur in dogs receiving allopurinol therapy. Dogs receiving therapy should be monitored for the development of urinary adverse effects from the beginning of treatment." + } +} \ No newline at end of file diff --git a/28495197.json b/28495197.json new file mode 100644 index 0000000000000000000000000000000000000000..e29772240d8592b35f3e241ee032e9559954183e --- /dev/null +++ b/28495197.json @@ -0,0 +1,8 @@ +{ + "id": "28495197", + "label": 0, + "article": { + "id": "28495197", + "text": "First-line treatment for canine leishmaniosis (CanL) is N-methylglucamine antimoniate (MGA) combined with allopurinol. However, in some dogs allopurinol may induce hyperxanthinuria leading to urolithiasis. Moreover, allopurinol resistance has recently been described in Leishmania infantum isolates from treated dogs with a relapse of the disease. Alternative treatments are thus needed. Since the type of host immune response strongly influences CanL progression and prognosis, dogs could benefit from treatments targeted at modulating such response, such as nucleotides and active hexose correlated compound (AHCC). The aim of this study was to evaluate the effects of an oral combination of nucleotides and AHCC in dogs with clinical leishmaniosis. Sixty-nine dogs with naturally-occurring clinical leishmaniosis were included in this multicenter, open-label, positively-controlled clinical trial and randomized to receive 10mg/kg allopurinol PO BID (allopurinol group) or 17mg/kg AHCC plus 32mg/kg nucleotides PO SID (supplement group) for 180 days. All dogs were also given 50mg/kg MGA SC BID during the first 28 days. At the time points 0, 30, and 180 days of the trial, dogs underwent a clinical examination, and blood, urine, and bone marrow samples were submitted for analytical tests. Final data analyses (allopurinol group: n=29; supplement group: n=24) revealed a significant improvement in both groups in clinical scores and ELISA-determined antibody titers after treatment. However, the supplement group showed a significantly lower clinical score (P=0.005) and significantly higher antibody titers (P=0.032) after 180 days, compared to the allopurinol group. RT-PCR parasite loads were reduced in groups (mean±SD supplement: 0.38±0.56 vs 5.23±18.9; allopurinol: 0.45±1.47 vs 3.09±8.36 parasites/ng of DNA), but there were no significant differences over time or between groups. During the study, 12 dogs in the allopurinol group developed xanthinuria (41%) compared to no dogs (0%) in the supplement group (P=0.000). Both treatments led to significantly increased CD4+/CD8+ ratio, and improvements in protein electrophoretic pattern and acute phase response. In conclusion, 6-month oral treatment with nucleotides and AHCC in addition to MGA showed similar efficacy to the current first-line treatment for CanL, without producing xanthinuria. This combination could be a good alternative to MGA-allopurinol combination treatment for CanL, especially for dogs suffering allopurinol-related adverse events." + } +} \ No newline at end of file diff --git a/28587840.json b/28587840.json new file mode 100644 index 0000000000000000000000000000000000000000..ac92ab03c2d0d94006b491ef1a5f30b94b12a99c --- /dev/null +++ b/28587840.json @@ -0,0 +1,8 @@ +{ + "id": "28587840", + "label": 0, + "article": { + "id": "28587840", + "text": "The chewing lice (Mallophaga) are common parasites of different animals. Most of them infest terrestrial and marine birds, including pigeons, doves, swans, cormorants and penguins. Mallophaga have not been found on marine mammals but only on terrestrial ones, including livestock and pets. Their bites damage cattle, sheep, goats, horses and poultry, causing itch and scratch and arousing phthiriasis and dermatitis. Notably, Mallophaga can vector important parasites, such as the filarial heartworm Sarconema eurycerca. Livestock losses due to chewing lice are often underestimated, maybe because farmers notice the presence of the biting lice only when the infestation is too high. In this review, we examined current knowledge on the various strategies available for Mallophaga control. The effective management of their populations has been obtained through the employ of several synthetic insecticides. However, pesticide overuse led to serious concerns for human health and the environment. Natural enemies of Mallophaga are scarcely studied. Their biological control with predators and parasites has not been explored yet. However, the entomopathogenic fungus Metarhizium anisopliae has been reported as effective in vitro and in vivo experiments against Damalinia bovis infestation on cattle. Furthermore, different Bacillus thuringiensis preparations have been tested against Mallophaga, the most effective were B. thuringiensis var. kurstaki, kenyae and morrisoni. Lastly, plant-borne insecticides have been evaluated against Mallophaga. Tested products mainly contained bioactive principles from two Meliaceae, Azadirachta indica, and Carapa guianensis. High efficacy of neem-borne preparations was reported, leading to the development of several products currently marketed. Overall, our review highlighted that our knowledge about Mallophaga vector activity and control is extremely patchy. Their control still relied on the employ of chemical pesticides widely used to fight other primary pests and vectors of livestock, such as ticks, while the development of eco-friendly control tool is scarce. Behavior-based control of Mallophaga, using pheromone-based lures or even the Sterile Insect Technique (SIT) may also represent a potential route for their control, but our limited knowledge on their behavioral ecology and chemical communication strongly limit any possible approach." + } +} \ No newline at end of file diff --git a/28917829.json b/28917829.json new file mode 100644 index 0000000000000000000000000000000000000000..931c47a9b5e8c0be4b9526824c84d287775fba79 --- /dev/null +++ b/28917829.json @@ -0,0 +1,8 @@ +{ + "id": "28917829", + "label": 0, + "article": { + "id": "28917829", + "text": "Geleophysic dysplasia, belonging to the group of acromelic dysplasia, is a rare genetic disease. Two genes, FBN1 and ADAMTSL2, were known to be linked to this disorder. The disorder presents as extreme short stature, short limbs, small hands and feet, stubby fingers and toes, joint stiffness, toe walking, skin thickening, progressive cardiac valvular thickening and characteristic facial features, including a round face with full cheeks. Here, we report the first Chinese case with geleophysic dysplasia type 1 based on clinical and genetic features. The boy was admitted because of severe physical growth retardation and mild motor retardation. Comprehensive medical evaluations were performed including metabolic studies, endocrine function examination, bone X-rays and echocardiography. Much delayed bone age and geleophysic dysplasia were found. Targeted next-generation sequencing was used to detect genetic mutations associated with skeletal dysplasia. Sanger sequencing was used to confirm the mutations in the patient. PCR amplification, cloing, and sequencing was used to determine the de novo mutation origin. Two compound heterozygous mutations were confirmed in the ADAMTSL2 gene of the patient. The c.340G \u003e A (p.Glu114Lys) mutation was a de novo heterozygous mutation, and our results suggested that it was located on the paternal allele. While the c.234-2A \u003e G inherited from his mother was a novel pathogenic heterozygous splicing mutation. Growth hormone deficiency had been observed in the patient. His growth velocity was improved by growth hormone supplementation. In conclusion, we have identified a novel splicing mutation of ADAMTSL2 carried by a Chinese boy with geleophysic dysplasia type 1. The patient was treated effectively with growth hormone supplementation." + } +} \ No newline at end of file diff --git a/29432500.json b/29432500.json new file mode 100644 index 0000000000000000000000000000000000000000..9281a6bac777310bf8c7b15e807dab2eee276cf8 --- /dev/null +++ b/29432500.json @@ -0,0 +1,8 @@ +{ + "id": "29432500", + "label": 0, + "article": { + "id": "29432500", + "text": "Many animal models in different species have been developed for mental and behavioral disorders. This review presents large animals (dog, ovine, swine, horse) as potential models of this disorders. The article was based on the researches that were published in the peer-reviewed journals. Aliterature research was carried out using the PubMed database. The above issues were discussed in the several problem groups in accordance with the WHO International Statistical Classification of Diseases and Related Health Problems 10thRevision (ICD-10), in particular regarding: organic, including symptomatic, disorders; mental disorders (Alzheimer's disease and Huntington's disease, pernicious anemia and hepatic encephalopathy, epilepsy, Parkinson's disease, Creutzfeldt-Jakob disease); behavioral disorders due to psychoactive substance use (alcoholic intoxication, abuse of morphine); schizophrenia and other schizotypal disorders (puerperal psychosis); mood (affective) disorders (depressive episode); neurotic, stress-related and somatoform disorders (posttraumatic stress disorder, obsessive-compulsive disorder); behavioral syndromes associated with physiological disturbances and physical factors (anxiety disorders, anorexia nervosa, narcolepsy); mental retardation (Cohen syndrome, Down syndrome, Hunter syndrome); behavioral and emotional disorders (attention deficit hyperactivity disorder). This data indicates many large animal disorders which can be models to examine the above human mental and behavioral disorders." + } +} \ No newline at end of file diff --git a/29599887.json b/29599887.json new file mode 100644 index 0000000000000000000000000000000000000000..df00c3583b70565f5ed034aeade62ad61b87a184 --- /dev/null +++ b/29599887.json @@ -0,0 +1,8 @@ +{ + "id": "29599887", + "label": 0, + "article": { + "id": "29599887", + "text": "Pepper's syndrome is a neuroblastoma that metastasizes to the liver. It affects infants younger than six months of age. It can regress spontaneously and is associated with a favorable prognosis in 80% of cases. Given its rarity, we here report two cases of Pepper's syndrome observed at the Charles de Gaulle university pediatric hospital center, Ouagadougou (Burkina Faso). Our study involved two female infants in whom the disease manifested as an increase in abdominal volume, hepatomegaly and signs of respiratory distress. Ultrasound enabled diagnosis, which was based on the nodular appearance of the liver in both cases and determination of the primary tumor in one case. Urinary catecholamine test confirmed the diagnosis in one case. Both patients died from complications related to liver compression, chemotherapy (in one of the cases) and lack of treatment (in the other case)." + } +} \ No newline at end of file diff --git a/29758347.json b/29758347.json new file mode 100644 index 0000000000000000000000000000000000000000..985f06f21466d889c808293c151d60dabe9d9165 --- /dev/null +++ b/29758347.json @@ -0,0 +1,8 @@ +{ + "id": "29758347", + "label": 0, + "article": { + "id": "29758347", + "text": "Cohen syndrome is a rare, genetic, connective-tissue disorder, which is caused by mutations in the gene COH1 (VPS13B, Vacuolar Protein Sorting 13 Homolog B) at the chromosome 8q22. The disease is rare reported, which major clinical features include postnatal microcephaly, obesity, short stature, intellectual disability, progressive retinal dystrophy, intermittent neutropenia and many other unusual facial feature. We report four patients in China who were diagnosed with Cohen syndrome by genetic testing and clinical manifestations. At the same time, we review the related literature, and further expound the molecular mechanism of the disease, a variety of clinical manifestations, treatment and prognosis." + } +} \ No newline at end of file diff --git a/29780020.json b/29780020.json new file mode 100644 index 0000000000000000000000000000000000000000..56887dc875a4251f38ca864cee6daf31b52bdc64 --- /dev/null +++ b/29780020.json @@ -0,0 +1,8 @@ +{ + "id": "29780020", + "label": 0, + "article": { + "id": "29780020", + "text": "A six-year-old male patient was admitted to our hospital due to itching and scalding crusts that persisted 10-15 days in both eyes. Upon biomicroscopic examination, 5-6 semi-translucent, yellowish brown living lice attached to the upper eyelashes and a large number of eggs were observed. Following application of pilocarpine hydrochloride (Pilomann 2%, Bausch-Lomb) and topical proparacaine hydrochloride (Alcaine 0.5%, Alcon), the paralyzed parasites and eggs were manually removed by pulling with forceps. The lice were identified as adult forms of pubic louse, Pthirus pubis, and its eggs. The patient was treated with pilocarpine hydrochloride, which was applied thrice a day combined with pure vaseline. One week later, no lice or eggs were seen on the eyelashes." + } +} \ No newline at end of file diff --git a/29875990.json b/29875990.json new file mode 100644 index 0000000000000000000000000000000000000000..8f2f752c8a932522af53ff51014c70b13e2f82a4 --- /dev/null +++ b/29875990.json @@ -0,0 +1,8 @@ +{ + "id": "29875990", + "label": 0, + "article": { + "id": "29875990", + "text": "We report the imaging appearances of a case of pathologically proven, neonatal neuroblastoma 4S with diffuse hepatic metastatic involvement at presentation. Patient had an abnormal appearing liver both by ultrasound and MR. There was no evidence for associated adrenal tumor by imaging. Lack of an associated adrenal mass led to initial misinterpretation of diffuse hepatic accumulation of MIBG seen with radionuclide scintigraphy. To the best our knowledge, this is the first report of metastatic neonatal 4S neuroblastoma without an adrenal (or extra-adrenal) primary identified either on pre- or post-natal imaging." + } +} \ No newline at end of file diff --git a/29935280.json b/29935280.json new file mode 100644 index 0000000000000000000000000000000000000000..79e1be476a16f305c1c43a1fa0d2e9b0a8631467 --- /dev/null +++ b/29935280.json @@ -0,0 +1,8 @@ +{ + "id": "29935280", + "label": 0, + "article": { + "id": "29935280", + "text": "BACKGROUND:\nThe aim of our study was to identify the genetic background of thiopurine-induced toxicity in a patient with a wild-type thiopurine methyltransferase genotype and activity. A 38-year-old Caucasian woman presented with cutaneous necrotizing vasculitis pancytopenia one month after starting azathioprine therapy.\n\nMETHODS:\nDuring a routine biochemical follow-up of the patient, undetectable serum uric acid (\u003c10 μl) was observed. A high performance liquid chromatography analysis of urinary purines revealed increased levels of xanthine (137 mmol/mol creatinine). The suspected diagnosis of hereditary xanthinuria, a rare autosomal recessive disorder of the last two steps of purine metabolism, was confirmed by sequence analysis.\n\nRESULTS:\nAn analysis of XDH/XO and AOX1 revealed common polymorphisms, while analysis of the MOCOS gene identified a rare homozygous variant c.362C \u003e T. Dysfunction of this variant was confirmed by significantly decreased xanthine dehydrogenase/oxidase activity in the patient's plasma (\u003c2% of control mean activity).\n\nCONCLUSIONS:\nWe present a biochemical, enzymatic, and molecular genetic case study suggesting an important association between a hitherto undescribed dysfunction variant in the MOCOS gene and thiopurine-induced toxicity. The identified variant c.362C \u003e T results in slower thiopurine metabolism caused by inhibition of 6-mercaptopurine oxidation (catabolism) to 6-thioxanthine and 6-thiouric acid, which increases the formation of the nucleotide 6-thioguanine, which is toxic. This is the first clinical case to identify the crucial role of the MOCOS gene in thiopurine intolerance and confirm the impact of genetic variability of purine enzymes on different therapeutic outcomes in patients undergoing thiopurine treatment." + } +} \ No newline at end of file diff --git a/30057829.json b/30057829.json new file mode 100644 index 0000000000000000000000000000000000000000..f5727ba77c2cd2a25cad41d24674694cc3279a32 --- /dev/null +++ b/30057829.json @@ -0,0 +1,8 @@ +{ + "id": "30057829", + "label": 0, + "article": { + "id": "30057829", + "text": "BACKGROUND:\nGeleophysic dysplasia is a rare multisystem disorder that principally affects the bones, joints, heart, and skin. This condition is inherited either in an autosomal dominant pattern due to mutations or in an autosomal recessive pattern due to mutations. Two patients with unaffected parents from unrelated families presented to their endocrinologist with severe short stature, resistant to growth hormone treatment. Routine endocrine tests did not reveal an underlying etiology. Exome sequencing was performed in each family. Our two patients, harboring heterozygous mutations p.Tyr1696Asp and p.Cys1748Ser, had common clinical symptoms such as severe short stature, characteristic facial features, short hands and feet, and limitation of joint movement. However, one patient had severe cardiac involvement whereas the other patient had tracheal stenosis requiring tracheostomy placement.\n\nCONCLUSIONS:\nPatients with severe dwarfism, skeletal anomalies, and other specific syndromic features (e.g., tracheal stenosis and cardiac valvulopathy) should undergo genetic testing to exclude acromelic dysplasia syndromes." + } +} \ No newline at end of file diff --git a/30157195.json b/30157195.json new file mode 100644 index 0000000000000000000000000000000000000000..c863f013c70b4f553b12227d45910c7308db14df --- /dev/null +++ b/30157195.json @@ -0,0 +1,8 @@ +{ + "id": "30157195", + "label": 0, + "article": { + "id": "30157195", + "text": "OBJECTIVE:\nTo identify in vitro inhibitors of xanthine crystallization that have potential for inhibiting the formation of xanthine crystals in urine and preventing the development of the renal calculi in patients with xanthinuria.\n\nMETHODS:\nThe formation of xanthine crystals in synthetic urine and the effects of 10 potential crystallization inhibitors were assessed using a kinetic turbidimetric system with a photometer. The maximum concentration tested for each compound was: 20 mg/L for 3-methylxanthine (3-MX); 40 mg/L for 7-methylxanthine (7-MX), 1-methylxanthine (1-MX), theobromine (TB), theophylline, paraxanthine, and caffeine; 45 mg/L for 1-methyluric acid; 80 mg/L for 1,3-dimethyluric acid; and 200 mg/L for hypoxanthine. Scanning electron microscopy was used to examine the morphology of the crystals formed when inhibitory effects were observed.\n\nRESULTS:\nOnly 7-MX, 3-MX, and 1-MX significantly inhibited xanthine crystallization at the tested concentrations. Mixtures of inhibitors had an additive effect rather than a synergistic effect on crystallization.\n\nCONCLUSION:\nTwo of the inhibitors identified here-7-MX and 3-MX-are major metabolites of TB. In particular, after TB consumption, 20% is excreted in the urine as TB, 21.5% as 3-MX, and 36% as 7-MX. Thus, consumption of theobromine could protect patients with xanthinuria from the development of renal xanthine calculi. Clinical trials are necessary to demonstrate these effects in vivo." + } +} \ No newline at end of file diff --git a/31350823.json b/31350823.json new file mode 100644 index 0000000000000000000000000000000000000000..2126867b5890f32c5e62bf2ffb5a201ce63a0ceb --- /dev/null +++ b/31350823.json @@ -0,0 +1,8 @@ +{ + "id": "31350823", + "label": 0, + "article": { + "id": "31350823", + "text": "BACKGROUND:\nGeleophysic dysplasia (GPHYSD) is a disorder characterized by dysmorphic features, stiff joints and cardiac involvement due to defects of TGF-β signaling. GPHYSD can be caused by mutations in FBN1, ADAMTLS2, and LTBP3 genes.\n\nMETHODS AND RESULTS:\nConsistent with previous reports, we found intracellular inclusions of unknown material by electron microscopy (EM) in skin fibroblasts of two GPHYSD individuals carrying FBN1 mutations. Moreover, we found that the storage material is enclosed within lysosomes and is associated with the upregulation of several lysosomal genes. Treatment of GPHYSD fibroblasts carrying FBN1 mutations with the angiotensin II receptor type 1 inhibitor losartan that inhibits TGF-β signaling did not reduce the storage but improved the extracellular deposition of fibrillin-1 microfibrils.\n\nCONCLUSION:\nLosartan is a promising candidate drug for treatment of GPHYSD due to FBN1 defects." + } +} \ No newline at end of file diff --git a/31745037.json b/31745037.json new file mode 100644 index 0000000000000000000000000000000000000000..ca5cf06ec67fd3ea1b9791b7be0045861fb0fa56 --- /dev/null +++ b/31745037.json @@ -0,0 +1,8 @@ +{ + "id": "31745037", + "label": 0, + "article": { + "id": "31745037", + "text": "Phthiriasis palpebrarum (PP) is the infestation of eyelids caused by the ectoparasite Phthirus pubis, frequently misdiagnosed as allergic conjunctivitis, blepharitis or dermatitis. There is no standard treatment of choice although various treatment modalities have been described. A 6-year-old male child with PP was successfully treated with local application of 20% fluorescein solution over the eyelashes and eyebrows of both the eyes, followed by the mechanical removal of all parasites and trimming of the eyelashes from the base and application of ophthalmic ointment." + } +} \ No newline at end of file diff --git a/31943017.json b/31943017.json new file mode 100644 index 0000000000000000000000000000000000000000..348393b08e617b8ee3810ff5db596682f05e72c6 --- /dev/null +++ b/31943017.json @@ -0,0 +1,8 @@ +{ + "id": "31943017", + "label": 0, + "article": { + "id": "31943017", + "text": "Mutations in each of the four human VPS13 (VPS13A-D) proteins are associated with distinct neurological disorders: chorea-acanthocytosis, Cohen syndrome, early-onset Parkinson's disease and spastic ataxia. Recent evidence suggests that the different VPS13 paralogs transport lipids between organelles at different membrane contact sites. How each VPS13 isoform is targeted to organelles is not known. We have shown that the localization of yeast Vps13 protein to membranes requires a conserved six-repeat region, the Vps13 Adaptor Binding (VAB) domain, which binds to organelle-specific adaptors. Here, we use a systematic mutagenesis strategy to determine the role of each repeat in recognizing each known adaptor. Our results show that mutation of invariant asparagines in repeats 1 and 6 strongly impacts the binding of all adaptors and blocks Vps13 membrane recruitment. However, we find that repeats 5-6 are sufficient for localization and interaction with adaptors. This supports a model where a single adaptor-binding site is found in the last two repeats of the VAB domain, while VAB domain repeat 1 may influence domain conformation. Importantly, a disease-causing mutation in VPS13D, which maps to the highly conserved asparagine residue in repeat 6, blocks adaptor binding and Vps13 membrane recruitment when modeled in yeast. Our findings are consistent with a conserved adaptor binding role for the VAB domain and suggest the presence of as-yet-unidentified adaptors in both yeast and humans." + } +} \ No newline at end of file diff --git a/32316042.json b/32316042.json new file mode 100644 index 0000000000000000000000000000000000000000..ffee35bb926521ed41cc1166c48eadf6ca34530d --- /dev/null +++ b/32316042.json @@ -0,0 +1,8 @@ +{ + "id": "32316042", + "label": 0, + "article": { + "id": "32316042", + "text": "BACKGROUND:\nPatients who have undergone Roux-en-Y gastric bypass (RYGB) are at increased risk of biliary disease necessitating endoscopic retrograde cholangiopancreatography (ERCP). The most widely used approaches to perform ERCP after RYGB are laparoscopy-assisted ERCP (LA-ERCP) and balloon enteroscopy-assisted ERCP (BEA-ERCP). There are few studies comparing these procedures. We aimed to compare the performance, benefits, and harms of LA-ERCP and BEA-ERCP in RYGB patients.\n\nMETHODS:\nWe identified all RYGB patients who underwent ERCP at two tertiary care endoscopy centers in Oslo, Norway between May 2013 and December 2017. One center performed BEA-ERCP, the other LA-ERCP. Procedure success was defined as fulfillment of the therapeutic or diagnostic aim, according to the procedure description. Adverse events were classified according to the Clavien-Dindo grading system.\n\nRESULTS:\nDuring the study period, 40 BEA-ERCP and 39 LA-ERCP procedures were performed in 68 patients. Procedure success rate was 72.5 % for BEA-ERCP and 87.2 % for LA-ERCP ( = 0.14). Adverse events occurred in 18 % of BEA-ERCP and 28 % of LA-ERCP ( = 0.23). Serious adverse events (Clavien-Dindo grade ≥ 3b) occurred in 2.5 % of BEA-ERCP and 7.7 % of LA-ERCP procedures ( = 0.36). Concomitant cholecystectomy was performed in 25 of the 39 LA-ERCP procedures. The median procedure times for LA-ERCP performed with and without concomitant cholecystectomy were 201 minutes and 140 minutes, respectively, and for BEA-ERCP was 125 minutes.\n\nCONCLUSIONS:\nIn experienced hands, both LA-ERCP and BEA-ERCP have high success rates after RYGB. The choice of approach should be individualized according to patient characteristics and available physician competence." + } +} \ No newline at end of file diff --git a/32447120.json b/32447120.json new file mode 100644 index 0000000000000000000000000000000000000000..fa1b4433c10ef5ecbc81f2021694e776191c3b76 --- /dev/null +++ b/32447120.json @@ -0,0 +1,8 @@ +{ + "id": "32447120", + "label": 0, + "article": { + "id": "32447120", + "text": "INTRODUCTION:\nParasitic infections of the eye are a major cause of ocular-surface diseases globally. While most infections are treatable, parasites can cause varying levels of damage mostly due to late diagnosis or misdiagnosis as a result of doctors' unfamiliarity with their characteristics of latency and crypsis, as well as lack of awareness by the patients.\n\nCASE REPORTS:\nIn this study, we present three cases of phthiriasis palpebrarum, thelaziasis, and ophthalmomyiasis, respectively. Two of the cases were treated at the clinic and did not recur. One patient refused treatment and was lost to follow-up.\n\nDISCUSSION:\nBy evaluating the natural histories, morphology, symptoms, clinical findings, and treatment of these parasitic diseases, we systematically analyzed several distinct and unique parasite characteristics, especially latency and crypsis. Furthermore, we have proposed specific examination techniques and methods as well as prevention and treatment strategies from these specific perspectives, aiming to prompt timely diagnoses and early interventions for these diseases by health care workers and improve the public's awareness of parasitic infections.\n\nCONCLUSION:\nParasitosis on the ocular surface is a global infectious disease, and prevention strategies include maintaining personal and environmental hygiene and limiting contact with animals. We recommend that health care workers should enhance their ability to detect and diagnose these diseases while promoting the public's awareness of them in the context of our new perspectives." + } +} \ No newline at end of file diff --git a/32478318.json b/32478318.json new file mode 100644 index 0000000000000000000000000000000000000000..213327dda32921fe5d0e8d70f0ef3624a1d591f9 --- /dev/null +++ b/32478318.json @@ -0,0 +1,8 @@ +{ + "id": "32478318", + "label": 0, + "article": { + "id": "32478318", + "text": "Prompt diagnosis in the emergency department in the case of a patient with emesis may be difficult due to the increasing prevalence of diseases which manifest with emesis. Furthermore, in the case of chronic symptomatology, management and therapy are even more complicated. One episode of emesis rarely causes complications, but severe or repetitive episodes of emesis can cause life-threatening complications. For this reason, the diagnosis of the underlying disease which manifests with emesis is mandatory to be established in a short time in order to choose the correct therapeutic option. In order to systemize the process of diagnosis, this clinical narrative review will discuss only rare causes of emesis." + } +} \ No newline at end of file diff --git a/32605629.json b/32605629.json new file mode 100644 index 0000000000000000000000000000000000000000..604700b833271404a878679aa0300577334fbf80 --- /dev/null +++ b/32605629.json @@ -0,0 +1,8 @@ +{ + "id": "32605629", + "label": 0, + "article": { + "id": "32605629", + "text": "BACKGROUND:\nCohen syndrome, an autosomal recessive syndrome, is a rare syndrome with diverse clinical manifestations including failure to thrive, hypotonia, hypermobile joints, microcephaly, intellectual disabilities, craniofacial and limb anomalies, neutropenia and a friendly character. It is associated with mutations of the vacuolar protein sorting 13 homolog B (VPS13B) gene, which is involved in the development of the ocular, hematological and central nervous systems. This gene encodes a transmembrane protein playing a crucial role in preserving the integrity of the Golgi complex. To date, more than 150 mutations of VPS13B have been reported in over 200 Cohen syndrome patients. Missense or nonsense mutations are the most common mutations.\n\nCASE PRESENTATION:\nA 4-year-old girl, born to consanguineous parents, was referred to the pediatric clinical immunology outpatient clinic for investigation of recurrent neutropenia with a history of recurrent infections in the past year. On physical examination, she had the characteristic facial features of Cohen syndrome, developmental delay and speech disorder. She had a cheerful disposition, and her mother gave a history of feeding difficulties in her first months of life. She did not present any ophthalmologic or cardiac abnormalities. Her lab results revealed moderate neutropenia. Serum IgG, IgM, IgA and IgE levels were normal. She fulfilled the clinical diagnostic criteria for Cohen syndrome. WES revealed a novel homozygous frameshift variant in VPS13B (LRG_351t1: c.7095del; p.Ser2366AlafsTer49). Currently, she is not experiencing any severe problem, and she undergoes irregular medical treatment once her neutrophil count decreases under the normal limit. Her verbal and motor abilities have improved as a result of speech and occupational therapies.\n\nCONCLUSION:\nWe reported a novel homozygous frameshift variant in VPS13B (LRG_351t1: c.7095del; p.Ser2366AlafsTer49) in a 4-year-old girl with Cohen syndrome. Cohen syndrome should be considered in differential diagnosis of any child with intellectual disability and neutropenia." + } +} \ No newline at end of file diff --git a/32642357.json b/32642357.json new file mode 100644 index 0000000000000000000000000000000000000000..054719c2386b971de79afb3122afdea176d0482d --- /dev/null +++ b/32642357.json @@ -0,0 +1,8 @@ +{ + "id": "32642357", + "label": 0, + "article": { + "id": "32642357", + "text": "Cohen syndrome is an extremely rare disease with characteristic somatic and multi-system features that severely affect vision. Ophthalmologists must consider Cohen syndrome when developmental delay, high-grade myopia, and retinal dystrophy are present in a child. Here we report a case of Cohen syndrome in a 10-year-old boy presenting with cystoid macular edema (CME), only the second reported case of its kind. This case illustrates the phenotypic variability that can occur in Cohen syndrome, with rare features in addition to CME including trace posterior subcapsular cataracts, growth hormone deficiency, mild vermian hypoplasia, a nasolacrimal cyst, hearing loss, and high-functioning intelligence quotient (IQ). Our patient did not have an identifiable second mutation even after extensive genetic testing, which raises questions about whether the patient has a novel gene variant for the disease or an autosomal dominant mode of inheritance exists for Cohen syndrome. In addition to peripheral vision loss, the rare appearance of macular edema can threaten the remaining vision and requires intervention. This case also demonstrates that, without a high index of suspicion, there can be considerable delay in diagnosing Cohen syndrome. Though little is known about the prevalence of many of the clinical features seen in our case in the Cohen syndrome population, this case raises awareness of the syndrome and the need to recognize various clinical features, perform genetic testing, and direct appropriate treatment to prevent complications and help improve quality of life." + } +} \ No newline at end of file diff --git a/32773395.json b/32773395.json new file mode 100644 index 0000000000000000000000000000000000000000..23120d0477d1edf0e3be522e093296edd812d69a --- /dev/null +++ b/32773395.json @@ -0,0 +1,8 @@ +{ + "id": "32773395", + "label": 0, + "article": { + "id": "32773395", + "text": "BACKGROUND:\nHereditary peripheral neuropathies are inherited disorders affecting the peripheral nervous system, including Charcot-Marie-Tooth disease, familial amyloid polyneuropathy and hereditary sensory and motor neuropathies. While the molecular basis of hereditary peripheral neuropathies has been extensively researched, interventional trials of pharmacological therapies are lacking.\n\nOBJECTIVE:\nWe collated evidence for the effectiveness of pharmacological and gene-based treatments for hereditary peripheral neuropathies.\n\nMETHODS:\nWe searched several databases for randomised controlled trials (RCT), observational studies and case reports of therapies in hereditary peripheral neuropathies. Two investigators extracted and analysed the data independently, assessing study quality using the Oxford Centre for Evidence Based Medicine 2011 Levels of Evidence in conjunction with the Jadad scale.\n\nRESULTS:\nOf the 2046 studies initially identified, 119 trials met our inclusion criteria, of which only 34 were carried over into our final analysis. Ascorbic acid was shown to have no therapeutic benefit in CMT1A, while a combination of baclofen, naltrexone and sorbitol (PXT3003) demonstrated some efficacy, but phase III data are incomplete. In TTR-related amyloid polyneuropathy tafamidis, patisiran, inotersen and revusiran showed significant benefit in high quality RCTs. Smaller studies showed the efficacy of L-serine for SPTLC1-related hereditary sensory neuropathy, riboflavin for Brown-Vialetto-Van Laere syndrome (SLC52A2/3) and phytanic acid-poor diet in Refsum disease (PHYH).\n\nCONCLUSIONS:\nThe 'treatable' variants highlighted in this project will be flagged in the treatabolome database to alert clinicians at the time of the diagnosis and enable timely treatment of patients with hereditary peripheral neuropathies." + } +} \ No newline at end of file diff --git a/32904930.json b/32904930.json new file mode 100644 index 0000000000000000000000000000000000000000..b5e1f547ed4032f0f96a3ca149b4d229246c70b0 --- /dev/null +++ b/32904930.json @@ -0,0 +1,8 @@ +{ + "id": "32904930", + "label": 0, + "article": { + "id": "32904930", + "text": "Refsum disease is a rare inherited metabolic disorder arising from a defect in peroxisomal metabolism. Patients lack the functional enzyme phytanoyl-CoA hydroxylase, resulting in perturbed alpha oxidation of fatty acids. Phytanic acid accumulates in nervous and adipose tissue and leads to several disease phenotypes including early-onset retinal degeneration, hearing loss, peripheral neuropathy, anosmia, and cerebellar ataxia, among others. Currently, restricting dietary phytanic acid is the only means of altering the chronic sequelae and the disease course. While dietary intervention has been demonstrated to improve peripheral neuropathy, ichthyosis, and ataxia, there have been no reports of improved retinal function in patients with Refsum disease. We describe the case of a 51-year-old patient with molecularly and biochemically confirmed Refsum disease who underwent electroretinography before and after beginning a phytanic acid-restricted diet. His post-intervention 30 Hz flicker electroretinogram demonstrated significantly improved waveform amplitudes and implicit times, suggesting improved retinal function. Thus, we propose that the possibility exists for some visual recovery in these patients and we highlight the utility of performing standardized electroretinography to assess treatment response in Refsum disease." + } +} \ No newline at end of file diff --git a/33025479.json b/33025479.json new file mode 100644 index 0000000000000000000000000000000000000000..4db28da79d9e0810f26dcf53eac7f52f168622bf --- /dev/null +++ b/33025479.json @@ -0,0 +1,8 @@ +{ + "id": "33025479", + "label": 0, + "article": { + "id": "33025479", + "text": "Cohen syndrome (CS) is an autosomal recessive congenital disorder characterized by mutation in the vacuolar protein sorting 13 homolog B (VPS13B; formerly COH1) gene. In the current study, a Chinese family has two young sibling cases having a developmental delay, physical obesity, high myopia, and a special face, which suspected to be CS. The purpose of the study was to identify variants and further analyze their pathogenicity for CS. Next-generation sequencing (NGS) revealed a compound heterozygous mutation in VPS13B gene in the proband, which comprises a frameshift mutation in NM_017890.4: c.10076_10077delCA (p.T3359fs*29) and a putative splice site mutation in c.6940 + 1G \u003e T. Both Minigene assay in vitro and splicing assay in vivo confirmed that the splicing mutation in c.6940 + 1G \u003e T generates a frameshift transcript with whole exon 38 skipping. Eventually, quantitative real-time PCR demonstrated that either of the two mutations can lead to degradation of the VPS13B gene at the transcriptional level. Functional studies of variants identified in CS patients are essential for their subsequent genetic counseling and prenatal diagnoses and could also be the start point for new therapeutic approaches, currently based only on symptomatic treatment." + } +} \ No newline at end of file diff --git a/33381333.json b/33381333.json new file mode 100644 index 0000000000000000000000000000000000000000..a55d259e80538c14da5c9b4dd45ff58a8591d51c --- /dev/null +++ b/33381333.json @@ -0,0 +1,8 @@ +{ + "id": "33381333", + "label": 0, + "article": { + "id": "33381333", + "text": "Portal hypertension caused by cirrhosis is the most common etiology of esophageal varices. However, abnormalities of the splenoportal axis in the absence of liver disease may also cause portal hypertension resulting in varices. We report a rare case of esophageal variceal bleed in a noncirrhotic patient with isolated splenomegaly secondary to chronic granulocyte colony stimulating factor (G-CSF) therapy. The patient is a 26-year-old male with Cohen syndrome who required long-term G-CSF treatment for chronic neutropenia. He presented with large volume hematemesis and pancytopenia in the setting of known splenomegaly with no evidence of cirrhosis. An urgent EGD revealed active variceal bleeding and portal hypertensive gastropathy. The patient was appropriately resuscitated and underwent a successful transjugular intrahepatic portosystemic shunt and CT-guided coil placement for the bleeding varices. We are the first to report variceal bleed as a complication of long-term G-CSF use, a life-threatening consequence that requires urgent intervention." + } +} \ No newline at end of file diff --git a/33427631.json b/33427631.json new file mode 100644 index 0000000000000000000000000000000000000000..6b9eb1cb11d2717830f1fe53389520fe1dda1f9a --- /dev/null +++ b/33427631.json @@ -0,0 +1,8 @@ +{ + "id": "33427631", + "label": 0, + "article": { + "id": "33427631", + "text": "Calpainopathies are inherited limb-girdle muscular dystrophies, most often following an autosomal recessive (AR) transmission. Autosomal dominant (AD) forms with less severe presentation are increasingly reported. Calpainopathies with autosomal recessive (AR) mutations of the calpain3 gene (CAPN3) are associated with limb girdle muscular dystrophy type R1 (LGMD-R1, OMIM 253600) also referred to as LGMD-2A according to the old nomenclature. LGMD-R1 is the commonest form of all LGMDs, with an estimated prevalence of 10 to 70 cases per million inhabitants, that is a cohort of between 670 and 4,200 patients in France theoritically. Patients present a symmetrical proximal axial myopathy manifesting itself between the first and second decade. The clinical course is variable. The level of Creatine- Kinase (CK) is usually high and there is no cardiac involvement. From a therapeutic perspective, the autosomal recessive form of calpainopathy is quite suitable to gene replacement strategies; the viability of recombinant AAV-mediated calpain 3 transfer has been demonstrated in animal models and clinical trials are expected in the coming years. Meanwhile, natural history studies are needed to prepare for future clinical trials." + } +} \ No newline at end of file diff --git a/33502714.json b/33502714.json new file mode 100644 index 0000000000000000000000000000000000000000..626b0d0874178326f708fa517263c0692805f58b --- /dev/null +++ b/33502714.json @@ -0,0 +1,8 @@ +{ + "id": "33502714", + "label": 0, + "article": { + "id": "33502714", + "text": "Molybdenum cofactor is essential for the activity of multiple enzymes including xanthine dehydrogenase. Molybdenum cofactor deficiencies are rare inborn errors of metabolism. Clinically, they present with intractable seizures, axial hypotonia, and hyperekplexia. They further develop cerebral atrophy, microcephaly, global developmental delay and ectopia lentis. We report a 5-year-old female with clinically, biochemically and genetically confirmed molybdenum cofactor deficiency type B due to compound heterozygous pathogenic variants in the molybdenum cofactor synthesis 2 gene found on whole exome sequencing. The xanthine stones were a key clue towards diagnosis. No mutation was detected in XDH gene. Implementation of a low-purine diet, urine alkalization and hydration lead to a near complete decrease in stone burden. The patient received pyridoxine supplementation with improvement in energy levels and attentiveness. Despite reports of high mortality at a young age, our patient was 9 years old at the time of this writing. Molybdenum cofactor deficiencies should be considered in neonates with early-onset seizures, hypotonia, and feeding difficulties. Screening with serum uric acid levels and empiric treatment may be considered while awaiting genetic results." + } +} \ No newline at end of file diff --git a/33548958.json b/33548958.json new file mode 100644 index 0000000000000000000000000000000000000000..463485f5f1c34b068c1d3f907f741e76a51fe22a --- /dev/null +++ b/33548958.json @@ -0,0 +1,8 @@ +{ + "id": "33548958", + "label": 0, + "article": { + "id": "33548958", + "text": "To explore the phenotypes and genotypes of molybdenum cofactor deficiency type B (MoCD-B) manifested as Leigh-like syndrome. The clinical data, laboratory tests, neuroimaging and gene results of one patient diagnosed as MoCD-B at Beijing Children's Hospital and Hebei Children's Hospital in December 2018 were collected. Related literature was searched and reviewed at Wanfang Data Knowledge Service Platform, China National Knowledge Infrastructure and PubMed (up to September 2020) by using terms \"MOCS2\" \"molybdenum cofactor deficiency\" \"Leigh-like syndrome,MOCS2\" \"molybdenum cofactor deficiency, Leigh-like syndrome\". The phenotypes and genotypes of MoCD-B were summarized. A 7 months and 14 days old boy with the chief complaint of \"cough for 6 days, abnormal posture for 4 days and fever for 2 days\" was admitted to Hebei Children' Hospital on December 2018. His abnormal posture presented as opisthotonos accompanied with dysphagia, without seizures. His previous psychomotor development was described as normal. He was born at term after an uneventful pregnancy to non-consanguineous parents. Blood test showed a slightly increased lactic acid and a significantly decreased uric acid. Urine metabolism test showed an obviously increased xanthine and hypoxanthine. Brain magnetic resonance imaging showed hyperintense signal on T2 weighted image and fluid attenuated inversion recovery in bilateral globus pallidus and pedunculus cerebri. The patient was diagnosed with Leigh-like syndrome. No obvious improvement was achieved after cocktail therapy and symptomatic treatment. The whole exome sequencing showed that the patient carried a homozygous variant of MOCS2 gene, c.19G\u003eT(p.Val7Phe), which was a previously reported pathogenic site in the literature and could cause MoCD-B. His parents carried a heterozygous variant respectively. A total of 41 MoCD-B cases with MOCS2 gene variants were collected through literature review and our study, among which 30 cases had full medical records. The onset ages of 23 (77%) cases were in neonate, manifesting with severe encephalopathy, including neonatal-onset intractable seizures, developmental delay, laboratory abnormalities included very low levels of serum and urinary uric acid, increased urinary levels of xanthine and hypoxanthine. Cranial imaging showed cerebral atrophy, cystic encephalomalacia, etc. The onset ages of 7 patients varied from 5 months to 23 years. Four cases had normal psychomotor development before disease onset. Neurological disorders appeared acutely or exacerbated after external triggers and all of them had basal ganglia involvement. Among the 30 cases, 3 cases had a relatively milder phenotype with the ability of brief communication and walking without or with support. Molybdenum cofactor deficiency is a rare disease. Most cases had severe phenotypes and poor outcomes, but some cases may have mild phenotype. MoCD-B caused by MOCS2 gene variants may manifest as Leigh-like syndrome with a normal psychomotor development before the trigger of infection strike. Hypouricemia, xanthinuria and hypoxanthinuria can be indicators of the disease. The presence of MOCS2 gene variants would confirm a final diagnosis." + } +} \ No newline at end of file diff --git a/33660358.json b/33660358.json new file mode 100644 index 0000000000000000000000000000000000000000..9c73e0bded7f7527391f593a7af97639df3d5d6a --- /dev/null +++ b/33660358.json @@ -0,0 +1,8 @@ +{ + "id": "33660358", + "label": 0, + "article": { + "id": "33660358", + "text": "We have reviewed the literature and have identified more than 100 diseases or conditions that are associated with raised concentrations of plasma total homocysteine. The commonest associations are with cardiovascular diseases and diseases of the central nervous system, but a large number of developmental and age-related conditions are also associated. Few other disease biomarkers have so many associations. The clinical importance of these associations becomes especially relevant if lowering plasma total homocysteine by B vitamin treatment can prevent disease and so improve health. Five diseases can at least in part be prevented by lowering total homocysteine: neural tube defects, impaired childhood cognition, macular degeneration, primary stroke, and cognitive impairment in the elderly. We conclude from our review that total homocysteine values in adults of 10 μmol/L or below are probably safe, but that values of 11 μmol/L or above may justify intervention. Homocysteine is more than a disease biomarker: it is a guide for the prevention of disease." + } +} \ No newline at end of file diff --git a/33676434.json b/33676434.json new file mode 100644 index 0000000000000000000000000000000000000000..c658ce923b668de477bfcebbde4abc9a7fa0a719 --- /dev/null +++ b/33676434.json @@ -0,0 +1,8 @@ +{ + "id": "33676434", + "label": 0, + "article": { + "id": "33676434", + "text": "BACKGROUND:\nPhthirus pubis is an obligate parasite of human beings. Demodex spp. is a much more common parasite of human beings. However, P. pubis infestation accompanied by Demodex mite infestation in eye has not been reported.\n\nCASE PRESENTATION:\nWe report the first case of Phthirus pubis and Demodex co-infestation on a 48-years-old woman. She presented to the hospital with itching and burning at her right eye for 2 weeks. Slit lamp examination revealed multiple nits and adults of P. pubis anchored to both upper and lower eyelashes. Eyelashes were trimmed, moxifloxacin eye ointment and fluorometholone eye drops were initiated daily. However, itching didn't improve after 2 weeks of treatment. Light microscopy examination of eyelashes revealed infestation with Demodex. The patient was treated with lid scrubs with 25% tea tree oil daily for 4 weeks and was completely cured.\n\nCONCLUSION:\nOur report shows the importance of an early and comprehensive diagnosis, because both phthiriasis palpebrarum and demodicosis can be confused with blepharitis." + } +} \ No newline at end of file diff --git a/33685072.json b/33685072.json new file mode 100644 index 0000000000000000000000000000000000000000..bab51779dbff177cf219b46b134f2050df0ac79f --- /dev/null +++ b/33685072.json @@ -0,0 +1,8 @@ +{ + "id": "33685072", + "label": 0, + "article": { + "id": "33685072", + "text": "Phthiriasis palpebrarum is a rare eyelid infestation caused by (pubic lice) that is often confused with other causes of blepharoconjunctivitis. In this study, we report the case of a 49-year-old male patient with phthiriasis palpebrarum who presented with itching and eye irritation in the left eye and had undergone treatment for conjunctivitis in the past month. Biomicroscopic examination revealed a dense population of motile and translucent lice and eggs, more intensely on the upper lid. For treatment, the lice were first cleaned mechanically, eyelashes were cut from the bottom, and eggs and lice were removed from the eye, after which petrolatum jelly (vsaseline) was applied to the lids for 10 days. In the control examination, no lice and eggs were observed." + } +} \ No newline at end of file diff --git a/33809364.json b/33809364.json new file mode 100644 index 0000000000000000000000000000000000000000..c43f35ed363270b5e0e6534f046a5fc4df8ed55e --- /dev/null +++ b/33809364.json @@ -0,0 +1,8 @@ +{ + "id": "33809364", + "label": 0, + "article": { + "id": "33809364", + "text": "The conserved VPS13 proteins constitute a new family of lipid transporters at membrane contact sites. These large proteins are suspected to bridge membranes and form a direct channel for lipid transport between organelles. Mutations in the 4 human homologs () are associated with a number of neurological disorders, but little is known about their precise functions or the relevant contact sites affected in disease. In contrast, yeast has a single Vps13 protein which is recruited to multiple organelles and contact sites. The yeast model system has proved useful for studying the function of Vps13 at different organelles and identifying the localization determinants responsible for its membrane targeting. In this review we describe recent advances in our understanding of VPS13 proteins with a focus on yeast research." + } +} \ No newline at end of file diff --git a/33816764.json b/33816764.json new file mode 100644 index 0000000000000000000000000000000000000000..7d07ea9147bcb968267a4663d655cca50ceb7cc4 --- /dev/null +++ b/33816764.json @@ -0,0 +1,8 @@ +{ + "id": "33816764", + "label": 0, + "article": { + "id": "33816764", + "text": "INTRODUCTION:\nElevated homocysteine (Hcy) and related metabolites accelerate Alzheimer's disease. Hcy-lowering B vitamins slow brain atrophy/cognitive decline in mild cognitive impairment (MCI). Modification with Hcy-thiolactone generates auto-immunogenic -Hcy-protein. We tested a hypothesis that anti--Hcy-protein autoantibodies predict cognition in individuals with MCI participating in a randomized, double-blind, placebo-controlled VITACOG trial of B vitamins.\n\nMETHODS:\nParticipants with MCI (n = 196, 76.8 years old, 60% women) were randomly assigned to receive a daily dose of folic acid (0.8 mg), vitamin B (0.5 mg), and B (20 mg) (n = 98) or placebo (n = 98) for 2 years. Cognition was analyzed by neuropsychological tests. Brain atrophy was quantified in a subset of patients (n = 167) by magnetic resonance imaging. Anti -Hcy-protein auto-antibodies were quantified by enzyme-linked immunosorbent assay. Associations among anti--Hcy-protein autoantibodies, cognition, and brain atrophy were examined by multiple regression analysis.\n\nRESULTS:\nAt baseline, anti--Hcy-protein autoantibodies were significantly associated with impaired global cognition (Mini-Mental State Examination [MMSE]), episodic memory (Hopkins Verbal Learning Test-revised), and attention/processing speed (Map Search). At the end of the study, anti--Hcy-protein autoantibodies were associated with impaired global cognition (MMSE) and attention/processing speed (Trail Making A). In the placebo group, baseline anti--Hcy-protein autoantibodies predicted, independently of Hcy, global cognition (Telephone Inventory for Cognitive Status modified [TICS-m]; MMSE) and attention/processing speed (Trail Making A) but not brain atrophy, at the end of study. B-vitamin treatment abrogated association of anti--Hcy-protein autoantibodies with cognition.\n\nDISCUSSION:\nThese findings suggest that anti--Hcy-protein autoantibodies can impair functional (attention/processing speed and global cognition), but not structural (brain atrophy), aspects of cognition. Anti--Hcy-protein autoantibodies are a new factor associated with impaired cognition, which could be ameliorated by B vitamins." + } +} \ No newline at end of file diff --git a/33823207.json b/33823207.json new file mode 100644 index 0000000000000000000000000000000000000000..e0004885940ec1f7c9260eae228cc2a0cc7863f4 --- /dev/null +++ b/33823207.json @@ -0,0 +1,8 @@ +{ + "id": "33823207", + "label": 0, + "article": { + "id": "33823207", + "text": "We report the anesthetic management with combined spinal-epidural in a patient with limb-girdle muscular dystrophy type 2A, submitted to abdominoplasty and liposuction. The patient had onset of symptoms at 8 years old, diagnosed by muscular biopsy, presenting muscle weakness in the scapular and pelvic girdles, with reduced mobility. We performed monitorization with noninvasive blood pressure, oximeter, thermometer, and electrocardiogram. In the postoperative period, she showed no clinical signs of rhabdomyolysis, myotonia, or adverse effects, maintaining hemodynamic stability. The anesthesia technique allowed spontaneous ventilation, monitoring of clinical parameters close to physiological conditions and used smaller doses of medication, reducing related risks." + } +} \ No newline at end of file diff --git a/33908178.json b/33908178.json new file mode 100644 index 0000000000000000000000000000000000000000..3fe1a738d0fc2b2611854dd561d0bbff1204dbf3 --- /dev/null +++ b/33908178.json @@ -0,0 +1,8 @@ +{ + "id": "33908178", + "label": 0, + "article": { + "id": "33908178", + "text": "Sleep-disordered breathing (SDB) is common in patients with skeletal dysplasias. The aim of our study was to analyze SDB and respiratory management in children with rare skeletal dysplasias. We performed a retrospective analysis of patients with spondyloepiphyseal dysplasia congenita (SEDC), metatropic dysplasia (MD), spondyloepimetaphyseal dysplasia (SEMD), acrodysostosis (ADO), geleophysic dysplasia (GD), acromicric dysplasia (AD), and spondylocostal dysplasia (SCD) between April 2014 and October 2020. Polygraphic data, clinical management, and patients' outcome were analyzed. Thirty-one patients were included (8 SEDC, 3 MD, 4 SEMD, 1 ADO, 4 GD, 3 AD, and 8 SCD). Sixteen patients had obstructive sleep apnea (OSA): 11 patients (2 with SEDC, 1 with SEMD, 1 with ADO, 1 with GD, 2 with AD, and 4 with SCD) had mild OSA, 2 (1 SEMD and 1 GD) had moderate OSA, and 3 (1 SEDC, 1 MD, 1 SEMD) had severe OSA. Adenotonsillectomy was performed in one patient with SCD and mild OSA, and at a later age in two other patients with ADO and AD. The two patients with moderate OSA were treated with noninvasive ventilation (NIV) because of nocturnal hypoxemia. The three patients with severe OSA were treated with adenotonsillectomy (1 SEDC), adeno-turbinectomy and continuous positive airway pressure (CPAP; 1 MD), and with NIV (1 SEMD) because of nocturnal hypoventilation. OSA and/or alveolar hypoventilation is common in patients with skeletal dysplasias, underlining the importance of systematic screening for SDB. CPAP and NIV are effective treatments for OSA and nocturnal hypoventilation/hypoxemia." + } +} \ No newline at end of file diff --git a/33974487.json b/33974487.json new file mode 100644 index 0000000000000000000000000000000000000000..26231b863e2dc0938dcf0a4c0c859b9dcb76d897 --- /dev/null +++ b/33974487.json @@ -0,0 +1,8 @@ +{ + "id": "33974487", + "label": 0, + "article": { + "id": "33974487", + "text": ": Cohen Syndrome (CS) is an autosomal recessive multisystemic disorder characterized by various ophthalmologic findings, including retinal dystrophy and associated cystoid macular edema (CME), in which there was no known effective treatment approach. We describe a CS patient with a homozygous c.62 T \u003e G, p.(Leu21*) mutation in the gene with a topical carbonic anhydrase inhibitor (CAI; brinzolamide %1, thrice daily) responding CME. A seven-year-old girl with an established diagnosis of CS was referred with a primary complaint of nyctalopia. On ophthalmologic examination, bilateral decreased visual acuity and normal-appearing macula with mild optic disc pallor were present. However, the detailed evaluation revealed bilateral blunted foveal reflexes, barely visible foveal pigmentation, and slightly attenuated retinal vessels without any peripheral retinal pigmentary changes in dilated fundus examination, and CME on optical coherence tomography. Bilateral topical brinzolamide thrice daily was initiated for CME. Visual acuity increased, and CME was resolved except for minimal schisis at the inner nuclear layer level at the third-month follow-up visit and remained stable up to one-year follow-up. CME reappeared after five months of self-discontinuation of the patient's therapy but resolved again with treatment resumption. We report the first case of CME secondary to rod-cone dystrophy associated with CS showing improvement in anatomy and visual acuity with a topical CAI." + } +} \ No newline at end of file diff --git a/34105174.json b/34105174.json new file mode 100644 index 0000000000000000000000000000000000000000..796b1e2e18e1a4ee1cad8bf4a111fbb22442d0b7 --- /dev/null +++ b/34105174.json @@ -0,0 +1,8 @@ +{ + "id": "34105174", + "label": 0, + "article": { + "id": "34105174", + "text": "INTRODUCTION/AIMS:\nIn this study, we examined the social and health impacts of the coronavirus disease 2019 (COVID-19) pandemic and social guidelines on people with muscular dystrophies.\n\nMETHODS:\nA prospective de-identified electronic survey was distributed to adults with self-reported facioscapulohumeral muscular dystrophy (FSHD), myotonic dystrophy (DM), and limb-girdle muscular dystrophy (LGMD) enrolled in national registries or with patient advocacy groups. The COVID-19 Impact Survey was developed by muscular dystrophy experts in association with patient collaborators and advocacy groups. The Perceived Stress Scale was used to measure perceived stress.\n\nRESULTS:\nRespondents (n = 774: 56% FSHD; 35% DM, and 9% LGMD) were mostly women and middle-aged (range 19-87 y). Rates of COVID-19 infections were low (\u003c1%), compliance with local social distancing guidelines and policies high (98%). Major challenges reported during the pandemic included: obtaining treatment (40%), managing stress (37%), social distancing (36%), and obtaining essentials (34%). The majority reported a slight worsening in their disease state. Respondents reported moderate stress levels (stress score = 15.4; range = 0-35), with higher stress levels reported by women and those under age 30 y. Three-quarters of participants who participated in telemedicine visits were satisfied with the encounters; however, most reported a preference for in-person visits.\n\nDISCUSSION:\nPeople with muscular dystrophy reported moderate stress and challenges during the COVID-19 pandemic. Interventions such as exercise and stress-coping strategies, including strategies specific to women or individuals \u003c30 y, may be important. Further investigation is needed into the role of telemedicine in the care of individuals with muscular dystrophy." + } +} \ No newline at end of file diff --git a/34110586.json b/34110586.json new file mode 100644 index 0000000000000000000000000000000000000000..9862d76cf6c85cf94d80d4720d3cb363e9df3ef3 --- /dev/null +++ b/34110586.json @@ -0,0 +1,8 @@ +{ + "id": "34110586", + "label": 0, + "article": { + "id": "34110586", + "text": "The limb-girdle muscular dystrophies (LGMD) are a collection of genetic diseases united in their phenotypical expression of pelvic and shoulder area weakness and wasting. More than 30 subtypes have been identified, five dominant and 26 recessive. The increase in the characterization of new genotypes in the family of LGMDs further adds to the heterogeneity of the disease. Meanwhile, better understanding of the phenotype led to the reconsideration of the disease definition, which resulted in eight old subtypes to be no longer recognized officially as LGMD and five new diseases to be added to the LGMD family. The unique variabilities of LGMD stem from genetic mutations, which then lead to protein and ultimately muscle dysfunction. Herein, we review the LGMD pathway, starting with the genetic mutations that encode proteins involved in muscle maintenance and repair, and including the genotype-phenotype relationship of the disease, the epidemiology, disease progression, burden of illness, and emerging treatments." + } +} \ No newline at end of file diff --git a/34385517.json b/34385517.json new file mode 100644 index 0000000000000000000000000000000000000000..a028bda918606f1e7179360142bff361928a1330 --- /dev/null +++ b/34385517.json @@ -0,0 +1,8 @@ +{ + "id": "34385517", + "label": 0, + "article": { + "id": "34385517", + "text": "Cohen syndrome (CS) is a rare syndromic form of rod-cone dystrophy. Recent case reports have suggested that cystoid maculopathy (CM) could affect CS patients with an early onset and high prevalence. Our study aims at improving our understanding and management of CM in CS patients through a retrospective case series of ten CS patients with identified pathogenic variants in VPS13B. Longitudinal optical coherence tomography (OCT) imaging was performed and treatment with carbonic anhydrase inhibitors (CAI) was provided to reduce the volume of cystoid spaces. CM affected eight out of ten patients in our cohort. The youngest patient showed a strong progression of macular cysts from the age of 4.5 to 5 years despite oral CAI medication. Other teenage and young adult patients showed stable macular cysts with and without treatment. One patient showed a moderate decrease of cystoid spaces in the absence of treatment at 22 years of age. Through a correlative analysis we found that the volume of cystoid spaces was positively correlated to the thickness of peripheral and macular photoreceptor-related layers. This study suggests that CAI treatments may not suffice to improve CM in CS patients, and that CM may resolve spontaneously during adulthood as photoreceptor dystrophy progresses." + } +} \ No newline at end of file diff --git a/34472379.json b/34472379.json new file mode 100644 index 0000000000000000000000000000000000000000..bd94568481804e60f6990c64cb255ab61e51aeaa --- /dev/null +++ b/34472379.json @@ -0,0 +1,8 @@ +{ + "id": "34472379", + "label": 0, + "article": { + "id": "34472379", + "text": "Limb-girdle muscular dystrophies (LGMDs) represent a major group of muscle disorders. Treatment is sorely needed and currently expanding based on safety and efficacy adopting principles of single-dosing gene therapy for monogenic autosomal recessive disorders. Gene therapy has made in-roads for LGMD and this review describes progress that has been achieved for these conditions. This review first provides a background on the definition and classification of LGMDs. The major effort focuses on progress in LGMD gene therapy, from experimental studies to clinical trials. The disorders discussed include the LGMDs where the most work has been done including calpainopathies (LGMD2A/R1), dysferlinopathies (LGMD2B/R2) and sarcoglycanopathies (LGMD2C/R5, LGMD2D/R3, LGMD2E/R4). Early success in clinical trials provides a template to move the field forward and potentially apply emerging technology like CRISPR/Cas9 that may enhance the scope and efficacy of gene therapy applied to patient care." + } +} \ No newline at end of file diff --git a/34513757.json b/34513757.json new file mode 100644 index 0000000000000000000000000000000000000000..8582de58457e9752088f8dfd01f90a9b432bf276 --- /dev/null +++ b/34513757.json @@ -0,0 +1,8 @@ +{ + "id": "34513757", + "label": 0, + "article": { + "id": "34513757", + "text": "Zellweger spectrum disorder (ZSD) is a heterogeneous group of autosomal recessive disorders characterized by a defect in peroxisome formation and attributable to mutations in the gene family. Patients with ZSD have profound neurologic impairments, including seizures, severe retardation, and dysmorphic features, and poor prognosis. Currently, there is no specific, effective treatment. Here, we investigated the effects of allogeneic hematopoietic stem cell transplantation (allo-HSCT) on -related ZSD. The suspected clinical proband was first diagnosed at the Department of Neurology of our hospital. The proband died soon after diagnosis, and his family was studied. We found that a brother had the same genetic alterations, and he was diagnosed with Infantile Refsum disease (IRD) as the mildest form of ZSD. We implemented treatment with allo-HSCT, at the request of the child's parents. After transplantation, we observed significant improvements in the clinical manifestations, very-long-chain fatty acids, and brain MRI. The patient has recovered well and not showed any abnormal clinical manifestations after 2 years of follow-up. We have achieved satisfactory short-term results in the treatment of ZSD-IRD with allo-HSCT. Long-term follow-up and observation will be performed to determine the long-term prognosis." + } +} \ No newline at end of file diff --git a/34514031.json b/34514031.json new file mode 100644 index 0000000000000000000000000000000000000000..fa20e4def1dcd830f0dd8c67298af6b155504167 --- /dev/null +++ b/34514031.json @@ -0,0 +1,8 @@ +{ + "id": "34514031", + "label": 0, + "article": { + "id": "34514031", + "text": "Limb girdle muscular dystrophy (LGMD) 2A/R1, caused by mutations in the gene and CAPN3 loss of function, is known to play a role in disease pathogenicity. In this study, AAVrh74.tMCK.CAPN3 was delivered systemically to two different age groups of CAPN3 knockout (KO) mice; each group included two treatment cohorts receiving low (1.17 × 10 vg/kg) and high (2.35 × 10 vg/kg) doses of the vector and untreated controls. Treatment efficacy was tested 20 weeks after gene delivery using functional (treadmill), physiological ( muscle contractility assay), and histopathological outcomes. AAV.CAPN3 gene therapy resulted in significant, robust improvements in functional outcomes and muscle physiology at low and high doses in both age groups. Histological analyses of skeletal muscle showed remodeling of muscle, a switch to fatigue-resistant oxidative fibers in females, and fiber size increases in both sexes. Safety studies revealed no organ tissue abnormalities; specifically, there was no histopathological evidence of cardiotoxicity. These results show that gene replacement therapy improved the phenotype in the CAPN3 KO mouse model at both doses independent of age at the time of vector administration. The improvements were supported by an absence of cardiotoxicity, showing the efficacy and safety of the AAV.CAPN3 vector as a potential gene therapy for LGMDR1." + } +} \ No newline at end of file diff --git a/34593652.json b/34593652.json new file mode 100644 index 0000000000000000000000000000000000000000..ce482fbe186b66b2f5ad92d0f28601373476ea18 --- /dev/null +++ b/34593652.json @@ -0,0 +1,8 @@ +{ + "id": "34593652", + "label": 0, + "article": { + "id": "34593652", + "text": "A teenage girl had the rare combined phenotype of xeroderma pigmentosum and trichothiodystrophy, resulting from mutations in the XPD (ERCC2) gene involved in nucleotide excision repair (NER). After treatment with antibiotics, including metronidazole for recurrent infections, she showed signs of acute and severe hepatotoxicity, which gradually resolved after withdrawal of the treatment. Cultured skin fibroblasts from the patient revealed cellular sensitivity to killing by metronidazole compared with cells from a range of other donors. This reveals that the metronidazole sensitivity was an intrinsic property of her cells. It is well recognized that patients with Cockayne syndrome, another NER disorder, are at high risk of metronidazole-induced hepatotoxicity, but this had not been reported in individuals with other NER disorders. We would urge extreme caution in the use of metronidazole in the management of individuals with the xeroderma pigmentosum and trichothiodystrophy overlap or trichothiodystrophy phenotypes." + } +} \ No newline at end of file diff --git a/34602484.json b/34602484.json new file mode 100644 index 0000000000000000000000000000000000000000..cfe92bcf882d4b08b969ef9b668508cf95b6a105 --- /dev/null +++ b/34602484.json @@ -0,0 +1,8 @@ +{ + "id": "34602484", + "label": 0, + "article": { + "id": "34602484", + "text": "BACKGROUND::\nMetals, silicon, and homocysteine are linked to Alzheimer’s disease. B vitamin therapy lowers homocysteine and slows brain atrophy and cognitive decline in mild cognitive impairment (MCI).\n\nOBJECTIVE::\nExamine metals and silicon as predictors of cognition/brain atrophy in MCI, their interaction with homocysteine and cysteine, and how B vitamins affect these relationships.\n\nMETHODS::\nMCI participants ( = 266, 77.6-year-old, 60.7% female) in VITACOG trial were randomized to receive daily folic acid (0.8 mg)/vitamin B (0.5 mg)/vitamin B (20 mg) ( = 133) or placebo for two years. At baseline and end-of-study, cranial MRIs were obtained from 168 participants, cognition was analyzed by neuropsychological tests, and serum iron, copper, arsenic, aluminum, and silicon quantified by inductively-coupled plasma mass spectrometry in 196 participants. Data were analyzed by bivariate and multiple regression.\n\nRESULTS::\nBaseline iron, cysteine, and homocysteine were significantly associated with brain atrophy rate. Homocysteine effects on brain atrophy rate were modified by iron and cysteine. At baseline, iron, copper, aluminum, and silicon were significantly associated with one or more domains of cognition: semantic memory, verbal episodic memory, attention/processing speed, and executive function. At end-of-study, baseline iron, copper, aluminum, and silicon predicted cognition in at least one domain: semantic memory, verbal episodic memory, visuospatial episodic memory, attention/processing speed, and global cognition in the placebo but not the B vitamin group.\n\nCONCLUSION::\nDisparate effects of serum iron, copper, aluminum, silicon, and homocysteine on cognition and brain atrophy in MCI suggest that cognitive impairment is independent of brain atrophy. These factors showed domain-specific associations with cognition, which were abrogated by B vitamin therapy." + } +} \ No newline at end of file diff --git a/34628793.json b/34628793.json new file mode 100644 index 0000000000000000000000000000000000000000..2846bfe0ad89b3093ed922e3518af97e22a094fb --- /dev/null +++ b/34628793.json @@ -0,0 +1,8 @@ +{ + "id": "34628793", + "label": 0, + "article": { + "id": "34628793", + "text": "Muscular dystrophies are a group of well-defined genetic disorders characterized by the variable distribution of muscle wasting and progressive weakness. The diagnosis and treatment of these diseases remain challenging due to genetic heterogeneity and clinical overlapping. Herein, we describe our 10 years' experience with the diagnosis and management of muscular dystrophy patients. In total, 169 patients were screened for pathogenic variants in eleven genes linked to frequent muscular dystrophies using MLPA and NGS sequencing panels. Most frequent muscular dystrophies found in the Mexican population were dystrophinopathies, dysferlinopathies and calpainopathies. Novel variants were found in genes: DMD, CAPN3, DYSF, and FKRP. For Duchenne muscular dystrophy, improvements in early diagnosis and prolonged ambulation were achieved, on the contrary, for limb-girdle muscular dystrophies and congenital muscular dystrophies, uncomplimentary follow-up and lack of detection strategies were observed. For most common muscular dystrophies, improvements in diagnosis and management have been achieved in the last 10 years, due to a collaborative effort done nationwide." + } +} \ No newline at end of file diff --git a/34664020.json b/34664020.json new file mode 100644 index 0000000000000000000000000000000000000000..6d1b25dc5b8dad9dc15c0b638e40c274d4c838de --- /dev/null +++ b/34664020.json @@ -0,0 +1,8 @@ +{ + "id": "34664020", + "label": 0, + "article": { + "id": "34664020", + "text": "Infantile Refsum disease is a rare peroxisomal biogenesis disorder characterized by impaired alpha-oxidation and accumulation of phytanic acid in the tissues. Patients often present with fundus changes resembling retinitis pigmentosa, developmental delay, sensorineural hearing loss, ataxia, and hepatomegaly. Traditionally, mainstay treatment for this condition has been a phytanic acid-restricted diet, although supplementation with either docosahexaenoic acid or cholic acid has rarely been described in the literature. We present a case of infantile Refsum disease in a child with retinitis pigmentosa-like ocular findings, sensorineural hearing loss, and self-resolving hepatic disease, who developed novel findings of macular edema refractory to carbonic anhydrase inhibitors. We describe management with a phytanic acid-restricted diet and combination docosahexaenoic acid, and cholic acid therapy, which helped to limit progression of her disease." + } +} \ No newline at end of file diff --git a/34724781.json b/34724781.json new file mode 100644 index 0000000000000000000000000000000000000000..aa40c896072b06824216aa48d95fe0cfac9876b1 --- /dev/null +++ b/34724781.json @@ -0,0 +1,8 @@ +{ + "id": "34724781", + "label": 0, + "article": { + "id": "34724781", + "text": "Cockayne syndrome (CS) is a rare progeroid disorder characterized by multisystem degeneration, including neurological dysfunction, for which deep brain stimulation (DBS) is a proposed treatment. This study represents only the third case of DBS for CS-associated movement disorder and the first in which both proposed targets had devices implanted, allowing for direct comparison. A case of DBS for CS-associated movement disorder is presented. Previous literature documents two cases with one targeting the ventral intermediate nucleus of the thalamus (VIM) and the other targeting the globus pallidus interna (GPi). Our patient underwent stimulation of GPi nuclei followed by repositioning to VIM nuclei with improved symptom control using VIM stimulation. In all cases, there was a significant clinical benefit without off-target effects. CS-associated movement disorder exhibits phenotypic variability for which DBS is a viable treatment. Target selection should be driven by clinical phenotype." + } +} \ No newline at end of file diff --git a/34728791.json b/34728791.json new file mode 100644 index 0000000000000000000000000000000000000000..2160fa1d92915c4f583b6fe76e49658f539a9b47 --- /dev/null +++ b/34728791.json @@ -0,0 +1,8 @@ +{ + "id": "34728791", + "label": 0, + "article": { + "id": "34728791", + "text": "BACKGROUND:\nThe DNA-damage immune-response (DDIR) signature is an immune-driven gene expression signature retrospectively validated as predicting response to anthracycline-based therapy. This feasibility study prospectively evaluates the use of this assay to predict neoadjuvant chemotherapy response in early breast cancer.\n\nMETHODS:\nThis feasibility study assessed the integration of a novel biomarker into clinical workflows. Tumour samples were collected from patients receiving standard of care neoadjuvant chemotherapy (FEC + /-taxane and anti-HER2 therapy as appropriate) at baseline, mid- and post-chemotherapy. Baseline DDIR signature scores were correlated with pathological treatment response. RNA sequencing was used to assess chemotherapy/response-related changes in biologically linked gene signatures.\n\nRESULTS:\nDDIR signature reports were available within 14 days for 97.8% of 46 patients (13 TNBC, 16 HER2 + ve, 27 ER + HER2-ve). Positive scores predicted response to treatment (odds ratio 4.67 for RCB 0-1 disease (95% CI 1.13-15.09, P = 0.032)). DDIR positivity correlated with immune infiltration and upregulated immune-checkpoint gene expression.\n\nCONCLUSIONS:\nThis study validates the DDIR signature as predictive of response to neoadjuvant chemotherapy which can be integrated into clinical workflows, potentially identifying a subgroup with high sensitivity to anthracycline chemotherapy. Transcriptomic data suggest induction with anthracycline-containing regimens in immune restricted, \"cold\" tumours may be effective for immune priming.\n\nTRIAL REGISTRATION:\nNot applicable (non-interventional study). CRUK Internal Database Number 14232." + } +} \ No newline at end of file diff --git a/34746125.json b/34746125.json new file mode 100644 index 0000000000000000000000000000000000000000..fe63ae769667a08a4a78a48eac2f6c7a542b743e --- /dev/null +++ b/34746125.json @@ -0,0 +1,8 @@ +{ + "id": "34746125", + "label": 0, + "article": { + "id": "34746125", + "text": "Topoisomerase 2 (TOP2) inhibitors are drugs widely used in the treatment of different types of cancer. Processing of their induced-lesions create double-strand breaks (DSBs) in the DNA, which is the main toxic mechanism of topoisomerase inhibitors to kill cancer cells. It was established that the Nucleotide Excision Repair pathway respond to TOP2-induced lesions, mainly through the Cockayne Syndrome B (CSB) protein. In this paper, we further define the mechanism and type of lesions induced by TOP2 inhibitors when CSB is abrogated. In the absence of TOP2, but not during pharmacological inhibition, an increase in R-Loops was detected. We also observed that CSB knockdown provokes the accumulation of DSBs induced by TOP2 inhibitors. Consistent with a functional interplay, interaction between CSB and TOP2 occurred after TOP2 inhibition. This was corroborated with DNA cleavage assays where CSB stimulated the activity of TOP2. Altogether, our results show that TOP2 is stimulated by the CSB protein and prevents the accumulation of R-loops/DSBs linked to genomic instability." + } +} \ No newline at end of file diff --git a/34768013.json b/34768013.json new file mode 100644 index 0000000000000000000000000000000000000000..94a3e67949d4e7af86cdab0622ea2e5ec29bc92c --- /dev/null +++ b/34768013.json @@ -0,0 +1,8 @@ +{ + "id": "34768013", + "label": 0, + "article": { + "id": "34768013", + "text": "Cockayne syndrome (CS) is a rare autosomal recessive genetic disorder characterized by growth failure and progressive multisystem dysfunction caused by deficient nucleotide excision repair. Whereas metronidazole (MTZ) hepatotoxicity is quite rare in the general population, cases of severe hepatic reaction to MTZ have been reported in CS patients. We report here the case of a 21-year-old CS patient who presented with jaundice following one week of treatment with MTZ combined with spiramycin for dental care. This case is the first one documented with a liver biopsy. Histopathological analysis revealed portal and lobular inflammation with predominance of neutrophils, ballooning degeneration and severe cholestasis without bile duct damage. The outcome was marked by regression of jaundice over 6 weeks. Analysis of this case highlights the probable responsibility of MTZ and adds support to the recommendation to strictly avoid the prescription of this drug in CS patients." + } +} \ No newline at end of file diff --git a/34829959.json b/34829959.json new file mode 100644 index 0000000000000000000000000000000000000000..00fb486b4bf376764954c60471e144a6ac2080f3 --- /dev/null +++ b/34829959.json @@ -0,0 +1,8 @@ +{ + "id": "34829959", + "label": 0, + "article": { + "id": "34829959", + "text": "Xanthine oxidoreductase (XOR) is an enzyme that catalyzes the two-step reaction from hypoxanthine to xanthine and from xanthine to uric acid in purine metabolism. XOR generally carries dehydrogenase activity (XDH) but is converted into an oxidase (XO) under various pathophysiologic conditions. The complex structure and enzymatic function of XOR have been well investigated by mutagenesis studies of mammalian XOR and structural analysis of XOR-inhibitor interactions. Three XOR inhibitors are currently used as hyperuricemia and gout therapeutics but are also expected to have potential effects other than uric acid reduction, such as suppressing XO-generating reactive oxygen species. Isolated XOR deficiency, xanthinuria type I, is a good model of the metabolic effects of XOR inhibitors. It is characterized by hypouricemia, markedly decreased uric acid excretion, and increased serum and urinary xanthine concentrations, with no clinically significant symptoms. The pathogenesis and relationship between mutations and XOR activity in xanthinuria are useful for elucidating the biological role of XOR and the details of the XOR reaction process. In this review, we aim to contribute to the basic science and clinical aspects of XOR by linking the mutations in xanthinuria to structural studies, in order to understand the function and reaction mechanism of XOR in vivo." + } +} \ No newline at end of file diff --git a/34853308.json b/34853308.json new file mode 100644 index 0000000000000000000000000000000000000000..afb42d6eff4e156d06da61b7babba1c43087169c --- /dev/null +++ b/34853308.json @@ -0,0 +1,8 @@ +{ + "id": "34853308", + "label": 0, + "article": { + "id": "34853308", + "text": "Transcription-coupled repair is essential for the removal of DNA lesions from the transcribed genome. The pathway is initiated by CSB protein binding to stalled RNA polymerase II. Mutations impairing CSB function cause severe genetic disease. Yet, the ATP-dependent mechanism by which CSB powers RNA polymerase to bypass certain lesions while triggering excision of others is incompletely understood. Here we build structural models of RNA polymerase II bound to the yeast CSB ortholog Rad26 in nucleotide-free and bound states. This enables simulations and graph-theoretical analyses to define partitioning of this complex into dynamic communities and delineate how its structural elements function together to remodel DNA. We identify an allosteric pathway coupling motions of the Rad26 ATPase modules to changes in RNA polymerase and DNA to unveil a structural mechanism for CSB-assisted progression past less bulky lesions. Our models allow functional interpretation of the effects of Cockayne syndrome disease mutations." + } +} \ No newline at end of file diff --git a/34860601.json b/34860601.json new file mode 100644 index 0000000000000000000000000000000000000000..adf025851e75489e20ace0c5ed95b5ecd435fec1 --- /dev/null +++ b/34860601.json @@ -0,0 +1,8 @@ +{ + "id": "34860601", + "label": 0, + "article": { + "id": "34860601", + "text": "BACKGROUND:\nPierre Robin Sequence (PRS) is characterized by micrognathia, glossoptosis, and upper airway obstruction. Early recognition and appropriate perinatal management is crucial for optimizing outcomes. This study aimed to evaluate 20-week fetal ultrasounds to determine if specific mandibular measurements could predict PRS diagnosis and disease severity.\n\nMETHODS:\nA retrospective case-control study of 48 patients with PRS and gender-matched controls was performed. Medical records were reviewed for respiratory and surgical interventions. Three parameters to assess micrognathia were measured on mid-sagittal profile ultrasound images: frontal nasal-mental angle (FNMA), facial-maxillary angle (FMA), and alveolar overjet. Student's t-test and univariate logistic regression was performed. P ≤ 0.05 was considered statistically significant.\n\nRESULTS:\nPatients with PRS demonstrated a significantly smaller mean FNMA compared to the control group, 129.3 ± 8.6° and 137.4 ± 3.2°, respectively (p \u003c 0.0001), as well as significantly smaller mean FMA, 63.2 ± 9.2° and 74.8 ± 6.1°, respectively (p \u003c 0.0001). The PRS group also demonstrated significantly larger mean alveolar overjet compared to the control group, 3.9 ± 1.4 mm and 2.1 ± 0.9 mm, respectively (p \u003c 0.0001). The odds of respiratory intervention increased among cases when FMA was \u003c68°. Additionally, there was a significant difference in median overjet between patients with PRS who did and did not require respiratory intervention.\n\nCONCLUSIONS:\nMandibular features on the 20-week ultrasound can be measured to predict diagnosis and severity of PRS. This is an important first step to prepare for potential respiratory intervention at delivery to minimize perinatal hypoxia. Alveolar overjet, previously not described in prenatal ultrasound literature, is measurable and has utility in prenatal screening for PRS, as do FMA and FNMA." + } +} \ No newline at end of file diff --git a/34871413.json b/34871413.json new file mode 100644 index 0000000000000000000000000000000000000000..0bcb873f17d454cfb86024d7e3e0ffcbcdf0701f --- /dev/null +++ b/34871413.json @@ -0,0 +1,8 @@ +{ + "id": "34871413", + "label": 0, + "article": { + "id": "34871413", + "text": "Cockayne syndrome group B (CSB) protein has been implicated in the repair of a variety of DNA lesions that induce replication stress. However, little is known about its role at stalled replication forks. Here, we report that CSB is recruited to stalled forks in a manner dependent upon its T1031 phosphorylation by CDK. While dispensable for MRE11 association with stalled forks in wild-type cells, CSB is required for further accumulation of MRE11 at stalled forks in BRCA1/2-deficient cells. CSB promotes MRE11-mediated fork degradation in BRCA1/2-deficient cells. CSB possesses an intrinsic ATP-dependent fork reversal activity in vitro, which is activated upon removal of its N-terminal region that is known to autoinhibit CSB's ATPase domain. CSB functions similarly to fork reversal factors SMARCAL1, ZRANB3 and HLTF to regulate slowdown in fork progression upon exposure to replication stress, indicative of a role of CSB in fork reversal in vivo. Furthermore, CSB not only acts epistatically with MRE11 to facilitate fork restart but also promotes RAD52-mediated break-induced replication repair of double-strand breaks arising from cleavage of stalled forks by MUS81 in BRCA1/2-deficient cells. Loss of CSB exacerbates chemosensitivity in BRCA1/2-deficient cells, underscoring an important role of CSB in the treatment of cancer lacking functional BRCA1/2." + } +} \ No newline at end of file diff --git a/34904106.json b/34904106.json new file mode 100644 index 0000000000000000000000000000000000000000..3844ce32a76380b1c78c1f771de1d86b4b1531d0 --- /dev/null +++ b/34904106.json @@ -0,0 +1,8 @@ +{ + "id": "34904106", + "label": 0, + "article": { + "id": "34904106", + "text": "BACKGROUND:\nCrab lice () infestation can occur at any age, to either males or females, and across all regions of the world. However, cases involving the eyelashes and adjacent eyelids (phthiriasis palpebrarum) are rare. Usually occurring as a sexually transmitted disease, crab lice can be spread by poor hygiene or in a dirty environment through direct contact with contaminated skin (hands) or textiles (towels and clothing).\n\nCASE SUMMARY:\nA 50-year-old woman presented to our hospital with a 2-wk history of chronic eyelid pain and itching in the right eye, which exacerbated in the evening hours and which had not resolved following a 1-wk course of antibiotics and corticosteroid ointments (for blepharitis diagnosis from another hospital). A careful ophthalmic slit-lamp and light microscope examination revealed multiple crab lice and nits on the right upper eyelashes; the right and left lower eyelashes were normal. Following the new diagnosis of phthiriasis palpebrarum, the patient was treated by removing the affected eyelashes, the crab lice, and their nits completely. Additionally, the eyelids were washed once with povidone-iodine. A follow-up examination at 2 wk later showed complete resolution of symptoms and no evidence of re-infection.\n\nCONCLUSION:\nThis case emphasizes the importance of correct diagnosis and complete removal of eyelashes, crab lice and nits to cure phthiriasis palpebrarum." + } +} \ No newline at end of file diff --git a/34980535.json b/34980535.json new file mode 100644 index 0000000000000000000000000000000000000000..a0ac3c34b93b6db6f9cb94dc00adc7fa83447a2b --- /dev/null +++ b/34980535.json @@ -0,0 +1,8 @@ +{ + "id": "34980535", + "label": 0, + "article": { + "id": "34980535", + "text": "Eosinophilic myositis belong to the idiopathic inflammatory myopathies and are defined by an inflammatory infiltrate composed of eosinophils within the muscle. To date, no consensus exists for diagnosis and care of such patients. The aim of this review was to describe clinical and histological presentation, treatment, and outcome of eosinophilic myositis based on a systematic review of all published histologically proven cases of eosinophilic myositis. A total of 453 records were identified in MEDLINE until November 2020. A total of 69 published cases were identified. The analysis of these allowed the distinction of the 3 previously described pathological subtypes: focal eosinophilic myositis (n = 17); diffuse eosinophilic myositis (n = 36); and eosinophilic perimyositis (n = 16). We propose a simple algorithm for diagnosis and treatment strategy for the care of patient with muscular symptoms and blood eosinophilia. This work also highlights eosinophilic myositis pathogenesis and the need for careful investigations in order to rule out differential diagnoses." + } +} \ No newline at end of file diff --git a/35028486.json b/35028486.json new file mode 100644 index 0000000000000000000000000000000000000000..47d18015527445c19f86c2c3e8a8c0c3e1ff6379 --- /dev/null +++ b/35028486.json @@ -0,0 +1,8 @@ +{ + "id": "35028486", + "label": 0, + "article": { + "id": "35028486", + "text": "Leishmaniosis in domestic ferrets () is a disease caused by , a parasite transmitted through the bite of an infected female phlebotomine sand fly. Among vertebrates, the dog is the primary domestic reservoir of the parasite; however, other domestic animals can be implicated such as cats. The first description of a clinical case of leishmaniosis in domestic ferrets was reported recently. As a result, new knowledge has been published including empirically based treatment protocols, confirmatory techniques to detect the presence of the parasite infection and seasonal variation in the antibodies against in apparently healthy domestic ferrets. The most common clinical signs observed are enlargement of peripheral lymph nodes and skin lesions such as papular and/or ulcerative dermatitis. Additionally, the most frequent laboratory alterations seen are hyperproteinaemia with hyperglobulinaemia and biochemical analytes alterations depending on the affected tissue. Two different therapeutic protocols have been described to treat domestic ferrets with leishmaniosis: meglumine antimoniate plus allopurinol protocol or miltefosine plus allopurinol protocol. These treatment protocols seemed to be able to control the infection, although the presence of xanthinuria could be detected. The susceptibility of domestic ferrets to , the clinical picture, treatment of infected animals and prevention are poorly understood, due to the scarcity of recent description in the literature. Different proposed diagnostic algorithms have been included for domestic ferrets with suspected leishmaniosis, clinically healthy domestic ferrets and animals as blood donors. In this sense, the present review provides updated data on scientific knowledge of leishmaniosis in ferrets." + } +} \ No newline at end of file diff --git a/35124321.json b/35124321.json new file mode 100644 index 0000000000000000000000000000000000000000..bd18c1bdf7f4af5fb5ce6f74b911fea14b047ea6 --- /dev/null +++ b/35124321.json @@ -0,0 +1,8 @@ +{ + "id": "35124321", + "label": 0, + "article": { + "id": "35124321", + "text": "BACKGROUND AND OBJECTIVES:\nFunction is an important outcome after stroke; traditional assessments may not capture functional deficits important to patients. We examined the validity of the Standard Assessment of Global Everyday Activities (SAGEA), a patient-reported outcome that assesses activities important to patients and for use in international clinical trials.\n\nMETHODS:\nThe NAVIGATE-ESUS trial evaluated rivaroxaban compared to aspirin in preventing recurrent stroke in 7213 participants. The Modified Rankin Scale (mRS), the National Institutes of Health Stroke Scale (NIHSS), and the SAGEA were collected at entry. Chi square tests were used to compare proportions and Spearman rank correlations were used to compare between measures. SAGEA was compared to the Modified Frailty Index (MFI) and the occurrence of infarct to examine criterion validity RESULTS: Participants were 67 years, 2/3 were male, and at baseline 30% had no disability and 58% had slight disability according to mRS scores. SAGEA was weakly correlated with the mRS (r=0.37), the NIHSS (r=0.29) and the MFI (r=0.30). Of the 2154 with an mRS score of 0, 61% reported difficulty on the SAGEA. The largest discrepancies between SAGEA and other measures were because of cognitive functional deficits detected by the SAGEA that were not identified on other assessments. A larger number of MRI identified infarcts (acute and covert) were associated with a higher SAGEA score (p=0.007).\n\nCONCLUSIONS:\nThe SAGEA is a simple, globally applicable measure of cognitive and functional abilities that identifies issues that other commonly used assessments of disability and function do not capture." + } +} \ No newline at end of file diff --git a/35227793.json b/35227793.json new file mode 100644 index 0000000000000000000000000000000000000000..27d09be4cb508206562a21a9e1a1d0af5e68b703 --- /dev/null +++ b/35227793.json @@ -0,0 +1,8 @@ +{ + "id": "35227793", + "label": 0, + "article": { + "id": "35227793", + "text": "BACKGROUND:\nA carbapenem-resistant Acinetobacter baumannii outbreak in the COVID intensive care unit of a community hospital was contained using multidrug resistant organism guidelines. The purpose of this study is to report on an outbreak investigation and containment strategy that was used, and to discuss prevention strategy.\n\nMETHODS:\nA multidisciplinary approach contained the spread of infection. Strategies implemented included consultation with experts, screening, and reversal of personal protective equipment conservation. Ensuring infection control best practices are maintained remain important efforts to reduce the spread of multidrug resistant organisms.\n\nRESULTS:\nFive patients with carbapenem-resistant Acinetobacter baumannii were identified from routine clinical cultures within one week and one patient was identified from active surveillance cultures.\n\nDISCUSSION:\nPersonal protective equipment conservation, strategies to prevent health care personnel exposure, and patient surge staffing protocols may have increased the likelihood of multidrug resistant organism transmission. Environmental and behavioral infection control regulations with effective administrative guidance, active surveillance cultures, and antimicrobial stewardship are critical to prevent future outbreaks.\n\nCONCLUSIONS:\nAfter outbreak containment strategies were implemented, no additional patients were identified with carbapenem-resistant Acinetobacter baumannii. Conventional infection prevention and control strategies were re-instituted. A multidisciplinary approach with continued focus on hand hygiene, environmental cleaning, and correct use of personal protective equipment needs to be put in place to successfully contain and prevent the spread of carbapenem resistant infections." + } +} \ No newline at end of file diff --git a/35240487.json b/35240487.json new file mode 100644 index 0000000000000000000000000000000000000000..264b4bb7b79e6a59b17148e57ebb15f268a18e97 --- /dev/null +++ b/35240487.json @@ -0,0 +1,8 @@ +{ + "id": "35240487", + "label": 0, + "article": { + "id": "35240487", + "text": "Xanthinuria is a significant adverse effect in dogs on long-term allopurinol for treatment of leishmaniosis. The study aims to investigate how the Iberian veterinary community (IVC) identifies, manages, and proactively prevents xanthinuria secondary to allopurinol treatment. A cross-sectional study was conducted using an online survey, translated into two languages, and disseminated to the IVC via social networking forums. Respondents were asked to share their treatment regimens, adverse effects attributed to treatment, as well as preventive and reactive measures against xanthuria. Of two-hundred and thirty respondents, 99.6% prescribe allopurinol for canine leishmaniosis. Xanthinuria was estimated to happen in less than one out of every four dogs by 91.7% of the clinicians. Xanthinuria has been detected by 71.6% of respondents at least once. Three out of every four respondents inform owners about deleterious effects of allopurinol, and 28.4% consider implementing a change in diet in advance of treatment as a proactive measure. To monitor xanthinuria, urinalysis and diagnostic imaging are used by 71.2% and 31% of clinicians respectively. When xanthinuria is detected, 43.2% of the respondents discontinue allopurinol, 24% replace it by nucleotide-analogs, 14.9% reduce its dosage, and 3.1% split its dosage but increase administration frequency. Additional measures are taken by 72.1% of the respondents, 59.4% of whom prescribe a low-purine diet. The IVC recognizes xanthinuria as a fairly common secondary effect of long-term allopurinol treatment in dogs with leishmaniosis and recommends periodically monitoring and preventive measures." + } +} \ No newline at end of file diff --git a/35292423.json b/35292423.json new file mode 100644 index 0000000000000000000000000000000000000000..e5f029beeadb7a67164abe21d0b3ea41a539fd81 --- /dev/null +++ b/35292423.json @@ -0,0 +1,8 @@ +{ + "id": "35292423", + "label": 0, + "article": { + "id": "35292423", + "text": "BACKGROUND:\nThe effect of interventions on functional impairment is an important outcome in stroke prevention trials and should be considered as an adjunct to counting discrete events. In the NAVIGATE-ESUS trial, 7213 patients with recent embolic strokes of undetermined source were randomized to rivaroxaban (15 mg once daily) or aspirin (100 mg daily). After 11 months there was no effect on the prevention of recurrent stroke.\n\nAIMS:\nTo determine the effect of rivaroxaban compared to aspirin on functional and cognitive outcomes.\n\nMETHODS:\nFunction and cognition were measured at baseline, 1 year, and study end using the Standard Assessment of Global Everyday Activities (SAGEA), a 15-item scale assessing cognitive, instrumental, and basic activities of daily living as well as mobility, and the Montreal Cognitive Assessment (MoCA). Changes in scores were calculated by subtracting either study end or 1-year scores from baseline, and differences in distributions were compared using the Mann-Whitney U test. SAGEA and MoCA scores were also correlated with recurrent stroke.\n\nRESULTS:\nFollow-up SAGEA scores were available in 6378 (88%) participants. There was no difference in change in function for those allocated to rivaroxaban compared to aspirin (Mann-Whitney U test, p = 0.8), with both distributions having a median (25p,75p) change of 0 (-2,1). Overall, more of those who experienced a recurrent stroke (n=247; mostly minor ischemic), reported functional difficulty at study end versus entry, compared with those who did not (51% versus 30%, chi-square test, p\u003c 0.001), and this was consistent across global regions. There was no difference in the change in cognition by treatment group, nor were recurrent strokes associated with a change in cognition.\n\nCONCLUSIONS:\nRivaroxaban, compared to aspirin, was not associated with changes in functional or cognitive status in patients with recent ESUS. The SAGEA scale detected changes in functional status associated with recurrent strokes in an international stroke population." + } +} \ No newline at end of file diff --git a/35325630.json b/35325630.json new file mode 100644 index 0000000000000000000000000000000000000000..c6556f0d7663498ada89a07d45663304034051b6 --- /dev/null +++ b/35325630.json @@ -0,0 +1,8 @@ +{ + "id": "35325630", + "label": 0, + "article": { + "id": "35325630", + "text": "DNA-damaging anti-cancer drugs are used clinically to induce cell death by causing DNA strand breaks or DNA replication stress. Camptothecin (CPT) and cisplatin are commonly used anti-cancer drugs, and their combined use enhances the anti-tumour effects. However, the mechanism underlying this enhanced effect has not been well studied. In this study, we analysed the combined effect of CPT and cisplatin or ultraviolet (UV) and found that CPT suppresses transcription recovery after UV damage and induces the disappearance of the Cockayne syndrome group B (CSB) protein, a transcription-coupled nucleotide excision repair (TC-NER) factor. This CPT-induced disappearance of CSB expression was suppressed by proteasome and transcription inhibitors. Moreover, CSB ubiquitination was detected after CPT treatment in a transcription-dependent manner, suggesting that the transcription stress caused by CPT induces CSB ubiquitination, resulting in CSB undetectability. However, Cockayne syndrome group A (CSA) and CUL4A were not involved in the CPT-induced CSB undetectability, suggesting that CSB ubiquitination caused by CPT is regulated differently from the UV response. However, cisplatin or UV sensitivity was enhanced by CPT even in CSB- or CSA-knockout cells. Furthermore, the excessive CSB expression, which suppressed CSB ubiquitination, did not cancel the combined effect of CPT. These results suggest that CPT blocks the repair of cisplatin or UV-induced DNA damage regardless of TC-NER status. CPT possibly compromised the alternative repair pathways other than TC-NER, leading to the suppression of transcription recovery and enhancement of cell killing." + } +} \ No newline at end of file diff --git a/35326048.json b/35326048.json new file mode 100644 index 0000000000000000000000000000000000000000..73adcf51de6689ab14d3a7e9823c0774d2432367 --- /dev/null +++ b/35326048.json @@ -0,0 +1,8 @@ +{ + "id": "35326048", + "label": 0, + "article": { + "id": "35326048", + "text": "PURPOSE:\nTo study the clinical presentations and outcomes of phthiriasis palpebrarum (PP) managed with combined treatment modality comprising of 20% fluorescein dye, mechanical removal of the ectoparasites, and topical application of antibiotic eye ointment with paraffin base.\n\nMETHODS:\nThis is a prospective interventional noncomparative hospital-based series of 13 patients of PP. All the patients underwent local application of 20% fluorescein dye over the eyelashes and eyebrows of both the eyes followed by the mechanical removal of all the ectoparasites and trimming of the eyelashes from the base followed by application of ophthalmic ointment.\n\nRESULTS:\nMean age of the patients was 28 ± 22 years (range 3-60 Years). Out of the total of 13 patients, 11 patients (85%) were having bilateral involvement. The mean duration of symptoms in 11 patients (rest 2 were accidental findings) was 4 ± 3 weeks (range 1-10 weeks). Three patients (23%) had a history of sexual contact with possible parasite-infested partners. Four patients (31%) had additional parasites in the pubic area or torso. All the patients were completely parasite free at the end of 1 month. There was no infestation of the treating medical personnel from the patient. The average follow-up was 8 ± 5 months (range 3-21 months).\n\nCONCLUSION:\nItching and irritation of the eyes were the most common presentations of PP. Combined treatment modality comprising of 20% fluorescein dye, mechanical removal of ectoparasites, and topical application of antibiotic eye ointment with paraffin base is effective in the management of PP." + } +} \ No newline at end of file diff --git a/35327453.json b/35327453.json new file mode 100644 index 0000000000000000000000000000000000000000..8b6266196a2090fb6928a7386e768059f6d18951 --- /dev/null +++ b/35327453.json @@ -0,0 +1,8 @@ +{ + "id": "35327453", + "label": 0, + "article": { + "id": "35327453", + "text": "Hypouricemia is recognized as a rare disorder, defined as a serum uric acid level of 2.0 mg/dL or less. Hypouricemia is divided into an overexcretion type and an underproduction type. The former typical disease is xanthinuria, and the latter is renal hypouricemia (RHUC). The frequency of nephrogenic hypouricemia due to a deficiency of URAT1 is high in Japan, accounting for most asymptomatic and persistent cases of hypouricemia. RHUC results in a high risk of exercise-induced acute kidney injury and urolithiasis. It is vital to promote research on RHUC, as this will lead not only to the elucidation of its pathophysiology but also to the development of new treatments for gout and hyperuricemia." + } +} \ No newline at end of file diff --git a/35366260.json b/35366260.json new file mode 100644 index 0000000000000000000000000000000000000000..f1cedfc9d2fb98ed85da45a7e4d87803a664e8b4 --- /dev/null +++ b/35366260.json @@ -0,0 +1,8 @@ +{ + "id": "35366260", + "label": 0, + "article": { + "id": "35366260", + "text": "Limb girdle muscular dystrophy type R1 disease is a progressive disease that is caused by mutations in the gene and involves the extremity muscles of the hip and shoulder girdle. The CAPN3 protein has proteolytic and non-proteolytic properties. The functions of the CAPN3 protein that have been determined so far can be listed as remodeling and combining contractile proteins in the sarcomere with the substrates with which it interacts, controlling the Ca flow in and out through the sarcoplasmic reticulum, and regulation of membrane repair and muscle regeneration. Even though there are several gene therapies, cellular therapies, and drug therapies, such as glucocorticoid treatment, AAV- mediated therapy, CRISPR-Cas9, induced pluripotent stem cells, MYO-029, and AMBMP, which are either in preclinical or clinical phases, or have been completed, there is no final cure. Inhibitors and small molecules (tauroursodeoxycholic acid, salubrinal, rapamycin, CDN1163, dwarf open reading frame) targeting ER stress factors that are thought to be effective in muscle loss can be considered potential therapy strategies. At present, little can be done to treat the progressive muscle wasting, loss of function, and premature mortality of patients with LGMDR1, and there is a pressing need for more research to develop potential therapies." + } +} \ No newline at end of file diff --git a/35393236.json b/35393236.json new file mode 100644 index 0000000000000000000000000000000000000000..359d38c08f662b37093b9e1c2c7d56efb8c79eec --- /dev/null +++ b/35393236.json @@ -0,0 +1,8 @@ +{ + "id": "35393236", + "label": 0, + "article": { + "id": "35393236", + "text": "Muscular dystrophies are a group of disorders that cause progressive muscle weakness. There is an increasing interest for the development of biomarkers for these disorders and specifically for Duchene Muscular Dystrophy. Limited research however, has been performed on the biomarkers' development for the most rare muscular dystrophies, like the Facioscapulohumeral Muscular Dystrophy, Limb-Girdle Muscular Dystrophy and Myotonic Dystrophy type 2. Here, we aimed to identify novel serum-based miRNA biomarkers for these rare muscular dystrophies, through high-throughput next-generation RNA sequencing. We identified many miRNAs that associate with muscular dystrophy patients compared to controls. Based on a series of selection criteria, the two best candidate miRNAs for each of these disorders were chosen and validated in a larger number of patients. Our results showed that miR-223-3p and miR-206 are promising serum-based biomarkers for Facioscapulohumeral Muscular Dystrophy type 1, miR-143-3p and miR-486-3p for Limb-Girdle Muscular Dystrophy type 2A whereas miR-363-3p and miR-25-3p associate with Myotonic Dystrophy type 2. Some of the identified miRNAs were significantly elevated in the serum of the patients compared to controls, whereas some others were lower. In conclusion, we provide new evidence that certain circulating miRNAs may be used as biomarkers for three types of rare muscular dystrophies." + } +} \ No newline at end of file diff --git a/35406459.json b/35406459.json new file mode 100644 index 0000000000000000000000000000000000000000..cf03d8d65242ef1e9043d9d90dc0428735669ff7 --- /dev/null +++ b/35406459.json @@ -0,0 +1,8 @@ +{ + "id": "35406459", + "label": 0, + "article": { + "id": "35406459", + "text": "Breast cancer (BC) is the most common cancer with the highest frequency of death among women. BC is highly heterogenic at the genetic, biological, and clinical level. Despite the significant improvements in diagnosis and treatments of BC, the high rate of cancer recurrence and resistance to treatment remains a major challenge in clinical practice. This issue is particularly relevant in Triple-Negative Breast Cancer (TNBC) subtype, for which chemotherapy remains the main standard therapeutic approach. Here, we observed that BC cells, belonging to different subtypes, including the TNBC, display an increased expression of Cockayne Syndrome group A (CSA) protein, which is involved in multiple functions such as DNA repair, transcription, mitochondrial homeostasis, and cell division and that recently was found to confer cell robustness when it is up-regulated. We demonstrated that CSA ablation by AntiSense Oligonucleotides (ASOs) drastically impairs tumorigenicity of BC cells by hampering their survival and proliferative capabilities without damaging normal cells. Moreover, suppression of CSA dramatically sensitizes BC cells to platinum and taxane derivatives, which are commonly used for BC first-line therapy, even at very low doses not harmful to normal cells. Finally, CSA ablation restores drug sensitivity in oxaliplatin-resistant cells. Based on these results, we conclude that CSA might be a very attractive target for the development of more effective anticancer therapies." + } +} \ No newline at end of file diff --git a/35441706.json b/35441706.json new file mode 100644 index 0000000000000000000000000000000000000000..945f4d64f3c7a27bbdc98895c5b3e06105b79bca --- /dev/null +++ b/35441706.json @@ -0,0 +1,8 @@ +{ + "id": "35441706", + "label": 0, + "article": { + "id": "35441706", + "text": "OBJECTIVE:\nThis study was undertaken to evaluate efficacy and long-term safety of triheptanoin in patients \u003e1 year old, not on a ketogenic diet, with drug-resistant seizures associated with glucose transporter 1 deficiency syndrome (Glut1DS).\n\nMETHODS:\nUX007G-CL201 was a randomized, double-blind, placebo-controlled trial. Following a 6-week baseline period, eligible patients were randomized 3:1 to triheptanoin or placebo. Dosing was titrated to 35% of total daily calories over 2 weeks. After an 8-week placebo-controlled period, all patients received open-label triheptanoin through Week 52.\n\nRESULTS:\nThe study included 36 patients (15 children, 13 adolescents, eight adults). A median 12.6% reduction in overall seizure frequency was observed in the triheptanoin arm relative to baseline, and a 13.5% difference was observed relative to placebo (p = .58). In patients with absence seizures only (n = 9), a median 62.2% reduction in seizure frequency was observed in the triheptanoin arm relative to baseline. Only one patient with absence seizures only was present in the control group, preventing comparison. No statistically significant differences in seizure frequency were observed. Common treatment-emergent adverse events included diarrhea, vomiting, abdominal pain, and nausea, mostly mild or moderate in severity. No serious adverse events were considered to be treatment related. One patient discontinued due to status epilepticus.\n\nSIGNIFICANCE:\nTriheptanoin did not significantly reduce seizure frequency in patients with Glut1DS not on the ketogenic diet. Treatment was associated with mild to moderate gastrointestinal treatment-related events; most resolved following dose reduction or interruption and/or medication for treatment. Triheptanoin was not associated with any long-term safety concerns when administered at dose levels up to 35% of total daily caloric intake for up to 1 year." + } +} \ No newline at end of file diff --git a/35455966.json b/35455966.json new file mode 100644 index 0000000000000000000000000000000000000000..34994636becb252fda8a4c5598ca213a314ef748 --- /dev/null +++ b/35455966.json @@ -0,0 +1,8 @@ +{ + "id": "35455966", + "label": 0, + "article": { + "id": "35455966", + "text": "Oxygen is important for lipid metabolism, being involved in both enzymatic transformations and oxidative reactivity, and is particularly influent when genetic diseases impair the repair machinery of the cells, such as described for Cockayne syndrome (CS). We used two cellular models of transformed fibroblasts defective for CSA and CSB genes and their normal counterparts, grown for 24 h under various oxygen tensions (hyperoxic 21%, physioxic 5% and hypoxic 1%) to examine the fatty acid-based membrane remodeling by GC analysis of fatty acid methyl esters derived from membrane phospholipids. Overall, we first distinguished differences due to oxygen tensions: (a) hyperoxia induced a general boost of desaturase enzymatic activity in both normal and defective CSA and CSB cell lines, increasing monounsaturated fatty acids (MUFA), whereas polyunsaturated fatty acids (PUFA) did not undergo oxidative consumption; (b) hypoxia slowed down desaturase activities, mostly in CSA cell lines and defective CSB, causing saturated fatty acids (SFA) to increase, whereas PUFA levels diminished, suggesting their involvement in hypoxia-related signaling. CSB-deprived cells are the most sensitive to oxidation and CSA-deprived cells are the most sensitive to the radical-based formation of trans fatty acids (TFA). The results point to the need to finely differentiate biological targets connected to genetic impairments and, consequently, suggest the better definition of cell protection and treatments through accurate molecular profiling that includes membrane lipidomes." + } +} \ No newline at end of file diff --git a/35491177.json b/35491177.json new file mode 100644 index 0000000000000000000000000000000000000000..cd04948730c9020d3a9575614efab4dffec9fd2e --- /dev/null +++ b/35491177.json @@ -0,0 +1,8 @@ +{ + "id": "35491177", + "label": 0, + "article": { + "id": "35491177", + "text": "Whether or not extremely low levels of serum uric acid (SUA) in xanthinuria are associated with impairment of the endothelial function and exercise-induced acute kidney injury (EIAKI) is unclear. A 59-year-old woman without EIAKI or urolithiasis had undetectable levels of UA in serum and urine and elevated levels of hypoxanthine and xanthine in urine. A genetic analysis revealed homozygous mutations in the XDH gene [c.1585 C\u003eT (p. Gln529*)]. Flow-mediated dilation was within the normal range. This is the first report of a case with extremely low levels of SUA, xanthinuria with novel mutations of xanthine dehydrogenase (XDH) and a normal endothelial function." + } +} \ No newline at end of file diff --git a/35623073.json b/35623073.json new file mode 100644 index 0000000000000000000000000000000000000000..bc5ff8d2a68404e8c503b984d39d35a9d49b884c --- /dev/null +++ b/35623073.json @@ -0,0 +1,8 @@ +{ + "id": "35623073", + "label": 0, + "article": { + "id": "35623073", + "text": "RATIONALE:\nWhereas metronidazole-induced hepatotoxicity is quite rare in the general population, in individuals carrying a nucleotide excision repair disorder, namely Cockayne syndrome, there is a high risk of developing this complication.\n\nPATIENT CONCERNS:\nWe report the case of a 44-year-old man, affected by xeroderma pigmentosum, who was admitted to the hospital presenting aspiration pneumoniae caused by worsening dysphagia and with severe hepatotoxicity during the hospitalization.\n\nDIAGNOSES:\nAcute hepatitis, which was leading to acute liver failure, occurred during antibiotic treatment with metronidazole and ceftazidime with an elevation of liver enzymes consistent with hepatocellular damage pattern.\n\nINTERVENTIONS:\nHydration with glucose 5% solution, pantoprazole and vitamin K were administered, meanwhile other causes of hepatitis were ruled out and the ongoing antibiotic treatment was stopped suspecting a drug-induced liver injury.\n\nOUTCOMES:\nLiver function nearly completely recovered 1 month later with a first rapid improvement, within few days, of aminotransferases and coagulation studies, and slower of cholestatic enzymes.\n\nLESSONS:\nWe describe the first case available in the literature of hepatotoxicity associated with metronidazole treatment in a xeroderma pigmentosum patient. Clinicians therefore, based on this report and according to the possible underlying mechanism shared by other genetic diseases characterized by alterations in the pathway of DNA-repair, should consider such adverse event also in patients affected by this rare disease." + } +} \ No newline at end of file diff --git a/35636725.json b/35636725.json new file mode 100644 index 0000000000000000000000000000000000000000..8985844351033b7204f87b62d1c9b0f3720bfcab --- /dev/null +++ b/35636725.json @@ -0,0 +1,8 @@ +{ + "id": "35636725", + "label": 0, + "article": { + "id": "35636725", + "text": "Canavan disease (CD) is an inherited leukodystrophy resulting from mutations in the gene encoding aspartoacylase (ASPA). ASPA is highly expressed in oligodendrocytes and catalyzes the cleavage of N-acetylaspartate (NAA) to produce aspartate and acetate. In this review, we examine the pathologies and clinical presentation in CD, the metabolism and transportation of NAA in the brain, and the hypothetical mechanisms whereby ASPA deficiency results in dysmyelination and a failure of normal brain development. We also discuss therapeutic options that could be used for the treatment of CD." + } +} \ No newline at end of file diff --git a/35637731.json b/35637731.json new file mode 100644 index 0000000000000000000000000000000000000000..da71a2e487a61db1f71e3da615df65d2064204a5 --- /dev/null +++ b/35637731.json @@ -0,0 +1,8 @@ +{ + "id": "35637731", + "label": 0, + "article": { + "id": "35637731", + "text": "Canavan disease (CD) is a devastating neurological disease that lacks effective therapy. Because CD is caused by mutations of the aspartoacylase () gene, we introduced the wild-type (WT) gene into patient iPSCs through lentiviral transduction or CRISPR/Cas9-mediated gene editing. We then differentiated the WT -expressing patient iPSCs (ASPA-CD iPSCs) into NPCs and showed that the resultant ASPA-CD NPCs exhibited potent ASPA enzymatic activity. The ASPA-CD NPCs were able to survive in brains of transplanted CD mice. The engrafted ASPA-CD NPCs reconstituted ASPA activity in CD mouse brains, reduced the abnormally elevated level of NAA in both brain tissues and cerebrospinal fluid (CSF), and rescued hallmark pathological phenotypes of the disease, including spongy degeneration, myelination defects, and motor function impairment in transplanted CD mice. These genetically modified patient iPSC-derived NPCs represent a promising cell therapy candidate for CD, a disease that has neither a cure nor a standard treatment." + } +} \ No newline at end of file diff --git a/35725315.json b/35725315.json new file mode 100644 index 0000000000000000000000000000000000000000..9e8b502c6a5581fd7cb5854fb3e8206cf8a09f37 --- /dev/null +++ b/35725315.json @@ -0,0 +1,8 @@ +{ + "id": "35725315", + "label": 0, + "article": { + "id": "35725315", + "text": "To investigate the method and efficacy of reconstruction of facial skin defects after removing the lesions by applying the V-Y subcutaneous pedicle flap. A retrospective analysis was performed on 23 patients with facial reconstruction by using V-Y subcutaneous pedicle flap in the Otolaryngology Department of Guangdong Integrated Traditional Chinese and Western Medicine Hospital from March 2012 to April 2021. Patient ages ranged from 45 to 85 years old, with a mean age of 66.5 years (14 males and 9 females). The facial lesion sites included cheek in 12 cases (nearly lower eyelid in 4 cases), nose in 4 cases, lips in 3 cases, temporal in 2 cases and mental region in 2 cases. The initial pathology included malignant tumors (7 cases of basal cell carcinoma (BCC), 2 cases of squamous cell carcinoma(SCC), and 1 case of malignant melanoma) and benign lesions (7 cases of keratoderma, 3 cases of intradermal nevus, 1 case of pilomatricoma, 1 case of cutaneous mixed tumor and 1 case of epidermal cyst). The V-Y subcutaneous facial pedicled flaps were designed reasonably after the facial lesions were excised. The advantages of blood supply, survival rate and adverse events of the flap were analyzed Chi-square test was used to compare the observation results of different types of patients. The primary focus of 23 patients was excised surgically, and intraoperative frozen-section examinations were performed for obtaining margins negative as far as possible. One positive margin was still found in 1 patient after multiple resection in our group. The defect sizes were 14 mm×12 mm-59 mm×54 mm. All the flaps survived. The adverse events were slight necrosis of the epidermis at the junction or vicinity of the three arms of \"Y\" shaped in 4 cases, but the wounds finally recovered by wet compress and dressing change. There were no significant differences in the incidences of adverse events between double and single pedicle flaps (4/19 . 0/4), between benign and malignant lesions (4/13 . 0/10), and between patients with and without underlying diseases (1/6 vs. 3/17) (χ values were 0.98, 3.56, 0.01, respectively, all \u003e0.05). There were no other major complications such as dehiscence, hematoma, eyelid ectropion and lip deformation. The patients with benign lesions were followed-up at least for 3 months, while those with malignant tumors were followed-up for 6-36 months postoperatively, without recurrence. V-Y subcutaneous facial pedicled skin flap may be a \"no-easy-necrotic\" local flap in the repair of small and medium-sized facial defects." + } +} \ No newline at end of file diff --git a/35743315.json b/35743315.json new file mode 100644 index 0000000000000000000000000000000000000000..bb7d9d017253c24dc200d89ff828ec80a56c5a2a --- /dev/null +++ b/35743315.json @@ -0,0 +1,8 @@ +{ + "id": "35743315", + "label": 0, + "article": { + "id": "35743315", + "text": "Mutations in the gene encoding laforin cause Lafora disease (LD), a progressive myoclonic epilepsy characterized by drug-resistant seizures and progressive neurological impairment. To date, rodents are the only available models for studying LD; however, their use for drug screening is limited by regulatory restrictions and high breeding costs. To investigate the role of laforin loss of function in early neurodevelopment, and to screen for possible new compounds for treating the disorder, we developed a zebrafish model of LD. Our results showed the zebrafish to be a faithful model of LD, exhibiting the main disease features, namely motor impairment and neuronal hyperexcitability with spontaneous seizures. The model also showed increased inflammatory response and apoptotic death, as well as an altered autophagy pathway that occurs early in development and likely contributes to the disease progression. Early administration of trehalose was found to be effective for rescuing motor impairment and neuronal hyperexcitability associated with seizures. Our study adds a new tool for investigating LD and might help to identify new treatment opportunities." + } +} \ No newline at end of file diff --git a/35751444.json b/35751444.json new file mode 100644 index 0000000000000000000000000000000000000000..91049bbea7eaeab32e47417720e2531d16339173 --- /dev/null +++ b/35751444.json @@ -0,0 +1,8 @@ +{ + "id": "35751444", + "label": 0, + "article": { + "id": "35751444", + "text": "Color-blindness, or more accurately, color vision deficiency (CVD), which is the inability or decreased ability to distinguish different colors, is one of the commonest visual disorders. Patients with schizophrenia usually have multiple types of visual processing impairments, including color vision impairments. Here, we present a case of schizophrenia with congenital CVD. The patient was aware of his color deficiency since elementary school. We assessed his ability to distinguish medicines based on their color, including those that he had been previously prescribed. Although he could distinguish all of the tablets, he could not distinguish the color of the blister packs, specifically that of the bromazepam 2 mg pack (green) from the 1 mg pack (red). This case suggests that CVD patients might misunderstand the color of medications, which might lead to medication errors, or poor drug adherence. The color universal design principle should be considered when designing tablets and their blister packs, in order to improve medication adherence." + } +} \ No newline at end of file diff --git a/35765401.json b/35765401.json new file mode 100644 index 0000000000000000000000000000000000000000..89f1586768b4596100045248729d4c6ae78f7ba6 --- /dev/null +++ b/35765401.json @@ -0,0 +1,8 @@ +{ + "id": "35765401", + "label": 0, + "article": { + "id": "35765401", + "text": "Phthiriasis palpebrarum is a rare parasitosis of the eyelashes caused by . This report describes an atypical case of this disease. A 72-year-old female patient suffered prolonged symptoms of severe left eye pruritus for 18 months, refractory to conventional eyelid hygienic measures, and anti-histaminic and corticosteroid medications. Slit-lamp examination showed multiple translucent oval structures adherent to the upper eyelashes, and 18 crab-like lice, which were mechanically removed and characterized as . Treatment was started with corticosteroid and antibiotic ointment, vaseline, and Blephademodex® wipes (Laboratoires Théa, Auvergne-Rhone-Alpes, France). After 2 weeks, all symptoms had subsided completely. Although rare, phthiriasis palpebrarum may be easily confused with frequent palpebral pathologies like blepharitis. A careful slit-lamp examination is central for proper evaluation and diagnosis. Mechanical removal of the lice is the most effective treatment but should be complemented by topical and/or systemic treatment. This report presented an atypical case of this disease." + } +} \ No newline at end of file diff --git a/35770766.json b/35770766.json new file mode 100644 index 0000000000000000000000000000000000000000..3882f04dd6b4ea6357dd1006eefbf27da32a29b5 --- /dev/null +++ b/35770766.json @@ -0,0 +1,8 @@ +{ + "id": "35770766", + "label": 0, + "article": { + "id": "35770766", + "text": "Epileptic myoclonus or myoclonic seizures can occur in idiopathic generalized epilepsy (IGE) and progressive myoclonus epilepsy (PME). However, symptomatic myoclonus which is stimulus-sensitive and provoked by movement is typically seen in PME and Lance-Adams syndrome. Symptomatic myoclonus is not always associated with epileptiform discharges on the electroencephalogram. Therapeutic interventions such as anti-seizure medications (ASMs), the ketogenic diet and vagus nerve stimulation are not always effective. There is emerging evidence that perampanel (PER), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, may be effective for the treatment of myoclonic seizures and symptomatic myoclonus. We performed a systematic review of the literature to assess the efficacy of PER as treatment for myoclonic seizures and symptomatic myoclonus. Twenty-seven studies with a total sample size of 260 patients were included. The efficacy of PER was analysed separately for myoclonic seizures and symptomatic myoclonus. In the group with myoclonic seizures, 50% responder, 75% responder and seizure freedom rates were reported as 74.3% (101/ 136), 60.3% (82/136) and 57.4% (78/136), respectively, with a follow-up duration of 6-12 months. However, in one post-hoc analysis of data from patients with IGE, the efficacy of PER as treatment for myoclonic seizures during the double-blind phase showed no significant difference compared to placebo. The efficacy of PER for symptomatic myoclonus was reported in a total of 119 patients. Four studies (n=88 patients) reported the efficacy of PER as a decrease in myoclonus score/scale. In the remaining 31 patients, symptomatic myoclonus resolved in three patients, decreased in 21 patients and seven patients showed no improvement. We also analysed the number of patients who were already on levetiracetam (LEV) or valproic acid (VPA) at the time of PER initiation; these data were available for 153 patients. Of these, 56.8% were on LEV and 75.1% were on VPA when PER was initiated. This systematic review suggests that PER maybe effective as treatment for drug-resistant myoclonic seizures and symptomatic myoclonus. It may also be effective in patients who have already failed to respond to LEV and VPA. These findings are preliminary yet encouraging. This study has several limitations, particularly given the scarcity of high-quality randomized controlled trials and marked heterogeneity regarding the type and results of the studies. Hence, the findings of this review should be viewed with considerable reservation." + } +} \ No newline at end of file diff --git a/35810394.json b/35810394.json new file mode 100644 index 0000000000000000000000000000000000000000..cd6634ce0e45532c6e4823561de388ae1bca58c9 --- /dev/null +++ b/35810394.json @@ -0,0 +1,8 @@ +{ + "id": "35810394", + "label": 0, + "article": { + "id": "35810394", + "text": "Inherited retinal diseases (IRDs) are a heterogeneous group of blinding disorders, which result in dysfunction or death of the light-sensing cone and rod photoreceptors. Despite individual IRDs (Inherited retinal disease) being rare, collectively, they affect up to 1:2000 people worldwide, causing a significant socioeconomic burden, especially when cone-mediated central vision is affected. This study uses the Pde6c mouse model of achromatopsia, a cone-specific vision loss IRD (Inherited retinal disease), to investigate the potential gene-independent therapeutic benefits of a histone demethylase inhibitor GSK-J4 on cone cell survival. We investigated the effects of GSK-J4 treatment on cone cell survival in vivo and ex vivo and changes in cone-specific gene expression via single-cell RNA sequencing. A single intravitreal GSK-J4 injection led to transcriptional changes in pathways involved in mitochondrial dysfunction, endoplasmic reticulum stress, among other key epigenetic pathways, highlighting the complex interplay between methylation and acetylation in healthy and diseased cones. Furthermore, continuous administration of GSK-J4 in retinal explants increased cone survival. Our results suggest that IRD (Inherited retinal disease)-affected cones respond positively to epigenetic modulation of histones, indicating the potential of this approach in developing a broad class of novel therapies to slow cone degeneration." + } +} \ No newline at end of file diff --git a/35833444.json b/35833444.json new file mode 100644 index 0000000000000000000000000000000000000000..c800107cfeb85401d07008434108265c1c34b249 --- /dev/null +++ b/35833444.json @@ -0,0 +1,8 @@ +{ + "id": "35833444", + "label": 0, + "article": { + "id": "35833444", + "text": "AIM:\nTo study neurotransmitter status in children with early epileptic and developmental and epileptic encephalopathy (DEE) and to explore the clinical response to dopaminergic and serotoninergic therapies in a group of patients.\n\nMETHOD:\nTwo hundred and five patients (111 males [54.1.%] and 94 females [45.9%], mean age 10 months at the onset of epilepsy [SD 1 year 1 month], range 0-3 year) with epileptic encephalopathy/DEE were recruited, including those with West syndrome, Ohtahara syndrome, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, myoclonic encephalopathy in non-progressive disorders, infantile spasms, Doose syndrome, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, and those unclassified. Cerebrospinal fluid (CSF) neurotransmitter studies and patients' medical records were reviewed. Additionally, we present clinical data of 10 patients with low CSF neurotransmitter levels who received dopaminergic/serotoninergic treatments.\n\nRESULTS:\nAbnormal neurotransmitter values were identified in 68 (33%) patients. 5-Hydroxyindoleacetic acid (5-HIAA) deficit was the most prevalent alteration (91%). Low CSF 5-HIAA levels were significantly higher in 1- to 3-year-old children. A negative significant correlation was found between 5-HIAA levels and epilepsy duration before CSF study (Spearman's ρ=-0.191, p=0.007). Abnormalities in deep grey matter were associated with low levels of CSF homovanillic acid and 5-HIAA. Ten patients with low CSF neurotransmitter levels received dopamine and/or serotonin therapies. Six of them showed initial decrease of seizure frequency and severity and maintained improvement in some neurodevelopmental skills.\n\nINTERPRETATION:\nA considerable number of patients showed neurotransmitter abnormalities. Age at seizure onset and duration of epilepsy before CSF study were the principal factors related to neurotransmitter depletion. Early monoamine supplementation would seem advisable as a neuroprotective strategy.\n\nWHAT THIS PAPER ADDS:\n5-Hydroxyindoleacetic acid homeostasis is especially vulnerable in patients with epileptic encephalopathy/developmental and epileptic encephalopathy. Age of seizure onset and duration of epilepsy are determinants of neurotransmitter depletion." + } +} \ No newline at end of file diff --git a/35835895.json b/35835895.json new file mode 100644 index 0000000000000000000000000000000000000000..b91f044660a7b6fcfd7f5909312e789a57ca0830 --- /dev/null +++ b/35835895.json @@ -0,0 +1,8 @@ +{ + "id": "35835895", + "label": 0, + "article": { + "id": "35835895", + "text": "Lafora disease (LD) is a fatal rare neurodegenerative disorder that affects young adolescents and has no treatment yet. The hallmark of LD is the presence of polyglucosan inclusions (PGs), called Lafora bodies (LBs), in the brain and peripheral tissues. LD is caused by mutations in either EPM2A or EPM2B genes, which, respectively, encode laforin, a glucan phosphatase, and malin, an E3-ubiquitin ligase, with identical clinical features. LD knockout mouse models (Epm2a - / - and Epm2b - / -) recapitulate PG body accumulation, as in the human pathology, and display alterations in glutamatergic transmission and neuroinflammatory pathways in the brain. In this work, we show the results of four pre-clinical trials based on the modulation of glutamatergic transmission (riluzole and memantine) and anti-neuroinflammatory interventions (resveratrol and minocycline) as therapeutical strategies in an Epm2b - / - mouse model. Drugs were administered in mice from 3 to 5 months of age, corresponding to early stage of the disease, and we evaluated the beneficial effect of the drugs by in vivo behavioral phenotyping and ex vivo histopathological brain analyses. The behavioral assessment was based on a battery of anxiety, cognitive, and neurodegenerative tests and the histopathological analyses included a panel of markers regarding PG accumulation, astrogliosis, and microgliosis. Overall, the outcome of ameliorating the excessive glutamatergic neurotransmission present in Epm2b - / - mice by memantine displayed therapeutic effectiveness at the behavioral levels. Modulation of neuroinflammation by resveratrol and minocycline also showed beneficial effects at the behavioral level. Therefore, our study suggests that both therapeutical strategies could be beneficial for the treatment of LD patients. A mouse model of Lafora disease (Epm2b-/-) was used to check the putative beneficial effect of different drugs aimed to ameliorate the alterations in glutamatergic transmission and/or neuroinflammation present in the model. Drugs in blue gave a more positive outcome than the rest." + } +} \ No newline at end of file diff --git a/35863881.json b/35863881.json new file mode 100644 index 0000000000000000000000000000000000000000..ad1ad9138319441bbfa553e191e40e2d532e721b --- /dev/null +++ b/35863881.json @@ -0,0 +1,8 @@ +{ + "id": "35863881", + "label": 0, + "article": { + "id": "35863881", + "text": "A 40-year-old woman presented with a 20 kg weight loss and asymmetrical hip and shoulder girdle muscle weakness; she had a raised serum creatine kinase and mild peripheral blood eosinophilia. There was no evidence of a parasitic infection or vasculitis. A muscle biopsy showed eosinophilic myositis. Following treatment with oral corticosteroid, methotrexate and intravenous immunoglobulin infusion, her weakness initially mildly improved and her serum creatine kinase reduced. However, despite continued immunosuppression her condition progressed over 3 years. The pattern of muscle weakness suggested a muscular dystrophy. Genetic testing confirmed heterozygous calpain mutations consistent with limb girdle muscular dystrophy type 2A." + } +} \ No newline at end of file diff --git a/35922766.json b/35922766.json new file mode 100644 index 0000000000000000000000000000000000000000..402095052a20c4feae48329522d8c8a8950c3601 --- /dev/null +++ b/35922766.json @@ -0,0 +1,8 @@ +{ + "id": "35922766", + "label": 0, + "article": { + "id": "35922766", + "text": "BACKGROUND:\nMyoclonus, Epilepsy and Ragged-Red-Fibers (MERRF) is a mitochondrial encephalomyopathy due to heteroplasmic mutations in mitochondrial DNA (mtDNA) most frequently affecting the tRNA gene at position m.8344A \u003e G. Defective tRNA severely impairs mitochondrial protein synthesis and respiratory chain when a high percentage of mutant heteroplasmy crosses the threshold for full-blown clinical phenotype. Therapy is currently limited to symptomatic management of myoclonic epilepsy, and supportive measures to counteract muscle weakness with co-factors/supplements.\n\nMETHODS:\nWe tested two therapeutic strategies to rescue mitochondrial function in cybrids and fibroblasts carrying different loads of the m.8344A \u003e G mutation. The first strategy was aimed at inducing mitochondrial biogenesis directly, over-expressing the master regulator PGC-1α, or indirectly, through the treatment with nicotinic acid, a NAD precursor. The second was aimed at stimulating the removal of damaged mitochondria through prolonged rapamycin treatment.\n\nRESULTS:\nThe first approach slightly increased mitochondrial protein expression and respiration in the wild type and intermediate-mutation load cells, but was ineffective in high-mutation load cell lines. This suggests that induction of mitochondrial biogenesis may not be sufficient to rescue mitochondrial dysfunction in MERRF cells with high-mutation load. The second approach, when administered chronically (4 weeks), induced a slight increase of mitochondrial respiration in fibroblasts with high-mutation load, and a significant improvement in fibroblasts with intermediate-mutation load, rescuing completely the bioenergetics defect. This effect was mediated by increased mitochondrial biogenesis, possibly related to the rapamycin-induced inhibition of the Mechanistic Target of Rapamycin Complex 1 (mTORC1) and the consequent activation of the Transcription Factor EB (TFEB).\n\nCONCLUSIONS:\nOverall, our results point to rapamycin-based therapy as a promising therapeutic option for MERRF." + } +} \ No newline at end of file diff --git a/35930270.json b/35930270.json new file mode 100644 index 0000000000000000000000000000000000000000..73d8dd26f7bb8c1d2d6afb66d97492899eb8f048 --- /dev/null +++ b/35930270.json @@ -0,0 +1,8 @@ +{ + "id": "35930270", + "label": 0, + "article": { + "id": "35930270", + "text": "PURPOSE:\nThis prospective study investigates longitudinal changes in retinal structure in patients with achromatopsia (ACHM) using optical coherence tomography (OCT).\n\nMETHODS:\nSeventeen patients (five adults, 12 children) with genetically confirmed CNGA3- or CNGB3-associated ACHM underwent ocular examination and OCT over a follow-up period of between 2 and 9.33 years (mean = 5.7 years). Foveal tomograms were qualitatively graded and were segmented for quantitative analysis: central macular thickness (CMt), outer nuclear layer thickness (ONLt), and size of the foveal hyporeflective zone (vertical HRZ thickness: HRZt and horizontal HRZ width: HRZw) were measured. Data were analyzed using linear mixed regression models. Both age and visit were included into the models, to explore the possibility that the rate of disease progression depends on patient age.\n\nRESULTS:\nFifteen of 17 patients (88%) showed longitudinal changes in retinal structure over the follow-up period. The most common patterns of progression was development of ellipsoid zone (EZ) disruption and HRZ. There was a significant increase in HRZt (P = 0.01) and HRZw (P = 0.001) between visits and no significant change in CMt and ONLt. Retinal parameters showed no difference in changes by genetic mutation (CNGA3 (n = 11), CNGB3 (n = 6)).\n\nCONCLUSIONS:\nThis study demonstrates clear longitudinal changes in foveal structure mainly in children, but also in adults with ACHM, over a long follow-up period. The longitudinal foveal changes suggest that treatment at an earlier age should be favored." + } +} \ No newline at end of file diff --git a/35942587.json b/35942587.json new file mode 100644 index 0000000000000000000000000000000000000000..93e850f2773a1aa56974db6f702c78e3ecdb7c4d --- /dev/null +++ b/35942587.json @@ -0,0 +1,8 @@ +{ + "id": "35942587", + "label": 0, + "article": { + "id": "35942587", + "text": "OBJECTIVES:\nShort stature is one of the most common reasons for consulting a paediatric endocrinologist. Targeted diagnosis of familial short stature can be challenging due to a broad spectrum of differential diagnoses.\n\nCASE PRESENTATION:\nHere we report a novel mutation in the fibrillin 1 gene in six family members causing a mild phenotype of acromicric dysplasia. Additionally, we present the effects of growth hormone therapy in one of the affected children.\n\nCONCLUSIONS:\nAcromicric dysplasia is a very rare skeletal dysplasia with a prevalence of \u003c1 of 1.000.000 with only about 60 cases being reported worldwide. It is characterized by short stature, acromelia, mild facial dysmorphy but normal intelligence. This study aims to exemplify the clinical and molecular features of -related acromicric dysplasia and illustrates its pleiotropy by presenting a new, mild phenotype." + } +} \ No newline at end of file diff --git a/35963004.json b/35963004.json new file mode 100644 index 0000000000000000000000000000000000000000..2d03153cc1395bac2ad9a6681d78d6634452136b --- /dev/null +++ b/35963004.json @@ -0,0 +1,8 @@ +{ + "id": "35963004", + "label": 0, + "article": { + "id": "35963004", + "text": "PURPOSE:\nTo propose a working framework for patients with inherited eye diseases presenting to ophthalmologists who are interested in assisted reproductive technology and preimplantation genetic testing.\n\nMETHODS:\nRetrospective chart review and case series of three families with inherited eye diseases who successfully underwent preimplantation genetic testing, in vitro fertilization, and birth of unaffected children.\n\nRESULTS:\nPreimplantation genetic testing was performed for three families with different inherited eye diseases, which included autosomal dominant retinitis pigmentosa, autosomal recessive achromatopsia, and X-linked Goltz syndrome. Preimplantation genetic testing led to the identification of unaffected embryos, which were then selected for in vitro fertilization and resulted in the birth of unaffected children.\n\nCONCLUSION:\nA close collaboration between patients, families, ophthalmologists, reproductive genetic counselors, and reproductive endocrinology and infertility specialists is the ideal model for taking care of patients interested in preimplantation genetic testing for preventing the transmission of inherited eye diseases." + } +} \ No newline at end of file diff --git a/35979206.json b/35979206.json new file mode 100644 index 0000000000000000000000000000000000000000..ba9b3e9707c2032342701059f121c3b6dd8e8c5a --- /dev/null +++ b/35979206.json @@ -0,0 +1,8 @@ +{ + "id": "35979206", + "label": 0, + "article": { + "id": "35979206", + "text": "SIGNIFICANCE:\nis an uncommon infection due to inoculating the eyelashes and surrounding tissues of the eye. Because of its rarity, it may be misdiagnosed as blepharitis or conjunctivitis clinically.\n\nPURPOSE:\nThis report described a rare case of corneal epithelial injury associated with .\n\nCASE REPORT:\nA 59-year-old woman presented with 1 month history of repeated episodes of itching and irritation symptoms in both eyes. A slit-lamp examination was performed, which revealed mild conjunctival hyperemia and corneal epithelial defects in both eyes. On closer examination, crab-like lice, nits, and red pinpoint excretions were seen on her eyelashes and eyelids bilaterally. Corneal fluorescein staining in both eyes was observed, and tear film break-up time (BUT) in each eye was 2 s. Numerous lice were also found attached to the scalp hair. Therefore, a clinical diagnosis of corneal epithelial injury associated with was made. For treatment, eyelashes with nits and/or lice were removed mechanically with a fine tweezers. Then, 0.01% Hypochlorous Acid eye wash was used to clean the eyelid margin twice daily. Also, she was prescribed a combination of Vitamin A Palmitate eye gel three times a day and Tobradex eye ointment once daily. Meanwhile, the patient was provided with suggestions on how to improve personal hygiene and environmental hygiene, including cutting of the scalp hair and the application of 0.01% permethrin rinse. One week later, no evidence of lice and nits of the eyelashes and scalp hair was found, and the patient's symptoms and signs also improved significantly.\n\nCONCLUSION:\nThis rare case suggested that the eyelashes of patients presenting with itching and irritation symptoms should be carefully examined with a slit-lamp. Besides removal of the parasites, attention should be paid to the treatment of corneal epithelial injury associated with ." + } +} \ No newline at end of file diff --git a/35998912.json b/35998912.json new file mode 100644 index 0000000000000000000000000000000000000000..917b67c9c48af25c126b33e8ecdfc60774e91923 --- /dev/null +++ b/35998912.json @@ -0,0 +1,8 @@ +{ + "id": "35998912", + "label": 0, + "article": { + "id": "35998912", + "text": "Recent advances in regenerative therapy have placed the treatment of previously incurable eye diseases within arms' reach. Achromatopsia is a severe monogenic heritable retinal disease that disrupts cone function from birth, leaving patients with complete colour blindness, low acuity, photosensitivity and nystagmus. While successful gene-replacement therapy in non-primate models of achromatopsia has raised widespread hopes for clinical treatment, it was yet to be determined if and how these therapies can induce new cone function in the human brain. Using a novel multimodal approach, we demonstrate for the first time that gene therapy can successfully activate dormant cone-mediated pathways in children with achromatopsia (CNGA3- and CNGB3-associated, 10-15 years). To test this, we combined functional MRI population receptive field mapping and psychophysics with stimuli that selectively measure cone photoreceptor signalling. We measured cortical and visual cone function before and after gene therapy in four paediatric patients, evaluating treatment-related change against benchmark data from untreated patients (n = 9) and normal-sighted participants (n = 28). After treatment, two of the four children displayed strong evidence for novel cone-mediated signals in visual cortex, with a retinotopic pattern that was not present in untreated achromatopsia and which is highly unlikely to emerge by chance. Importantly, this change was paired with a significant improvement in psychophysical measures of cone-mediated visual function. These improvements were specific to the treated eye, and provide strong evidence for successful read-out and use of new cone-mediated information. These data show for the first time that gene replacement therapy in achromatopsia within the plastic period of development can awaken dormant cone-signalling pathways after years of deprivation. This reveals unprecedented neural plasticity in the developing human nervous system and offers great promise for emerging regenerative therapies." + } +} \ No newline at end of file diff --git a/36074078.json b/36074078.json new file mode 100644 index 0000000000000000000000000000000000000000..ed5691d1610da6985f72aa28d68538a684c070c9 --- /dev/null +++ b/36074078.json @@ -0,0 +1,8 @@ +{ + "id": "36074078", + "label": 0, + "article": { + "id": "36074078", + "text": "PURPOSE:\nCardiac involvement in limb-girdle muscular dystrophy (LGMD)2A and LGMD2B, the most common subgroups of LGMD, is controversial. Our study aims to determine whether myocardial dysfunction develops in LGMD2A and LGMD2B patients.\n\nMETHODS:\nThe study included 16 LGMD2A, 12 LGMD2B patients, and 48 healthy individuals. Comparisons included demographic, clinical, and laboratory parameters of LGMD2A and LGMD2B subgroups and traditional echocardiography and two-dimensional speckle tracking echocardiography (2D-STE) parameters with the normal population.\n\nRESULTS:\nThe median age was 33 (22-39 interquartile range [IQR]) in the LGMD2A group, 33 (27-38 IQR) in the LGMD2B group, and 28 (25-35 IQR) in the control group. The left ventricular (LV) ejection fraction of both LGMD2A and LGMD2B groups was similar to the control group (p = 0.296 and p = 0.918). Apical 4-chamber longitudinal strain (LS), Apical 2-chamber LS, Apical 3-chamber LS, left ventricular global longitudinal strain (LVGLS)-mid-myocardial, LVGLS-endocardium, and LVGLS-epicardium were lower (less negative) in the LGMD2B group compared to the control group (p = 0.006, p = 0.001, p \u003c 0.001, p \u003c 0.001, p \u003c 0.001, and p \u003c 0.001, respectively).\n\nCONCLUSION:\nLV 2D-STE parameters of LGMD2A patients were similar to the control group, while they decreased significantly (less negative) in LGMD2B patients, indicating that LV subclinical myocardial dysfunction may develop in LGMD2B patients." + } +} \ No newline at end of file diff --git a/36098450.json b/36098450.json new file mode 100644 index 0000000000000000000000000000000000000000..38c7d4378ba2f8042cbb507c26d195e6a5afcb05 --- /dev/null +++ b/36098450.json @@ -0,0 +1,8 @@ +{ + "id": "36098450", + "label": 0, + "article": { + "id": "36098450", + "text": "INTRODUCTION:\nMioclonic progressive epilepsy (MPE) includes a clinical and genetical heterogeneous group of neuro-degenerative disorders that associate spontaneous and action-induced myoclonus as well as progressive cognitive impairment. Lafora`s disease is a subtype of MPE with autosomical recessive inheritance due to a mutation in EPM2A or EPM2B genes. Seizures, especially myoclonus, are often refractary to antiepileptic drugs (AD).\n\nCASE REPORT:\nIn this article we report a patient with Lafora´s disease diagnosis, previously resistant to several AD tested with good and sustained response to zonisamide. Indeed, we describe a brief review about the efficacy of zonisamida in MPE.\n\nCONCLUSION:\nZonisamide may be considered as a good therapeutic alternative in MPE." + } +} \ No newline at end of file diff --git a/36142121.json b/36142121.json new file mode 100644 index 0000000000000000000000000000000000000000..71b779761d2dcda870c3ec0bcbbfbb9f93fe2dc5 --- /dev/null +++ b/36142121.json @@ -0,0 +1,8 @@ +{ + "id": "36142121", + "label": 0, + "article": { + "id": "36142121", + "text": "A variety of endogenous and exogenous insults are capable of impeding replication fork progression, leading to replication stress. Several SNF2 fork remodelers have been shown to play critical roles in resolving this replication stress, utilizing different pathways dependent upon the nature of the DNA lesion, location on the DNA, and the stage of the cell cycle, to complete DNA replication in a manner preserving genetic integrity. Under certain conditions, however, the attempted repair may lead to additional genetic instability. Cockayne syndrome group B (CSB) protein, a SNF2 chromatin remodeler best known for its role in transcription-coupled nucleotide excision repair, has recently been shown to catalyze fork reversal, a pathway that can provide stability of stalled forks and allow resumption of DNA synthesis without chromosome breakage. Prolonged stalling of replication forks may collapse to give rise to DNA double-strand breaks, which are preferentially repaired by homology-directed recombination. CSB plays a role in repairing collapsed forks by promoting break-induced replication in S phase and early mitosis. In this review, we discuss roles of CSB in regulating the sources of replication stress, replication stress response, as well as the implications of CSB for cancer therapy." + } +} \ No newline at end of file diff --git a/36157516.json b/36157516.json new file mode 100644 index 0000000000000000000000000000000000000000..3855587272721daf8fdcd7e91b20e73fa36f1c93 --- /dev/null +++ b/36157516.json @@ -0,0 +1,8 @@ +{ + "id": "36157516", + "label": 0, + "article": { + "id": "36157516", + "text": "Pilomatrixoma is a follicular benign tumor of unknown etiology that originates in the matrix of a hair follicle. It develops more frequently in children and young adults, with a slight predominance in female patients. It is a slow-growing tumor that presents as a mobile nodule, firm, and with well-defined borders. The present study aimed to report the clinical, histopathologic, and radiographic aspects of pilomatrixoma in the cheek area of a 20-year-old female patient as the established treatment at an oral maxillofacial department. Pilomatrixoma is rarely included in the differential diagnosis of masses and nodules in the skin, and it is often confused with other nodular lesions, such as epidermoid cysts. The diagnostic method to identify this entity is an incisional biopsy. Because of its high incidence in the head and neck region, oral surgeons should be well-acquainted with this type of tumor so that it can be included as a diagnostic hypothesis of masses and nodules of the head and neck." + } +} \ No newline at end of file diff --git a/36159182.json b/36159182.json new file mode 100644 index 0000000000000000000000000000000000000000..438945f12660dec115e7cbf7f2496dc67256b040 --- /dev/null +++ b/36159182.json @@ -0,0 +1,8 @@ +{ + "id": "36159182", + "label": 0, + "article": { + "id": "36159182", + "text": "Patients with chronic headaches sometimes prefer non-pharmacological methods for pain management. We have shown previously that green light exposure (GLED, Green Light Emitting Diode) reversed thermal hyperalgesia and mechanical allodynia in a rat model of neuropathic pain. This effect is mediated through the visual system. Moreover, we recently showed that GLED was effective in decreasing the severity of headache pain and the number of headache-days per month in migraine patients. The visual system is comprised of image-forming and non-image-forming pathways; however, the contribution of different photosensitive cells to the effect of GLED is not yet known. Here, we report a 66-year-old man with headaches attributed to other disorders of homeostasis and color blindness who was recruited in the GLED study. The subject, diagnosed with protanomaly, cannot differentiate green, yellow, orange, and red colors. After completing the GLED exposure protocol, the subject noted significant decreases in headache pain intensity without reduction in the number of headache-days per month. The subject also reported improvement in the quality of his sleep. These findings suggest that green light therapy mediates the decrease of the headache pain intensity through non-image-forming intrinsically photosensitive retinal ganglion cells. However, the subject did not report a change in the frequency of his headaches, suggesting the involvement of cones in reduction of headache frequency by GLED. This is the first case reported of a colorblind man with chronic headache using GLED to manage his headache pain and may increase our understanding of the contribution of different photosensitive cells in mediating the pain-relieving effects of GLED." + } +} \ No newline at end of file diff --git a/36162988.json b/36162988.json new file mode 100644 index 0000000000000000000000000000000000000000..4f1bb0542e275c8d96723c9c1fa98bf046ac949f --- /dev/null +++ b/36162988.json @@ -0,0 +1,8 @@ +{ + "id": "36162988", + "label": 0, + "article": { + "id": "36162988", + "text": "PURPOSE:\nAlström Syndrome (AS) is an autosomal recessive hereditary disease with the characteristics of multiorgan dysfunction. Due to the heterogeneity of clinical manifestations of AS, genetic testing is crucial for the diagnosis of AS. Herein, we used whole-exome sequencing (WES) to determine the genetic causes and characterize the clinical features of three affected patients in two Chinese families with Alström Syndrome.\n\nMATERIALS AND METHODS:\nThree affected patients (initially diagnosed as achromatopsia). and five asymptomatic members were recruited for both genetic and clinical tests. The complete ophthalmic examinations and systemic examinations were performed on all participants. Whole exome sequencing (WES) was performed for mutation detection. The silico analysis was also applied to predict the pathogenesis of identified pathogenic variants.\n\nRESULTS:\nIn family 1, the proband showed low vision, hyperopia, photophobia, nystagmus, and total color blindness. DNA analysis revealed that she carried a compound heterozygote with two novel pathogenic variants in the ALMS1 gene NM_015120.4:c.10379del (NP_055935.4:p.(Asp2252Tyr)) and NM_015120.4:c.11641_11642del (NP_055935.4:p.(Val3881ThrfsTer11)). Further systemic examinations showed short stature, acanthosis nigricans, and sensorineural hearing loss. In family 2, two affected siblings presented the low vision, hyperopia, photophobia, nystagmus, and total color blindness. DNA analysis revealed that they carried a same compound heterozygote with two novel pathogenic variants in the ALMS1 gene NM_015120.4:c.10379del (NP_055935.4:p.(Asn3460IlefsTer49)), NM_015120.4:c.10819C \u003e T (NP_055935.4:p.(Arg3607Trp)). Further systemic examinations showed obesity and mild abnormalities of lipid metabolism. According to the genetic testing results and further systemic analysis, the three affected patients were finally diagnosed as Alström Syndrome (AS).\n\nCONCLUSIONS:\nWe found two new compound heterozygous pathogenic variants of the ALMS1 gene and determined the diagnosis as Alström Syndrome in three patients of two Chinese families. Our study extends the genotypic and phenotypic spectrums for ALMS1 -AS and emphasizes the importance of gene testing in assisting the clinical diagnosis for cases with phenotypic diversities, which would help the AS patients with early diagnosis and treatment to reduce future systemic damage." + } +} \ No newline at end of file diff --git a/36190439.json b/36190439.json new file mode 100644 index 0000000000000000000000000000000000000000..1641b60fa370cc2e4147ff8e7852880443abe9c9 --- /dev/null +++ b/36190439.json @@ -0,0 +1,8 @@ +{ + "id": "36190439", + "label": 0, + "article": { + "id": "36190439", + "text": "Repair of genomic DNA is a fundamental housekeeping process that quietly maintains the health of our genomes. The consequences of a genetic defect affecting a component of this delicate mechanism are quite harmful, characterized by a cascade of premature aging that injures a variety of organs, including the nervous system. One part of the nervous system that is impaired in certain DNA repair disorders is the peripheral nerve. Chronic motor, sensory, and sensorimotor polyneuropathies have all been observed in affected individuals, with specific physiologies associated with different categories of DNA repair disorders. Cockayne syndrome has classically been linked to demyelinating polyneuropathies, whereas xeroderma pigmentosum has long been associated with axonal polyneuropathies. Three additional recessive DNA repair disorders are associated with neuropathies, including trichothiodystrophy, Werner syndrome, and ataxia-telangiectasia. Although plausible biological explanations exist for why the peripheral nerves are specifically vulnerable to impairments of DNA repair, specific mechanisms such as oxidative stress remain largely unexplored in this context, and bear further study. It is also unclear why different DNA repair disorders manifest with different types of neuropathy, and why neuropathy is not universally present in those diseases. Longitudinal physiological monitoring of these neuropathies with serial electrodiagnostic studies may provide valuable noninvasive outcome data in the context of future natural history studies, and thus the responses of these neuropathies may become sentinel outcome measures for future clinical trials of treatments currently in development such as adeno-associated virus gene replacement therapies." + } +} \ No newline at end of file diff --git a/36192771.json b/36192771.json new file mode 100644 index 0000000000000000000000000000000000000000..a93c57181ca1bcbf50670398112f03647fe698a9 --- /dev/null +++ b/36192771.json @@ -0,0 +1,8 @@ +{ + "id": "36192771", + "label": 0, + "article": { + "id": "36192771", + "text": "BACKGROUND:\nLafora disease is a rare genetic disorder involving glycogen metabolism disorder. It is inherited by autosomal recessive pattern presenting as a progressive myoclonus epilepsy and neurologic deterioration beginning in adolescence. It is characterized by Lafora bodies in tissues such as brain, skin, muscle, and liver.\n\nCASE PRESENTATION:\nWe report a rare case of Lafora disease in a 16-year-old Albanian girl who presented at a tertiary health care center with generalized tonic-clonic seizures, eyelid twitches, hallucinations, headache, and cognitive dysfunction. She was initially treated for generalized epilepsy and received an antiepileptic drug. However, owing to resistance of seizures to this antiepileptic drug, a second drug was introduced. However, seizures continued despite compliance with therapy, and general neurological status began to deteriorate. The child began to have hallucinations and decline of cognitive function. She developed dysarthria and unsteady gait. When admitted to the hospital, blood tests and imaging examinations were planned. The blood tests were unremarkable. There was no relevant family history and no consanguinity. Electroencephalography showed multifocal discharges in both hemispheres, and brain magnetic resonance imaging revealed no abnormality. Axillary skin biopsy revealed inclusion bodies in apocrine glands. Consequently, the child was referred to an advanced center for genetic testing, which also confirmed diagnosis of Lafora disease with a positive mutation on NHLRC1 gene.\n\nCONCLUSIONS:\nEven though rare as a condition, Lafora disease should be considered on differential diagnosis in progressive and drug-refractory epilepsy in adolescents, especially when followed by cognitive decline." + } +} \ No newline at end of file diff --git a/36203564.json b/36203564.json new file mode 100644 index 0000000000000000000000000000000000000000..8a65c05090d5698abe483f21861b48acbff40f88 --- /dev/null +++ b/36203564.json @@ -0,0 +1,8 @@ +{ + "id": "36203564", + "label": 0, + "article": { + "id": "36203564", + "text": "INTRODUCTION:\nTherapeutic options are critically needed for children with refractory very early onset inflammatory bowel disease (VEO-IBD). Our aim was to evaluate clinical response to canakinumab, an anti-IL-1β monoclonal antibody, in patients with VEO-IBD whose phenotype resembles those with monogenic autoinflammatory disease.\n\nMETHODS:\nThis is a single center retrospective study of patients with VEO-IBD with autoinflammatory phenotype (AIP) in the absence of identified monogenic disease treated with canakinumab for \u003e6 months. AIP was defined as confirmed IBD with associated signs of systemic inflammation in the absence of infection, including leukocytosis, markedly elevated inflammatory markers, and extraintestinal manifestations (recurrent fevers, oral ulcers, arthritis). Primary outcomes included clinical response in disease activity indices after 6 months of therapy. Secondary outcomes included rate of AIP signs and symptoms, growth, surgery, steroid use, hospitalizations, and adverse events.\n\nRESULTS:\nNineteen patients were included: 47% with infantile onset, 58% classified as IBD-U, and 42% classified as CD. At baseline, 37% were biologic naïve, and canakinumab was used as dual therapy in 74% of patients. Clinical response was achieved in 89% with statistically significant improvement in PCDAI and PUCAI. Clinical remission was achieved in 32% of patients. There was significant improvement in the clinical manifestations of AIP and the biochemical markers of disease. Number of hospitalizations (p\u003c0.01) and length of stay (p\u003c0.05) decreased. Growth improved with median weight-for-length Z-score increasing from -1.01 to 1.1 in children less than 2 years old. There were minimal adverse events identified during the study period.\n\nCONCLUSION:\nCanakinumab may be an effective and safe treatment for a subset of children with VEO-IBD with AIP, as well as older patients with IBD. This study highlights the importance of a precision medicine approach in children with VEO-IBD." + } +} \ No newline at end of file diff --git a/36214494.json b/36214494.json new file mode 100644 index 0000000000000000000000000000000000000000..a79649c602ac1588c296e719f688b08d7cbcb3b8 --- /dev/null +++ b/36214494.json @@ -0,0 +1,8 @@ +{ + "id": "36214494", + "label": 0, + "article": { + "id": "36214494", + "text": "BACKGROUND:\nAs pilomatricoma is a common adnexal skin tumor often occurring in exposed areas, dermatologists focus on minimizing postsurgical scarring.\n\nMETHODS:\nThis retrospective study included patients aged \u003c 19 years who underwent surgical treatment for pilomatricoma at a single university hospital from 2015 to 2021. Patient demographics, tumor characteristics, and surgical outcomes were analyzed according to the surgical methods including punch incision and elliptical excision.\n\nRESULTS:\nOverall, 75 patients and 79 lesions were included in the study. The mean age of the patients was 8.4 years, and 48 patients (64.0%) were females. The face was the most common site of pilomatricoma (51.9%), and within the face, the cheeks were the most common sites. No recurrence was observed in the elliptical excision group, while one case of recurrence (4.5%) was observed in the punch incision group. The mean length of the wound was 2.00 cm in the elliptical excision group, which was longer than that in the punch incision group (0.49 cm; \u003c .001).\n\nCONCLUSIONS:\nConsidering that surgery is the gold standard treatment for pilomatricoma, punch incision may be useful as an alternative surgical option for pilomatricoma in children." + } +} \ No newline at end of file diff --git a/36239343.json b/36239343.json new file mode 100644 index 0000000000000000000000000000000000000000..cfa2db83309bd6082fc51944bfe80b7e0e329ded --- /dev/null +++ b/36239343.json @@ -0,0 +1,8 @@ +{ + "id": "36239343", + "label": 0, + "article": { + "id": "36239343", + "text": "Trapped neutrophil syndrome is a rare congenital disease recognized in Border Collies and is characterized by persistent neutropenia with myeloid hyperplasia. The mechanism of neutropenia has not been described. We document the case of a young Border Collie diagnosed with trapped neutrophil syndrome based on clinical features, blood and bone marrow evaluation, and presence of the associated homozygous mutation. Results from flow cytometric and storage studies suggested lower neutrophil survival time. The dog had substantial neutrophilic inflammation in multiple organs, indicating that neutrophils could leave the marrow and enter tissues, making the term \"trapped\" neutrophil syndrome a misnomer." + } +} \ No newline at end of file diff --git a/36254071.json b/36254071.json new file mode 100644 index 0000000000000000000000000000000000000000..53374ef55abff35fbd4400320e49270734114159 --- /dev/null +++ b/36254071.json @@ -0,0 +1,8 @@ +{ + "id": "36254071", + "label": 0, + "article": { + "id": "36254071", + "text": "RATIONALE:\nWe report the case of a patient who developed asymptomatic bilateral papillitis after coronavirus disease 2019 (COVID-19) vaccination.\n\nPATIENT CONCERNS:\nA 61-year-old man presented to our tertiary clinic with bilateral optic disc edema, which was incidentally detected during his visit to a primary ophthalmology clinic. He had received an adenovirus-vectored COVID-19 vaccine 2 weeks before the optic disc edema was detected and had experienced no ocular discomfort, except for a floater in his right eye. Although his visual acuity was normal and he had no color vision deficiencies or marked visual field defects, the optic disc edema worsened over several days. Orbital magnetic resonance imaging showed no optic tract enhancement, and lumbar puncture revealed normal cerebrospinal fluid pressure. The patient tested negative for aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies and Leber hereditary optic neuropathy-associated gene mutations.\n\nDIAGNOSIS:\nThe patient was diagnosed with bilateral papillitis, possibly induced by the COVID-19 vaccination.\n\nINTERVENTIONS:\nThe patient received steroid pulse therapy with methylprednisolone (500 mg/day) for 3 days followed by an oral prednisolone taper for 3 weeks.\n\nOUTCOMES:\nThe patient's papillitis started to subside 3 weeks after he received systemic steroid therapy and completely resolved without any sequelae 2 months later. A year after the diagnosis, the fundus remained stable without disease recurrence or optic disc atrophy.\n\nLESSONS:\nHealthy individuals receiving COVID-19 vaccines may present with various manifestations of optic neuritis. In the present case, the patient presented with asymptomatic progressive bilateral optic disc edema and had a favorable long-term course after receiving steroid therapy." + } +} \ No newline at end of file diff --git a/36282306.json b/36282306.json new file mode 100644 index 0000000000000000000000000000000000000000..01b157d81e1abaced7ab01dae0fc0ebf418e062b --- /dev/null +++ b/36282306.json @@ -0,0 +1,8 @@ +{ + "id": "36282306", + "label": 0, + "article": { + "id": "36282306", + "text": "Pilomatricomas are benign tumors of the hair follicle that occur frequently in the scalp region. They occur most often in children. We describe a case of pilomatricoma in a teenager, referred to neurosurgery for excision. This diagnosis should be considered in the workup of scalp lesions, and this case report should serve to draw attention to this entity." + } +} \ No newline at end of file diff --git a/36303102.json b/36303102.json new file mode 100644 index 0000000000000000000000000000000000000000..062a0e2c14b2189f3ee8c9e1cb0e0d87eaab8eab --- /dev/null +++ b/36303102.json @@ -0,0 +1,8 @@ +{ + "id": "36303102", + "label": 0, + "article": { + "id": "36303102", + "text": "Lafora disease is a fatal form of progressive myoclonic epilepsy caused by mutations in the EPM2A or NHLRC1/EPM2B genes that usually appears during adolescence. The Epm2a and Epm2b knock-out mouse models of the disease develop behavioral and neurological alterations similar to those observed in patients. The aim of this work is to analyze whether early treatment with metformin (from conception to adulthood) ameliorates the formation of Lafora bodies and improves the behavioral and neurological outcomes observed with late treatment (during 2 months at 10 months of age). We also evaluated the benefits of metformin in patients with Lafora disease. To assess neurological improvements due to metformin administration in the two mouse models, we evaluated the effects on pentylenetetrazol sensitivity, posturing, motor coordination and activity, and memory. We also analyzed the effects on Lafora bodies, neurodegeneration, and astrogliosis. Furthermore, we conducted a follow-up study of an initial cohort of 18 patients with Lafora disease, 8 treated with metformin and 10 untreated. Our results indicate that early metformin was more effective than late metformin in Lafora disease mouse models improving neurological alterations of both models such as neuronal hyperexcitability, motor and memory alterations, neurodegeneration, and astrogliosis and decreasing the formation of Lafora bodies. Moreover, patients receiving metformin had a slower progression of the disease. Overall, early treatment improves the outcome seen with late metformin treatment in the two knock-out mouse models of Lafora disease. Metformin-treated patients exhibited an ameliorated course of the disease with slower deterioration of their daily living activities." + } +} \ No newline at end of file diff --git a/36308430.json b/36308430.json new file mode 100644 index 0000000000000000000000000000000000000000..6f40a15c25d94d50bd29f312fce188dc573c09ba --- /dev/null +++ b/36308430.json @@ -0,0 +1,8 @@ +{ + "id": "36308430", + "label": 0, + "article": { + "id": "36308430", + "text": "TFIIH is a complex essential for transcription of protein-coding genes by RNA polymerase II, DNA repair of UV-lesions and transcription of rRNA by RNA polymerase I. Mutations in TFIIH cause the cancer prone DNA-repair disorder xeroderma pigmentosum (XP) and the developmental and premature aging disorders trichothiodystrophy (TTD) and Cockayne syndrome. A total of 50% of the TTD cases are caused by TFIIH mutations. Using TFIIH mutant patient cells from TTD and XP subjects we can show that the stress-sensitivity of the proteome is reduced in TTD, but not in XP. Using three different methods to investigate the accuracy of protein synthesis by the ribosome, we demonstrate that translational fidelity of the ribosomes of TTD, but not XP cells, is decreased. The process of ribosomal synthesis and maturation is affected in TTD cells and can lead to instable ribosomes. Isolated ribosomes from TTD patients show an elevated error rate when challenged with oxidized mRNA, explaining the oxidative hypersensitivity of TTD cells. Treatment of TTD cells with N-acetyl cysteine normalized the increased translational error-rate and restored translational fidelity. Here we describe a pathomechanism that might be relevant for our understanding of impaired development and aging-associated neurodegeneration." + } +} \ No newline at end of file diff --git a/36309462.json b/36309462.json new file mode 100644 index 0000000000000000000000000000000000000000..765befacdab5a10c74b39108ab755837076703e7 --- /dev/null +++ b/36309462.json @@ -0,0 +1,8 @@ +{ + "id": "36309462", + "label": 0, + "article": { + "id": "36309462", + "text": "Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a rare inherited autosomal recessive disease due to bi-allelic mutations in the ASAH1 gene. SMA-PME is characterized by progressive muscle weakness from three to seven years of age, accompanied by epilepsy, intractable seizures, and sometimes sensorineural hearing loss. To the best of our knowledge, 47 cases have been reported. The present study reports five patients from four different families affected by SMA-PME characterized by progressive myoclonic epilepsy, proximal weakness, and lower motor neuron disease, as proven by electrodiagnostic studies. Genetic analysis identified two different mutations in the ASAH1 (NM_177924.4) gene, a previously reported pathogenic variant, c.125C\u003eT (p.Thr42Met), and a novel likely pathogenic variant c.109C\u003eA (p.Pro37Thr). In addition to reporting a novel pathogenic variant in the ASAH1 gene causing SMA-PME disease, this study compares the signs, phenotypic, and genetic findings of the case series with previous reports and discusses some symptomatic treatments." + } +} \ No newline at end of file diff --git a/36325744.json b/36325744.json new file mode 100644 index 0000000000000000000000000000000000000000..459c71588e2b2e2c1912ca017cc8b0c58dba3e97 --- /dev/null +++ b/36325744.json @@ -0,0 +1,8 @@ +{ + "id": "36325744", + "label": 0, + "article": { + "id": "36325744", + "text": "OBJECTIVE:\nThe objectives of this study were to define the clinical and biochemical spectrum of spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) and to determine if aberrant cellular ceramide accumulation could be normalized by enzyme replacement.\n\nMETHODS:\nClinical features of 6 patients with SMA-PME were assessed by retrospective chart review, and a literature review of 24 previously published cases was performed. Leukocyte enzyme activity of acid ceramidase was assessed with a fluorescence-based assay. Skin fibroblast ceramide content and was assessed by high performance liquid chromatography, electrospray ionization tandem mass spectroscopy. Enzyme replacement was assessed using recombinant human acid ceramidase (rhAC) in vitro.\n\nRESULTS:\nThe six new patients showed the hallmark features of SMA-PME, with variable initial symptom and age of onset. Five of six patients carried at least one of the recurrent SMA-PME variants observed in two specific codons of ASAH1. A review of 30 total cases revealed that patients who were homozygous for the most common c.125C \u003e T variant presented in the first decade of life with limb-girdle weakness as the initial symptom. Sensorineural hearing loss was associated with the c.456A \u003e C variant. Leukocyte acid ceramidase activity varied from 4.1%-13.1% of controls. Ceramide species in fibroblasts were detected and total cellular ceramide content was elevated by 2 to 9-fold compared to controls. Treatment with rhAC normalized ceramide profiles in cultured fibroblasts to control levels within 48 h.\n\nINTERPRETATION:\nThis study details the genotype-phenotype correlations observed in SMA-PME and shows the impact of rhAC to correct the abnormal cellular ceramide profile in cells." + } +} \ No newline at end of file diff --git a/36347473.json b/36347473.json new file mode 100644 index 0000000000000000000000000000000000000000..3b9afd09b1f27be82c9727b4b2a152d6064f72b7 --- /dev/null +++ b/36347473.json @@ -0,0 +1,8 @@ +{ + "id": "36347473", + "label": 0, + "article": { + "id": "36347473", + "text": "Several types of molecular therapy have become a novel opportunity in the precision treatment of hereditary neuromuscular disorders. This cursive review of gene therapy in hereditary myopathies will focus on selected current phase 1 to 3 trials of common adult hereditary myopathies such as Becker muscular dystrophy, facioscapulohumeral muscular dystrophy, calpainopathy, and dysferlinopathy. The treatment options for Pompe disease serve as an example for hereditary metabolic myopathies." + } +} \ No newline at end of file diff --git a/36356931.json b/36356931.json new file mode 100644 index 0000000000000000000000000000000000000000..66892efa5c2d286a9545cef64bc4db4c831f68f1 --- /dev/null +++ b/36356931.json @@ -0,0 +1,8 @@ +{ + "id": "36356931", + "label": 0, + "article": { + "id": "36356931", + "text": "Cyclodextrin (CD), a cyclic oligosaccharide, is a pharmaceutical additive that improves the solubility of hydrophobic compounds. Recent research has focused on the potential active pharmaceutical abilities of CD. Lysosomal storage diseases are inherited metabolic diseases characterized by lysosomal dysfunction and abnormal lipid storage. Niemann-Pick disease type C (NPC) is caused by mutations in cholesterol transporter genes (NPC1, NPC2) and is characterized by cholesterol accumulation in lysosomes. A biocompatible cholesterol solubilizer 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) was recently used in NPC patients for compassionate use and in clinical trials. HP-β-CD is an attractive drug candidate for NPC; however, its adverse effects, such as ototoxicity, should be solved. In this review, we discuss the current use of HP-β-CD in basic and clinical research and discuss alternative CD derivatives that may outperform HP-β-CD, which should be considered for clinical use. The potential of CD therapy for the treatment of other lysosomal storage diseases is also discussed." + } +} \ No newline at end of file diff --git a/36365206.json b/36365206.json new file mode 100644 index 0000000000000000000000000000000000000000..c1a8d4a829bea09c22927463221bc1e99bb75ead --- /dev/null +++ b/36365206.json @@ -0,0 +1,8 @@ +{ + "id": "36365206", + "label": 0, + "article": { + "id": "36365206", + "text": "Antisense oligonucleotides (ASOs) are disease-modifying agents affecting protein-coding and noncoding ribonucleic acids. Depending on the chemical modification and the location of hybridization, ASOs are able to reduce the level of toxic proteins, increase the level of functional protein, or modify the structure of impaired protein to improve function. There are multiple challenges in delivering ASOs to their site of action. Chemical modifications in the phosphodiester bond, nucleotide sugar, and nucleobase can increase structural thermodynamic stability and prevent ASO degradation. Furthermore, different particles, including viral vectors, conjugated peptides, conjugated antibodies, and nanocarriers, may improve ASO delivery. To date, six ASOs have been approved by the US Food and Drug Administration (FDA) in three neurological disorders: spinal muscular atrophy, Duchenne muscular dystrophy, and polyneuropathy caused by hereditary transthyretin amyloidosis. Ongoing preclinical and clinical studies are assessing the safety and efficacy of ASOs in multiple genetic and acquired neurological conditions. The current review provides an update on underlying mechanisms, design, chemical modifications, and delivery of ASOs. The administration of FDA-approved ASOs in neurological disorders is described, and current evidence on the safety and efficacy of ASOs in other neurological conditions, including pediatric neurological disorders, is reviewed." + } +} \ No newline at end of file diff --git a/36383381.json b/36383381.json new file mode 100644 index 0000000000000000000000000000000000000000..267cd18db9a33334ef00cf5b10896a2298c409c3 --- /dev/null +++ b/36383381.json @@ -0,0 +1,8 @@ +{ + "id": "36383381", + "label": 0, + "article": { + "id": "36383381", + "text": "IMPORTANCE:\nCancer screening deficits during the first year of the COVID-19 pandemic were found to persist into 2021. Cancer-related deaths over the next decade are projected to increase if these deficits are not addressed.\n\nOBJECTIVE:\nTo assess whether participation in a nationwide quality improvement (QI) collaborative, Return-to-Screening, was associated with restoration of cancer screening.\n\nDESIGN, SETTING, AND PARTICIPANTS:\nAccredited cancer programs electively enrolled in this QI study. Project-specific targets were established on the basis of differences in mean monthly screening test volumes (MTVs) between representative prepandemic (September 2019 and January 2020) and pandemic (September 2020 and January 2021) periods to restore prepandemic volumes and achieve a minimum of 10% increase in MTV. Local QI teams implemented evidence-based screening interventions from June to November 2021 (intervention period), iteratively adjusting interventions according to their MTVs and target. Interrupted time series analyses was used to identify the intervention effect. Data analysis was performed from January to April 2022.\n\nEXPOSURES:\nCollaborative QI support included provision of a Return-to-Screening plan-do-study-act protocol, evidence-based screening interventions, QI education, programmatic coordination, and calculation of screening deficits and targets.\n\nMAIN OUTCOMES AND MEASURES:\nThe primary outcome was the proportion of QI projects reaching target MTV and counterfactual differences in the aggregate number of screening tests across time periods.\n\nRESULTS:\nOf 859 cancer screening QI projects (452 for breast cancer, 134 for colorectal cancer, 244 for lung cancer, and 29 for cervical cancer) conducted by 786 accredited cancer programs, 676 projects (79%) reached their target MTV. There were no hospital characteristics associated with increased likelihood of reaching target MTV except for disease site (lung vs breast, odds ratio, 2.8; 95% CI, 1.7 to 4.7). During the preintervention period (April to May 2021), there was a decrease in the mean MTV (slope, -13.1 tests per month; 95% CI, -23.1 to -3.2 tests per month). Interventions were associated with a significant immediate (slope, 101.0 tests per month; 95% CI, 49.1 to 153.0 tests per month) and sustained (slope, 36.3 tests per month; 95% CI, 5.3 to 67.3 tests per month) increase in MTVs relative to the preintervention trends. Additional screening tests were performed during the intervention period compared with the prepandemic period (170 748 tests), the pandemic period (210 450 tests), and the preintervention period (722 427 tests).\n\nCONCLUSIONS AND RELEVANCE:\nIn this QI study, participation in a national Return-to-Screening collaborative with a multifaceted QI intervention was associated with improvements in cancer screening. Future collaborative QI endeavors leveraging accreditation infrastructure may help address other gaps in cancer care." + } +} \ No newline at end of file diff --git a/36399011.json b/36399011.json new file mode 100644 index 0000000000000000000000000000000000000000..538c5406ff91bd032d6fea8e654ffc756403c8d7 --- /dev/null +++ b/36399011.json @@ -0,0 +1,8 @@ +{ + "id": "36399011", + "label": 0, + "article": { + "id": "36399011", + "text": "OBJECTIVES:\nClassic galactosemia is a galactose metabolism disorder due to galactose-1-phosphate uridyltransferase deficiency. In this study we report the clinical features of a cohort of children with classic galactosemia.\n\nMETHODS:\nA retrospective evaluation was made of the files of 42 cases followed up for a diagnosis of classic galactosemia between January 2000 and December 2021. The data were collected of clinical, laboratory and genetic characteristics.\n\nRESULTS:\nThe cases comprised of 25 (59.5%) girls and 17 (40.5%) boys with a median age of 15 days (range, 1 day to 9 years) at diagnosis. In addition, thirty-six cases (92.3%) could be diagnosed before they were 4 months old by hospitalization with various clinical findings, primarily liver dysfunction. The most common complaints on presentation were jaundice (78.4%) and vomiting (27%) and the most frequently seen genetic pathogenic variant was c.563A\u003eG (p.Gln188Arg) (92.4%).\n\nCONCLUSIONS:\nIt can be emphasized that there is a need for a neonatal screening program for classic galactosemia to be able to increase the possibility of early diagnosis and to be able to start treatment before the development of a severe clinical picture." + } +} \ No newline at end of file diff --git a/36405442.json b/36405442.json new file mode 100644 index 0000000000000000000000000000000000000000..d8e15d1e6a500bf0510fb6cec83bae7a13c413fb --- /dev/null +++ b/36405442.json @@ -0,0 +1,8 @@ +{ + "id": "36405442", + "label": 0, + "article": { + "id": "36405442", + "text": "A 30-year-old woman with a phenotypic presentation of retinitis pigmentosa (RP) presented with a 5-day history of painless, acute vision loss in her right eye, with visual acuity dropping from 20/30 to hand motions. Optical coherence tomography of the right macula showed near-complete loss of the ellipsoid layer. Treatment with a prolonged course of oral prednisone resulted in a complete structural regeneration of the ellipsoid layer and improvement of visual acuity to 20/50, with eccentric fixation. Tests for infectious diseases, autoimmune disorders, and rare RP mimic syndromes (eg, Refsum disease) were negative. The patient has remained stable since. We favor a diagnosis of two separate pathologies and suggest a designation of acute zonal occult outer retinopathy (AZOOR) in RP for this previously unreported presentation." + } +} \ No newline at end of file diff --git a/36415442.json b/36415442.json new file mode 100644 index 0000000000000000000000000000000000000000..1933e114b9c52c542f176a447b7429af7ea4e22d --- /dev/null +++ b/36415442.json @@ -0,0 +1,8 @@ +{ + "id": "36415442", + "label": 0, + "article": { + "id": "36415442", + "text": "Females belonging to the reproductive age group may face challenges regarding infertility or miscarriage due to conditions such as premature ovarian failure (POF). It is the condition that happens when a female's ovaries stop working before she is 40. The majority of the causes of POF cases are idiopathic. Other reasons include genetic disorders (Turner's syndrome, bone morphogenetic protein 15 () mutation, galactosemia, mutation of forkhead box protein L2 (), growth differentiation factor-9 (), mutation of luteinizing hormone (LH) and follicle-stimulating hormone receptors (), etc.), enzymatic mutation such as aromatase, autoimmune disorders (Addison's disease, vitiligo, systemic lupus erythematosus, myasthenia gravis, autoimmune thyroiditis, autoimmune polyglandular syndrome, etc.), vaccination, and environmental factors (cigarette smoking, toxins, and infections). Many attempts have been made to treat POF by various methods. Some of the methods of treatment include hormone replacement therapy (HRT), melatonin therapy, dehydroepiandrosterone (DHEA) therapy, and stem cell therapy. Stem cell therapy has proven to be the most efficient form for treating POF as compared to all other options. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) are the best among the other sources of mesenchymal stem cells (MSCs) for the treatment of POF as they have a painless extraction procedure. They have a tremendous capacity for self-repair and regeneration, which helps them in restoring degenerated ovaries. This review includes information on the causes of POF, its efficacious therapeutic approaches, and the impact of transplantation of human umbilical cord mesenchymal stem cells (hUCMSCs) as an option for the therapy of POF. Numerous studies conducted on stem cell therapy prove that it is an effective approach for the treatment of sterility." + } +} \ No newline at end of file diff --git a/36431844.json b/36431844.json new file mode 100644 index 0000000000000000000000000000000000000000..dab28650d0a6f8e1cb41e03c92984a238ea60c56 --- /dev/null +++ b/36431844.json @@ -0,0 +1,8 @@ +{ + "id": "36431844", + "label": 0, + "article": { + "id": "36431844", + "text": "The application of 2-hydroxypropyl-beta-cyclodextrin (HPBCD) in the treatment of the rare cholesterol and lipid storage disorder Niemann-Pick disease type C opened new perspectives in the development of an efficient therapy. Even if the systemic administration of HPBCD was found to be effective, its low permeability across the blood-brain barrier (BBB) limited the positive neurological effects. Nevertheless, the cellular interactions of HPBCD with brain capillary endothelial cells have not been investigated in detail. In this study, the cytotoxicity, permeability, and cellular internalization of HPBCD on primary rat and immortalized human (hCMEC/D3) brain capillary endothelial cells were investigated. HPBCD shows no cytotoxicity on endothelial cells up to 100 µM, measured by impedance kinetics. Using a fluorescent derivative of HPBCD (FITC-HPBCD) the permeability measurements reveal that on an in vitro triple co-culture BBB model, FITC-HPBCD has low permeability, 0.50 × 10 cm/s, while on hCMEC/D3 cell layers, the permeability is higher, 1.86 × 10 cm/s. FITC-HPBCD enters brain capillary endothelial cells, is detected in cytoplasmic vesicles and rarely localized in lysosomes. The cellular internalization of HPBCD at the BBB can help to develop new strategies for improved HPBCD effects after systemic administration." + } +} \ No newline at end of file diff --git a/36444359.json b/36444359.json new file mode 100644 index 0000000000000000000000000000000000000000..574fc982e05d20b5ff96f3854052178c79dced4f --- /dev/null +++ b/36444359.json @@ -0,0 +1,8 @@ +{ + "id": "36444359", + "label": 0, + "article": { + "id": "36444359", + "text": "INTRODUCTION:\nMetastatic involvement of at least one nonregional lymph node currently renders patients with esophageal cancer as having stage IV disease. However, the management and outcomes of patients whose sole determinant of stage IV status is nonregional lymph nodes (abbreviated as \"stage IV-nodal\" disease) have not been fully characterized.\n\nMETHODS:\nIn this retrospective cohort study, the National Cancer Database was queried to identify patients 18 years of age or older who were diagnosed with stage IV esophageal cancer between 2016 and 2019. Survival was assessed by Kaplan-Meier analysis and Cox models in the overall sample and a propensity-matched sample. Patients with \"stage IV-nodal\" disease were compared with patients with systemic metastases involving a single organ or multiple organs.\n\nRESULTS:\nOverall, 11,589 patients with clinical stage IV esophageal cancer were identified, including 1331 (11.5%) patients with stage IV-nodal disease. Patients with stage IV-nodal disease were more likely to receive chemotherapy (77%) than those with single systemic organ metastases (64%) and multiorgan metastases (63%) ( \u003c 0.0001); patients with stage IV-nodal disease were also more likely to receive radiation (49%) than those with single systemic organ metastases (40%) and multiorgan metastases (39%) ( \u003c 0.0001). Squamous cell carcinoma (OR = 1.58, 95% confidence interval [CI]: 1.34-1.86, \u003c 0.0001) and academic facility type (OR = 1.24, 95% CI: 1.09-1.4, = 0.0009) were associated with higher likelihood of the stage IV-nodal presentation. Patients with stage IV-nodal disease experienced superior survival (hazard ratio = 0.72, 95% CI: 0.66-0.78, \u003c 0.0001) than those with stage IV-single systemic metastases (reference group) and stage IV-multiorgan disease (hazard ratio = 1.30, 95% CI: 1.24-1.37).\n\nCONCLUSIONS:\nApproximately 12% of patients with stage IV esophageal cancer lack systemic metastases at presentation. These patients with stage IV-nodal disease are more likely to receive treatment and experience superior survival. Further study of the stage IV-nodal population and consideration of a potential stage IV subclassification system is justified." + } +} \ No newline at end of file diff --git a/36447062.json b/36447062.json new file mode 100644 index 0000000000000000000000000000000000000000..65ed798cc3d80d29c3db9e4b06323df1b00b3ee7 --- /dev/null +++ b/36447062.json @@ -0,0 +1,8 @@ +{ + "id": "36447062", + "label": 0, + "article": { + "id": "36447062", + "text": "Niemann-Pick C disease (NPC) is an autosomal recessive genetic disorder resulting from mutation in one of two cholesterol transport genes: NPC1 or NPC2, causing accumulation of unesterified cholesterol, together with glycosphingolipids, within the endosomal/lysosomal compartment of cells. The result is a severe disease in both multiple peripheral organs and the central nervous system, causing neurodegeneration and early death. However, the pathophysiological mechanisms of NPC1 remain poorly understood. Recent studies have shown that the primary lysosomal defect found in fibroblasts from NPC1 patients is accompanied by a deregulation of mitochondrial organization and function. There is currently no cure for NPC1, but recently the potential of β-cyclodextrin (β-CD) for the treatment of the disease was discovered, which resulted in the redistribution of cholesterol from subcellular compartments to the circulation and increased longevity in an animal model of NPC1. Considering the above, the present work evaluated the in vitro therapeutic potential of β-CD to reduce cholesterol in fibroblasts from NPC1 patients. β-CD was used in its free and nanoparticulate form. We also evaluated the β-CD potential to restore mitochondrial functions, as well as the beneficial combined effects of treatment with antioxidants N-Acetylcysteine (NAC) and Coenzyme Q10 (CoQ10). Besides, we evaluated oxidative and nitrative stress parameters in NPC1 patients. We showed that oxidative and nitrative stress could contribute to the pathophysiology of NPC1, as the levels of lipoperoxidation and the nitrite and nitrate levels were increased in these patients when compared to healthy individuals, as well as DNA damage. The nanoparticles containing β-CD reduced the cholesterol accumulated in the NPC1 fibroblasts. This result was potentiated by the concomitant use of the nanoparticles with the antioxidants NAC and CoQ10 compared to those presented by healthy individuals cells ́. In addition, treatments combining β-CD nanoparticles and antioxidants could reduce mitochondrial oxidative stress, demonstrating advantages compared to free β-CD. The results obtained are promising regarding the combined use of β-CD loaded nanoparticles and antioxidants in the treatment of NPC1 disease." + } +} \ No newline at end of file diff --git a/36455410.json b/36455410.json new file mode 100644 index 0000000000000000000000000000000000000000..3f1129887fff791feb99c7efb67ff693e6a8419f --- /dev/null +++ b/36455410.json @@ -0,0 +1,8 @@ +{ + "id": "36455410", + "label": 0, + "article": { + "id": "36455410", + "text": "BACKGROUND:\nNiemann-Pick disease type C (NPC) is a rare prematurely fatal lysosomal lipid storage disease with limited therapeutic options. The prominent neuropathological hallmarks include hypomyelination and cerebellar atrophy. We previously demonstrated the efficacy of recombinant human heat shock protein 70 (rhHSP70) in preclinical models of the disease. It reduced glycosphingolipid levels in the central nervous system (CNS), improving cerebellar myelination and improved behavioural phenotypes in Npc1 (Npc1) mice. Furthermore, treatment with arimoclomol, a well-characterised HSP amplifier, attenuated lysosomal storage in NPC patient fibroblasts and improved neurological symptoms in Npc1 mice. Taken together, these findings prompted the investigation of the effects of HSP amplification on CNS myelination.\n\nMETHODS:\nWe administered bimoclomol daily or rhHSP70 6 times per week to Npc1 (BALB/cNctr-Npc1/J, also named Npc1) mice by intraperitoneal injection from P7 through P34 to investigate the impact on CNS myelination. The Src-kinase inhibitor saracatinib was administered with/without bimoclomol twice daily to explore the contribution of Fyn kinase to bimoclomol's effects.\n\nFINDINGS:\nTreatment with either bimoclomol or rhHSP70 improved myelination and increased the numbers of mature oligodendrocytes (OLs) as well as the ratio of active-to-inactive forms of phosphorylated Fyn kinase in the cerebellum of Npc1 mice. Additionally, treatment with bimoclomol preserved cerebellar weight, an effect that was abrogated when co-administered with saracatinib, an inhibitor of Fyn kinase. Bimoclomol-treated mice also exhibited increased numbers of immature OLs within the cortex.\n\nINTERPRETATION:\nThese data increase our understanding of the mechanisms by which HSP70 regulates myelination and provide further support for the clinical development of HSP-amplifying therapies in the treatment of NPC.\n\nFUNDING:\nFunding for this study was provided by Orphazyme A/S (Copenhagen, Denmark) and a Pathfinder Award from The Wellcome Trust." + } +} \ No newline at end of file diff --git a/36470574.json b/36470574.json new file mode 100644 index 0000000000000000000000000000000000000000..3206cd15a7f1538b8303147873d864ac97b856df --- /dev/null +++ b/36470574.json @@ -0,0 +1,8 @@ +{ + "id": "36470574", + "label": 0, + "article": { + "id": "36470574", + "text": "PURPOSE:\nNiemann-Pick disease type C1 (NPC1) is a neurodegenerative lysosomal disorder caused by pathogenic variants in NPC1. Disease progression is monitored using the NPC Neurological Severity Scale, but there are currently no established validated or qualified biomarkers. Neurofilament light chain (NfL) is being investigated as a biomarker in multiple neurodegenerative diseases.\n\nMETHODS:\nCross-sectional and longitudinal cerebrospinal fluid (CSF) samples were obtained from 116 individuals with NPC1. NfL levels were measured using a solid-phase sandwich enzyme-linked immunosorbent assay and compared with age-appropriate non-NPC1 comparison samples.\n\nRESULTS:\nMedian levels of NfL were elevated at baseline (1152 [680-1840] pg/mL) in NPC1 compared with controls (167 [82-372] pg/mL; P \u003c .001). Elevated NfL levels were associated with more severe disease as assessed by both the 17-domain and 5-domain NPC Neurological Severity Score. Associations were also observed with ambulation, fine motor, speech, and swallowing scores. Although treatment with the investigational drug 2-hydroxypropyl-β-cyclodextrin (adrabetadex) did not decrease CSF NfL levels, miglustat therapy over time was associated with a decrease (odds ratio = 0.77, 95% CI = 0.62-0.96).\n\nCONCLUSION:\nCSF NfL levels are increased in individuals with NPC1, associated with clinical disease severity, and decreased with miglustat therapy. These data suggest that NfL is a biomarker that may have utility in future therapeutic trials." + } +} \ No newline at end of file diff --git a/36474335.json b/36474335.json new file mode 100644 index 0000000000000000000000000000000000000000..68ce45dbdb365246bad959cfeaae9171539c508d --- /dev/null +++ b/36474335.json @@ -0,0 +1,8 @@ +{ + "id": "36474335", + "label": 0, + "article": { + "id": "36474335", + "text": "The mammalian retina lacks regenerative potency to replace damaged or degenerated cells. Therefore, traumatic or genetic insults that lead to the degeneration of retinal neurons or retinal pigment epithelium (RPE) cells alter visual perception and ultimately can lead to blindness. The advent of human stem cells and their exploitation for vision restoration approaches has boosted the field. Traditionally, animal models-mostly rodents-have been generated and used to mimic certain monogenetic hereditary diseases. Of note, some models were extremely useful to develop specific gene therapies, for example for Retinitis Pigmentosa, Leber congenital amaurosis and achromatopsia. However, complex multifactorial diseases are not well recapitulated in rodent models such as age-related macular degeneration (AMD) as rodents lack a macula. Here, human stem cells are extremely valuable to advance the development of therapies. Particularly, cell replacement therapy is of enormous importance to treat retinal degenerative diseases. Moreover, different retinal degenerative disorders require the transplantation of unique cell types. The most advanced one is to substitute the RPE cells, which stabilize the light-sensitive photoreceptors. Some diseases require also the transplantation of photoreceptors. Depending on the disease pattern, both approaches can also be combined. Within this article, I briefly feature the underlying principle of cell replacement therapies, demonstrate some successes and discuss certain shortcomings of these approaches for clinical application." + } +} \ No newline at end of file diff --git a/36477475.json b/36477475.json new file mode 100644 index 0000000000000000000000000000000000000000..89b3ccaf576e32761df0c18b898a205924c3e770 --- /dev/null +++ b/36477475.json @@ -0,0 +1,8 @@ +{ + "id": "36477475", + "label": 0, + "article": { + "id": "36477475", + "text": "OBJECTIVE:\nTo evaluate efficacy of a novel adeno-associated virus (AAV) vector, AAV2/4-RS1, for retinal rescue in the retinoschisin knockout (Rs1-KO) mouse model of X-linked retinoschisis (XLRS). Brinzolamide (Azopt®), a carbonic anhydrase inhibitor, was tested for its ability to potentiate the effects of AAV2/4-RS1.\n\nMETHODS:\nAAV2/4-RS1 with a cytomegalovirus (CMV) promoter (2x1012 viral genomes/mL) was delivered to Rs1-KO mice via intravitreal (N = 5; 1μL) or subretinal (N = 21; 2μL) injections at postnatal day 60-90. Eleven mice treated with subretinal therapy also received topical Azopt® twice a day. Serial full field electroretinography (ERG) was performed starting at day 50-60 post-injection. Mice were evaluated using a visually guided swim assay (VGSA) in light and dark conditions. The experimental groups were compared to untreated Rs1-KO (N = 11), wild-type (N = 12), and Rs1-KO mice receiving only Azopt® (N = 5). Immunofluorescence staining was performed to assess RS1 protein expression following treatment.\n\nRESULTS:\nThe ERG b/a ratio was significantly higher in the subretinal plus Azopt® (p\u003c0.0001), subretinal without Azopt® (p = 0.0002), and intravitreal (p = 0.01) treated eyes compared to untreated eyes. There was a highly significant subretinal treatment effect on ERG amplitudes collectively at 7-9 months post-injection (p = 0.0003). Cones showed more effect than rods. The subretinal group showed improved time to platform in the dark VGSA compared to untreated mice (p\u003c0.0001). RS1 protein expression was detected in the outer retina in subretinal treated mice and in the inner retina in intravitreal treated mice.\n\nCONCLUSIONS:\nAAV2/4-RS1 shows promise for improving retinal phenotype in the Rs1-KO mouse model. Subretinal delivery was superior to intravitreal. Topical brinzolamide did not improve efficacy. AAV2/4-RS1 may be considered as a potential treatment for XLRS patients." + } +} \ No newline at end of file diff --git a/36482560.json b/36482560.json new file mode 100644 index 0000000000000000000000000000000000000000..56819b9d57131954a70435ccfc40bf82748e32b1 --- /dev/null +++ b/36482560.json @@ -0,0 +1,8 @@ +{ + "id": "36482560", + "label": 0, + "article": { + "id": "36482560", + "text": "BACKGROUND:\nNiemann-Pick disease Type C (NPC) is a genetic, incurable, neurodegenerative disorder. This orphan disease is most frequently caused by mutations in the NPC1 protein, resulting in intralysossomal cholesterol accumulation. NPC1 is found in neuronal cell bodies, axon terminals and synaptosomes, suggesting it plays a role in lysosomal degradation pathway and in synaptic transmission. Neuronal function is especially vulnerable to NPC1 deficiency and synaptic changes seem a key element in disease development. Currently, Miglustat (Zavesca®) is the only approved treatment for NPC. However, preclinical evidence showed that low-dose Efavirenz reverted synaptic defects through pharmacological activation of the enzyme CYP46.\n\nMETHODS:\nThis is a single-center, phase II clinical trial to evaluate the efficacy and safety of Efavirenz in addition to standard of care in patients diagnosed with adult or late juvenile-onset NPC with cognitive impairment. All enrolled patients will be treated orally with 25 mg/d of Efavirenz for 52 weeks (1 year). Secondary objectives include evaluating clinical (neurological and neuropsychological questionnaires) and biological (imaging and biochemical biomarkers) parameters.\n\nDISCUSSION:\nNPC is still an unmet medical need. Although different therapeutic approaches are under study, this is the first clinical trial (to the best of our knowledge) studying the effects of Efavirenz in adult- and late-juvenile-onset NPC. Despite the small sample size and the single-arm design, we expect the results to show Efavirenz's capacity of activating the CYP46 enzyme to compensate for NPC1 deficiency and correct synaptic changes, therefore compensating cognitive and psychiatric changes in these patients. This study may provide direct benefit to enrolled patients in terms of slowing down the disease progression." + } +} \ No newline at end of file diff --git a/36511274.json b/36511274.json new file mode 100644 index 0000000000000000000000000000000000000000..d4affa72c1cd1f1016ccabe311aa1a0c695db1d0 --- /dev/null +++ b/36511274.json @@ -0,0 +1,8 @@ +{ + "id": "36511274", + "label": 0, + "article": { + "id": "36511274", + "text": "OBJECTIVE:\nBile acid intermediates, 3α,7α,12α-trihydroxycholestanoic acid (THCA) and 3α,7α-dihydroxycholestanoic acid (DHCA), are metabolized in peroxisomes. Some peroxisomal disorders (PDs), such as Zellweger spectrum disorder (ZSD), show an accumulation of bile acid intermediates. In particular, ABCD3 deficiency and acyl-CoA-oxidase 2 deficiency are characterized by these metabolite abnormalities. In patients with ZSD, levels of bile acid intermediates can be lowered by a primary bile acid supplementation treatment; therefore, measuring their levels could help evaluate treatment effectiveness. Here, we established a method for the quantitative determination of bile acid intermediates (THCA/DHCA) for differentiating PDs and assessing bile acid treatment.\n\nMETHODS:\nSerum samples, obtained from patients with several forms of ZSD as well as peroxisomal β-oxidation enzyme deficiencies, were deproteinized and analyzed using liquid chromatography-mass spectrometry.\n\nRESULTS:\nLevels of the bile acid intermediates increased significantly in patients with Zellweger syndrome (ZS) and slightly in patients with neonatal adrenoleukodystrophy and infantile Refsum disease (IRD), reflecting the severity of these diseases. One patient with ZS treated with primary bile acids for 6 months showed slightly decreased serum DHCA levels but significantly increased serum THCA levels. One patient with IRD who underwent living-donor liver transplantation showed a rapid decrease in serum THCA and DHCA levels, which remained undetected for 6 years. In all controls, THCA and DHCA levels were below the detection limit.\n\nCONCLUSION:\nThe analytical method developed in this study is useful for diagnosing various PD and validating bile acid treatment. Additionally, it can help predict the prognosis of patients with PD and support treatment strategies." + } +} \ No newline at end of file diff --git a/36512573.json b/36512573.json new file mode 100644 index 0000000000000000000000000000000000000000..90b41196575d26713db7860e4c4ec893c63658f8 --- /dev/null +++ b/36512573.json @@ -0,0 +1,8 @@ +{ + "id": "36512573", + "label": 0, + "article": { + "id": "36512573", + "text": "BACKGROUND:\nHypergonadotropic hypogonadism is a burdensome complication of classic galactosemia (CG), an inborn error of galactose metabolism that invariably affects female patients. Since its recognition in 1979, data have become available regarding the clinical spectrum, and the impact on fertility. Many women have been counseled for infertility and the majority never try to conceive, yet spontaneous pregnancies can occur. Onset and mechanism of damage have not been elucidated, yet new insights at the molecular level are becoming available that might greatly benefit our understanding. Fertility preservation options have expanded, and treatments to mitigate this complication either by directly rescuing the metabolic defect or by influencing the cascade of events are being explored.\n\nOBJECTIVE AND RATIONALE:\nThe aims are to review: the clinical picture and the need to revisit the counseling paradigm; insights into the onset and mechanism of damage at the molecular level; and current treatments to mitigate ovarian damage.\n\nSEARCH METHODS:\nIn addition to the work on this topic by the authors, the PubMed database has been used to search for peer-reviewed articles and reviews using the following terms: 'classic galactosemia', 'gonadal damage', 'primary ovarian insufficiency', 'fertility', 'animal models' and 'fertility preservation' in combination with other keywords related to the subject area. All relevant publications until August 2022 have been critically evaluated and reviewed.\n\nOUTCOMES:\nA diagnosis of premature ovarian insufficiency (POI) results in a significant psychological burden with a high incidence of depression and anxiety that urges adequate counseling at an early stage, appropriate treatment and timely discussion of fertility preservation options. The cause of POI in CG is unknown, but evidence exists of dysregulation in pathways crucial for folliculogenesis such as phosphatidylinositol 3-kinase/protein kinase B, inositol pathway, mitogen-activated protein kinase, insulin-like growth factor-1 and transforming growth factor-beta signaling. Recent findings from the GalT gene-trapped (GalTKO) mouse model suggest that early molecular changes in 1-month-old ovaries elicit an accelerated growth activation and burnout of primordial follicles, resembling the progressive ovarian failure seen in patients. Although data on safety and efficacy outcomes are still limited, ovarian tissue cryopreservation can be a fertility preservation option. Treatments to overcome the genetic defect, for example nucleic acid therapy such as mRNA or gene therapy, or that influence the cascade of events are being explored at the (pre-)clinical level.\n\nWIDER IMPLICATIONS:\nElucidation of the molecular pathways underlying POI of any origin can greatly advance our insight into the pathogenesis and open new treatment avenues. Alterations in these molecular pathways might serve as markers of disease progression and efficiency of new treatment options." + } +} \ No newline at end of file diff --git a/36516904.json b/36516904.json new file mode 100644 index 0000000000000000000000000000000000000000..17019a0618532869ae443bfa7868ef46e6affe24 --- /dev/null +++ b/36516904.json @@ -0,0 +1,8 @@ +{ + "id": "36516904", + "label": 0, + "article": { + "id": "36516904", + "text": "Recently, we proposed a method to assess cell-specific retinal functions based on the frequency-dependent responses to sinusoidal transcorneal electrostimulation. In this study, we evaluated the alterations in responsiveness in achromatopsia patients to explore the frequency-selectivity of photoreceptors. The electrical stimulation was applied to one eye of genetically confirmed achromatopsia patients via corneal electrodes. The stimulus was composed of amplitude-modulated sine waves with variable carrier frequencies (4-30 Hz) and a steady low-frequency envelope. The retinal responsiveness across the spectrum was calculated based on the velocity and the synchronicity of the electrically evoked pupillary oscillations. Achromats displayed a characteristic peak in responsiveness in the 6-10 Hz range. In contrast, stimulus frequencies above 16 Hz elicited only weak pupil responses and weak phosphenes. Compared to the tuning curve of the healthy retina, responses to low-frequency stimulation appear to reflect mainly rod activation while higher frequencies seem to activate cones. The possibility to examine cell-specific retinal functions independently from their responses to light may improve our understanding of the structural changes in the retina induced by gene therapy." + } +} \ No newline at end of file diff --git a/36523442.json b/36523442.json new file mode 100644 index 0000000000000000000000000000000000000000..ee0cdac10208e15464dd5927b31c2317f306e87e --- /dev/null +++ b/36523442.json @@ -0,0 +1,8 @@ +{ + "id": "36523442", + "label": 0, + "article": { + "id": "36523442", + "text": "BACKGROUND:\nImpaired driving ability in patients with Alzheimer's disease (AD) is associated with a decline in cognitive processes and a deterioration of their basic sensory visual functions. Although a variety of ocular abnormalities have been described in patients with AD, little is known about the impact of those visual disorders on their driving performance.\n\nAIM:\nAim of this mini-review is to provide an update on the driving ability of patients with dementia and summarize the primary visual disorders affecting their driving behavior.\n\nMETHODS:\nDatabases were screened for studies investigating dementia, associated visual abnormalities and driving ability.\n\nRESULTS:\nThere is consistent evidence that dementia affects driving ability. Patients with dementia present with a variety of visual disorders, such as visual acuity reduction, visual field defects, impaired contrast sensitivity, decline in color vision and age-related pathological changes, that may have a negative impact on their driving ability. However, there is a paucity in studies describing the impact of oculovisual decline on the driving ability of AD subjects. A bidirectional association between cognitive and visual impairment (VI) has been described.\n\nCONCLUSION:\nGiven the bidirectional association between VI and dementia, vision screening and cognitive assessment of the older driver should aim to identify at-risk individuals and employ timely strategies for treatment of both cognitive and ocular problems. Future studies should characterize the basic visual sensory status of AD patients participating in driving studies, and investigate the impact of vision abnormalities on their driving performance." + } +} \ No newline at end of file diff --git a/36542255.json b/36542255.json new file mode 100644 index 0000000000000000000000000000000000000000..b18d83fff7deb5a959d5e38cfc7c7f0c53f7bbff --- /dev/null +++ b/36542255.json @@ -0,0 +1,8 @@ +{ + "id": "36542255", + "label": 0, + "article": { + "id": "36542255", + "text": "INTRODUCTION:\nTo investigate the feasibility and safety of scleral ultraviolet A (UVA) cross-linking (scleral CXL) on pathologically blindness.\n\nMETHODS:\nThis was a prospective, observational clinical study. Five patients with monocular blindness due to pathological myopic maculopathy were enrolled. Eyes with best corrected visual acuity (BCVA) under 0.05 were defined as experimental eyes. The fellow eyes were defined as control eyes. Patients first underwent posterior scleral reinforcement (PSR) surgery in the control eye. Thereafter, scleral CXL surgery was performed in the experimental eye on the same day. Visual acuity, BCVA, slit lamp biomicroscopic examination, intraocular pressure measurement, corneal specula microscopies, axis length measurement, funduscopy with pupil dilation, color fundus photography, full-field flash electroretinography, optical coherence tomography, and color Doppler flow imaging were performed at baseline, 1 week, 1 month, 3 months, 6 months, and 12 months after surgery.\n\nRESULTS:\nNo signs of inflammation were observed after operation and throughout the follow-up period. Retinoschisis was improved, while choroidal neovascularization fibrosis and retinal and choroidal atrophy were unchanged after scleral CXL. There were no statistically significant differences in the ophthalmic artery, central retinal artery, and posterior ciliary artery parameters of color Doppler flow imaging or in retinal thickness, within experimental and control eyes, at baseline, 1 week, 1 month, 3 months, or 12 months (P \u003e 0.05).\n\nCONCLUSIONS:\nThis pilot study verified the feasibility and safety of scleral CXL on human blindness. The UVA-CXL on the sclera of human eyes seems to have the same effect as PSR in preventing progressive pathological myopia in the future.\n\nTRIAL REGISTRATION:\nChinese Clinical Trial Registry (ChiCTR2100042422)." + } +} \ No newline at end of file diff --git a/36550674.json b/36550674.json new file mode 100644 index 0000000000000000000000000000000000000000..ebbdef0e24465e570dda4f8734806c58ddd97e30 --- /dev/null +++ b/36550674.json @@ -0,0 +1,8 @@ +{ + "id": "36550674", + "label": 0, + "article": { + "id": "36550674", + "text": "Pilomatrix carcinoma is a rare, locally aggressive variant of pilomatrixoma with a high rate of recurrence and risk of distant metastasis. We report an unusual presentation of a pilomatrix carcinoma in a 4-year-old male child who presented with recurrent lesions on his left cheek. At the age of 1 month of life, he presented with a soft tissue swelling on his left cheek. The lesion showed a circumscribed proliferation of basaloid cells with central areas of eosinophilic ghost shadow cells and intermediate cells. Basaloid nests showed round to oval, hyperchromatic nuclei with open nuclear chromatin, prominent nucleoli and frequent mitoses but no marked nuclear pleomorphism or infiltration was identified. The lesion recurred twice at the same site. Both recurrences showed similar morphology as the primary tumour however there were extensive areas of stromal necrosis, infiltrating edges, frequent mitoses with atypical forms, and lymphovascular invasion. There was no marked nuclear pleomorphism. Morphological features favoured a diagnosis of pilomatrix carcinoma. The child is still on follow-up and no recurrence has been identified to date. Pilomatric carcinoma is rarely reported in infants. Due to its rarity, aggressive histological features may be missed." + } +} \ No newline at end of file diff --git a/36558607.json b/36558607.json new file mode 100644 index 0000000000000000000000000000000000000000..6f64401b3772a6c1c8d07bc4bd476c87a30e0379 --- /dev/null +++ b/36558607.json @@ -0,0 +1,8 @@ +{ + "id": "36558607", + "label": 0, + "article": { + "id": "36558607", + "text": "Approximately 8% of Caucasian males and 0.5% of females have congenital red-green color vision deficiencies (CVD), and a number of eye diseases are accompanied by acquired CVD. This feature issue includes ten contributions regarding existing and proposed algorithms and devices intended to help CVD subjects compensate for their color deficiencies. It also addresses limitations in the effectiveness of CVD aids for subjects with different types and degrees of color vision deficiency." + } +} \ No newline at end of file diff --git a/36568275.json b/36568275.json new file mode 100644 index 0000000000000000000000000000000000000000..860e650208372efe7332430b0db542c513e4b621 --- /dev/null +++ b/36568275.json @@ -0,0 +1,8 @@ +{ + "id": "36568275", + "label": 0, + "article": { + "id": "36568275", + "text": "The leukodystrophy Canavan disease is a fatal white matter disorder caused by loss-of-function mutations of the aspartoacylase-encoding gene. There are no effective treatments available and experimental gene therapy trials have failed to provide sufficient amelioration from Canavan disease symptoms. Preclinical studies suggest that Canavan disease-like pathology can be addressed by either gene replacement therapy or by lowering the expression of the N-acetyl-L-aspartate synthesizing enzyme NAT8L. Both approaches individually prevent or even reverse pathological aspects in Canavan disease mice. Here, we combined both strategies and assessed whether intracranial adeno-associated virus-mediated gene delivery to a Canavan disease mouse model at 12 weeks allows for reversal of existing pathology. This was enabled by a single vector dual-function approach. and biopotency assessment revealed significant knockdown of neuronal paired with robust ectopic aspartoacylase expression. Following nomination of the most efficient cassette designs, we performed proof-of-concept studies in post-symptomatic -null mice. Late-stage gene therapy resulted in a decrease of brain vacuoles and long-term reversal of all pathological hallmarks, including loss of body weight, locomotor impairments, elevated N-acetyl-L-aspartate levels, astrogliosis, and demyelination. These data suggest feasibility of a dual-function vector combination therapy, directed at replacing aspartoacylase with concomitantly suppressing N-acetyl-L-aspartate production, which holds potential to permanently alleviate Canavan disease symptoms and expands the therapeutic window towards a treatment option for adult subjects." + } +} \ No newline at end of file diff --git a/36578644.json b/36578644.json new file mode 100644 index 0000000000000000000000000000000000000000..d4be58696ffdd9705587897bea93b4e205c97bd3 --- /dev/null +++ b/36578644.json @@ -0,0 +1,8 @@ +{ + "id": "36578644", + "label": 0, + "article": { + "id": "36578644", + "text": "Hereditary retinal dystrophies (HRDs), such as retinitis pigmentosa, Leber's congenital amaurosis (LCA), Usher syndrome, and retinoschisis, are a group of genetic retinal disorders exhibiting both genetic and phenotypic heterogeneity. Symptoms include progressive retinal degeneration and constricted visual field. Some patients will be legal or completely blind. Advanced sequencing technologies improve the genetic diagnosis of HRD and lead to a new era of research into gene-targeted therapies. Following the first Food and Drug Administration approval of gene augmentation therapy for LCA caused by mutations, multiple clinical trials are currently underway applying different techniques. In this review, we provide an overview of gene therapy for HRD and emphasize four distinct approaches to gene-targeted therapy that have the potential to slow or even reverse retinal degeneration: (1) viral vector-based and nonviral gene delivery, (2) RNA-based antisense oligonucleotide, (3) genome editing by the Clustered Regularly Interspaced Short Palindromic Repeat/cas9 system, and (4) optogenetics gene therapy." + } +} \ No newline at end of file diff --git a/36581191.json b/36581191.json new file mode 100644 index 0000000000000000000000000000000000000000..bda6609d4ab1f8047cf267d3f500105245aea1dd --- /dev/null +++ b/36581191.json @@ -0,0 +1,8 @@ +{ + "id": "36581191", + "label": 0, + "article": { + "id": "36581191", + "text": "PURPOSE:\nTo assess the long-term safety and efficacy of AAV2-REP1 in choroideremia (CHM) patients, and to test a potential antisense oligonucleotide therapy for CHM.\n\nDESIGN:\nExtended, prospective phase 1/2 clinical trial and laboratory investigation.\n\nMETHODS:\nFive patients who received a single subfoveal injection of AAV2-REP1 were studied. The long-term safety was evaluated by ophthalmic examination, spectral domain optical coherence tomography, and fundus autofluorescence (FAF) for up to 5 years. Functional and structural changes were determined by different test modalities. Four antisense oligonucleotides (ASOs) were designed to treat the CHM c.1245-521A\u003eG mutation, which was present in 2 patients within this trial.\n\nRESULTS:\nSubject P3 experienced a localized intraretinal immune response that resulted in a significant loss of preserved retinal pigment epithelium (RPE). P4 experienced an exacerbation of peripheral retinoschisis. P2 had a constant ≥15-letter best-corrected visual acuity (BCVA) gain in the treated eye, whereas P5 had ≥15-letter BCVA improvement once in the untreated eye. The preserved FAF areas declined more rapidly in the treated eyes compared to the untreated eyes (P = .043). A customized 25-mer ASO recovered 83.2% to 95.0% of the normal RNA and 57.5% of the normal protein in fibroblasts from 2 trial patients.\n\nCONCLUSIONS:\nIntraretinal inflammation triggered by AAV2-REP1 subretinal injection stabilized after 2 years but resulted in permanent damage to the retinal structure. Long-term progression of the disease was seen in both treated and untreated eyes, casting doubt as to the effectiveness of this approach in late-stage CHM. Alternative approaches such as ASO may have a therapeutic effect in a subgroup of CHM patients." + } +} \ No newline at end of file diff --git a/36582858.json b/36582858.json new file mode 100644 index 0000000000000000000000000000000000000000..160c2b6a833ce4c56cb20e3712d71a890b27b43d --- /dev/null +++ b/36582858.json @@ -0,0 +1,8 @@ +{ + "id": "36582858", + "label": 0, + "article": { + "id": "36582858", + "text": "INTRODUCTION:\nPilomatricoma is a rare and benign tumor affecting children and adolescents. It originates from the matrix cells of hair follicles, the usual sites being head-neck and upper extremities. Due to its rarity, it is often misdiagnosed delaying definitive treatment. We report a case of pilomatricoma over the left gluteal region in a young Nepalese girl that was initially thought to be a calcified granuloma.\n\nCASE PRESENTATION:\nA six-year-old girl presented with a painful swelling over the left buttock for one year that was gradually increasing in size. On examination, a solitary, well-circumscribed, tender swelling with hard consistency and a bumpy irregular surface measuring 3 × 2 cm was noted over the subcutaneous plane of the left gluteal region. Surgical excision of the mass was done which demonstrated features of pilomatricoma on histopathological examination (HPE). She recovered and remained disease-free at one year follow-up.\n\nCONCLUSION:\nThis case highlights one of the handful presentations of pilomatricoma involving the buttock. Pilomatricoma is rarely considered a differential diagnosis of benign masses, the diagnosis of which is ascertained mostly after an HPE of the excised specimen. Surgical excision with clear margins is not only diagnostic but therapeutic in most situations." + } +} \ No newline at end of file diff --git a/36608914.json b/36608914.json new file mode 100644 index 0000000000000000000000000000000000000000..4f96602e08e13501a282bc15797e349c605c6ab6 --- /dev/null +++ b/36608914.json @@ -0,0 +1,8 @@ +{ + "id": "36608914", + "label": 0, + "article": { + "id": "36608914", + "text": "Niemann-Pick type C1 (NPC1) is a fatal inherited disease, caused by pathogenic variants in NPC1 gene, which leads to intracellular accumulation of non-esterified cholesterol and glycosphingolipids. This accumulation leads to a wide range of clinical manifestations, including neurological and cognitive impairment as well as psychiatric disorders. The pathophysiology of cerebral damage involves loss of Purkinje cells, synaptic disturbance, and demyelination. Miglustat, a reversible inhibitor of glucosylceramide synthase, is an approved treatment for NPC1 and can slow neurological damage. The aim of this study was to assess the levels of peripheric neurodegeneration biomarkers of NPC1 patients, namely brain-derived neurotrophic factor (BDNF), platelet-derived growth factors (PDGF-AA and PDGF-AB/BB), neural cell adhesion molecule (NCAM), PAI-1 Total and Cathepsin-D, as well as the levels of cholestane-3β,5α,6β-triol (3β,5α,6β-triol), a biomarker for NPC1. Molecular analysis of the NPC1 patients under study was performed by next generation sequencing (NGS) in cultured fibroblasts. We observed that NPC1 patients treated with miglustat have a significant decrease in PAI-1 total and PDGF-AA concentrations, and no alteration in BDNF, NCAM, PDGF-AB/BB and Cathepsin D. We also found that NPC1 patients treated with miglustat have normalized levels of 3β,5α,6β-triol. The molecular analysis showed four described mutations, and for two patients was not possible to identify the second mutated allele. Our results indicate that the decrease of PAI-1 and PDGF-AA in NPC1 patients could be involved in the pathophysiology of this disease. This is the first work to analyze those plasmatic markers of neurodegenerative processes in NPC1 patients." + } +} \ No newline at end of file diff --git a/36614015.json b/36614015.json new file mode 100644 index 0000000000000000000000000000000000000000..70954311aaccbd00969338fd011723e71afe2f38 --- /dev/null +++ b/36614015.json @@ -0,0 +1,8 @@ +{ + "id": "36614015", + "label": 0, + "article": { + "id": "36614015", + "text": "Niemann-Pick Type C1 (NPC1, MIM 257220) is a rare, progressive, lethal, inherited autosomal-recessive endolysosomal storage disease caused by mutations in the leading to intracellular lipid storage. We analyzed mostly not jet known alterations of the weights of 14 different organs in the BALB/cNctr-/-J Jackson mice in female and male and mice under various treatment strategies. Mice were treated with (i) no therapy, (ii) vehicle injection, (iii) a combination of miglustat, allopregnanolone, and 2-hydroxypropyl-ß-cyclodextrin (HPßCD), (iv) miglustat, and (v) HPßCD alone starting at P7 and repeated weekly throughout life. The 12 respective male and female wild-type mice groups were evaluated in parallel. In total, 351 mice (176 , 175 ) were dissected at P65. In both sexes, the body weights of None and Sham mice were lower than those of respective mice. The influence of the mutation and/or sex on the weights of various organs, however, differed considerably. In males, and mice had comparable absolute weights of lungs, spleen, and adrenal glands. In mice, smaller weights of hearts, livers, kidneys, testes, vesicular, and scent glands were found. In female mice, ovaries, and uteri were significantly smaller. In mice, relative organ weights, i.e., normalized with body weights, were sex-specifically altered to different extents by the different therapies. The combination of miglustat, allopregnanolone, and the sterol chelator HPßCD partly normalized the weights of more organs than miglustat or HPßCD mono-therapies." + } +} \ No newline at end of file diff --git a/36615667.json b/36615667.json new file mode 100644 index 0000000000000000000000000000000000000000..5c69238a186490b960faf98a1ec023353780e5b9 --- /dev/null +++ b/36615667.json @@ -0,0 +1,8 @@ +{ + "id": "36615667", + "label": 0, + "article": { + "id": "36615667", + "text": "Galactosemia is an inborn metabolic disorder caused by a deficient activity in one of the enzymes involved in the metabolism of galactose. The first description of galactosemia in newborns dates from 1908, ever since complex research has been performed on cell and animal models to gain more insights into the molecular and clinical bases of this challenging disease. In galactosemia, the newborn appears to be born in proper health, having a window of opportunity before developing major morbidities that may even be fatal following ingestion of milk that contains galactose. Galactosemia cannot be cured, but its negative consequences on health can be avoided by establishing precocious diagnosis and treatment. All the foods that contain galactose should be eliminated from the diet when there is a suspicion of galactosemia. The neonatal screening for galactosemia can urge early diagnosis and intervention, preventing complications. All galactosemia types may be detected during the screening of newborns for this disorder. The major target is, however, galactose-1-phosphate uridyltransferase (GALT) deficiency galactosemia, which is diagnosed by applying a combination of total galactose and GALT enzyme analysis as well as, in certain programs, mutation screening. Most critically, infants who exhibit symptoms suggestive of galactosemia should undergo in-depth testing for this condition even when the newborn screening shows normal results. The decision to enroll global screening for galactosemia among the specific population still faces many challenges. In this context, the present narrative review provides an updated overview of the incidence, clinical manifestations, diagnosis, therapy, and prognosis of galactosemia, questioning under the dome of these aspects related to the disease the value of its neonatal monitoring." + } +} \ No newline at end of file diff --git a/36619359.json b/36619359.json new file mode 100644 index 0000000000000000000000000000000000000000..a1ae5c993471791b15f8e091fcdfcc5abe461df6 --- /dev/null +++ b/36619359.json @@ -0,0 +1,8 @@ +{ + "id": "36619359", + "label": 0, + "article": { + "id": "36619359", + "text": "The aim of this case report was to present an unusual case of peripapillary retinoschisis (PPRS) associated with ocular hypotony after glaucoma surgery. It refers to a 78-year-old man with primary open-angle glaucoma who developed PPRS while hypotonous. Optical coherence tomography of the peripapillary and the macular area of the right eye revealed PPRS temporally and nasally to the optic disc, more prominent at the level of the outer nuclear layer and less so at the inner nuclear layer. The PPRS completely regressed after 1 month of treatment and restoration of intraocular pressure to normal levels. This case report highlights the fact that PPRS in glaucoma patients may present in the setting of ocular hypotony and appears to resolve when the hypotony is successfully managed. Hydrostatic pressure gradient across retinal vasculature that allows movement of fluid into the extracellular spaces is a potential mechanism for the development of PPRS in ocular hypotony." + } +} \ No newline at end of file diff --git a/36638890.json b/36638890.json new file mode 100644 index 0000000000000000000000000000000000000000..8c68a724103a7b3cdcccb8b8b494de57293cae40 --- /dev/null +++ b/36638890.json @@ -0,0 +1,8 @@ +{ + "id": "36638890", + "label": 0, + "article": { + "id": "36638890", + "text": "Laforin and Malin are two proteins that are encoded by the genes EPM2A and EPM2B, respectively. Laforin is a glucan phosphatase and Malin is an E3-ubiquitin ligase, and these two proteins function as a complex. Mutations occurring at the level of one of the two genes lead to the accumulation of an aberrant form of glycogen meant to cluster in polyglucosans that go under the name of Lafora bodies. Individuals affected by the appearance of these polyglucosans, especially at the cerebral level, experience progressive neurodegeneration and several episodes of epilepsy leading to the manifestation of a fatal form of a rare disease called Lafora disease (LD), for which, to date, no treatment is available. Despite the different dysfunctions described for this disease, many molecular aspects still demand elucidation. An effective way to unknot some of the nodes that prevent the achievement of better knowledge of LD is to focus on the substrates that are ubiquitinated by the E3-ubiquitin ligase Malin. Some substrates have already been provided by previous studies based on protein-protein interaction techniques and have been associated with some alterations that mark the disease. In this work, we have used an unbiased alternative approach based on the activity of Malin as an E3-ubiquitin ligase. We report the discovery of novel bonafide substrates of Malin and have characterized one of them more deeply, namely PIP-dependent Rac exchanger 1 (P-Rex1). The analysis conducted upon this substrate sets the genesis of the delineation of a molecular pathway that leads to altered glucose uptake, which could be one of the origin of the accumulation of the polyglucosans present in the disease." + } +} \ No newline at end of file diff --git a/36640220.json b/36640220.json new file mode 100644 index 0000000000000000000000000000000000000000..c94bd683e0d5217ea71bc3422717b6ffefbee8dd --- /dev/null +++ b/36640220.json @@ -0,0 +1,8 @@ +{ + "id": "36640220", + "label": 0, + "article": { + "id": "36640220", + "text": "Characterizing bedside oculomotor deficits is a critical factor in defining the clinical presentation of hereditary ataxias. Quantitative assessments are increasingly available and have significant advantages, including comparability over time, reduced examiner dependency, and sensitivity to subtle changes. To delineate the potential of quantitative oculomotor assessments as digital-motor outcome measures for clinical trials in ataxia, we searched MEDLINE for articles reporting on quantitative eye movement recordings in genetically confirmed or suspected hereditary ataxias, asking which paradigms are most promising for capturing disease progression and treatment response. Eighty-nine manuscripts identified reported on 1541 patients, including spinocerebellar ataxias (SCA2, n = 421), SCA3 (n = 268), SCA6 (n = 117), other SCAs (n = 97), Friedreich ataxia (FRDA, n = 178), Niemann-Pick disease type C (NPC, n = 57), and ataxia-telangiectasia (n = 85) as largest cohorts. Whereas most studies reported discriminatory power of oculomotor assessments in diagnostics, few explored their value for monitoring genotype-specific disease progression (n = 2; SCA2) or treatment response (n = 8; SCA2, FRDA, NPC, ataxia-telangiectasia, episodic-ataxia 4). Oculomotor parameters correlated with disease severity measures including clinical scores (n = 18 studies (SARA: n = 9)), chronological measures (e.g., age, disease duration, time-to-symptom onset; n = 17), genetic stratification (n = 9), and imaging measures of atrophy (n = 5). Recurrent correlations across many ataxias (SCA2/3/17, FRDA, NPC) suggest saccadic eye movements as potentially generic quantitative oculomotor outcome. Recommendation of other paradigms was limited by the scarcity of cross-validating correlations, except saccadic intrusions (FRDA), pursuit eye movements (SCA17), and quantitative head-impulse testing (SCA3/6). This work aids in understanding the current knowledge of quantitative oculomotor parameters in hereditary ataxias, and identifies gaps for validation as potential trial outcome measures in specific ataxia genotypes." + } +} \ No newline at end of file diff --git a/36678278.json b/36678278.json new file mode 100644 index 0000000000000000000000000000000000000000..81d26f6478f67d7a60b889b6bce255bb390c54c1 --- /dev/null +++ b/36678278.json @@ -0,0 +1,8 @@ +{ + "id": "36678278", + "label": 0, + "article": { + "id": "36678278", + "text": "Iodine is an essential mineral required for the synthesis of thyroid hormones. Iodine plays a critical role in growth and neurocognitive development. Classical galactosaemia is a disorder resulting from an inborn error in galactose metabolism. Its current management consists of life-long lactose and galactose dietary restriction. This study estimated dietary intakes of iodine in infants and children with classical galactosaemia in the Republic of Ireland. The diets of 43 participants (aged 7 months-18 years) with classical galactosaemia were assessed for iodine intake using an iodine-specific food frequency questionnaire. Intakes were compared to the European Food Safety Authority (EFSA) dietary recommendations for iodine intake. The potential role of iodine fortification of dairy alternative products was also examined. There were no significant differences observed between sex, ethnicity and parental education and meeting dietary iodine recommendations. Differences, however, were seen between age groups, causing the p value to approach statistical significance ( = 0.06). Infants consuming infant formula were likely to meet iodine recommendations. However, over half (53%) of children aged 1-18 years had average intakes below the recommendations for age. For these children, consumption of iodine-fortified dairy alternative milk was the leading source of iodine in the diets, followed by fish/shellfish and eggs. An assessment of iodine intake should be undertaken during dietetic reviews for those with classical galactosaemia. Mandatory iodine fortification of all dairy alternative products would result in 92% of the total population cohort meeting iodine recommendations based on their current consumption." + } +} \ No newline at end of file diff --git a/36690462.json b/36690462.json new file mode 100644 index 0000000000000000000000000000000000000000..bb269c4106f2d5c1b0248a85859d903381f36839 --- /dev/null +++ b/36690462.json @@ -0,0 +1,8 @@ +{ + "id": "36690462", + "label": 0, + "article": { + "id": "36690462", + "text": "X-linked retinoschisis (XLRS) is an inherited vitreoretinal dystrophy causing visual impairment in males starting at a young age with an estimated prevalence of 1:5000 to 1:25,000. The condition was first observed in two affected brothers by Josef Haas in 1898 and is clinically diagnosed by characteristic intraretinal cysts arranged in a petaloid \"spoke-wheel\" pattern centered in the macula. When clinical electroretinogram (ERG) testing began in the 1960s, XLRS was noted to have a characteristic reduction of the dark-adapted b-wave amplitude despite normal or usually nearly normal a-wave amplitudes, which became known as the \"electronegative ERG response\" of XLRS disease. The causative gene, , was identified on the X-chromosome in 1997 and led to understanding the molecular and cellular basis of the condition, discerning the structure and function of the retinoschisin protein, and generating XLRS murine models. Along with parallel development of gene delivery vectors suitable for targeting retinal diseases, successful gene augmentation therapy was demonstrated by rescuing the XLRS phenotype in mouse. Two human phase I/II therapeutic XLRS gene augmentation studies were initiated; and although these did not yield definitive improvement in visual function, they gave significant new knowledge and experience, which positions the field for further near-term clinical testing with enhanced, next-generation gene therapy for XLRS patients." + } +} \ No newline at end of file diff --git a/36695789.json b/36695789.json new file mode 100644 index 0000000000000000000000000000000000000000..4b082f42d7855c79bdb8fb17a8d57fc3f4ae316a --- /dev/null +++ b/36695789.json @@ -0,0 +1,8 @@ +{ + "id": "36695789", + "label": 0, + "article": { + "id": "36695789", + "text": "PURPOSE:\nFoveal herniation occurs when neuroretinal tissue protrudes through and above the level of an epiretinal membrane. This study describes the visual symptoms and spectral domain optical coherence tomography findings associated with foveal herniation and evaluates the postoperative visual, anatomical, and surgical outcomes.\n\nMETHODS:\nA multicenter retrospective review of patients diagnosed with epiretinal membrane identified 59 patients with preoperative foveal herniation on spectral domain optical coherence tomography. Data regarding visual symptoms, preoperative and postoperative best-corrected visual acuity (BCVA), central retinal thickness, macular volume, and size of foveal herniation were collected, and statistical analysis was performed.\n\nRESULTS:\nA total of 58 of the 59 patients with foveal herniation underwent surgical epiretinal membrane peeling, with foveal contour restored in 53.5% of patients after surgery. Average BCVA improved from 20/80 to 20/40 Snellen equivalent at most-recent postoperative visit (P \u003c 0.0001). The average central retinal thickness decreased from 632 µm to 432 µm (P \u003c 0.0001) and the average macular volume decreased from 11.3 mm3 to 9.5 mm3 (P \u003c 0.0001) at 3 months postoperatively. Preoperatively, greater herniation height was associated with worse BCVA (P = 0.008), greater central retinal thickness (P = 0.01), retinoschisis, cystoid macular edema, foveolar detachment, ellipsoid zone abnormality, and external limiting membrane abnormalities (P \u003c 0.05). Postoperatively, there was a decrease in retinoschisis, cystoid macular edema, foveolar detachment, ellipsoid zone, and external limiting membrane abnormality (P \u003c 0.05) on spectral domain optical coherence tomography.\n\nCONCLUSION:\nPatients with larger foveal herniation height had greater preoperative central retinal thickness, worse preoperative and postoperative BCVA, and more intraretinal abnormalities on spectral domain optical coherence tomography. Surgical epiretinal membrane peeling in patients with foveal herniation resulted in a significant improvement in patients' BCVA and microstructural abnormalities." + } +} \ No newline at end of file diff --git a/36695803.json b/36695803.json new file mode 100644 index 0000000000000000000000000000000000000000..75e59358a3ce8aa813b09abd95bc86d909dd74f0 --- /dev/null +++ b/36695803.json @@ -0,0 +1,8 @@ +{ + "id": "36695803", + "label": 0, + "article": { + "id": "36695803", + "text": "PURPOSE:\nTo describe clinical characteristics and outcomes of children with early-onset X-linked retinoschisis.\n\nMETHODS:\nIn this retrospective consecutive case series, we included children diagnosed with symptomatic X-linked retinoschisis younger than 2 years. Presenting signs, clinical characteristics, treatments, and outcomes were recorded.\n\nRESULTS:\nSeven patients (14 eyes) with a mean age of 17.14 ± 6.28 months were included. Strabismus was the most common presenting symptom (6 of 7 patients, 86%). Clinical signs at the first diagnosis included peripheral retinoschisis in 13 eyes (13/14, 93%), of which 5 (5/13, 38%) were bullous, vitreous hemorrhage in 3 eyes (3/14, 21%), and retinal detachment in 3 eyes (3/14, 21%). The macula was involved in all eyes: It was detached in 2 eyes (2/14, 14%) and involved in the peripheral schisis in 4 eyes (4/14, 29%). In all remaining eyes, optical coherence tomography revealed foveoschisis. Six eyes (6/14, 42%) received surgery. At the last follow-up, visual acuity, when available, ranged from no light perception to 20/40, and no children had persistent retinal detachment.\n\nCONCLUSION:\nChildren with early-onset X-linked retinoschisis had severe forms. All children had peripheral retinoschisis which was often bullous and extended to the macula. Diagnosis is often clinical but handheld optical coherence tomography can be helpful in atypical forms. Complications requiring surgical management are frequent." + } +} \ No newline at end of file diff --git a/36709461.json b/36709461.json new file mode 100644 index 0000000000000000000000000000000000000000..91f646f3fcc637370df030989f9c177fb123773c --- /dev/null +++ b/36709461.json @@ -0,0 +1,8 @@ +{ + "id": "36709461", + "label": 0, + "article": { + "id": "36709461", + "text": "BACKGROUND:\nHairy cell leukemia (HCL) is an indolent chronic lymphoproliferative disorder and first-line treatment with either intravenous or subcutaneous cladribine generally leads to long-lasting remissions.\n\nMETHOD:\nAll 131 patients with hairy-cell leukemia (HCL) were analyzed, with a median follow-up of 91 months. Data is from 2007 to 2020. We evaluated the response rate to cladribine as the first line and the response rate to cladribine with or without rituximab in relapsed patients. Further, we assessed relapse-free survival, complications, and secondary malignancy.\n\nRESULTS:\nAfter a median follow-up of 91 months, the recurrence rate was 24%. The 5-year and 10-year RFS rates were 85% and 66%, respectively. Adding rituximab to 2-CDA leads to a better response rate than just cladribine (90% vs. 27.3%, p-value = 0.002) in the relapsed patients.\n\nCONCLUSION:\nHCL patients have long-term survival when cladribine is the first line of treatment. Furthermore, adding rituximab to cladribine leads to a higher response rate." + } +} \ No newline at end of file diff --git a/36710632.json b/36710632.json new file mode 100644 index 0000000000000000000000000000000000000000..6d22566cee99673587acab0d293ae41fe7235966 --- /dev/null +++ b/36710632.json @@ -0,0 +1,8 @@ +{ + "id": "36710632", + "label": 0, + "article": { + "id": "36710632", + "text": "OBJECTIVES:\nTo provide clinical guidance for early diagnosis and effective management of primary cesarean scar choriocarcinoma, which is an extremely rare but highly malignant trophoblastic tumor.\n\nMETHODS:\nThis retrospective case series summarized the clinical courses of seven patients diagnosed with cesarean scar choriocarcinoma.\n\nRESULTS:\nWe identified two patients in our institution with cesarean scar choriocarcinoma. In addition, details of the previous five patients were extracted from databases and analyzed to provide more clinical information. The seven patients had an average age of 31.14 years, their tumor sizes ranged from 2.0 to 6.5 cm, and their pretreatment serum β-human chorionic gonadotropin (β-hCG) levels ranged from 3664 to 312 468 mIU/mL. All the patients were categorized as having FIGO Stage I disease, with four patients at low risk and three at high risk. Six of the seven were misdiagnosed with ectopic pregnancy before pathologic examination.\n\nCONCLUSIONS:\nClinicians should pay attention to masses in cesarean scar and to continuous elevation of serum β-hCG levels after treatment. When cesarean scar choriocarcinoma is suspected, diagnostic surgery can be chosen for tentative treatment and pathologic sampling. Salvage EMA-CO chemotherapy (etoposide, actinomycin D, methotrexate, cyclophosphamide and vincristine) should be performed as early as possible to prevent metastasis and recurrence after pathologic diagnosis." + } +} \ No newline at end of file diff --git a/36713531.json b/36713531.json new file mode 100644 index 0000000000000000000000000000000000000000..730c61dc8beb6a29d39727f5b2b6b0512fd7e02b --- /dev/null +++ b/36713531.json @@ -0,0 +1,8 @@ +{ + "id": "36713531", + "label": 0, + "article": { + "id": "36713531", + "text": "Hairy cell leukemia (HCL) is a rare mature B-cell lymphoproliferative disorder and most often presents as classic hairy cell leukemia. This entity is characterized by an indolent course and the presence of the V600E mutation. We report the case of an 80-year-old man with a history of classical hairy cell leukemia who presented with fatigue, dizziness, shortness of breath, blurring of vision, and headache. His initial diagnosis was 9 years prior, and he received treatments with cladribine, pentostatin, and rituximab. The workup showed an elevated white blood cell count with atypical lymphocytes, anemia, and thrombocytopenia. A peripheral blood smear confirmed HCL relapse, and a magnetic resonance imaging (MRI) of the brain showed diffuse, nonenhancing masses in the supratentorial and infratentorial regions of the brain. He was initiated on treatment with vemurafenib, with improvements in his white blood cell count and a recovery of his platelet count and hemoglobin. A repeat MRI of the brain after 3 months showed complete resolution of the lesions. Vemurafenib was discontinued after 6 months, with bone marrow biopsy showing no evidence of residual hairy cell leukemia. There have only been limited reports of HCL involvement in the central nervous system in the literature. Due to the rarity of the condition, it is not clear which treatments can be effective for intracranial disease control. Our report shows the successful use of vemurafenib, resulting in complete remission of relapsed HCL with CNS involvement." + } +} \ No newline at end of file diff --git a/36719165.json b/36719165.json new file mode 100644 index 0000000000000000000000000000000000000000..8108ce9fc7e84be5c616320f98338b944f5911c8 --- /dev/null +++ b/36719165.json @@ -0,0 +1,8 @@ +{ + "id": "36719165", + "label": 0, + "article": { + "id": "36719165", + "text": "Congenital disorders of glycosylation (CDG) and Niemann-Pick type C (NPC) disease are inborn errors of metabolism that can both present with infantile-onset severe liver disease and other multisystemic manifestations. Plasma bile acid and N-palmitoyl-O-phosphocholineserine (PPCS) are screening biomarkers with proposed improved sensitivity and specificity for NPC. We report an infant with ATP6AP1-CDG who presented with cholestatic liver failure and elevated plasma oxysterols and bile acid, mimicking NPC clinically and biochemically. On further investigation, PPCS, but not the bile acid derivative N-(3β,5α,6β-trihydroxy-cholan-24-oyl) glycine (TCG), were elevated in plasma samples from individuals with ATP6AP1-, ALG1-, ALG8-, and PMM2-CDG. These findings highlight the importance of keeping CDG within the diagnostic differential when evaluating children with early onset severe liver disease and elevated bile acid or PPCS to prevent delayed diagnosis and treatment." + } +} \ No newline at end of file diff --git a/36722740.json b/36722740.json new file mode 100644 index 0000000000000000000000000000000000000000..c9cb111d2c6caadb3c7b35c3b3ee24734e1b996a --- /dev/null +++ b/36722740.json @@ -0,0 +1,8 @@ +{ + "id": "36722740", + "label": 0, + "article": { + "id": "36722740", + "text": "BACKGROUND:\nClassical galactosaemia is a life-threatening disorder of carbohydrate metabolism, and the primary treatment is a lifelong galactose-restricted diet commenced in infancy. Adherence to restrictive diets can be burdensome for patients and their families; however, little is known about the impact on caregivers.\n\nAIM:\nThis study aims to determine the nutrition-related knowledge, perceptions, practices, and barriers of caregivers related to the therapeutic diet for classical galactosaemia.\n\nMETHODS:\nAn online survey was conducted among 98 eligible members of the Galactosaemia Support Group using a novel questionnaire. Descriptive and inferential analyses were performed using Microsoft Excel 2021 and Stata/MP (version 17.0), respectively. Forty-three caregivers participated in the study. RESULTS AND CONCLUSION: Of those who participated, 98% had high levels of dietary knowledge. Caregivers' knowledge scores ( = 17.9, standard deviation [SD] = 1.7) were positively correlated with educational level (r = 0.383, p = 0.013). High attitudinal scores ( = 32.5, SD = 5.5) obtained by most caregivers (65%) revealed an overall positive attitude towards the galactosaemia diet. Negative perceptions of being unable to feed their child breast milk (49%) were apparent, and this perception was positively correlated with caregivers' intention to feed their child breast milk (r = 0.450, p = 0.003). Caregivers' concerns about the safety of their child in social settings (79%) and feeling that their child was excluded in social settings (49%) were clear barriers. A multidisciplinary approach to galactosaemia management is warranted, with healthcare interventions focusing on addressing caregivers' negative perceptions and barriers related to the diet to enable tailored support and facilitate lifelong compliance." + } +} \ No newline at end of file diff --git a/36727091.json b/36727091.json new file mode 100644 index 0000000000000000000000000000000000000000..f84a5982fc152577be2b17f3b60645d4e1e07b6d --- /dev/null +++ b/36727091.json @@ -0,0 +1,8 @@ +{ + "id": "36727091", + "label": 0, + "article": { + "id": "36727091", + "text": "Altered autophagy is a hallmark of neurodegeneration but how autophagy is regulated in the brain and dysfunctional autophagy leads to neuronal death has remained cryptic. Being a key cellular waste-recycling and housekeeping system, autophagy is implicated in a range of brain disorders and altering autophagy flux could be an effective therapeutic strategy and has the potential for clinical applications down the road. Tight regulation of proteins and organelles in order to meet the needs of complex neuronal physiology suggests that there is distinct regulatory pattern of neuronal autophagy as compared to non-neuronal cells and nervous system might have its own separate regulator of autophagy. Evidence has shown that circRNAs participates in the biological processes of autophagosome assembly. The regulatory networks between circRNAs, autophagy, and neurodegeneration remains unknown and warrants further investigation. Understanding the interplay between autophagy, circRNAs and neurodegeneration requires a knowledge of the multiple steps and regulatory interactions involved in the autophagy pathway which might provide a valuable resource for the diagnosis and therapy of neurodegenerative diseases. In this review, we aimed to summarize the latest studies on the role of brain-protective mechanisms of autophagy associated circRNAs in neurodegenerative diseases (including Alzheimer's disease, Parkinson's disease, Huntington's disease, Spinal Muscular Atrophy, Amyotrophic Lateral Sclerosis, and Friedreich's ataxia) and how this knowledge can be leveraged for the development of novel therapeutics against them. Autophagy stimulation might be potential one-size-fits-all therapy for neurodegenerative disease as per considerable body of evidence, therefore future research on brain-protective mechanisms of autophagy associated circRNAs will illuminate an important feature of nervous system biology and will open the door to new approaches for treating neurodegenerative diseases." + } +} \ No newline at end of file diff --git a/36729281.json b/36729281.json new file mode 100644 index 0000000000000000000000000000000000000000..e88c519d1292e0a18e5c9ec6ff9e2ac0a24309ee --- /dev/null +++ b/36729281.json @@ -0,0 +1,8 @@ +{ + "id": "36729281", + "label": 0, + "article": { + "id": "36729281", + "text": "BACKGROUND:\nFanconi-Debré-de Toni syndrome (also known as Fanconi renotubular syndrome, or FRST) profoundly increased the understanding of the functions of the proximal convoluted tubule (PCT) and provided important insights into the pathophysiology of several kidney diseases and drug toxicities.\n\nDATA SOURCES:\nWe searched Pubmed and Scopus databases to find relevant articles about FRST. This review article focuses on the physiology of the PCT, as well as on the physiopathology of FRST in children, its diagnosis, and treatment.\n\nRESULTS:\nFRST encompasses a wide variety of inherited and acquired PCT alterations that lead to impairment of PCT reabsorption. In children, FRST often presents as a secondary feature of systemic disorders that impair energy supply, such as Lowe's syndrome, Dent's disease, cystinosis, hereditary fructose intolerance, galactosemia, tyrosinemia, Alport syndrome, and Wilson's disease. Although rare, congenital causes of FRST greatly impact the morbidity and mortality of patients and impose diagnostic challenges. Furthermore, its treatment is diverse and considers the ability of the clinician to identify the correct etiology of the disease.\n\nCONCLUSION:\nThe early diagnosis and treatment of pediatric patients with FRST improve the prognosis and the quality of life." + } +} \ No newline at end of file diff --git a/36730380.json b/36730380.json new file mode 100644 index 0000000000000000000000000000000000000000..6884192a8a985fb36663cbd46b41c04f327be970 --- /dev/null +++ b/36730380.json @@ -0,0 +1,8 @@ +{ + "id": "36730380", + "label": 0, + "article": { + "id": "36730380", + "text": "The cardiovascular system requires iron to maintain its high energy demands and metabolic activity. Iron plays a critical role in oxygen transport and storage, mitochondrial function, and enzyme activity. However, excess iron is also cardiotoxic due to its ability to catalyze the formation of reactive oxygen species and promote oxidative damage. While mammalian cells have several redundant iron import mechanisms, they are equipped with a single iron-exporting protein, which makes the cardiovascular system particularly sensitive to iron overload. As a result, iron levels are tightly regulated at many levels to maintain homeostasis. Iron dysregulation ranges from iron deficiency to iron overload and is seen in many types of cardiovascular disease, including heart failure, myocardial infarction, anthracycline-induced cardiotoxicity, and Friedreich's ataxia. Recently, the use of intravenous iron therapy has been advocated in patients with heart failure and certain criteria for iron deficiency. Here, we provide an overview of systemic and cellular iron homeostasis in the context of cardiovascular physiology, iron deficiency, and iron overload in cardiovascular disease, current therapeutic strategies, and future perspectives." + } +} \ No newline at end of file diff --git a/36735458.json b/36735458.json new file mode 100644 index 0000000000000000000000000000000000000000..6a9004e5f7715bec2bbf6f77816ed4cf72c61635 --- /dev/null +++ b/36735458.json @@ -0,0 +1,8 @@ +{ + "id": "36735458", + "label": 0, + "article": { + "id": "36735458", + "text": "Myoclonus can be epileptic or nonepileptic. Epileptic myoclonus has been defined in clinical, neurophysiological, and neuroanatomical terms. Juvenile myoclonic epilepsy (JME) is typically considered to be an adolescent-onset idiopathic generalized epilepsy with a combination of myoclonic, generalized tonic-clonic, and absence seizures and normal cognitive status that responds well to anti-seizure medications but requires lifelong treatment. EEG shows generalized epileptiform discharges and photosensitivity. Recent observations indicate that the clinical picture of JME is heterogeneous and a number of neuropsychological and imaging studies have shown structural and functional abnormalities in the frontal lobes and thalamus. Advances in neurophysiology and imaging suggest that JME may not be a truly generalized epilepsy, in that restricted cortical and subcortical networks appear to be involved rather than the entire brain. Some patients with JME may be refractory to anti-seizure medications and attempts have been made to identify neurophysiological biomarkers predicting resistance. Progressive myoclonic epilepsy is a syndrome with multiple specific causes. It is distinct from JME because of the occurrence of progressive neurologic dysfunction in addition to myoclonus and generalized tonic-clonic seizures but may sometimes be difficult to distinguish from JME or misdiagnosed as drug-resistant JME. This article provides an overview of progressive myoclonic epilepsy and focuses on the clinical and neurophysiological findings in the two most commonly recognized forms of progressive myoclonic epilepsy-Unverricht-Lundborg disease (EPM1) and Lafora disease (EPM2). A variety of neurophysiological tests can be used to distinguish between JME and progressive myoclonic epilepsy and between EPM1 and EPM2." + } +} \ No newline at end of file diff --git a/36741498.json b/36741498.json new file mode 100644 index 0000000000000000000000000000000000000000..f016bfe4cd9c5b496edfd9a22fa059b67da12729 --- /dev/null +++ b/36741498.json @@ -0,0 +1,8 @@ +{ + "id": "36741498", + "label": 0, + "article": { + "id": "36741498", + "text": "BACKGROUND:\nLow-risk gestational trophoblastic neoplasia could be cured in the case of appropriate management with single-agent chemotherapy. This study was carried out to compare the efficacy of single-dose methotrexate versus Actinomycin-D in low-risk gestational trophoblastic neoplasia to analyze the most effective agent.\n\nMETHODS:\nThis retrospective cohort study was conducted on the medical record of 170 cases with the diagnosis of low-risk gestational trophoblastic neoplasia from 2012 to 2019 to evaluate the response rate of single-dose weekly-methotrexate versus biweekly-Actinomycin-D.\n\nRESULTS:\nSingle agent chemotherapy was required in 170 patients with final risk score of less than 7. Among the 100 cases under weekly-methotrexate therapy, 29 patients were required second-line chemotherapy with Actinomycin-D and combination therapy which means complete remission of 71% with methotrexate, in comparison with 78.5% in the other group. Resistance was mostly seen in patients with documented choriocarcinoma in histology who had not received timely diagnosis and treatment.\n\nCONCLUSION:\nIndividualized decision in the management of low-risk gestational trophoblastic neoplasia cases, based on histology, HCG, and history is the corn stone in successful treatment." + } +} \ No newline at end of file diff --git a/36755518.json b/36755518.json new file mode 100644 index 0000000000000000000000000000000000000000..c7428ab7f91c8007fc887464afc64e793023a2c7 --- /dev/null +++ b/36755518.json @@ -0,0 +1,8 @@ +{ + "id": "36755518", + "label": 0, + "article": { + "id": "36755518", + "text": "In the absence of YFH1, the yeast ortholog of the human FXN gene, budding yeast Saccharomyces cerevisiae experience similar problems to those of cells with Friedreich's ataxia (FRDA). The comparable phenotypic traits consist of impaired respiration, problems in iron homeostasis, decreased oxidative stress tolerance, and diminished iron-sulfur cluster synthesis, rendering yeast of potential use in FRDA modeling and drug trials. Deferiprone, an iron chelator, is one of the long-term studied potential drugs for FRDA, whereas metformin is a biguanide prescribed to treat type 2 diabetes. In the present study, the effects of deferiprone and metformin treatment on the yeast FRDA model are explored via RNA-sequencing analyses. The comparative inquiry of transcriptome data reveals new promising roles for metformin in FRDA treatment since deferiprone and metformin treatments produce overlapping transcriptional and phenotypic responses in YFH1Δ cells. The results revealed that both deferiprone and metformin treatment does not rescue aerobic respiration in YFH1Δ cells, but they alleviate the FRDA phenotype probably by triggering the retrograde mitochondria-to-nucleus signaling." + } +} \ No newline at end of file diff --git a/36759243.json b/36759243.json new file mode 100644 index 0000000000000000000000000000000000000000..27069d76fe9e2035ce8c0a6bf7102eca4fb05eff --- /dev/null +++ b/36759243.json @@ -0,0 +1,8 @@ +{ + "id": "36759243", + "label": 0, + "article": { + "id": "36759243", + "text": "PURPOSE:\nTo explore the clinical characteristics, imaging features, and differential diagnosis of periocular pilomatrixoma in children and provide evidence for clinical diagnosis and treatment.\n\nMETHODS:\nRetrospective analysis of the clinical characteristics, preliminary diagnosis, imaging features, treatment, and follow-up of the cases of pediatric periocular pilomatrixoma treated at our hospital.\n\nRESULTS:\nA total of 59 patients from 4 months to 13 years of age (median age 4 years) were collected; 18 cases (30.51%) were misdiagnosed as other diseases in preliminary diagnoses. Seven cases underwent computed tomography (CT) examination, with CT value ranging from 63.4 Hounsfield Units (HU) to 952.0 HU (median value 151.0 HU). Six cases underwent magnetic resonance imaging (MRI) examination; two patients underwent an enhanced scan. The results showed that the rim of the lesion was enhanced, but the contents were not enhanced. All patients underwent surgical treatment. No recurrence was found from 1 month to 5 years of follow-up.\n\nCONCLUSIONS:\nPeriocular pilomatrixoma is a relatively common tumor in children, which can easily be misdiagnosed clinically as other diseases, such as sebaceous and dermoid cysts. Although not generally recommended, CT can be of significant value in the diagnosis of pilomatrixoma. MRI is of little value in the diagnosis of this disease. If CT images show high or density, the possibility of pilomatrixoma should be considered." + } +} \ No newline at end of file diff --git a/36771301.json b/36771301.json new file mode 100644 index 0000000000000000000000000000000000000000..338c47f8fe66dfb82819a8c1d3e4b7262091d6f2 --- /dev/null +++ b/36771301.json @@ -0,0 +1,8 @@ +{ + "id": "36771301", + "label": 0, + "article": { + "id": "36771301", + "text": "In galactosaemia, a strict galactose-free diet is necessary to prevent or resolve acute symptoms in infants. However, because the body produces up to 10 times more galactose than is found in a galactose-restricted diet, excessively restrictive diets should be avoided in children and adults to prevent nutritional deficiencies. Since cheese is a nutritional source of the calcium necessary for bone health, the latest international guidelines on the management of classical galactosaemia (2017) allow the consumption of cured cheeses with less than 25 mg of galactose/100 g and recommend that each country verifies the adequacy of the cheeses, since most mature cheeses do not always have a lower galactose content. In total, 32 cheese samples were purchased (19 Spanish and 13 international cheeses), and their lactose and galactose contents were analysed using ion chromatography with pulsed amperometric detection (IC-PAD). Five Spanish cheeses contained less than 25 mg of galactose/100 g: García Baquero semi-cured cheese; Hacendado, Gran Reserva and Mahón cured cheeses; and García Baquero Reserva 12-month cured cheese. In addition, eight international cheeses were confirmed as suitable: Comté, Gouda, Gruyere, Maasdam, Parmigiano, Edam, Emmental, and some samples of Cheddar. In addition to the well-known low-galactose Swiss and Dutch cheeses, according to the current results, five Spanish cheeses can be safely consumed. The greater availability of types of cheese favours better bone health in patients with galactosaemia." + } +} \ No newline at end of file diff --git a/36777637.json b/36777637.json new file mode 100644 index 0000000000000000000000000000000000000000..c9f7d79dd75d9aabb0a810aa6b1ca7d204d7aa4f --- /dev/null +++ b/36777637.json @@ -0,0 +1,8 @@ +{ + "id": "36777637", + "label": 0, + "article": { + "id": "36777637", + "text": "INTRODUCTION:\nFriedreich's ataxia (FRDA) is an inherited recessive neurodegenerative disorder caused by a homozygous guanine-adenine-adenine (GAA) repeat expansion within intron 1 of the gene, which encodes the essential mitochondrial protein frataxin. There is still no effective therapy for FRDA, therefore the development of optimal cell and animal models of the disease is one of the priorities for preclinical therapeutic testing.\n\nMETHODS:\nWe obtained the latest FRDA humanized mouse model that was generated on the basis of our previous YG8sR, by Jackson laboratory [YG8JR, :YG8s(GAA) \u003e 800]. We characterized the behavioral, cellular, molecular and epigenetics properties of the YG8JR model, which has the largest GAA repeat sizes compared to all the current FRDA mouse models.\n\nRESULTS:\nWe found statistically significant behavioral deficits, together with reduced levels of frataxin mRNA and protein, and aconitase activity in YG8JR mice compared with control Y47JR mice. YG8JR mice exhibit intergenerational GAA repeat instability by the analysis of parent and offspring tissue samples. Somatic GAA repeat instability was also detected in individual brain and cerebellum tissue samples. In addition, increased DNA methylation of CpG U13 was identified in GAA repeat region in the brain, cerebellum, and heart tissues. Furthermore, we show decreased histone H3K9 acetylation and increased H3K9 methylation of YG8JR cerebellum tissues within the gene, upstream and downstream of the GAA repeat region compared to Y47JR controls.\n\nDISCUSSION:\nThese studies provide a detailed characterization of the GAA repeat expansion-based YG8JR transgenic mouse models that will help investigations of FRDA disease mechanisms and therapy." + } +} \ No newline at end of file diff --git a/36781946.json b/36781946.json new file mode 100644 index 0000000000000000000000000000000000000000..d1f6946f030d127227beee4d53442076aad1f528 --- /dev/null +++ b/36781946.json @@ -0,0 +1,8 @@ +{ + "id": "36781946", + "label": 0, + "article": { + "id": "36781946", + "text": "Most Friedreich ataxia (FRDA) cases are caused by the elongation of the GAA repeat (GAAr) sequence in the first intron of the FXN gene, leading to a decrease of the frataxin protein expression. Deletion of this GAAr with CRISPR/Cas9 technology leads to an increase in frataxin expression in vitro. We are therefore aiming to develop FRDA treatment based on the deletion of GAAr with CRISPR/Cas9 technology using a single AAV expressing a small Cas9 (CjCas9) and two single guide RNAs (sgRNAs) targeting the FXN gene. This AAV was intraperitoneally administrated to YG8sR (250-300 GAAr) and to YG8-800 (800 GAAr) mice. DNA and RNA were extracted from different organs a month later. PCR amplification of part of intron 1 of the FXN gene detected some GAAr deletion in some cells in heart and liver of both mouse models, but the editing rate was not sufficient to cause an increase in frataxin mRNA in the heart. However, the correlation observed between the editing rate and the distribution of AAV suggests a possible therapy based on the removal of the GAAr with a better delivery tool of the CRISPR/Cas9 system." + } +} \ No newline at end of file diff --git a/36791560.json b/36791560.json new file mode 100644 index 0000000000000000000000000000000000000000..99fe16b343d0dee6ab406d25142d0186ac200608 --- /dev/null +++ b/36791560.json @@ -0,0 +1,8 @@ +{ + "id": "36791560", + "label": 0, + "article": { + "id": "36791560", + "text": "Enzyme replacement therapy (ERT) has been used to treat a few of the many existing diseases which are originated from the lack of, or low enzymatic activity. Exogenous enzymes are administered to contend with the enzymatic activity deficiency. Enzymatic nanoreactors based on the enzyme encapsulation inside of virus-like particles (VLPs) appear as an interesting alternative for ERT. VLPs are excellent delivery vehicles for therapeutic enzymes as they are biodegradable, uniformly organized, and porous nanostructures that transport and could protect the biocatalyst from the external environment without much affecting the bioactivity. Consequently, significant efforts have been made in the production processes of virus-based enzymatic nanoreactors and their functionalization, which are critically reviewed. The use of virus-based enzymatic nanoreactors for the treatment of lysosomal storage diseases such as Gaucher, Fabry, and Pompe diseases, as well as potential therapies for galactosemia, and Hurler and Hunter syndromes are discussed." + } +} \ No newline at end of file diff --git a/36791574.json b/36791574.json new file mode 100644 index 0000000000000000000000000000000000000000..ad211382117001e8cc825a37613a1fde99783fe9 --- /dev/null +++ b/36791574.json @@ -0,0 +1,8 @@ +{ + "id": "36791574", + "label": 0, + "article": { + "id": "36791574", + "text": "BACKGROUND:\nCockayne syndrome (CS) is a DNA repair disorder primarily associated with pathogenic variants in ERCC6 and ERCC8. As in other Mendelian disorders, there are a number of genetically unsolved CS cases.\n\nMETHODS:\nWe ascertained five individuals with monoallelic pathogenic variants in MORC2, previously associated with three dominantly inherited phenotypes: an axonal form of Charcot-Marie-Tooth disease type 2Z; a syndrome of developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy; and a rare form of spinal muscular atrophy.\n\nRESULTS:\nOne of these individuals bore a strong phenotypic resemblance to CS. We then identified monoallelic pathogenic MORC2 variants in three of five genetically unsolved individuals with a clinical diagnosis of CS. In total, we identified eight individuals with MORC2-related disorder, four of whom had clinical features strongly suggestive of CS.\n\nCONCLUSIONS:\nOur findings indicate that some forms of MORC2-related disorder have phenotypic similarities to CS, including features of accelerated aging. Unlike classic DNA repair disorders, MORC2-related disorder does not appear to be associated with a defect in transcription-coupled nucleotide excision repair and follows a dominant pattern of inheritance with variants typically arising de novo. Such de novo pathogenic variants present particular challenges with regard to both initial gene discovery and diagnostic evaluations. MORC2 should be included in diagnostic genetic test panels targeting the evaluation of microcephaly and/or suspected DNA repair disorders. Future studies of MORC2 and its protein product, coupled with further phenotypic characterization, will help to optimize the diagnosis, understanding, and therapy of the associated disorders." + } +} \ No newline at end of file diff --git a/36800320.json b/36800320.json new file mode 100644 index 0000000000000000000000000000000000000000..946a7af0f5af252d344f8b155df208fce88aebea --- /dev/null +++ b/36800320.json @@ -0,0 +1,8 @@ +{ + "id": "36800320", + "label": 0, + "article": { + "id": "36800320", + "text": "Friedreich's ataxia (FRDA) is caused primarily by expanded GAA repeats in intron 1 of both alleles of the gene, which causes transcriptional silencing and reduced expression of frataxin mRNA and protein. FRDA is characterized by slowly progressive ataxia and cardiomyopathy. Symptoms generally appear during adolescence, and patients slowly progress to wheelchair dependency usually in the late teens or early twenties with death on average in the 4th decade. There are two known mature proteoforms of frataxin. Mitochondrial frataxin (frataxin-M) is a 130-amino acid protein with a molecular weight of 14,268 Da, and there is an alternatively spliced N-terminally acetylated 135-amino acid form (frataxin-E) with a molecular weight of 14,953 Da found in erythrocytes. There is reduced expression of frataxin in the heart and brain, but frataxin is not secreted into the systemic circulation, so it cannot be analyzed in serum or plasma. Blood is a readily accessible biofluid that contains numerous different cell types that express frataxin. We have found that pig blood can serve as an excellent surrogate matrix to validate an assay for frataxin proteoforms because pig frataxin is lost during the immunoprecipitation step used to isolate human frataxin. Frataxin-M is expressed in blood cells that contain mitochondria, whereas extra-mitochondrial frataxin-E is found in erythrocytes. This means that the analysis of frataxin in whole blood provides information on the concentration of both proteoforms without having to isolate the individual cell types. In the current study, we observed that the distributions of frataxin levels for a sample of 25 healthy controls and 50 FRDA patients were completely separated from each other, suggesting 100% specificity and 100% sensitivity for distinguishing healthy controls from FRDA cases, a very unusual finding for a biomarker assay. Additionally, frataxin levels were significantly correlated with the GAA repeat length and age of onset with higher correlations for extra-mitochondrial frataxin-E than those for mitochondrial frataxin-M. These findings auger well for using frataxin levels measured by the validated stable isotope dilution ultrahigh-performance liquid chromatography-multiple reaction monitoring/mass spectrometry assay to monitor therapeutic interventions and the natural history of FRDA. Our study also illustrates the utility of using whole blood for protein disease biomarker discovery and validation." + } +} \ No newline at end of file diff --git a/36804094.json b/36804094.json new file mode 100644 index 0000000000000000000000000000000000000000..050e9bbcd6786e29ce189d122d2ae7c6e92fe527 --- /dev/null +++ b/36804094.json @@ -0,0 +1,8 @@ +{ + "id": "36804094", + "label": 0, + "article": { + "id": "36804094", + "text": "BACKGROUND:\nMyotonic dystrophy type 1 results from an RNA gain-of-function mutation, in which DM1 protein kinase (DMPK) transcripts carrying expanded trinucleotide repeats exert deleterious effects. Antisense oligonucleotides (ASOs) provide a promising approach to treatment of myotonic dystrophy type 1 because they reduce toxic RNA levels. We aimed to investigate the safety of baliforsen (ISIS 598769), an ASO targeting DMPK mRNA.\n\nMETHODS:\nIn this dose-escalation phase 1/2a trial, adults aged 20-55 years with myotonic dystrophy type 1 were enrolled at seven tertiary referral centres in the USA and randomly assigned via an interactive web or phone response system to subcutaneous injections of baliforsen 100 mg, 200 mg, or 300 mg, or placebo (6:2 randomisation at each dose level), or to baliforsen 400 mg or 600 mg, or placebo (10:2 randomisation at each dose level), on days 1, 3, 5, 8, 15, 22, 29, and 36. Sponsor personnel directly involved with the trial, participants, and all study personnel were masked to treatment assignments. The primary outcome measure was safety in all participants who received at least one dose of study drug up to day 134. This trial is registered with ClinicalTrials.gov (NCT02312011), and is complete.\n\nFINDINGS:\nBetween Dec 12, 2014, and Feb 22, 2016, 49 participants were enrolled and randomly assigned to baliforsen 100 mg (n=7, one patient not dosed), 200 mg (n=6), 300 mg (n=6), 400 mg (n=10), 600 mg (n=10), or placebo (n=10). The safety population comprised 48 participants who received at least one dose of study drug. Treatment-emergent adverse events were reported for 36 (95%) of 38 participants assigned to baliforsen and nine (90%) of ten participants assigned to placebo. Aside from injection-site reactions, common treatment-emergent adverse events were headache (baliforsen: ten [26%] of 38 participants; placebo: four [40%] of ten participants), contusion (baliforsen: seven [18%] of 38; placebo: one [10%] of ten), and nausea (baliforsen: six [16%] of 38; placebo: two [20%] of ten). Most adverse events (baliforsen: 425 [86%] of 494; placebo: 62 [85%] of 73) were mild in severity. One participant (baliforsen 600 mg) developed transient thrombocytopenia considered potentially treatment related. Baliforsen concentrations in skeletal muscle increased with dose.\n\nINTERPRETATION:\nBaliforsen was generally well tolerated. However, skeletal muscle drug concentrations were below levels predicted to achieve substantial target reduction. These results support the further investigation of ASOs as a therapeutic approach for myotonic dystrophy type 1, but suggest improved drug delivery to muscle is needed.\n\nFUNDING:\nIonis Pharmaceuticals, Biogen." + } +} \ No newline at end of file diff --git a/36804125.json b/36804125.json new file mode 100644 index 0000000000000000000000000000000000000000..5aa777c77c7aa08d5e91328509b9613b494129d5 --- /dev/null +++ b/36804125.json @@ -0,0 +1,8 @@ +{ + "id": "36804125", + "label": 0, + "article": { + "id": "36804125", + "text": "Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease. The disease involves excessive accumulation of fibroblasts and myofibroblasts, and myofibroblasts differentiated by pro-fibrotic factors promote the deposition of extracellular matrix proteins such as collagen and fibronectin. Transforming growth factor-β1 is a pro-fibrotic factor that promotes fibroblast-to-myofibroblast differentiation (FMD). Therefore, inhibition of FMD may be an effective strategy for IPF treatment. In this study, we screened the anti-FMD effects of various iminosugars and showed that some compounds, including N-butyldeoxynojirimycin (NB-DNJ, miglustat, an inhibitor of glucosylceramide synthase (GCS)), a clinically approved drug for treating Niemann-Pick disease type C and Gaucher disease type 1, inhibited TGF-β1-induced FMD by inhibiting the nuclear translocation of Smad2/3. N-butyldeoxygalactonojirimycin having GCS inhibitory effect did not attenuate the TGF-β1-induced FMD, suggesting that NB-DNJ exerts the anti-FMD effects by GCS inhibitory effect independent manner. N-butyldeoxynojirimycin did not inhibit TGF-β1-induced Smad2/3 phosphorylation. In a mouse model of bleomycin (BLM)-induced pulmonary fibrosis, intratracheal or oral administration of NB-DNJ at an early fibrotic stage markedly ameliorated lung injury and deterioration of respiratory functions, such as specific airway resistance, tidal volume, and peak expiratory flow. Furthermore, the anti-fibrotic effects of NB-DNJ in the BLM-induced lung injury model were similar to those of pirfenidone and nintedanib, which are clinically approved drugs for the treatment of IPF. These results suggest that NB-DNJ may be effective for IPF treatment." + } +} \ No newline at end of file diff --git a/36804165.json b/36804165.json new file mode 100644 index 0000000000000000000000000000000000000000..7ded25de986a5f01458aa8dc8523e5d49f4cc2fa --- /dev/null +++ b/36804165.json @@ -0,0 +1,8 @@ +{ + "id": "36804165", + "label": 0, + "article": { + "id": "36804165", + "text": "INTRODUCTION OR BACKGROUND:\nPilomatrix carcinoma is a rare malignant neoplasm arising from the root of hair follicles, with only 150 cases described in the world literature. It is most commonly seen in the head and neck region.\n\nCASE PRESENTATION:\nWe describe a case of malignant pilomatrix carcinoma in a 62-year-old gentleman presenting as a solitary globular mass over the right anterior chest wall along with a brief review of literature.\n\nDISCUSSION AND CONCLUSION:\nSurgical excision with a wide margin is the current standard of care for chest wall pilomatrix carcinoma and is associated with the least recurrence. Role of radiation as definitive treatment of the primary or as adjuvant therapy has not been clearly established." + } +} \ No newline at end of file diff --git a/36806180.json b/36806180.json new file mode 100644 index 0000000000000000000000000000000000000000..f8b3ecd91183270d5470cabf2a0fa9f4e6b3b87f --- /dev/null +++ b/36806180.json @@ -0,0 +1,8 @@ +{ + "id": "36806180", + "label": 0, + "article": { + "id": "36806180", + "text": "Ataxias are progressive diseases that are usually the result of cerebellar degeneration. Ataxias are divided into genetic, sporadic degenerative and acquired (secondary) forms. While there are established therapies for acquired (secondary) ataxias, genetic and sporadic degenerative ataxias are currently not medically treatable. For these ataxias, the development of somatic gene therapies is a promising avenue. The goals of gene therapies for genetic ataxias are to inactivate deleterious genes by gene silencing or to replace or correct a non-functional gene. Another option, which may also be considered for sporadic degenerative ataxias, are therapies that involve transferring new or modified genes. Gene therapies are being actively developed for the more common ataxias, such as Friedreich's ataxia, certain spinocerebellar ataxias, and multiple system atrphy, and initial phase I trials are underway." + } +} \ No newline at end of file diff --git a/36809552.json b/36809552.json new file mode 100644 index 0000000000000000000000000000000000000000..18a7704526d2c01e6ae078343fbb5d1b9432e657 --- /dev/null +++ b/36809552.json @@ -0,0 +1,8 @@ +{ + "id": "36809552", + "label": 0, + "article": { + "id": "36809552", + "text": "Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare, incurable genetic disease that belongs to the group of polyglutamine (polyQ) diseases. DRPLA is the most common in the Japanese population; however, its global prevalence is also increasing due to better clinical recognition. It is characterized by cerebellar ataxia, myoclonus, epilepsy, dementia, and chorea. DRPLA is caused by dynamic mutation of CAG repeat expansion in ATN1 gene encoding the atrophin-1 protein. In the cascade of molecular disturbances, the pathological form of atrophin-1 is the initial factor, which has not been precisely characterized so far. Reports indicate that DRPLA is associated with disrupted protein-protein interactions (in which an expanded polyQ tract plays a crucial role), as well as gene expression deregulation. There is a great need to design efficient therapy that would address the underlying neurodegenerative process and thus prevent or alleviate DRPLA symptoms. An in-depth understanding of the normal atrophin-1 function and mutant atrophin-1 dysfunction is crucial for this purpose. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society." + } +} \ No newline at end of file diff --git a/36812416.json b/36812416.json new file mode 100644 index 0000000000000000000000000000000000000000..5788efb237a60dcbdc79b9a554a5cac990069b9b --- /dev/null +++ b/36812416.json @@ -0,0 +1,8 @@ +{ + "id": "36812416", + "label": 0, + "article": { + "id": "36812416", + "text": "PURPOSE:\nTo evaluate the efficacy of anterior segment optical coherent tomography (AS OCT) in estimating the length of the pars plana and optimizing the sclerotomy entry site in vitrectomy for highly myopic eyes, facilitating membrane peeling.\n\nMETHODS:\nTwenty-three eyes with myopic traction maculopathy were studied. The pars plana was examined using two methods: preoperative AS OCT and intraoperative measurement. The distance from the limbus to the ora serrata in two groups was measured to compare differences in length. The actual length of the entry site from the limbus and forceps used were noted in all eyes studied.\n\nRESULTS:\nThe mean axial length was 29.2 ± 2.3 mm for all 23 eyes. The average length between the limbus and ora serrata measured with AS OCT and intraoperative examination was 6,710 µ m (SD ± 459) and 6,671 µ m (SD ± 402), respectively, in the superotemporal region ( P \u003e 0.05), and 6,340 µ m (SD ± 321) and 6,204 µ m (SD ± 402), respectively, in the superonasal region ( P \u003e0.05). The mean length of the entry site from the limbus was 6.2 mm, and 28-mm forceps were used in 17 of 23 eyes (77%).\n\nCONCLUSION:\nThe length of the pars plana varies depending on the axial length of the eye. Preoperative AS OCT enables accurate measurement of the pars plana in eyes with high myopia. AS OCT examination can help determine the optimal site for sclerotomy, allowing easier access to the macular region for membrane peeling in highly myopic eyes." + } +} \ No newline at end of file diff --git a/36812958.json b/36812958.json new file mode 100644 index 0000000000000000000000000000000000000000..d5164d2b5a4a37e7599ed90c72dca9f36ea33f87 --- /dev/null +++ b/36812958.json @@ -0,0 +1,8 @@ +{ + "id": "36812958", + "label": 0, + "article": { + "id": "36812958", + "text": "Refsum disease is an inherited peroxisomal disorder caused by severe deficiency of phytanoyl-CoA hydroxylase activity. Affected patients develop severe cardiomyopathy of poorly known pathogenesis that may lead to a fatal outcome. Since phytanic acid (Phyt) concentrations are highly increased in tissues of individuals with this disease, it is conceivable that this branched-chain fatty acid is cardiotoxic. The present study investigated whether Phyt (10-30 μM) could disturb important mitochondrial functions in rat heart mitochondria. We also determined the influence of Phyt (50-100 μM) on cell viability (MTT reduction) in cardiac cells (H9C2). Phyt markedly increased mitochondrial state 4 (resting) and decreased state 3 (ADP-stimulated) and uncoupled (CCCP-stimulated) respirations, besides reducing the respiratory control ratio, ATP synthesis and the activities of the respiratory chain complexes I-III, II, and II-III. This fatty acid also reduced mitochondrial membrane potential and induced swelling in mitochondria supplemented by exogenous Ca, which were prevented by cyclosporin A alone or combined with ADP, suggesting the involvement of the mitochondrial permeability transition (MPT) pore opening. Mitochondrial NAD(P)H content and Ca retention capacity were also decreased by Phyt in the presence of Ca. Finally, Phyt significantly reduced cellular viability (MTT reduction) in cultured cardiomyocytes. The present data indicate that Phyt, at concentrations found in the plasma of patients with Refsum disease, disrupts by multiple mechanisms mitochondrial bioenergetics and Ca homeostasis, which could presumably be involved in the cardiomyopathy of this disease." + } +} \ No newline at end of file diff --git a/36820110.json b/36820110.json new file mode 100644 index 0000000000000000000000000000000000000000..482cdb2905a29263819f72e3695cf8d66992174a --- /dev/null +++ b/36820110.json @@ -0,0 +1,8 @@ +{ + "id": "36820110", + "label": 0, + "article": { + "id": "36820110", + "text": "Hairy cell leukemia (HCL) is an infrequently encountered chronic B-lymphocyte hematological malignancy, which is found to be more prevalent in males. HCL can present with a myriad of nonspecific symptoms involving the reticuloendothelial system. Usually, patients are diagnosed after an incidental finding of pancytopenia. In the majority of cases, HCL follows an indolent course, and many patients remain asymptomatic. Treatment with nucleoside analogs is the first line of treatment and is indicated for patients with severe anemia, thrombocytopenia, neutropenia, or severe systemic symptoms. Here, we report an atypical case of a 41-year-old Hispanic female who presented with menorrhagia and iron deficiency anemia. She was diagnosed with HCL after a bone marrow biopsy demonstrated the characteristic \"hairy projections.\"" + } +} \ No newline at end of file diff --git a/36823305.json b/36823305.json new file mode 100644 index 0000000000000000000000000000000000000000..85caf72ed9adfcd7063908b439848d7509cf2ab2 --- /dev/null +++ b/36823305.json @@ -0,0 +1,8 @@ +{ + "id": "36823305", + "label": 0, + "article": { + "id": "36823305", + "text": "The late endosome/lysosome (LE/Lys) lipid bis(monoacylglycero)phosphate (BMP) plays major roles in cargo sorting and degradation, regulation of cholesterol and intercellular communication and has been linked to viral infection and neurodegeneration. Although BMP was initially described over fifty years ago, the enzymes regulating its synthesis remain unknown. The first step in the BMP biosynthetic pathway is the conversion of phosphatidylglycerol (PG) into lysophosphatidylglycerol (LPG) by a phospholipase A2 (PLA2) enzyme. Here we report that this enzyme is lysosomal PLA2 (LPLA2). We show that LPLA2 is sufficient to convert PG into LPG in vitro. We show that modulating LPLA2 levels regulates BMP levels in HeLa cells, and affects downstream pathways such as LE/Lys morphology and cholesterol levels. Finally, we show that in a model of Niemann-Pick disease type C, overexpressing LPLA2 alleviates the LE/Lys cholesterol accumulation phenotype. Altogether, we shed new light on BMP biosynthesis and contribute tools to regulate BMP-dependent pathways." + } +} \ No newline at end of file diff --git a/36826132.json b/36826132.json new file mode 100644 index 0000000000000000000000000000000000000000..e9f5951431a2558fceb072575c915dedf06779b7 --- /dev/null +++ b/36826132.json @@ -0,0 +1,8 @@ +{ + "id": "36826132", + "label": 0, + "article": { + "id": "36826132", + "text": "Gestational choriocarcinoma of the ovary is an exceptionally rare and highly aggressive tumor. Preoperative diagnosis of extrauterine choriocarcinoma is difficult due to nonspecific clinical presentation and its resemblance to ectopic pregnancy. Without molecular genetic analysis, it is not possible to reliably differentiate gestational from non-gestational choriocarcinoma. Here, we present a case of a 44-year-old woman who presented to our emergency department with complaints of pelvic pain, vaginal bleeding, and amenorrhea. Because of a recent history of conservatively managed ectopic pregnancy, the patient underwent emergency laparoscopy. Right-sided salpingo-oophorectomy was performed due to intraoperatively suspected ovarian ectopic pregnancy. Histopathology results revealed the diagnosis of ovarian choriocarcinoma of possible gestational origin. It was classified as FIGO stage IV and WHO ultra-high-risk, and she underwent multi-agent chemotherapy without major complications. She has remained in complete remission after a 12-month follow-up. Considering the rarity of this diagnosis, we conducted a literature review including all published cases of suspected gestational choriocarcinomas of the ovary. We conclude that due to the rarity of this entity, preoperative differentiating between ovarian ectopic pregnancy and ovarian choriocarcinoma is extremely challenging, and without molecular genetic analysis, it is not possible to identify the genetic origin of the tumor." + } +} \ No newline at end of file diff --git a/36829773.json b/36829773.json new file mode 100644 index 0000000000000000000000000000000000000000..8f44752b0d8edb3a6214b3db7b27504c05ac60a5 --- /dev/null +++ b/36829773.json @@ -0,0 +1,8 @@ +{ + "id": "36829773", + "label": 0, + "article": { + "id": "36829773", + "text": "Protein aggregation, mitochondrial dysfunction, iron dyshomeostasis, increased oxidative damage and inflammation are pathognomonic features of Parkinson's disease (PD) and other neurodegenerative disorders characterized by abnormal iron accumulation. Moreover, the existence of positive feed-back loops between these pathological components, which accelerate, and sometimes make irreversible, the neurodegenerative process, is apparent. At present, the available treatments for PD aim to relieve the symptoms, thus improving quality of life, but no treatments to stop the progression of the disease are available. Recently, the use of multifunctional compounds with the capacity to attack several of the key components of neurodegenerative processes has been proposed as a strategy to slow down the progression of neurodegenerative processes. For the treatment of PD specifically, the necessary properties of new-generation drugs should include mitochondrial destination, the center of iron-reactive oxygen species interaction, iron chelation capacity to decrease iron-mediated oxidative damage, the capacity to quench free radicals to decrease the risk of ferroptotic neuronal death, the capacity to disrupt α-synuclein aggregates and the capacity to decrease inflammatory conditions. Desirable additional characteristics are dopaminergic neurons to lessen unwanted secondary effects during long-term treatment, and the inhibition of the MAO-B and COMPT activities to increase intraneuronal dopamine content. On the basis of the published evidence, in this work, we review the molecular basis underlying the pathological events associated with PD and the clinical trials that have used single-target drugs to stop the progress of the disease. We also review the current information on multifunctional compounds that may be used for the treatment of PD and discuss the chemical characteristics that underlie their functionality. As a projection, some of these compounds or modifications could be used to treat diseases that share common pathology features with PD, such as Friedreich's ataxia, Multiple sclerosis, Huntington disease and Alzheimer's disease." + } +} \ No newline at end of file diff --git a/36830806.json b/36830806.json new file mode 100644 index 0000000000000000000000000000000000000000..8ee1b699b178da8e0c4dc42485de8ff6f571778e --- /dev/null +++ b/36830806.json @@ -0,0 +1,8 @@ +{ + "id": "36830806", + "label": 0, + "article": { + "id": "36830806", + "text": "The visual process begins with the absorption of photons by photopigments of cone and rod photoreceptors in the retina. In this process, the signal is first amplified by a cyclic guanosine monophosphate (cGMP)-based signaling cascade and then converted into an electrical signal by cyclic nucleotide-gated (CNG) channels. CNG channels are purely ligand-gated channels whose activity can be controlled by cGMP, which induces a depolarizing Na/Ca current upon binding to the channel. Structurally, CNG channels belong to the superfamily of pore-loop cation channels and share structural similarities with hyperpolarization-activated cyclic nucleotide (HCN) and voltage-gated potassium (KCN) channels. Cone and rod photoreceptors express distinct CNG channels encoded by homologous genes. Mutations in the genes encoding the rod CNG channel ( and ) result in retinitis-pigmentosa-type blindness. Mutations in the genes encoding the cone CNG channel ( and ) lead to achromatopsia. Here, we review the molecular properties of CNG channels and describe their physiological and pathophysiological roles in the retina. Moreover, we summarize recent activities in the field of gene therapy aimed at developing the first gene therapies for CNG channelopathies." + } +} \ No newline at end of file diff --git a/36833417.json b/36833417.json new file mode 100644 index 0000000000000000000000000000000000000000..d9758538ce6e39131d25f4473c5cbac29ed6c41c --- /dev/null +++ b/36833417.json @@ -0,0 +1,8 @@ +{ + "id": "36833417", + "label": 0, + "article": { + "id": "36833417", + "text": "Limb-Girdle Muscular Dystrophy Type R1 (LGMDR1; formerly LGMD2A), characterized by progressive hip and shoulder muscle weakness, is caused by mutations in . In zebrafish, mediates Def-dependent degradation of p53 in the liver and intestines. We show that is expressed in the muscle. To model LGMDR1 in zebrafish, we generated three deletion mutants in and a positive-control mutant (Duchenne muscular dystrophy). Two partial deletion mutants showed transcript-level reduction, whereas the RNA-less mutant lacked mRNA. All homozygous mutants were developmentally-normal adult-viable animals. Mutants in were homozygous-lethal. Bathing wild-type and mutants in 0.8% methylcellulose (MC) for 3 days beginning 2 days post-fertilization resulted in significantly pronounced (20-30%) birefringence-detectable muscle abnormalities in mutant embryos. Evans Blue staining for sarcolemma integrity loss was strongly positive in homozygotes, negative in wild-type embryos, and negative in MC-treated mutants, suggesting membrane instability is not a primary muscle pathology determinant. Increased birefringence-detected muscle abnormalities in mutants compared to wild-type animals were observed following induced hypertonia by exposure to cholinesterase inhibitor, azinphos-methyl, reinforcing the MC results. These mutant fish represent a novel tractable model for studying the mechanisms underlying muscle repair and remodeling, and as a preclinical tool for whole-animal therapeutics and behavioral screening in LGMDR1." + } +} \ No newline at end of file diff --git a/36835061.json b/36835061.json new file mode 100644 index 0000000000000000000000000000000000000000..1029e48e9d70f91277aa4469cecb5c99aa471a09 --- /dev/null +++ b/36835061.json @@ -0,0 +1,8 @@ +{ + "id": "36835061", + "label": 0, + "article": { + "id": "36835061", + "text": "Achromatopsia is an autosomal recessive disorder, in which cone photoreceptors undergo progressive degeneration, causing color blindness and poor visual acuity, among other significant eye affectations. It belongs to a group of inherited retinal dystrophies that currently have no treatment. Although functional improvements have been reported in several ongoing gene therapy studies, more efforts and research should be carried out to enhance their clinical application. In recent years, genome editing has arisen as one of the most promising tools for personalized medicine. In this study, we aimed to correct a homozygous pathogenic variant in hiPSCs derived from a patient affected by achromatopsia through CRISPR/Cas9 and TALENs technologies. Here, we demonstrate high efficiency in gene editing by CRISPR/Cas9 but not with TALENs approximation. Despite a few of the edited clones displaying heterozygous on-target defects, the proportion of corrected clones with a potentially restored wild-type PDE6C protein was more than half of the total clones analyzed. In addition, none of them presented off-target aberrations. These results significantly contribute to advances in single-nucleotide gene editing and the development of future strategies for the treatment of achromatopsia." + } +} \ No newline at end of file diff --git a/36835965.json b/36835965.json new file mode 100644 index 0000000000000000000000000000000000000000..1bc0c472c7866d4231de5e1e1ca6a15dac95a2ed --- /dev/null +++ b/36835965.json @@ -0,0 +1,8 @@ +{ + "id": "36835965", + "label": 0, + "article": { + "id": "36835965", + "text": "Macular dystrophies are a heterogeneous group of genetic disorders that often severely threatens the bilateral central vision of the affected patient. While advances in molecular genetics have been instrumental in the understanding and diagnosis of these disorders, there remains significant phenotypical variation among patients within any particular subset of macular dystrophies. Electrophysiological testing remains a vital tool not only to characterize vision loss for differential diagnosis but also to understand the pathophysiology of these disorders and to monitor the treatment effect, potentially leading to therapeutic advances. This review summarizes the application of electrophysiological testing in macular dystrophies, including Stargardt disease, bestrophinopathies, X-linked retinoschisis, Sorsby fundus dystrophy, Doyne honeycomb retina dystrophy, autosomal dominant drusen, occult macular dystrophy, North Carolina macular dystrophy, pattern dystrophy, and central areolar choroidal dystrophy." + } +} \ No newline at end of file diff --git a/36841867.json b/36841867.json new file mode 100644 index 0000000000000000000000000000000000000000..457d1a9313e594458fc687eeebcea19bf7482975 --- /dev/null +++ b/36841867.json @@ -0,0 +1,8 @@ +{ + "id": "36841867", + "label": 0, + "article": { + "id": "36841867", + "text": "BACKGROUND:\nPathological myopia (PM) is closely associated with blinding ocular morbidities. Identifying biomarkers can provide clues on pathogeneses. This study aimed to identify metabolic biomarkers and underlying mechanisms in the vitreous humour (VH) of PM patients with complications.\n\nMETHODS:\nVH samples were collected from 39 PM patients with rhegmatogenous retinal detachment (RRD) (n = 23) or macular hole (MH)/myopic retinoschisis (MRS) (n = 16) and 23 controls (MH with axial length \u003c 26 mm) who underwent surgical treatment. VH metabolomic profiles were investigated using ultra-performance liquid chromatography‒mass spectrometry. The area under the receiver operating characteristic curve (AUC) was computed to identify potential biomarkers for PM diagnosis.\n\nRESULTS:\nBioinformatics analysis identified nineteen and four metabolites altered in positive and negative modes, respectively, and these metabolites were involved in tryptophan metabolism. Receiver operating characteristic analysis showed that seventeen metabolites (AUC \u003e 0.6) in the positive mode and uric acid in the negative mode represent potential biomarkers for PM with complications (AUC = 0.894). Pairwise and pathway analyses among the RRD-PM, MH/MRS-PM and control groups showed that tryptophan metabolism and uric acid were closely correlated with PM. Altered metabolites and pathways in our study were characterized by increased oxidative stress and altered energy metabolism. These results contribute to a better understanding of myopia progression with or without related complications.\n\nCONCLUSIONS:\nOur study provides metabolomic signatures and related immunopathological features in the VH of PM patients, revealing new insight into the prevention and treatment of PM and related complications." + } +} \ No newline at end of file diff --git a/36846845.json b/36846845.json new file mode 100644 index 0000000000000000000000000000000000000000..5b30c0965945f4ba7f22cdf2e0672c56adf04515 --- /dev/null +++ b/36846845.json @@ -0,0 +1,8 @@ +{ + "id": "36846845", + "label": 0, + "article": { + "id": "36846845", + "text": "Testicular choriocarcinoma is a rare and aggressive subtype of nonseminomatous germ cell tumors accounting for \u003c1% of all germ cell tumors. We report an unusual case of testicular choriocarcinoma metastasis that presents as hemorrhagic shock. Diagnosis was unsuspected and difficult with vast other potential causes. This case highlights the importance of proper foundational workup and management that ultimately led to the appropriate definitive treatment of unusual manifestations of undiagnosed metastatic choriocarcinoma in a critical patient." + } +} \ No newline at end of file diff --git a/36849851.json b/36849851.json new file mode 100644 index 0000000000000000000000000000000000000000..66b2b868324a13c15cd78a74d9a7babd2dfee595 --- /dev/null +++ b/36849851.json @@ -0,0 +1,8 @@ +{ + "id": "36849851", + "label": 0, + "article": { + "id": "36849851", + "text": "We describe a case report of pediatric pars planitis complicated with massive exudative retinal detachment (ERD). A 7-year-old presented with visual acuity (VA) in the right eye (RE) of 6/9 and in the left eye (LE) 6/15. Fundoscopy revealed BE inferior retinoschisis, vitritis and snowballs. He was treated with systemic immunosuppressants. RE retinoschisis resolved within 2 months. Three years later presented with LE VA 6/60 and total ERD. Systemic and intravitreal steroids were administered. Due to refractoriness, he underwent 360° scleral buckle and drainage of subretinal fluid. No retinal breaks or traction were detected. Five months postoperatively LE VA was 6/7.5. Long-term stable outcome was maintained. We report a challenging total ERD as a complication of pars planitis. Although extensive and non-responsive to medical therapy, complete resolution and improvement in vision was achieved with surgical intervention and systemic immunosuppression. We speculate that uncontrolled chronic vasculitic process culminated in diffuse ERD." + } +} \ No newline at end of file diff --git a/36855200.json b/36855200.json new file mode 100644 index 0000000000000000000000000000000000000000..c7c929e43cad94fdab51aaea1c61a2309b7db955 --- /dev/null +++ b/36855200.json @@ -0,0 +1,8 @@ +{ + "id": "36855200", + "label": 0, + "article": { + "id": "36855200", + "text": "BACKGROUND:\nAnaplastic thyroid cancer (ATC) is one of the most aggressive malignancies, representing less than 5% of all thyroid carcinomas. Τhe median survival is limited to months due to the resistance of ATC to surgery, radioiodine therapy, radiotherapy and chemotherapy. This review will cover novel agents involving several cellular signaling pathways including the BRAF pathway. The BRAF inhibitor vemurafenib improves survival among patients with metastatic melanoma, hairy-cell leukemia and intracranial neoplasms with BRAF gene mutations. The frequency of a BRAF (V600E) mutation in ATC is about 25%.\n\nCASE PRESENTATION:\nWe report the first case of a marked partial response to adjuvant first line monotherapy with vemurafenib in BRAF V600E-mutated ATC. The 78-year-old man showed a sustained response for 7 months, thereafter scans revealed progressive disease and the patient died 10 months after first diagnosis. This case report is accompanied by a comprehensive review of current strategies and tools for ATC treatment.\n\nCONCLUSIONS:\nThis case and the review of current data confirm the benefit of BRAF inhibition in BRAF-mutated ATC, limited by acquired resistance to targeted therapy." + } +} \ No newline at end of file diff --git a/36868127.json b/36868127.json new file mode 100644 index 0000000000000000000000000000000000000000..626c5a475414290b390706122f12c658d5235a65 --- /dev/null +++ b/36868127.json @@ -0,0 +1,8 @@ +{ + "id": "36868127", + "label": 0, + "article": { + "id": "36868127", + "text": "Tideglusib is a non-competitive GSK-3β inhibitor which contain 1,2,4-thiadiazolidine-3,5-dione moiety, and now mainly used for progressive supranuclear palsy due to the lack of some primary cognitive endpoints and secondary endpoints in a phase IIb trail for Alzheimer's disease. Additionally, insufficient evidence exists to support that there are obvious covalent bonds between Tideglusib and GSK-3β. Targeted covalent inhibition strategy could improve the binding efficiency, selectivity and duration of kinase inhibitors. Based on the above premise, two series of targeted compounds with acryloyl warheads were designed and synthesized. The kinase inhibitory activity of the selected compound 10a with better neuroprotective effect improved 2.7 fold than that of Tideglusib. After the preliminary screening of GSK-3β inhibition and neuroprotective activity, the mechanism action of the selected compound 10a was investigated in vitro and in vivo. The results confirmed that 10a with excellent selectivity among the whole tested kinases could significantly reduce the expressions of APP and p-Tau via increasing the level of p-GSK-3β. The pharmacodynamic assay in vivo showed that 10a could markedly improve the learning and memory functions in AD mice induced by AlCl combined with d-galactose. At the same time, the damage of hippocampal neurons in AD mice was obviously reduced. Accordingly, the introduction of acryloyl warheads could increase the GSK-3β inhibitory activity of 1,2,4-thiadiazolidine-3,5-dione derivatives, and the selected compound 10a deserves further research as an effective GSK-3β inhibitor for the potential treatment of AD." + } +} \ No newline at end of file diff --git a/36869283.json b/36869283.json new file mode 100644 index 0000000000000000000000000000000000000000..0c5962eec66519c8774a5c298de3659963aa9902 --- /dev/null +++ b/36869283.json @@ -0,0 +1,8 @@ +{ + "id": "36869283", + "label": 0, + "article": { + "id": "36869283", + "text": "BACKGROUND:\nSubepidermal calcified nodule (SCN) is a type of calcinosis cutis that usually occurs in children. The lesions in the SCN resemble those of other skin diseases, such as pilomatrixoma, molluscum contagiosum, and juvenile xanthogranuloma, leading to a high rate of misdiagnoses. Noninvasive in vivo imaging techniques, represented by dermoscopy and reflectance confocal microscopy (RCM), have dramatically accelerated skin cancer research over the past decade, and their applications have greatly expanded into other skin disorders. However, the features of an SCN in dermoscopy and RCM have yet to be reported previously. Combining these novel approaches with conventional histopathological examinations is a promising method for increasing diagnostic accuracy.\n\nCASE PRESENTATION:\nWe report on a case of SCN of the eyelid diagnosed with the aid of dermoscopy and RCM. A 14-year-old male patient who presented with a painless yellowish-white papule on his left upper eyelid was previously diagnosed with a common wart. Unfortunately, treatment with recombinant human interferon gel was not effective. To achieve a correct diagnosis, dermoscopy and RCM were performed. The former showed closely grouped multiple yellowish-white clods surrounded by linear vessels, and the latter exhibited hyperrefractile material nests at the dermal-epidermal junction level. The alternative diagnoses were, therefore, excluded because of in vivo characterizations. Subsequent surgical excision, histological examination, and von Kossa staining were performed. Pathology showed hyperkeratosis of the epidermis, a downward-directed basal-layer expansion, and small amorphous basophilic deposits scattered throughout the papillary dermis. The von Kossa staining confirmed calcium deposits in the lesion. An SCN was then diagnosed. During the 6-month follow-up, no relapse was observed.\n\nCONCLUSIONS:\nPatients with SCN could benefit from dermoscopy and RCM, which help achieve an accurate diagnosis. Clinicians should consider the possibility of an SCN for an adolescent patient with painless yellowish-white papules." + } +} \ No newline at end of file diff --git a/36872667.json b/36872667.json new file mode 100644 index 0000000000000000000000000000000000000000..60dbde55885a9d0061df556403fa9b89541fc24c --- /dev/null +++ b/36872667.json @@ -0,0 +1,8 @@ +{ + "id": "36872667", + "label": 0, + "article": { + "id": "36872667", + "text": "The extended use of ethambutol beyond 2 months for treating tuberculosis has increased risk of optic neuropathy. We performed a systematic review of studies evaluating optic neuropathy in extended ethambutol use since 2010 and compared the outcome with a similar systematic review (1965-2010) by Ezer et al. Literature search was conducted in PubMed, Medline, EMBASE, and Cochrane databases. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Main outcome measures were visual acuity, color vision, visual field defects, optical coherence tomography (OCT), and visual evoked potential (VEP). The JBI Critical Appraisal Checklists were used for quality assessment. Twelve studies were selected (out of 639 studies) for analysis of ethambutol optic neuropathy. Visual acuity improvement after stopping ethambutol was statistically significant. Similar improvement was not noted for other outcome measures. On comparing the results of this review with those by Ezer et al., significant improvement was noted in visual acuity, color vision, and visual field defects. Moreover, more patients reported increased optic nerve toxicity, color vision defects, and visual field defects in the present review. Hence, we conclude that the extended use of ethambutol beyond 2 months results in significant optic nerve toxicity. Further randomized controlled trials with different populations are needed to understand the magnitude of this issue." + } +} \ No newline at end of file diff --git a/36873086.json b/36873086.json new file mode 100644 index 0000000000000000000000000000000000000000..79d8034516b592ebae4440d6e714791f1a1f449b --- /dev/null +++ b/36873086.json @@ -0,0 +1,8 @@ +{ + "id": "36873086", + "label": 0, + "article": { + "id": "36873086", + "text": "Newborn screening (NBS) for classical galactosaemia (CG) facilitates early diagnosis and treatment to prevent life-threatening complications, but remains controversial, and screening protocols vary widely between programmes. False-negatives associated with first-tier screening of total galactose metabolites (TGAL) are infrequently reported; however, newborns with TGAL below the screening threshold have not been systematically studied. Following the diagnosis of CG in two siblings missed by NBS, a retrospective cohort study of infants with TGAL just below the cut-off (1.5 mmol/L blood) was conducted. Children born in New Zealand (NZ) from 2011 to 2019, with TGAL 1.0-1.49 mmol/L on NBS were identified from the national metabolic screening programme (NMSP) database, and clinical coding data and medical records were reviewed. sequencing was performed if CG could not be excluded following review of medical records. 328 infants with TGAL 1.0-1.49 mmol/L on NBS were identified, of whom 35 had ICD-10 codes relevant to CG including vomiting, poor feeding, weight loss, failure to thrive, jaundice, hepatitis, urinary tract infection, sepsis, intracranial hypertension and death. CG could be excluded in 34/35, due to documentation of clinical improvement with continued dietary galactose intake, or a clear alternative aetiology. sequencing in the remaining individual confirmed Duarte-variant galactosaemia (DG). In conclusion, undiagnosed CG appears to be rare in those with TGAL 1.0-1.49 mmol/L on NBS; however, our recent experience with missed cases is nevertheless concerning. Further work is required to establish the optimum screening strategy, to maximize the early detection of CG without excess false-positives." + } +} \ No newline at end of file diff --git a/36873091.json b/36873091.json new file mode 100644 index 0000000000000000000000000000000000000000..ee75f47c0dcc38cd46bc35b3ccadd03069505b9e --- /dev/null +++ b/36873091.json @@ -0,0 +1,8 @@ +{ + "id": "36873091", + "label": 0, + "article": { + "id": "36873091", + "text": "We report successful heart transplantation in a phosphoglucomutase 1 deficient (PGM1-CDG) patient. She presented with facial dysmorphism, bifid uvula and structural heart defects. Newborn screening was positive for classic galactosemia. The patient was on a galactose-free diet for 8 months. Eventually, whole exome sequencing excluded the galactosemia and revealed PGM1-CDG. Oral D-galactose therapy was started. Rapid deterioration of the progressive dilated cardiomyopathy prompted heart transplantation at the age of 12 months. Cardiac function was stable in the first 18 months of follow-up, and hematologic, hepatic, and endocrine laboratory findings improved during D-galactose therapy. The latter therapy improves several systemic symptoms and biochemical abnormalities in PGM1-CDG but does not correct the heart failure related to cardiomyopathy. Heart transplantation has so far only been described in DOLK-CDG." + } +} \ No newline at end of file diff --git a/36875645.json b/36875645.json new file mode 100644 index 0000000000000000000000000000000000000000..c6ff11fa071b66484f6bc259f24e25ca6365e3ac --- /dev/null +++ b/36875645.json @@ -0,0 +1,8 @@ +{ + "id": "36875645", + "label": 0, + "article": { + "id": "36875645", + "text": "Neurodegenerative Diseases (NDDs) are a group of disorders that cause progressive deficits of neuronal function. Recent evidence argues that sphingolipid metabolism is affected in a surprisingly broad set of NDDs. These include some lysosomal storage diseases (LSDs), hereditary sensory and autonomous neuropathy (HSAN), hereditary spastic paraplegia (HSP), infantile neuroaxonal dystrophy (INAD), Friedreich's ataxia (FRDA), as well as some forms of amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Many of these diseases have been modeled in melanogaster and are associated with elevated levels of ceramides. Similar changes have also been reported in vertebrate cells and mouse models. Here, we summarize studies using fly models and/or patient samples which demonstrate the nature of the defects in sphingolipid metabolism, the organelles that are implicated, the cell types that are initially affected, and potential therapeutics for these diseases." + } +} \ No newline at end of file diff --git a/36879687.json b/36879687.json new file mode 100644 index 0000000000000000000000000000000000000000..166094d77bf6ae8d31864ab817d6ec9819c42a81 --- /dev/null +++ b/36879687.json @@ -0,0 +1,8 @@ +{ + "id": "36879687", + "label": 0, + "article": { + "id": "36879687", + "text": "A rare cause of cerebral hemorrhage is the metastasis of choriocarcinoma from gynecology. Herein, we report a case of a patient with brain metastasis of choriocarcinoma with cerebral hemorrhage. A 14-year-old female who had undergone surgery for a hydatidiform molar pregnancy presented with a disturbance of consciousness due to cerebral hemorrhage. Imaging studies revealed the presence of a cerebral aneurysm and several mass lesions in the lung field, and high serum beta-human chorionic gonadotropin level was confirmed. Thus, we suspected cerebral hemorrhage caused by brain metastasis of choriocarcinoma. She went into a coma, and an emergency craniotomy was performed to remove the hematoma and aneurysm. The pathology of the aneurysm was pseudoaneurysm due to the rupture of the vascular wall caused by increasing metastatic cells from choriocarcinoma in the cerebrovascular wall. Therefore, multidrug chemotherapy was immediately initiated. The choriocarcinoma, including the metastatic lesions, is in remission. To improve the outcome of choriocarcinoma, it must be diagnosed early, and treatment should be immediately started. Moreover, neurosurgeons should be aware of such diseases and consider them as one of the differential diagnoses, particularly in females of reproductive age with cerebral hemorrhage." + } +} \ No newline at end of file diff --git a/36883111.json b/36883111.json new file mode 100644 index 0000000000000000000000000000000000000000..c9ca4bbab9e2142e2c137e72f5e9b32af8b547de --- /dev/null +++ b/36883111.json @@ -0,0 +1,8 @@ +{ + "id": "36883111", + "label": 0, + "article": { + "id": "36883111", + "text": "Hairy cell leukemia (HCL) is a distinct lymphoproliferative disorder with unique circulating lymphocyte morphology. It is now regarded as an indolent disease yet treatable with purine analogs. We are going to present a complete long-term clinical and prognostic report of our HCL patients as a large cohort in Iran. All patients diagnosed with HCL, according to the World Health Organization (WHO) criteria, were enrolled in this study. They were referred to our academic center between 1995 and 2020. Treatment with a daily cladribine regimen was initiated as indicated and patients were followed. Survival data and clinical outcomes of patients were calculated. A total of 50 patients were studied (76% male). The median time to treatment was 4.8 months and complete remission was achieved in 92% of patients. Nine patients (18%) experienced relapse with a median time to relapse of 47 months. After a median follow-up of 51 months, the median OS was not reached and after 234 months, the overall survival rate was 86%. Survival was worse in patients with non-classic HCL (vHCL) compared to classic HCL. Our long-term follow-up data confirmed the favorable outcomes of Iranian HCL patients with cladribine and provide a useful viewpoint of the disease." + } +} \ No newline at end of file diff --git a/36890515.json b/36890515.json new file mode 100644 index 0000000000000000000000000000000000000000..29a470a6ec779c15b8b78ab740a4d632522f5548 --- /dev/null +++ b/36890515.json @@ -0,0 +1,8 @@ +{ + "id": "36890515", + "label": 0, + "article": { + "id": "36890515", + "text": "BACKGROUND:\nPrimary pulmonary choriocarcinoma (PPC) is a highly malignant intrapulmonary tumor with a notorious prognosis. Few clinical studies have been undertaken to investigate the clinical characteristics and prognosis of PPC.\n\nMATERIAL AND METHODS:\nWe systematically conducted a retrospective analysis of patients with PPC in the literature published in PubMed and CNKI databases until March 31, 2022. The primary outcome was all-cause mortality. Survival curves were depicted using the Kaplan‒Meier method and compared using the stratified log-rank test. A Cox proportional hazards model was used to estimate the prognostic factors.\n\nRESULTS:\nA total of 68 patients were included, which consisted of 32 females and 36 males, with an average age of (44.5 ± 16.8) years old, ranging from 19 to 77 years. The clinical characteristics were mostly cough (49.2%), dyspnea (22.2%), hemoptysis (39.7%) and chest pain (39.7%). Kaplan‒Meier analysis showed that sex, age, hemoptysis, metastasis and treatment combining surgery with chemotherapy had a significant effect on survival. There were no effects on other outcomes. Furthermore, univariate and multivariable Cox regression analyses showed that the impact of the treatment combining surgery with chemotherapy on OS showed independent prognostic significance.\n\nCONCLUSION:\nPPC is a rare disease that lacks specific clinical features. Early diagnosis with optimal management is a significant goal. Surgery followed by adjuvant chemotherapy may be the best treatment for PPC." + } +} \ No newline at end of file diff --git a/36894028.json b/36894028.json new file mode 100644 index 0000000000000000000000000000000000000000..273c1c2a6312c0a4de6a513f95ab1bcff1748fb2 --- /dev/null +++ b/36894028.json @@ -0,0 +1,8 @@ +{ + "id": "36894028", + "label": 0, + "article": { + "id": "36894028", + "text": "Ferroptosis is a type of regulated cell death characterized by intracellular accumulation of iron and reactive oxygen species, inhibition of system Xc-, glutathione depletion, nicotinamide adenine dinucleotide phosphate oxidation and lipid peroxidation. Since its discovery and characterization in 2012, many efforts have been made to reveal the underlying mechanisms, modulating compounds, and its involvement in disease pathways. Ferroptosis inducers include erastin, sorafenib, sulfasalazine and glutamate, which, by inhibiting system Xc-, prevent the import of cysteine into the cells. RSL3, statins, Ml162 and Ml210 induce ferroptosis by inhibiting glutathione peroxidase 4 (GPX4), which is responsible for preventing the formation of lipid peroxides, and FIN56 and withaferin trigger GPX4 degradation. On the other side, ferroptosis inhibitors include ferrostatin-1, liproxstatin-1, α-tocopherol, zileuton, FSP1, CoQ10 and BH4, which interrupt the lipid peroxidation cascade. Additionally, deferoxamine, deferiprone and N-acetylcysteine, by targeting other cellular pathways, have also been classified as ferroptosis inhibitors. Increased evidence has established the involvement of ferroptosis in distinct brain diseases, including Alzheimer's, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, multiple sclerosis, and Friedreich's ataxia. Thus, a deep understanding of how ferroptosis contributes to these diseases, and how it can be modulated, can open a new window of opportunities for novel therapeutic strategies and targets. Other studies have shown a sensitivity of cancer cells with mutated RAS to ferroptosis induction and that chemotherapeutic agents and ferroptosis inducers synergize in tumor treatment. Thus, it is tempting to consider that ferroptosis may arise as a target mechanistic pathway for the treatment of brain tumors. Therefore, this work provides an up-to-date review on the molecular and cellular mechanisms of ferroptosis and their involvement in brain diseases. In addition, information on the main ferroptosis inducers and inhibitors and their molecular targets is also provided." + } +} \ No newline at end of file diff --git a/36903645.json b/36903645.json new file mode 100644 index 0000000000000000000000000000000000000000..b6dd416d00508e400e8ddf62e74738762113c5f8 --- /dev/null +++ b/36903645.json @@ -0,0 +1,8 @@ +{ + "id": "36903645", + "label": 0, + "article": { + "id": "36903645", + "text": "In the last few decades, there has been a growing interest in Bruton's tyrosine kinase (BTK) and the compounds that target it. BTK is a downstream mediator of the B-cell receptor (BCR) signaling pathway and affects B-cell proliferation and differentiation. Evidence demonstrating the expression of BTK on the majority of hematological cells has led to the hypothesis that BTK inhibitors (BTKIs) such as ibrutinib can be an effective treatment for leukemias and lymphomas. However, a growing body of experimental and clinical data has demonstrated the significance of BTK, not just in B-cell malignancies, but also in solid tumors, such as breast, ovarian, colorectal, and prostate cancers. In addition, enhanced BTK activity is correlated with autoimmune disease. This gave rise to the hypothesis that BTK inhibitors can be beneficial in the therapy of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), Sjögren's syndrome (SS), allergies, and asthma. In this review article, we summarize the most recent findings regarding this kinase as well as the most advanced BTK inhibitors that have been developed to date and their clinical applications mainly in cancer and chronic inflammatory disease patients." + } +} \ No newline at end of file diff --git a/36906942.json b/36906942.json new file mode 100644 index 0000000000000000000000000000000000000000..e142f94cb564f2725ca9f54e2cad216d5203311d --- /dev/null +++ b/36906942.json @@ -0,0 +1,8 @@ +{ + "id": "36906942", + "label": 0, + "article": { + "id": "36906942", + "text": "INTRODUCTION:\nSplenic B-cell lymphomas are rare and understudied entities. Splenectomy is frequently required for specific pathological diagnosis in patients with splenic B-cell lymphomas other than classical hairy cell leukemia (cHCL), and can be effective and durable therapy. Our study investigated the diagnostic and therapeutic role of splenectomy for non-cHCL indolent splenic B-cell lymphomas.\n\nMETHODS:\nObservational study of patients with non-cHCL splenic B-cell lymphoma undergoing splenectomy between 1 August 2011 and 1 August 2021 at the University of Rochester Medical Center. The comparison cohort was patients categorized as having non-cHCL splenic B-cell lymphoma who did not undergo splenectomy.\n\nRESULTS:\nForty-nine patients (median age 68 years) had splenectomy (SMZL n = 33, HCLv n = 9, SDRPL n = 7) with median follow up of 3.9 years post splenectomy. One patient had fatal post-operative complications. Post-operative hospitalization was ≤ 4 days for 61% and ≤ 10 days for 94% of patients. Splenectomy was initial therapy for 30 patients. Of the 19 patients who had previous medical therapy, splenectomy changed their lymphoma diagnosis in 5 (26%). Twenty-one patients without splenectomy were clinically categorized as having non-cHCL splenic B-cell lymphoma. Nine required medical treatment for progressive lymphoma and of these 3 (33%) required re-treatment for lymphoma progression compared to 16% of patients following first line splenectomy.\n\nCONCLUSION:\nSplenectomy is useful for the diagnosis of non-cHCL splenic B-cell lymphomas with comparable risk/benefit profile and remission duration to medical therapy. Patients with suspected non-cHCL splenic lymphomas should be considered for referral to a high-volume center with experience in performing splenectomies for definitive diagnosis and treatment." + } +} \ No newline at end of file diff --git a/36911665.json b/36911665.json new file mode 100644 index 0000000000000000000000000000000000000000..fd4b4a768a1005f9c8d6a76213c7125a0d24ea2c --- /dev/null +++ b/36911665.json @@ -0,0 +1,8 @@ +{ + "id": "36911665", + "label": 0, + "article": { + "id": "36911665", + "text": "Hemolytic-uremic syndrome (HUS) can occur as a complication of an infection with Shiga-toxin (Stx)-producing . Patients typically present with acute kidney injury, microangiopathic hemolytic anemia and thrombocytopenia. There is evidence that Stx-induced renal damage propagates a pro-inflammatory response. To date, therapy is limited to organ-supportive strategies. Bruton's tyrosine kinase (BTK) plays a pivotal role in recruitment and function of immune cells and its inhibition was recently shown to improve renal function in experimental sepsis and lupus nephritis. We hypothesized that attenuating the evoked immune response by BTK-inhibitors (BTKi) ameliorates outcome in HUS. We investigated the effect of daily oral administration of the BTKi ibrutinib (30 mg/kg) and acalabrutinib (3 mg/kg) in mice with Stx-induced HUS at day 7. After BTKi administration, we observed attenuated disease progression in mice with HUS. These findings were associated with less BTK and downstream phospholipase-C-gamma-2 activation in the spleen and, subsequently, a reduced renal invasion of BTK-positive cells including neutrophils. Only ibrutinib treatment diminished renal invasion of macrophages, improved acute kidney injury and dysfunction (plasma levels of NGAL and urea) and reduced hemolysis (plasma levels of bilirubin and LDH activity). In conclusion, we report here for the first time that BTK inhibition attenuates the course of disease in murine HUS. We suggest that the observed reduction of renal immune cell invasion contributes - at least in part - to this effect. Further translational studies are needed to evaluate BTK as a potential target for HUS therapy to overcome currently limited treatment options." + } +} \ No newline at end of file diff --git a/36912866.json b/36912866.json new file mode 100644 index 0000000000000000000000000000000000000000..07373b40280d730af339e6da00a301b8e68b2e1d --- /dev/null +++ b/36912866.json @@ -0,0 +1,8 @@ +{ + "id": "36912866", + "label": 0, + "article": { + "id": "36912866", + "text": "Bruton's tyrosine kinase (BTK) plays an essential role in B-cell receptor (BCR)-mediated signaling as well as the downstream signaling pathway for Fc receptors (FcRs). Targeting BTK for B-cell malignancies by interfering with BCR signaling has been clinically validated by some covalent inhibitors, but suboptimal kinase selectivity may lead to some adverse effects, which also makes the clinical development of autoimmune disease therapy more challenging. The structure-activity relationship (SAR) starting from zanubrutinib (-) leads to a series of highly selective BTK inhibitors, in which - is located in the ATP binding pocket and has similar hinge binding to ATP but exhibits high selectivity over other kinases (EGFR, Tec, etc.). With an excellent pharmacokinetic profile as well as demonstrated efficacy studies in oncology and autoimmune disease models, - has been declared a preclinical candidate. However, - showed an inferior toxicity profile compared to that of -." + } +} \ No newline at end of file diff --git a/36920149.json b/36920149.json new file mode 100644 index 0000000000000000000000000000000000000000..b8c1bf946cc1a8dfbed28edd618fbb3ae2532358 --- /dev/null +++ b/36920149.json @@ -0,0 +1,8 @@ +{ + "id": "36920149", + "label": 0, + "article": { + "id": "36920149", + "text": "Niemann-Pick, type C (NPC) is a fatal, neurovisceral lysosomal storage disorder with progressive neurodegeneration and no FDA-approved therapy. Significant efforts have been focused on the development of therapeutic options, and 2-hydroxypropyl-β-cyclodextrin (HP--CD) has emerged as a promising candidate. In cell culture, HP--CD ameliorates cholesterol storage in endo/lysosomes, a hallmark of the disorder. Furthermore, in animal studies, treatment with HP--CD delays neurodegeneration and extends lifespan. While HP--CD has been promising and , a clear understanding of the mechanism(s) of action is lacking. Utilizing a neuron-like cell culture model of SH-SY5Y differentiated cells and U18666A to induce the NPC phenotype, we report here a large-scale mass-spectrometry-based proteomic study to evaluate proteome changes upon treatment with these small molecules. In this study, we show that differentiated SH-SY5Y cells display morphological changes representative of neuronal-like cells along with increased levels of proliferation markers. Inhibition of the NPC cholesterol transporter 1 protein by U18666A resulted in increased levels of known NPC markers including SCARB2/LIMP2 and LAMP2. Finally, investigation of HP--CD treatment was performed where we observe that, although HP--CD reduces cholesterol storage, levels of NPC1 and NPC2 are not normalized to control levels. This finding further supports the need for a proteostasis strategy for NPC drug development. Moreover, proteins that were dysregulated in the U18666A model of NPC and normalized to control levels suggest that HP--CD promotes exocytosis in this neuron-like model. Utilizing state of the art mass spectrometry analysis, these data demonstrate newly reported changes with pharmacological perturbations related to NPC disease and provide insight into the mechanisms of HP--CD as a potential therapeutic." + } +} \ No newline at end of file diff --git a/36927170.json b/36927170.json new file mode 100644 index 0000000000000000000000000000000000000000..27b5c00d103325e130809b055658d4f41d5ab446 --- /dev/null +++ b/36927170.json @@ -0,0 +1,8 @@ +{ + "id": "36927170", + "label": 0, + "article": { + "id": "36927170", + "text": "BACKGROUND:\nX-linked retinoschisis (XLRS) is a rare inherited bilateral retinal degeneration caused by mutations in RS1 gene, occurring exclusively in men. Various ocular complications associated with XLRS are reported, and angle closure glaucoma in these eyes is one such complication that is refractory and needs surgery for intraocular pressure control. Glaucoma surgery in these eyes often results in refractory malignant glaucoma with its serious sequelae. Several surgical modifications to prevent this complication have been tried with no or limited success.\n\nMETHODOLOGY:\nIn this report, we present a case of XLRS in a young male with a 22-year follow-up. We have described the natural history and progression of retinal disease and glaucoma.\n\nRESULTS:\nRefractory angle closure glaucoma in our patient was treated with core vitrectomy, phacoemulsification with intraocular lens implantation, and irido-zonulo-hyaloido-vitrectomy. This helped in successful deepening of anterior chamber, good IOP control, and preventing malignant glaucoma.\n\nCONCLUSION:\nOur case highlights the role of vitrectomy in managing the secondary angle closure glaucoma in eyes with X-LRS." + } +} \ No newline at end of file diff --git a/36931901.json b/36931901.json new file mode 100644 index 0000000000000000000000000000000000000000..8b4915c39795a879e201a180084e7a663ccdec4a --- /dev/null +++ b/36931901.json @@ -0,0 +1,8 @@ +{ + "id": "36931901", + "label": 0, + "article": { + "id": "36931901", + "text": "INTRODUCTION:\nHairy cell leukemia (HCL) is a rare subtype of indolent lymphoid leukemia originating from a mature B lymphocyte. The standard first-line treatment for classic HCL, and HCL variant (HCLv), consists of purine nucleoside analogs (PNA), with or without rituximab. However, almost half of patients relapse and require subsequent therapy.\n\nAREAS COVERED:\nThis article summarizes recent achievements in the treatment of relapsed and refractory HCL. A literature search was conducted of the PubMed and MEDLINE database for articles in English. Publications from 2010 through January 2023 were scrutinized. The search terms used were hairy cell leukemia in conjunction with BRAF inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, CD20 monoclonal antibodies, relapsed, refractory and variant.The growing understanding of HCL biology has allowed the design of several new, chemotherapy-free targeted drugs which have demonstrated encouraging efficacy in early clinical trials.\n\nEXPERT OPINION:\nNovel drugs will soon be available to assist standard therapy for HCL and HCLv among patients with suboptimal results following PNA treatment. In particular, the BRAF inhibitors vemurafenib and dabrafenib, with or without rituximab, have revolutionized treatment of patients with relapsed or refractory disease." + } +} \ No newline at end of file diff --git a/36933007.json b/36933007.json new file mode 100644 index 0000000000000000000000000000000000000000..2018d634e506a2daebda160152757c3b10f73246 --- /dev/null +++ b/36933007.json @@ -0,0 +1,8 @@ +{ + "id": "36933007", + "label": 0, + "article": { + "id": "36933007", + "text": "Depression is one of the most frequent neuropsychiatric symptoms in progressive supranuclear palsy (PSP), a four-repeat tauopathy and most common atypical parkinsonian disorder, but its pathophysiology and pathogenesis are poorly understood. Pubmed/Medline was systematically analyzed until January 2023, with focus on the prevalence, major clinical features, neuroimaging findings and treatment options of depression in PSP. The average prevalence of depression in PSP is around 50%; it does usually not correlate with most other clinical parameters. Depression is associated with multi-regional patterns of morphometric gray matter variations, e.g., reduced thickness of temporo-parieto-occipital cortices, and altered functional orbitofrontal and medial frontal circuits with disturbances of mood-related brain networks. Unfortunately, no specific neuropathological data about depression in PSP are available. Antidepressive and electroconvulsive therapies are effective in improving symptoms; the efficacy of transcranial stimulation needs further confirmation. Depression in PSP is a common symptom, related to multi-regional patterns of cerebral disturbances and complex pathogenic mechanisms that deserve further elucidation as a basis for adequate treatment to improve the quality of life in this fatal disease." + } +} \ No newline at end of file diff --git a/36936798.json b/36936798.json new file mode 100644 index 0000000000000000000000000000000000000000..203980a8b06c046e8f1bc311b651d7ef4f2269e0 --- /dev/null +++ b/36936798.json @@ -0,0 +1,8 @@ +{ + "id": "36936798", + "label": 0, + "article": { + "id": "36936798", + "text": "PURPOSE:\nThis study sought to determine if children with childhood apraxia of speech (CAS) plus another major diagnosis (CAS+) are equivalent in communication and motor profiles to those with a primary diagnosis of CAS and no indication or report of any other diagnosis (CAS-Primary).\n\nMETHOD:\nThis retrospective case-control study included a chart review of 143 children who were suspected of having CAS at Children's Hospital-Wisconsin between 1998 and 2004. Participants were between 30 and 127 months old and included 107 males. Participants were assigned to the suspected CAS-Primary group ( = 114) if they had characteristics of CAS but no other major diagnosis (e.g., galactosemia) and to the CAS+ group ( = 29) if a comorbid diagnosis was present. Groups were compared across demographic, communication, and motor characteristics.\n\nRESULTS:\nChildren with CAS+ evidenced more severe motor profiles than those with CAS-Primary, χ = (1, = 122) = 4.952, = .026, and a small-to-medium effect size (Φ = .201). On average, communication profiles also tended to be more severe among those with CAS+ wherein receptive language was poorer and phonemic inventories were smaller than those with CAS-Primary.\n\nCONCLUSIONS:\nThese retrospective data suggest that comorbid diagnosis may play an important role in communication and motor development in children with suspected CAS. These exploratory findings should motivate future prospective studies that consider the role of concomitant diagnoses in symptom profile and response to treatment in children with CAS." + } +} \ No newline at end of file diff --git a/36937509.json b/36937509.json new file mode 100644 index 0000000000000000000000000000000000000000..83bd12564d9c17827537f76a0a834d331157cd63 --- /dev/null +++ b/36937509.json @@ -0,0 +1,8 @@ +{ + "id": "36937509", + "label": 0, + "article": { + "id": "36937509", + "text": "We report a 63-year-old female patient with progressive supranuclear palsy (PSP). She presented predominant postural instability and \"saccadic ping-pong gaze\" (SPPG). She had unprovoked falls recurrently within a year from the onset of gait disturbance. She tended to fall backward with eye closure but had no freezing of gait on examination. She showed no signs of nuchal dystonia, limb tremor, rigidity, spasticity, or ataxia. The dopaminergic response was negative. On the initial examination, her vertical eye movements were normal, but frequent macro square wave jerks and SPPG were observed. SPPG consisted of short-cycle, horizontal conjugate irregular pendular oscillations of the eye position from the midpoint with superimposed small saccades. SPPG was observed usually in the dark, not in the daylight, and with eye closure by using electrooculogram and infrared charge-coupled device imaging. One and a half years after the first examination, she was diagnosed as probable PSP with vertical supranuclear gaze palsy. SPPG was first described in patients who are unconscious by Johkura in 1998 as a \"saccadic\" variant of \"ping-pong gaze (PPG).\" PPG, short-cycle periodic alternating gaze, has been described in comatose patients since 1967. On the other hand, abnormal eye movement, which looks the same as SPPG in coma, has been described in conscious patients with PSP or spinocerebellar degeneration (SCD) in Japanese literature since 1975. However, it has been called \"transient alternating saccades (TAS).\" Nowadays, we believe it is more appropriate to call this abnormal eye movement \"SPPG\" instead of TAS. Here, we propose that PSP, a neuro-degenerative disease, should be added as one of the etiologies of SPPG. We discuss the differences between PPG/SPPG in coma and SPPG in PSP and the possible pathophysiological mechanism of SPPG in relation to cerebellar oculomotor dysfunctions." + } +} \ No newline at end of file diff --git a/36942146.json b/36942146.json new file mode 100644 index 0000000000000000000000000000000000000000..365aa699d705ae9992ffbb91da2ca9f33b6ef568 --- /dev/null +++ b/36942146.json @@ -0,0 +1,8 @@ +{ + "id": "36942146", + "label": 0, + "article": { + "id": "36942146", + "text": "Pilomatricoma, formerly known as calcifying epithelioma of Malherbe, is a rare, benign, annexic skin tumor developed from the cells of the pilar matrix. The cure without recurrence is the rule after complete surgical excision. Clinical diagnosis is challenging. Actually, differential diagnosis include malignant pilomatricoma or trichomatrical carcinoma with significant aggressive potential. However, the diagnosis of pilomatricoma must remain clinical and be confirmed histologically. We report the rare case of a pilomatricoma, in an unusual location in the thigh." + } +} \ No newline at end of file diff --git a/36943212.json b/36943212.json new file mode 100644 index 0000000000000000000000000000000000000000..78be1cf0d5f15ade4034cb885950573d52ad971e --- /dev/null +++ b/36943212.json @@ -0,0 +1,8 @@ +{ + "id": "36943212", + "label": 0, + "article": { + "id": "36943212", + "text": "IMPORTANCE:\nChronic lymphocytic leukemia (CLL), defined by a minimum of 5 × 109/L monoclonal B cells in the blood, affects more than 200 000 people and is associated with approximately 4410 deaths in the US annually. CLL is associated with an immunocompromised state and an increased rate of complications from infections.\n\nOBSERVATIONS:\nAt the time of diagnosis, the median age of patients with CLL is 70 years, and an estimated 95% of patients have at least 1 medical comorbidity. Approximately 70% to 80% of patients with CLL are asymptomatic at the time of diagnosis, and one-third will never require treatment for CLL. Prognostic models have been developed to estimate the time to first treatment and the overall survival, but for patients who are asymptomatic, irrespective of disease risk category, clinical observation is the standard of care. Patients with symptomatic disease who have bulky or progressive lymphadenopathy or hepatosplenomegaly and those with a low neutrophil count, anemia, or thrombocytopenia and/or symptoms of fever, drenching night sweats, and weight loss (B symptoms) should be offered treatment. For these patients, first-line treatment consists of a regimen containing either a covalent Bruton tyrosine kinase (BTK) inhibitor (acalabrutinib, zanubrutinib, or ibrutinib) or a B-cell leukemia/lymphoma 2 (BCL2) inhibitor (venetoclax). There is no evidence that starting either class before the other improves outcomes. The covalent BTK inhibitors are typically used indefinitely. Survival rates are approximately 88% at 4 years for acalabrutinib, 94% at 2 years for zanubrutinib, and 78% at 7 years for ibrutinib. Venetoclax is prescribed in combination with obinutuzumab, a monoclonal anti-CD20 antibody, in first-line treatment for 1 year (overall survival, 82% at 5-year follow-up). A noncovalent BTK inhibitor, pitobrutinib, has shown an overall response rate of more than 70% after failure of covalent BTK inhibitors and venetoclax. Phosphoinositide 3'-kinase (PI3K) inhibitors (idelalisib and duvelisib) can be prescribed for disease that progresses with BTK inhibitors and venetoclax, but patients require close monitoring for adverse events such as autoimmune conditions and infections. In patients with multiple relapses, chimeric antigen receptor T-cell (CAR-T) therapy with lisocabtagene maraleucel was associated with a 45% complete response rate. The only potential cure for CLL is allogeneic hematopoietic cell transplant, which remains an option after use of targeted agents.\n\nCONCLUSIONS AND RELEVANCE:\nMore than 200 000 people in the US are living with a CLL diagnosis, and CLL causes approximately 4410 deaths each year in the US. Approximately two-thirds of patients eventually need treatment. Highly effective novel targeted agents include BTK inhibitors such as acalabrutinib, zanubrutinib, ibrutinib, and pirtobrutinib or BCL2 inhibitors such as venetoclax." + } +} \ No newline at end of file diff --git a/36945167.json b/36945167.json new file mode 100644 index 0000000000000000000000000000000000000000..f497f98445b9ae07f1b118aad048d33cd6492601 --- /dev/null +++ b/36945167.json @@ -0,0 +1,8 @@ +{ + "id": "36945167", + "label": 0, + "article": { + "id": "36945167", + "text": "OBJECTIVE:\nTo determine the outcomes of allogeneic HSCT in children with primary immune system disorders (PID).\n\nSTUDY DESIGN:\nDescriptive Cross-sectional study. Place and Duration of the Study: Armed Forces bone marrow transplant centre / National Institute of Bone Marrow Transplant (AFBMTC / NIBMT), Rawalpindi, Pakistan, from October 2012 to December 2021.\n\nMETHODOLOGY:\nData of all cases undergoing HSCT for immune system disorders were analysed for variables affecting outcome and overall survival in the first 180 days after allogeneic HSCT. All patients presenting to AFBMTC / NIBMT with PID, age \u003c12 years. Patients with organ dysfunction secondary to repeated infections were excluded from the study. Data of all patients and their donors undergoing HSCT for immune system disorders were analysed for variables affecting outcome and overall survival in the first 180 days after allogeneic bone marrow transplant. Neutrophil engraftment was defined as absolute neutrophil count ≥0.5 × 109/L for 3 consecutive days, while platelet engraftment as platelet count ≥20 × 109/L without platelet transfusion for one week. Overall survival (OS) was taken as time from the date of HSCT till day + 180 post-transplant.\n\nRESULTS:\nA total of 42children including 29 boys and 13 girls underwent HSCT for PID. The mean age was 2.1±2.8 years. Underlying diagnosis was haemophagocytic lymphohistiocytosis (HLH), severe immune deficiency (SCID), leukocyte adhesion defect (LAD), X-linked agammaglobulinemia, chronic granulomatous disease (CGD) and Job's syndrome in 18 (42.9%), 16 (38.1%), 3(7.1%), 2 (4.8%), 2 (4.8%) and 1 (2.4%) patients respectively. Thirty-one (73.8%) children had fully HLA-matched donors while 11 (26.2%) had haplo-matched donors. Major immediate post-transplant complications were febrile neutropenia, mucositis and SOS/VOD in 31 (73.8%), 9 (21.4%) and 4 (10.0%) cases, respectively. Eight (19.0%) had CMV reactivation, acute GVHD was seen in 17 (40.4%) cases, while 1 (2.3%) case had chronic GVHD. Twelve (28.6%) patients died, out of which 5 had graft failure, 3 had VOD, 2 had pneumonia, 1 had severe GVHD, and 1 died due to seizures. Overall survival (OS) in this study was 71.4% with survival reaching up to 80.6% in fully matched HSCT.\n\nCONCLUSION:\nHLH and SCID were the commonest immune disorders requiring HSCT. Graft failure leading to neutropenic sepsis was the commonest cause of mortality. OS was better in fully matched HSCT as compared to haplo-identical HSCT.\n\nKEY WORDS:\nImmune deficiency, Severe combined immunodeficiency, Haematopoietic stem cell transplantation." + } +} \ No newline at end of file diff --git a/36945313.json b/36945313.json new file mode 100644 index 0000000000000000000000000000000000000000..2ec5d8e7381a265ccc56cc7e80b608fe536703ef --- /dev/null +++ b/36945313.json @@ -0,0 +1,8 @@ +{ + "id": "36945313", + "label": 0, + "article": { + "id": "36945313", + "text": "BACKGROUND:\nProgressive Myoclonic Epilepsy (PME) is a heterogeneous group of pathologies associating epileptic seizures and other neurological and non-neurological disorders.\n\nOBJECTIVES:\nWe aim to characterize patients with symptoms of PME and identify the underlying genetic disorder.\n\nMETHODS:\nAfter informed consent, the patients seen in the protocol for hereditary neurological diseases and presenting signs of epilepsy without a secondary cause were clinically evaluated over a three-year period in the Department of Neurology of the CHU Point \"G\". EEG, brain imaging and laboratory tests were performed to consolidate our diagnosis. DNA was extracted for genetic analysis.\n\nRESULTS:\n141 families including five families with PME totaling eight cases were enrolled. The predominant symptoms in our patients were myoclonus in 87.5% (N = 8), followed by GTCS and cognitive impairment in 50%, each. A notion of parental consanguinity was found in 60% and autosomal recessive transmission evoked in 80% (N = 5). The EEG was pathological in 62.5% and imaging showed ponto-cerebellar atrophy in 25% (N = 8). The combination of sodium valproate and clonazepam was the main treatment. One case of death was recorded.\n\nCONCLUSION:\nWe report cases of PME in Mali with a possibility of discovering new genes." + } +} \ No newline at end of file diff --git a/36964509.json b/36964509.json new file mode 100644 index 0000000000000000000000000000000000000000..db312d420de1ba5885109212ba4fa7b465e8e6d8 --- /dev/null +++ b/36964509.json @@ -0,0 +1,8 @@ +{ + "id": "36964509", + "label": 0, + "article": { + "id": "36964509", + "text": "BACKGROUND:\nThe coinfection between cytomegalovirus (CMV) and either human herpesvirus-6 (HHV-6) or HHV-7 in renal transplant recipients is well known; however, there have been few reports of coinfection of CMV associated with HHV-8. This paper presents a first case of acute gastric ulcer and duodenitis associated with CMV and HHV-8 coinfection after renal transplantation.\n\nCASE PRESENTATION:\nA 33-year-old male with a history of kidney transplantation was admitted to hospital because of postural epigastric pain. The recipient was CMV seropositive prior to transplantation and received trimethoprim-sulfamethoxazole without universal prophylaxis. Approximately 5 months after renal transplant, the recipient complained postural epigastric pain. An endoscopy revealed diffuse ulcerative lesions in the lower body and in the antrum of the stomach, as well as several erythematous mucosal lesions in the duodenum. Histopathologic examination identified CMV inclusions consistent with invasive CMV disease and immunohistochemical staining showed positive results for HHV-8 and CMV. No tumorous diseases such as Kaposi's sarcoma were detected. After 3 weeks of intravenous ganciclovir treatment, we observed that serum CMV PCR remained within the normal range and clinical symptoms improved. A follow-up endoscopy performed 3 weeks later showed that the severity of the above mentioned lesions had improved.\n\nCONCLUSIONS:\nWe report the first case of a renal transplant recipient diagnosed with acute gastric ulcer and duodenitis associated with coinfection of CMV and HHV-8. Ganciclovir appears to be effective in diseases associated with coinfection of CMV and HHV-8." + } +} \ No newline at end of file diff --git a/36967646.json b/36967646.json new file mode 100644 index 0000000000000000000000000000000000000000..b2580f157fab357f0cb47d91bc154406b61e9be5 --- /dev/null +++ b/36967646.json @@ -0,0 +1,8 @@ +{ + "id": "36967646", + "label": 0, + "article": { + "id": "36967646", + "text": "BACKGROUND:\nMycosis fungoides (MF) is the most common cutaneous T-cell lymphoma. Skin-directed therapies, including phototherapy, are the first-line treatment modalities. Psoralen plus ultraviolet A light photochemotherapy (PUVA) is quite effective in controlling the disease; however, long-term adverse effects, particularly carcinogenesis, are the cons of this treatment.\n\nOBJECTIVE:\nThere are various studies on the negative impact of PUVA on skin cancer in patients with autoimmune skin diseases. The data on the long-term effects of phototherapy on MF patients are scarce.\n\nMETHODS:\nAll MF cases that received PUVA alone or combined with other treatments at a single tertiary center were analyzed. This study compared the development of non-melanoma skin cancers, melanoma, and solid organ tumors in MF patients with at least 5-year follow-up data with age- and sex-matched controls.\n\nRESULTS:\nA total of 104 patients were included in the study. Ninety-two malignancies were detected in 16 (15.4%) patients, and six developed multiple malignancies. Skin cancers consisted of 56 basal cell carcinomas, 16 Bowen's disease, four squamous cell carcinomas, three melanomas, two basosquamous cell carcinomas, one Kaposi sarcoma, and one keratoacanthoma were found in nine (8.7%) patients. Eight patients developed three solid cancers and six lymphomas. The risk of developing skin cancer was associated with the total number of PUVA sessions (\u003c250 vs ≥250 sessions; hazard ratio (HR) 4.44, 95% confidence interval (CI) 1.033-19.068; p = .045). 9 (13.2%) of 68 patients who had follow-ups for at least 5 years developed skin cancer. Compared to an age- and sex-matched cohort, the prevalence of new skin cancer was considerably greater (p = .009).\n\nCONCLUSIONS:\nPatients with MF are predisposed to develop secondary malignancies, and continual exposure to PUVA may potentiate this risk. Annual digital dermoscopic follow-up in MF patients treated with UVA is advised for early diagnosis and treatment of secondary cutaneous malignancies." + } +} \ No newline at end of file diff --git a/36968992.json b/36968992.json new file mode 100644 index 0000000000000000000000000000000000000000..0ee2cec42adedb9c91eb7dbd16ba11b9b5efc4cd --- /dev/null +++ b/36968992.json @@ -0,0 +1,8 @@ +{ + "id": "36968992", + "label": 0, + "article": { + "id": "36968992", + "text": "Canavan disease is a rare fetal inherited leukodystrophy, caused by accumulation of N-acetyl-aspartate in the brain. Here, we report a child presented with frequent intractable seizures and visual impairment. A 14-month-old female infant with a complaint of the absence of neck holding and generalized tonic-clonic seizures was referred to our hospital. Macrocephaly, setting sun eyes, tremor, and hypotonia were observed. Funduscopy showed optic atrophy. Our patient's flash visual evoked potential showed blindness. Her brain magnetic resonance imaging showed diffuse white matter in subcortical, basal ganglia, and dorsal pons. Electroencephalography showed diffuse slow and sharp waves. The genetic study detected a hemizygous mutation in the aspartoacylase gene. Our patient was diagnosed with Canavan disease and began anticonvulsant treatment. However, seizures were not under control. Then, her medications were discontinued, and clobazam and primidone were administered. In conclusion, starting clobazam and primidone may help prevent frequently intractable seizures in Canavan disease patients." + } +} \ No newline at end of file diff --git a/36968995.json b/36968995.json new file mode 100644 index 0000000000000000000000000000000000000000..c7bd7cdc107ceb240509185e0974a91143d68991 --- /dev/null +++ b/36968995.json @@ -0,0 +1,8 @@ +{ + "id": "36968995", + "label": 0, + "article": { + "id": "36968995", + "text": "Hairy cell leukemia (HCL) is an incurable, rare lymphoproliferative hematological malignancy of mature B cAlthough first line therapy with purine analogues leads to positive results, almost half of HCL patients relapse after 5-10 years, and standard treatment may not be an option due to intolerance or refractoriness. Proliferation and survival of HCL cells is regulated by surrounding accessory cells and soluble signals present in the tumor microenvironment, which actively contributes to disease progression. studies show that different therapeutic approaches tested in HCL impact the tumor microenvironment, and that this milieu offers a protection affecting treatment efficacy. Herein we explore the effects of the tumor microenvironment to different approved and experimental therapeutic options for HCL. Dissecting the complex interactions between leukemia cells and their milieu will be essential to develop new targeted therapies for HCL patients." + } +} \ No newline at end of file diff --git a/36969340.json b/36969340.json new file mode 100644 index 0000000000000000000000000000000000000000..44c01de096bf38094d959f914d4e4404e9977656 --- /dev/null +++ b/36969340.json @@ -0,0 +1,8 @@ +{ + "id": "36969340", + "label": 0, + "article": { + "id": "36969340", + "text": "BACKGROUND:\nFaecal microbiota transplantation (FMT) has demonstrated efficacy in treating gastrointestinal (GI) diseases, such as infection (CDI) and inflammatory bowel disease (IBD). GI dysfunction is a frequent and occasionally dominating symptom of progressive supranuclear palsy-Richardson's syndrome (PSP-RS). However, it is not known whether FMT has clinical efficacy for PSP-RS.\n\nMETHODS:\nThis 36-week, randomised, placebo-controlled, parallel-group, phase 2 clinical trial was performed at a university tertiary referral hospital in China. From August 15 2021 to December 31 2021, a total of 68 newly diagnosed patients with PSP-RS (male 40 [59%], female 28 [41%]) who had never received any antiparkinsonian medications were enrolled and randomly assigned to receive either healthy donor FMT (n = 34, FMT group) or a mixture of 0.9% saline and food colouring (E150c) as sham transplantation (n = 34, placebo group) through transendoscopic enteral tubing (TET). Two days after oral antibiotics, participants received 1 week of transplantation. After an interval of 4 weeks, retransplantation was performed. Then, the last transplantation was given after another interval of 4 weeks, and the participants were followed up for 24 weeks (week 36). Clinicaltrials.gov identifier: ChiCTR-2100045397.\n\nFINDINGS:\nAmong 68 patients who were randomised (mean age, 67.2 (SD 5.1); 40 [59%] were male, 28 [41%] were female), 63 participants completed the trial. Efficacy analyses were performed on the intention-to-treat (ITT) analysis set. At week 16, the mean PSP Rating Scale (PSPRS) scores (the primary outcome) improved from 40.1 (SD 7.6) to 36.9 (SD 5.9) in the FMT group, whereas the scores changed from 40.1 (SD 6.9) to 41.7 (SD 6.2) in the placebo group, for a treatment benefit of 4.3 (95% CI, 3.2-5.4) ( \u003c 0.0001). After 3-cycle intervention, symptoms of constipation, depression, and anxiety (the secondary outcome) improved significantly at week 16 in the FMT group compared with the placebo group, the majority of which were maintained at the 24-week follow-up (week 36).\n\nINTERPRETATION:\nOur findings suggest that, compared with placebo, FMT treatment significantly improved motor and nonmotor symptoms in patients with PSP-RS, as well as reduced intestinal inflammation and enhanced the intestinal barrier by regulating the intestinal microbiota composition.\n\nFUNDING:\nThe National Natural Science Foundation of China (No. 82122022, 82171248, 81873791, and 82230084), Natural Science Foundation of Henan Province for Excellent Young Scholars (no. 202300410357), and Henan Province Young and Middle-Aged Health Science and Technology Innovation Talent Project (YXKC2020033)." + } +} \ No newline at end of file diff --git a/36970548.json b/36970548.json new file mode 100644 index 0000000000000000000000000000000000000000..f60c87e5f67c858166ea82480616a6b81f8ef984 --- /dev/null +++ b/36970548.json @@ -0,0 +1,8 @@ +{ + "id": "36970548", + "label": 0, + "article": { + "id": "36970548", + "text": "Substantial challenges in study design and methodology exist during clinical trial development to examine treatment response in patients with a rare disease, especially those with predominant central nervous system involvement and heterogeneity in clinical manifestations and natural history. Here we discuss crucial decisions which may significantly impact success of the study, including patient selection and recruitment, identification and selection of endpoints, determination of the study duration, consideration of control groups including natural history controls, and selection of appropriate statistical analyses. We review strategies for the successful development of a clinical trial to evaluate treatment of a rare disease with a focus on inborn errors of metabolism (IEMs) that present with movement disorders. The strategies presented using pantothenate kinase-associated neurodegeneration (PKAN) as the rare disease example can be applied to other rare diseases, particularly IEMs with movement disorders (e.g., other neurodegeneration with brain iron accumulation disorders, lysosomal storage disorders). The significant challenges associated with designing a clinical trial in rare disease can sometimes be successfully met through strategic engagement with experts in the rare disease, seeking regulatory and biostatistical guidance, and early involvement of patients and families. In addition to these strategies, we discuss the urgent need for a paradigm shift within the regulatory processes to help accelerate medical product development and bring new innovations and advances to patients with rare neurodegenerative diseases who need them earlier in disease progression and prior to clinical manifestations." + } +} \ No newline at end of file diff --git a/36970934.json b/36970934.json new file mode 100644 index 0000000000000000000000000000000000000000..f47a225482a9e2c30a5ccd8dfbbc396e932e5b27 --- /dev/null +++ b/36970934.json @@ -0,0 +1,8 @@ +{ + "id": "36970934", + "label": 0, + "article": { + "id": "36970934", + "text": "Xanthinuria is a clinically significant form of urolithiasis in cats with poor clinical outcomes and limited treatment options. In humans, xanthinuria has an autosomal recessive mode of inheritance, with variants in xanthine dehydrogenase (XDH) and molybdenum cofactor sulfurase (MOCOS) responsible for cases. While causative genetic variants have not been identified in the domestic cat, a recessive mode of inheritance has been suggested. DNA was extracted from EDTA-stabilised blood obtained from a Domestic Shorthair cat with clinically confirmed xanthinuria. Whole-genome sequencing and variant assessment in XDH and MOCOS identified XDH:c.2042C\u003eT (XDH:p.(A681V)) as a candidate causative variant for xanthinuria in this cat. The variant is located in a highly conserved part of the molybdenum-pterin co-factor domain, responsible for catalysing the hydroxylation of hypoxanthine to xanthine and uric acid. Variants in this domain of XDH have been shown to disrupt enzyme function and to cause xanthinuria in other species. When assessed in the wider cat population, the variant had an allele frequency of 15.8%, with 0.9% of the animals assessed homozygous for the alternative allele. Cats diagnosed with xanthinuria should be tested for this variant to validate its clinical relevance in the wider population." + } +} \ No newline at end of file diff --git a/36974561.json b/36974561.json new file mode 100644 index 0000000000000000000000000000000000000000..285561324623adbe1b57d838b52de3229cc52af2 --- /dev/null +++ b/36974561.json @@ -0,0 +1,8 @@ +{ + "id": "36974561", + "label": 0, + "article": { + "id": "36974561", + "text": "PURPOSE:\nWe evaluated the trends in incidence of Kaposi's sarcoma (KS) and Non-Hodgkin's lymphoma (NHL) over the two decades in northern Thailand during which access to antiretroviral treatments (ART) in Thailand was scaled up.\n\nMETHODS:\nThis is retrospective observational study. Data from 1998 to 2017 of patients diagnosed with KS and NHL from three long-standing, population-based cancer registries in northern Thailand (Chiang Mai, Lampang and Lamphun) were used to describe trends in age-adjusted incidence rate (ASR) of these cancers. The annual percent change (APC) of incidence rates were evaluated over this timeframe.\n\nRESULTS:\nThe incidence of KS significantly increased from 1998 to 2017 in males (APC of 6.9%) and very low incidence for evaluating change in female. NHL incidence significantly increased from 1998 to 2017, 2.2% and 1.8% per year in males and females, respectively (p\u003c0.001).\n\nCONCLUSION:\nIn the last two decades, the incidence of KS in male and NHL in both sexes have increased in northern Thailand, while the incidence of KS in female remained low. The change in incidences in opposite to the decline in HIV prevalence and increase ART coverage rate supported that other associated factors attributable to the development of KS and NHL should be looked for i.e., environmental, occupational exposures and other infections." + } +} \ No newline at end of file diff --git a/36977552.json b/36977552.json new file mode 100644 index 0000000000000000000000000000000000000000..c527282786b11bdb37beb41d5577e8786b95c968 --- /dev/null +++ b/36977552.json @@ -0,0 +1,8 @@ +{ + "id": "36977552", + "label": 0, + "article": { + "id": "36977552", + "text": "BACKGROUND:\nMeasuring systemic inflammatory markers may improve clinical prognosis and help identify targetable pathways for treatment in patients with autosomal dominant forms of frontotemporal lobar degeneration (FTLD).\n\nMETHODS:\nWe measured plasma concentrations of IL-6, TNFα and YKL-40 in pathogenic variant carriers () and non-carrier family members enrolled in the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium. We evaluated associations between baseline plasma inflammation and rate of clinical and neuroimaging changes (linear mixed effects models with standardised (z) outcomes). We compared inflammation between asymptomatic carriers who remained clinically normal ('asymptomatic non-converters') and those who became symptomatic ('asymptomatic converters') using area under the curve analyses. Discrimination accuracy was compared with that of plasma neurofilament light chain (NfL).\n\nRESULTS:\nWe studied 394 participants (non-carriers=143, =117, =62, =72). In , higher TNFα was associated with faster functional decline (B=0.12 (0.02, 0.22), p=0.02) and temporal lobe atrophy. In higher TNFα was associated with faster functional decline (B=0.09 (0.03, 0.16), p=0.006) and cognitive decline (B=-0.16 (-0.22, -0.10), p\u003c0.001), while higher IL-6 was associated with faster functional decline (B=0.12 (0.03, 0.21), p=0.01). TNFα was higher in asymptomatic converters than non-converters (β=0.29 (0.09, 0.48), p=0.004) and improved discriminability compared with plasma NfL alone (ΔR=0.16, p=0.007; NfL: OR=1.4 (1.03, 1.9), p=0.03; TNFα: OR=7.7 (1.7, 31.7), p=0.007).\n\nCONCLUSIONS:\nSystemic proinflammatory protein measurement, particularly TNFα, may improve clinical prognosis in autosomal dominant FTLD pathogenic variant carriers who are not yet exhibiting severe impairment. Integrating TNFα with markers of neuronal dysfunction like NfL could optimise detection of impending symptom conversion in asymptomatic pathogenic variant carriers and may help personalise therapeutic approaches." + } +} \ No newline at end of file diff --git a/36979413.json b/36979413.json new file mode 100644 index 0000000000000000000000000000000000000000..5c729dfee3b7f6d6ca3a5b1b606b22f4a46186f6 --- /dev/null +++ b/36979413.json @@ -0,0 +1,8 @@ +{ + "id": "36979413", + "label": 0, + "article": { + "id": "36979413", + "text": "In recent years, advances in science and technology have improved our quality of life, enabling us to tackle diseases and increase human life expectancy. However, longevity is accompanied by an accretion in the frequency of age-related neurodegenerative diseases, creating a growing burden, with pervasive social impact for human societies. The cost of managing such chronic disorders and the lack of effective treatments highlight the need to decipher their molecular and genetic underpinnings, in order to discover new therapeutic targets. In this effort, the nematode serves as a powerful tool to recapitulate several disease-related phenotypes and provides a highly malleable genetic model that allows the implementation of multidisciplinary approaches, in addition to large-scale genetic and pharmacological screens. Its anatomical transparency allows the use of co-expressed fluorescent proteins to track the progress of neurodegeneration. Moreover, the functional conservation of neuronal processes, along with the high homology between nematode and human genomes, render extremely suitable for the study of human neurodegenerative disorders. This review describes nematode models used to study neurodegeneration and underscores their contribution in the effort to dissect the molecular basis of human diseases and identify novel gene targets with therapeutic potential." + } +} \ No newline at end of file diff --git a/36979459.json b/36979459.json new file mode 100644 index 0000000000000000000000000000000000000000..a4ea9370ce95fb72e7bb76d36d9d4f8767e169ca --- /dev/null +++ b/36979459.json @@ -0,0 +1,8 @@ +{ + "id": "36979459", + "label": 0, + "article": { + "id": "36979459", + "text": "The radiation protection strategy with chemical agents has long been based on an antioxidative approach consisting in reducing the number of radical oxygen and nitrogen species responsible for the formation of the radiation-induced (RI) DNA damage, notably the DNA double-strand breaks (DSB), whose subset participates in the RI lethal effect as unrepairable damage. Conversely, a DSB repair-stimulating strategy that may be called the \"pro-episkevic\" approach (from the ancient Greek , meaning repair) can be proposed. The pro-episkevic approach directly derives from a mechanistic model based on the RI nucleoshuttling of the ATM protein (RIANS) and contributes to increase the number of DSB managed by NHEJ, the most predominant DSB repair and signaling pathway in mammalians. Here, three radioresistant and three radiosensitive human fibroblast cell lines were pretreated with antioxidative agents (N-acetylcysteine or amifostine) or to two pro-episkevic agents (zoledronate or pravastatin or both (ZOPRA)) before X-ray irradiation. The fate of the RI DSB was analyzed by using γH2AX and pATM immunofluorescence. While amifostine pretreatment appeared to be the most efficient antioxidative process, ZOPRA shows the most powerful radiation protection, suggesting that the pro-episkevic strategy may be an alternative to the antioxidative one. Additional investigations are needed to develop some new drugs that may elicit both antioxidative and pro-episkevic properties and to quantify the radiation protection action of both types of drugs applied concomitantly." + } +} \ No newline at end of file diff --git a/36980669.json b/36980669.json new file mode 100644 index 0000000000000000000000000000000000000000..19d7f29d0b8924258191b5d9d68f76593fd9cc68 --- /dev/null +++ b/36980669.json @@ -0,0 +1,8 @@ +{ + "id": "36980669", + "label": 0, + "article": { + "id": "36980669", + "text": "Cancers display dynamic interactions with their complex microenvironments that influence tumor growth, invasiveness, and immune evasion, thereby also influencing potential resistance to therapeutic treatments. The tumor microenvironment (TME) includes cells of the immune system, the extracellular matrix, blood vessels, and other cell types, such as fibroblasts or adipocytes. Various cell types forming this TME secrete exosomes, and molecules thereby released into the TME have been shown to be important mediators of cellular communication and interplay. Specific stressors in the TME, such as hypoxia, starvation, inflammation, and damage, can furthermore induce autophagy, a fundamental cellular process that degrades and recycles molecules and subcellular components, and recently it has been demonstrated that the small non-coding vault RNA1-1 plays a role as a regulator of autophagy and the coordinated lysosomal expression and regulation (CLEAR) network. Here, we demonstrate for the first time that intra-tumoral damage following effective therapeutic treatment is linked to specific intracellular synthesis and subsequent exosomal release of vault RNAs in endocrine tumors in vitro and in vivo. While we observed a subsequent upregulation of autophagic markers under classical chemotherapeutic conditions, a downregulation of autophagy could be detected under conditions strongly involving inflammatory cascades." + } +} \ No newline at end of file diff --git a/36980963.json b/36980963.json new file mode 100644 index 0000000000000000000000000000000000000000..ff8196d0191dc6118462a3d13ab837c365ae3d2c --- /dev/null +++ b/36980963.json @@ -0,0 +1,8 @@ +{ + "id": "36980963", + "label": 0, + "article": { + "id": "36980963", + "text": "Achromatopsia is a rare congenital condition with cone photoreceptor dysfunction causing color blindness, reduced vision, nystagmus and photophobia. New treatments are being developed, but the current evidence is still conflicting regarding possible progression over time, and there is no clear genotype-phenotype correlation. This natural history study aimed to further explore the course of disease and potential clinical differences between various genotypes. The retrospective design allowed for the study of a large cohort with a long follow-up. Patients were identified from the Danish national registries. If not already available, genetic analysis was offered to the patient. Clinical data from 1945-2022 were retrieved from medical records and included best-corrected visual acuity (BCVA), color vision, refractive error, nystagmus, visual fields and fundoscopic findings. We identified variants believed to be disease causing in five of the known achromatopsia genes: ; ; ; and ; and novel variants were identified in and . Progressive deterioration of BCVA only attributable to achromatopsia was found in three of 58 patients. Progressive phenotype was seen with variants in and The results indicate that myopia could be more frequently occurring with variants in , and and support the evidence that achromatopsia is a predominantly stationary condition with respect to BCVA. Although a clear genotype-phenotype correlation can still not be concluded, there may be differences in phenotypical characteristics with variants in different genes." + } +} \ No newline at end of file diff --git a/36980998.json b/36980998.json new file mode 100644 index 0000000000000000000000000000000000000000..a408fe7ada89ea4fa8b66b4bc64f2bb1f9d0b43a --- /dev/null +++ b/36980998.json @@ -0,0 +1,8 @@ +{ + "id": "36980998", + "label": 0, + "article": { + "id": "36980998", + "text": "The Multidisciplinary Ophthalmic Genetics Clinic (MOGC) at the University of Michigan Kellogg Eye Center aims to provide medical and ophthalmic genetics care to patients with inherited ocular conditions. We have developed a clinical and referral workflow where each patient undergoes coordinated evaluation by our multidisciplinary team followed by discussions on diagnosis, prognosis, and genetic testing. Testing approaches are specific to each patient and can be targeted (single-gene, gene panel), broad (chromosomal microarray, whole-exome sequencing), or a combination. We hypothesize that this clinic model improves patient outcomes and quality of care. A retrospective chart review of patients in the MOGC from July 2020 to October 2022 revealed that the most common referral diagnoses were congenital cataracts, optic neuropathy, and microphthalmia, with 52% syndromic cases. Within this patient cohort, we saw a 76% uptake for genetic testing, among which 33% received a diagnostic test result. Our results support a tailored approach to genetic testing for specific conditions. Through case examples, we highlight the power and impact of our clinic. By integrating ophthalmic care with medical genetics and counseling, the MOGC has not only helped solve individual patient diagnostic challenges but has aided the greater population in novel genetic discoveries and research towards targeted therapeutics." + } +} \ No newline at end of file diff --git a/36982988.json b/36982988.json new file mode 100644 index 0000000000000000000000000000000000000000..58dc3207b907938b7931f01d469257d45bcc1a3a --- /dev/null +++ b/36982988.json @@ -0,0 +1,8 @@ +{ + "id": "36982988", + "label": 0, + "article": { + "id": "36982988", + "text": "Alpha-Synuclein (α-Syn) is one of the most important molecules involved in the pathogenesis of Parkinson's disease and related disorders, synucleinopathies, but also in several other neurodegenerative disorders with a more elusive role. This review analyzes the activities of α-Syn, in different conformational states, monomeric, oligomeric and fibrils, in relation to neuronal dysfunction. The neuronal damage induced by α-Syn in various conformers will be analyzed in relation to its capacity to spread the intracellular aggregation seeds with a prion-like mechanism. In view of the prominent role of inflammation in virtually all neurodegenerative disorders, the activity of α-Syn will also be illustrated considering its influence on glial reactivity. We and others have described the interaction between general inflammation and cerebral dysfunctional activity of α-Syn. Differences in microglia and astrocyte activation have also been observed when in vivo the presence of α-Syn oligomers has been combined with a lasting peripheral inflammatory effect. The reactivity of microglia was amplified, while astrocytes were damaged by the double stimulus, opening new perspectives for the control of inflammation in synucleinopathies. Starting from our studies in experimental models, we extended the perspective to find useful pointers to orient future research and potential therapeutic strategies in neurodegenerative disorders." + } +} \ No newline at end of file diff --git a/36985703.json b/36985703.json new file mode 100644 index 0000000000000000000000000000000000000000..d46492daebf493ebbdc850659457769328404a71 --- /dev/null +++ b/36985703.json @@ -0,0 +1,8 @@ +{ + "id": "36985703", + "label": 0, + "article": { + "id": "36985703", + "text": "Availability of PET imaging radiotracers targeting α-synuclein aggregates is important for early diagnosis of Parkinson's disease and related α-synucleinopathies, as well as for the development of new therapeutics. Derived from a pyrazole backbone, C-labelled derivatives of anle138b (3-(1,3-benzodioxol-5-yl)-5-(3-bromophenyl)-1-pyrazole)-an inhibitor of α-synuclein and prion protein oligomerization-are currently in active development as the candidates for PET imaging α-syn aggregates. This work outlines the synthesis of a radiotracer based on the original structure of anle138b, labelled with fluorine-18 isotope, eminently suitable for PET imaging due to half-life and decay energy characteristics (97% β+ decay, 109.7 min half-life, and 635 keV positron energy). A three-step radiosynthesis was developed starting from 6-[F]fluoropiperonal (6-[F]FP) that was prepared using (piperonyl)(phenyl)iodonium bromide as a labelling precursor. The obtained 6-[F]FP was used directly in the condensation reaction with tosylhydrazide followed by 1,3-cycloaddition of the intermediate with 3'-bromophenylacetylene eliminating any midway without any intermediate purifications. This one-pot approach allowed the complete synthesis of [F]anle138b within 105 min with RCY of 15 ± 3% ( = 3) and in the range of 32-78 GBq/µmol. The [F]fluoride processing and synthesis were performed in a custom-built semi-automated module, but the method can be implemented in all the modern automated platforms. While there is definitely space for further optimization, the procedure developed is well suited for preclinical studies of this novel radiotracer in animal models and/or cell cultures." + } +} \ No newline at end of file diff --git a/36987710.json b/36987710.json new file mode 100644 index 0000000000000000000000000000000000000000..f828a1af816bfc38f8c8bcf5c49aa09001cf34dd --- /dev/null +++ b/36987710.json @@ -0,0 +1,8 @@ +{ + "id": "36987710", + "label": 0, + "article": { + "id": "36987710", + "text": "INTRODUCTION:\nNivolumab is an immune checkpoint inhibitor used to treat advanced renal cell carcinoma (RCC). Adrenal insufficiency has been reported as an adverse event associated with nivolumab. We report a case of adrenal insufficiency that occurred more than 1 year after the initiation of nivolumab while patient was still receiving treatment.\n\nCASE REPORT:\nThe patient was a 90-year-old Japanese woman. Fatigue and decreased cortisol levels were observed after 15 courses of nivolumab.\n\nMANAGEMENT \u0026 OUTCOME:\nThe symptoms improved with the initiation of oral hydrocortisone 30 mg once a day. Nivolumab was not resumed, and the patient is still under outpatient observation.\n\nDISCUSSION:\nThis is the first report of RCC with adrenal insufficiency occurring more than 1 year after the initiation of the nivolumab regimen. Symptoms of adrenal insufficiency are similar to those of cancer progression. When symptoms of fatigue occur in patients receiving nivolumab, adrenal insufficiency should be suspected, regardless of the duration from nivolumab initiation." + } +} \ No newline at end of file diff --git a/36989489.json b/36989489.json new file mode 100644 index 0000000000000000000000000000000000000000..2e187ca6c8e0bcc4fe2d44868a1f0756b68b9d68 --- /dev/null +++ b/36989489.json @@ -0,0 +1,8 @@ +{ + "id": "36989489", + "label": 0, + "article": { + "id": "36989489", + "text": "IL-7 supports the growth and chemoresistance of T-cell acute lymphoblastic leukemia (T-ALL), particularly the early T-cell precursor subtype (ETP-ALL), which frequently has activating mutations of IL-7 signaling. STAT5 is an attractive therapeutic target because it is almost universally activated in ETP-ALL, even in the absence of mutations of upstream activators such as the IL-7R, JAK and FLT3. To examine the role of activated STAT5 in ETP-ALL, we have used a Lmo2-transgenic (Lmo2Tg) mouse model in which we can monitor chemoresistant pre-leukemia (pre-LSCs) and leukemia stem cells (LSCs) that drive T-ALL development and relapse following chemotherapy. Using IL-7R-deficient Lmo2Tg mice, we show that IL-7 signaling was not required for the formation of pre-LSCs but essential for their expansion and clonal evolution into LSCs to generate T-ALL. Activated STAT5B was sufficient for the development of T-ALL in IL-7R; Lmo2Tg mice, indicating that inhibition of STAT5 is required to block the supportive signals provided by IL-7. To further understand the role of activated STAT5 in LSCs of ETP-ALL, we developed a new transgenic mouse that enables T-cell specific and doxycycline-inducible expression of the constitutively activated STAT5B1*6 mutant. Expression of STAT5B1*6 in T-cells had no effect alone but promoted expansion and chemoresistance of LSCs in Lmo2Tg mice. Pharmacologic inhibition of STAT5 with Pimozide induced differentiation and loss of LSCs, whilst enhancing response to chemotherapy. Furthermore, Pimozide significantly reduced leukemia burden in vivo and overcame chemoresistance of patient-derived ETP-ALL xenografts. Overall, our results demonstrate that STAT5 is an attractive therapeutic target for eradicating LSCs in ETP-ALL." + } +} \ No newline at end of file diff --git a/36989958.json b/36989958.json new file mode 100644 index 0000000000000000000000000000000000000000..a0148e7c97385162efa7571a588a0a3dec16a707 --- /dev/null +++ b/36989958.json @@ -0,0 +1,8 @@ +{ + "id": "36989958", + "label": 0, + "article": { + "id": "36989958", + "text": "A novel class of aminopyrimidine-based Bruton's tyrosine kinase (BTK) and FMS-like tyrosine kinase 3 (FLT3) dual-target inhibitors based on the BTK inhibitor spebrutinib was designed for the treatment of acute myeloid leukemia. Representative compounds 14d, 14g, 14j and 14m effectively inhibited BTK, FLT3, and FLT3(D835Y) mutant activities with low nanomolar IC's. These compounds displayed potent antiproliferative activities against leukemia cells with IC's of 0.29-950 nM. In particular, 14m had IC values 101-1045 times lower than those of spebrutinib against all cancer cell lines tested. Compound 14m effectively induced autophagy and apoptosis in MV-4-11 cells through regulating related proteins in a dose-dependent manner. Finally, intraperitoneal administration of 14m at 20 mg/kg significantly repressed the growth of MV-4-11 cells with a TGI value of 95.68% with no apparent toxicity. These BTK/FLT3 dual-target inhibitors represent promising leads for further structural optimization and antitumor mechanism studies." + } +} \ No newline at end of file diff --git a/36991253.json b/36991253.json new file mode 100644 index 0000000000000000000000000000000000000000..218cfd5abfcc72e1c9a8150cfe712513efae6210 --- /dev/null +++ b/36991253.json @@ -0,0 +1,8 @@ +{ + "id": "36991253", + "label": 0, + "article": { + "id": "36991253", + "text": "CONTEXT:\nSquamous cell carcinoma (SCC) is the second most common type of skin cancer caused by malignant keratinocytes. Multiple studies have shown that protein mutations have a significant impact on the development and progression of cancer, including SCC. We attempted to decode the effect of single amino acid mutations in the Bruton's tyrosine kinase (BTK) protein in this study. Molecular dynamic (MD) simulations were performed on selected deleterious mutations of the BTK protein, revealing that the variants adversely affect the protein, indicating that they may contribute to the prognosis of SCC by making the protein unstable. Then, we investigated the interaction between the protein and its mutants with ibrutinib, a drug designed to treat SCC. Even though the mutations have deleterious effects on protein structure, they bind to ibrutinib similarly to their wild type counterpart. This study demonstrates that the effect of detected missense mutations is unfavorable and can result in function loss, which is severe for SCC, but that ibrutinib-based therapy can still be effective on them, and the mutations can be used as biomarkers for Ibrutinib-based treatment.\n\nMETHODS:\nSeven different computational techniques were used to compute the effect of SAVs in accordance with the experimental requirements of this study. To understand the differences in protein and mutant dynamics, MD simulation and trajectory analysis, including RMSD, RMSF, PCA, and contact analysis, were performed. The free binding energy and its decomposition for each protein-drug complex were determined using docking, MM-GBSA, MM-PBSA, and interaction analysis (wild and mutants)." + } +} \ No newline at end of file diff --git a/36993690.json b/36993690.json new file mode 100644 index 0000000000000000000000000000000000000000..7cd0e6903fb3b5c96e4381a530b171d39e1e2bcc --- /dev/null +++ b/36993690.json @@ -0,0 +1,8 @@ +{ + "id": "36993690", + "label": 0, + "article": { + "id": "36993690", + "text": "BACKGROUND:\nImpairment of the blood-brain barrier (BBB) is considered to be a common feature among neurodegenerative diseases, including Alzheimer's, Parkinson's and prion diseases. In prion disease, increased BBB permeability was reported 40 years ago, yet the mechanisms behind the loss of BBB integrity have never been explored. Recently, we showed that reactive astrocytes associated with prion diseases are neurotoxic. The current work examines the potential link between astrocyte reactivity and BBB breakdown.\n\nRESULTS:\nIn prion-infected mice, the loss of BBB integrity and aberrant localization of aquaporin 4 (AQP4), a sign of retraction of astrocytic endfeet from blood vessels, were noticeable prior to disease onset. Gaps in cell-to-cell junctions along blood vessels, together with downregulation of Occludin, Claudin-5 and VE-cadherin, which constitute tight and adherens junctions, suggested that loss of BBB integrity is linked with degeneration of vascular endothelial cells. In contrast to cells isolated from non-infected adult mice, endothelial cells originating from prion-infected mice displayed disease-associated changes, including lower levels of Occludin, Claudin-5 and VE-cadherin expression, impaired tight and adherens junctions, and reduced trans-endothelial electrical resistance (TEER). Endothelial cells isolated from non-infected mice, when co-cultured with reactive astrocytes isolated from prion-infected animals or treated with media conditioned by the reactive astrocytes, developed the disease-associated phenotype observed in the endothelial cells from prion-infected mice. Reactive astrocytes were found to produce high levels of secreted IL-6, and treatment of endothelial monolayers originating from non-infected animals with recombinant IL-6 alone reduced their TEER. Remarkably, treatment with extracellular vesicles produced by normal astrocytes partially reversed the disease phenotype of endothelial cells isolated from prion-infected animals.\n\nCONCLUSIONS:\nTo our knowledge, the current work is the first to illustrate early BBB breakdown in prion disease and to document that reactive astrocytes associated with prion disease are detrimental to BBB integrity. Moreover, our findings suggest that the harmful effects are linked to proinflammatory factors secreted by reactive astrocytes." + } +} \ No newline at end of file diff --git a/36995092.json b/36995092.json new file mode 100644 index 0000000000000000000000000000000000000000..a4f7111a32ef163fd74c8aec94cc582f9ecaf76a --- /dev/null +++ b/36995092.json @@ -0,0 +1,8 @@ +{ + "id": "36995092", + "label": 0, + "article": { + "id": "36995092", + "text": "Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi sarcoma (KS), the plasmablastic form of multicentric Castleman's disease, and primary effusion lymphoma. In sub-Saharan Africa, KS is the most common HIV-related malignancy and one of the most common childhood cancers. Immunosuppressed patients, including HIV-infected patients, are more prone to KSHV-associated disease. KSHV encodes a viral protein kinase (vPK) that is expressed from ORF36. KSHV vPK contributes to the optimal production of infectious viral progeny and upregulation of protein synthesis. To elucidate the interactions of vPK with cellular proteins in KSHV-infected cells, we used a bottom-up proteomics approach and identified host protein ubiquitin-specific peptidase 9X-linked (USP9X) as a potential interactor of vPK. Subsequently, we validated this interaction using a co-immunoprecipitation assay. We report that both the ubiquitin-like and the catalytic domains of USP9X are important for association with vPK. To uncover the biological relevance of the USP9X/vPK interaction, we investigated whether the knockdown of USP9X would modulate viral reactivation. Our data suggest that depletion of USP9X inhibits both viral reactivation and the production of infectious virions. Understanding how USP9X influences the reactivation of KSHV will provide insights into how cellular deubiquitinases regulate viral kinase activity and how viruses co-opt cellular deubiquitinases to propagate infection. Hence, characterizing the roles of USP9X and vPK during KSHV infection constitutes a first step toward identifying a potentially critical interaction that could be targeted by future therapeutics. Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi sarcoma (KS), the plasmablastic form of multicentric Castleman's disease, and primary effusion lymphoma. In sub-Saharan Africa, KS is the most common HIV-related malignancy. KSHV encodes a viral protein kinase (vPK) that aids viral replication. To elucidate the interactions of vPK with cellular proteins in KSHV-infected cells, we used an affinity purification approach and identified host protein ubiquitin-specific peptidase 9X-linked (USP9X) as a potential interactor of vPK. Depletion of USP9X inhibits both viral reactivation and the production of infectious virions. Overall, our data suggest a proviral role for USP9X." + } +} \ No newline at end of file diff --git a/36995447.json b/36995447.json new file mode 100644 index 0000000000000000000000000000000000000000..4db325e0f0303ccacc79707afec930a7293bcb82 --- /dev/null +++ b/36995447.json @@ -0,0 +1,8 @@ +{ + "id": "36995447", + "label": 0, + "article": { + "id": "36995447", + "text": "Tumor markers in CNS germ cell tumors (GCTs) include human chorionic gonadotropin (HCG) and alpha fetoprotein (AFP), which have significant diagnostic implications, as elevation of either one leads to clinical diagnosis of non-germinomatous GCTs without histopathological confirmation, justifying intensified chemotherapy and irradiation. The current study, based on an international cohort of histopathologically verified GCTs that underwent biopsy (n = 85) or resection (n = 76), sought to better define the clinical role and prognostic significance of tumor markers from serum and CSF in this challenging patient population. We found that HCG was elevated only in cases with a germinoma or choriocarcinoma component, and there existed a clear cut-off HCG value between the two. AFP was often elevated in GCTs without a yolk sac tumor component, especially immature teratoma. HCG was elevated only in CSF in 3-of-52 cases, and AFP was elevated only in serum in 7-of-49 cases, emphasizing the potential utilization of both serum and CSF studies. Immature teratoma demonstrated unfavorable prognosis independent of tumor marker status, with 56% 5-year overall survival; however, co-existent germinoma components indicated a more favorable prognosis. Taken together, the study findings emphasize the importance for routine assessment and guarded interpretation of tumor markers in CNS GCTs." + } +} \ No newline at end of file diff --git a/36996787.json b/36996787.json new file mode 100644 index 0000000000000000000000000000000000000000..515f4f1e385241b90928b5c614226f1f2336dd36 --- /dev/null +++ b/36996787.json @@ -0,0 +1,8 @@ +{ + "id": "36996787", + "label": 0, + "article": { + "id": "36996787", + "text": "INTRODUCTION:\nPrimary effusion lymphoma (PEL) is a malignant lymphomatous effusion, which by definition is Kaposi sarcoma herpesvirus/human herpesvirus 8-positive. PEL typically occurs in HIV-infected patients, but can also occur in HIV-negative individuals, including in organ transplant recipients. Tyrosine kinase inhibitors (TKIs) are currently the standard of care for patients with chronic myeloid leukemia (CML), BCR::ABL1-positive. Although TKIs are extremely effective in treating CML, they alter T-cell function by inhibiting peripheral T-cell migration and altering T-cell trafficking and have been associated with the development of pleural effusions.\n\nCASE PRESENTATION:\nWe report a case of PEL in a young, relatively immunocompetent patient with no history of organ transplant receiving dasatinib for CML, BCR::ABL1-positive.\n\nDISCUSSION:\nWe hypothesize that the loss of T-cell function secondary to TKI therapy (dasatinib) may have resulted in the unchecked cellular proliferation of KSHV-infected cells, leading to the emergence of a PEL. We recommend cytologic investigation and KSHV testing in patients being treated with dasatinib for CML who present with persistent or recurrent effusions." + } +} \ No newline at end of file diff --git a/36998325.json b/36998325.json new file mode 100644 index 0000000000000000000000000000000000000000..572bd4300ec997b0b517364039669c45a954ef74 --- /dev/null +++ b/36998325.json @@ -0,0 +1,8 @@ +{ + "id": "36998325", + "label": 0, + "article": { + "id": "36998325", + "text": "Epithelioid trophoblastic tumor (ETT) is a rare malignancy arising from neoplastic proliferation of chorionic-type intermediate trophoblasts. ETT poses significant challenges to clinicians in the diagnosis and treatment and can hence lead to a poor prognosis. We report a unique case of metastatic ETT in a HIV-positive patient." + } +} \ No newline at end of file diff --git a/36998457.json b/36998457.json new file mode 100644 index 0000000000000000000000000000000000000000..30a46df710b6107533413a85296115b0764d961d --- /dev/null +++ b/36998457.json @@ -0,0 +1,8 @@ +{ + "id": "36998457", + "label": 0, + "article": { + "id": "36998457", + "text": "Minimal/measurable residual disease (MRD) monitoring is progressively changing the management of hematologic malignancies. The possibility of detecting the persistence/reappearance of disease in patients in apparent clinical remission offers a refined risk stratification and a treatment decision making tool. Several molecular techniques are employed to monitor MRD, from conventional real-time quantitative polymerase chain reaction (RQ-PCR) to next generation sequencing and digital droplet PCR (ddPCR), in different tissues or compartments through the detection of fusion genes, immunoglobulin and T-cell receptor gene rearrangements or disease-specific mutations. RQ-PCR is still the gold standard for MRD analysis despite some limitations. ddPCR, considered the third-generation PCR, yields a direct, absolute, and accurate detection and quantification of low-abundance nucleic acids. In the setting of MRD monitoring it carries the major advantage of not requiring a reference standard curve built with the diagnostic sample dilution and of allowing to reduce the number of samples below the quantitative range. At present, the broad use of ddPCR to monitor MRD in the clinical practice is limited by the lack of international guidelines. Its application within clinical trials is nonetheless progressively growing both in acute lymphoblastic leukemia as well as in chronic lymphocytic leukemia and non-Hodgkin lymphomas. The aim of this review is to summarize the accumulating data on the use of ddPCR for MRD monitoring in chronic lymphoid malignancies and to highlight how this new technique is likely to enter into the clinical practice." + } +} \ No newline at end of file diff --git a/36998957.json b/36998957.json new file mode 100644 index 0000000000000000000000000000000000000000..c3fc128acb49f3a28d03e403c8765502dab9ab18 --- /dev/null +++ b/36998957.json @@ -0,0 +1,8 @@ +{ + "id": "36998957", + "label": 0, + "article": { + "id": "36998957", + "text": "BACKGROUND:\nRenal clear cell carcinoma (RCC) is a malignant tumor of the genitourinary system with a predilection for males. The most common metastatic sites are the lung, liver, lymph nodes, contralateral kidney or adrenal gland, however, skin metastasis has only been seen in 1.0%-3.3% of cases. The most common site of skin metastasis is the scalp, and metastasis to the nasal ala region is rare.\n\nCASE SUMMARY:\nA 55-year-old man with clear cell carcinoma of the left kidney was treated with pembrolizumab and axitinib for half a year after surgery and was found to have a red mass on his right nasal ala for 3 mo. The skin lesion of the patient grew rapidly to the size of 2.0 cm × 2.0 cm × 1.2 cm after discontinuation of targeted drug therapy due to the coronavirus disease 2019 epidemic. The patient was finally diagnosed with skin metastasis of RCC in our hospital. The patient refused to undergo surgical resection and the tumor shrank rapidly after resuming target therapy for 2 wk.\n\nCONCLUSION:\nIt is rare for an RCC to metastasize to the skin of the nasal ala region. The tumor size change of this patient before and after treatment with targeted drugs shows the effectiveness of combination therapy for skin metastasis." + } +} \ No newline at end of file diff --git a/36998968.json b/36998968.json new file mode 100644 index 0000000000000000000000000000000000000000..db4626a23afc14c5f10b3abd8758bad0360d0986 --- /dev/null +++ b/36998968.json @@ -0,0 +1,8 @@ +{ + "id": "36998968", + "label": 0, + "article": { + "id": "36998968", + "text": "BACKGROUND:\nAcromicric dysplasia (AD) is a rare skeletal dysplasia. Its incidence is \u003c 1/1000000, and only approximately 60 cases are reported worldwide. It is a disease characterized by severe short stature, short hands and feet, facial abnormalities, normal intelligence, and bone abnormalities. Unlike other skeletal dysplasia, AD has a mild clinical phenotype, mainly characterized by short stature. Extensive endocrine examination has not revealed a potential cause. The clinical effect of growth hormone therapy is still uncertain.\n\nCASE SUMMARY:\nWe report a clinical phenotype of AD associated with mutations in the fibrillin 1 () (OMIM 102370) gene c.5183C\u003eT (p. Ala1728Val) in three people from a Chinese family. A 4-year-old member of the family first visited the hospital because of slow growth and short stature for 2 years, but no abnormalities were found after a series of laboratory tests, echocardiography, pituitary magnetic resonance imaging, and ophthalmological examination. Recombinant human growth hormone (rhGH) was used to treat the patient for \u003e 5 years. The efficacy of rhGH was apparent in the first year of treatment; the height increased from -3.64 standard deviation score (SDS) to -2.88 SDS, while the efficacy weakened from the second year. However, long-term follow-up is required to clarify the efficacy of rhGH.\n\nCONCLUSION:\n-related AD has genetic heterogeneity and/or clinical variability, which brings challenges to the evaluation of clinical treatment. rhGH is effective for treatment of AD, but long-term follow-up is needed to clarify the effect." + } +} \ No newline at end of file diff --git a/36999388.json b/36999388.json new file mode 100644 index 0000000000000000000000000000000000000000..2fdd2b8d9098a57d3ae644e48044996452a3b2a5 --- /dev/null +++ b/36999388.json @@ -0,0 +1,8 @@ +{ + "id": "36999388", + "label": 0, + "article": { + "id": "36999388", + "text": "The coronavirus disease 2019 (COVID-19), which is an infection caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), spread worldwide including Japan. This COVID-19 pandemic has changed the way of life around the world. To prevent the spread of infection, several COVID-19 vaccines were rapidly developed and their vaccination is recommended. While safety and effectiveness of these vaccines have been shown, various adverse reactions occur with a certain frequency. Pilomatricoma is a benign subcutaneous tumor. Cause of pilomatricoma is unclear, however, an external insult could be a cause of part of pilomatricoma. Herein, we report a rare case of pilomatricoma after COVID-19 vaccination. Pilomatricoma should be included in the differential diagnoses of nodular lesions arising after vaccination sites, including the COVID-19 vaccine." + } +} \ No newline at end of file diff --git a/37001415.json b/37001415.json new file mode 100644 index 0000000000000000000000000000000000000000..86d03f0821c1f0f36318a5fe86063bc83bd98118 --- /dev/null +++ b/37001415.json @@ -0,0 +1,8 @@ +{ + "id": "37001415", + "label": 0, + "article": { + "id": "37001415", + "text": "not required for reviews." + } +} \ No newline at end of file diff --git a/37002662.json b/37002662.json new file mode 100644 index 0000000000000000000000000000000000000000..73883d23f329733647b3d76189a7b513e9fbe9dd --- /dev/null +++ b/37002662.json @@ -0,0 +1,8 @@ +{ + "id": "37002662", + "label": 0, + "article": { + "id": "37002662", + "text": "BACKGROUND:\nKaposi's sarcoma (KS) is a rare multifocal angiogenic tumor often seen in immunocompromised setting such as acquired immunodeficiency syndrome (AIDS) or organ transplantation recipients. Pemphigus vulgaris (PV) is a rare blistering disorder with mucocutaneous involvement for which immunosuppressive therapy has long been the core of treatment. Iatrogenic form of KS has been reported infrequently in pemphigus patients as a result of long-term immunosuppressive therapy.\n\nCASE:\nWe describe a 39-year-old male patient with confirmed diagnosis of PV who developed KS after receiving immunosuppressive agents for his pemphigus. KS was initially localized to the oral cavity with features mimicking exacerbation of his pemphigus.\n\nCONCLUSION:\nThis interesting case of KS suggests that dermatologists visiting patients with pemphigus with discomfort in the oral cavity should have a high degree of awareness and consider other differential diagnoses along with merely an exacerbation of PV." + } +} \ No newline at end of file diff --git a/37004673.json b/37004673.json new file mode 100644 index 0000000000000000000000000000000000000000..18b466eeb388ecce815eb30c04251edc93c4a16c --- /dev/null +++ b/37004673.json @@ -0,0 +1,8 @@ +{ + "id": "37004673", + "label": 0, + "article": { + "id": "37004673", + "text": "Pirtobrutinib (Jaypirca), a highly selective, non-covalent, reversible Bruton's tyrosine kinase (BTK) inhibitor, is being developed by Eli Lilly and Company (Lilly) for the treatment of B-cell leukemias and lymphomas. In January 2023, pirtobrutinib was approved in the USA under the Accelerated Approval pathway for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. This article summarizes the milestones in the development of pirtobrutinib leading to this first approval for the treatment of adult patients with relapsed or refractory MCL." + } +} \ No newline at end of file diff --git a/37004844.json b/37004844.json new file mode 100644 index 0000000000000000000000000000000000000000..e86ac3ad48d031d3e41cb15497fefa1f18d9ed52 --- /dev/null +++ b/37004844.json @@ -0,0 +1,8 @@ +{ + "id": "37004844", + "label": 0, + "article": { + "id": "37004844", + "text": "Tau aggregation is a hallmark of several neurodegenerative disorders, such as Alzheimer's disease (AD), frontotemporal dementia, and progressive supranuclear palsy. Hyperphosphorylated tau is believed to contribute to the degeneration of neurons and the development of these complex diseases. Therefore, one potential treatment for these illnesses is to prevent or counteract tau aggregation. In recent years, interest has been increasing in developing nature-derived tau aggregation inhibitors as a potential treatment for neurodegenerative disorders. Researchers have become increasingly interested in natural compounds with multifunctional features, such as flavonoids, alkaloids, resveratrol, and curcumin, since these molecules can interact simultaneously with the various targets of AD. Recent studies have demonstrated that several natural compounds can inhibit tau aggregation and promote the disassembly of pre-formed tau aggregates. Nature-derived tau aggregation inhibitors hold promise as a potential treatment for neurodegenerative disorders. However, it is important to note that more research is needed to fully understand the mechanisms by which these compounds exert their effects, safety and efficacy in preclinical and clinical studies. Nature-derived inhibitors of tau aggregation are a promising new direction in the research of neurodegenerative complexities. This review focuses on the natural products that have proven to be a rich supply for inhibitors in tau aggregation and their uses in neurodegenerative complexities, including AD." + } +} \ No newline at end of file diff --git a/37006058.json b/37006058.json new file mode 100644 index 0000000000000000000000000000000000000000..c284e4bf28c721a12870336184158a2ddaf8512e --- /dev/null +++ b/37006058.json @@ -0,0 +1,8 @@ +{ + "id": "37006058", + "label": 0, + "article": { + "id": "37006058", + "text": "AIMS:\nTo evaluate the effect of the combination of irradiation and AZD0156 on apoptosis, cell cycle progression, and clonogenic survival in human breast cancer and fibroblast cells.\n\nMETHODS AND MATERIAL:\nEstrogen receptor-positive breast cancer cell line MCF-7 and healthy lung fibroblast cell line WI-38 were obtained. Following employing proliferation analysis, cytotoxicity analysis was done to calculate the IC50 values of AZD0156 in MCF-7 and WI-38 cell lines. Following the application of AZD0156 and irradiation, flow cytometry analysis was performed for evaluating cell cycle distribution and the extent of apoptosis. Plating efficiency and surviving fraction were calculated for the clonogenic assay.\n\nSTATISTICAL ANALYSIS USED:\nSPSS Statistics for Windows, Version 17.0. (SPSS Inc. Chicago) and GraphPad Prism Version 6.0 for Windows (GraphPad Software, San Diego, California USA) softwares were used to analyze data.\n\nRESULTS:\nAZD0156 and irradiation dose of 2-10 Gy had no effect on apoptosis on MCF-7 cells. The combination treatment of AZD0156 and 2 Gy, 4 Gy, 6 Gy, 8 Gy, and 10 Gy irradiation induced G/G phase arrest by 1.79, 1.79, 1.50, 1.25, and 1.52-fold compared to the control group, respectively on MCF-7 cell lines. Combination treatment of AZD0156 and each different irradiation dose affected clonogenic survival owing to increased radiosensitivity (p: 0.02). AZD0156 and irradiation dose of 2 Gy, 4 Gy, 6 Gy, 8 Gy, and 10 Gy decreased the cell viability rate of WI-38 cells by 1.05, 1.18, 1.22, 1.04, and 1.05-fold compared to the control group, respectively. No efficacy was detected on cell cycle analysis, and clonogenic survival was not significantly decreased in WI-38 cells.\n\nCONCLUSION:\nThe combination use of irradiation and AZD0156 has improved efficacy of tumor cell-specific cell cycle arrest and decreasing clonogenic survival." + } +} \ No newline at end of file diff --git a/37008546.json b/37008546.json new file mode 100644 index 0000000000000000000000000000000000000000..9ea9563ea7b026252fbd2fc059e40ae87887d21b --- /dev/null +++ b/37008546.json @@ -0,0 +1,8 @@ +{ + "id": "37008546", + "label": 0, + "article": { + "id": "37008546", + "text": "PURPOSE:\nThe rapid and noninvasive nature of optical coherence tomography angiography (OCTA) makes it a potentially valuable tool for imaging the retina in children. With the optimization of tabletop systems and the development of experimental handheld OCTA devices, there is expanded potential for OCTA in the clinic and the operating room. This article reviews the utility of OCTA in some of the most common pediatric retinal disorders.\n\nMETHODS:\nA thorough computerized PubMed search was performed to review relevant published journal articles to contextualize and identify the role of OCTA in common retinal disorders with vascular involvement affecting children. Pertinent results and findings from original investigations and case reports were summarized.\n\nRESULTS:\nThe ability to quickly collect both qualitative and quantitative information about retinal microvasculature, in both the clinic and operating room settings, with OCTA, has led to the uncovering of microvascular features and morphologic changes in many pediatric retinal disorders such as Coats Disease, familial exudative vitreoretinopathy, incontinentia pigmenti, sickle cell retinopathy, Stargardt Disease, X-linked juvenile retinoschisis, retinopathy of prematurity, diabetic retinopathy in type 1 diabetes, pediatric retinal tumors, and choroidal neovascularization.\n\nCONCLUSIONS:\nOCTA is a relevant tool to aid early detection, guide intervention, monitor treatment response, and understand pathogenesis in a number of pediatric retinal disorders." + } +} \ No newline at end of file diff --git a/37008782.json b/37008782.json new file mode 100644 index 0000000000000000000000000000000000000000..73368a978856422fd58e47399fbfd30071c29d9d --- /dev/null +++ b/37008782.json @@ -0,0 +1,8 @@ +{ + "id": "37008782", + "label": 0, + "article": { + "id": "37008782", + "text": "Niemann Pick disease type C (NPC) is an autosomal recessive neurodegenerative lysosomal disorder characterized by an accumulation of lipids in different organs. Clinical manifestations can start at any age and include hepatosplenomegaly, intellectual impairment, and cerebellar ataxia. is the most common causal gene, with over 460 different mutations with heterogeneous pathological consequences. We generated a zebrafish NPC1 model by CRISPR/Cas9 carrying a homozygous mutation in exon 22, which encodes the end of the cysteine-rich luminal loop of the protein. This is the first zebrafish model with a mutation in this gene region, which is frequently involved in the human disease. We observed a high lethality in mutants, with all larvae dying before reaching the adult stage. mutant larvae were smaller than wild type (wt) and their motor function was impaired. We observed vacuolar aggregations positive to cholesterol and sphingomyelin staining in the liver, intestine, renal tubules and cerebral gray matter of mutant larvae. RNAseq comparison between mutants and controls showed 284 differentially expressed genes, including genes with functions in neurodevelopment, lipid exchange and metabolism, muscle contraction, cytoskeleton, angiogenesis, and hematopoiesis. Lipidomic analysis revealed significant reduction of cholesteryl esters and increase of sphingomyelin in the mutants. Compared to previously available zebrafish models, our model seems to recapitulate better the early onset forms of the NPC disease. Thus, this new model of NPC will allow future research in the cellular and molecular causes/consequences of the disease and on the search for new treatments." + } +} \ No newline at end of file diff --git a/37009366.json b/37009366.json new file mode 100644 index 0000000000000000000000000000000000000000..1cddc44fc10dd514b8cede870c8ee6d407b0ee86 --- /dev/null +++ b/37009366.json @@ -0,0 +1,8 @@ +{ + "id": "37009366", + "label": 0, + "article": { + "id": "37009366", + "text": "Testicular tumors are one of the most commonly observed malignancies among men. An aggressive and rare subtype of the disease, testicular choriocarcinoma, has a worse prognosis due to the tendency of early hematogenous spread to multiple organs and advanced symptoms at presentation time. Characteristic features of choriocarcinoma include elevated beta human chorionic gonadotropin (β-hCG) in a young male with testicular mass. However, when the primary testicular tumor overutilizes its blood supply and spontaneously regresses, it is presumed to have been \"burnt out\" with remnants evident by metastatic retroperitoneal lymphadenopathy, scarred tissue, and calcifications. Treatment of advanced testicular cancer may be complicated by a rare entity known as choriocarcinoma syndrome, distinguished by rapid and fatal hemorrhaging of metastatic tumor sites. Prior described cases of choriocarcinoma syndrome involve pulmonary and gastrointestinal hemorrhages. We present an uncommon case of a 34-year-old male with a \"burnt out\" metastatic mixed testicular cancer who presented with choriocarcinoma syndrome (CS) treated with chemotherapy but developed deadly hemorrhaging of brain metastases. In addition, with the assistance of ChatGPT, we report our experience with this OpenAI tool and its potential uses in medical literature writing." + } +} \ No newline at end of file diff --git a/37010434.json b/37010434.json new file mode 100644 index 0000000000000000000000000000000000000000..b6f6ecedb0e16e1e73fbe3679d3e9fdbfe899d63 --- /dev/null +++ b/37010434.json @@ -0,0 +1,8 @@ +{ + "id": "37010434", + "label": 0, + "article": { + "id": "37010434", + "text": "Intrinsic immunity is the frontline of host defense against invading pathogens. To combat viral infection, mammalian hosts deploy cell-intrinsic effectors to block viral replication prior to the onset of innate and adaptive immunity. In this study, SMCHD1 is identified as a pivotal cellular factor that restricts Kaposi's sarcoma-associated herpesvirus (KSHV) lytic reactivation through a genome-wide CRISPR-Cas9 knockout screen. Genome-wide chromatin profiling revealed that SMCHD1 associates with the KSHV genome, most prominently the origin of lytic DNA replication (ORI-Lyt). SMCHD1 mutants defective in DNA binding could not bind ORI-Lyt and failed to restrict KSHV lytic replication. Moreover, SMCHD1 functioned as a pan-herpesvirus restriction factor that potently suppressed a wide range of herpesviruses, including alpha, beta, and gamma subfamilies. SMCHD1 deficiency facilitated the replication of a murine herpesvirus . These findings uncovered SMCHD1 as a restriction factor against herpesviruses, and this could be harnessed for the development of antiviral therapies to limit viral infection. Intrinsic immunity represents the frontline of host defense against invading pathogens. However, our understanding of cell-intrinsic antiviral effectors remains limited. In this study, we identified SMCHD1 as a cell-intrinsic restriction factor that controlled KSHV lytic reactivation. Moreover, SMCHD1 restricted the replication of a wide range of herpesviruses by targeting the origins of viral DNA replication (ORIs), and SMCHD1 deficiency facilitated the replication of a murine herpesvirus . This study helps us to better understand intrinsic antiviral immunity, which may be harnessed to develop new therapeutics for the treatment of herpesvirus infection and the related diseases." + } +} \ No newline at end of file diff --git a/37010841.json b/37010841.json new file mode 100644 index 0000000000000000000000000000000000000000..d5ff1d3c58a3d67c1bc8c7728f81e526496c9944 --- /dev/null +++ b/37010841.json @@ -0,0 +1,8 @@ +{ + "id": "37010841", + "label": 0, + "article": { + "id": "37010841", + "text": "IMPORTANCE:\nPlasma phosphorylated tau217 (p-tau217), a biomarker of Alzheimer disease (AD), is of special interest in corticobasal syndrome (CBS) because autopsy studies have revealed AD is the driving neuropathology in up to 40% of cases. This differentiates CBS from other 4-repeat tauopathy (4RT)-associated syndromes, such as progressive supranuclear palsy Richardson syndrome (PSP-RS) and nonfluent primary progressive aphasia (nfvPPA), where underlying frontotemporal lobar degeneration (FTLD) is typically the primary neuropathology.\n\nOBJECTIVE:\nTo validate plasma p-tau217 against positron emission tomography (PET) in 4RT-associated syndromes, especially CBS.\n\nDESIGN, SETTING, AND PARTICIPANTS:\nThis multicohort study with 6, 12, and 24-month follow-up recruited adult participants between January 2011 and September 2020 from 8 tertiary care centers in the 4RT Neuroimaging Initiative (4RTNI). All participants with CBS (n = 113), PSP-RS (n = 121), and nfvPPA (n = 39) were included; other diagnoses were excluded due to rarity (n = 29). Individuals with PET-confirmed AD (n = 54) and PET-negative cognitively normal control individuals (n = 59) were evaluated at University of California San Francisco. Operators were blinded to the cohort.\n\nMAIN OUTCOME AND MEASURES:\nPlasma p-tau217, measured by Meso Scale Discovery electrochemiluminescence, was validated against amyloid-β (Aβ) and flortaucipir (FTP) PET. Imaging analyses used voxel-based morphometry and bayesian linear mixed-effects modeling. Clinical biomarker associations were evaluated using longitudinal mixed-effect modeling.\n\nRESULTS:\nOf 386 participants, 199 (52%) were female, and the mean (SD) age was 68 (8) years. Plasma p-tau217 was elevated in patients with CBS with positive Aβ PET results (mean [SD], 0.57 [0.43] pg/mL) or FTP PET (mean [SD], 0.75 [0.30] pg/mL) to concentrations comparable to control individuals with AD (mean [SD], 0.72 [0.37]), whereas PSP-RS and nfvPPA showed no increase relative to control. Within CBS, p-tau217 had excellent diagnostic performance with area under the receiver operating characteristic curve (AUC) for Aβ PET of 0.87 (95% CI, 0.76-0.98; P \u003c .001) and FTP PET of 0.93 (95% CI, 0.83-1.00; P \u003c .001). At baseline, individuals with CBS-AD (n = 12), defined by a PET-validated plasma p-tau217 cutoff 0.25 pg/mL or greater, had increased temporoparietal atrophy at baseline compared to individuals with CBS-FTLD (n = 39), whereas longitudinally, individuals with CBS-FTLD had faster brainstem atrophy rates. Individuals with CBS-FTLD also progressed more rapidly on a modified version of the PSP Rating Scale than those with CBS-AD (mean [SD], 3.5 [0.5] vs 0.8 [0.8] points/year; P = .005).\n\nCONCLUSIONS AND RELEVANCE:\nIn this cohort study, plasma p-tau217 had excellent diagnostic performance for identifying Aβ or FTP PET positivity within CBS with likely underlying AD pathology. Plasma P-tau217 may be a useful and inexpensive biomarker to select patients for CBS clinical trials." + } +} \ No newline at end of file diff --git a/37014788.json b/37014788.json new file mode 100644 index 0000000000000000000000000000000000000000..54cde2a9954e4dd0a1cf44ad34ec2ec49dff156a --- /dev/null +++ b/37014788.json @@ -0,0 +1,8 @@ +{ + "id": "37014788", + "label": 0, + "article": { + "id": "37014788", + "text": "Apolipoprotein E (ApoE)'s ϵ4 alle is the most important genetic risk factor for late onset Alzheimer's Disease (AD). Cell-surface heparan sulfate (HS) is a cofactor for ApoE/LRP1 interaction and the prion-like spread of tau pathology between cells. 3-O-sulfo (3-O-S) modification of HS has been linked to AD through its interaction with tau, and enhanced levels of 3-O-sulfated HS and 3-O-sulfotransferases in the AD brain. In this study, we characterized ApoE/HS interactions in wildtype ApoE3, AD-linked ApoE4, and AD-protective ApoE2 and ApoE3-Christchurch. Glycan microarray and SPR assays revealed that all ApoE isoforms recognized 3-O-S. NMR titration localized ApoE/3-O-S binding to the vicinity of the canonical HS binding motif. In cells, the knockout of HS3ST1-a major 3-O sulfotransferase-reduced cell surface binding and uptake of ApoE. 3-O-S is thus recognized by both tau and ApoE, suggesting that the interplay between 3-O-sulfated HS, tau and ApoE isoforms may modulate AD risk." + } +} \ No newline at end of file diff --git a/37014877.json b/37014877.json new file mode 100644 index 0000000000000000000000000000000000000000..1f0a555ded643c0357bf5057555cc8809abb2152 --- /dev/null +++ b/37014877.json @@ -0,0 +1,8 @@ +{ + "id": "37014877", + "label": 0, + "article": { + "id": "37014877", + "text": "Intracellular accumulation of tau protein is a hallmark of Alzheimer's Disease and Progressive Supranuclear Palsy, as well as other neurodegenerative disorders collectively known as tauopathies. Despite our increasing understanding of the mechanisms leading to the initiation and progression of tau pathology, the field still lacks appropriate disease models to facilitate drug discovery. Here, we established a novel and modulatable seeding-based neuronal model of full-length 4R tau accumulation using humanized mouse cortical neurons and seeds from P301S human tau transgenic animals. The model shows specific and consistent formation of intraneuronal insoluble full-length 4R tau inclusions, which are positive for known markers of tau pathology (AT8, PHF-1, MC-1), and creates seeding competent tau. The formation of new inclusions can be prevented by treatment with tau siRNA, providing a robust internal control for use in qualifying the assessment of potential therapeutic candidates aimed at reducing the intracellular pool of tau. In addition, the experimental set up and data analysis techniques used provide consistent results in larger-scale designs that required multiple rounds of independent experiments, making this is a versatile and valuable cellular model for fundamental and early pre-clinical research of tau-targeted therapies." + } +} \ No newline at end of file diff --git a/37016537.json b/37016537.json new file mode 100644 index 0000000000000000000000000000000000000000..3f00c2c65e9c4900ed8c68ea2221cb2155f45b24 --- /dev/null +++ b/37016537.json @@ -0,0 +1,8 @@ +{ + "id": "37016537", + "label": 0, + "article": { + "id": "37016537", + "text": "Triple-negative breast cancer (TNBC), which accounts for 10%-20% of breast cancer cases, is characterized by a higher metastasis rate, higher recurrence risk, and worse prognosis. Traditional treatments such as chemotherapy, surgery, and radiotherapy have limited therapeutic effects. Although immune checkpoint blockade (ICB) therapy represented by anti-programmed death 1 (aPD-1) antibody has made further progress in treating TNBC, its therapeutic effect is still not optimistic. Ataxia telangiectasia mutated (ATM) is a critical factor in the DNA damage response (DDR) pathway, which is associated with the development of tumors. Recent studies have found that it can regulate the tumor immune microenvironment, affecting ICB responsiveness. Inhibition of ATM could enhance ICB therapy by promoting mitochondrial DNA cytoplasmic leakage and activating the innate immune signaling pathway. To explore the effect of ATM siRNA(siATM) on the ICB responsiveness of TNBC, we designed and synthesized nanoparticles using 1,2-dioleoyl-glycero-3-phosphatidylcholine (DOPC) liposomes to deliver siATM. and experiments demonstrated that DOPC/siATM could enhance the ability of siRNA to enter tumor cells and effectively inhibit the expression of ATM protein. Our study found that nanoparticles carrying siATM could activate cytotoxic T lymphocytes and regulate the immunosuppressive tumor microenvironment (ITM) by activating the cGAS-STING pathway. Its combination with aPD-1 may be a potential way to improve the efficacy of TNBC." + } +} \ No newline at end of file diff --git a/37017348.json b/37017348.json new file mode 100644 index 0000000000000000000000000000000000000000..efd7e6b6afc9732faba58ecebebc6ead1b5efe02 --- /dev/null +++ b/37017348.json @@ -0,0 +1,8 @@ +{ + "id": "37017348", + "label": 0, + "article": { + "id": "37017348", + "text": "Infections are among the leading causes of morbidity and mortality in lymphoproliferative malignancies such as multiple myeloma (MM) and chronic lymphocytic leukemia (CLL). The causes of infections are often multifactorial and may be due to disease- or treatment-related factors. New therapies have improved survival in lymphoproliferative malignancies, resulting in an increased incidence of secondary immune deficiencies (SID) in these diseases." + } +} \ No newline at end of file diff --git a/37017400.json b/37017400.json new file mode 100644 index 0000000000000000000000000000000000000000..6c354e98ddbb1ea76435c216a03ffc2d4e2565be --- /dev/null +++ b/37017400.json @@ -0,0 +1,8 @@ +{ + "id": "37017400", + "label": 0, + "article": { + "id": "37017400", + "text": "Surgical resection is rarely employed for the treatment of metastatic gastric cancer, especially in patients with adrenal metastases, which usually indicate advanced systemic dissemination. Few published case reports have thus described the use of adrenalectomy for adrenal metastases from gastric cancer. In addition, most primary gastric malignancies are gastric adenocarcinomas, and gastric large cell neuroendocrine carcinoma (GLCNEC) is less common and has a poor prognosis. We report the case of a 71-year-old man who was diagnosed with solitary adrenal metastases 10 months after radical resection for GLCNEC and who was treated by adrenalectomy. He was followed-up for 9 months after adrenalectomy, with no further evidence of disease at his last follow-up examination. This case indicates that elective surgical resection may be feasible, even in rare cases of GLCNEC metastases to the adrenal glands, provided that the patient meets certain criteria, including solitary, metachronous tumors less than 4 cm." + } +} \ No newline at end of file diff --git a/37018629.json b/37018629.json new file mode 100644 index 0000000000000000000000000000000000000000..5bd8e37e5e48e98a0aa113f791633d0e441c6fb9 --- /dev/null +++ b/37018629.json @@ -0,0 +1,8 @@ +{ + "id": "37018629", + "label": 0, + "article": { + "id": "37018629", + "text": "STUDY QUESTION:\nAre genetic disorders and congenital malformations associated with premature ovarian insufficiency (POI)?\n\nSUMMARY ANSWER:\nA wide range of genetic disorder and congenital malformation diagnoses are associated with POI, especially early onset POI.\n\nWHAT IS KNOWN ALREADY:\nPOI is known to be associated with some genetic disorders, such as Turner syndrome and Fragile X premutation. Multiple genetic syndromes, such as ataxia teleangiectasia and galactosemia, have also been associated with an increased risk of POI, and many of these genetic syndromes manifest with various congenital malformations. In previous studies, a genetic aetiology has been found for 7-15% of POI cases.\n\nSTUDY DESIGN, SIZE, DURATION:\nThis population-based study included 5011 women diagnosed with POI in 1988-2017. The data were collected from various national registries and covers women with POI nationwide.\n\nPARTICIPANTS/MATERIALS, SETTING, METHODS:\nWe identified 5011 women diagnosed with POI from 1988 to 2017 from the drug reimbursement registry of the Social Insurance Institution of Finland. Women with surgical POI (bilateral oophorectomy for benign indications) were not included. We selected four population controls per woman with POI matched by month and year of birth and municipality of residence. Diagnostic codes for genetic disorders and congenital malformations (GD/CM) for the cases and controls were searched from the Hospital Discharge Register. Binary logistic regression was used to compare the odds for GD/CM among cases and controls. To minimize bias, for the statistical analyses, we excluded diagnoses which were reported \u003c2 years prior to the index date.\n\nMAIN RESULTS AND THE ROLE OF CHANCE:\nOf the women with POI, 15.9% (n = 797) had at least one diagnostic code for GD or CM. The odds ratio (OR) for Turner syndrome was 275 (95% CI 68.1-1110), and for other sex chromosome abnormalities, it was 12.7 (95% CI 4.1-39.1). For autosomal single gene disorders, the OR was 16.5 (95% CI 6.2-43.7). Women with POI had a higher odds of having a GD/CM diagnosis in all categories. The OR for GD/CM diagnoses was highest among the youngest POI patients (10-14 years old, OR 24.1, 95% CI 15.1-38.2). The odds of having POI were higher the more GD or CM diagnoses a woman had.\n\nLIMITATIONS, REASONS FOR CAUTION:\nSome women with POI might not have sought help for their symptoms and therefore remain undiagnosed. Due to the register-based nature of our study, we did not have access to more specific genetic diagnoses than international classification of diseases offers.\n\nWIDER IMPLICATIONS OF THE FINDINGS:\nGD/CM diagnoses were strongly associated with POI, especially when POI was diagnosed at a young age. The risk of POI was highest in women with multiple GD/CM diagnoses. Early onset POI can be a sign of underlying genetic disorder or congenital anomaly, and this should serve as a reminder for clinicians to consider further examinations. To avoid unnecessary delay in the diagnosis of POI and starting relevant hormone replacement therapy treatment, clinicians should be aware of these associations.\n\nSTUDY FUNDING/COMPETING INTEREST(S):\nOulu University Hospital financially supported this work. H.S. has received personal grants from the Finnish Menopause Society, Oulu Medical Research Foundation, and Finnish Research Foundation of Gynaecology and Obstetrics. S.S. has received grants from the Finnish Menopause Society, the Finnish Medical Foundation, and the Juho Vainio Foundation. None of the authors have any competing interests to declare.\n\nTRIAL REGISTRATION NUMBER:\nN/A." + } +} \ No newline at end of file diff --git a/37018730.json b/37018730.json new file mode 100644 index 0000000000000000000000000000000000000000..348f6842e7658cc2896010ad7266e238e2a30817 --- /dev/null +++ b/37018730.json @@ -0,0 +1,8 @@ +{ + "id": "37018730", + "label": 0, + "article": { + "id": "37018730", + "text": "T-cell lymphoblastic lymphoma (T-LLy) and T-cell acute lymphoblastic leukemia (T-ALL) have historically been considered a spectrum of the same disease. However, recent evidence demonstrating differential responses to chemotherapy raise the possibility that T-LLy and T-ALL are distinct clinical and biologic entities. Here, we examine differences between the two diseases and use illustrative cases to highlight key recommendations on how to best treat newly diagnosed and relapsed/refractory T-LLy patients. We discuss results of recent clinical trials incorporating use of nelarabine and bortezomib, choice of induction steroid, role of cranial radiotherapy, and risk stratification markers to identify patients at highest risk of relapse and to further refine current treatment strategies. Because prognosis for relapsed or refractory T-LLy patients is poor, we discuss ongoing investigations incorporating novel therapies, including immunotherapeutics, into upfront and salvage regimens and the role of hematopoietic stem cell transplantation." + } +} \ No newline at end of file diff --git a/37020198.json b/37020198.json new file mode 100644 index 0000000000000000000000000000000000000000..50d93831c1b0167fc6164cc0751eb975e96d24fc --- /dev/null +++ b/37020198.json @@ -0,0 +1,8 @@ +{ + "id": "37020198", + "label": 0, + "article": { + "id": "37020198", + "text": "BACKGROUND:\nPediatric cancer is the leading cause of disease-related death in children and the need for better therapeutic options remains urgent. Due to the limited number of patients, target and drug development for pediatrics is often supplemented by data from studies focused on adult cancers. Recent evidence shows that pediatric cancers possess different vulnerabilities that should be explored independently from adult cancers.\n\nMETHODS:\nUsing the publicly available Genomics of Drug Sensitivity in Cancer database, we explore therapeutic targets and biomarkers specific to the pediatric solid malignancies Ewing sarcoma, medulloblastoma, neuroblastoma, osteosarcoma, and rhabdomyosarcoma. Results are validated using cell viability assays and high-throughput drug screens are used to identify synergistic combinations.\n\nRESULTS:\nUsing published drug screening data, PARP is identified as a drug target of interest across multiple different pediatric malignancies. We validate these findings, and we show that efficacy can be improved when combined with conventional chemotherapeutics, namely topoisomerase inhibitors. Additionally, using gene set enrichment analysis, we identify ribosome biogenesis as a potential biomarker for PARP inhibition in pediatric cancer cell lines.\n\nCONCLUSION:\nCollectively, our results provide evidence to support the further development of PARP inhibition and the combination with TOP1 inhibition as a therapeutic approach in solid pediatric malignancies. Additionally, we propose ribosome biogenesis as a component to PARP inhibitor sensitivity that should be further investigated to help maximize the potential utility of PARP inhibition and combinations across pediatric solid malignancies." + } +} \ No newline at end of file diff --git a/37020231.json b/37020231.json new file mode 100644 index 0000000000000000000000000000000000000000..f309123198ab8ffe7395f14a62d1b41a2191c178 --- /dev/null +++ b/37020231.json @@ -0,0 +1,8 @@ +{ + "id": "37020231", + "label": 0, + "article": { + "id": "37020231", + "text": "BACKGROUND:\nDonor-derived CD7-directed chimeric antigen receptor (CAR) T cells showed feasibility and early efficacy in patients with refractory or relapsed T-cell acute lymphoblastic leukemia (r/r T-ALL), in a previous phase I trial report, at a median follow-up of 6.3 months. Here we report long-term safety and activity of the therapy after a 2-year follow-up.\n\nMETHODS:\nParticipants received CD7-directed CAR T cells derived from prior stem cell transplantation (SCT) donors or from HLA-matched new donors after lymphodepletion. The target dose was 1 × 10 (± 30%) CAR T cells per kg of patient weight. The primary endpoint was safety with efficacy secondary. This report focuses on the long-term follow-up and discusses them in the context of previously reported early outcomes.\n\nRESULTS:\nTwenty participants were enrolled and received infusion with CD7 CAR T cells. After a median follow-up time of 27.0 (range, 24.0-29.3) months, the overall response rate and complete response rate were 95% (19/20 patients) and 85% (17/20 patients), respectively, and 35% (7/20) of patients proceeded to SCT. Six patients experienced disease relapse with a median time-to-relapse of 6 (range, 4.0-10.9) months, and 4 of these 6 patients were found to have lost CD7 expression on tumor cells. Progression-free survival (PFS) and overall survival (OS) rates 24 months after treatment were respectively 36.8% (95% CI, 13.8-59.8%) and 42.3% (95% CI, 18.8-65.8%), with median PFS and OS of respectively 11.0 (95% CI, 6.7-12.5) months and 18.3 (95% CI, 12.5-20.8) months. Previously reported short-term adverse events (\u003c 30 days after treatment) included grade 3-4 cytokine release syndrome (CRS; 10%) and grade 1-2 graft-versus-host disease (GVHD; 60%). Serious adverse events reported \u003e 30 days after treatment included five infections and one grade 4 intestinal GVHD. Despite good CD7 CAR T-cell persistence, non-CAR T and natural killer cells were predominantly CD7-negative and eventually returned to normal levels in about half of the participants.\n\nCONCLUSIONS:\nIn this 2-year follow-up analysis, donor-derived CD7 CAR T-cell treatment demonstrated durable efficacy in a subset of patients with r/r T-ALL. Disease relapse was the main cause of treatment failure, and severe infection was a noteworthy late-onset adverse event.\n\nTRIAL REGISTRATION:\nChiCTR2000034762." + } +} \ No newline at end of file diff --git a/37020276.json b/37020276.json new file mode 100644 index 0000000000000000000000000000000000000000..9710275f70c7710c3533914dacd8b59509f35a67 --- /dev/null +++ b/37020276.json @@ -0,0 +1,8 @@ +{ + "id": "37020276", + "label": 0, + "article": { + "id": "37020276", + "text": "BACKGROUND:\nGenomic alterations, including loss of function in chromosome band 11q22-23, are frequently observed in neuroblastoma, which is the most common extracranial childhood tumour. In neuroblastoma, ATM, a DNA damage response-associated gene located on 11q22-23, has been linked to tumorigenicity. Genetic changes in ATM are heterozygous in most tumours. However, it is unclear how ATM is associated with tumorigenesis and cancer aggressiveness.\n\nMETHODS:\nTo elucidate its molecular mechanism of action, we established ATM-inactivated NGP and CHP-134 neuroblastoma cell lines using CRISPR/Cas9 genome editing. The knock out cells were rigorously characterized by analyzing proliferation, colony forming abilities and responses to PARP inhibitor (Olaparib). Western blot analyses were performed to detect different protein expression related to DNA repair pathway. ShRNA lentiviral vectors were used to knockdown ATM expression in SK-N-AS and SK-N-SH neuroblastoma cell lines. ATM knock out cells were stably transfected with FANCD2 expression plasmid to over-expressed the FANCD2. Moreover, knock out cells were treated with proteasome inhibitor MG132 to determine the protein stability of FANCD2. FANCD2, RAD51 and γH2AX protein expressions were determined by Immunofluorescence microscopy.\n\nRESULTS:\nHaploinsufficient ATM resulted in increased proliferation (p \u003c 0.01) and cell survival following PARP inhibitor (olaparib) treatment. However, complete ATM knockout decreased proliferation (p \u003c 0.01) and promoted cell susceptibility to olaparib (p \u003c 0.01). Complete loss of ATM suppressed the expression of DNA repair-associated molecules FANCD2 and RAD51 and induced DNA damage in neuroblastoma cells. A marked downregulation of FANCD2 expression was also observed in shRNA-mediated ATM-knockdown neuroblastoma cells. Inhibitor experiments demonstrated that the degradation of FANCD2 was regulated at the protein level through the ubiquitin-proteasome pathway. Reintroduction of FANCD2 expression is sufficient to reverse decreased proliferation mediated by ATM depletion.\n\nCONCLUSIONS:\nOur study revealed the molecular mechanism underlying ATM heterozygosity in neuroblastomas and elucidated that ATM inactivation enhances the susceptibility of neuroblastoma cells to olaparib treatment. These findings might be useful in the treatment of high-risk NB patients showing ATM zygosity and aggressive cancer progression in future." + } +} \ No newline at end of file diff --git a/37020384.json b/37020384.json new file mode 100644 index 0000000000000000000000000000000000000000..a95d3e6e6bef74be8ea9217c8b55a44fe6853998 --- /dev/null +++ b/37020384.json @@ -0,0 +1,8 @@ +{ + "id": "37020384", + "label": 0, + "article": { + "id": "37020384", + "text": "Rolipram is a selective phosphodiesterase-4 (PDE4) inhibitor. The effect of rolipram on the metastasis of choriocarcinoma is barely known. Here, we evaluated the role of rolipram in the migration and invasion of human choriocarcinoma cells in vitro. Human choriocarcinoma cells lines JEG3 and JAR were used in this study. The expression profile of PDE4 subfamily members in choriocarcinoma cells was evaluated using real-time PCR. The migration and invasion properties of choriocarcinoma cells before and after inhibition of PDE4 by rolipram or RNAi-directed knockdown were evaluated in vitro. Expression levels of MMP9, TIMP1, E-cadherin, vimentin, TGFβ1, SMAD1, and SMAD4 of choriocarcinoma cells were compared before and after rolipram treatment, RNAi-directed knockdown of PDE4D, and overexpression of PDE4D. We found PDE4D was the most commonly expressed isoform of PDE4 both in JEG3 and JAR cells. Rolipram and knockdown of PDE4D were efficient to inhibit the migration and invasion of choriocarcinoma cells in vitro, accompanied by decreased expression of MMP9 and TIMP1. Furthermore, rolipram and knockdown of PDE4D promoted the expression of E-cadherin but reduced the expression of vimentin in choriocarcinoma cells, and overexpression of PDE4D decreased the expression of E-cadherin but promoted the expression of vimentin. Rolipram suppressed migration and invasion of human choriocarcinoma cells in vitro, possibly by inhibiting epithelial-mesenchymal transition through PDE4 inhibition." + } +} \ No newline at end of file diff --git a/37020431.json b/37020431.json new file mode 100644 index 0000000000000000000000000000000000000000..5ed688009c39f424d95433754a5f473489740229 --- /dev/null +++ b/37020431.json @@ -0,0 +1,8 @@ +{ + "id": "37020431", + "label": 0, + "article": { + "id": "37020431", + "text": "The aim was to develop and update a guideline which would improve the quality of care offered to women with gestational and non-gestational trophoblastic disease, a group of diseases characterized by their rarity and biological heterogeneity. In accordance with the method used to compile S2k-guidelines, the guideline authors carried out a search of the literature (MEDLINE) for the period 1/2020 to 12/2021 and evaluated the recent literature. No key questions were formulated. No structured literature search with methodical evaluation and assessment of the level of evidence was carried out. The text of the precursor version of the guideline from 2019 was updated based on the most recent literature, and new statements and recommendations were drafted. The updated guideline contains recommendations for the diagnosis and therapy of women with hydatidiform mole (partial and complete moles), gestational trophoblastic neoplasia after pregnancy or without prior pregnancy, persistent trophoblastic disease after molar pregnancy, invasive moles, choriocarcinoma, placental site nodules, placental site trophoblastic tumor, hyperplasia at the implantation site und epithelioid trophoblastic tumor. Separate chapters cover the determination and assessment of human chorionic gonadotropin (hCG), histopathological evaluation of specimens, and the appropriate molecular pathological and immunohistochemical diagnostic procedures. Separate chapters on immunotherapy, surgical therapy, multiple pregnancies with simultaneous trophoblastic disease, and pregnancy after trophoblastic disease were formulated, and the corresponding recommendations agreed upon." + } +} \ No newline at end of file diff --git a/37020528.json b/37020528.json new file mode 100644 index 0000000000000000000000000000000000000000..fba15c35e10efa704e8ce1df8b869bfae94869f2 --- /dev/null +++ b/37020528.json @@ -0,0 +1,8 @@ +{ + "id": "37020528", + "label": 0, + "article": { + "id": "37020528", + "text": "Drug resistance and relapse of T-cell acute lymphoblastic leukemia (T-ALL) remain significant concerns for physicians; hence, the development and screening of effective targeted drugs remain important. Considering that STAT3 is emerging as a potential therapeutic target for T-ALL, T-ALL cell lines (MOLT-4 and CUTLL1) were treated with BP-1-102, a small-molecule inhibitor that blocks STAT3 phosphorylation. Cell Counting Kit-8 assay and colony formation assay results showed that BP-1-102 inhibited T-ALL cell proliferation and colony formation. Flow cytometry and morphological results demonstrated that BP-1-102 dramatically induced apoptosis and caused cell cycle arrest at the G/G phase in T-ALL cell lines. Western blotting results indicated that BP-1-102 suppressed the JAK2/STAT3/c-Myc pathway activity in T-ALL cell lines. In conclusion, BP-1-102 suppressed the JAK2/STAT3/c-Myc signaling pathway in T-ALL cells and exerted various antitumor effects, representing a promising targeted antitumor inhibitor." + } +} \ No newline at end of file diff --git a/37020843.json b/37020843.json new file mode 100644 index 0000000000000000000000000000000000000000..72960c3f12d34c4e54fbac9ddafa0e84388ee92a --- /dev/null +++ b/37020843.json @@ -0,0 +1,8 @@ +{ + "id": "37020843", + "label": 0, + "article": { + "id": "37020843", + "text": "Intussusception is the invagination of a proximal bowel segment into a distal segment causing bowel obstruction, especially in children. In some cases, it can be caused by a pathological lead point, such as Burkitt lymphoma. Burkitt lymphoma has several patterns of clinical presentations, such as jaw or facial bone tumor in the endemic form, in contrast to an abdominal presentation most often with massive disease and ascites. We describe a case of a 4-year-old male who presented bowel obstruction. Using X-ray and ultrasound findings, ileocecal intussusception was then diagnosed. Resection and anastomosis was performed after multiple trials of failed hydrostatic reduction. On the pathology report of the resected segment, Burkitt lymphoma was found to be the cause and chemotherapy was initiated. The patient is doing well and is following up every 6 months for 2 years. A pathological lead point, especially Burkitt lymphoma, should be suspected in patients with failed conservative treatment, and prompt diagnosis of the pathology should be performed to prevent further sequela of the disease." + } +} \ No newline at end of file diff --git a/37021299.json b/37021299.json new file mode 100644 index 0000000000000000000000000000000000000000..377583423e7ee4f03a2d809dda2a0dac6afaf1b0 --- /dev/null +++ b/37021299.json @@ -0,0 +1,8 @@ +{ + "id": "37021299", + "label": 0, + "article": { + "id": "37021299", + "text": "Based on the literature, there are only three reports available to date on synchronous Kaposi sarcoma (KS) and renal cell carcinoma (RCC), at least to the best of our knowledge. The present study reports a rare case of synchronous classic KS and clear cell RCC. A 69-year-old male presented with painful, purplish nodular lesions on the dorsal aspect of his hands and feet. He had no chronic medical illnesses or prior surgical interventions. An excisional biopsy of one of the lesions revealed a nodular dermal lesion with numerous vascular channels and interlacing spindle cells. A 2.5 cm-enhancing mass was found in a contrast-enhanced computed tomography scan of the abdomen, suggesting RCC or metastasis. A partial nephrectomy was performed, and the histopathological findings were consistent with clear cell RCC. The patient responded well to paclitaxel and topical imiquimod (5%), and the skin lesions disappeared. Both KS and RCC are vascular tumors, and their pathogenesis is commonly affected by an angiogenic factor known as vascular endothelial growth factor (VEGF). A complete response of KS was observed after sorafenib, an inhibitor of VEGF receptors, was administered for the treatment of metastatic renal cancer. This reinforces the fact that there is a common therapeutic and pathogenetic pathway between these two neoplasms. Synchronous KS and clear cell RCC are rare findings. Their simultaneous appearance may be triggered by the common enhancing angiogenic factor, VEGF." + } +} \ No newline at end of file diff --git a/37022631.json b/37022631.json new file mode 100644 index 0000000000000000000000000000000000000000..1b8db76e1f26217af79e1a0b4de4a9c73c8dacf3 --- /dev/null +++ b/37022631.json @@ -0,0 +1,8 @@ +{ + "id": "37022631", + "label": 0, + "article": { + "id": "37022631", + "text": "BACKGROUND:\nLeiomyosarcoma is classified as a soft tissue sarcoma. In adults, leiomyosarcoma is the most common malignancy affecting the vascular system; however, vascular leiomyosarcoma in children is extremely rare as most pediatric soft tissue tumors are rhabdomyosarcomas. The survival rate is very low, and incomplete resection is a poor prognostic factor. There is also a high rate of distant recurrence, with the lungs and liver being the most common sites of metastasis. There is no established effective chemotherapy, and complete surgical resection is the only potentially curative treatment for leiomyosarcoma.\n\nCASE PRESENTATION:\nA 15-year-old female patient with no significant medical history presented with severe upper abdominal pain and was admitted. Abdominal contrast-enhanced computed tomography and magnetic resonance imaging showed a large retroperitoneal tumor protruding into the lumen of the inferior vena cava behind the liver and multiple small nodules, and metastasis to the liver was suspected. The tumor was 6 × 4 × 5 cm in diameter, located just behind the hepatic hilar structures, and was suspected to infiltrate into the right portal vein. The tumor was diagnosed as a leiomyosarcoma through an open tumor biopsy. As the multiple liver metastases were located only in the right lobe of the liver on imaging, we performed tumor resection with right hepatectomy and replacement of the inferior vena cava (IVC). The postoperative course was uneventful; however, on postoperative day 51, distant metastatic recurrences were found in the remaining liver and right lung. The patient was immediately started on chemotherapy and trabectedin proved to be the most effective drug in the treatment regimen; however, severe side effects, such as hepatotoxicity, prevented timely administration, and the patient passed away 19 months after surgery.\n\nCONCLUSIONS:\nIVC resection and reconstruction combined with right hepatectomy were able to be safely performed even in a pediatric case. To improve the prognosis of leiomyosarcoma with multiple metastases, an effective treatment strategy combining surgical treatment and chemotherapy, including molecularly targeted drugs, should be established as early as possible." + } +} \ No newline at end of file diff --git a/37025922.json b/37025922.json new file mode 100644 index 0000000000000000000000000000000000000000..8acd2e477f491bbdf78bd4e22686917a5699679d --- /dev/null +++ b/37025922.json @@ -0,0 +1,8 @@ +{ + "id": "37025922", + "label": 0, + "article": { + "id": "37025922", + "text": "INTRODUCTION:\nThanks to recent advances in synthetic methodology, water-soluble fullerene nanomaterials that interfere with biomolecules, especially DNA/RNA and selected proteins, have been found with tremendous potential for applications in nanomedicine. Herein, we describe the synthesis and evaluation of a water-soluble glycine-derived [60]fullerene hexakisadduct (HDGF) with T symmetry, which is a first-in-class BTK protein inhibitor.\n\nMETHODS:\nWe synthesized and characterized glycine derived [60]fullerene using NMR, ESI-MS, and ATR-FT-IR. DLS and zeta potential were measured and high-resolution transmission electron microscopy (HRTEM) observations were performed. The chemical composition of the water-soluble fullerene nanomaterial was examined by X-ray photoelectron spectrometry. To observe aggregate formation, the cryo-TEM analysis was carried out. The docking studies and molecular dynamic simulations were performed to determine interactions between HDGF and BTK. The in vitro cytotoxicity was evaluated on RAJI and K562 blood cancer cell lines. Subsequently, we examined the induction of cell death by autophagy and apoptosis by determining the expression levels of crucial genes and caspases. We investigated the direct association of HDGF on inhibition of the BTK signalling pathway by examining changes in the calcium levels in RAJI cells after treatment. The inhibitory potential of HDGF against non-receptor tyrosine kinases was evaluated. Finally, we assessed the effects of HDGF and ibrutinib on the expression of the BTK protein and downstream signal transduction in RAJI cells following anti-IgM stimulation.\n\nRESULTS:\nComputational studies revealed that the inhibitory activity of the obtained [60]fullerene derivative is multifaceted: it hampers the BTK active site, interacting directly with the catalytic residues, rendering it inaccessible to phosphorylation, and binds to residues that form the ATP binding pocket. The anticancer activity of produced carbon nanomaterial revealed that it inhibited the BTK protein and its downstream pathways, including PLC and Akt proteins, at the cellular level. The mechanistic studies suggested the formation of autophagosomes (increased gene expression of and ) and two caspases (caspase-3 and -9) were responsible for the activation and progression of apoptosis.\n\nCONCLUSION:\nThese data illustrate the potential of fullerene-based BTK protein inhibitors as nanotherapeutics for blood cancer and provide helpful information to support the future development of fullerene nanomaterials as a novel class of enzyme inhibitors." + } +} \ No newline at end of file diff --git a/37026918.json b/37026918.json new file mode 100644 index 0000000000000000000000000000000000000000..3597039bd516b817bcbccaaa935c71f6928b0338 --- /dev/null +++ b/37026918.json @@ -0,0 +1,8 @@ +{ + "id": "37026918", + "label": 0, + "article": { + "id": "37026918", + "text": "Recent studies have identified a novel programmed cell death based on copper, named cuproptosis. However, as an anti-cuproptosis gene, the functional roles, definite mechanisms and prognostic value of CDKN2A in pan-cancer are largely unclear. The GEPIA2, cancer genome atlas (TCGA), the tumor immune estimation resource 2.0 and CPTAC databases were performed to validate the differential expression of CDKN2A in 33 tumors. The clinical features and survival prognosis analysis were conducted by GEPIA2 and UALCAN web tool. Genetic alteration analysis of CDKN2A in pan-cancer was also evaluated. Furthermore, the functional roles of CDKN2A were explored via DNA methylation analysis, tumor microenvironment, infiltration of immune cells, enrichment analysis and gene co-expression associated with cuproptosis and immune regulation. The CDKN2A expression, both at the transcriptional and translational level, was obviously upregulated in most cancer patients, which might lead to poor survival in certain cancer types. CDKN2A expression was significantly associated with tumor pathological stages in some cancer types. In adrenocortical carcinoma (ACC) and kidney renal clear cell carcinoma (KIRC), DNA methylation of CDKN2A was explored to induce poor clinical outcomes. Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis indicated that CDKN2A expression was closely related to several cancer-associated signaling pathways, such as the p53 signaling pathway, Cellular senescence, DNA replication and Cell cycle signaling pathways. Gene set enrichment analysis (GSEA) analysis suggested that aberrantly expressed CDKN2A took part in the cell cycle regulation, immune regulation and mitochondrial signaling pathways in certain cancer patients. In addition, aberrant CDKN2A expression was closely correlated to immune infiltration and the levels of immune-regulatory genes. The study deeply defined the concrete roles of cuproptosis-related gene CDKN2A in tumorigenesis. The results provided new insights and pieces of evidence for treatment." + } +} \ No newline at end of file diff --git a/37027192.json b/37027192.json new file mode 100644 index 0000000000000000000000000000000000000000..53bd4a744c1e8721d54a93a543e21af5352313c5 --- /dev/null +++ b/37027192.json @@ -0,0 +1,8 @@ +{ + "id": "37027192", + "label": 0, + "article": { + "id": "37027192", + "text": "OBJECTIVE:\nIn Friedreich ́s Ataxia (FRDA), the most affected tissues are not accessible to sampling and available transcriptomic findings originate from blood-derived cells and animal models. Herein, we aimed at dissecting for the first time the pathophysiology of FRDA by means of RNA-sequencing in an affected tissue sampled in vivo.\n\nMETHODS:\nSkeletal muscle biopsies were collected from seven FRDA patients before and after treatment with recombinant human Erythropoietin (rhuEPO) within a clinical trial. Total RNA extraction, 3'-mRNA library preparation and sequencing were performed according to standard procedures. We tested for differential gene expression with DESeq2 and performed gene set enrichment analysis with respect to control subjects.\n\nRESULTS:\nFRDA transcriptomes showed 1873 genes differentially expressed from controls. Two main signatures emerged: 1) a global downregulation of the mitochondrial transcriptome as well as of ribosome/translational machinery and 2) an upregulation of genes related to transcription and chromatin regulation, especially of repressor terms. Downregulation of the mitochondrial transcriptome was more profound than previously shown in other cellular systems. Furthermore, we observed in FRDA patients a marked upregulation of leptin, the master regulator of energy homeostasis. RhuEPO treatment further enhanced leptin expression.\n\nINTERPRETATION:\nOur findings reflect a double hit in the pathophysiology of FRDA: a transcriptional/translational issue, and a profound mitochondrial failure downstream. Leptin upregulation in the skeletal muscle in FRDA may represent a compensatory mechanism of mitochondrial dysfunction, which is amenable to pharmacological boosting. Skeletal muscle transcriptomics is a valuable biomarker to monitor therapeutic interventions in FRDA." + } +} \ No newline at end of file diff --git a/37027246.json b/37027246.json new file mode 100644 index 0000000000000000000000000000000000000000..f626836f3435e2c892ca00ef62c029f57d63fb1c --- /dev/null +++ b/37027246.json @@ -0,0 +1,8 @@ +{ + "id": "37027246", + "label": 0, + "article": { + "id": "37027246", + "text": "Given the shortage of fludarabine, alternative preparative lymphodepleting regimens for CAR-T-cell therapy need to be identified. We present a case of relapsed/refractory B-cell acute lymphoblastic leukemia requiring multiple lines of salvage therapy with persistent extensive disease, who underwent lymphodepletion with clofarabine and cyclophosphamide before tisagenlecleucel CD19+ CAR-T-cell infusion with eventual remission. We offer evidence of clofarabine's activity against B-cell acute lymphoblastic leukemia in combination with tisagenlecleucel therapy. In this patient, clofarabine did not decrease CAR-T-cell effectiveness, supported by presence of cytokine release syndrome and ultimate minimal residual disease negativity both on flow cytometry and next-generation sequencing." + } +} \ No newline at end of file diff --git a/37027952.json b/37027952.json new file mode 100644 index 0000000000000000000000000000000000000000..b0971cb2f8aa69c340b8e4823423e201e5b360a7 --- /dev/null +++ b/37027952.json @@ -0,0 +1,8 @@ +{ + "id": "37027952", + "label": 0, + "article": { + "id": "37027952", + "text": "Understanding oncogenic processes and underlying mechanisms to advance research into human tumors is critical for effective treatment. Studies have shown that Metal regulatory transcription factor 2（MTF2) drives malignant progression in liver cancer and glioma. However, no systematic pan-cancer analysis of MTF2 has been performed. Here, we use University of California Santa Cruz, Cancer Genome Atlas , Genotype-Tissue Expression data, Tumor Immune Estimation Resource, and Clinical Proteomic Tumor Analysis Consortium bioinformatics tools to explore differential expression of MTF2 across different tumor types. MTF2 was found to be highly expressed in the cancer lines that were available through the respective databases included in the study, and overexpression of MTF2 may lead to a poor prognosis in tumor patients such as glioblastoma multiforme, brain lower grade glioma, KIPAN, LIHC, adrenocortical carcinoma, etc. We also validated MTF2 mutations in cancer, compared MTF2 methylation levels in normal and primary tumor tissues, analyzed the association of MTF2 with the immune microenvironment, and validated the functional role of MTF2 in glioma U87 and U251 and breast cancer MDA-MB-231 cell lines by cytometry. This also indicates that MTF2 has a promising application prospect in cancer treatment." + } +} \ No newline at end of file diff --git a/37028800.json b/37028800.json new file mode 100644 index 0000000000000000000000000000000000000000..c35abb24fd5a7c94cf42958b5d354102a08e1c8e --- /dev/null +++ b/37028800.json @@ -0,0 +1,8 @@ +{ + "id": "37028800", + "label": 0, + "article": { + "id": "37028800", + "text": "Anaplastic classic Kaposi sarcoma (CKS) is an extremely rare pathologic variant of CKS characterized by high aggressiveness and poor prognosis. We report the clinical course of this malignant histologic form in an otherwise healthy 67-year-old male from Apulia in Southern Italy. The anaplastic progression arose during a long history of CKS and developed after multiple local and systemic treatments. The extremely aggressive and chemorefractory nature of the disease dictated amputation of a lower limb and, later, surgery for metastatic pulmonary involvement. At subsequent relapse, therapy with the anti-PD-1 inhibitor pembrolizumab was started. The immunotherapy was selected based on the PD-L1 expression in the tumor and tumor microenvironment. Remarkably, PD-1 blockade induced a complete and durable response in the patient, with a disease-free survival that has exceeded 18 months, and follow-up is still ongoing." + } +} \ No newline at end of file diff --git a/37029565.json b/37029565.json new file mode 100644 index 0000000000000000000000000000000000000000..eab2daaa070380846b4e93d7afab6ddb776f7e56 --- /dev/null +++ b/37029565.json @@ -0,0 +1,8 @@ +{ + "id": "37029565", + "label": 0, + "article": { + "id": "37029565", + "text": "Cell cycle checkpoint activation promotes DNA damage repair, which is highly associated with the chemoresistance of various cancers including acute myeloid leukemia (AML). Selective cell cycle checkpoint inhibitors are strongly demanded to overcome chemoresistance, but remain unexplored. A selective nano cell cycle checkpoint inhibitor (NCCI: citric acid capped ultra-small iron oxide nanoparticles) that can catalytically inhibit the cell cycle checkpoint of AML to boost the chemotherapeutic efficacy of genotoxic agents is now reported. NCCI can selectively accumulate in AML cells and convert H O to OH to cleave heat shock protein 90, leading to the degradation of ataxia telangiectasia and Rad3-related proteinand checkpoint kinase 1, and the subsequent dysfunction of the G2/M checkpoint. Consequently, NCCI revitalizes the anti-AML efficacy of cytarabine that is previously ineffective both in vitro and in vivo. This study offers new insights into designing selective cell cycle checkpoint inhibitors for biomedical applications." + } +} \ No newline at end of file diff --git a/37032137.json b/37032137.json new file mode 100644 index 0000000000000000000000000000000000000000..5a5739d5c1ff25ae297e4b1bb6f0427fbf8cac3a --- /dev/null +++ b/37032137.json @@ -0,0 +1,8 @@ +{ + "id": "37032137", + "label": 0, + "article": { + "id": "37032137", + "text": "To evaluate the clinical characteristics, treatment response, and outcomes in patients with classical hairy cell leukemia (cHCL) and HCL variant (HCL-V). This is a retrospective case series study. Between January 2011 and December 2021, clinical data of 30 patients newly with diagnosed HCL at Peking Union Medical College Hospital were analyzed. The main outcome measures include clinical characteristics, treatment efficacy and survival. The Kaplan-Meier method was used for survival analysis. Twenty-one cases of cHCL and 9 cases of HCL-v were included. The median age at diagnosis was 55.5 (range, 30-86) years, with the ratio of male to female 2.75∶1. The main clinical manifestations included fatigue in 11 cases (36.7%), abdominal distension in 7 cases (23.3%), and infection in 4 cases, while 8 cases were asymptomatic. Splenomegaly was reported in 24 cases (80.0%), including 7 (23.3%) with megalosplenia. The white blood cell count, lymphocyte count, and the proportion of peripheral hairy cells in HCL-v group were significantly higher than those in cHCL group, whereas the development of anemia, thrombocytopenia, and monocytopenia in cHCL group was more remarkable than that in HCL-v group (all 0.05). The BRAF-V600E gene mutation was detected only in cHCL patients (11/14 vs. 0/9, 0.001). In terms of immunophenotype, the expression of CD25, CD103, CD123 and CD200 in cHCL group (20/20, 20/20, 4/7, 7/17) were all stronger than those in HCL-v group (3/9, 7/9, 0/4, 2/8). Twenty-two patients were treated, of which 13 cases (12 cases of cHCL and 1 case of HCL-v) with cladribine, and 9 cases (4 cHCL and 5 HCL-v) with interferon. Complete remission rate and overall response rate were comparable between cladribine and interferon treatment groups (both 0.05). The median follow-up time was 31 (range, 1-125) months, and the median overall survival (OS) of the entire group was 125 months. The 5-year OS rate in HCL-v patients represented a trend of inferior (50.0% vs. 95.0%, 0.207). The clinical features of HCL are unspecific, which includes fatigue, splenomegaly and recurrent infection. The clinical features, immunophenotype, treatment response and prognosis of HCL-v are different from those of cHCL. BRAF-V600E gene mutation is suggested as a key marker for differential diagnosis. Cladribine is recommended as front-line regimen of cHCL patients with satisfactory efficacy and prognosis. Conversely, response and clinical outcome in HCL-v patients still need to be improved." + } +} \ No newline at end of file diff --git a/37032328.json b/37032328.json new file mode 100644 index 0000000000000000000000000000000000000000..b3ecf06c3514620ae23e3fbb061b2dc41903758d --- /dev/null +++ b/37032328.json @@ -0,0 +1,8 @@ +{ + "id": "37032328", + "label": 0, + "article": { + "id": "37032328", + "text": "Neuroinflammation is an important component of many neurodegenerative diseases, whether as a primary cause or a secondary outcome. For that reason, either as diagnostic tools or to monitor progression and/or pharmacological interventions, there is a need for robust biomarkers of neuroinflammation in the brain. Mitochondrial TSPO (18 kDa Translocator protein) is one of few available biomarkers of neuroinflammation for which there are clinically available PET imaging agents. In this study, we further characterised neuroinflammation in a mouse model of prion-induced chronic neurodegeneration (ME7) including a pharmacological intervention via a CSF1R inhibitor. This was achieved by autoradiographic binding of the second-generation TSPO tracer, [3H]PBR28, along with a more comprehensive examination of the cellular contributors to the TSPO signal changes by immunohistochemistry. We observed regional increases of TSPO in the ME7 mouse brains, particularly in the hippocampus, cortex and thalamus. This increased TSPO signal was detected in the cells of microglia/macrophage lineage as well as in astrocytes, endothelial cells and neurons. Importantly, we show that the selective CSF1R inhibitor, JNJ-40346527 (JNJ527), attenuated the disease-dependent increase in TSPO signal, particularly in the dentate gyrus of the hippocampus, where JNJ527 attenuated the number of Iba1+ microglia and neurons, but not GFAP+ astrocytes or endothelial cells. These findings suggest that [3H]PBR28 quantitative autoradiography in combination with immunohistochemistry are important translational tools for detecting and quantifying neuroinflammation, and its treatments, in neurodegenerative disease. Furthermore, we demonstrate that although TSPO overexpression in the ME7 brains was driven by various cell types, the therapeutic effect of the CSF1R inhibitor was primarily to modulate TSPO expression in microglia and neurons, which identifies an important route of biological action of this particular CSF1R inhibitor and provides an example of a cell-specific effect of this type of therapeutic agent on the neuroinflammatory process." + } +} \ No newline at end of file diff --git a/37033102.json b/37033102.json new file mode 100644 index 0000000000000000000000000000000000000000..2033a6bbe583ff677cd13a45fac0fd7df686de2f --- /dev/null +++ b/37033102.json @@ -0,0 +1,8 @@ +{ + "id": "37033102", + "label": 0, + "article": { + "id": "37033102", + "text": "Alveolar rhabdomyosarcoma (ARMS) is more common in children and rare in adults. A small number of cases in the stomach of an adult have been documented. The present study describes a case of primary gastric ARMS in a 20-year-old healthy female. The patient was admitted to Handan Central Hospital (Handan, China) with intermittent abdominal pain for \u003e1 month, which was noticeable and progressively worsened after meals, with black stools. Gastroscopy revealed a 2.5-cm ulcer on the side of the greater curvature of the gastric body, and a pathological biopsy revealed a neuroendocrine neoplasm. An enhanced abdominal computed tomography (CT) scan indicated a thickening and an ulcerated mass measuring ~4.5×2.0 cm at the gastric body, with the tumor showing poor enhancement. Finally, a laparoscopic distal gastrectomy was performed. The postoperative pathology combined with immunohistochemical staining indicated that the patient had primary alveolar RMS of the stomach. The present case suggests that an early diagnosis of gastric adenoid RMS is extremely difficult. However, this disease must be investigated in any young person who presents with a gastric mass. The current study presents a rare case of primary ARMS occurring in the stomach; however, more research on this disease is necessary to improve the clinical diagnosis and treatment." + } +} \ No newline at end of file diff --git a/37033919.json b/37033919.json new file mode 100644 index 0000000000000000000000000000000000000000..1f7ce3be6e141b200999e61dbb028fa6be1ea5fd --- /dev/null +++ b/37033919.json @@ -0,0 +1,8 @@ +{ + "id": "37033919", + "label": 0, + "article": { + "id": "37033919", + "text": "INTRODUCTION:\nThe ubiquitous Epstein-Barr virus (EBV) is an oncogenic herpes virus associated with several human malignancies. EBV is an immune-evasive pathogen that promotes CD8 T cell exhaustion and dysregulates CD4 T cell functions. Burkitt lymphoma (BL) is frequently associated with EBV infections. Since BL relapses after conventional therapies are difficult to treat, we evaluated prospective off-the-shelf edited CAR-T cell therapies targeting CD19 or the EBV gp350 cell surface antigen.\n\nMETHODS:\nWe used CRISPR/Cas9 gene editing methods to knock in (KI) the CD19CAR.CD28z or gp350CAR.CD28z into the T cell receptor (TCR) alpha chain () locus.\n\nRESULTS:\nApplying upscaled methods with the ExPERT ATx MaxCyte system, KI efficacy was ~20% of the total ~2 × 10 TCR-knocked-out (KO) generated cells. TCRCAR-T cells were co-cultured with the gp350CD19 BL cell lines Daudi (infected with type 1 EBV) or with Jiyoye (harboring a lytic type 2 EBV). Both types of CAR-T cells showed cytotoxic effects against the BL lines . CD8CAR-T cells showed higher persistency than CD4CAR-T cells after co-culture with BL and upregulation of the activation/exhaustion markers PD-1, LAG-3, and TIM-3. Two preclinical xenograft models were set up with Nod.Rag.Gamma mice injected intravenously (i.v.) with 2 × 10 Daudi/fLuc-GFP or with Jiyoye/fLuc-GFP cells. Compared with the non-treated controls, mice challenged with BL and treated with CD19CAR-T cells showed delayed lymphoma dissemination with lower EBV DNA load. Notably, for the Jiyoye/fLuc-GFP model, almost exclusively CD4 CD19CAR-T cells were detectable at the endpoint analyses in the bone marrow, with increased frequencies of regulatory T cells (T) and TIM-3CD4 T cells. Administration of gp350CAR-T cells to mice after Jiyoye/GFP-fLuc challenge did not inhibit BL growth but reduced the EBV DNA load in the bone marrow and promoted gp350 antigen escape. CD8PD-1LAG-3 gp350CAR-T cells were predominant in the bone marrow.\n\nDISCUSSION:\nThe two types of TCRCAR-T cells showed different therapeutic effects and dynamics. These findings reflect the complexities of the immune escape mechanisms of EBV, which may interfere with the CAR-T cell property and potency and should be taken into account for future clinical translation." + } +} \ No newline at end of file diff --git a/37034581.json b/37034581.json new file mode 100644 index 0000000000000000000000000000000000000000..13c1299fde2ba7cc9a365837e3d9d60de8d84566 --- /dev/null +++ b/37034581.json @@ -0,0 +1,8 @@ +{ + "id": "37034581", + "label": 0, + "article": { + "id": "37034581", + "text": "T-cell Acute Lymphoblastic Leukemia (T-ALL) is a hematological malignancy in need of novel therapeutic approaches. Here, we identify the ATP-citrate lyase ACLY as a novel therapeutic target in T-ALL. Our results show that ACLY is overexpressed in T-ALL, and its expression correlates with NOTCH1 activity. To test the effects of ACLY in leukemia progression and the response to NOTCH1 inhibition, we developed an isogenic model of NOTCH1-induced conditional knockout leukemia. Importantly, we observed intrinsic antileukemic effects upon loss of ACLY, which further synergized with NOTCH1 inhibition . Gene expression profiling analyses showed that the transcriptional signature of ACLY loss very significantly correlates with the signature of NOTCH1 inhibition , with significantly downregulated pathways related to oxidative phosphorylation, electron transport chain, ribosomal biogenesis and nucleosome biology. Consistently, metabolomic profiling upon ACLY loss revealed a metabolic crisis with accumulation of nucleotide intermediates and reduced levels of several amino acids. Overall, our results identify a link between NOTCH1 and ACLY and unveil ACLY as a novel promising target for T-ALL treatment." + } +} \ No newline at end of file diff --git a/37035916.json b/37035916.json new file mode 100644 index 0000000000000000000000000000000000000000..7f6ed403c87ac476e0bf6d988059f0c54700d55c --- /dev/null +++ b/37035916.json @@ -0,0 +1,8 @@ +{ + "id": "37035916", + "label": 0, + "article": { + "id": "37035916", + "text": "BACKGROUND:\nPrion-like transmission of amyloid-ß through cadaveric dura, decades after neurosurgical procedures, has been hypothesized as an iatrogenic cause of cerebral amyloid angiopathy (CAA). We investigated new and previously described patients to assess the clinical profile, radiological features, and outcome of this presumed iatrogenic CAA-subtype (iCAA).\n\nMETHODS:\nPatients were collected from our prospective lobar hemorrhage and CAA database (n=251) with patients presenting to our hospital between 2008 and 2022. In addition, we identified patients with iCAA from 2 other Dutch CAA-expertise hospitals and performed a systematic literature-search for previously described patients. We classified patients according to the previously proposed diagnostic criteria for iCAA, assessed clinical and radiological disease features, and calculated intracerebral hemorrhage (ICH)-recurrence rates. We evaluated the spatial colocalization of cadaveric dura placement and CAA-associated magnetic resonance imaging markers.\n\nRESULTS:\nWe included 49 patients (74% men, mean age 43 years [range, 27-84]); 15 from our database (6% [95% CI, 3%-10%]; 45% of patients \u003c55 years), 3 from the 2 other CAA-expertise hospitals, and 31 from the literature. We classified 43% (n=21; 1 newly identified patient) as probable and 57% (n=28) as possible iCAA. Patients presented with lobar ICH (57%), transient focal neurological episodes (12%), or seizures (8%). ICH-recurrence rate in the new patients (16/100 person-years [95% CI, 7-32], median follow-up 18 months) was lower than in the previously described patients (77/100 person-years [95% CI, 59-99], median follow-up 18 months). One patient had a 10 year interlude without ICH-recurrence. We identified no clear spatial relationship between dura placement and CAA-associated magnetic resonance imaging markers. During follow-up (median, 18 months), 20% of the patients developed transient focal neurological episodes and 20% cognitively declined.\n\nCONCLUSIONS:\niCAA seems common in patients presenting with nonhereditary CAA under the age of 55. Clinical and radiological features are comparable with sCAA. After diagnosis, multiple ICH-recurrences but also long symptom-free intervals can occur. Harmonized registries are necessary to identify and understand this potentially underrecognized CAA-subtype." + } +} \ No newline at end of file diff --git a/37036164.json b/37036164.json new file mode 100644 index 0000000000000000000000000000000000000000..ccbdd00b021c2b3ffbc672c771ed722eafad4306 --- /dev/null +++ b/37036164.json @@ -0,0 +1,8 @@ +{ + "id": "37036164", + "label": 0, + "article": { + "id": "37036164", + "text": "Outcomes for patients with relapsed and refractory (R/R) T-cell acute lymphoblastic leukemia (T-ALL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are dismal, with few available treatments. Recently, identification of cancer patients harboring neurotrophic tropomyosin receptor kinase (NTRK) gene fusions is constantly increasing, especially with the advent of NTRK inhibitors. However, the role of ETV6-NTRK3 in T-ALL has not been investigated. This case represented the first detailed report of T-ALL patient harboring a cryptic ETV6-NTRK3 fusion with an unfavorable prognosis, not only because of leukemia resistant to the standard multiagent chemotherapy but also early relapse after allo-HSCT. Acquired EP300 mutation was found at relapse, which could explain the cause of recurrence and affect the follow-up treatment. Combined targeted therapy like larotrectinib allied with pan-targeted BCL-2 inhibitor venetoclax, may be a potential maintenance treatment in R/R ETV6-NTRK3 positive leukemia after allo-HSCT. The leukemic clonal evolution might be revealed through transcriptome sequencing and overcome by drugs with universal targets. Our case demonstrated that both comprehensive profiling techniques (such as transcriptome sequencing, multiparameter flow cytometry, and digital droplet polymerase chain reaction) and a multimodality treatment strategy were critical for anticipating an early relapse and personalized therapy of R/R T-cell leukemia." + } +} \ No newline at end of file diff --git a/37037308.json b/37037308.json new file mode 100644 index 0000000000000000000000000000000000000000..bc23d78559deaa8ee1a32f8cfb46e20b42f8f290 --- /dev/null +++ b/37037308.json @@ -0,0 +1,8 @@ +{ + "id": "37037308", + "label": 0, + "article": { + "id": "37037308", + "text": "Small molecules that bind to oligomeric protein species such as membrane proteins and fibrils are of clinical interest for development of therapeutics and diagnostics. Definition of the binding site at atomic resolution via NMR is often challenging due to low binding stoichiometry of the small molecule. For fibrils and aggregation intermediates grown in the presence of lipids, we report atomic-resolution contacts to the small molecule at sub nm distance via solid-state NMR using dynamic nuclear polarization (DNP) and orthogonally labelled samples of the protein and the small molecule. We apply this approach to α-synuclein (αS) aggregates in complex with the small molecule anle138b, which is a clinical drug candidate for disease modifying therapy. The small central pyrazole moiety of anle138b is detected in close proximity to the protein backbone and differences in the contacts between fibrils and early intermediates are observed. For intermediate species, the 100 K condition for DNP helps to preserve the aggregation state, while for both fibrils and oligomers, the DNP enhancement is essential to obtain sufficient sensitivity." + } +} \ No newline at end of file diff --git a/37038230.json b/37038230.json new file mode 100644 index 0000000000000000000000000000000000000000..5032da7aa5364c62096ca6b5b7fa7a6c64f528e6 --- /dev/null +++ b/37038230.json @@ -0,0 +1,8 @@ +{ + "id": "37038230", + "label": 0, + "article": { + "id": "37038230", + "text": "Relapse is a major limitation of chimeric antigen receptor (CAR) T-cell therapy. Here, we speculated that decitabine (DAC) in combination with fludarabine and cyclophosphamide (FC) as a lymphodepletion regimen may improve the efficacy of CD19/CD22 CAR T-cell therapy. Fourteen of 26 patients with relapsed/refractory B cell acute lymphoblastic leukemia (r/r B-ALL) without remission before lymphodepletion treatment were treated with DAC (total dose 100 mg/m in 3 days) followed by the FC regimen (DAC group), while twelve patients received the FC regimen (CON group). On Day 28 after CAR T-cells infusion, no significant differences in complete remission (CR) and minimal residual disease negative CR rates were found between both groups. However, there were significant differences in overall survival (OS) and leukemia-free survival (LFS) between two groups: 3-year OS, 92.3% (DAC) versus 41.7% (CON), P = 0.005 and 3-year LFS, 92.9% (DAC) versus 27.3% (CON), P \u003c 0.001. There was no significant difference in the incidence of cytokine release syndrome between both groups. Median time to platelet and neutrophil counts recovery was similar in both groups. All adverse events were reversible and manageable. In conclusion, DAC in combination with the FC lymphodepletion regimen may be a new treatment option that can improve the efficacy of CAR T-cell therapy in r/r B-ALL." + } +} \ No newline at end of file diff --git a/37038342.json b/37038342.json new file mode 100644 index 0000000000000000000000000000000000000000..55d6be270175123f1bae864f18c4affa32a3e651 --- /dev/null +++ b/37038342.json @@ -0,0 +1,8 @@ +{ + "id": "37038342", + "label": 0, + "article": { + "id": "37038342", + "text": "OBJECTIVE:\nThis retrospective study aimed to observe the efficacy of transcatheter arterial chemoembolization (TACE) combined with sirolimus in the treatment of haemangioma combined with the Kasabach-Merritt phenomenon (KMP).\n\nMETHODS:\nA total of 11 infants with KMP who were treated at our hospital from January 2016 to September 2021 were selected and treated with arteriosclerosis embolotherapy using a microsphere emulsion formed by bleomycin + ultra-fluid lipiodol + dexamethasone + contrast agent or bleomycin mixed microspheres as the embolising agent. The patients were administered sirolimus orally after TACE. The clinical efficacy and examination indicators before and after treatment were observed and compared.\n\nRESULTS:\nThe 11 infants underwent TACE treatment by arteriosclerosis embolotherapy a total of 21 times; of these cases, 10 were cured, and 1 showed a moderate response. There were no cases of non-response or death. The platelet count rose from 10.0 (7.0, 18.0) x 10/L before TACE to 236.0 (188.0, 275.0) x 10/L six months after the first TACE, and the tumour size decreased from 49.0 (43.0, 111.7) cm before TACE to 7.0 (3.5, 17.0) cm six months after the first TACE. The differences were statistically significant (the Z values were -2.943 and -2.934, respectively, \u003c 0.05).\n\nCONCLUSION:\nThe combination of TACE and sirolimus has significant efficacy on critical children with KMP." + } +} \ No newline at end of file diff --git a/37040756.json b/37040756.json new file mode 100644 index 0000000000000000000000000000000000000000..14286959dc14d81342ff1f1deae7bfe872205806 --- /dev/null +++ b/37040756.json @@ -0,0 +1,8 @@ +{ + "id": "37040756", + "label": 0, + "article": { + "id": "37040756", + "text": "The objective of this study was to determine the prevalence, incidence, and clinical diagnostic accuracy for neuropathologically diagnosed progressive supranuclear palsy (PSP) with data from a longitudinal clinicopathological study using Rainwater criteria to define neuropathological PSP. Of 954 autopsy cases, 101 met Rainwater criteria for the neuropathologic diagnosis of PSP. Of these, 87 were termed clinicopathological PSP as they also had either dementia or parkinsonism or both. The prevalence of clinicopathologically defined PSP subjects in the entire autopsy dataset was 9.1%, while the incidence rate was estimated at 780 per 100 000 persons per year, roughly 50-fold greater than most previous clinically determined PSP incidence estimates. A clinical diagnosis of PSP was 99.6% specific but only 9.2% sensitive based on first examination, and 99.3% specific and 20.7% sensitive based on the final clinical exam. Of the clinicopathologically defined PSP cases, 35/87 (∼40%) had no form of parkinsonism at first assessment, while this decreased to 18/83 (21.7%) at final assessment. Our study confirms a high specificity but low sensitivity for the clinical diagnosis of PSP. The low clinical sensitivity for PSP is likely primarily responsible for previous underestimates of the PSP population incidence rate." + } +} \ No newline at end of file diff --git a/37041011.json b/37041011.json new file mode 100644 index 0000000000000000000000000000000000000000..aa28d962ea0dd4ac8bd54927a47bf080548da82f --- /dev/null +++ b/37041011.json @@ -0,0 +1,8 @@ +{ + "id": "37041011", + "label": 0, + "article": { + "id": "37041011", + "text": "BACKGROUND:\nHypophysitis is a serious adverse event stemming from immune checkpoint inhibitor (ICI) therapy for malignancy. This study aimed to characterize ICI-induced hypophysitis, identify diagnostic challenges, and evaluate an association with survival in a large cancer cohort.\n\nMETHODS:\nWe performed a retrospective cohort study of adult patients with cancer who received ICIs between December 1, 2012, and December 31, 2019. We identified 839 patients who received CTLA-4, PD-1, or PD-L1 inhibitors or a combination thereof who were followed for a median of 19.4 months. Hypophysitis was defined as MRI evidence of pituitary gland and/or stalk enlargement or biochemical evidence of hypopituitarism if not explained by another etiology.\n\nRESULTS:\nA total of 16 (1.9%) patients developed hypophysitis a median of 7 months after ICI initiation, with most patients having melanoma (9/16; 56.2%) or renal cell carcinoma (4/16; 25%). Two patients also had exogenous glucocorticoid exposure but exhibited secondary hypothyroidism and secondary adrenal insufficiency (AI). Median age at the start of ICI was 61.3 years and 57% were men. Patients who developed hypophysitis were younger compared with those who did not develop hypophysitis (median age, 57 vs 65 years; P=.011). Hypophysitis occurred most frequently after combination therapy (13.7%) compared with CTLA-4 monotherapy (1.9%), PD-1 monotherapy (1.2%), and PD-L1 monotherapy (0.8%) (P\u003c.0001). Pituitary gland enlargement on MRI occurred more frequently after CTLA-4 inhibitor monotherapy or combination therapy (5/7; 71.4%) compared with PD-1/PD-L1 inhibitor monotherapy (1/6; 16.7%). The survival benefit of hypophysitis was not apparent after addressing immortal time bias and adjusting for other variables affecting patient outcomes.\n\nCONCLUSIONS:\nSecondary AI occurred in all patients, and secondary hypothyroidism occurred in half. Classic pituitary gland enlargement is usually absent in PD-1/PD-L1 inhibitor-induced hypophysitis. Further pituitary evaluation must be conducted to differentiate secondary AI resulting from exogenous glucocorticoids and hypophysitis in patients with cancer receiving ICIs. The link between hypophysitis and ICI efficacy needs further investigation." + } +} \ No newline at end of file diff --git a/37041653.json b/37041653.json new file mode 100644 index 0000000000000000000000000000000000000000..320ace1448b07cf1e68998674d54f9c2900f75b1 --- /dev/null +++ b/37041653.json @@ -0,0 +1,8 @@ +{ + "id": "37041653", + "label": 0, + "article": { + "id": "37041653", + "text": "BACKGROUND:\nBarth syndrome (BTHS) is a rare genetic disease that is characterized by cardiomyopathy, skeletal myopathy, neutropenia, and growth abnormalities and often leads to death in childhood. Recently, elamipretide has been tested as a potential first disease-modifying drug. This study aimed to identify patients with BTHS who may respond to elamipretide, based on continuous physiological measurements acquired through wearable devices.\n\nRESULTS:\nData from a randomized, double-blind, placebo-controlled crossover trial of 12 patients with BTHS were used, including physiological time series data measured using a wearable device (heart rate, respiratory rate, activity, and posture) and functional scores. The latter included the 6-minute walk test (6MWT), Patient-Reported Outcomes Measurement Information System (PROMIS) fatigue score, SWAY Balance Mobile Application score (SWAY balance score), BTHS Symptom Assessment (BTHS-SA) Total Fatigue score, muscle strength by handheld dynamometry, 5 times sit-and-stand test (5XSST), and monolysocardiolipin to cardiolipin ratio (MLCL:CL). Groups were created through median split of the functional scores into \"highest score\" and \"lowest score\", and \"best response to elamipretide\" and \"worst response to elamipretide\". Agglomerative hierarchical clustering (AHC) models were implemented to assess whether physiological data could classify patients according to functional status and distinguish non-responders from responders to elamipretide. AHC models clustered patients according to their functional status with accuracies of 60-93%, with the greatest accuracies for 6MWT (93%), PROMIS (87%), and SWAY balance score (80%). Another set of AHC models clustered patients with respect to their response to treatment with elamipretide with perfect accuracy (all 100%).\n\nCONCLUSIONS:\nIn this proof-of-concept study, we demonstrated that continuously acquired physiological measurements from wearable devices can be used to predict functional status and response to treatment among patients with BTHS." + } +} \ No newline at end of file diff --git a/37043366.json b/37043366.json new file mode 100644 index 0000000000000000000000000000000000000000..d293a884c1184d0a603bcdede0a813e47d27f6dd --- /dev/null +++ b/37043366.json @@ -0,0 +1,8 @@ +{ + "id": "37043366", + "label": 0, + "article": { + "id": "37043366", + "text": "In some primaries African American race/ethnicity predisposes to higher stage and worse survival. We tested for differences in cancer specific mortality (CSM) and other-cause mortality (OCM) in patients with adrenocortical carcinoma (ACC) according to African American vs. Caucasian race/ethnicity. We hypothesized that African Americans present with higher tumor stage and grade, do not receive the same treatment and benefit of lower survival than Caucasians. Within Surveillance, Epidemiology, and End Results database, we identified 1016 ACC patients: 123 (12.1%) African Americans vs. 893 (87.9%) Caucasians. Propensity score matching (age, sex, marital status, grade, T, N and M stages, treatment type), cumulative incidence plots Poisson-smoothing and competing risk regression (CRR) were used. Compared to Caucasians, African Americans were more frequently unmarried (56.9% vs. 35.5%, p \u003c 0.001). No clinically meaningful or statistically significant differences were observed for age, grade, T, N, and M stages, as well as for treatment type (all p \u003e 0.05). After propensity score matching (1:4), 123 African Americans and 492 Caucasians remained and were included in CRR analysis. In multivariable CRR models, CSM and OCM rates were not different between the two race/ethnicities (hazard ratio: 0.84, p = 0.3). In African Americans five-year CSM rates were 31.2% and 75.3% in respectively European Network for the Study of Adrenal Tumors (ENSAT) stages I-II and III-IV vs. 32.9% and 75.4% in Caucasians. Overall five-year OCM rates were 11.0% vs. 10.1% in respectively African Americans and Caucasians. Unlike other primaries, in ACC African American race/ethnicity is not associated with higher disease stage at initial diagnosis or worse survival." + } +} \ No newline at end of file diff --git a/37043976.json b/37043976.json new file mode 100644 index 0000000000000000000000000000000000000000..8c4ebc5bf96c4a16461a5962658702b32954c82d --- /dev/null +++ b/37043976.json @@ -0,0 +1,8 @@ +{ + "id": "37043976", + "label": 0, + "article": { + "id": "37043976", + "text": "As an autoimmune disorder, vitiligo is characterized by depigmented skin macules. CD8T cells and macrophages enrichment promote the onset of vitiligo, while the role of macrophages to CD8T is not well deciphered. To develop a mouse model of vitiligo with prominent epidermal depigmentation, Krt14-Kitl* transgenic mice containing an elevated number of melanocytes in the epidermis with membrane-bound Kit ligand (Kitl*) were adoptively transferred with premelanosome protein (PMEL) CD8 T cells. On the other hand, Krt14-Kitl* mice were mated with ubiquitin-specific protease 34 (USP34) mice to decipher the role of USP34 in vitiligo. Vitiligo scores and PMEL CD8 T cell enrichment were detected with flow cytometry. Human peripheral blood mononuclear cells (PBMCs) or mice bone marrow-derived macrophages (BMDMs) were incubated with lipopolysaccharide (LPS), CpG, or co-incubated with KU-55933, an ataxia telangiectasia-mutated (ATM) inhibitor. Chemokine (C-C motif) ligand 2 (CCL2), Ccl5, and interleukin (Il)-12α expression was assayed with real-time PCR, and p-IKKα/β was assayed with Western blots. USP34 was up-regulated in the PBMCs of vitiligo patients and LPS-stimulated BMDMs. USP34 deficiency did not affect the differentiation of CD11bF4/80 macrophages in the bone marrow. Immunoprecipitation demonstrated the interaction between USP34 and ATM. USP34 deficiency or KU-55933 administration promoted the induction of Ccl2, Ccl5, Il12α, and p-IKKα/β in LPS or CpG stimulated BMDMs; KU-55933 administration could not affect the expression of the above molecules in USP34 deficient BMDMs. It further revealed that USP34 deficiency promoted the development of vitiligo with increased PMEL CD8 T cell enrichment, which was not affected by KU-55933 administration. USP34 deficiency in macrophages promotes the onset of vitiligo with increased PMEL CD8 T cell enrichment, and USP34/ATM complex can be considered as a therapy target." + } +} \ No newline at end of file diff --git a/37046342.json b/37046342.json new file mode 100644 index 0000000000000000000000000000000000000000..908ec5d32e756940ec5b9a2ad57d96d5c327b598 --- /dev/null +++ b/37046342.json @@ -0,0 +1,8 @@ +{ + "id": "37046342", + "label": 0, + "article": { + "id": "37046342", + "text": "BACKGROUND:\nPediatric adrenocortical tumors include both benign adenomas and highly virulent malignant tumors. However, they are very rare among children. The aim of this study is to evaluate the clinicopathological data of children presenting with adrenocortical tumors and assess their survival in a South Asian population.\n\nCASE PRESENTATION:\nThis is a retrospective cohort study that includes patients diagnosed with adrenocortical tumors from August 2020 to August 2022 followed-up at Lady Ridgeway Hospital. Seven children were diagnosed with adrenal cortical tumors. Their ages ranged from 10 months to 6.5 years. Five of them were boys. All displayed signs of peripheral precocious puberty. One boy phenotypically had features of Beckwith-Wiedemann syndrome. The median time for diagnosis after the onset of symptoms was 4.4 months. The preoperative diagnosis was based on clinical manifestations, elevated dehydroepiandrosterone sulfate levels, and suprarenal masses on computed tomography. All five boys had right-sided suprarenal masses, while the two girls had them on the left side. All underwent surgery for tumor resection. The diagnosis was confirmed based on the histopathology of the adrenal specimens. Four children had a Wieneke score of 4 or more, suggesting the possibility of adrenocortical carcinoma; however, only two of them behaved as malignant tumors. To date, two children have developed local recurrences within a very short period.\n\nCONCLUSION:\nAdrenocortical tumors are uncommon in children, and treatment options are limited. To identify early recurrences, routine clinical, radiological, and biochemical examinations at least once every 6-8 weeks is important." + } +} \ No newline at end of file diff --git a/37046711.json b/37046711.json new file mode 100644 index 0000000000000000000000000000000000000000..3fae89c19b9fc9a0f5a6bc4dbff71ac42bbefef6 --- /dev/null +++ b/37046711.json @@ -0,0 +1,8 @@ +{ + "id": "37046711", + "label": 0, + "article": { + "id": "37046711", + "text": "Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma (STS) in childhood. Whereas more than 90% of patients with localized low-risk RMS can be cured, metastatic RMS have a dismal outcome, with survival rates of less than 30%. The HD CWS-96 trial showed an improved outcome for patients receiving maintenance therapy after completing intensive chemotherapy. Consequently, the international clinical trials CWS-IV 2002 and CWS DOK IV 2004 on metastatic disease of STS of the Cooperative Weichteilsarkom Studiengruppe (CWS) were designed in addition to the CWS-2002P trial for localized RMS disease. All patients received a multimodal intensive treatment regimen. To maintain remission, three options were compared: long-term maintenance therapy (LTMT) versus allogeneic hematopoietic stem cell transplantation (alloHSCT) versus high-dose chemotherapy (HDCT). A total of 176 pediatric patients with a histologically confirmed diagnosis of metastatic RMS or RMS-like tumor were included. A total of 89 patients receiving LTML showed a significantly better outcome, with an event-free survival (EFS) of 41% and an overall survival (OS) of 53%, than alloHSCT ( = 21, EFS 19%, = 0.02, OS 24%, = 0.002). The outcome of LTML was slightly improved compared to HDCT ( = 13, EFS 35%, OS 34%). In conclusion, our data suggest that in patients suffering from metastatic RMS, long-term maintenance therapy is a superior strategy in terms of EFS and OS compared to alloHSCT. EFS and OS of HDCT are similar in these strategies; however, the therapeutic burden of LTMT is much lower." + } +} \ No newline at end of file diff --git a/37046794.json b/37046794.json new file mode 100644 index 0000000000000000000000000000000000000000..36dea1a42d55d4d276597d85b3c56e5a8696f56a --- /dev/null +++ b/37046794.json @@ -0,0 +1,8 @@ +{ + "id": "37046794", + "label": 0, + "article": { + "id": "37046794", + "text": "The clinical significance of Epstein-Barr virus (EBV) cannot be understated. Not only does it infect approximately 90% of the world's population, but it is also associated with numerous pathologies. Diseases linked to this virus include hematologic malignancies such as diffuse large B-cell lymphoma, Hodgkin lymphoma, Burkitt lymphoma, primary CNS lymphoma, and NK/T-cell lymphoma, epithelial malignancies such as nasopharyngeal carcinoma and gastric cancer, autoimmune diseases such as multiple sclerosis, Graves' disease, and lupus. While treatment for these disease states is ever evolving, much work remains to more fully elucidate the relationship between EBV, its associated disease states, and their treatments. This paper begins with an overview of EBV latency and latency-associated proteins. It will then review EBV's contributions to select hematologic malignancies with a focus on the contribution of latent proteins as well as their associated management." + } +} \ No newline at end of file diff --git a/37046832.json b/37046832.json new file mode 100644 index 0000000000000000000000000000000000000000..9a42567e4beb2b1a1a5701ae44f46e2cfe742190 --- /dev/null +++ b/37046832.json @@ -0,0 +1,8 @@ +{ + "id": "37046832", + "label": 0, + "article": { + "id": "37046832", + "text": "HIV-associated epidemic Kaposi sarcoma (EpKS) remains one of the most prevalent cancers in sub-Saharan Africa despite the widespread uptake of anti-retroviral therapy and HIV-1 suppression. In an effort to define potential therapeutic targets against KS tumors, we analyzed previously published KS bulk tumor transcriptomics to identify cell surface biomarkers. In addition to upregulated gene expression (\u003e6-fold) in the EpKS tumor microenvironment, biomarkers were selected for correlation with KSHV latency-associated nuclear antigen (LANA) expression. The cell surface glycoprotein genes identified were KDR, FLT4, ADAM12, UNC5A, ZP2, and OX40, as well as the endothelial lineage determinants Prox-1 and CD34. Each protein was evaluated for its expression and co-localization with KSHV LANA using multi-color immunofluorescence in KS tissues, KSHV-infected L1T2 cells, uninfected TIVE cells, and murine L1T2 tumor xenografts. Five surface glycoproteins (KDR, FLT4, UNC5A, ADAM12, and CD34) were associated with LANA-positive cells but were also detected in uninfected cells in the KS microenvironment. L1T2 cultures showed evidence of only FLT4, KDR, and UNC5A, whereas mouse L1T2 xenografts recapitulated human KS cell surface expression profiles, with the exception of CD34 and Prox-1. In KS tumors, most LANA-positive cells co-expressed markers of vascular as well as lymphatic endothelial lineages, suggesting KS-associated dedifferentiation to a more mesenchymal/progenitor phenotype." + } +} \ No newline at end of file diff --git a/37047060.json b/37047060.json new file mode 100644 index 0000000000000000000000000000000000000000..200932df0c293a488ed8a2e6007e8bc4422d7d24 --- /dev/null +++ b/37047060.json @@ -0,0 +1,8 @@ +{ + "id": "37047060", + "label": 0, + "article": { + "id": "37047060", + "text": "Pelvic organ prolapse (POP) represents a major health care burden in women, but its underlying pathophysiological mechanisms have not been elucidated. We first used a case-control design to perform an exome chip study in 526 women with POP and 960 control women to identify single nucleotide variants (SNVs) associated with the disease. We then integrated the functional interactions between the POP candidate proteins derived from the exome chip study and other POP candidate molecules into a molecular landscape. We found significant associations between POP and SNVs in 54 genes. The proteins encoded by 26 of these genes fit into the molecular landscape, together with 43 other POP candidate molecules. The POP landscape is located in and around epithelial cells and fibroblasts of the urogenital tract and harbors four interacting biological processes-epithelial-mesenchymal transition, immune response, modulation of the extracellular matrix, and fibroblast function-that are regulated by sex hormones and TGFB1. Our findings were corroborated by enrichment analyses of differential gene expression data from an independent POP cohort. Lastly, based on the landscape and using vaginal fibroblasts from women with POP, we predicted and showed that metformin alters gene expression in these fibroblasts in a beneficial direction. In conclusion, our integrated molecular landscape of POP provides insights into the biological processes underlying the disease and clues towards novel treatments." + } +} \ No newline at end of file diff --git a/37047224.json b/37047224.json new file mode 100644 index 0000000000000000000000000000000000000000..527f27ef391e34c827b02969731ec776288ea4e4 --- /dev/null +++ b/37047224.json @@ -0,0 +1,8 @@ +{ + "id": "37047224", + "label": 0, + "article": { + "id": "37047224", + "text": "There is a large unmet medical need to develop disease-modifying treatment options for individuals with age-related degenerative diseases of the central nervous system. The sigma-2 receptor (S2R), encoded by , is expressed in brain and retinal cells, and regulates cell functions via its co-receptor progesterone receptor membrane component 1 (PGRMC1), and through other protein-protein interactions. Studies describing functions of S2R involve the manipulation of expression or pharmacological modulation using exogenous small-molecule ligands. These studies demonstrate that S2R modulates key pathways involved in age-related diseases including autophagy, trafficking, oxidative stress, and amyloid-β and α-synuclein toxicity. Furthermore, S2R modulation can ameliorate functional deficits in cell-based and animal models of disease. This review summarizes the current evidence-based understanding of S2R biology and function, and its potential as a therapeutic target for age-related degenerative diseases of the central nervous system, including Alzheimer's disease, α-synucleinopathies, and dry age-related macular degeneration." + } +} \ No newline at end of file diff --git a/37047515.json b/37047515.json new file mode 100644 index 0000000000000000000000000000000000000000..111d54c933aa44c4c925f79d16f4c17bd3e4b798 --- /dev/null +++ b/37047515.json @@ -0,0 +1,8 @@ +{ + "id": "37047515", + "label": 0, + "article": { + "id": "37047515", + "text": "Death-associated protein kinase 1 (DAPK1), a Ca/calmodulin-dependent serine/threonine kinase, mediates various neuronal functions, including cell death. Abnormal upregulation of DAPK1 is observed in human patients with neurological diseases, such as Alzheimer's disease (AD) and epilepsy. Ablation of DAPK1 expression and suppression of DAPK1 activity attenuates neuropathology and behavior impairments. However, whether DAPK1 regulates gene expression in the brain, and whether its gene profile is implicated in neuronal disorders, remains elusive. To reveal the function and pathogenic role of DAPK1 in neurological diseases in the brain, differential transcriptional profiling was performed in the brains of DAPK1 knockout (DAPK1-KO) mice compared with those of wild-type (WT) mice by RNA sequencing. We showed significantly altered genes in the cerebral cortex, hippocampus, brain stem, and cerebellum of both male and female DAPK1-KO mice compared to those in WT mice, respectively. The genes are implicated in multiple neural-related pathways, including: AD, Parkinson's disease (PD), Huntington's disease (HD), neurodegeneration, glutamatergic synapse, and GABAergic synapse pathways. Moreover, our findings imply that the potassium voltage-gated channel subfamily A member 1 (Kcna1) may be involved in the modulation of DAPK1 in epilepsy. Our study provides insight into the pathological role of DAPK1 in the regulatory networks in the brain and new therapeutic strategies for the treatment of neurological diseases." + } +} \ No newline at end of file diff --git a/37047683.json b/37047683.json new file mode 100644 index 0000000000000000000000000000000000000000..0e7da57997bf418c0afdd77aafc82c407cae886a --- /dev/null +++ b/37047683.json @@ -0,0 +1,8 @@ +{ + "id": "37047683", + "label": 0, + "article": { + "id": "37047683", + "text": "The seroprevalence of Kaposi sarcoma-associated herpesvirus (KSHV) and the incidence of endemic Kaposi sarcoma (KS) overlap with regions of malaria endemicity in sub-Saharan Africa. Multiple studies have shown an increased risk of KSHV seroconversion in children from high malaria compared to low malaria regions; however, the impact of acute episodes of () malaria on KSHV's biphasic life cycle and lytic reactivation has not been determined. Here, we examined KSHV serological profiles and viral loads in 134 children with acute malaria and 221 healthy children from high malaria regions in Kisumu, as well as 77 healthy children from low malaria regions in Nandi. We assayed KSHV, Epstein-Barr virus (EBV), and malaria antibody responses in these three by multiplexed Luminex assay. We confirmed that KSHV seroprevalence was significantly associated with malaria endemicity (OR = 1.95, 1.18-3.24 95% CI, = 0.01) with 71-77% seropositivity in high-malaria (Kisumu) compared to 28% in low-malaria (Nandi) regions. Furthermore, KSHV serological profiles during acute malaria episodes were distinct from age-matched non-malaria-infected children from the same region. Paired IgG levels also varied after malaria treatment, with significantly higher anti-ORF59 at day 0 but elevated ORF38, ORF73, and K8.1 at day 3. Acute malaria episodes is characterized by perturbation of KSHV latency in seropositive children, providing further evidence that malaria endemicity contributes to the observed increase in endemic KS incidence in sub-Saharan Africa." + } +} \ No newline at end of file diff --git a/37047709.json b/37047709.json new file mode 100644 index 0000000000000000000000000000000000000000..6dd696cac4fdcb5b483d4e07df05cb5bbbcf86a9 --- /dev/null +++ b/37047709.json @@ -0,0 +1,8 @@ +{ + "id": "37047709", + "label": 0, + "article": { + "id": "37047709", + "text": "Interferons (IFNs), divided into type I, type II, and type III IFNs represent proteins that are secreted from cells in response to various stimuli and provide important information for understanding the evolution, structure, and function of the immune system, as well as the signaling pathways of other cytokines and their receptors. They exert comparable, but also distinct physiologic and pathophysiologic activities accompanied by pleiotropic effects, such as the modulation of host responses against bacterial and viral infections, tumor surveillance, innate and adaptive immune responses. IFNs were the first cytokines used for the treatment of tumor patients including hairy leukemia, renal cell carcinoma, and melanoma. However, tumor cells often develop a transient or permanent resistance to IFNs, which has been linked to the escape of tumor cells and unresponsiveness to immunotherapies. In addition, loss-of-function mutations in IFN signaling components have been associated with susceptibility to infectious diseases, such as COVID-19 and mycobacterial infections. In this review, we summarize general features of the three IFN families and their function, the expression and activity of the different IFN signal transduction pathways, and their role in tumor immune evasion and pathogen clearance, with links to alterations in the major histocompatibility complex (MHC) class I and II antigen processing machinery (APM). In addition, we discuss insights regarding the clinical applications of IFNs alone or in combination with other therapeutic options including immunotherapies as well as strategies reversing the deficient IFN signaling. Therefore, this review provides an overview on the function and clinical relevance of the different IFN family members, with a specific focus on the MHC pathways in cancers and infections and their contribution to immune escape of tumors." + } +} \ No newline at end of file diff --git a/37047766.json b/37047766.json new file mode 100644 index 0000000000000000000000000000000000000000..00bdf81fbd75e5120d0729b089719805a2371d30 --- /dev/null +++ b/37047766.json @@ -0,0 +1,8 @@ +{ + "id": "37047766", + "label": 0, + "article": { + "id": "37047766", + "text": "Altered RNA editing has been linked to several neurodevelopmental disorders, including autism spectrum disorder (ASD) and intellectual disability, in addition to depression, schizophrenia, some cancers, viral infections and autoimmune disorders. The human ADAR2 is a potential therapeutic target for managing these various disorders due to its crucial role in adenosine to inosine editing. This study applied consensus scoring to rank potential ADAR2 inhibitors after performing molecular docking with AutoDock Vina and Glide (Maestro), using a library of 35,161 compounds obtained from traditional Chinese medicine. A total of 47 compounds were predicted to be good binders of the human ADAR2 and had insignificant toxicity concerns. Molecular dynamics (MD) simulations, including the molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) procedure, also emphasized the binding of the shortlisted compounds. The potential compounds had plausible binding free energies ranging from -81.304 to -1068.26 kJ/mol from the MM/PBSA calculations. ZINC000085511995, a naphthoquinone had more negative binding free energy (-1068.26 kJ/mol) than inositol hexakisphosphate (IHP) [-873.873 kJ/mol], an agonist and a strong binder of ADAR2. The potential displacement of IHP by ZINC000085511995 in the IHP binding site of ADAR2 could be explored for possible deactivation of ADAR2. Bayesian-based biological activity prediction corroborates the neuropharmacological, antineoplastic and antiviral activity of the potential lead compounds. All the potential lead compounds, except ZINC000014612330 and ZINC000013462928, were predicted to be inhibitors of various deaminases. The potential lead compounds also had probability of activity (Pa) \u003e 0.442 and probability of inactivity (Pi) \u003c 0.116 values for treating acute neurologic disorders, except for ZINC000085996580 and ZINC000013462928. Pursuing these compounds for their anti-ADAR2 activities holds a promising future, especially against neurological disorders, some cancers and viral infections caused by RNA viruses. Molecular interaction, hydrogen bond and per-residue decomposition analyses predicted Arg400, Arg401, Lys519, Trp687, Glu689, and Lys690 as hot-spot residues in the ADAR2 IHP binding site. Most of the top compounds were observed to have naphthoquinone, indole, furanocoumarin or benzofuran moieties. Serotonin and tryptophan, which are beneficial in digestive regulation, improving sleep cycle and mood, are indole derivatives. These chemical series may have the potential to treat neurological disorders, prion diseases, some cancers, specific viral infections, metabolic disorders and eating disorders through the disruption of ADAR2 pathways. A total of nine potential lead compounds were shortlisted as plausible modulators of ADAR2." + } +} \ No newline at end of file diff --git a/37047801.json b/37047801.json new file mode 100644 index 0000000000000000000000000000000000000000..c6c0cc196e2955ffed1fa9f8e5dbc98bc67d6c77 --- /dev/null +++ b/37047801.json @@ -0,0 +1,8 @@ +{ + "id": "37047801", + "label": 0, + "article": { + "id": "37047801", + "text": "BACKGROUND:\nAdrenocortical cancer (ACC) is a rare malignancy with a dismal prognosis. The treatment includes mitotane and EDP chemotherapy (etoposide, doxorubicin, and cisplatin). However, new therapeutic approaches for advanced ACC are needed, particularly targeting the metastatic process. Here, we deepen the role of progesterone as a new potential drug for ACC, in line with its antitumoral effect in other cancers.\n\nMETHODS:\nNCI-H295R, MUC-1, and TVBF-7 cell lines were used and xenografted in zebrafish embryos. Migration and invasion were studied using transwell assays, and MMP2 activity was studied using zymography. Apoptosis and cell cycle were analyzed by flow cytometry.\n\nRESULTS:\nProgesterone significantly reduced xenograft tumor area and metastases formation in embryos injected with metastatic lines, MUC-1 and TVBF-7. These results were confirmed in vitro, where the reduction of invasion was mediated, at least in part, by the decrease in MMP2 levels. Progesterone exerted a long-lasting effect in metastatic cells. Progesterone caused apoptosis in NCI-H295R and MUC-1, inducing changes in the cell-cycle distribution, while autophagy was predominantly activated in TVBF-7 cells.\n\nCONCLUSION:\nOur results give support to the role of progesterone in ACC. The involvement of its analog (megestrol acetate) in reducing ACC progression in ACC patients undergoing EDP-M therapy is now under investigation in the PESETA phase II clinical study." + } +} \ No newline at end of file diff --git a/37047805.json b/37047805.json new file mode 100644 index 0000000000000000000000000000000000000000..99fc58345a2acd95c429e06346489af8b98eb6f4 --- /dev/null +++ b/37047805.json @@ -0,0 +1,8 @@ +{ + "id": "37047805", + "label": 0, + "article": { + "id": "37047805", + "text": "Graves' disease (GD) is a thyroid-specific autoimmune disease with a high prevalence worldwide. The disease is primarily mediated by B cells, which produce autoantibodies against the thyroid-stimulating hormone receptor (TSHR), chronically stimulating it and leading to high levels of thyroid hormones in the body. Interest in characterizing the immune response in GD has motivated many phenotyping studies. The immunophenotype of the cells involved and the interplay between them and their secreted factors are crucial to understanding disease progression and future treatment options. T cell populations are markedly distinct, including increased levels of Th17 and follicular helper T cells (Tfh), while Treg cells appear to be impaired. Some B cells subsets are autoreactive, and anti-TSHR antibodies are the key disease-causing outcome of this interplay. Though some consensus across phenotyping studies will be discussed here, there are also complexities that are yet to be resolved. A better understanding of the immunophenotype of Graves' disease can lead to improved treatment strategies and novel drug targets." + } +} \ No newline at end of file diff --git a/37048058.json b/37048058.json new file mode 100644 index 0000000000000000000000000000000000000000..98a5c8fe5d810f34132196b03568753f723972db --- /dev/null +++ b/37048058.json @@ -0,0 +1,8 @@ +{ + "id": "37048058", + "label": 0, + "article": { + "id": "37048058", + "text": "Tauopathies are neurodegenerative disorders involving the accumulation of tau isoforms in cell subpopulations such as astrocytes. The origins of the 3R and 4R isoforms of tau that accumulate in astrocytes remain unclear. Extracellular vesicles (EVs) were isolated from primary neurons overexpressing 1N3R or 1N4R tau or from human brain extracts (progressive supranuclear palsy or Pick disease patients or controls) and characterized (electron microscopy, nanoparticle tracking analysis (NTA), proteomics). After the isolated EVs were added to primary astrocytes or human iPSC-derived astrocytes, tau transfer and mitochondrial system function were evaluated (ELISA, immunofluorescence, MitoTracker staining). We demonstrated that neurons in which 3R or 4R tau accumulated had the capacity to transfer tau to astrocytes and that EVs were essential for the propagation of both isoforms of tau. Treatment with tau-containing EVs disrupted the astrocytic mitochondrial system, altering mitochondrial morphology, dynamics, and redox state. Although similar levels of 3R and 4R tau were transferred, 3R tau-containing EVs were significantly more damaging to astrocytes than 4R tau-containing EVs. Moreover, EVs isolated from the brain fluid of patients with different tauopathies affected mitochondrial function in astrocytes derived from human iPSCs. Our data indicate that tau pathology spreads to surrounding astrocytes via EVs-mediated transfer and modifies their function." + } +} \ No newline at end of file diff --git a/37048082.json b/37048082.json new file mode 100644 index 0000000000000000000000000000000000000000..a468226aaa52c23cf4e3cf2f132479e3b428aac7 --- /dev/null +++ b/37048082.json @@ -0,0 +1,8 @@ +{ + "id": "37048082", + "label": 0, + "article": { + "id": "37048082", + "text": "Ionizing radiation (IR) is an important means of tumor treatment in addition to surgery and drugs. Attempts have been made to improve the efficiency of radiotherapy by identifying the various biological effects of IR on cells. Components of the tumor microenvironment, such as macrophages, fibroblasts, and vascular endothelial cells, influence cancer treatment outcomes through communication with tumor cells. In this study, we found that IR selectively increased the production of CXC motif chemokine ligand 10 (CXCL10), which is emerging as an important biomarker for determining the prognosis of anticancer treatments, without changing the levels of CXCL9 and CXCL11 in murine J774A.1 macrophages. Pretreatment with KU55933, an ataxia telangiectasia mutated (ATM) kinase inhibitor, significantly inhibited IR-induced CXCL10 production. In contrast, pretreatment with N-acetyl-cysteine or glutathione, a reactive oxygen species scavenger, did not inhibit IR-induced CXCL10 production. Further, we attempted to identify the intracellular molecular target associated with the IR-induced increase in CXCL10 secretion by J774A.1 macrophages. IR phosphorylated p38 mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 1 (STAT1) in J774A.1 macrophages, and p38 MAPK and STAT1 were involved in CXCL10 via IR using pharmacological inhibitors (SB203580 and fludarabine, respectively) and the siRNA technique." + } +} \ No newline at end of file diff --git a/37048111.json b/37048111.json new file mode 100644 index 0000000000000000000000000000000000000000..568b9c920d55b94cf42cd9d0de1ea0d4cee500d5 --- /dev/null +++ b/37048111.json @@ -0,0 +1,8 @@ +{ + "id": "37048111", + "label": 0, + "article": { + "id": "37048111", + "text": "The PARP inhibitor (PARPi) olaparib is currently the drug of choice for serous ovarian cancer (OC), especially in patients with homologous recombination (HR) repair deficiency associated with deleterious mutations. Unfortunately, OC patients who fail to respond to PARPi or relapse after treatment have limited therapeutic options. To elucidate olaparib resistance and enhance the efficacy of olaparib, intracellular factors exploited by OC cells to achieve decreased sensitivity to PARPi were examined. An olaparib-resistant OC cell line, PEO1-OR, was established from PEO1 cells. The anticancer activity and action of olaparib combined with inhibitors of the ATR/CHK1 pathway (ceralasertib as ATRi, MK-8776 as CHK1i) in olaparib-sensitive and -resistant OC cell lines were evaluated. Whole-exome sequencing revealed that PEO1-OR cells acquire resistance through subclonal enrichment of secondary mutations that restore functional full-length protein. Moreover, PEO1-OR cells upregulate HR repair-promoting factors (BRCA1, BRCA2, RAD51) and PARP1. Olaparib-inducible activation of the ATR/CHK1 pathway and G2/M arrest is abrogated in olaparib-resistant cells. Drug sensitivity assays revealed that PEO1-OR cells are less sensitive to ATRi and CHK1i agents. Combined treatment is less effective in olaparib-resistant cells considering inhibition of metabolic activity, colony formation, survival, accumulation of DNA double-strand breaks, and chromosomal aberrations. However, synergistic antitumor activity between compounds is achievable in PEO1-OR cells. Collectively, olaparib-resistant cells display co-existing HR repair-related mechanisms that confer resistance to olaparib, which may be effectively utilized to resensitize them to PARPi via combination therapy. Importantly, the addition of ATR/CHK1 pathway inhibitors to olaparib has the potential to overcome acquired resistance to PARPi." + } +} \ No newline at end of file diff --git a/37048113.json b/37048113.json new file mode 100644 index 0000000000000000000000000000000000000000..bcdbd23a381133f816589a7938824aa655f27a9e --- /dev/null +++ b/37048113.json @@ -0,0 +1,8 @@ +{ + "id": "37048113", + "label": 0, + "article": { + "id": "37048113", + "text": "Human neuronal loss occurs through different cellular mechanisms, mainly studied in vitro. Here, we characterized neuronal death in , a marine colonial tunicate that shares substantial genomic homology with mammals and has a life history in which controlled neurodegeneration happens simultaneously in the brains of adult zooids during a cyclical phase named takeover. Using an ultrastructural and transcriptomic approach, we described neuronal death forms in adult zooids before and during the takeover phase while comparing adult zooids in takeover with their buds where brains are refining their structure. At takeover, we found in neurons clear morphologic signs of apoptosis (i.e., chromatin condensation, lobed nuclei), necrosis (swollen cytoplasm) and autophagy (autophagosomes, autolysosomes and degradative multilamellar bodies). These results were confirmed by transcriptomic analyses that highlighted the specific genes involved in these cell death pathways. Moreover, the presence of tubulovesicular structures in the brain medulla alongside the over-expression of prion disease genes in late cycle suggested a cell-to-cell, prion-like propagation recalling the conformational disorders typical of some human neurodegenerative diseases. We suggest that improved understanding of how neuronal alterations are regulated in the repeated degeneration-regeneration program of may yield mechanistic insights relevant to the study of human neurodegenerative diseases." + } +} \ No newline at end of file diff --git a/37049785.json b/37049785.json new file mode 100644 index 0000000000000000000000000000000000000000..12f4f3171d656e253256e19e856013a446352037 --- /dev/null +++ b/37049785.json @@ -0,0 +1,8 @@ +{ + "id": "37049785", + "label": 0, + "article": { + "id": "37049785", + "text": "Idebenone (IDE), a synthetic short-chain analogue of coenzyme Q10, is a potent antioxidant able to prevent lipid peroxidation and stimulate nerve growth factor. Due to these properties, IDE could potentially be active towards cerebral disorders, but its poor water solubility limits its clinical application. Octanoyl-β-cyclodextrin is an amphiphilic cyclodextrin (ACyD8) bearing, on average, ten octanoyl substituents able to self-assemble in aqueous solutions, forming various typologies of supramolecular nanoassemblies. Here, we developed nanoparticles based on ACyD8 (ACyD8-NPs) for the potential intranasal administration of IDE to treat neurological disorders, such as Alzheimer's Disease. Nanoparticles were prepared using the nanoprecipitation method and were characterized for their size, zeta potential and morphology. STEM images showed spherical particles, with smooth surfaces and sizes of about 100 nm, suitable for the proposed therapeutical aim. The ACyD8-NPs effectively loaded IDE, showing a high encapsulation efficiency and drug loading percentage. To evaluate the host/guest interaction, UV-vis titration, mono- and two-dimensional NMR analyses, and molecular modeling studies were performed. IDE showed a high affinity for the ACyD8 cavity, forming a 1:1 inclusion complex with a high association constant. A biphasic and sustained release of IDE was observed from the ACyD8-NPs, and, after a burst effect of about 40%, the release was prolonged over 10 days. In vitro studies confirmed the lack of toxicity of the IDE/ACyD8-NPs on neuronal SH-SY5Y cells, and they demonstrated their antioxidant effect upon HO exposure, as a general source of ROS." + } +} \ No newline at end of file diff --git a/37050997.json b/37050997.json new file mode 100644 index 0000000000000000000000000000000000000000..fe2022a8adcf1cf4e5603db073ac4bd9193c5256 --- /dev/null +++ b/37050997.json @@ -0,0 +1,8 @@ +{ + "id": "37050997", + "label": 0, + "article": { + "id": "37050997", + "text": "Graves' disease is an autoimmune condition in which the patient develops autoantibodies that stimulate the thyroid gland, leading to thyrotoxicosis. We report the case of a 29-year-old female who presented one month postpartum with typical symptoms and signs of thyrotoxicosis. Biochemical and radiological investigations confirmed thyrotoxicosis due to Graves' disease. She received methimazole (MMI) treatment, leading to an allergic reaction in the form of a generalized rash on the body precluding its use. We later started the treatment with propylthiouracil, which she initially tolerated well. During her treatment, she became pregnant and delivered a baby girl by cesarean section at 37 weeks of gestation. The baby developed neonatal thyrotoxicosis due to the transplacental transmission of maternal thyrotropin receptor antibodies. Thyrotoxicosis was short-lived, without consequences, and treated with antithyroid drugs. Three months after delivery, thyroid hormone levels rose considerably, requiring higher doses of propylthiouracil, which resulted in severe hepatic dysfunction, and therefore we stopped the therapy. We admitted her to the hospital for rapid correction of thyroid hormones using steroids, supersaturated potassium iodide, and cholestyramine before she underwent a total thyroidectomy. Our case highlights the challenges the patients and clinicians can face while managing Graves' disease. We discuss the role of a multidisciplinary team approach to care and the options available for treatment in such difficult situations." + } +} \ No newline at end of file diff --git a/37051252.json b/37051252.json new file mode 100644 index 0000000000000000000000000000000000000000..1ced3a03acf9557a79fd668e3dee5a3ee4b68e5d --- /dev/null +++ b/37051252.json @@ -0,0 +1,8 @@ +{ + "id": "37051252", + "label": 0, + "article": { + "id": "37051252", + "text": "INTRODUCTION:\nWhile complement is a contributor to disease severity in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, all three complement pathways might be activated by the virus. Lectin pathway activation occurs through different pattern recognition molecules, including mannan binding lectin (MBL), a protein shown to interact with SARS-CoV-2 proteins. However, the exact role of lectin pathway activation and its key pattern recognition molecule MBL in COVID-19 is still not fully understood.\n\nMETHODS:\nWe therefore investigated activation of the lectin pathway in two independent cohorts of SARS-CoV-2 infected patients, while also analysing MBL protein levels and potential effects of the six major single nucleotide polymorphisms (SNPs) found in the MBL2 gene on COVID-19 severity and outcome.\n\nRESULTS:\nWe show that the lectin pathway is activated in acute COVID-19, indicated by the correlation between complement activation product levels of the MASP-1/C1-INH complex (p=0.0011) and C4d (p\u003c0.0001) and COVID-19 severity. Despite this, genetic variations in MBL2 are not associated with susceptibility to SARS-CoV-2 infection or disease outcomes such as mortality and the development of Long COVID.\n\nCONCLUSION:\nIn conclusion, activation of the MBL-LP only plays a minor role in COVID-19 pathogenesis, since no clinically meaningful, consistent associations with disease outcomes were noted." + } +} \ No newline at end of file diff --git a/37051264.json b/37051264.json new file mode 100644 index 0000000000000000000000000000000000000000..004dc5afa4133eb74fd3b6bc65bd9dd2cfcd08a3 --- /dev/null +++ b/37051264.json @@ -0,0 +1,8 @@ +{ + "id": "37051264", + "label": 0, + "article": { + "id": "37051264", + "text": "Atopic dermatitis (AD) is an inflammatory skin disease characterized by epidermal barrier disruption, Th2 immune responses to skin allergens and microbial dysbiosis within affected lesions. Studies within the past decade have revealed genetic and environmental factors contributing to AD in children. Obesity is a metabolic disorder that often manifests early in life and is associated with reduced bacterial diversity, leading to skin colonization with lipophilic bacteria and intestinal colonization with pro-inflammatory species. These changes impair epithelial barriers and promote Th17 responses, which may worsen the severity of AD symptoms. While few studies have examined the contribution of microbiota in obesity-induced allergies, there is emerging evidence that PPAR-γ may be an effective therapeutic target. This review discusses the microbiome in pediatric AD, treatment with probiotics, how disease is altered by obesity and potential therapeutic effects of PPAR-γ agonists. While healthy skin contains diverse species adapted for specific niches, lesional skin is highly colonized with which perpetuates the inflammatory reaction. Treatments for AD should help to restore microbial diversity in the skin and intestine, as well as epithelial barrier function. Pre-clinical models have shown that PPAR-γ agonists can suppress Th17 responses, IgE production and mast cell function, while improving the epidermal barrier and microbial homeostasis. Overall, PPAR-γ agonists may be effective in a subset of patients with AD, and future studies should distinguish their metabolic and anti-inflammatory effects in order to inform the best therapies." + } +} \ No newline at end of file diff --git a/37052304.json b/37052304.json new file mode 100644 index 0000000000000000000000000000000000000000..708076f09fa34fc1ec1a741bcfad08398fd66f25 --- /dev/null +++ b/37052304.json @@ -0,0 +1,8 @@ +{ + "id": "37052304", + "label": 0, + "article": { + "id": "37052304", + "text": "Adrenohepatic fusion (AHF) is a union of the right adrenal gland and the liver with intermingling of parenchymal adrenal and liver cells. The phenomenon can be of clinical importance when evaluating patients with adrenal tumors. Using conventional imaging techniques such as computed tomography, a benign adrenal adenoma developing in an adrenohepatic fusion may mimic an invasive hepatocellular carcinoma or adrenal cortical carcinoma. This study presents a comprehensive review of the literature and shows a prevalence of 5.6 percent in autopsy studies. Moreover, 19 patients with adrenal masses in AHF are presented together with their clinical data." + } +} \ No newline at end of file diff --git a/37053322.json b/37053322.json new file mode 100644 index 0000000000000000000000000000000000000000..0f4e896efdc66b9f5a114ec311f2ca29da51f729 --- /dev/null +++ b/37053322.json @@ -0,0 +1,8 @@ +{ + "id": "37053322", + "label": 0, + "article": { + "id": "37053322", + "text": "Modern contraception ushered in an era of improved family planning, but more than 60 years after approval of \"the pill,\" product gaps and unmet needs still exist. Nearly 250 million women worldwide who want to delay or avoid pregnancy do so ineffectively or not at all, and the principal mechanism of male contraception, condoms, has not changed in 100 years. As a result, about half of the pregnancies that occur globally each year are unintended. Increasing contraceptive options and uptake will curtail abortions, empower women and men, promote healthy families, and moderate population growth that overtaxes the environment. This Review addresses the history of contraception, shortcomings in contraceptive methods, promising approaches for male and female contraception, and simultaneous protection against unintended pregnancy and sexually transmitted infections." + } +} \ No newline at end of file diff --git a/37053555.json b/37053555.json new file mode 100644 index 0000000000000000000000000000000000000000..ad32a93b37036cd2692e100c20f6fed285cb79b2 --- /dev/null +++ b/37053555.json @@ -0,0 +1,8 @@ +{ + "id": "37053555", + "label": 0, + "article": { + "id": "37053555", + "text": "Post-transplant lymphoproliferative disorders (PTLD) represent a broad spectrum of lymphoid proliferations, frequently associated with Epstein-Barr Virus (EBV) infection. The molecular profile of pediatric monomorphic PTLDs (mPTLD) has not been elucidated and it is unknown whether they display similar genetic features as their counterpart in adult and immunocompetent (IMC) pediatric patients. In this study, we investigated 31 pediatric mPTLD after solid organ transplantation, including 24 diffuse large B-cell lymphomas (DLBCL), mostly classified as activated B-cell, and seven Burkitt lymphoma (BL), 93% of which were EBV positive. We performed an integrated molecular approach, including fluorescence in situ hybridization, targeted gene sequencing and copy-number (CN) arrays. Overall, PTLD-BL carried mutations in MYC,ID3, DDX3X, ARID1A or CCND3 resembling IMC-BL, higher mutational burden than PTLD-DLBCL and less CN alterations than IMC-BL. PTLD-DLBCL showed a very heterogeneous genomic profile with fewer mutations and CN alterations than IMC-DLBCL. Epigenetic modifiers and genes of Notch pathway were the most recurrently mutated in PTLD-DLBCL (both 28%). Mutations in cell cycle and Notch pathways correlated with worse outcome. All seven PTLD-BL were alive after treatment with pediatric B-cell Non-Hodgkin Lymphoma protocols, whereas 54% of DLBCL patients were cured with immunosuppression reduction, rituximab and/or low-dose chemotherapy. These findings highlight the low complexity of pediatric PTLD-DLBCL, their good response to low intensity treatment and the shared pathogenesis between PTLD-BL and EBV+ IMC-BL. We also suggest new potential parameters that could help in the diagnosis and the design of better therapeutic strategies for these patients." + } +} \ No newline at end of file diff --git a/37054761.json b/37054761.json new file mode 100644 index 0000000000000000000000000000000000000000..4ef015066b37934d1fe8759b9eb48461720da085 --- /dev/null +++ b/37054761.json @@ -0,0 +1,8 @@ +{ + "id": "37054761", + "label": 0, + "article": { + "id": "37054761", + "text": "l-DOPA, a dopamine precursor, is commonly used as a treatment for patients with conditions such as Parkinson's disease. This therapeutic l-DOPA, as well as the dopamine derived from l-DOPA, can be deactivated via metabolism by catechol-O-methyltransferase (COMT). Targeted inhibition of COMT prolongs the effectiveness of l-DOPA and dopamine, resulting in a net increase in pharmacological efficiency of the treatment strategy. Following the completion of a previous ab initio computational analysis of 6-substituted dopamine derivatives, several novel catecholic ligands with a previously unexplored neutral tail functionality were synthesized in good yields and their structures were confirmed. The ability of the catecholic nitriles and 6-substituted dopamine analogues to inhibit COMT was tested. The nitrile derivatives inhibited COMT most effectively, in agreement with our previous computational work. pKa values were used to further examine the factors involved with the inhibition and molecular docking studies were performed to support the ab initio and experimental work. The nitrile derivatives with a nitro substituent show the most promise as inhibitors, confirming that both the neutral tail and the electron withdrawing group are essential on this class of inhibitors." + } +} \ No newline at end of file diff --git a/37054779.json b/37054779.json new file mode 100644 index 0000000000000000000000000000000000000000..d5a38bc8eeb23564e4b5dd3e5badf9da3cde12e9 --- /dev/null +++ b/37054779.json @@ -0,0 +1,8 @@ +{ + "id": "37054779", + "label": 0, + "article": { + "id": "37054779", + "text": "Choroid plexus carcinoma (CPC) is a rare infantile brain tumor with an aggressive clinical course that often leaves children with debilitating side effects due to aggressive and toxic chemotherapies. Development of novel therapeutical strategies for this disease have been extremely limited owing to the rarity of the disease and the paucity of biologically relevant substrates. We conducted the first high-throughput screen (HTS) on a human patient-derived CPC cell line (Children Cancer Hospital Egypt, CCHE-45) and identified 427 top hits highlighting key molecular targets in CPC. Furthermore, a combination screen with a wide variety of targets revealed multiple synergistic combinations that may pave the way for novel therapeutical strategies against CPC. Based on in vitro efficiency, central nervous system (CNS) penetrance ability and feasible translational potential, two combinations using a DNA alkylating or topoisomerase inhibitors in combination with an ataxia telangiectasia mutated and rad3 (ATR) inhibitor (topotecan/elimusertib and melphalan/elimusertib respectively) were validated in vitro and in vivo. Pharmacokinetic assays established increased brain penetrance with intra-arterial (IA) delivery over intra-venous (IV) delivery and demonstrated a higher CNS penetrance for the combination melphalan/elimusertib. The mechanisms of synergistic activity for melphalan/elimusertib were assessed through transcriptome analyses and showed dysregulation of key oncogenic pathways (e.g. MYC, mammalian target of rapamycin mTOR, p53) and activation of critical biological processes (e.g. DNA repair, apoptosis, hypoxia, interferon gamma). Importantly, IA administration of melphalan combined with elimusertib led to a significant increase in survival in a CPC genetic mouse model. In conclusion, this study is, to the best of our knowledge, the first that identifies multiple promising combinatorial therapeutics for CPC and emphasizes the potential of IA delivery for the treatment of CPC." + } +} \ No newline at end of file diff --git a/37055181.json b/37055181.json new file mode 100644 index 0000000000000000000000000000000000000000..e2839e2c568e32e423bc7e6b48faaa6782d13412 --- /dev/null +++ b/37055181.json @@ -0,0 +1,8 @@ +{ + "id": "37055181", + "label": 0, + "article": { + "id": "37055181", + "text": "Huntington's disease (HD) is an autosomal-dominant neurodegenerative disease characterized by progressive motor and cognitive impairments, with no disease-modifying therapies yet available. HD pathophysiology involves evident impairment in glutamatergic neurotransmission leading to severe striatal neurodegeneration. The vesicular glutamate transporter-3 (VGLUT3) regulates the striatal network that is centrally affected by HD. Nevertheless, current evidence on the role of VGLUT3 in HD pathophysiology is lacking. Here, we crossed mice lacking gene ( ) with heterozygous knock-in mouse model of HD ( ). Longitudinal assessment of motor and cognitive functions from 6-15 months of age reveals that VGLUT3 deletion rescues motor coordination and short-term memory deficits in both male and female mice. VGLUT3 deletion also rescues neuronal loss likely via the activation of Akt and ERK1/2 in the striatum of mice of both sexes. Interestingly, the rescue in neuronal survival in mice is accompanied by a reduction in the number of nuclear mutant huntingtin (mHTT) aggregates with no change in the total aggregate levels or microgliosis. Collectively, these findings provide novel evidence that VGLUT3, despite its limited expression, can be a vital contributor to HD pathophysiology and a viable target for HD therapeutics.Dysregulation of the striatal network centrally contributes to the pathophysiology of Huntington's Disease (HD). The atypical vesicular glutamate transporter-3 (VGLUT3) has been shown to regulate several major striatal pathologies such as addiction, eating disorders, or L-DOPA-induced dyskinesia. Yet, our understanding of VGLUT3's role in HD remains unclear. We report here that deletion of the () gene rescues the deficits in both motor and cognitive functions in HD mice of both sexes. We also find that VGLUT3 deletion activates neuronal survival signaling and reduces nuclear aggregation of abnormal huntingtin proteins and striatal neuron loss in HD mice. Our novel findings highlight the vital contribution of VGLUT3 in HD pathophysiology that can be exploited for HD therapeutic management." + } +} \ No newline at end of file diff --git a/37055865.json b/37055865.json new file mode 100644 index 0000000000000000000000000000000000000000..61e198595f953d73f1fa8d82ed4312c418781e97 --- /dev/null +++ b/37055865.json @@ -0,0 +1,8 @@ +{ + "id": "37055865", + "label": 0, + "article": { + "id": "37055865", + "text": "Redox homeostasis refers to the balance between the production of reactive oxygen species (ROS) as well as reactive nitrogen species (RNS), and their elimination by antioxidants. It is linked to all important cellular activities and oxidative stress is a result of imbalance between pro-oxidants and antioxidant species. Oxidative stress perturbs many cellular activities, including processes that maintain the integrity of DNA. Nucleic acids are highly reactive and therefore particularly susceptible to damage. The DNA damage response detects and repairs these DNA lesions. Efficient DNA repair processes are therefore essential for maintaining cellular viability, but they decline considerably during aging. DNA damage and deficiencies in DNA repair are increasingly described in age-related neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease. Furthermore, oxidative stress has long been associated with these conditions. Moreover, both redox dysregulation and DNA damage increase significantly during aging, which is the biggest risk factor for neurodegenerative diseases. However, the links between redox dysfunction and DNA damage, and their joint contributions to pathophysiology in these conditions, are only just emerging. This review will discuss these associations and address the increasing evidence for redox dysregulation as an important and major source of DNA damage in neurodegenerative disorders. Understanding these connections may facilitate a better understanding of disease mechanisms, and ultimately lead to the design of better therapeutic strategies based on preventing both redox dysregulation and DNA damage." + } +} \ No newline at end of file diff --git a/37056551.json b/37056551.json new file mode 100644 index 0000000000000000000000000000000000000000..ca57471990bd24e030ff24caba5228c61b253f45 --- /dev/null +++ b/37056551.json @@ -0,0 +1,8 @@ +{ + "id": "37056551", + "label": 0, + "article": { + "id": "37056551", + "text": "Nelson syndrome (NS) is a dangerous condition that can sometimes manifest after bilateral adrenalectomy (BA), typically in treating Cushing's disease. It is defined by the collection of systemic signs and symptoms that can arise in a state where there are chronically and massively elevated levels of adrenocorticotropic hormone (ACTH). Traditionally it may manifest from six months to 24 years following the loss of both adrenal glands, with the meantime of development being 15 years following BA. The diagnostic criteria are controversial, with historically many different methods being used, ranging from visual field defects and an enlarged pituitary corticotrophinoma to elevated plasma ACTH levels and skin hyperpigmentation. What remains consistent between criteria is that it is secondary to total BA, traditionally in treating refractory Cushing's disease. We describe here a rare case of a patient diagnosed with bilateral renal cell carcinoma (RCC) treated with right partial and left total nephrectomy, and incidental BA, presenting with the symptoms and signs of NS. Although NS classically presents following total BA for the treatment of Cushing disease, further research is required to look for etiologies of Nelson's-like pathology outside the context of Cushing's disease treatment, thereby necessitating a change to the traditional diagnostic criteria for the syndrome to identify cases that would otherwise go untreated. In addition, this case report's outlining, drafting, and conclusions were written in part by or with the support of Chat Generative Pre-Trained Transformer (ChatGPT), a large language transformer open-source artificial intelligence." + } +} \ No newline at end of file diff --git a/37056990.json b/37056990.json new file mode 100644 index 0000000000000000000000000000000000000000..8d9abd45e9afe6df892c845d38e56f8119365f62 --- /dev/null +++ b/37056990.json @@ -0,0 +1,8 @@ +{ + "id": "37056990", + "label": 0, + "article": { + "id": "37056990", + "text": "Dimethyl fumarate (DMF) is FDA-approved for use in patients with relapsing multiple sclerosis, and it processes neuroprotection in several experimental settings; however, its impact on combating Huntington's disease (HD) remains elusive. This study aimed to explore the role of DMF post-treatment on HD mediated endoplasmic reticulum (ER) stress response in a selective striatal degeneration HD model. Rats, exposed to 3-nitropropionic acid, were either left untreated or post-treated with DMF for 14 days. DMF reduced locomotion deficits in both the open field and beam walk paradigms, boosted the striatal dopamine (DA) content, improved its architecture at the microscopic level, and hindered astrogliosis. Mechanistically, DMF limited the activation of two of the ER stress arms in the striatum by reducing p-IRE1α, p-JNK, and p-PERK protein expressions besides the CHOP/GADD153 content. Downstream from both ER stress arms' suppression, DMF inhibited the intrinsic apoptotic pathway, as shown by the decrease in Bax and active caspase-3 while raising Bcl-2. DMF also decreased oxidative stress markers indicated by a decline in both reactive oxygen species and malondialdehyde while boosting glutathione. Meanwhile, it enhanced p-AKT to activate /phosphorylate mTOR and stimulate the CREB/BDNF/TrkB trajectory, which, in a positive feedforward loop, activates AKT again. DMF also downregulated the expression of miRNA-634, which negatively regulates AKT, to foster survival kinase activation. This study features a focal novel point on the DMF therapeutic ability to reduce HD motor manifestations its ability to enhance DA and suppress the IRE1α/JNK and PERK/CHOP/GADD153 hubs to inhibit the mitochondrial apoptotic pathway through activating the AKT/mTOR and BDNF/TrkB/AKT/CREB signaling pathways and abating miRNA-634 and oxidative stress." + } +} \ No newline at end of file diff --git a/37058198.json b/37058198.json new file mode 100644 index 0000000000000000000000000000000000000000..f01c3254311f9a3b2ca2a74991a2891ff4f2f9d2 --- /dev/null +++ b/37058198.json @@ -0,0 +1,8 @@ +{ + "id": "37058198", + "label": 0, + "article": { + "id": "37058198", + "text": "PURPOSE:\nPatients with antibody deficiencies often receive maintenance treatment with donor plasma-derived immunoglobulin (Ig) preparations to decrease the incidence and severity of infections. We have previously shown that IgG antibodies to the original SARS-CoV-2 strain were not consistently present in off-the-shelf Ig batches produced up to approximately 18 months after the first identified case of COVID-19 in the USA and that Ig batches with anti-SARS-CoV-2 IgG primarily contained vaccine-induced spike specific antibodies. This study aimed to investigate the degree of cross-reactivity between vaccine-induced anti-SARS-CoV-2 antibodies against Wuhan strain and subsequent viral variants.\n\nMETHODS:\nSamples were collected from 74 Ig batches supplied by three different commercial manufacturers. All batches were used at the Immunodeficiency Unit at the Karolinska University Hospital from the start of the SARS-CoV-2 pandemic until September 2022. Antibody quantity and potential to neutralize virus entry into host cells were assessed against the original SARS-CoV-2 Wuhan strain and the following nine variants: Alpha, Beta, Delta, IHU, and the Omicron BA.1, BA.1.1, BA.1 with spike mutation L452R, BA.2, and BA.3.\n\nRESULTS:\nIg batches produced approximately 18 months after the SARS-CoV-2 outbreak (from around July 2021) and later consistently contained high quantities of antibodies that bind the Wuhan strain. The Ig batches had overall low reactivity to the SARS-CoV-2 nucleocapsid, which implies that plasma donor spike IgG essentially is the result of vaccination. We assessed the degree of cross-reactivity towards each virus variant by plotting the variant/Wuhan strain ratio, which was consistent regardless of production date, suggesting cross-reactivity with vaccine-induced antibodies rather than virus exposure in the plasma donor population. Viral variants that emerged later during the pandemic systematically had a lower reactivity ratio, except for the Delta and IHU variants. The Ig batches displayed markedly low neutralizing potential towards the Beta variant and all tested Omicron variants.\n\nCONCLUSION:\nCommercial Ig batches currently contain large quantities of SARS-CoV-2 vaccine-induced antibodies. Cross-reactivity with variant strains is evident but varies, with markedly low neutralizing potential observed against Omicron variants." + } +} \ No newline at end of file diff --git a/37058324.json b/37058324.json new file mode 100644 index 0000000000000000000000000000000000000000..3e25c8a9e9e949b9440abab00b5099733459db88 --- /dev/null +++ b/37058324.json @@ -0,0 +1,8 @@ +{ + "id": "37058324", + "label": 0, + "article": { + "id": "37058324", + "text": "INTRODUCTION:\nB-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common neoplasm in children. One of the long known recurrent rearrangements in BCP-ALL is t(1;19)(q23;p13.3)/TCF3::PBX1. However, other TCF3 gene rearrangements were also described that are associated with significant difference in ALL prognosis.\n\nMETHODS:\nThe current study aimed to analyze the spectrum of TCF3 gene rearrangements in children in Russian Federation. A cohort of 203 patients with BCP-ALL was selected based on FISH screening and was studied by karyotyping, FISH, RT-PCR and high throughput sequencing.\n\nRESULTS:\nT(1;19)(q23;p13.3)/TCF3::PBX1 is the most common aberration in TCF3-positive pediatric BCP-ALL (87.7%), with its unbalanced form prevailing. It resulted from TCF3::PBX1 exon 16-exon 3 fusion junction (86.2%) or unconventional exon 16-exon 4 junction (1.5%). Rarer events included t(12;19)(p13;p13.3)/TCF3::ZNF384 (6.4%) and t(17;19)(q21-q22;p13.3)/TCF3::HLF (1.5%). The latter translocations demonstrated high molecular heterogeneity and complex structure-four distinct transcripts were shown for TCF3::ZNF384 and each patient with TCF3::HLF had a unique transcript. These features hamper TCF3 rearrangement primary detection by molecular methods and brings FISH screening to the fore. A case of novel TCF3::TLX1 fusion in a patient with t(10;19)(q24;p13) was also discovered. Survival analysis within the national pediatric ALL treatment protocol demonstrated the severe prognosis of TCF3::HLF compared to both TCF3::PBX1 and TCF3::ZNF384.\n\nCONCLUSION:\nSo, high molecular heterogeneity of TCF3 gene rearrangement in pediatric BCP-ALL was demonstrated and a novel fusion gene TCF3::TLX1 was described." + } +} \ No newline at end of file diff --git a/37059834.json b/37059834.json new file mode 100644 index 0000000000000000000000000000000000000000..5f2d31efd7e64dfcbcabaa890614adac740c50c2 --- /dev/null +++ b/37059834.json @@ -0,0 +1,8 @@ +{ + "id": "37059834", + "label": 0, + "article": { + "id": "37059834", + "text": "BRAFV600E alterations are prevalent across multiple tumors. Here we present final efficacy and safety results of a phase 2 basket trial of dabrafenib (BRAF kinase inhibitor) plus trametinib (MEK inhibitor) in eight cohorts of patients with BRAFV600E-mutated advanced rare cancers: anaplastic thyroid carcinoma (n = 36), biliary tract cancer (n = 43), gastrointestinal stromal tumor (n = 1), adenocarcinoma of the small intestine (n = 3), low-grade glioma (n = 13), high-grade glioma (n = 45), hairy cell leukemia (n = 55) and multiple myeloma (n = 19). The primary endpoint of investigator-assessed overall response rate in these cohorts was 56%, 53%, 0%, 67%, 54%, 33%, 89% and 50%, respectively. Secondary endpoints were median duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Median DoR was 14.4 months, 8.9 months, not reached, 7.7 months, not reached, 31.2 months, not reached and 11.1 months, respectively. Median PFS was 6.7 months, 9.0 months, not reached, not evaluable, 9.5 months, 5.5 months, not evaluable and 6.3 months, respectively. Median OS was 14.5 months, 13.5 months, not reached, 21.8 months, not evaluable, 17.6 months, not evaluable and 33.9 months, respectively. The most frequent (≥20% of patients) treatment-related adverse events were pyrexia (40.8%), fatigue (25.7%), chills (25.7%), nausea (23.8%) and rash (20.4%). The encouraging tumor-agnostic activity of dabrafenib plus trametinib suggests that this could be a promising treatment approach for some patients with BRAFV600E-mutated advanced rare cancers. ClinicalTrials.gov registration: NCT02034110 ." + } +} \ No newline at end of file diff --git a/37060084.json b/37060084.json new file mode 100644 index 0000000000000000000000000000000000000000..7c6759215e580b2455cea3af9de28ba0aebb35b8 --- /dev/null +++ b/37060084.json @@ -0,0 +1,8 @@ +{ + "id": "37060084", + "label": 0, + "article": { + "id": "37060084", + "text": "BACKGROUND:\nThe therapeutic effect of selenium has been demonstrated in mild Graves' ophthalmopathy (GO) in a European region where selenium status is suboptimal. However, there is a lack of evidence to support selenium use in selenium-sufficient areas. The aim of this study is to evaluate the therapeutic effect of selenium in mild-to-moderate GO in selenium-sufficient South Korea.\n\nMETHODS:\nThe SeGOSS trial is a multicenter, prospective, randomized, open-label trial in South Korea. Eighty-four patients aged 19 years or older with mild-to-moderate GO will be randomized to receive either vitamin B complex alone or vitamin B complex with selenium for 6 months with three monthly follow-up visits. The primary outcome is comparison of the improvement in quality of life at 6 months from baseline between the control and selenium groups. The secondary outcomes are intergroup differences in changes in quality of life at 3 months, clinical activity of GO at 3 and 6 months, thyroid autoantibody titers at 3 and 6 months, and the response rate at 3 and 6 months from baseline. Quality of life will be measured by questionnaire for patients with GO, and the clinical activity of GO will be evaluated by the clinical activity score (CAS). A positive response is defined as either changes in the CAS \u003c 0 or the changes in the GO-QOL score ≥ 6.\n\nDISCUSSION:\nThe SeGOSS study will evaluate the therapeutic potential of selenium for mild-to-moderate GO in a selenium-sufficient area and provide support in tailoring better treatment for GO.\n\nTRIAL REGISTRATION:\nKCT0004040. Retrospectively registered on 5 June 2019. https://cris.nih.go.kr/cris/search/detailSearch.do/14160 ." + } +} \ No newline at end of file diff --git a/37060174.json b/37060174.json new file mode 100644 index 0000000000000000000000000000000000000000..91e36456fd85405ddfd412fff77c818282e333d1 --- /dev/null +++ b/37060174.json @@ -0,0 +1,8 @@ +{ + "id": "37060174", + "label": 0, + "article": { + "id": "37060174", + "text": "OBJECTIVE:\nRecent studies have found that human Friedreich ataxia patients have dysfunction of transmission in the auditory neural pathways. Here, we characterize hearing deficits in a mouse model of Friedreich ataxia and compare these to a clinical population.\n\nMETHODS:\nSixteen mice with a C57BL/6 background were evaluated. Eight were YG8Pook/J animals (Friedreich ataxia phenotype) and eight wild-type mice served as controls. Auditory function was assessed between ages 6 and 12 months using otoacoustic emissions and auditory steady-state responses. At study end, motor deficit was assessed using Rotorod testing and inner ear tissue was examined. Thirty-seven individuals with Friedreich ataxia underwent auditory steady-state evoked potential assessment and response amplitudes were compared with functional hearing ability (speech perception-in-noise) and disease status was measured by the Friedreich Ataxia Rating Scale.\n\nRESULTS:\nThe YG8Pook/J mice showed anatomic and functional abnormality. While otoacoustic emission responses from the cochlear hair cells were mildly affected, auditory steady-state responses showed exaggerated amplitude reductions as the animals aged with Friedreich ataxia mice showing a 50-60% decrease compared to controls who showed only a 20-25% reduction (F = 17.90, p \u003c 0.00). Furthermore, the YG8Pook/J mice had fewer surviving spiral ganglion neurons, indicating greater degeneration of the auditory nerve. Neuronal density was 20-25% lower depending on cochlear region (F = 45.02, p \u003c 0.001). In human participants, auditory steady-state response amplitudes were correlated with both Consonant-Nucleus-Consonant word scores and Friedreich Ataxia Rating Scale score.\n\nINTERPRETATION:\nThis study found degenerative changes in auditory structure and function in YG8Pook/J mice, indicating that auditory measures in these animals may provide a model for testing Friedreich ataxia treatments. In addition, auditory steady-state response findings in a clinical population suggested that these scalp-recorded potentials may serve as an objective biomarker for disease progress in affected individuals." + } +} \ No newline at end of file diff --git a/37061341.json b/37061341.json new file mode 100644 index 0000000000000000000000000000000000000000..3e0f72bfa82847be08111d82b88bc4840a25b519 --- /dev/null +++ b/37061341.json @@ -0,0 +1,8 @@ +{ + "id": "37061341", + "label": 0, + "article": { + "id": "37061341", + "text": "The regulatory proteins, cyclins, and cyclin-dependent kinases (CDKs) control the cell cycle progression. CDK4 gene mutations are associated with certain cancers such as melanoma, breast cancer, and rhabdomyosarcoma. Therefore, understanding the mechanisms of cell cycle control and cell proliferation is essential in developing cancer treatment regimens. In this study, we obtained cancer-causing CDK4 mutations from the COSMIC database and subjected them to a series of in silico analyses to identify the most significant mutations. An overall of 238 mutations (119 missense mutations) retrieved from the COSMIC database were investigated for the pathogenic and destabilizing properties using the PredictSNP and iStable algorithms. Further, the amino acid position of the most pathogenic and destabilizing mutations were analyzed to understand the nature of amino acid conservation across the species during the evolution. We observed that the missense mutations G201R and G201D were more significant and the Glycine at position 201 was found to highly conserved. These significant mutations were subjected to molecular dynamics simulation analysis to understand the protein's structural changes. The results from molecular dynamics simulations revealed that both G201R and G201D of CDK4 are capable of altering the protein's native form. On comparison among the most significant mutations, G201R disrupted the protein structure higher than the protein with G201D." + } +} \ No newline at end of file diff --git a/37061367.json b/37061367.json new file mode 100644 index 0000000000000000000000000000000000000000..a0cacdd2682fd338659272712c32ca90047361d0 --- /dev/null +++ b/37061367.json @@ -0,0 +1,8 @@ +{ + "id": "37061367", + "label": 0, + "article": { + "id": "37061367", + "text": "The adrenocortical carcinoma (ACC) is a primary malignant tumor developed from the adrenal cortex, defined by a Weiss score≥3. Its prognosis is poor and depends mainly on the stage of the disease at diagnosis. Care is organized in France by the multidisciplinary expert centers of the national ENDOCAN-COMETE \"Adrenal Cancers\" network, certified by the National Cancer Institute. This document updates the guidelines for the management of ACC in adults based on the most robust data in the literature. It's divided into 11 chapters: (1) circumstances of discovery; (2) pre-therapeutic assessment; (3) diagnosis of ACC; (4) oncogenetics; (5) prognostic classifications; (6) treatment of hormonal hypersecretion; (7) treatment of localized forms; (8) treatment of relapses; (9) treatment of advanced forms; (10) follow-up; (11) the particular case of ACC and pregnancy. R0 resection of all localized ACC remains an unmet need and it must be performed in expert centers. Flow-charts for the therapeutic management of localized ACC, relapse or advanced ACC are provided. It was written by the experts from the national ENDOCAN-COMETE network and validated by all French Societies involved in the management of these patients (endocrinology, medical oncology, endocrine surgery, urology, pathology, genetics, nuclear medicine, radiology, interventional radiology)." + } +} \ No newline at end of file diff --git a/37061549.json b/37061549.json new file mode 100644 index 0000000000000000000000000000000000000000..4c842dfd4c48ae0a49024f9220c07ce00b0d54a7 --- /dev/null +++ b/37061549.json @@ -0,0 +1,8 @@ +{ + "id": "37061549", + "label": 0, + "article": { + "id": "37061549", + "text": "This work proposes a new class of explainable prognostic models for longitudinal data classification using triclusters. A new temporally constrained triclustering algorithm, termed TCtriCluster, is proposed to comprehensively find informative temporal patterns common to a subset of patients in a subset of features (triclusters), and use them as discriminative features within a state-of-the-art classifier with guarantees of interpretability. The proposed approach further enhances prediction with the potentialities of model explainability by revealing clinically relevant disease progression patterns underlying prognostics, describing features used for classification. The proposed methodology is used in the Amyotrophic Lateral Sclerosis (ALS) Portuguese cohort (N = 1321), providing the first comprehensive assessment of the prognostic limits of five notable clinical endpoints: need for non-invasive ventilation (NIV); need for an auxiliary communication device; need for percutaneous endoscopic gastrostomy (PEG); need for a caregiver; and need for a wheelchair. Triclustering-based predictors outperform state-of-the-art alternatives, being able to predict the need for auxiliary communication device (within 180 days) and the need for PEG (within 90 days) with an AUC above 90%. The approach was validated in clinical practice, supporting healthcare professionals in understanding the link between the highly heterogeneous patterns of ALS disease progression and the prognosis." + } +} \ No newline at end of file diff --git a/37062155.json b/37062155.json new file mode 100644 index 0000000000000000000000000000000000000000..caff70932979c755c9f5316e04e558c754abebac --- /dev/null +++ b/37062155.json @@ -0,0 +1,8 @@ +{ + "id": "37062155", + "label": 0, + "article": { + "id": "37062155", + "text": "BACKGROUND AND OBJECTIVE:\nSurvival analysis is widely applied for assessing the expected duration of patient status towards event occurrences such as mortality in healthcare domain, which is generally considered as a time-to-event problem. Patients with multiple complications have high mortality risks and oftentimes require specific intensive care and clinical treatments. The progression of complications is time-varying according to disease development and intrinsic interactions between complications with respect to mortality are uncertain. Classical methods for mortality prediction and survival analysis in critical care, such as risk scoring systems and cause-specific survival models, were not designed for this multi-event survival analysis problem and able to measure the competing risks of death for mutually exclusive events. In addition, multivariate temporal information of complications is not taken into consideration while estimating differentiated mortality risks in the early stage.\n\nMETHODS:\nIn this paper, we propose a novel multi-event survival analysis solution using a tree-based autoregressive survival model of multi-modal electronic health record data. Specifically, we focus on modeling the temporal trajectory of complications and estimating the mortality risk associated with multiple potential complications simultaneously. In dynamic modeling, no assumptions are made for the relationships between time-dependent variables and risk transition over time.\n\nRESULTS:\nValidated with the eICU database, our model achieves a better prediction performance with C-index ranging in 74-80%, compared to state-of-the-art machine learning methods in the literature, for the complications of acute respiratory distress syndrome and cardiovascular disease cases.\n\nCONCLUSIONS:\nOur model provides the distinguishable mortality risk curves over time for specific complications and the track of risk development that could potentially support the ICU resource reallocation." + } +} \ No newline at end of file diff --git a/37062469.json b/37062469.json new file mode 100644 index 0000000000000000000000000000000000000000..89f8988b282f9dd928f14b905d0611a1815f3013 --- /dev/null +++ b/37062469.json @@ -0,0 +1,8 @@ +{ + "id": "37062469", + "label": 0, + "article": { + "id": "37062469", + "text": "When tumoral cell expansion exceeds the vascular supply, regions of hypoxia or low oxygen concentration are generated promoting the formation of new vessels through cell proliferation and migration. Viral G protein-coupled receptor (vGPCR) is associated to Kaposi's sarcoma pathology and induces a paracrine transformation when is stably expressed in murine endothelial cells activating hypoxia-induced transcription factors. Previously, we reported the antiproliferative actions of 1α,25-dihydroxyvitamin D (1α,25(OH)D) in endothelial cells transformed by the vGPCR (SVEC-vGPCR). Herein, we further investigated if pro-angiogenic factors as AP-1, HIF-1α and VEGF are modulated by 1α,25(OH)D. We found by qRT-PCR analysis that the mRNA level of JunB, a negative regulator of cell proliferation, was similarly increased at all-time points tested after 1α,25(OH)D treatment in SVEC-vGPCR cells. Also, mRNA levels of the pro-angiogenic factor c-Fos, which induces tumor invasion, were only decreased during one short period treatment. In addition, Hif-1α mRNA and protein levels were significantly reduced after 1α,25(OH)D treatment in a VDR dependent fashion. However, mRNA levels of the angiogenic activator Vegf, promoted in turn by Hif-1α expression, were surprisingly high depending on VDR expression as well. Moreover, Egr-1, which has been reported to induce VEGF expression independently of HIF-1α, diminished its expression with 1α,25(OH)D treatment, fact that was related to the decline of p-ERK1/2. Altogether, these results suggest a negative modulation of some pro-angiogenic factors like AP-1 and HIF-1α, as part of the antiproliferative mechanism of 1α,25(OH)D in SVEC-vGPCR endothelial cells." + } +} \ No newline at end of file diff --git a/37062767.json b/37062767.json new file mode 100644 index 0000000000000000000000000000000000000000..3ade021d2f203869e5d2a8deef030b689e5b5a8d --- /dev/null +++ b/37062767.json @@ -0,0 +1,8 @@ +{ + "id": "37062767", + "label": 0, + "article": { + "id": "37062767", + "text": "Ultrasound-enhanced delivery of therapeutic-loaded echogenic liposomes is under development for vascular applications using the EkoSonic Endovascular System. In this study, fibrin-targeted echogenic liposomes loaded with an anti-inflammatory agent were characterized before and after infusion through an EkoSonic catheter. Cavitation activity was nucleated by Definity or fibrin-targeted, drug-loaded echogenic liposomes infused and insonified with EkoSonic catheters. Passive cavitation imaging was used to quantify and map bubble activity in a flow phantom mimicking porcine arterial flow. Cavitation was sustained during 3-min infusions of Definity or echogenic liposomes along the distal 6 cm treatment zone of the catheter. Though the EkoSonic catheter was not designed specifically for cavitation nucleation, infusion of drug-loaded echogenic liposomes can be employed to trigger and sustain bubble activity for enhanced intravascular drug delivery." + } +} \ No newline at end of file diff --git a/37063844.json b/37063844.json new file mode 100644 index 0000000000000000000000000000000000000000..be15991d659a4c4fb8d6eadd11f326c0ffa2ef0b --- /dev/null +++ b/37063844.json @@ -0,0 +1,8 @@ +{ + "id": "37063844", + "label": 0, + "article": { + "id": "37063844", + "text": "Neurodegenerative diseases (NDs) are chronic conditions that result in progressive damage to the nervous system, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic lateral sclerosis (ALS). Age is a major risk factor for NDs. Telomere shortening is a biological marker of cellular aging, and telomerase reverse transcriptase (TERT) has been shown to slow down this process by maintaining telomere length. The blood-brain barrier (BBB) makes the brain a unique immune organ, and while the number of T cells present in the central nervous system is limited, they play an important role in NDs. Research suggests that NDs can be influenced by modulating peripheral T cell immune responses, and that TERT may play a significant role in T cell senescence and NDs. This review focuses on the current state of research on TERT in NDs and explores the potential connections between TERT, T cells, and NDs. Further studies on aging and telomeres may provide valuable insights for developing therapeutic strategies for age-related diseases." + } +} \ No newline at end of file diff --git a/37063907.json b/37063907.json new file mode 100644 index 0000000000000000000000000000000000000000..2701401ba9ee85a31d37a6d139e8813882f64d45 --- /dev/null +++ b/37063907.json @@ -0,0 +1,8 @@ +{ + "id": "37063907", + "label": 0, + "article": { + "id": "37063907", + "text": "PURPOSE:\nPatients with X-linked agammaglobulinemia (XLA) are characterized by humoral impairment and are routinely treated with intravenous immunoglobulin (IVIG). In this study, we aimed to investigate the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in IVIG preparations harvested globally and evaluate the transfer of SARS-CoV-2 antibodies to the XLA patient.\n\nMETHODS:\nA single-center, prospective cohort study was conducted in the period of November 2020 to November 2022. Clinical and laboratory data, specifically, SARS-CoV-2 spike IgG levels from the serum of 115 IVIG preparations given to 5 XLA patient were collected. Concurrently, SARS-CoV-2 spike IgG levels from the serum of the 5 XLA was collected monthly.\n\nRESULTS:\nFive XLA patients were evaluated within the study period. All were treated monthly with commercial IVIG preparations. A total of 115 IVIG treatments were given over the study period. The origin country and the date of IVIG harvesting was obtained for 111 (96%) of the treatments. Fifty-four IVIG preparations (49%) were harvested during the COVID-19 pandemic of which 76% were positive (\u003e50AU/mL) for SARS-CoV-2 spike antibodies which were subsequently transmitted to the XLA patients in an approximate 10-fold reduction. SARS-CoV2 spike IgG was first detected in IVIG batches that completed their harvest date by September 2021. Positive products were harvested from origin countries with a documented prevalence over 2,000 per 100,000 population.\n\nCONCLUSION:\nAs the prevalence of COVID-19 infections rises, detection of SARS-CoV-2 spike IgG in commercial IVIG products increases and is then transmitted to the patient. Future studies are needed to investigate the neutralizing capabilities of SARS-CoV-2 IgG and whether titer levels in IVIG remain consistent as the incidence of infection and vaccination rates in the population changes." + } +} \ No newline at end of file diff --git a/37064774.json b/37064774.json new file mode 100644 index 0000000000000000000000000000000000000000..d4924d3016e52559a338d02fec2b0461b7c1172e --- /dev/null +++ b/37064774.json @@ -0,0 +1,8 @@ +{ + "id": "37064774", + "label": 0, + "article": { + "id": "37064774", + "text": "Adrenal and spinal metastases of hepatocellular carcinoma (HCC) are rare entities with significant morbidity and mortality, particularly after liver transplantation (LT). We report a case of a 49-year-old man who underwent LT for hepatitis B-related end-stage liver disease and HCC (single 4.5 cm lesion [T1N0], without vascular invasion) in 2016. Eighteen months later, adrenal metastasis and hepatitis B seropositive conversion were developed with normal serum tumor. Adrenal metastasis was treated with radiation therapy (RT) and hepatitis B showed spontaneous seronegative conversion. However, 35 months later, spinal metastasis occurred with elevation of the protein induced by vitamin K absence or antagonist-II (PIVKA-II) level (197 mAU/mL), along with hepatitis B seropositive conversion. After sorafenib, sequential regorafenib with RT led to partial response of the spinal lesions, along with hepatitis B seronegative conversion and normal PIVKA-II levels. After 9 months of regorafenib combined with RT, two recurrent lesions were found, as well as hepatitis B seropositive conversion and lesions were treated with transarterial chemoembolization. The patient survived for more than 71 months after LT and 53 months after recurrence under various combinations of therapy. Combined systemic and locoregional therapies can be a treatment option for HCC recurrence, even in LT patients." + } +} \ No newline at end of file diff --git a/37064812.json b/37064812.json new file mode 100644 index 0000000000000000000000000000000000000000..ef9b1146e985ae9dac3b588f9c2f5f73195aac27 --- /dev/null +++ b/37064812.json @@ -0,0 +1,8 @@ +{ + "id": "37064812", + "label": 0, + "article": { + "id": "37064812", + "text": "Many neurodegenerative diseases, including Huntington's disease (HD) and Alzheimer's disease (AD), occur due to an accumulation of aggregation-prone proteins, which results in neuronal death. Studies in animal and cell models show that reducing the levels of these proteins mitigates disease phenotypes. We previously reported a small molecule, NCT-504, which reduces cellular levels of mutant huntingtin (mHTT) in patient fibroblasts as well as mouse striatal and cortical neurons from an Hdh mutant mouse. Here, we show that NCT-504 has a broader potential, and in addition reduces levels of Tau, a protein associated with Alzheimer's disease, as well as other tauopathies. We find that in untreated cells, Tau and mHTT are degraded via autophagy. Notably, treatment with NCT-504 diverts these proteins to multivesicular bodies (MVB) and the ESCRT pathway. Specifically, NCT-504 causes a proliferation of endolysosomal organelles including MVB, and an enhanced association of mHTT and Tau with endosomes and MVB. Importantly, depletion of proteins that act late in the ESCRT pathway blocked NCT-504 dependent degradation of Tau. Moreover, NCT-504-mediated degradation of Tau occurred in cells where Atg7 is depleted, which indicates that this pathway is independent of canonical autophagy. Together, these studies reveal that upregulation of traffic through an ESCRT-dependent MVB pathway may provide a therapeutic approach for neurodegenerative diseases." + } +} \ No newline at end of file diff --git a/37065386.json b/37065386.json new file mode 100644 index 0000000000000000000000000000000000000000..e1e185c486649400a18620b64ac42d85b3251c90 --- /dev/null +++ b/37065386.json @@ -0,0 +1,8 @@ +{ + "id": "37065386", + "label": 0, + "article": { + "id": "37065386", + "text": "Motor neuron disease is a degenerative condition involving both upper motor neurons (UMN) and lower motor neurons (LMN). While amyotrophic lateral sclerosis (ALS) is an overlap of upper and lower motor neuron involvement, primary lateral sclerosis (PLS) is predominantly an upper motor neuron involvement with lower motor involvement seen in the later stages of illness. Diagnostic criteria rely on clinical features and electrodiagnostic tests such as electromyography (EMG). EMG predominantly helps in determining lower motor neuron involvement. No definitive objective measures are currently available to determine upper motor neuron involvement. We describe a patient diagnosed with PLS based on consensus diagnostic criteria. The patient had absent LMN features both clinically and on EMG. Magnetic resonance imaging (MRI) was significant for hypointense signals in the bilateral motor strip area on susceptibility weighted sequence, suggesting a surrogate marker of degeneration involving motor neurons in the brain. Early recognition of this MRI pattern called motor band sign (MBS) can help determine the earlier diagnosis of this neurodegenerative condition, potentially translating to better treatment and outcome measures." + } +} \ No newline at end of file diff --git a/37067227.json b/37067227.json new file mode 100644 index 0000000000000000000000000000000000000000..8ec9990b898cc30c66810856f082986e6cf761d9 --- /dev/null +++ b/37067227.json @@ -0,0 +1,8 @@ +{ + "id": "37067227", + "label": 0, + "article": { + "id": "37067227", + "text": "SUMMARY:\nAutoimmune polyglandular syndrome (APS) type 2 is characterized by the presence of Addison's disease (AD) along with autoimmune thyroid disease and/or type 1 diabetes. APS type 2 is known as Schmidt's syndrome when autoimmune adrenal insufficiency is associated with chronic lymphocytic thyroiditis. We report a very rare case of a 28-year-old female patient who had Schmidt's syndrome revealed by a thyroid storm (TS) concomitant with an acute adrenal crisis. The onset of AD resulted in a surgical emergency. The patient presented with cardiogenic shock and an acute abdomen. The precipitation factor was Hashitoxicosis presented as TS. This life-threatening condition was successfully reversed with aggressive medical therapy based on antithyroid drugs and intravenous glucocorticoids. This hyperthyroid phase lasted for a period of 8 months. The patient eventually developed hypothyroidism, suggesting that Hashimoto's thyroiditis was the most likely diagnosis. She was started on levothyroxine replacement therapy and remained euthyroid on levothyroxine. The case we describe had several diagnostic pitfalls that are discussed both at the start as well as during the evolution.\n\nLEARNING POINTS:\nAutoimmune diseases can appear concomitantly or succeed each other over time. The clinician must be vigilant to detect these diseases in time in order to avoid a misdiagnosis of a life-threatening emergency such as adrenal insufficiency or thyroid storm. Thyroid storm is an uncommon but life-threatening manifestation of hyperthyroidism. Diagnosis is dependent on clinical symptoms, and no specific laboratory tests are available. Glucocorticoids should be used in the treatment of thyroid storm because they have an inhibitory effect on peripheral conversion of T4 to T3. In patients who have severe thyrotoxicosis, especially in conjunction with hypotension, treatment with glucocorticoids has become standard practice because of the possibility of relative adrenal insufficiency or the possibility of undiagnosed Addison's disease. The differential diagnosis of hyperthyroidism can be challenging. Graves' disease can be discussed in view of the severity of the clinical presentation and the prolonged duration of the hyperthyroid phase. Hashitoxicosis is the initial hyperthyroid phase in chronic autoimmune thyroiditis. The hyperthyroid phase is always followed by definitive resolution, with persistent euthyroidism and no hyperthyroid relapses. Synthetic antithyroid drugs may be prescribed during the hyperthyroid phase of Hashimoto thyroiditis if the clinical presentation is severe and the duration of the hyperthyroid phase is prolonged." + } +} \ No newline at end of file diff --git a/37069149.json b/37069149.json new file mode 100644 index 0000000000000000000000000000000000000000..2dbbe24d4ed524cb714bdc94ba8fa7079564f7d0 --- /dev/null +++ b/37069149.json @@ -0,0 +1,8 @@ +{ + "id": "37069149", + "label": 0, + "article": { + "id": "37069149", + "text": "Loss of function of the von Hippel-Lindau (VHL) tumor suppressor gene is a hallmark of clear cell renal cell carcinoma (ccRCC). The importance of heterogeneity in the loss of this tumor suppressor has been under reported. To study the impact of intratumoral VHL heterogeneity observed in human ccRCC, we engineered VHL gene deletion in four RCC models, including a new primary tumor cell line derived from an aggressive metastatic case. The VHL gene-deleted (VHL-KO) cells underwent epithelial-to-mesenchymal transition (EMT) and exhibited increased motility but diminished proliferation and tumorigenicity compared to the parental VHL-expressing (VHL) cells. Renal tumors with either VHL or VHL-KO cells alone exhibit minimal metastatic potential. Combined tumors displayed rampant lung metastases, highlighting a novel cooperative metastatic mechanism. The poorly proliferative VHL-KO cells stimulated the proliferation, EMT, and motility of neighboring VHL cells. Periostin (POSTN), a soluble protein overexpressed and secreted by VHL non-expressing (VHL) cells, promoted metastasis by enhancing the motility of VHL-WT cells and facilitating tumor cell vascular escape. Genetic deletion or antibody blockade of POSTN dramatically suppressed lung metastases in our preclinical models. This work supports a new strategy to halt the progression of ccRCC by disrupting the critical metastatic crosstalk between heterogeneous cell populations within a tumor." + } +} \ No newline at end of file diff --git a/37069193.json b/37069193.json new file mode 100644 index 0000000000000000000000000000000000000000..8a1ba588cc4039e52862406f921e164090b981f7 --- /dev/null +++ b/37069193.json @@ -0,0 +1,8 @@ +{ + "id": "37069193", + "label": 0, + "article": { + "id": "37069193", + "text": "Digital health technologies can provide continuous monitoring and objective, real-world measures of Parkinson's disease (PD), but have primarily been evaluated in small, single-site studies. In this 12-month, multicenter observational study, we evaluated whether a smartwatch and smartphone application could measure features of early PD. 82 individuals with early, untreated PD and 50 age-matched controls wore research-grade sensors, a smartwatch, and a smartphone while performing standardized assessments in the clinic. At home, participants wore the smartwatch for seven days after each clinic visit and completed motor, speech and cognitive tasks on the smartphone every other week. Features derived from the devices, particularly arm swing, the proportion of time with tremor, and finger tapping, differed significantly between individuals with early PD and age-matched controls and had variable correlation with traditional assessments. Longitudinal assessments will inform the value of these digital measures for use in future clinical trials." + } +} \ No newline at end of file diff --git a/37069439.json b/37069439.json new file mode 100644 index 0000000000000000000000000000000000000000..306172bf17050ba9b69111963092948e8078df6f --- /dev/null +++ b/37069439.json @@ -0,0 +1,8 @@ +{ + "id": "37069439", + "label": 0, + "article": { + "id": "37069439", + "text": "BACKGROUND:\nProgressive supranuclear palsy (PSP) is a rare and fatal neurodegenerative movement disorder with no disease modifying therapy currently available. Data on the costs associated with PSP are scarce. This study aims to assess the direct medical expenditure of patients with PSP (PwPSP) throughout disease course.\n\nMETHODS:\nThis retrospective cohort study is based on the data of a large state-mandated health provider in Israel. We identified PwPSP who were initially diagnosed between 2000 and 2017. Each PwPSP was randomly matched to three health-plan members without PSP by birth-year, sex, and socioeconomic status. Healthcare resources' utilization and related costs were assessed.\n\nRESULTS:\nWe identified 88 eligible PwPSP and 264 people in the reference group; mean age at diagnosis was 72.6 years (SD = 8.4) and 53.4% were female. The annual direct costs of PwPSP have risen over time, reaching US$ 21,637 in the fifth year and US$ 36,693 in the tenth year of follow-up vs US$ 8910 in the year prior diagnosis. Compared to people without PSP, PwPSP had substantially higher medical expenditure during the years prior- and post-index date.\n\nCONCLUSION:\nThe present study demonstrates higher economic burden, which increases with time, in PwPSP as compared to those without." + } +} \ No newline at end of file diff --git a/37069469.json b/37069469.json new file mode 100644 index 0000000000000000000000000000000000000000..f6ab9cc32eb4590a2c1d5b74d20c3a9284079e45 --- /dev/null +++ b/37069469.json @@ -0,0 +1,8 @@ +{ + "id": "37069469", + "label": 0, + "article": { + "id": "37069469", + "text": "OBJECTIVES:\nThis study provides a systematic review and meta-analysis of randomized controlled trials (RCTs) investigating the safety and efficacy of lithium in amyotrophic lateral sclerosis (ALS) patients.\n\nMETHODS:\nPubMed, Web of Science, Cochrane CENTRAL, Scopus, and Your Journals@Ovid were searched up to 9 December 2022. RCTs investigating lithium, either alone or with any supplement, in ALS patients were included. Meta-analysis was performed using RevMan and results are presented in forest plot.\n\nRESULTS:\nFour RCTs with 469 patients met the inclusion criteria and were included in our study. Lithium doses varied among the included studies and one study used a combined therapy of lithium with valproate. Meta-analysis showed no difference between lithium and placebo regarding severe adverse events (odds ratio = 1.13, 95% confidence interval: 0.73 to 1.75, P = 0.58). No significant differences were observed with regard to survival rate between the two groups (hazard ratio = 0.95, 95% confidence interval: 0.65 to 1.37, P = 0.77). There were also no significant differences between the two groups with regard to average changes of revised amyotrophic lateral sclerosis functional rating scale (P = 0.35) and forced vital capacity percentage predicted (P = 0.73). Subgroup analysis showed no significant differences regarding all investigated outcomes either for lithium alone or lithium with valproate.\n\nCONCLUSION:\nCurrent evidence suggests a safety profile with no benefit of lithium for ALS. However, given the limited number of RCTs and the safety findings, we recommend further well-designed RCTs to investigate lithium and valproate in ALS patients." + } +} \ No newline at end of file diff --git a/37069516.json b/37069516.json new file mode 100644 index 0000000000000000000000000000000000000000..94eec6b52f162590485ebcc42f1f3f999fa7a920 --- /dev/null +++ b/37069516.json @@ -0,0 +1,8 @@ +{ + "id": "37069516", + "label": 0, + "article": { + "id": "37069516", + "text": "BACKGROUND:\nX-linked retinoschisis (XLRS), due to mutations in the RS1 gene, is a common genetically determined form of macular degeneration. This report describes an unusual case of angle-closure glaucoma (ACG) with XLRS and discusses the treatment.\n\nCASE PRESENTATION:\nA 39-year-old Chinese man with an X chromosome-recessive inherited c.489G \u003e A variant in the RS1 gene was diagnosed as XLRS and ACG, presenting with cystic macular lesions, shallow anterior chamber depth (ACD), and angle-closure with uncontrolled intraocular pressure (IOP). Malignant glaucoma occurred following trabeculectomy combining phacoemulsification with intraocular lens (IOL) implantation and goniosynechialysis. Subsequent anterior vitrectomy and irido-zonulo-hyaloid-vitrectomy (IZHV) effectively lowered IOP and deepened ACD, but the cystic cavity became larger.\n\nCONCLUSIONS:\nThere is a potential risk of malignant glaucoma in ACG patients with XLRS after filtering surgery. Although anterior vitrectomy can effectively resolve aqueous misdirection, the macular retinoschisis may get worse. Awareness of this risk may aid in surgical planning and postoperative management in these patients." + } +} \ No newline at end of file diff --git a/37071261.json b/37071261.json new file mode 100644 index 0000000000000000000000000000000000000000..e0acf8625021a6117a8e85afb95a51056792b0a1 --- /dev/null +++ b/37071261.json @@ -0,0 +1,8 @@ +{ + "id": "37071261", + "label": 0, + "article": { + "id": "37071261", + "text": "BACKGROUND:\nRectovaginal fistula (RVF) is a troublesome and refractory complication after low anterior resection (LAR) for rectal cancer. An omental flap repair was performed for the RVF caused due to Crohn's disease and childbirth trauma. However, there are few cases of an omental flap repair for RVF after LAR. Herein, we present a successfully repaired case of RVF by omental flap coverage after LAR for rectal cancer.\n\nCASE PRESENTATION:\nA 50-year-old female patient with advanced rectal cancer underwent laparoscopic LAR with double-stapling technique anastomosis and achieved curative resection. She complained of a stool from the vagina and was diagnosed with RVF on the postoperative day (POD) 18. Conservative therapy was ineffective. We performed laparoscopic fistula resection and direct closure of the vagina and rectum, designed the omentum that could reach the pelvis, repaired RVF by omental flap coverage, and performed transverse colostomy on POD 25. She was discharged on initial POD 48. Seven months after the initial operation, colostomy closure was administered. There was no recurrence of RVF found 1 year after the initial operation.\n\nCONCLUSIONS:\nThe patient achieved an omental flap coverage for RVF. We successfully performed the omental flap coverage repair in patients with RVF after the leakage of LAR. An omental flap may become an alternative treatment for muscle flap or an effective treatment for RVF." + } +} \ No newline at end of file diff --git a/37071269.json b/37071269.json new file mode 100644 index 0000000000000000000000000000000000000000..96ce7c4ae9f6bbf48440ad1e9f5245be366356c1 --- /dev/null +++ b/37071269.json @@ -0,0 +1,8 @@ +{ + "id": "37071269", + "label": 0, + "article": { + "id": "37071269", + "text": "Lung cancer is amongst the most pervasive malignancies having high mortality rates. It is broadly grouped into non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). The concept of personalized medicine has overshadowed the conventional chemotherapy given to all patients with lung cancer. The targeted therapy is given to a particular population having specific mutations to help in the better management of lung cancer. The targeting pathways for NSCLC include the epidermal growth factor receptor, vascular endothelial growth factor receptor, MET (Mesenchymal epithelial transition factor) oncogene, Kirsten rat sarcoma viral oncogene (KRAS), and anaplastic lymphoma kinase (ALK). SCLC targeting pathway includes Poly (ADP-ribose) polymerases (PARP) inhibitors, checkpoint kinase 1 (CHK 1) pathway, WEE1 pathway, Ataxia Telangiectasia and Rad3-related (ATR)/Ataxia telangiectasia mutated (ATM), and Delta-like canonical Notch ligand 3 (DLL-Immune checkpoint inhibitors like programmed cell death protein 1 (PD-1)/ programmed death-ligand 1 (PD-L1) inhibitors and Cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) blockade are also utilized in the management of lung cancer. Many of the targeted therapies are still under development and require clinical trials to establish their safety and efficacy. This review summarizes the mechanism of molecular targets and immune-mediated targets, recently approved drugs, and their clinical trials for lung cancer." + } +} \ No newline at end of file diff --git a/37071533.json b/37071533.json new file mode 100644 index 0000000000000000000000000000000000000000..ab8ce2df498d4bcc317d83be64adb50835f10076 --- /dev/null +++ b/37071533.json @@ -0,0 +1,8 @@ +{ + "id": "37071533", + "label": 0, + "article": { + "id": "37071533", + "text": "Genital herpes is characterized by recurrent episodes of epithelial blistering. The mechanisms causing this pathology are ill defined. Using a mouse model of vaginal herpes simplex virus 2 (HSV-2) infection, we show that interleukin-18 (IL-18) acts upon natural killer (NK) cells to promote accumulation of the serine protease granzyme B in the vagina, coinciding with vaginal epithelial ulceration. Genetic loss of granzyme B or therapeutic inhibition by a specific protease inhibitor reduces disease and restores epithelial integrity without altering viral control. Distinct effects of granzyme B and perforin deficiency on pathology indicates that granzyme B acts independent of its classic cytotoxic role. IL-18 and granzyme B are markedly elevated in human herpetic ulcers compared with non-herpetic ulcers, suggesting engagement of these pathways in HSV-infected patients. Our study reveals a role for granzyme B in destructing mucosal epithelium during HSV-2 infection, identifying a therapeutic target to augment treatment of genital herpes." + } +} \ No newline at end of file diff --git a/37071691.json b/37071691.json new file mode 100644 index 0000000000000000000000000000000000000000..958457f03b0c988261e6e281fcdb1f7a4a25fd28 --- /dev/null +++ b/37071691.json @@ -0,0 +1,8 @@ +{ + "id": "37071691", + "label": 0, + "article": { + "id": "37071691", + "text": "AIM:\nTo explore and gain knowledge of the experiences and needs among patients with amyotrophic lateral sclerosis (ALS) of their decision-making processes whether to choose invasive home mechanical ventilation or not.\n\nDESIGN:\nA qualitative study.\n\nMETHODS:\nA phenomenological-hermeneutic approach influenced by Ricoeur's interpretation theory was used. Seven patients with ALS were interviewed. The Consolidated Criteria for Reporting Qualitative Research checklist was used for reporting.\n\nRESULTS:\nThree themes were evident in patients' accounts of the decision-making process: (1) being taken care of directly after receiving the diagnosis, (2) living in uncertainty about what the future would bring and (3) doubt causing patients with ALS to change their minds. Patients with ALS were burdened with everyday life challenging decision-making processes about future treatment and doubt caused patients to change their minds about their future treatment. It is necessary to support patients in their decision-making processes using shared decision-making.\n\nPATIENT OR PUBLIC CONTRIBUTION:\nNo Patient or Public Contribution." + } +} \ No newline at end of file diff --git a/37071796.json b/37071796.json new file mode 100644 index 0000000000000000000000000000000000000000..dd1b4e81ca57cc1d55bd81618eb3c56ffb72386a --- /dev/null +++ b/37071796.json @@ -0,0 +1,8 @@ +{ + "id": "37071796", + "label": 0, + "article": { + "id": "37071796", + "text": "OBJECTIVE:\nTo identify factors associated with acute kidney injury in patients undergoing extracorporeal membrane oxygenation.\n\nMETHOD:\nRetrospective cohort study conducted in an adult Intensive Care Unit with patients undergoing extracorporeal membrane oxygenation from 2012 to 2021. The research used the Kidney Disease Improving Global Outcomes as criteria for definition and classification of acute kidney injury. A multiple logistic regression model was developed to analyze the associated factors.\n\nRESULTS:\nThe sample was composed of 122 individuals, of these, 98 developed acute kidney injury (80.3%). In multiple regression, the associated factors found were vasopressin use, Nursing Activities Score, and glomerular filtration rate.\n\nCONCLUSION:\nThe use of vasopressin, the Nursing Activities Score, and the glomerular filtration rate were considered as factors related to the development of acute kidney injury in patients undergoing extracorporeal membrane oxygenation." + } +} \ No newline at end of file diff --git a/37072664.json b/37072664.json new file mode 100644 index 0000000000000000000000000000000000000000..2c138f98434bd7cce574f8bc96b4513582e74554 --- /dev/null +++ b/37072664.json @@ -0,0 +1,8 @@ +{ + "id": "37072664", + "label": 0, + "article": { + "id": "37072664", + "text": "T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignant blood disorder with a high rate of relapse. Patients relapse as a result of minimal residual disease (MRD), which originates from residual T-ALL cells in the bone marrow microenvironment (BMM). In the present study, it is observed that adipocytes increase dramatically in the BMM of T-ALL patients after exposure to chemotherapeutic drugs. Then, it is proved that adipocytes attract T-ALL cells by releasing CXCL13 and support leukemia cell survival by activating the Notch1 signaling pathway via DLL1 and Notch1 binding. Furthermore, it is verified that dexamethasone (DEX) induces adipogenic differentiation by enhancing the expression of SREBF1 in bone marrow mesenchymal stromal cells (BMSCs), and an SREBF1 inhibitor significantly decreases the adipogenic potential of BMSCs and the subsequent ability of adipocytes to support T-ALL cells in vitro and in vivo. These findings confirm that the differentiation of BMSCs to adipocytes induced by DEX contributes to MRD in T-ALL and provides an auxiliary clinical treatment to reduce the recurrence rate." + } +} \ No newline at end of file diff --git a/37074033.json b/37074033.json new file mode 100644 index 0000000000000000000000000000000000000000..d8e7de01062533fd6a1118c4f07fbe4e22d29246 --- /dev/null +++ b/37074033.json @@ -0,0 +1,8 @@ +{ + "id": "37074033", + "label": 0, + "article": { + "id": "37074033", + "text": "Upregulation of the anti-apoptotic protein MCL-1 has been implicated in chemotherapy resistance and poor clinical outcomes in B-cell lymphoma (BCL). We report the activity of AMG176, a direct, selective MCL-1 inhibitor, in preclinical models of BCL. A panel of cell lines representing diffuse large B-cell lymphoma (DLBCL), double-hit lymphoma (DHL) and Burkitt's lymphoma (BL) was selected. AMG176 induced apoptotic cell death in a dose- and time-dependent manner in all BCL cell lines. Baseline MCL-1 expression was not predictive of response. AMG176 exhibited impressive synergy with venetoclax and chemotherapeutic agents, less so with proteasomal inhibitors, and antagonism with anti-CD20 monoclonal antibodies. The activity of AMG176 could not be confirmed in murine models of BCL. Combination therapy targeting MCL-1 and BCL-2 may provide an alternative therapeutic approach in BCL, however optimal patient selection will remain the key to obtaining high response rates and tolerability." + } +} \ No newline at end of file diff --git a/37074093.json b/37074093.json new file mode 100644 index 0000000000000000000000000000000000000000..17dd9ac4c9d77403286ad89589f17c252f3fc24d --- /dev/null +++ b/37074093.json @@ -0,0 +1,8 @@ +{ + "id": "37074093", + "label": 0, + "article": { + "id": "37074093", + "text": "Thyroid storm is a rare but life-threatening condition mainly triggered by infection and abrupt discontinuation of antithyroid drug therapy for Graves' disease. Pancytopenia is a rare adverse reaction to antithyroid drugs. We present a 13-year-old girl with thyroid storm and pancytopenia with symptoms similar to those of methimazole-induced pancytopenia. Although in this context the use of methimazole is still under debate, due to multiple normal complete blood counts monitored during fever, sepsis-induced pancytopenia with thyroid storm was considered, and methimazole treatment combined with methylprednisolone and meropenem was able to resolve both pancytopenia and thyroid storm. During the period of infection and antithyroid drug therapy, close monitoring of complete blood count may help differentiate the aetiology of pancytopenia. This is the first paediatric case report that outlines the use of methimazole in the management of thyroid storm with pancytopenia." + } +} \ No newline at end of file diff --git a/37075449.json b/37075449.json new file mode 100644 index 0000000000000000000000000000000000000000..978bc09214f9f2019929f348f8d4033e430a9387 --- /dev/null +++ b/37075449.json @@ -0,0 +1,8 @@ +{ + "id": "37075449", + "label": 0, + "article": { + "id": "37075449", + "text": "OBJECTIVE:\nHashimoto's thyroiditis, also known as chronic lymphocytic thyroiditis or autoimmune thyroiditis, is a considerable part of the spectrum of chronic autoimmune thyroid gland disorders which is pathologically associated with various degrees of lymphocytic infiltration. The purpose of the present study was to evaluate whether cartilage thickness is affected in patients with Hashimoto's thyroiditis or not in thyroidology.\n\nMETHODS:\nA total of 61 individuals had been evaluated in this case-control study, including 32 euthyroid Hashimoto's thyroiditis patients and 29 healthy subjects comparable in age, sex, and body mass index. The patients with a history of knee trauma or knee surgery, an additional systemic disease such as diabetes mellitus, or an inflammatory disease like rheumatoid arthritis, systemic lupus erythematosus, and scleroderma had not been included in the study. The thickness of the femoral articular cartilage was measured using B-mode ultrasonography, and the right lateral condyle, right intercondylar area, right medial condyle, left medial condyle, left intercondylar area, and left lateral condyle were also measured.\n\nRESULTS:\nNo statistically significant difference between patients with Hashimoto's thyroiditis diagnosis and healthy controls in terms of age, age groups, gender, and body mass index (p\u003e0.05).\n\nCONCLUSION:\nAs a consequence, no obvious connection between autoimmune markers and cartilage thickness in patients with Hashimoto's thyroiditis was recognized. Although the diverse manifestation of Hashimoto's thyroiditis could be observed, it seems to be no liaison between thyroid autoimmunity and cartilage thickness." + } +} \ No newline at end of file diff --git a/37075586.json b/37075586.json new file mode 100644 index 0000000000000000000000000000000000000000..284b8a27be8ab2c0636506760fcf47fa867234ea --- /dev/null +++ b/37075586.json @@ -0,0 +1,8 @@ +{ + "id": "37075586", + "label": 0, + "article": { + "id": "37075586", + "text": "Consanguineous marriages in Middle Eastern and North African (MENA) countries are deeply-rooted tradition and highly prevalent resulting into increased prevalence of autosomal recessive diseases including Inborn Errors of Immunity (IEIs). Molecular genetic testing is an important diagnostic tool for IEIs since it provides a definite diagnosis, genotype-phenotype correlation, and guide therapy. In this review, we will discuss the current state and challenges of genomic and variome studies in MENA region populations, as well as the importance of funding advanced genome projects. In addition, we will review the MENA underlying molecular genetic defects of over 2457 patients published with the common IEIs, where autosomal recessive mode of inheritance accounts for 76% of cases with increased prevalence of combined immunodeficiency diseases (50%). The efforts made in the last three decades in terms of international collaboration and of in situ capacity building in MENA region countries led to the discovery of more than 150 novel genes involved in IEIs. Expanding sequencing studies within the MENA will undoubtedly be a unique asset for the IEI genetics which can advance research, and support precise genomic diagnostics and therapeutics." + } +} \ No newline at end of file diff --git a/37075701.json b/37075701.json new file mode 100644 index 0000000000000000000000000000000000000000..24ee5fcb517d6d7d7cc3e80e885ffe05f846e203 --- /dev/null +++ b/37075701.json @@ -0,0 +1,8 @@ +{ + "id": "37075701", + "label": 0, + "article": { + "id": "37075701", + "text": "Enzalutamide (ENZA), a second-generation androgen receptor antagonist, has significantly increased progression-free and overall survival of patients with metastatic prostate cancer (PCa). However, resistance remains a prominent obstacle in treatment. Utilizing a kinome-wide CRISPR-Cas9 knockout screen, we identified casein kinase 1α (CK1α) as a therapeutic target to overcome ENZA resistance. Depletion or pharmacologic inhibition of CK1α enhanced ENZA efficacy in ENZA-resistant cells and patient-derived xenografts. Mechanistically, CK1α phosphorylates the serine residue S1270 and modulates the protein abundance of ataxia telangiectasia mutated (ATM), a primary initiator of DNA double-strand break (DSB)-response signaling, which is compromised in ENZA-resistant cells and patients. Inhibition of CK1α stabilizes ATM, resulting in the restoration of DSB signaling, and thus increases ENZA-induced cell death and growth arrest. Our study details a therapeutic approach for ENZA-resistant PCa and characterizes a particular perspective for the function of CK1α in the regulation of DNA-damage response." + } +} \ No newline at end of file diff --git a/37075809.json b/37075809.json new file mode 100644 index 0000000000000000000000000000000000000000..da724da8bdb642743f77696c35ec950a066bd8df --- /dev/null +++ b/37075809.json @@ -0,0 +1,8 @@ +{ + "id": "37075809", + "label": 0, + "article": { + "id": "37075809", + "text": "Inflammatory bowel disease encompasses Crohn's disease and ulcerative colitis and is characterized by uncontrolled, relapsing, and remitting course of inflammation in the gastrointestinal tract. Artificial intelligence represents a new era within the field of gastroenterology, and the amount of research surrounding artificial intelligence in patients with inflammatory bowel disease is on the rise. As clinical trial outcomes and treatment targets evolve in inflammatory bowel disease, artificial intelligence may prove as a valuable tool for providing accurate, consistent, and reproducible evaluations of endoscopic appearance and histologic activity, thereby optimizing the diagnosis process and identifying disease severity. Furthermore, as the applications of artificial intelligence for inflammatory bowel disease continue to expand, they may present an ideal opportunity for improving disease management by predicting treatment response to biologic therapies and for refining the standard of care by setting the basis for future treatment personalization and cost reduction. The purpose of this review is to provide an overview of the unmet needs in the management of inflammatory bowel disease in clinical practice and how artificial intelligence tools can address these gaps to transform patient care." + } +} \ No newline at end of file diff --git a/37076694.json b/37076694.json new file mode 100644 index 0000000000000000000000000000000000000000..c1c0a5adc3f219af29ada93f6c01c5340f774551 --- /dev/null +++ b/37076694.json @@ -0,0 +1,8 @@ +{ + "id": "37076694", + "label": 0, + "article": { + "id": "37076694", + "text": "LCK is a novel therapeutic target in ~40% of T-cell acute lymphoblastic leukemia (T-ALL), and dasatinib and ponatinib can act as LCK inhibitors with therapeutic effects. We herein report a comprehensive preclinical pharmacokinetic and pharmacodynamic evaluation of dasatinib and ponatinib in LCK-activated T-ALL. In 51 human T-ALL cases, these two drugs showed similar patterns of cytotoxic activity, with ponatinib being slightly more potent. Given orally in mice, ponatinib was associated with slower clearance with a longer T and higher AUC, although maximum pLCK inhibition was comparable between the two drugs. After establishing the exposure-to-response models, we simulated the steady-state pLCK inhibitory effects of each drug at currently approved dosages in humans: dasatinib at 140 mg and ponatinib at 45 mg once daily are both sufficient to achieve \u003e50% pLCK inhibition for 13.0 and 13.9 h/day, respectively, comparable to pharmacodynamic profiles of these agents in BCR::ABL1 leukemias. Moreover, we developed a dasatinib-resistant T-ALL cell line model with LCK T316I mutation, in which ponatinib retained partial activity against LCK. In conclusion, we described the pharmacokinetic and pharmacodynamic profiles of dasatinib and ponatinib as LCK inhibitors in T-ALL, providing critical data for the development of human trials of these agents." + } +} \ No newline at end of file diff --git a/37077128.json b/37077128.json new file mode 100644 index 0000000000000000000000000000000000000000..99d759b0f0fb58185b0293762e0f46ef573c0f79 --- /dev/null +++ b/37077128.json @@ -0,0 +1,8 @@ +{ + "id": "37077128", + "label": 0, + "article": { + "id": "37077128", + "text": "This paper evaluates global health responses to the COVID-19 pandemic through the 'two regimes of global health' framework. This framework juxtaposes global health security, which contains the threat of emerging diseases to wealthy states, with humanitarian biomedicine, which emphasises neglected diseases and equitable access to treatments. To what extent did the security/access divide characterise the response to COVID-19? Did global health frames evolve during the pandemic?Analysis focused on public statements from the World Health Organization (WHO), the humanitarian nonprofit Médecins Sans Frontières (MSF), and the American Centers for Disease Control and Prevention (CDC). Following a content analysis of 486 documents released in the first two years of the pandemic, the research yielded three findings. First, the CDC and MSF affirmed the framework; they exemplified the security/access divide, with the CDC containing threats to Americans and MSF addressing the plight of vulnerable populations. Second, surprisingly, despite its reputation as a central actor in global health security, the WHO articulated both regime priorities and, third, after the initial outbreak, it began to favour humanitarianism. For the WHO, security remained, but was reconfigured: instead of traditional security, global human health security was emphasised - collective wellbeing was rooted in access and equity." + } +} \ No newline at end of file diff --git a/37077352.json b/37077352.json new file mode 100644 index 0000000000000000000000000000000000000000..38f05ab17a728eff4a161c53f7c7f0938d1a1347 --- /dev/null +++ b/37077352.json @@ -0,0 +1,8 @@ +{ + "id": "37077352", + "label": 0, + "article": { + "id": "37077352", + "text": "Iodine is a crucial trace element for the human body and the basic raw material for the synthesis of thyroid hormones. Oral inorganic iodine includes dietary iodine and therapeutic iodine, both of which are closely associated with thyroid immunity and metabolism. Graves' disease (GD), also known as diffuse toxic goiter, is characterized by hyperthyroidism and high iodine metabolism. Clinically, patients diagnosed with GD are often asked to limit iodine intake or even avoid iodine in their diet. The latest research has demonstrated that the interference of dietary iodine with antithyroid drugs (ATDs) treatment may be overestimated. In addition, as a medication for GD treatment, the administration of inorganic iodine has shown positive results in patients with mild hyperthyroidism, a low thyroid autoantibody concentration, a small thyroid volume, a high iodine diet and so on. Inorganic iodine may also be used as an alternative when patients experience side effects with traditional ATDs and for those who still prefer conservative treatment. Due to its low teratogenicity, blood toxicity and bone marrow toxicity, inorganic iodine plays a unique role in special populations, such as pregnant or lactating patients and patients receiving tumor radiotherapy or chemotherapy. In this review, the research progress, biological function, doses and effects, applicable populations and specific applications of dietary iodine and therapeutic iodine are summarized to provide references for the diagnosis and treatment of GD, thus improving the quality of life of GD patients." + } +} \ No newline at end of file diff --git a/37077359.json b/37077359.json new file mode 100644 index 0000000000000000000000000000000000000000..d22bc71ed91fefab0695b4da987866c2e957dae5 --- /dev/null +++ b/37077359.json @@ -0,0 +1,8 @@ +{ + "id": "37077359", + "label": 0, + "article": { + "id": "37077359", + "text": "OBJECTIVE:\nHypogonadism is common in male patients with adrenocortical carcinoma (ACC) who are under treatment with mitotane, but the phenomenon is underestimated, and its prevalence has been poorly studied. This single-center retrospective longitudinal study was undertaken to assess the frequency of testosterone deficiency before and after mitotane therapy, the possible mechanism involved, and the relationship between hypogonadism with serum mitotane levels and prognosis.\n\nRESEARCH DESIGN AND METHODS:\nConsecutive male ACC patients followed at the Medical Oncology of Spedali Civili Hospital in Brescia underwent hormonal assessment to detect testosterone deficiency at baseline and during mitotane therapy.\n\nRESULTS:\nA total of 24 patients entered the study. Of these patients, 10 (41.7%) already had testosterone deficiency at baseline. During follow-up, total testosterone (TT) showed a biphasic evolution over time with an increase in the first 6 months followed by a subsequent progressive decrease until 36 months. Sex hormone binding globulin (SHBG) progressively increased, and calculated free testosterone (cFT) progressively decreased. Based on cFT evaluation, the proportion of hypogonadic patients progressively increased with a cumulative prevalence of 87.5% over the study course. A negative correlation was observed between serum mitotane levels \u003e14 mg/L and TT and cFT.\n\nCONCLUSION:\nTestosterone deficiency is common in men with ACC prior to mitotane treatment. In addition, this therapy exposes these patients to further elevated risk of hypogonadism that should be promptly detected and counteracted, since it might have a negative impact on quality of life." + } +} \ No newline at end of file diff --git a/37077564.json b/37077564.json new file mode 100644 index 0000000000000000000000000000000000000000..4e509e9a7e4066ccf04d65ddaf38bb4237aa36a6 --- /dev/null +++ b/37077564.json @@ -0,0 +1,8 @@ +{ + "id": "37077564", + "label": 0, + "article": { + "id": "37077564", + "text": "INTRODUCTION:\nRare neurodevelopmental disorders, including inherited white matter disorders or leukodystrophies, often present a diagnostic challenge on a genetic level given the large number of causal genes associated with a range of disease subtypes. This study aims to demonstrate the challenges and lessons learned in the genetic investigations of leukodystrophies through presentation of a series of cases solved using exome or genome sequencing.\n\nMETHODS:\nEach of the six patients had a leukodystrophy associated with hypomyelination or delayed myelination on MRI, and inconclusive clinical diagnostic genetic testing results. We performed next generation sequencing (case-based exome or genome sequencing) to further investigate the genetic cause of disease.\n\nRESULTS:\nFollowing different lines of investigation, molecular diagnoses were obtained for each case, with patients harboring pathogenic variants in a range of genes including , and . We describe the lessons learned in reaching the genetic diagnosis, including the importance of (a) utilizing proper multi-gene panels in clinical testing, (b) assessing the reliability of biochemical assays in supporting diagnoses, and (c) understanding the limitations of exome sequencing methods in regard to CNV detection and region coverage in GC-rich areas.\n\nDISCUSSION:\nThis study illustrates the importance of applying a collaborative diagnostic approach by combining detailed phenotyping data and metabolic results from the clinical environment with advanced next generation sequencing analysis techniques from the research environment to increase the diagnostic yield in patients with genetically unresolved leukodystrophies." + } +} \ No newline at end of file diff --git a/37077714.json b/37077714.json new file mode 100644 index 0000000000000000000000000000000000000000..ca6e2e0d0708f1403dd5c851d02c29fe80010b6c --- /dev/null +++ b/37077714.json @@ -0,0 +1,8 @@ +{ + "id": "37077714", + "label": 0, + "article": { + "id": "37077714", + "text": "Primary drug resistance and minimal residual disease are major challenges in the treatment of B cell neoplasms. Therefore, this study aimed to identify a novel treatment capable of eradicating malignant B cells and drug-resistant disease. Oncolytic viruses eradicate malignant cells by direct oncolysis and activation of anti-tumor immunity, have proven anti-cancer efficacy, and are safe and well tolerated in clinical use. Here, we demonstrate that the oncolytic virus coxsackievirus A21 can kill a range of B cell neoplasms, irrespective of an anti-viral interferon response. Moreover, CVA21 retained its capacity to kill drug-resistant B cell neoplasms, where drug resistance was induced by co-culture with tumor microenvironment support. In some cases, CVA21 efficacy was actually enhanced, in accordance with increased expression of the viral entry receptor ICAM-1. Importantly, the data confirmed preferential killing of malignant B cells and CVA21 dependence on oncogenic B cell signaling pathways. Significantly, CVA21 also activated natural killer (NK) cells to kill neoplastic B cells and drug-resistant B cells remained susceptible to NK cell-mediated lysis. Overall, these data reveal a dual mode of action of CVA21 against drug-resistant B cells and support the development of CVA21 for the treatment of B cell neoplasms." + } +} \ No newline at end of file diff --git a/37077825.json b/37077825.json new file mode 100644 index 0000000000000000000000000000000000000000..8ca2c60d0bf5920beaa487438d5177044f9bc6b2 --- /dev/null +++ b/37077825.json @@ -0,0 +1,8 @@ +{ + "id": "37077825", + "label": 0, + "article": { + "id": "37077825", + "text": "T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with poor prognosis. The oncogene encodes a master transcription factor that is activated in the majority of human T-ALLs. In the present study, we have performed a large-scale screening with small-molecule drugs to find clinically useful inhibitors of gene expression in T-ALL. We identified several pharmacological agents that potentially could be used to treat MYB-driven malignancies. In particular, treatment with the synthetic oleanane triterpenoids (OTs) bardoxolone methyl and omaveloxolone decreased gene activity and expression of MYB downstream target genes in T-ALL cells with constitutive gene activation. Notably, treatment with bardoxolone methyl and omaveloxolone led to a dose-dependent reduction in cell viability and induction of apoptosis at low nanomolar concentrations. In contrast, normal bone marrow-derived cells were unaffected at these concentrations. Bardoxolone methyl and omaveloxolone treatment downregulated the expression of DNA repair genes and sensitized T-ALL cells to doxorubicin, a drug that is part of the standard therapy of T-ALL. OT treatment may thus potentiate DNA-damaging chemotherapy through attenuation of DNA repair. Taken together, our results indicate that synthetic OTs may be useful in the treatment of T-ALL and potentially also in other MYB-driven malignancies." + } +} \ No newline at end of file diff --git a/37078608.json b/37078608.json new file mode 100644 index 0000000000000000000000000000000000000000..a0a244dd1558d4eb86b2f0577395742f32ae0a0f --- /dev/null +++ b/37078608.json @@ -0,0 +1,8 @@ +{ + "id": "37078608", + "label": 0, + "article": { + "id": "37078608", + "text": "BACKGROUND:\nMetagenomic Next Generation Sequencing (mNGS) was used to assess patients with primary or secondary Immune Deficiencies (PIDs and SIDs) presenting with immunopathological conditions related to immunodysregulation.\n\nMETHODS:\n30 patients with PIDs and SIDs presenting symptoms related to immunodysregulation and 59 asymptomatic patients with similar PIDs and SIDs were enrolled. mNGS was performed on organ biopsy. Specific AiV RT-PCR was used to confirm Aichi virus (AiV) infection and screen the other subjects. In situ hybridization assay (ISH) was done on AiV infected organs to identify infected cells. Virus genotype was determined by phylogenetic analysis.\n\nRESULTS:\nAiV sequences were detected by mNGS in tissue samples of 5 patients and by RT-PCR in peripheral samples of another patient who all presented with PID and long-lasting multi-organ involvement, including hepatitis, splenomegaly and nephritis in 4. CD8+ T cell infiltration was a hallmark of the disease.RT-PCR detected intermittent low viral loads in urine and plasma from infected patients but in none of the other subjects. Viral detection stopped after immune reconstitution obtained by hematopoietic stem cell transplantation. ISH demonstrated the presence of the AiV RNA in hepatocytes (n = 1) and spleen tissue (n = 2). AiV belonged to genotype A (n = 2) or B (n = 3).\n\nCONCLUSIONS:\nThe similarity of the clinical presentation, the detection of AiV in a sub-group of patients suffering from immunodysregulation, its absence in asymptomatic patients, the detection of viral genome in infected organs by ISH, and the reversibility of symptoms after treatment argue for AiV causality." + } +} \ No newline at end of file diff --git a/37079339.json b/37079339.json new file mode 100644 index 0000000000000000000000000000000000000000..02b13e346fb35c64307829fdaaa905e9ccf80702 --- /dev/null +++ b/37079339.json @@ -0,0 +1,8 @@ +{ + "id": "37079339", + "label": 0, + "article": { + "id": "37079339", + "text": "Ataxia Telangiectasia and Rad3-Related Protein (ATR) kinase regulates a key cell regulatory node for maintaining genomic integrity by preventing replication fork collapse. ATR inhibition has been shown to increase replication stress resulting in DNA double strand breaks (DSBs) and cancer cell death, and several inhibitors are under clinical investigation for cancer therapy. However, activation of cell cycle checkpoints controlled by Ataxia Telangiectasia Mutated (ATM) kinase could minimize the lethal consequences of ATR inhibition and protect cancer cells. Here, we investigate ATR-ATM functional relationship and potential therapeutic implications. In cancer cells with functional ATM and p53 signaling, selective suppression of ATR catalytic activity by M6620 induced G1 phase arrest to prevent S-phase entry with unrepaired DSBs. The selective ATM inhibitors, M3541 and M4076, suppressed both ATM-dependent cell cycle checkpoints and DSB repair, lowered the p53 protective barrier and extended the life of ATR inhibitor induced DSBs. Combination treatment amplified the fraction of cells with structural chromosomal defects and enhanced cancer cell death. ATM inhibitor synergistically potentiated the ATR inhibitor efficacy in cancer cells in vitro and increased ATR inhibitor efficacy in vivo at doses that did not show overt toxicities. Further, a combination study in 26 patient-derived xenograft models of triple negative breast cancer with the newer generation ATR inhibitor M4344 and ATM inhibitor M4076 demonstrated substantial improvement in efficacy and survival compared to single-agent M4344, suggesting a novel and potentially broad combination approach to cancer therapy." + } +} \ No newline at end of file diff --git a/37079465.json b/37079465.json new file mode 100644 index 0000000000000000000000000000000000000000..7704a099c5f534c787883e20f6a1ab3dda860f50 --- /dev/null +++ b/37079465.json @@ -0,0 +1,8 @@ +{ + "id": "37079465", + "label": 0, + "article": { + "id": "37079465", + "text": "BACKGROUND:\nPatient-reported outcome measures (PROMs) provide clinicians and consumers a platform to inform and improve healthcare planning and management. Aboriginal people experience disproportionately high rates of chronic diseases, including type 2 diabetes. Treatment and management require holistic approaches that draw on culturally relevant resources and assessment tools. This study explored perceptions of Aboriginal people about two diabetes management-related PROMs (PROMIS-29, PAID Scale).\n\nMETHODS:\nTwenty-nine Aboriginal people living with diabetes in the Shoalhaven discussed two PROMs in one of four focus groups or at an individual interview. Preliminary data coding was conducted by clinician researchers, with thematic analysis overseen by Aboriginal co-researchers. Subsequent individual interviews with participants were undertaken to seek further feedback and articulate what is needed to improve methods of evaluating Aboriginal people's self-reported quality of life and diabetes management.\n\nRESULTS:\nThe PROMs did not capture information or knowledge that Aboriginal people considered relevant to their diabetes-related health care. Participants' recommendations included adapting survey materials to be more culturally sensitive; for example, by improving the alignment of measures with common day-to-day activities. This study also describes a genuine collaborative, Aboriginal community-guided approach to evaluate 'fit-for-purpose' diabetes management tools.\n\nCONCLUSIONS:\nAppropriate evaluation methods are paramount to address the disproportionate burden of diabetes experienced by Aboriginal peoples and overcome inverse diabetes care. Our learnings will contribute to development of tools, resources or methods that capture culturally tailored outcome measures. Study findings are relevant to clinicians and researchers using and/or developing Patient Reported Measures, particularly in relation to the practicality of tools for First Nations peoples." + } +} \ No newline at end of file diff --git a/37079571.json b/37079571.json new file mode 100644 index 0000000000000000000000000000000000000000..520e9c47432671956fc977e65f65cba5d4da8632 --- /dev/null +++ b/37079571.json @@ -0,0 +1,8 @@ +{ + "id": "37079571", + "label": 0, + "article": { + "id": "37079571", + "text": "BACKGROUND:\nAdvances in multiplex polymerase chain reaction (PCR) methods have enabled the simultaneous detection of multiple respiratory viruses. We aimed to estimate the clinical and virologic impacts of influenza and other respiratory virus co-infection in children.\n\nMETHODS:\nWe enrolled 38 and 35 children diagnosed with influenza and treated with baloxavir marboxil (baloxavir) and oseltamivir, respectively. We performed quantitative reverse transcription-PCR to detect and measure the levels of noninfluenza viruses from 3 nasopharyngeal swab samples collected before and on days 3 and 5 after the initial antiviral dose. We assessed patients' clinical information using questionnaires.\n\nRESULTS:\nOne or more respiratory viruses other than influenza virus were detected in 26 (35.6%) of 73 children before antiviral treatment. The influenza virus load and clinical characteristics on the day of influenza onset were similar between children with and without virus co-infections. Of the 26 and 32 children without the emergence of the reduced baloxavir and oseltamivir susceptible variants after treatment, 8 (30.8%) and 7 (21.9%) children were dually co-infected with human rhinovirus only, respectively. The level of human rhinovirus RNA on day 0 in these children was less than -3 log10 that of influenza virus RNA, and the human rhinovirus co-infection had no impact on the disease course either clinically or virologically.\n\nCONCLUSIONS:\nWhen multiple respiratory viruses are detected in the same patient, it is necessary to assess clinical symptoms as well as the levels of detected viruses to determine which virus contributes to the development of illness." + } +} \ No newline at end of file diff --git a/37079999.json b/37079999.json new file mode 100644 index 0000000000000000000000000000000000000000..c1adb4470996735137434b0f40bc4d13b47206b9 --- /dev/null +++ b/37079999.json @@ -0,0 +1,8 @@ +{ + "id": "37079999", + "label": 0, + "article": { + "id": "37079999", + "text": "PURPOSE:\nDespite advances in the treatment of B-cell acute lymphoblastic leukemia (B-ALL), outcomes for relapsed/refractory (R/R) disease remain poor. Preclinical studies suggest that the combination of the CDK4/6 inhibitor palbociclib and dexamethasone may be effective in targeting leukemic cell growth. We conducted a phase I study of escalating doses of palbociclib in combination with dexamethasone in adults with R/R B-ALL.\n\nMETHODS:\nCycle 1 consisted of single agent palbociclib given for 7 days and continued for 28 additional days in combination with dexamethasone 20 mg daily. Palbociclib dosing began at 100 mg daily. Patients with a response were eligible for maintenance consisting of 1 week of palbociclib plus dexamethasone (20 mg daily × 2 days, 16 mg daily × 2 days, 12 mg daily × 2 days, 6 mg daily × 1 day), followed by 3 weeks of palbociclib alone. Safety, efficacy, and the expression of phospho-RB and c-MYB/BCL-2 were measured.\n\nCONCLUSIONS:\nSeven patients were treated on study before it was closed early due to slow accrual. No dose limiting toxicities were identified. One patient had a complete response with incomplete hematologic recovery, suggesting possible efficacy of the treatment. Reduction in CD34+ cells, p-RB, c-MYB, and BCL-2 expression also suggested on-target therapy effects." + } +} \ No newline at end of file diff --git a/37080243.json b/37080243.json new file mode 100644 index 0000000000000000000000000000000000000000..ab312a4fb637ce56fabe78a8a42b559e51469d11 --- /dev/null +++ b/37080243.json @@ -0,0 +1,8 @@ +{ + "id": "37080243", + "label": 0, + "article": { + "id": "37080243", + "text": "PURPOSE:\nThyroid receptor antibodies can quantify thyroid eye disease activity, predict outcomes and aid timing of interventions. The type and generation of assay is frequently unspecified, complicating meta-analyses. To determine the clinical and biochemical relationships between a second-generation thyrotropin receptor-binding inhibition antibody (TRAb) immunoassay, detecting stimulatory and blocking antibodies, with the thyroid stimulating immunoglobulin (TSI) bridging immunoassay detecting the stimulatory component only.\n\nMETHODS:\nRetrospective review of 100 consecutive patients attending a regional specialist service. For each patient and visit, both a TRAb and TSI were performed, and a clinical activity score (CAS) recorded.\n\nRESULTS:\nA significant positive correlation between TRAb and TSI (rho = 0.828, p \u003c 0.01) but a weaker correlation between the assays and CAS (TRAb: rho = 0.439, p \u003c 0.01; TSI: r = 0.357, p \u003c 0.01) were found. In 10% of the episodic data, patients had a TRAb level that was disproportionately high (39.41 ± 52.84 IU/L), compared to their TSI levels (9.53 ± 12.10 IU/L) with a higher-than-average CAS (2.47 ± 1.78; range, 0-5). Within 12 months of diagnosis, a significant positive correlation between CAS and TRAb (rho = 0.503, p \u003c 0.01) as well as between CAS and TSI (rho = 0.329, p \u003c 0.01) were found. In patients with a diagnosis over 12 months, the correlation with CAS for both TSI and TRAb were Spearman rank correlation coefficient of 0.347 (p \u003c 0.01) and 0.327 (p \u003c 0.01), respectively.\n\nCONCLUSIONS:\nTRAb and TSI correlate strongly and to a lesser extent with the CAS. For most patients, TRAb can be replaced with the more economical TSI. TRAb also correlates better with newly diagnosed, more active patients than TSI. In a subset of patients, blocking antibodies may play a significant pathogenic role, requiring different treatment and monitoring. Further studies are required to investigate this relationship." + } +} \ No newline at end of file diff --git a/37080298.json b/37080298.json new file mode 100644 index 0000000000000000000000000000000000000000..b54661b7bdf3515e7b0349764ada67f45a7cc12f --- /dev/null +++ b/37080298.json @@ -0,0 +1,8 @@ +{ + "id": "37080298", + "label": 0, + "article": { + "id": "37080298", + "text": "OBJECTIVE:\nAutoantibodies (Ab) against the thyrotropin receptor (TSH-R-Ab) are key mediators for the pathogenesis of Graves' disease (GD). TSH-R-Ab degradation was evaluated using several immunoassays within an exploratory, controlled trial in patients with GD receiving a monoclonal antibody (mAb) targeting the neonatal crystallizable fragment receptor (FcRn).\n\nMETHODS:\nSerial measurements of TSH-R-Ab serum levels were performed using three different binding and cell-based assays in GD patients either on medication or on placebo.\n\nRESULTS:\nIn contrast to placebo where no changes were observed, a 12-week mAb therapy led to an early and significant decrease (\u003e 60%) of the serum TSH-R-Ab serum levels in patients with thyroidal and extra-thyroidal GD, as unanimously shown in all three assays. These marked changes were noted already at week seven post baseline (P\u003c0.0001 for the binding immunoassay and for the luciferase (readout) bioassay. The three TSH-R-Ab binding and bioassays highly correlated in the samples of both study groups (binding immunoassay versus luciferase bioassay r = 0.91, P \u003c 0.001, binding vs. cyclic adenosine monophosphate (cAMP) bioassay, r = 0.86, P \u003c 0.001, luciferase versus cAMP bioassay, r = 0.71, P = 0.006). The serological results correlated with the course of the extra-thyroidal clinical parameters of GD, i.e. clinical activity score and proptosis.\n\nCONCLUSIONS:\nTargeting the FcRn markedly reduces the disease-specific TSH-R-Ab in patients with GD. The novel and rapid TSH-R-Ab bioassay improves diagnosis and management of GD patients." + } +} \ No newline at end of file diff --git a/37080587.json b/37080587.json new file mode 100644 index 0000000000000000000000000000000000000000..bd86039c92605ecbce4a26a336e5943157fe182d --- /dev/null +++ b/37080587.json @@ -0,0 +1,8 @@ +{ + "id": "37080587", + "label": 0, + "article": { + "id": "37080587", + "text": "OBJECTIVE:\nPerianal Crohn's disease (pCD) occurs in up to 40% of patients with CD and is associated with poor quality of life, limited treatment responses and poorly understood aetiology. We performed a genetic association study comparing CD subjects with and without perianal disease and subsequently performed functional follow-up studies for a pCD associated SNP in ().\n\nDESIGN:\nImmunochip-based meta-analysis on 4056 pCD and 11 088 patients with CD from three independent cohorts was performed. Serological and clinical variables were analysed by regression analyses. Risk allele of rs4151651 was introduced into human CFB plasmid by site-directed mutagenesis. Binding of recombinant G252 or S252 CFB to C3b and its cleavage was determined in cell-free assays. Macrophage phagocytosis in presence of recombinant CFB or serum from risk, or protective CD or healthy subjects was assessed by flow cytometry.\n\nRESULTS:\nPerianal complications were associated with colonic involvement, OmpC and ASCA serology, and serology quartile sum score. We identified a genetic association for pCD (rs4151651), a non-synonymous SNP (G252S) in , in all three cohorts. Recombinant S252 CFB had reduced binding to C3b, its cleavage was impaired, and complement-driven phagocytosis and cytokine secretion were reduced compared with G252 CFB. Serine 252 generates a de novo glycosylation site in CFB. Serum from homozygous risk patients displayed significantly decreased macrophage phagocytosis compared with non-risk serum.\n\nCONCLUSION:\npCD-associated rs4151651 in is a loss-of-function mutation that impairs its cleavage, activation of alternative complement pathway, and pathogen phagocytosis thus implicating the alternative complement pathway and CFB in pCD aetiology." + } +} \ No newline at end of file diff --git a/37080623.json b/37080623.json new file mode 100644 index 0000000000000000000000000000000000000000..4f145e13d21bbf1953e729a22b9e7763838e9533 --- /dev/null +++ b/37080623.json @@ -0,0 +1,8 @@ +{ + "id": "37080623", + "label": 0, + "article": { + "id": "37080623", + "text": "INTRODUCTION:\nMyopia is a major cause of degenerative eye disease and increases the risk of secondary visual impairment. Mitigating its progression therefore has great potential of clinically relevant benefit as shown by using highly diluted atropine eye drops in children of Asian origin. However, limited evidence is available regarding the efficacy and safety of low-dose atropine therapy in non-Asian populations. Hence, the Low-dose AtropIne for Myopia Control in Children (AIM) study will test the efficacy and safety of 0.02% atropine vs placebo in a German population.\n\nMETHODS AND ANALYSIS:\nAIM is a national, multicentre, prospective, randomised, placebo-controlled, double-blind trial with two parallel arms. The primary objective is to assess the efficacy of atropine 0.02% eyedrops for myopia control in children of Caucasian origin. The primary outcome is the change in cycloplegic refraction after 1 year of treatment (D/year). Secondary and tertiary outcome measures comprise the change in axial length (mm/year) in children treated with 0.02% atropine compared with placebo, the myopic progression of participants treated with 0.01% compared with 0.02% atropine (D/year and mm/year), and the safety profile of both 0.02% and 0.01% atropine. Furthermore, the myopic progression 1 year after cessation of therapy with 0.02% atropine will be evaluated. Inclusion criteria are an age of 8-12 years and myopia of -1 D to -6 D with an estimated annual myopia progression of ≥0.5 D. After randomisation, patients will receive either atropine 0.02% (arm A) or placebo eye drops (arm B) in the first year of treatment. In the second year, they will continue to receive atropine 0.02% (arm A) or switch to atropine 0.01% (arm B). In the third year, they will switch to placebo (arm A) or continue with atropine 0.01% (arm B). To achieve a statistical power of 80%, the calculated sample size is 300. The trial has started in October 2021 with a planned recruitment period of 18 months.\n\nETHICS AND DISSEMINATION:\nAIM has been approved by the Central Ethics Committee of the University Medical Center Freiburg (21-1106), local ethics committees of each participating centre and the German Federal Institute for Drugs and Medical Devices (61-3910-4044659). It complies with the Declaration of Helsinki, local laws and ICH-GCP. Results and underlying data from this trial will be disseminated through peer-reviewed publications and conference presentations.\n\nTRIAL REGISTRATION NUMBER:\nNCT03865160." + } +} \ No newline at end of file diff --git a/37080885.json b/37080885.json new file mode 100644 index 0000000000000000000000000000000000000000..e36fda185113623a7668751e8f308224f07a57df --- /dev/null +++ b/37080885.json @@ -0,0 +1,8 @@ +{ + "id": "37080885", + "label": 0, + "article": { + "id": "37080885", + "text": "Gastroparesis is a gastric motility disorder characterized by delayed gastric emptying. It is a rare disease and difficult to treat effectively; management is a dilemma for gastroenterologists and surgeons alike. We conducted a systematic review of the literature to evaluate current diagnostic tools as well as treatment options. We describe key elements in the pathophysiology of the disease, in addition to current evidence on treatment alternatives, including nutritional considerations, medical and surgical options, and related outcomes." + } +} \ No newline at end of file diff --git a/37080969.json b/37080969.json new file mode 100644 index 0000000000000000000000000000000000000000..bd483580a82bedce8b4ed7c6eda2e5b7432f308c --- /dev/null +++ b/37080969.json @@ -0,0 +1,8 @@ +{ + "id": "37080969", + "label": 0, + "article": { + "id": "37080969", + "text": "Amyotrophic Lateral Sclerosis (ALS) causes motor neuron degeneration, with 97% of cases exhibiting TDP-43 proteinopathy. Elucidating pathomechanisms has been hampered by disease heterogeneity and difficulties accessing motor neurons. Human induced pluripotent stem cell-derived motor neurons (iPSMNs) offer a solution; however, studies have typically been limited to underpowered cohorts. Here, we present a comprehensive compendium of 429 iPSMNs from 15 datasets, and 271 post-mortem spinal cord samples. Using reproducible bioinformatic workflows, we identify robust upregulation of p53 signalling in ALS in both iPSMNs and post-mortem spinal cord. p53 activation is greatest with C9orf72 repeat expansions but is weakest with SOD1 and FUS mutations. TDP-43 depletion potentiates p53 activation in both post-mortem neuronal nuclei and cell culture, thereby functionally linking p53 activation with TDP-43 depletion. ALS iPSMNs and post-mortem tissue display enrichment of splicing alterations, somatic mutations, and gene fusions, possibly contributing to the DNA damage response." + } +} \ No newline at end of file diff --git a/37081671.json b/37081671.json new file mode 100644 index 0000000000000000000000000000000000000000..197ef0dcd1d011143f27c6117d042ded1ed52c6c --- /dev/null +++ b/37081671.json @@ -0,0 +1,8 @@ +{ + "id": "37081671", + "label": 0, + "article": { + "id": "37081671", + "text": "Pleomorphic rhabdomyosarcoma (PRMS) predominantly arises in adult skeletal musculature and is usually associated with poor prognosis. Thus, effective treatments must be developed. PRMS is a rare tumor; therefore, it is critical to develop an experimental system to understand the cellular and molecular mechanisms of PRMS. We previously demonstrated that PRMS develops after p53 gene deletion and oncogenic K-Ras expression in the skeletal muscle tissue. In that study, oncogenic K-Ras-expressing cells were diverse and the period until disease onset was difficult to control. In this study, we developed an experimental system to address this problem. Single cell-derived murine cell lines, designated as RMS310 and RMSg2, were established by limiting the dilution of cells from a lung metastatic tumor colony that were positive for various cancer stem cells and activated skeletal muscle-resident stem/progenitor cell marker genes by RT-PCR. All cell lines stably recapitulated the histological characteristics of human PRMS as bizarre giant cells, desmin-positive cells, and lung metastases in C57BL/6 mice. All subclones of the RMSg2 cells by the limiting dilution in vitro could seed PRMS subcutaneously, and as few as 500 RMSg2 cells were sufficient to form tumors. These results suggest that the RMSg2 cells are multipotent cancer cells that partially combine the properties of skeletal muscle-resident stem/progenitor cells and high tumorigenicity. Thus, our model system's capacity to regenerate tumor tissue in vivo and maintain stable cells in vitro makes it useful for developing therapeutics to treat PRMS." + } +} \ No newline at end of file diff --git a/37081771.json b/37081771.json new file mode 100644 index 0000000000000000000000000000000000000000..66e8793728e34f19bb1ff000c669d4832cebf7cc --- /dev/null +++ b/37081771.json @@ -0,0 +1,8 @@ +{ + "id": "37081771", + "label": 0, + "article": { + "id": "37081771", + "text": "BACKGROUND:\nRacial and ethnic disparities have been demonstrated in pediatric and adult cancers. However, there is no consensus on whether such disparities exist in the presentation, treatment, and outcome of patients with rhabdomyosarcoma (RMS).\n\nMETHODS:\nPatient information from the seven most recent RMS clinical trials was obtained from the Children's Oncology Group (COG). Chi-squared analyses were used to compare patient, tumor, and treatment characteristics across racial and ethnic groups. Pairwise analyses comparing Non-Hispanic Black (NHB) versus Non-Hispanic White (NHW) racial groups and Hispanic versus NHW ethnic groups were conducted for significant characteristics. Kaplan-Meier method and Wilcoxon signed-rank tests were performed to analyze outcomes.\n\nRESULTS:\nIn the overall cohort (n = 2157), patients' self-identified race/ethnicity was: 0.4% American Indian/Alaska Native, 2.6% Asian, 12.6% Hispanic, 0.2% Native American/other Pacific Islander, 12.8% NHB, 61.9% NHW, and 9.6% unknown. Six characteristics differed by race/ethnicity: age, histology, IRS group, invasiveness, metastatic disease, and FOXO1 fusion partner. Five were significant in pairwise comparisons: NHB patients were more likely to present at age ≥ 10 years and with invasive tumors than NHW patients; Hispanic patients were more likely to present with alveolar histology, metastatic disease, and IRS group IV disease than NHW patients. No differences were found in event free or overall survival of the entire cohort, in risk group-based subset analyses, or among patients with high-risk characteristics significant on pairwise analysis.\n\nCONCLUSIONS:\nWhile NHB and Hispanic patients enrolled in COG trials presented with higher risk features than NHW patients, there were no outcome differences by racial or ethnic group." + } +} \ No newline at end of file diff --git a/37082124.json b/37082124.json new file mode 100644 index 0000000000000000000000000000000000000000..5bdf75a727a9aadebc6b5b6d1fdd03823670164d --- /dev/null +++ b/37082124.json @@ -0,0 +1,8 @@ +{ + "id": "37082124", + "label": 0, + "article": { + "id": "37082124", + "text": "Graves' disease (GD) is caused by an autoimmune formation of autoantibodies and autoreactive T-cells against the thyroid stimulating hormone receptor (TSHR). The autoimmune reaction does not only lead to overstimulation of the thyroid gland, but very often also to an immune reaction against antigens within the orbital tissue leading to thyroid eye disease, which is characterized by activation of orbital fibroblasts, orbital generation of adipocytes and myofibroblasts and increased hyaluronan production in the orbit. Thyroid eye disease is the most common extra-thyroidal manifestation of the autoimmune Graves' disease. Several studies indicate an important role of sphingolipids, in particular the acid sphingomyelinase/ceramide system and sphingosine 1-phosphate in thyroid eye disease. Here, we discuss how the biophysical properties of sphingolipids contribute to cell signaling, in particular in the context of thyroid eye disease. We further review the role of the acid sphingomyelinase/ceramide system in autoimmune diseases and its function in T lymphocytes to provide some novel hypotheses for the pathogenesis of thyroid eye disease and potentially allowing the development of novel treatments." + } +} \ No newline at end of file diff --git a/37082130.json b/37082130.json new file mode 100644 index 0000000000000000000000000000000000000000..06d072293815874d658da840b1b46df59581032e --- /dev/null +++ b/37082130.json @@ -0,0 +1,8 @@ +{ + "id": "37082130", + "label": 0, + "article": { + "id": "37082130", + "text": "PURPOSE:\nSeverity of Graves' orbitopathy (GO) shows wide individual differences. For optimal treatment, it is important to be able to predict the natural course of the disease as accurate as possible to counteract with anti-inflammatory and surgical treatment. Therefore, we aimed to further elucidate the impact of sex, age and smoking on GO.\n\nMETHODS:\nWe collected the clinical and demographic data of all patients of our tertiary referral center from January 2008 till December 2018 and analyzed it with descriptive statistics. Only patients with a complete data set were included in the further analysis. Odds ratio's for moderate-to-severe and sight-threatening GO in relation to age, sex and smoking were calculated by means of multivariate logistic regression models.\n\nRESULTS:\nWe evaluated the data of 4260 patient with GO and complete data sets. Most of these were women (83%). There were no significant differences between male and female patients regarding smoking habits and thyroid treatment. Men were significantly older at initial manifestation of TED (51.8 vs. 49.9y, p\u003c0.01) and showed significant more often severe stages (61% vs. 53%, p\u003c0.0001). Therefore, they needed significantly more intense treatment with steroids, irradiation, orbital decompression and muscle surgery. In multivariate logistic regression analyses age (OR 0.97, 95% CI:0.97-0.98, p\u003c0.0001), male sex (OR 1.64, 95% CI:1.38-1.9, p\u003c0.0001), smoking (OR 1.19, 95% CI:1.04-1.36, p=0.01), Grave's disease (OR 1.55, 95% CI:1.26-1.90, p\u003c0.0001) and history of radioiodine treatment (RAI) (OR 2.44, 95% CI:2.10-2.86, p\u003c0.0001) showed an significant association with severe stages of GO.\n\nDISCUSSION:\nOur retrospective analysis showed once more that women are more often afflicted by GO. In contrast, men seem to be more severely afflicted and in need of anti-inflammatory and surgical treatments. This might be due to a different approach to the health system and resilience to GO specific symptoms, as well as previously described worse thyroid control. Estrogen mediated effects might also play a role as in other autoimmune diseases and should be subject of further trials. Besides the biological sex, smoking could again be confirmed as serious risk factor for severe GO. Of note, RAI was associated with more severe stages of GO, which should be subject to further investigation." + } +} \ No newline at end of file diff --git a/37082807.json b/37082807.json new file mode 100644 index 0000000000000000000000000000000000000000..c723f1244f45355860e2bae32d27ad6bf69da43b --- /dev/null +++ b/37082807.json @@ -0,0 +1,8 @@ +{ + "id": "37082807", + "label": 0, + "article": { + "id": "37082807", + "text": "Whether initiation of statins could increase survival free of dementia and disability in adults aged ≥75 years is unknown. PREVENTABLE, a double-blind, placebo-controlled randomized pragmatic clinical trial, will compare high-intensity statin therapy (atorvastatin 40 mg) with placebo in 20,000 community-dwelling adults aged ≥75 years without cardiovascular disease, disability, or dementia at baseline. Exclusion criteria include statin use in the prior year or for \u003e5 years and inability to take a statin. Potential participants are identified using computable phenotypes derived from the electronic health record and local referrals from the community. Participants will undergo baseline cognitive testing, with physical testing and a blinded lipid panel if feasible. Cognitive testing and disability screening will be conducted annually. Multiple data sources will be queried for cardiovascular events, dementia, and disability; survival is site-reported and supplemented by a National Death Index search. The primary outcome is survival free of new dementia or persisting disability. Co-secondary outcomes are a composite of cardiovascular death, hospitalization for unstable angina or myocardial infarction, heart failure, stroke, or coronary revascularization; and a composite of mild cognitive impairment or dementia. Ancillary studies will offer mechanistic insights into the effects of statins on key outcomes. Biorepository samples are obtained and stored for future study. These results will inform the benefit of statins for increasing survival free of dementia and disability among older adults. This is a pioneering pragmatic study testing important questions with low participant burden to align with the needs of the growing population of older adults." + } +} \ No newline at end of file diff --git a/37082926.json b/37082926.json new file mode 100644 index 0000000000000000000000000000000000000000..be7e461e8571a25fa212ee6fbed13f1e0c5bea40 --- /dev/null +++ b/37082926.json @@ -0,0 +1,8 @@ +{ + "id": "37082926", + "label": 0, + "article": { + "id": "37082926", + "text": "Rhabdomyosarcoma with rearrangement is a newly introduced spindle cell neoplasm showing predilection for craniofacial bones exhibiting highly aggressive nature and poor prognosis. Therefore, an attempt was made to delineate the entity for improved understanding and treatment outcomes through comprehensive analysis of the clinicopathological and molecular characteristics. An electronic search was carried out using MEDLINE by PubMed, Scopus, Google scholar, Cochrane library, and EMBASE databases. Original articles and case reports involving intraosseous rhabdomyosarcoma arising in head and neck region with fusion were included. Data were compiled and risk of bias was analyzed using JBI tool. Thirteen eligible articles were included for the quantitative analysis, which revealed 33 cases with fusion. Majority of the affected individuals were females (58%) with mandible being the common site. Most of the patients died within few months after diagnosis demonstrating a low mean survival rate (30 months). Odds ratio, overall survival and disease-free survival were calculated and analyzed statistically concluding that intraosseous rhabdomyosarcomas harboring fusion are found to be novel and dreadful neoplasms. The predilection for young age with poor prognosis exhibited by these lesions demand early diagnosis and specific treatment planning to curtail mortality." + } +} \ No newline at end of file diff --git a/37083216.json b/37083216.json new file mode 100644 index 0000000000000000000000000000000000000000..5669c143ef670cb452341cad98f869e476fb914a --- /dev/null +++ b/37083216.json @@ -0,0 +1,8 @@ +{ + "id": "37083216", + "label": 0, + "article": { + "id": "37083216", + "text": "BACKGROUND:\nTo assess the outcomes of pediatric patients with undifferentiated embryonal sarcoma of the liver (UESL) and treatment including at least surgery and systemic chemotherapy.\n\nMETHODS:\nThis study included patients aged up to 21 years with a pathological diagnosis of UESL prospectively enrolled from 1995 to 2016 in three European trials focusing on the effects of surgical margins, preoperative chemotherapy, use of radiotherapy (RT), and chemotherapy.\n\nRESULTS:\nOut of 65 patients with a median age at diagnosis of 8.7 years (0.6-20.8), 15 had T2 tumors, and one had lymph node spread, 14 were Intergroup Rhabdomyosarcoma Study (IRS) I, nine IRS II, 38 IRS III, and four IRS IV. Twenty-eight upfront surgeries resulted in five operative spillages and 11 infiltrated surgical margins, whereas 37 delayed surgeries resulted in no spillages (p = .0119) and three infiltrated margins (p = .0238). All patients received chemotherapy, including anthracyclines in 47. RT was administered in 15 patients. With a median follow-up of 78.6 months, 5-year overall and event-free survivals (EFS) were 90.1% (95% confidence interval [CI]: 79.2-95.5) and 89.1% (95% CI: 78.4-94.6), respectively. Two out four local relapses had previous infiltrated margins and two out of three patients with metastatic relapses received reduced doses of alkylating agents. Infiltrated margins (p = .1607), T2 stage (p = .3870), use of RT (p = .8731), and anthracycline-based chemotherapy (p = .1181) were not correlated with EFS.\n\nCONCLUSIONS:\nMultimodal therapy improved the outcome of UESL. Neoadjuvant chemotherapy for pediatric patients increases the probability of complete surgical resection. The role of anthracyclines and RT for localized disease remains unclear." + } +} \ No newline at end of file diff --git a/37083797.json b/37083797.json new file mode 100644 index 0000000000000000000000000000000000000000..9d534d6835da5824ba6823e4f3d371b631842863 --- /dev/null +++ b/37083797.json @@ -0,0 +1,8 @@ +{ + "id": "37083797", + "label": 0, + "article": { + "id": "37083797", + "text": "RATIONALE:\nAmyotrophic lateral sclerosis is a rare disease that cannot be cured. We report a case of a patient with amyotrophic lateral sclerosis whose pulmonary function and quality of life were improved by a combined tui na treatment and Western medicine.\n\nPATIENT CONCERNS:\nA 48-year-old male was diagnosed with ALS 1 year ago and was treated with western medicine and herbal medicine with no significant effect. This time, he was admitted to our department because of slurred speech, coughing and choking, and weakness of the left upper limb for more than 1 year.\n\nINTERVENTION AND OUTCOME:\nAfter 1 month of treatment with tui na and traditional western medicine, the patient's lung function and quality of life improved and he was discharged from the hospital.\n\nDIAGNOSES:\nMotor neuron disease. Amyotrophic lateral sclerosis.\n\nLESSONS:\nThe physiological function of ALS patients can be improved through the intervention of tui na." + } +} \ No newline at end of file diff --git a/37084075.json b/37084075.json new file mode 100644 index 0000000000000000000000000000000000000000..7adc590f03ed81c372d5bc6348ff68a3ae17e283 --- /dev/null +++ b/37084075.json @@ -0,0 +1,8 @@ +{ + "id": "37084075", + "label": 0, + "article": { + "id": "37084075", + "text": "BACKGROUND:\nLimited data exist on the clinical behavior of pediatric non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) with distant metastases at onset, and a clear standard of care has not yet been defined.\n\nMETHODS:\nThis cohort study reports on pediatric adult-type metastatic NRSTS enrolled in two concurrent prospective European studies, i.e., the randomized BERNIE study and the single-arm MTS 2008 study developed by the European paediatric Soft tissue sarcoma Study Group. Treatment programs were originally designed for patients with metastatic rhabdomyosarcoma, i.e., nine courses of multidrug chemotherapy (with or without bevacizumab in the BERNIE study), followed by 12 cycles of maintenance therapy, whereas radiotherapy and/or surgery (on primary tumor and/or metastases) were delayed until after seven courses of chemotherapy had been administered.\n\nRESULTS:\nThe study included 61 patients \u003c21 years old treated from July 2008 to December 2016. The lung was the site of metastases in 75% of the cases. All patients received multi-agent chemotherapy, 44% had local therapy to primary tumor, and 18% had treatment of metastases. Median time to progression/relapse was 6 months. A high rate of tumor progression was observed during the initial part of the chemotherapy program. With a median follow-up of 41.5 months (range, 2-111 months), 3-year event-free survival and overall survival were 15.4% (95% confidence interval [CI], 7.6-25.7) and 34.9% (95% CI, 22.7-47.5), respectively. There were no statistically significant differences in outcome depending on the type of treatment administered.\n\nCONCLUSIONS:\nThe study confirmed the overall poor outcome for patients with metastatic NRSTS, whose treatment remains a challenge.\n\nPLAIN LANGUAGE SUMMARY:\nPediatric non-rhabdomyosarcoma soft tissue sarcomas form a heterogeneous group of rare tumors. Although recent international studies have defined the standard of care for patients with localized disease, limited data are available on the clinical behavior of patients with distant metastases. This study on 61 metastatic cases treated on two prospective European protocols confirms that the chances of survival of such patients are often dismal and a standard treatment is still lacking." + } +} \ No newline at end of file diff --git a/37084132.json b/37084132.json new file mode 100644 index 0000000000000000000000000000000000000000..4c15371a88d375b79d78f420c706eb56e1a4c2d7 --- /dev/null +++ b/37084132.json @@ -0,0 +1,8 @@ +{ + "id": "37084132", + "label": 0, + "article": { + "id": "37084132", + "text": "After Fontan operation, decreased venous capacitance and venoconstriction are adaptive mechanisms to maintain venous return and cardiac output. The consequent higher venous pressure may adversely impact end-organ function, exercise capacity and result in worse clinical outcomes. This pilot study evaluated the safety and effect of isosorbide dinitrate (ISDN), a venodilator, on exercise capacity, peripheral venous pressure (PVP), and liver stiffness in patients with Fontan circulation. In this prospective single-arm trial, 15 individuals with Fontan circulation were evaluated at baseline and after 4 weeks of therapeutic treatment with ISDN. Primary aims were to assess the safety of ISDN and the effect on maximal exercise. We also aimed to evaluate the effect of ISDN on ultrasound-assessed liver stiffness, markers of submaximal exercise, and PVP at rest and peak exercise. Repeated measures t-tests were used to assess change in variables of interest in response to ISDN. Mean age was 23.5 ± 9.2 years (range 11.2-39.0 years), and 10/15 (67%) were male. There was no statistically significant change in peak VO (1401 ± 428 to 1428 ± 436 mL/min, p = 0.128), but VO at the anaerobic threshold increased (1087 ± 313 to 1115 ± 302 mL/min, p = 0.03). ISDN was also associated with a lower peak exercise PVP (22.5 ± 4.5 to 20.6 ± 3.0 mmHg, p = 0.015). Liver stiffness was lower with ISDN, though the difference was not statistically significant (2.3 ± 0.4 to 2.1 ± 0.5 m/s, p = 0.079). Of the patients completing the trial, mild headache was common (67%), but there were no major adverse events. Treatment with ISDN for 4 weeks is well-tolerated in patients with a Fontan circulation. ISDN is associated with an increase in VO at anaerobic threshold, lower peak PVP, and a trend toward lower liver stiffness. Larger, longer duration studies will be necessary to define the impact of ISDN on clinical outcomes in the Fontan circulation.Clinical Trial Registration: URL: https://clinicaltrials.gov . Unique identifier: NCT04297241." + } +} \ No newline at end of file diff --git a/37084724.json b/37084724.json new file mode 100644 index 0000000000000000000000000000000000000000..d5ed3290796488731e7f490d7b45f20fe00a23fc --- /dev/null +++ b/37084724.json @@ -0,0 +1,8 @@ +{ + "id": "37084724", + "label": 0, + "article": { + "id": "37084724", + "text": "Human induced pluripotent stem cells (iPSCs) are a renewable cell source that can be differentiated into neural progenitor cells (iNPCs) and transduced with glial cell line-derived neurotrophic factor (iNPC-GDNFs). The goal of the current study is to characterize iNPC-GDNFs and test their therapeutic potential and safety. Single-nuclei RNA-seq show iNPC-GDNFs express NPC markers. iNPC-GDNFs delivered into the subretinal space of the Royal College of Surgeons rodent model of retinal degeneration preserve photoreceptors and visual function. Additionally, iNPC-GDNF transplants in the spinal cord of SOD1 amyotrophic lateral sclerosis (ALS) rats preserve motor neurons. Finally, iNPC-GDNF transplants in the spinal cord of athymic nude rats survive and produce GDNF for 9 months, with no signs of tumor formation or continual cell proliferation. iNPC-GDNFs survive long-term, are safe, and provide neuroprotection in models of both retinal degeneration and ALS, indicating their potential as a combined cell and gene therapy for various neurodegenerative diseases." + } +} \ No newline at end of file diff --git a/37084729.json b/37084729.json new file mode 100644 index 0000000000000000000000000000000000000000..7f4ad084124a9bc1e7e8c1cda7f3577338ce23ff --- /dev/null +++ b/37084729.json @@ -0,0 +1,8 @@ +{ + "id": "37084729", + "label": 0, + "article": { + "id": "37084729", + "text": "Cell-based therapies are being developed for various neurodegenerative diseases that affect the central nervous system (CNS). Concomitantly, the roles of individual cell types in neurodegenerative pathology are being uncovered by genetic and single-cell studies. With a greater understanding of cellular contributions to health and disease and with the arrival of promising approaches to modulate them, effective therapeutic cell products are now emerging. This review examines how the ability to generate diverse CNS cell types from stem cells, along with a deeper understanding of cell-type-specific functions and pathology, is advancing preclinical development of cell products for the treatment of neurodegenerative diseases." + } +} \ No newline at end of file diff --git a/37085005.json b/37085005.json new file mode 100644 index 0000000000000000000000000000000000000000..eca896070ce576796c97c8ad110fe7a16f6d0b0c --- /dev/null +++ b/37085005.json @@ -0,0 +1,8 @@ +{ + "id": "37085005", + "label": 0, + "article": { + "id": "37085005", + "text": "Mitochondrial damage is a central mechanism involved in neurological disorders as Alzheimer's, and Parkinson's disease and amyotrophic lateral sclerosis. Energy production is the most studied mitochondrial function; however, mitochondria are also involved in processes like calcium buffering homeostasis, and cell death control during apoptosis and necrosis. Using transmission electron microscopy, in this in vivo study in males rats we describe ultrastructural mitochondrial alterations of spinal motor neurons along chronic AMPA-induced excitotoxicity, which has been described as one of the most relevant mechanisms in ALS disease. Mitochondrial alterations begin with a crest swelling, which progresses to a full mitochondrial swelling and crest disruption. Changes on the mitochondrial morphology from elongated to a circular shape also occur along the AMPA-excitotoxicity process. In addition, by combining the TUNEL assay and immunohistochemistry for mitochondrial enzymes, we show evidence of mitochondrial DNA damage. Evidence of mitochondrial alterations during an AMPA-excitotoxic event is relevant because resembles the mitochondrial alterations previously reported in ALS patients and in transgenic familial ALS models, suggesting that a chronic excitotoxic model can be related to sporadic ALS (as has been shown in recent papers), which represent more than the 90% of the ALS cases. Understanding the mechanisms involved in motor neuron degenerative process, such as the ultrastructural mitochondrial changes permits to design strategies for MN-degeneration treatments in ALS." + } +} \ No newline at end of file diff --git a/37085149.json b/37085149.json new file mode 100644 index 0000000000000000000000000000000000000000..acad989145c9bea17bfc5e71144135de417288fa --- /dev/null +++ b/37085149.json @@ -0,0 +1,8 @@ +{ + "id": "37085149", + "label": 0, + "article": { + "id": "37085149", + "text": "OBJECTIVES:\nSession 2 of the 2021 Society for Hematopathology and European Association for Haematopathology Workshop collected examples of lineage infidelity and transdifferentiation in B-lineage neoplasms, including after targeted therapy.\n\nMETHODS:\nTwenty cases were submitted. Whole-exome sequencing and genome-wide RNA expression analysis were available on a limited subsample.\n\nRESULTS:\nA diagnosis of B-cell acute lymphoblastic leukemia (B-ALL) was rendered on at least 1 biopsy from 13 patients. There was 1 case of acute myeloid leukemia (AML); the remaining 6 cases were mature B-cell neoplasms. Targeted therapy was administered in 7 cases of B-ALL and 4 cases of mature B-cell neoplasms. Six cases of B-ALL underwent lineage switch to AML or mixed-phenotype acute leukemia at relapse, 5 of which had rearranged KMT2A. Changes in maturational state without lineage switch were observed in 2 cases. Examples of de novo aberrant T-cell antigen expression (n = 2) were seen among the mature B-cell lymphoma cohort, and their presence correlated with alterations in tumor cell gene expression patterns.\n\nCONCLUSIONS:\nThis cohort of cases enabled us to illustrate, discuss, and review current concepts of lineage switch and aberrant antigen expression in a variety of B-cell neoplasms and draw attention to the role targeted therapies may have in predisposing neoplasms to transdifferentiation as well as other, less expected changes in maturational status." + } +} \ No newline at end of file diff --git a/37085223.json b/37085223.json new file mode 100644 index 0000000000000000000000000000000000000000..31b20d2f80244db972f8bb87f8c322a091b068d7 --- /dev/null +++ b/37085223.json @@ -0,0 +1,8 @@ +{ + "id": "37085223", + "label": 0, + "article": { + "id": "37085223", + "text": "The coronavirus disease 2019 (COVID-19) pandemic has seen an increase in global cases of severe acute respiratory distress syndrome (ARDS), with a concomitant increased demand for extracorporeal membrane oxygenation (ECMO). Outcomes of patients with severe ARDS due to COVID-19 infection receiving ECMO support are evolving. The need for surge capacity, practical and ethical limitations on implementing ECMO, and the prolonged duration of ECMO support in patients with COVID-19-related ARDS has revealed limitations in organization and resource utilization. Coordination of efforts at multiple levels, from research to implementation, resulted in numerous innovations in the delivery of ECMO." + } +} \ No newline at end of file diff --git a/37085329.json b/37085329.json new file mode 100644 index 0000000000000000000000000000000000000000..d713a6353903de2fb727872e8b90dcd493e3a16d --- /dev/null +++ b/37085329.json @@ -0,0 +1,8 @@ +{ + "id": "37085329", + "label": 0, + "article": { + "id": "37085329", + "text": "OBJECTIVE:\nLate-phase clinical trials for neurodegenerative diseases have a low probability of success. Here we introduce an algorithm that optimizes the planning of interim analyses for clinical trials in Amyotrophic Lateral Sclerosis (ALS) to better use the time and resources available, and minimize the exposure of patients to ineffective or harmful drugs.\n\nMETHODS:\nA simulation-based algorithm was developed to determine the optimal interim analysis scheme by integrating prior knowledge about the success rate of ALS clinical trials with drug-specific information obtained in early phase studies. Interim analysis schemes were optimized by varying the number and timing of interim analyses, together with their decision rules about when to stop a trial. The algorithm was applied retrospectively to three clinical trials that investigated the efficacy of diaphragm pacing or ceftriaxone on survival in patients with ALS. Outcomes were additionally compared to conventional interim designs.\n\nRESULTS:\nWe evaluated 183 to 1351 unique interim analysis schemes for each trial. Application of the optimal designs correctly established lack of efficacy, would have concluded all studies 1.2 to 19.4 months earlier (reduction of 4.6 to 57.7% in trial duration) and could have reduced the number of randomized patients by 1.7 to 58.1%. By means of simulation, we illustrate the efficiency for other treatment scenarios. The optimized interim analysis schemes outperformed conventional interim designs in most scenarios.\n\nCONCLUSIONS:\nOur algorithm uses prior knowledge to determine the uncertainty of the expected treatment effect in ALS clinical trials and optimizes the planning of interim analyses. Improving futility monitoring in ALS could minimize the exposure of patients to ineffective or harmful treatments, and result in significant ethical and efficiency gains." + } +} \ No newline at end of file diff --git a/37086162.json b/37086162.json new file mode 100644 index 0000000000000000000000000000000000000000..0f2dc9e48eb7d715159b28a80a126231557b46d6 --- /dev/null +++ b/37086162.json @@ -0,0 +1,8 @@ +{ + "id": "37086162", + "label": 0, + "article": { + "id": "37086162", + "text": "OBJECTIVE:\nIn moyamoya disease (MMD), blood flow to the internal carotid artery (ICA) system is supplied via the basal fine vascular network, leptomeningeal anastomoses, and transdural collateral vessels from the external carotid artery (ECA). After revascularization, there is a dramatic change in cerebral perfusion to the ECA system. Understanding this shift in blood supply is important for evaluating treatment efficacy and elucidating the postoperative pathophysiology. However, anatomical and quantitative methods for doing so have not yet been established. In the present study, selective intraarterial injection CT angiography (iaCTA) was performed in patients with MMD, and blood supply changes in each arterial system before and after revascularization surgery were evaluated.\n\nMETHODS:\nThis study included 10 hemispheres in 10 patients who underwent combined revascularization surgery for adult MMD. Digital subtraction angiography was performed before and 3 months after surgery, and selective iaCTA was performed from the ICA, ECA, and vertebral artery (VA) at the same times in a hybrid CT/digital subtraction angiography suite. The anatomical distribution of each vessel was determined and perfusion volume was measured quantitatively on contrast-enhanced axial CT images.\n\nRESULTS:\nSelective iaCTA clearly depicted the anatomical distribution of perfusion for each vessel. Conversion of blood supply from the ICA and VA to the ECA system was observed in the cerebral cortices and insulae but not in the basal ganglia. The mean volume of perfusion territories of the ECA (preoperative 0.9 cm3, postoperative 98.8 cm3); ICA (preoperative 225.7 cm3, postoperative 159.3 cm3); and VA (preoperative 244.0 cm3, postoperative 163.6 cm3) in the cerebral hemispheres changed significantly after revascularization. There was a correlation between increase in the ECA territory volume and decrease in the VA territory volume due to revascularization (R = -0.84, p \u003c 0.005).\n\nCONCLUSIONS:\nSelective iaCTA enabled clear visualization of anatomical changes in each vascular perfusion territory and quantitative measurement of each perfusion volume. Perfusion conversion to the ECA system after bypass surgery was observed in the cortical regions and in the insulae on the bypass operation sides, but not in the basal ganglia. Combined revascularization promoted the development of ECA-perfused territory, which correlated with a decrease in hemodynamic burden of the posterior cerebral artery." + } +} \ No newline at end of file diff --git a/37086568.json b/37086568.json new file mode 100644 index 0000000000000000000000000000000000000000..261d6aa37903bfe90da43aa14ee66097f35fcf86 --- /dev/null +++ b/37086568.json @@ -0,0 +1,8 @@ +{ + "id": "37086568", + "label": 0, + "article": { + "id": "37086568", + "text": "BACKGROUND:\nCLN3 is an autosomal recessive lysosomal disorder with intracellular accumulation of ceroid-lipofuscins. CLN3 classically has onset around 4-6 years of age involving vision loss, followed by developmental regression and seizures. Symptoms are progressive and result in premature death. Because treatments are under development, here we explore magnetic resonance spectroscopy (MRS) measurements of metabolite levels in the brain as a potential objective outcome measures.\n\nMETHODS:\nIndividuals with genetically confirmed CLN3 were enrolled from October 2017-November 2021 in a prospective natural history study (NCT033007304). Baseline concentrations of brain metabolites measured by MRS were compared to concurrently collected dimensional assessment measures: Vineland-3 Adaptive Behavior Composite (ABC) score, verbal intelligence quotient (VIQ), and the Physical, Capability with actual vision, and Clinical global impression of change sub-domains of the Unified Batten Disease Rating Scale (UBDRS).\n\nRESULTS:\n27 participants with typical CLN3 presentation (15F:12M; ages 6.0-20.7 years) completed MRS, ABC, and UBDRS; 20 (12F:8M; ages 6.5-20.7 years) also completed the VIQ assessment. N-acetyl aspartate [B(95% CI) = -0.61(-0.78;-0.45)] and glutamine/glutamate/GABA [B(95% CI) = -0.82(-1.04;-0.6)] in the parietal gray matter (PGM) decreased across the ages. The strongest correlations between MRS metabolite measurements and the clinical severity assessments were found with N-acetyl aspartate [VIQ (ρ = 0.58), Vineland-3 ABC (ρ = 0.59), UBDRS |ρ| range = (0.57;0.7)] and glutamine/glutamate/GABA [VIQ (ρ = 0.57), Vineland-3 ABC (ρ = 0.60), UBDRS |ρ| range = (0.59;0.77)] measured in the midline PGM. These correlations were accounted for when age was considered.\n\nCONCLUSIONS:\nBased on their correlations to established assessments, NAA and glutamine/glutamate/GABA measured in the midline parietal gray matter may be useful indicators of CLN3 disease state. In a clinical trial, divergence of the MRS measurements and clinical severity markers from age may be useful as surrogate measures for treatment responses." + } +} \ No newline at end of file diff --git a/37086581.json b/37086581.json new file mode 100644 index 0000000000000000000000000000000000000000..dafcfa8d3e6a2acd984acf55963f4c978fdd962d --- /dev/null +++ b/37086581.json @@ -0,0 +1,8 @@ +{ + "id": "37086581", + "label": 0, + "article": { + "id": "37086581", + "text": "Targeting ataxia telangiectasia mutated and Rad3-related (ATR) kinase is being pursued as a new therapeutic strategy for the treatment of advanced solid tumor with specific DNA damage response deficiency. Herein, we report a series of pyrido[3,2-d]pyrimidine derivatives with potent ATR inhibitory activity through structure-based drug design. Among them, the representative compound 10q exhibited excellent potency against ATR in both biochemical and cellular assays. More importantly, 10q exhibited good liver microsomes stability in different species and also showed moderate inhibitory activity against HT-29 cells in combination treatment with the ATM inhibitor AZD1390. Thus, this work provides a promising lead compound against ATR for further study." + } +} \ No newline at end of file diff --git a/37086950.json b/37086950.json new file mode 100644 index 0000000000000000000000000000000000000000..16caecf00fcc2667d9c9866b2d951f912d864972 --- /dev/null +++ b/37086950.json @@ -0,0 +1,8 @@ +{ + "id": "37086950", + "label": 0, + "article": { + "id": "37086950", + "text": "PURPOSE:\nTo identify initial features associated with significant recovery in patients with Graves' disease dysthyroid optic neuropathy (DON) treated according to EUGOGO guidelines by intravenous glucocorticoids (ivGC) and decompression surgery in first and second line, respectively.\n\nPATIENTS AND METHODS:\nConsecutive patients referred to our expert multidisciplinary consultation over a 6-year period underwent systematic exploration: endocrine assessment, ophthalmic examination and radiological exploration. Visual recovery, based on best corrected visual acuity (BCVA) and visual field (VF), were evaluated at baseline, 1 week and 6 months. Baseline parameters were then tested for prognostic value on univariate and multivariate analyses.\n\nRESULTS:\nThirty-eight patients (69 eyes) with DON were included. Significant recovery at 6 months was found in 48/69 eyes (70%), partial recovery in 18/69 (26%), and no recovery in 3/69 (4%). Fifty-one eyes (28 patients) required surgical decompression after ivGC. These patients showed more severe presentation at diagnosis, had received significantly less GC for Graves' orbitopathy before onset of DON, and showed greater fat prolapse on CT scans compared to non-operated patients. On multivariate analysis, male gender (p=0.001), cumulative GC dose \u003e1 g before DON diagnosis (p=0.048) and initial BCVA ≤0.3 (p=0.004) were significantly associated with better outcomes, whereas Clinical Activity Score \u003e5 (p=0.013) was associated with a poorer outcome.\n\nCONCLUSION:\nThis study confirms a generally favorable 6-month recovery rate in DON treated according to EUGOGO guidelines and provides new information on baseline predictors of poor evolution. These results may help the respective indications for medical and surgical treatment to be more effectively combined in the future." + } +} \ No newline at end of file diff --git a/37087441.json b/37087441.json new file mode 100644 index 0000000000000000000000000000000000000000..0c6c3c1bfee6549978d0c17781964050cf4ad07d --- /dev/null +++ b/37087441.json @@ -0,0 +1,8 @@ +{ + "id": "37087441", + "label": 0, + "article": { + "id": "37087441", + "text": "BACKGROUND:\nStandard platinum-based therapy for ovarian cancer is inefficient against ovarian clear cell carcinoma (OCCC). OCCC is a distinct subtype of epithelial ovarian cancer. OCCC constitutes 25% of ovarian cancers in East Asia (Japan, Korea, China, Singapore) and 6-10% in Europe and North America. The cancer is characterized by frequent inactivation of ARID1A and 10% of cases of endometriosis progression to OCCC. The aim of this study was to identify drugs that are either FDA-approved or in clinical trials for the treatment of OCCC.\n\nRESULTS:\nHigh throughput screening of 166 compounds that are either FDA-approved, in clinical trials or are in pre-clinical studies identified several cytotoxic compounds against OCCC. ARID1A knockdown cells were more sensitive to inhibitors of either mTOR (PP242), dual mTOR/PI3K (GDC0941), ATR (AZD6738) or MDM2 (RG7388) compared to control cells. Also, compounds targeting BH3 domain (AZD4320) and SRC (AZD0530) displayed preferential cytotoxicity against ARID1A mutant cell lines. In addition, WEE1 inhibitor (AZD1775) showed broad cytotoxicity toward OCCC cell lines, irrespective of ARID1A status.\n\nCONCLUSIONS:\nIn a selection of 166 compounds we showed that inhibitors of ATR and WEE1 were cytotoxic against a panel of OCCC cell lines. These two drugs are already in other clinical trials, making them ideal candidates for treatment of OCCC." + } +} \ No newline at end of file diff --git a/37087463.json b/37087463.json new file mode 100644 index 0000000000000000000000000000000000000000..355c6a19316bf122f4bd64f6f1cdf9f5659775a2 --- /dev/null +++ b/37087463.json @@ -0,0 +1,8 @@ +{ + "id": "37087463", + "label": 0, + "article": { + "id": "37087463", + "text": "BACKGROUND:\nNeutrophils have a critical role in the pathogenesis of rheumatoid arthritis (RA) with immune system dysfunction. However, the molecular mechanisms of this process mediated by neutrophils still remain elusive. The purpose of the present study is to identify hub genes in neutrophils for diagnosis and treatment of RA utilizing publicly available datasets.\n\nMETHODS:\nGene expression profiles were downloaded from the Gene Expression Omnibus, and batch-corrected and normalized expression data were obtained using the ComBat package. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were used to conduct significantly functional analysis and crucial pathways. The resulting co-expression genes modules and hub genes were generated based on the weighted gene co-expression network analysis and visualization by Cytoscape. Flow cytometry was conducted to detect reactive oxygen species (ROS) levels in neutrophils.\n\nRESULTS:\nNeutrophils underwent transcriptional changes in synovial fluid (SF) of RA patients, different from peripheral blood of healthy controls or patients with RA. Especially, glycolysis, HIF-1 signaling, NADH metabolism, and oxidative stress were affected. These hub genes were strongly linked with classical glycolysis-related genes (ENO1, GAPDH, and PKM) responsible for ROS production. The antioxidant enzyme glutathione peroxidase 3 (GPX3), a ROS scavenger, was first identified as a hub gene in RA neutrophils. Neutrophils from patients with autoinflammatory and autoimmune diseases had markedly enhanced ROS levels, most notably in RA SF.\n\nCONCLUSION:\nThis research recognized hub genes and explored the characteristics of neutrophils in RA. Our findings suggest that the novel hub gene GPX3 is involved in the neutrophil-driven oxidative stress-mediated pathogenesis of RA. It has the potency to be a target for neutrophil-directed RA therapy." + } +} \ No newline at end of file diff --git a/37088586.json b/37088586.json new file mode 100644 index 0000000000000000000000000000000000000000..d12c25ad95c5d0ba6a621e66b1312fd7e0f024c5 --- /dev/null +++ b/37088586.json @@ -0,0 +1,8 @@ +{ + "id": "37088586", + "label": 0, + "article": { + "id": "37088586", + "text": "BACKGROUND:\n/Objectives: Effects of chemotherapy on gut microbiota have been reported in various carcinomas. The current study aimed to evaluate the changes in the gut microbiota before and after neoadjuvant chemotherapy (NAC) in patients with resectable (R) and borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC) and understand their clinical implications.\n\nMETHODS:\nTwenty patients diagnosed with R/BR-PDAC were included in this study. Stool samples were collected at two points, before and after NAC, for microbiota analysis using 16S ribosomal RNA (16S rRNA) gene sequences.\n\nRESULTS:\nOf the 20 patients, 18 (90%) were treated with gemcitabine plus S-1 as NAC, and the remaining patients received gemcitabine plus nab-paclitaxel and a fluorouracil, leucovorin, irinotecan, and oxaliplatin combination. No significant differences were observed in the α- and β-diversity before and after NAC. Bacterial diversity was not associated with Evans classification (histological grade of tumor destruction by NAC) or postoperative complications. The relative abundance of Actinobacteria phylum after NAC was significantly lower than that before NAC (P = 0.02). At the genus level, the relative abundance of Bifidobacterium before NAC in patients with Evans grade 2 disease was significantly higher than that in patients with Evans grade 1 disease (P = 0.03). Patients with Evans grade 2 lost significantly more Bifidobacterium than patients with Evans grade 1 (P = 0.01).\n\nCONCLUSIONS:\nThe diversity of gut microbiota was neither decreased by NAC for R/BR-PDAC nor associated with postoperative complications. Lower incidence of Bifidobacterium genus before NAC may be associated with a lower pathological response to NAC." + } +} \ No newline at end of file diff --git a/37088611.json b/37088611.json new file mode 100644 index 0000000000000000000000000000000000000000..fad5b44fcfdeae3e7a08fb75ecf7de3e6425c6ff --- /dev/null +++ b/37088611.json @@ -0,0 +1,8 @@ +{ + "id": "37088611", + "label": 0, + "article": { + "id": "37088611", + "text": "Prion diseases are a group of neurodegenerative diseases. The disease-causing agent is a protein (PrP), that is normally produced in the nervous system, aggregated in an abnormal form. The abnormal protein, known as prion (PrP), is capable of self-propagation promoting the misfolding of the normal protein (PrP). These conditions can be acquired sporadically, genetically, or infectiously either by eating meat contaminated with prions or from iatrogenic exposure. The diagnosis of these diseases is often challenging. The use of highly sensitive and specific diagnostic tools, such as MRI and RT-QuIC, may aid in the diagnosis. Neuropathological examination of brain tissue ensures a definite diagnosis. At present, no treatment significantly improves the course of prion diseases; however, an early diagnosis is of paramount importance for patient care decision planning, infection control purposes, and genetic counseling." + } +} \ No newline at end of file diff --git a/37090478.json b/37090478.json new file mode 100644 index 0000000000000000000000000000000000000000..652985e0a7e06d937f4f4386b6e9aad5a5ef25dc --- /dev/null +++ b/37090478.json @@ -0,0 +1,8 @@ +{ + "id": "37090478", + "label": 0, + "article": { + "id": "37090478", + "text": "One obstacle to the development of gene therapies for the central nervous system is the lack of workflows for quantifying transduction efficiency in affected neural networks and ultimately predicting therapeutic potential. We integrated data from a brain cell atlas with 3D or 2D semi-automated quantification of transduced cells in segmented images to predict AAV transduction efficiency in multiple brain regions. We used this workflow to estimate the transduction efficiency of AAV2/rh.10 and AAV2.retro co-injection in the corticostriatal network affected in Huntington's disease. We then validated our pipeline in gene editing experiments targeting both human and mouse huntingtin genes in transgenic and wild-type mice, respectively. Our analysis predicted that 54% of striatal cells and 7% of cortical cells would be edited in highly transduced areas. Remarkably, in the treated animals, huntingtin gene inactivation reached 54.5% and 9.6%, respectively. These results demonstrate the power of this workflow to predict transduction efficiency and the therapeutic potential of gene therapies in the central nervous system." + } +} \ No newline at end of file diff --git a/37090544.json b/37090544.json new file mode 100644 index 0000000000000000000000000000000000000000..de22509183f0feeb9b663547f1852a56679e5a6c --- /dev/null +++ b/37090544.json @@ -0,0 +1,8 @@ +{ + "id": "37090544", + "label": 0, + "article": { + "id": "37090544", + "text": "BACKGROUND:\nGlucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive enzymatic disorder, particularly prevalent in Africa, Asia and the Middle East. In the US, about 14% of black men are affected. Individuals with G6PD deficiency are often asymptomatic but may develop hemolysis following an infection or upon consumption of specific medications. Despite some evidence that G6PD deficiency affects the immune system, the long- term health risks associated with G6PD deficiency had not been studied in a large population.\n\nMETHODS:\nIn this retrospective cohort study, health records from G6PD deficient individuals were compared to matched controls in a national healthcare provider in Israel (Leumit Health Services). Rates of infectious diseases, allergic conditions and autoimmune disorders were compared between groups.\n\nRESULTS:\nThe cohort included 7,473 G6PD deficient subjects (68.7% men) matched with 29,892 control subjects (4:1 ratio) of the same age, gender, socioeconomic status and ethnic group, followed during 14.3±6.2 years.Significantly increased rates for autoimmune disorders, infectious diseases and allergic conditions were observed throughout this period. Notable increases were observed for rheumatoid arthritis (OR 2.41, p\u003c0.001), systemic lupus erythematosus (OR 4.56, p\u003c0.001), scleroderma (OR 6.87, p\u003c0.001), pernicious anemia (OR=18.70, P\u003c0.001), fibromyalgia (OR 1.98, p\u003c0.001), Graves' disease (OR 1.46, P=0.001), and Hashimoto's thyroiditis (OR 1.26, P=0.001). These findings were corroborated with elevated rates of positive autoimmune serology and higher rates of treatment with medications commonly used to treat autoimmune conditions in the G6PD deficient group.\n\nCONCLUSION:\nG6PD deficient individuals suffer from higher rates of autoimmune disorders, infectious diseases, and allergic conditions." + } +} \ No newline at end of file diff --git a/37090611.json b/37090611.json new file mode 100644 index 0000000000000000000000000000000000000000..eac3f28ab32854001dc25bcd0f4695674e9c5a2e --- /dev/null +++ b/37090611.json @@ -0,0 +1,8 @@ +{ + "id": "37090611", + "label": 0, + "article": { + "id": "37090611", + "text": "Treatments for neurodegenerative disorders remain rare, although recent FDA approvals, such as Lecanemab and Aducanumab for Alzheimer's Disease, highlight the importance of a mechanistic approach in creating disease modifying therapies. As a large portion of the global population is aging, there is an urgent need for therapeutics that can stop disease progression and eliminate symptoms. In this study, we create an open framework and resource for evidence based identification of therapeutic targets for neurodegenerative disease. We use Summary-data-based Mendelian Randomization to identify genetic targets for drug discovery and repurposing. In parallel, we provide mechanistic insights into disease processes and potential network-level consequences of gene-based therapeutics. We identified 116 Alzheimer's disease, 3 amyotrophic lateral sclerosis, 5 Lewy body dementia, 46 Parkinson's disease, and 9 Progressive supranuclear palsy target genes passing multiple test corrections (p \u003c 2.95E-06 and p \u003e 0.01). We created a therapeutic scheme to classify our identified target genes into strata based on druggability and approved therapeutics - classifying 41 targets, 3 targets, and 115 targets. Our class of genes provides a springboard for new opportunities in drug discovery, development and repurposing in the pre-competitive space. We also provide a user-friendly web platform to help users explore potential therapeutic targets for neurodegenerative diseases, decreasing activation energy for the community [ https://nih-card-ndd-smr-home-syboky.streamlit.app/ ]." + } +} \ No newline at end of file diff --git a/37090693.json b/37090693.json new file mode 100644 index 0000000000000000000000000000000000000000..c9998303ec6496962f79fec21dfc548e9936d9f8 --- /dev/null +++ b/37090693.json @@ -0,0 +1,8 @@ +{ + "id": "37090693", + "label": 0, + "article": { + "id": "37090693", + "text": "OBJECTIVE:\nAn analysis of the clinical features of autoimmune encephalitis accompanied by anti-amphiphysin antibodies.\n\nMETHODS:\nThe data of encephalitis patients with anti-amphiphysin antibodies were retrospectively evaluated, including demographics, neurological and laboratory findings, imaging, treatment, and prognostic predictions.\n\nRESULTS:\nTen patients aged between 29 and 78 years (median age 52 years) were included. The male: female ratio was 4:6. Limbic encephalitis was found in nine patients while epileptic seizures were present in seven patients. All patients showed anti-amphiphysin antibody positivity in sera while one ninth was positive for CSF antibody. The EEG findings were abnormal, including reductions in background activity, and the presence of diffuse slow waves, sharp waves, and spikes and waves. Five patients showed signs of increased T2 signals in the medial temporal lobe on MRI while PET showed either hyper- or hypo-metabolic changes in several brain regions, including the temporal lobe, hippocampus, basal ganglia, frontal and parietal cortices. Nine of ten patients were treated with immunotherapy, with improvements of varying degrees. There was a significant reduction in seizure frequency, and all patients were seizure-free at last follow-up.\n\nCONCLUSION:\nAutoimmune encephalitis with anti-amphiphysin antibodies has a variety of clinical manifestations. The most common symptom is limbic encephalitis. Although relief from seizures can be achieved relatively easily, many patients suffer psychiatric, cognitive, and sleep sequelae. The disease was found to be associated with a lower incidence of cancer than has been previously reported for paraneoplastic neurologic syndromes." + } +} \ No newline at end of file diff --git a/37090700.json b/37090700.json new file mode 100644 index 0000000000000000000000000000000000000000..ef45b3e2182bcd478d4696b4a1141a4b3f253252 --- /dev/null +++ b/37090700.json @@ -0,0 +1,8 @@ +{ + "id": "37090700", + "label": 0, + "article": { + "id": "37090700", + "text": "CONTEXT:\nSevere acute respiratory syndrome-coronavirus 2 (COVID-19) vaccines may incur changes in thyroid functions followed by mood changes, and patients with Hashimoto thyroiditis (HT) were suggested to bear a higher risk.\n\nOBJECTIVES:\nWe primarily aim to find whether COVID-19 vaccination could induce potential subsequent thyroid function and mood changes. The secondary aim was to find inflammatory biomarkers associated with risk.\n\nMETHODS:\nThe retrospective, multi-center study recruited patients with HT receiving COVID-19-inactivated vaccines. C-reactive proteins (CRPs), thyroid-stimulating hormones (TSHs), and mood changes were studied before and after vaccination during a follow-up of a 6-month period. Independent association was investigated between incidence of mood state, thyroid functions, and inflammatory markers. Propensity score-matched comparisons between the vaccine and control groups were carried out to investigate the difference.\n\nRESULTS:\nFinal analysis included 2,765 patients with HT in the vaccine group and 1,288 patients in the control group. In the matched analysis, TSH increase and mood change incidence were both significantly higher in the vaccine group (11.9% versus 6.1% for TSH increase and 12.7% versus 8.4% for mood change incidence). An increase in CRP was associated with mood change (p\u003c 0.01 by the Kaplan-Meier method) and severity (r = 0.75) after vaccination. Baseline CRP, TSH, and antibodies of thyroid peroxidase (anti-TPO) were found to predict incidence of mood changes.\n\nCONCLUSION:\nCOVID-19 vaccination seemed to induce increased levels and incidence of TSH surge followed by mood changes in patients with HT. Higher levels of pre-vaccine serum TSH, CRP, and anti-TPO values were associated with higher incidence in the early post-vaccine phase." + } +} \ No newline at end of file diff --git a/37090716.json b/37090716.json new file mode 100644 index 0000000000000000000000000000000000000000..62c229f1258346b7d5673089d80b0d89e38bb569 --- /dev/null +++ b/37090716.json @@ -0,0 +1,8 @@ +{ + "id": "37090716", + "label": 0, + "article": { + "id": "37090716", + "text": "INTRODUCTION:\n(Asp) infections constitute a major cause of morbidity and mortality in patients following allogeneic hematopoietic stem cell transplantation (HSCT). In the context of insufficient host immunity, antifungal drugs show only limited efficacy. Faster and increased T-cell reconstitution correlated with a favorable outcome and a cell-based therapy approach strongly indicated successful clearance of fungal infections. Nevertheless, complex and cost- or time-intensive protocols hampered their implementation into clinical application.\n\nMETHODS:\nTo facilitate the clinical-scale manufacturing process of -specific T cells (ATCs) and to enable immediate (within 24 hours) and sustained (12 days later) treatment of patients with invasive aspergillosis (IA), we adapted and combined two complementary good manufacturing practice (GMP)-compliant approaches, i) the direct magnetic enrichment of Interferon-gamma (IFN-γ) secreting ATCs using the small-scale Cytokine Secretion Assay (CSA) and ii) a short-term T-cell culture expansion (STE), respectively. We further compared stimulation with two standardized and commercially available products: Asp-lysate and a pool of overlapping peptides derived from different Asp-proteins (PepMix).\n\nRESULTS:\nFor the fast CSA-based approach we detected IFN-γ ATCs after Asp-lysate- as well as PepMix-stimulation but with a significantly higher enrichment efficiency for stimulation with the Asp-lysate when compared to the PepMix. In contrast, the STE approach resulted in comparably high ATC expansion rates by using Asp-lysate or PepMix. Independent of the stimulus, predominantly CD4 helper T cells with a central-memory phenotype were expanded while CD8 T cells mainly showed an effector-memory phenotype. ATCs were highly functional and cytotoxic as determined by secretion of granzyme-B and IFN-γ.\n\nDISCUSSION:\nFor patients with IA, the immediate adoptive transfer of IFN-γ ATCs followed by the administration of short-term expanded ATCs from the same donor, might be a promising therapeutic option to improve the clinical outcome." + } +} \ No newline at end of file diff --git a/37091173.json b/37091173.json new file mode 100644 index 0000000000000000000000000000000000000000..a65a4cb11e5ffabed3cfd1a6d1a9d5a81ba4028e --- /dev/null +++ b/37091173.json @@ -0,0 +1,8 @@ +{ + "id": "37091173", + "label": 0, + "article": { + "id": "37091173", + "text": "Neuroblastoma (NB) is children's most prevalent solid malignant tumor, accounting for 15% of childhood cancer mortality. Non-coding RNA is important in NB pathogenesis. As a newly identified non-coding RNA, abnormal regulation (abnormal up-regulation or down-regulation) of the circRNAs expression is implicated in the tumorigenesis of various tumors, including NB. CircRNAs primarily regulate the expression of microRNA (miRNA) target genes by microRNA (miRNA) sponge adsorption. Clinical evidence suggests that the expression of certain circRNAs is associated with the prognosis and clinical features of NB and hence may be exploited as a biomarker or therapeutic target. This review examines circRNAs that have been demonstrated to play a function in NB." + } +} \ No newline at end of file diff --git a/37092231.json b/37092231.json new file mode 100644 index 0000000000000000000000000000000000000000..30ce7446ffa286a7acb14f64756b1dfa3c84c8ca --- /dev/null +++ b/37092231.json @@ -0,0 +1,8 @@ +{ + "id": "37092231", + "label": 0, + "article": { + "id": "37092231", + "text": "Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. The disease, characterized by motor, cognitive, and psychiatric impairments, is caused by the expansion of a CAG repeat in the huntingtin gene. Despite the discovery of the mutation in 1993, no disease-modifying treatments are yet available. Understanding the molecular and cellular mechanisms involved in HD is therefore crucial for the development of novel treatments. Emerging research has found that HD might be classified as a secondary tauopathy, with the presence of tau insoluble aggregates in late HD. Increased total tau protein levels have been observed in both HD patients and animal models of HD. Tau hyperphosphorylation, the main feature of tau pathology, has also been investigated and our own published results suggest that the protein phosphorylation machinery is dysregulated in the early stages of HD in R6/1 transgenic mice, primarily in the cortex and striatum. Protein phosphorylation, catalysed by kinases, regulates numerous cellular mechanisms and has been shown to be dysregulated in other neurodegenerative disorders, including Alzheimer's disease. While it is still unclear how the mutation in the huntingtin gene leads to tau dysregulation in HD, several hypotheses have been explored. Evidence suggests that the mutant huntingtin does not directly interact with tau, but instead interacts with tau kinases, phosphatases, and proteins involved in tau alternative splicing, which could result in tau dysregulation as observed in HD. Altogether, there is increasing evidence that tau is undergoing pathological changes in HD and may be a good therapeutic target." + } +} \ No newline at end of file diff --git a/37092992.json b/37092992.json new file mode 100644 index 0000000000000000000000000000000000000000..0fa99f211b28a5a2c3d3fc66c64dad5fe545b147 --- /dev/null +++ b/37092992.json @@ -0,0 +1,8 @@ +{ + "id": "37092992", + "label": 0, + "article": { + "id": "37092992", + "text": "Isolated extramedullary relapse of acute lymphoblastic leukemia (ALL) in the breast is extremely rare. We herein report a case of a 38-year-old female with B cell ALL, who had isolated extramedullary relapse initially in the left breast and subsequently in the right breast, 3 and 4 years, respectively, after hematopoietic allogenic stem cell transplantation. She was successfully salvaged with bilateral whole breast radiotherapy, 24 Gy/12 fractions/2.5 weeks. This brief report highlights the importance of awareness of extramedullary leukemic relapse in the breast as one of the differential diagnoses of breast masses in the context of ALL. Since these tumors are extremely radioresponsive, radiation therapy is a safe and effective treatment option for isolated extramedullary relapse of ALL in the breast." + } +} \ No newline at end of file diff --git a/37093743.json b/37093743.json new file mode 100644 index 0000000000000000000000000000000000000000..207fe4f0cfa4f682b22c88b9ea3947ec18edb306 --- /dev/null +++ b/37093743.json @@ -0,0 +1,8 @@ +{ + "id": "37093743", + "label": 0, + "article": { + "id": "37093743", + "text": "Although transferrin (Tf) is a glycoprotein best known for its role in iron delivery, iron-independent functions have also been reported. Here, we assessed apoTf (aTf) treatment effects on Neuro-2a (N2a) cells, a mouse neuroblastoma cell line which, once differentiated, shares many properties with neurons, including process outgrowth, expression of selective neuronal markers, and electrical activity. We first examined the binding of Tf to its receptor (TfR) in our model and verified that, like neurons, N2a cells can internalize Tf from the culture medium. Next, studies on neuronal developmental parameters showed that Tf increases N2a survival through a decrease in apoptosis. Additionally, Tf accelerated the morphological development of N2a cells by promoting neurite outgrowth. These pro-differentiating effects were also observed in primary cultures of mouse cortical neurons treated with aTf, as neurons matured at a higher rate than controls and showed a decrease in the expression of early neuronal markers. Further experiments in iron-enriched and iron-deficient media showed that Tf preserved its pro-differentiation properties in N2a cells, with results hinting at a modulatory role for iron. Moreover, N2a-microglia co-cultures revealed an increase in IL-10 upon aTf treatment, which may be thought to favor N2a differentiation. Taken together, these findings suggest that Tf reduces cell death and favors the neuronal differentiation process, thus making Tf a promising candidate to be used in regenerative strategies for neurodegenerative diseases." + } +} \ No newline at end of file diff --git a/37094450.json b/37094450.json new file mode 100644 index 0000000000000000000000000000000000000000..f31be6d13684963957995cd1062d92e2ad4d9050 --- /dev/null +++ b/37094450.json @@ -0,0 +1,8 @@ +{ + "id": "37094450", + "label": 0, + "article": { + "id": "37094450", + "text": "The modulatory interactions between neurotensin (NT) and the dopaminergic neurotransmitter system in the brain suggest that NT may be associated with the progression of Parkinson's disease (PD). NT exerts its neurophysiological effects by interactions with the human NT receptors type 1 (hNTS1) and 2 (hNTS2). Therefore, both receptor subtypes are promising targets for the development of novel NT-based analogs for the treatment of PD. In this study, we used a virtually guided molecular modeling approach to predict the activity of NT(8-13) analogs by investigating the docking models of ligands designed for binding to the human NTS1 and NTS2 receptors. The importance of the residues at positions 8 and/or 9 for hNTS1 and hNTS2 receptor binding affinity was experimentally confirmed by radioligand binding assays. Further in vitro ADME profiling and in vivo studies revealed that, compared to the parent peptide NT(8-13), compound 10 exhibited improved stability and BBB permeability combined with a significant enhancement of the motor function and memory in a mouse model of PD. The herein reported NTS1/NTS2 dual-specific NT(8-13) analogs represent an attractive tool for the development of therapeutic strategies against PD and potentially other CNS disorders." + } +} \ No newline at end of file diff --git a/37094596.json b/37094596.json new file mode 100644 index 0000000000000000000000000000000000000000..00b6e36d4201c5a416fde91c403dfff3917c05da --- /dev/null +++ b/37094596.json @@ -0,0 +1,8 @@ +{ + "id": "37094596", + "label": 0, + "article": { + "id": "37094596", + "text": "BACKGROUND:\nSurvival of children and adolescents with high-risk, mature B-cell non-Hodgkin lymphoma is improved by the addition of rituximab to chemotherapy. The effect of rituximab on immune reconstitution after therapy has not been well described. Herein, we evaluate the immune effects of the addition of rituximab to intensive chemotherapy, a prespecified secondary aim of the Inter-B-NHL Ritux 2010 trial.\n\nMETHODS:\nThe Inter-B-NHL Ritux 2010 trial was an international, open-label, randomised, phase 3 trial in children (age 6 months to 18 years) with high-risk, mature B-cell non-Hodgkin lymphoma, comparing chemotherapy alone or chemotherapy with rituximab. Measures of immune status were completed at baseline, 1 month from the end of treatment, and 1 year from the start of therapy, and yearly thereafter until normalised. For this secondary analysis, we report on the proportions of patients with low lymphocyte counts and immunoglobulin concentrations at these timepoints with total lymphocyte count, B-cell count, and IgG concentration as the main endpoints. Other endpoints of interest included exposure to immunoglobulin replacement therapy and vaccine serologies. The population assessed for immune endpoints was the eligible per-protocol population with at least one immune parameter at one timepoint. Comparisons of immune status were made between the randomised treatment groups. Safety in the post-therapy period was assessed in the population eligible for the immunity study who were followed up at least 3 months after the end of treatment and without cancer-related events. The Inter-B-NHL Ritux 2010 study was registered with ClinicalTrials.gov, NCT01516580; status completed, with analyses of secondary aims ongoing.\n\nFINDINGS:\nFrom Dec 19, 2011, to June 13, 2017, 421 patients (344 [82%] boys and 77 [18%] girls; mean age was 8·8 years [SD 4·1]) were enrolled and had immune data at baseline during follow-up, or both. The study population included randomly assigned patients (n=289) and a non-randomised cohort enrolled after the planned interim analysis (n=132). At baseline, 99 (34%) of 290 patients with available data (excluding patients with bone marrow disease with peripheral blast cells) had lymphopenia, and 178 (48%) of 368 had hypogammaglobulinemia. 1 month from the end of therapy, patients who received chemotherapy with rituximab were more likely than those who received chemotherapy alone to have lymphopenia (86 [81%] of 106 vs 53 (60%) of 89, odds ratio [OR] 2·92 [95% CI 1·53-5·57], p=0·0011), B-cell lymphopenia (72 [96%] of 75 vs 36 [64%] of 56, OR 13·33 [3·71-47·84], p\u003c0·0001), and hypogammaglobulinemia (67 [71%] of 95 vs 37 [47%] of 79, OR 2·72 [1·45-5·07], p=0·0017). Differences remained at 1 year for hypogammaglobulinemia only (52 [55%] of 94 vs 16 [25%] of 63, OR 3·64 [1·81-7·31], p=0·0003). Patients in the chemotherapy with rituximab group were more likely than those in the chemotherapy group to receive immunoglobulin replacement (26 [16%] 164 vs nine [7%] of 158, hazard ratio [HR] 2·63 [95% CI 1·23-5·62], p=0·010), mainly due to low immunoglobulin concentration. In the combined treatment groups, including non-randomly assigned patients, the proportion of patients who had loss of protective serologies to a vaccine preventable infection varied from four (9%) of 47 for polio to 21 (42%) of 50 for Streptococcus pneumoniae (pneumococcus). One patient (chemotherapy with rituximab group) had a life-threatening infectious event of polymicrobial bacterial sepsis reported 2 months after the final chemotherapy administration.\n\nINTERPRETATION:\nChildren with high-risk mature B-cell non-Hodgkin lymphoma receiving chemotherapy with rituximab were at risk of prolonged hypogammaglobulinemia, although severe infections were rare. Strategies for immunoglobulin replacement and revaccination are needed.\n\nFUNDING:\nClinical Research Hospital Program of the French Ministry of Health, Cancer Research UK, National Institute for Health Research Clinical Research Network in England, Children's Cancer Foundation Hong Kong, US National Cancer Institute, F Hoffmann-La Roche." + } +} \ No newline at end of file diff --git a/37094855.json b/37094855.json new file mode 100644 index 0000000000000000000000000000000000000000..5021ecf9ff258a317e26fb4bec46f50adceaefba --- /dev/null +++ b/37094855.json @@ -0,0 +1,8 @@ +{ + "id": "37094855", + "label": 0, + "article": { + "id": "37094855", + "text": "OBJECTIVE:\nCircular RNAs (circRNAs) are rich in miRNA-binding sites, which serve as miRNA sponges or competitive endogenous RNAs (ceRNAs). In the central nervous system, circRNAs are relevant to many neurological disorders including Alzheimer's disease (AD). Dementia associated with AD is correlated with the conversion of the β-Amyloid (Aβ) peptides from soluble monomers to aggregated oligomers and insoluble fibrils. Downregulation of circHOMER1 (circ_0006916) expression level is observed in AD female cases. Thus, this study investigates whether circHOMER1 prevents fibrillar Aβ (fAβ)-induced cell damage.\n\nMETHODS:\nThe levels of sAβ in cerebrospinal fluid (CSF) of amyloid-positive normal cognition (NC) individuals, mild cognitive impairment (MCI) individuals, and AD patients were measured. For studies, the SH-SY5Y cells were treated with 10 μM of fAβ or soluble Aβ (sAβ). RNase R treatment and actinomycin D treatment were used to identify the characteristics of circHOMER1. Gene expression was measured by RT-qPCR. Protein levels were measured using western blotting. Cell viability and apoptosis were estimated by MTT assays and flow cytometry. The binding relationship of miR-217 and circHOMER1 (HOMER1) was verified by luciferase reporter assays.\n\nRESULTS:\nCircHOMER1 was more stable in SH-SY5Y cells than linear HOMER1. CircHOMER1 upregulation ameliorates the fAβ-induced cell apoptosis and circHOMER1 downregulation reversed the anti-apoptotic roles of sAβ. Mechanistically, miR-217 interacted with circHOMER1 (HOMER1). Moreover, miR-217 upregulation or HOMER1 downregulation exacerbates the fAβ-induced cell damage.\n\nCONCLUSIONS:\nCircHOMER1 (hsa_circ_0006916) ameliorates the fAβ-induced cell injury via the miR-217/HOMER1 axis." + } +} \ No newline at end of file diff --git a/37094904.json b/37094904.json new file mode 100644 index 0000000000000000000000000000000000000000..2236bc2355cd143afbafdf3b6ee33992ff83385e --- /dev/null +++ b/37094904.json @@ -0,0 +1,8 @@ +{ + "id": "37094904", + "label": 0, + "article": { + "id": "37094904", + "text": "High-risk neuroblastoma (HR-NB) is an aggressive childhood cancer that responds poorly to currently available therapies and is associated with only about a 50% 5-year survival rate. MYCN amplification is a critical driver of these aggressive tumors, but so far there have not been any approved treatments to effectively treat HR-NB by targeting MYCN or its downstream effectors. Thus, the identification of novel molecular targets and therapeutic strategies to treat children diagnosed with HR-NB represents an urgent unmet medical need. Here, we conducted a targeted siRNA screening and identified TATA box-binding protein-associated factor RNA polymerase I subunit D, TAF1D, as a critical regulator of the cell cycle and proliferation in HR-NB cells. Analysis of three independent primary NB cohorts determined that high TAF1D expression correlated with MYCN-amplified, high-risk disease and poor clinical outcomes. TAF1D knockdown more robustly inhibited cell proliferation in MYCN-amplified NB cells compared with MYCN-non-amplified NB cells, as well as suppressed colony formation and inhibited tumor growth in a xenograft mouse model of MYCN-amplified NB. RNA-seq analysis revealed that TAF1D knockdown downregulates the expression of genes associated with the G2/M transition, including the master cell-cycle regulator, cell-cycle-dependent kinase 1 (CDK1), resulting in cell-cycle arrest at G2/M. Our findings demonstrate that TAF1D is a key oncogenic regulator of MYCN-amplified HR-NB and suggest that therapeutic targeting of TAF1D may be a viable strategy to treat HR-NB patients by blocking cell-cycle progression and the proliferation of tumor cells." + } +} \ No newline at end of file diff --git a/37095094.json b/37095094.json new file mode 100644 index 0000000000000000000000000000000000000000..516d31e12052440606fb3391333126d93f1e6ec8 --- /dev/null +++ b/37095094.json @@ -0,0 +1,8 @@ +{ + "id": "37095094", + "label": 0, + "article": { + "id": "37095094", + "text": "Chimeric antigen receptor-T (CAR-T) therapy remains to be investigated in T-cell malignancies. CD7 is an ideal target for T-cell malignancies but is also expressed on normal T cells, which may cause CAR-T cell fratricide. Donor-derived anti-CD7 CAR-T cells using endoplasmic reticulum retention have shown efficacy in patients with T-cell acute lymphoblastic leukemia (ALL). Here we launched a phase I trial to explore differences between autologous and allogeneic anti-CD7 CAR-T therapies in T-cell ALL and lymphoma. Ten patients were treated and 5 received autologous CAR-T therapies. No dose-limiting toxicity or neurotoxicity was observed. Grade 1-2 cytokine release syndrome occurred in 7 patients, and grade 3 in 1 patient. Grade 1-2 graft-versus-host diseases were observed in 2 patients. Seven patients had bone marrow infiltration, and 100% of them achieved complete remission with negative minimal residual disease within one month. Two-fifths of patients achieved extramedullary or extranodular remission. The median follow-up was 6 (range, 2.7-14) months and bridging transplantation was not administrated. Patients treated with allogeneic CAR-T cells had higher remission rate, less recurrence and more durable CAR-T survival than those receiving autologous products. Allogeneic CAR-T cells appeared to be a better option for patients with T-cell malignancies." + } +} \ No newline at end of file diff --git a/37095273.json b/37095273.json new file mode 100644 index 0000000000000000000000000000000000000000..72aaab622c89d9c8fd729b43aef04c3a6be05a99 --- /dev/null +++ b/37095273.json @@ -0,0 +1,8 @@ +{ + "id": "37095273", + "label": 0, + "article": { + "id": "37095273", + "text": "BACKGROUND:\nSpontaneous regression (SR) of cancer occurs in 1 in 60,000-100,000 patients. This phenomenon has been reported in almost all cancer types, most commonly neuroblastoma, renal cell carcinoma, malignant melanoma, and lymphoma/leukemia. However, SR in colorectal cancer (CRC) is extremely rare, particularly in advanced cases. Hence, this report describes a very rare case of spontaneous regression of advanced transverse colon cancer.\n\nCASE PRESENTATION:\nA 76-year-old female with anemia was diagnosed with a type II well-differentiated adenocarcinoma in the middle transverse colon. Two months later, a second colonoscopy examination was performed for preoperative marking, and it revealed tumor shrinkage and a shift to type 0-IIc morphology. Endoscopic tattooing was then performed, followed by a laparoscopic partial resection of the transverse colon with D3 lymph node dissection. However, the resected specimen contained no tumor, and colonoscopy showed no tumor remnants in the remaining colon. Histopathological examination revealed mucosal regeneration and a mucus nodule in between the submucosal and muscular layers, with no cancer cells detected. Immunohistochemical analysis revealed the loss of MutL homolog 1 (MLH1) and postmeiotic segregation increased 2 (PMS2) expression in the cancer cells of biopsied specimens, suggesting deficient mismatch repair (dMMR). The patient continues to be followed up until 6 years postoperatively, and no recurrence has been observed. In this study, we also reviewed similar reported cases of spontaneous regression of cancer involving dMMR.\n\nCONCLUSION:\nThis study presents a rare case of spontaneous regression of advanced transverse colon cancer wherein dMMR is strongly involved. However, further accumulation of similar cases is needed to elucidate this phenomenon and to develop new treatment strategies for CRC." + } +} \ No newline at end of file diff --git a/37095343.json b/37095343.json new file mode 100644 index 0000000000000000000000000000000000000000..9a30fbbe2490b76f4374fb595b7730d12c610d4c --- /dev/null +++ b/37095343.json @@ -0,0 +1,8 @@ +{ + "id": "37095343", + "label": 0, + "article": { + "id": "37095343", + "text": "BACKGROUND:\nCoronavirus disease (COVID-19) vaccination is recommended for patients undergoing renal replacement therapy (RRT), including hemodialysis (HD), peritoneal dialysis (PD), and kidney transplantation (KT). However, the difference in the immune response between RRT patients and healthy individuals after mRNA vaccines remains uncertain.\n\nMETHODS:\nThis retrospective observational study evaluated the anti-severe-acute-respiratory-syndrome-coronavirus-2 (anti-SARS-CoV-2) IgG antibody acquisition, titers and their changes, normal response rate (reaching titers of healthy individuals), factors associated with a normal response, and effectiveness of booster vaccination in Japanese RRT patients.\n\nRESULTS:\nMost HD and PD patients acquired anti-SARS-CoV-2 IgG antibodies after the second vaccination; however, their antibody titers and normal response rates (62-75%) were low compared with those of healthy subjects. Approximately 62% of KT recipients acquired antibodies, but the normal response rate was low (23%). Anti-SARS-CoV-2 IgG antibody waning occurred in the control, HD, and PD groups, while negative or very low titers remained in KT recipients. Third booster vaccination was effective in most HD and PD patients. However, the effect was mild in KT recipients - only 58% reached a normal response level. Multivariate logistic regression analyses demonstrated that younger age, higher serum albumin level, and RRT other than KT were significantly associated with a normal response after the second vaccination.\n\nCONCLUSIONS:\nRRT patients, particularly KT recipients, exhibited poor vaccine responses. Booster vaccination would be beneficial for HD and PD patients; however, its effect in KT recipients was mild. Further COVID-19 vaccinations using the latest vaccine or alternative procedures should be considered in RRT patients." + } +} \ No newline at end of file diff --git a/37096012.json b/37096012.json new file mode 100644 index 0000000000000000000000000000000000000000..dcd1709afcf653473af664b664e1922d6aa70e6a --- /dev/null +++ b/37096012.json @@ -0,0 +1,8 @@ +{ + "id": "37096012", + "label": 0, + "article": { + "id": "37096012", + "text": "Riedel's thyroiditis is a rare disease of chronic inflammation with fibrotic infiltration of the thyroid gland and its surrounding vital structures. Due to its low incidence, there are often delays in diagnosis as it is commonly mistaken for other thyroid diseases. We report the case of a 34-year-old female patient who presented with a firm, enlarged mass in the neck, compression symptoms, and hypothyroidism. Lab tests showed elevated A-TG (thyroglobulin antibodies) and A-TPO (thyroid peroxidase antibodies) levels. Based on the disease presentation and supporting lab findings, the patient was misdiagnosed with Hashimoto's thyroiditis and treated accordingly. Yet the patient's symptoms grew progressively worse. She was discovered to have severe tracheal compression and bilateral RLN (recurrent laryngeal nerve) palsy. Tracheotomy became a necessary surgical intervention after the development of respiratory failure, but this procedure was complicated by the development of an intraoperative pneumothorax. After an open biopsy, histology revealed Riedel's thyroiditis. A new treatment was introduced, with which the patient's condition improved. However, she continued to suffer from the open tracheocutaneous fistula left by the tracheostomy, which adversely affected her everyday life. A follow-up operation was performed to close the fistula. In this case report, we discuss the consequences of misdiagnosing the patient and delaying the appropriate treatment for her disease." + } +} \ No newline at end of file diff --git a/37096265.json b/37096265.json new file mode 100644 index 0000000000000000000000000000000000000000..a425154c3666eaa5ed6fdd474b64a4db444086b9 --- /dev/null +++ b/37096265.json @@ -0,0 +1,8 @@ +{ + "id": "37096265", + "label": 0, + "article": { + "id": "37096265", + "text": "To summarize the clinical data and prognosis of children with Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) common genes. This was a retrospective cohort study.Clinical data of 56 children with Ph-like ALL common gene cases (Ph-like ALL positive group) treated from January 2017 to January 2022 in the First Affiliated Hospital of Zhengzhou University, Henan Children's Hospital, Henan Cancer's Hospital and Henan Provincial People's Hospital were collected, 69 children with other high-risk B cell acute lymphoblastic leukemia (B-ALL) at the same time and the same age were selected as the negative group. The clinical characteristics and prognosis of two groups were analyzed retrospectively. Comparisons between groups were performed using Mann-Whitney test and test. Kaplan-Meier method was used for survival curve, Log-Rank test was used for univariate analysis, and the Cox regression model was used for multivariate prognosis analysis. Among 56 Ph-like ALL positive patients, there were 30 males and 26 females, and 15 cases were over 10 years old. There were 69 patients in Ph-like ALL negative group. Compared with the negative group, the children in positive group were older (6.4 (4.2, 11.2) 4.7 (2.8, 8.4) years), and hyperleukocytosis (≥50×10/L) was more common (25% (14/56) 9% (6/69)), the differences were statistically significant (both \u003c0.05). In the Ph-like ALL positive group, 32 cases were positive for IK6 (1 case was co-expressed with IK6 and EBF1-PDGFRB), 24 cases were IK6-negative, of which 9 cases were CRLF2 positive (including 2 cases with P2RY8-CRLF2, 7 cases with CRLF2 high expression), 5 cases were PDGFRB rearrangement, 4 cases were ABL1 rearrangement, 4 cases were JAK2 rearrangement, 1 case was ABL2 rearrangement and 1 case was EPOR rearrangement. The follow-up time of Ph-like ALL positive group was 22 (12, 40) months, and 32 (20, 45) months for negative group. The 3-year overall survival (OS) rate of positive group was significantly lower than the negative group ((72±7) % (86±5) %, =4.59, \u003c0.05). Compared with the 24 IK6-negative patients, the 3-year event free survival (EFS) rate of 32 IK6 positive patients was higher, the difference was statistically significant ((88±9) % (65±14) %, =5.37, \u003c0.05). Multivariate Cox regression analysis showed that the bone marrow minimal residual disease (MRD) not turning negative at the end of first induction (=4.12, 95% 1.13-15.03) independent prognostic risk factor for patient with Ph-like ALL common genes. Children with Ph-like ALL common genes were older than other high-risk B-ALL patients at diagnosis, with high white blood cells and lower survival rate. The bone marrow MRD not turning negative at the end of first induction were independent prognostic risk factor for children with Ph-like ALL common gene." + } +} \ No newline at end of file diff --git a/37096505.json b/37096505.json new file mode 100644 index 0000000000000000000000000000000000000000..1ba10629e415620d3ded864fb2390ed931ac6ed4 --- /dev/null +++ b/37096505.json @@ -0,0 +1,8 @@ +{ + "id": "37096505", + "label": 0, + "article": { + "id": "37096505", + "text": "OBJECTIVE:\nTo analyze the characteristics and prognosis of acute leukemia(AL) with fusion gene.\n\nMETHODS:\nThe clinical data of 17 patients over 14 years old newly diagnosed with positive AL admitted in Institute of Hematology and Blood Diseases Hospital from August 2017 to May 2021 were analyzed retrospectively.\n\nRESULTS:\nAmong the 17 positive patients, 13 cases were diagnosed as T-ALL (ETP 3 cases, Pro-T-ALL 6 cases, Pre-T-ALL 3 cases, Medullary-T-ALL 1 case), AML 3 cases (2 cases M5, 1 case M0) and ALAL 1 case. Thirteen patients presented extramedullary infiltration at initial diagnosis. All 17 patients received treatment, and a total of 16 cases achieved complete remission (CR), including 12 cases in patients with T-ALL. The total median OS and RFS time were 23 (3-50) months and 21 (0-48) months, respectively. Eleven patients received allogeneic hematopoietic stem cell transplantation(allo-HSCT), with median OS time of 37.5 (5-50) months and median RFS time of 29.5 (5-48) months. The median OS time of 6 patients in chemotherapy-only group was 10.5 (3-41) months, and median RFS time of 6.5 (3-39) months. The OS and RFS of patients with transplantation group were better than those of chemotherapy-only group (=0.038). Among the 4 patients who relapsed or refractory after allo-HSCT, the fusion gene did not turn negative before transplantation. While, in the group of 7 patients who have not relapsed after allo-HSCT till now, the fusion gene expression of 5 patients turned negative before transplantation and other 2 of them were still positive.\n\nCONCLUSION:\nThe fusion site of SET-NUP214 fusion gene is relatively fixed in AL patients, often accompanied by extramedullary infiltration. The chemotherapy effect of this disease is poor, and allo-HSCT may improve its prognosis." + } +} \ No newline at end of file diff --git a/37096543.json b/37096543.json new file mode 100644 index 0000000000000000000000000000000000000000..537ec89ee368ccef9a7877f16be7b6c4c7a66b5e --- /dev/null +++ b/37096543.json @@ -0,0 +1,8 @@ +{ + "id": "37096543", + "label": 0, + "article": { + "id": "37096543", + "text": "Extramedullary plasma cell tumor (EMP) is a kind of plasma cell tumor, and its pathogenesis is not completely clear. According to whether it is independent of myeloma disease, it can be divided into primary and secondary EMP, which have different biological and clinical characteristics. Primary EMP has low invasion, fewer cytogenetic and molecular genetic abnormalities and good prognosis, and surgery and / or radiotherapy are the mainly treatments. Secondary EMP, as the extramedullary invasive progression of multiple myeloma (MM), is often accompanied by high-risk cellular and molecular genetic abnormalities and poor prognosis, chemotherapy, immunotherapy and hematopoietic stem cell transplantation are the mainly treatment. This paper reviews the latest research progress of EMP in the pathogenesis, cytogenetics molecular genetics and treatment, so as to provide reference for clinical work." + } +} \ No newline at end of file diff --git a/37096638.json b/37096638.json new file mode 100644 index 0000000000000000000000000000000000000000..0864d6f989fdf2720f90ce1fe7effec728264946 --- /dev/null +++ b/37096638.json @@ -0,0 +1,8 @@ +{ + "id": "37096638", + "label": 0, + "article": { + "id": "37096638", + "text": "International Myeloma Working Group (IMWG) response criteria require refrigerated 24-hour urine specimens for most patients. However, given that serum free light chain testing has been shown to outperform 24-hour urine immunofixation as a prognostic marker, the importance of maintaining urine testing options or requirements within each level of IMWG response criteria has not been investigated. We analyzed responses to induction therapy for all transplant-eligible patients with multiple myeloma at our institution over a 3-year period using traditional versus 'urine-free' IMWG response criteria (where references to urine were removed from the descriptions for every depth of response). Of 281 evaluable patients, responses changed for only 4% of patients (95% confidence interval 2-7%) using urine-free criteria. Our results call into question the continued requirement for 24-hour urine measurements as part of IMWG response assessments for all patients. Research into the prognostic performance of urine-free IMWG criteria is ongoing." + } +} \ No newline at end of file diff --git a/37097319.json b/37097319.json new file mode 100644 index 0000000000000000000000000000000000000000..710e65dad2597e1fd9b69e11eae0181d970d2584 --- /dev/null +++ b/37097319.json @@ -0,0 +1,8 @@ +{ + "id": "37097319", + "label": 0, + "article": { + "id": "37097319", + "text": "INTRODUCTION:\nSupervision, tailoring, and flexibility have been proposed as key program elements for delivering successful exercise programs for people with multiple myeloma (MM). However, no studies to date have evaluated the acceptability of an intervention employing these components. The aim of this study was to determine the acceptability of a virtually supported exercise program and eHealth application for people with MM.\n\nMETHODS:\nA qualitative description approach was used. One-on-one interviews were conducted with participants who completed the exercise program. Content analysis was used to analyze verbatim transcripts from interviews.\n\nRESULTS:\nTwenty participants were interviewed (64.9 ± 6.7 years of age, n = 12 females). Participants had positive perceptions of the exercise program. Two themes emerged related to strengths/limitations: One Size Does Not Fit All (sub-themes: Supportive \u0026 Responsive Programming and Diverse Exercise Opportunities), and App Usability. Supportive and Responsive Programming was a main strength of the program, characterized as programming that was tailored, involved active support, and delivered by appropriate personnel. The inclusion of Diverse Exercise Opportunities was also regarded as a strength, as it accommodated the preferences of all participants. Related to App Usability, participants felt the app was simple and user friendly but had a few less intuitive components.\n\nCONCLUSION:\nThe virtually supported exercise program and eHealth application were acceptable for people with MM. Programs should employ tailoring, active support, and appropriate personnel to bolster acceptability and include both supervised and flexible exercise formats. eHealth apps should be simple to use so technology proficiency is not a barrier to participation." + } +} \ No newline at end of file diff --git a/37097334.json b/37097334.json new file mode 100644 index 0000000000000000000000000000000000000000..10dd884b26c464bcacd27506f27e509e0b3eac52 --- /dev/null +++ b/37097334.json @@ -0,0 +1,8 @@ +{ + "id": "37097334", + "label": 0, + "article": { + "id": "37097334", + "text": "Neuroblastoma arises when immature neural precursor cells do not mature into specialized cells. Although retinoic acid (RA), a pro-differentiation agent, improves the survival of low-grade neuroblastoma, resistance to retinoic acid is found in high-grade neuroblastoma patients. Histone deacetylases (HDAC) inhibitors induce differentiation and arrest the growth of cancer cells; however, HDAC inhibitors are FDA-approved mostly for liquid tumors. Therefore, combining histone deacetylase (HDAC) inhibitors and retinoic acid can be explored as a strategy to trigger the differentiation of neuroblastoma cells and to overcome resistance to retinoic acid. Based on this rationale, in this study, we linked evernyl group and menadione-triazole motifs to synthesize evernyl-based menadione-triazole hybrids and asked if the hybrids cooperate with retinoic acid to trigger the differentiation of neuroblastoma cells. To answer this question, we treated neuroblastoma cells using evernyl-based menadione-triazole hybrids (6a-6i) or RA or both and examined the differentiation of neuroblastoma cells. Among the hybrids, we found that compound 6b inhibits class-I HDAC activity, induces differentiation, and RA co-treatments increase 6b-induced differentiation of neuroblastoma cells. In addition, 6b reduces cell proliferation, induces expression of differentiation-specific microRNAs leading to N-Myc downregulation, and RA co-treatments enhance the 6b-induced effects. We observed that 6b and RA trigger a switch from glycolysis to oxidative phosphorylation, maintain mitochondrial polarization, and increase oxygen consumption rate. We conclude that in evernyl-based menadione-triazole hybrid, 6b cooperates with RA to induce differentiation of neuroblastoma cells. Based on our results, we suggest that combining RA and 6b can be pursued as therapy for neuroblastoma. Schematic representation of RA and 6b in inducing differentiation of neuroblastoma cells." + } +} \ No newline at end of file diff --git a/37097532.json b/37097532.json new file mode 100644 index 0000000000000000000000000000000000000000..11a3026074213126dc10e6771a1c77a2aa5965a3 --- /dev/null +++ b/37097532.json @@ -0,0 +1,8 @@ +{ + "id": "37097532", + "label": 0, + "article": { + "id": "37097532", + "text": "BACKGROUND:\nDuring chemotherapy for multiple myeloma, symptoms include those related to the disease, as well as adverse effects of the treatment. Few studies have explored the relationships between these symptoms. Network analysis could identify the core symptom in the symptom network.\n\nOBJECTIVE:\nThe aim of this study was to explore the core symptom in multiple myeloma patients undergoing chemotherapy.\n\nMETHODS:\nThis was a cross-sectional study in which sequential sampling was used to recruit 177 participants from Hunan, China. Demographic and clinical characteristics were surveyed using a self-developed instrument. The symptoms of chemotherapy-treated multiple myeloma, including pain, fatigue, worry, nausea, and vomiting, were measured using a questionnaire with good reliability and validity. The mean ± SD, frequency, and percentages were used as descriptive statistics. Network analysis was used to estimate the correlation between symptoms.\n\nRESULTS:\nThe results showed that 70% of multiple myeloma patients using chemotherapy exhibited pain. In the network analysis, worrying was the dominant symptom, and the strongest relationship was between nausea and vomiting in chemotherapy-treated multiple myeloma patients' symptoms.\n\nCONCLUSION:\nWorrying is the core symptom of multiple myeloma patients. Interventions could be most effective if there is a symptom management focus on worrying when providing care to chemotherapy-treated multiple myeloma patients. Nausea combined with vomiting could be better managed, which would decrease the cost of health care. Understanding the relationship between the symptoms of multiple myeloma patients undergoing chemotherapy is beneficial for precise symptom management.\n\nIMPLICATIONS FOR PRACTICE:\nNurses and health care teams should be a priority to intervene in the worrying for chemotherapy-treated multiple myeloma patients to maximize the effectiveness of an intervention. Except, nausea and vomiting should be managed together in a clinical setting." + } +} \ No newline at end of file diff --git a/37097545.json b/37097545.json new file mode 100644 index 0000000000000000000000000000000000000000..af6fd647d9cd7e33aff376443ecfba45f900c3b8 --- /dev/null +++ b/37097545.json @@ -0,0 +1,8 @@ +{ + "id": "37097545", + "label": 0, + "article": { + "id": "37097545", + "text": "PURPOSE OF REVIEW:\nThis article summarizes the current state of knowledge of hairy cell leukemia (HCL) regarding presentation, diagnosis, therapy, and monitoring, including perspectives on emergent therapies.\n\nRECENT FINDINGS:\nOver the past decade, there has been enormous progress in the understanding of the biology of HCL which has led to the development of novel therapeutic strategies. The maturation of data regarding existing management strategies has also lent considerable insight into therapeutic outcomes and prognosis of patients treated with chemo- or chemoimmunotherapy. Purine nucleoside analogs remain the cornerstone of treatment, and the addition of rituximab has deepened and prolonged responses in the upfront and relapsed setting. Targeted therapies now have a more defined role in the management of HCL, with BRAF inhibitors now having a potential in the first-line setting in selected cases as well as in relapse. Next-generation sequencing for the identification of targetable mutations, evaluation of measurable residual disease, and risk stratification continue to be areas of active investigation. Recent advances in HCL have led to more effective therapeutics in the upfront and relapsed setting. Future efforts will focus on identifying patients with high-risk disease who require intensified regimens. Multicenter collaborations are the key to improving overall survival and quality of life in this rare disease." + } +} \ No newline at end of file diff --git a/37097611.json b/37097611.json new file mode 100644 index 0000000000000000000000000000000000000000..4faf36bf84972ae1d6c0a680cd37ad4247d1d1ef --- /dev/null +++ b/37097611.json @@ -0,0 +1,8 @@ +{ + "id": "37097611", + "label": 0, + "article": { + "id": "37097611", + "text": "PURPOSE:\nAddition of ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) to poly-ADP ribose polymerase inhibitors (PARPi) overcomes PARPi-resistance in high grade serous ovarian cancer (HGSOC) cell and mouse models. We present the results of an investigator-initiated study of combination PARPi(olaparib) and ATRi(ceralasertib) in patients with acquired PARPi-resistant HGSOC.\n\nPATIENTS AND METHODS:\nEligible patients had recurrent, platinum-sensitive BRCA1/2 mutated or homologous recombination (HR) deficient HGSOC and clinically benefited from PARPi (response by imaging/CA-125 or duration of maintenance therapy; \u003e12 months 1st-line or \u003e6 months ≥2nd-line) before progression. No intervening chemotherapy was permitted. Patients received olaparib 300mg twice daily and ceralasertib 160mg daily on days 1-7 of a 28-day cycle. Primary objectives were safety and objective response rate (ORR).\n\nRESULTS:\nThirteen patients enrolled were evaluable for safety and 12 for efficacy. 62%(n=8) had germline BRCA1/2 mutations, 23% (n=3) somatic BRCA1/2 mutations, and 15%(n=2) HR-deficient tumors. Prior PARPi indication was treatment for recurrence (54%, n=7), 2nd line-maintenance (38%, n=5), and frontline treatment with carboplatin/paclitaxel (8%, n=1). There were 6 partial responses yielding an ORR of 50% (95% CI:0.15, 0.72). Median treatment duration was 8 cycles (range 4-23+). Grade(G) 3/4 toxicities were 38%(n=5); 15%(n=2) G3 anemia, 23%(n=3) G3 thrombocytopenia, 8% (n=1) G4 neutropenia. Four patients required dose-reductions. No patient discontinued treatment due to toxicity.\n\nCONCLUSION:\nCombination olaparib and ceralasertib is tolerable and shows activity in HR-deficient platinum-sensitive recurrent HGSOC that benefited and then progressed with PARPi as the penultimate regimen. These data suggest that ceralasertib re-sensitizes PARPi resistant HGSOCs to olaparib, warranting further investigation." + } +} \ No newline at end of file diff --git a/37097894.json b/37097894.json new file mode 100644 index 0000000000000000000000000000000000000000..10e1b22241f17ec0cdc3d452dbe6fcac9061d987 --- /dev/null +++ b/37097894.json @@ -0,0 +1,8 @@ +{ + "id": "37097894", + "label": 0, + "article": { + "id": "37097894", + "text": "OBJECTIVES:\nTo evaluate enthesitis treatment response, including time to resolution and data from multiple enthesitis instruments, in patients with psoriatic arthritis (PsA) treated with secukinumab or adalimumab for 52 weeks.\n\nMETHODS:\nIn this post hoc analysis of the EXCEED study, patients receiving secukinumab 300 mg or adalimumab 40 mg per the label were grouped by presence or absence of baseline enthesitis based on the Leeds Enthesitis Index (LEI) and the Spondyloarthritis Research Consortium of Canada Enthesitis Index (SPARCC). Efficacy was assessed according to several enthesitis-related instruments using nonresponder imputation for the achievement of enthesitis resolution (LEI/SPARCC = 0), Kaplan-Meier analysis for time to resolution, and as-observed data for other outcomes.\n\nRESULTS:\nEnthesitis was present at baseline in 498 of 851 patients (58.5%) as assessed by LEI and in 632 of 853 patients (74.1%) as assessed by SPARCC. Patients with baseline enthesitis generally presented with greater disease activity. Similar proportions of patients receiving secukinumab or adalimumab achieved resolution of LEI and SPARCC at Weeks 24 (secukinumab: LEI/SPARCC, 49.6%/45.8%; adalimumab: LEI/SPARCC, 43.6%/43.5%) and 52 (secukinumab: LEI/SPARCC, 60.7%/53.2%; adalimumab: LEI/SPARCC, 55.3%/51.4%), with comparable mean time to enthesitis resolution. Improvements were similar for both drugs at individual enthesitis sites. Resolution of enthesitis with secukinumab or adalimumab was associated with improvements in quality of life at week 52.\n\nCONCLUSION:\nSecukinumab and adalimumab showed similar efficacy, including time to resolution, with respect to resolution of enthesitis. Inhibition of interleukin 17 with secukinumab reduced clinical enthesitis similarly to tumor necrosis factor alpha inhibition.\n\nTRIAL REGISTRATION:\nClinicalTrials.gov, NCT02745080." + } +} \ No newline at end of file diff --git a/37098238.json b/37098238.json new file mode 100644 index 0000000000000000000000000000000000000000..bc0e4157a9b1938f0cf1adcfe9d38ddd16b9e415 --- /dev/null +++ b/37098238.json @@ -0,0 +1,8 @@ +{ + "id": "37098238", + "label": 0, + "article": { + "id": "37098238", + "text": "PURPOSE:\nIn 2006, Children's Oncology Group (COG) reclassified subgroups of toddlers diagnosed with neuroblastoma from high-risk to intermediate-risk, when the age cutoff for high-risk assignment was raised from 365 days (12 months) to 547 days (18 months). The primary aim of this retrospective study was to determine if excellent outcome was maintained after assigned reduction of therapy.\n\nPATIENTS AND METHODS:\nChildren \u003c3 years old at diagnosis, enrolled on a COG biology study from 1990 to 2018, were eligible (n = 9,189). Assigned therapy was reduced for two cohorts of interest on the basis of the age cutoff change: 365-546 days old with International Neuroblastoma Staging System (INSS) stage 4, not amplified (), favorable International Neuroblastoma Pathology Classification (INPC), hyperdiploid tumors (12-18mo/Stage4/FavBiology), and 365-546 days old with INSS stage 3, and unfavorable INPC tumors (12-18mo/Stage3//Unfav). Log-rank tests compared event-free survival (EFS) and overall survival (OS) curves.\n\nRESULTS:\nFor 12-18mo/Stage4/FavBiology, 5-year EFS/OS (± SE) before (≤2006; n = 40) versus after (\u003e2006; n = 55) assigned reduction in therapy was similar: 89% ± 5.1%/89% ± 5.1% versus 87% ± 4.6%/94% ± 3.2% ( = .7; = .4, respectively). For 12-18mo/Stage3//Unfav, the 5-year EFS and OS were both 100%, before (n = 6) and after (n = 4) 2006. The 12-18mo/Stage4/FavBiology plus 12-18mo/Stage3//Unfav classified as high-risk ≤2006 had an EFS/OS of 91% ± 4.4%/91% ± 4.5% versus 38% ± 1.3%/43% ± 1.3% for all other high-risk patients \u003c3 years old ( \u003c .0001; \u003c .0001, respectively). The 12-18mo/Stage4/FavBiology plus 12-18mo/Stage3//Unfav classified as intermediate-risk \u003e2006 had an EFS/OS of 88% ± 4.3%/95% ± 2.9% versus 88% ± 0.9%/95% ± 0.6% for all other intermediate-risk patients \u003c3 years old ( = .87; = .85, respectively).\n\nCONCLUSION:\nExcellent outcome was maintained among subsets of toddlers with neuroblastoma assigned to reduced treatment after reclassification of risk group from high to intermediate on the basis of new age cutoffs. Importantly, as documented in prior trials, intermediate-risk therapy is not associated with the degree of acute toxicity and late effects commonly observed with high-risk regimens." + } +} \ No newline at end of file diff --git a/37098643.json b/37098643.json new file mode 100644 index 0000000000000000000000000000000000000000..592e5b91293dbcf56e018d7b0f1bce7baa1565ef --- /dev/null +++ b/37098643.json @@ -0,0 +1,8 @@ +{ + "id": "37098643", + "label": 0, + "article": { + "id": "37098643", + "text": "Myelodysplastic syndromes (MDS) consist of a group of hematological malignancies characterized by ineffective hematopoiesis, cytogenetic abnormalities, and often a high risk of transformation to acute myeloid leukemia (AML). So far, there have been only a very limited number of studies assessing the epigenetics component contributing to the pathophysiology of these disorders, but not a single study assessing this at a genome-wide level. Here, we implemented a generic high throughput epigenomics approach, using methylated DNA sequencing (MeD-seq) of LpnPI digested fragments to identify potential epigenomic targets associated with MDS subtypes. Our results highlighted that PCDHG and ZNF gene families harbor potential epigenomic targets, which have been shown to be differentially methylated in a variety of comparisons between different MDS subtypes. Specifically, CpG islands, transcription start sites and post-transcriptional start sites within ZNF124, ZNF497 and PCDHG family are differentially methylated with fold change above 3,5. Overall, these findings highlight important aspects of the epigenomic component of MDS syndromes pathogenesis and the pharmacoepigenomic basis to the hypomethylating agents drug treatment response, while this generic high throughput whole epigenome sequencing approach could be readily implemented to other genetic diseases with a strong epigenetic component." + } +} \ No newline at end of file diff --git a/37099029.json b/37099029.json new file mode 100644 index 0000000000000000000000000000000000000000..2997e0b8a1507e5a23bd7657ceb89779429eee5a --- /dev/null +++ b/37099029.json @@ -0,0 +1,8 @@ +{ + "id": "37099029", + "label": 0, + "article": { + "id": "37099029", + "text": "Consensus Panel 5 (CP5) of the 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-11; held in October 2022) was tasked with reviewing the current data on the coronavirus disease-2019 (COVID-19) prophylaxis and management in patients with Waldenstrom's Macroglobulinemia (WM). The key recommendations from IWWM-11 CP5 included the following: Booster vaccines for SARS-CoV-2 should be recommended to all patients with WM. Variant-specific booster vaccines, such as the bivalent vaccine for the ancestral Wuhan strain and the Omicron BA.4.5 strain, are important as novel mutants emerge and become dominant in the community. A temporary interruption in Bruton's Tyrosine Kinase-inhibitor (BTKi) or chemoimmunotherapy before vaccination might be considered. Patients under treatment with rituximab or BTK-inhibitors have lower antibody responses against SARS-CoV-2; thus, they should continue to follow preventive measures, including mask wearing and avoiding crowded places. Patients with WM are candidates for preexposure prophylaxis, if available and relevant to the dominant SARS-CoV-2 strains in a specific area. Oral antivirals should be offered to all symptomatic WM patients with mild to moderate COVID-19 regardless of vaccination, disease status or treatment, as soon as possible after the positive test and within 5 days of COVID-19-related symptom onset. Coadministration of ibrutinib or venetoclax with ritonavir should be avoided. In these patients, remdesivir offers an effective alternative. Patients with asymptomatic or oligosymptomatic COVID-19 should not interrupt treatment with a BTK inhibitor. Infection prophylaxis is essential in patients with WM and include general preventive measures, prophylaxis with antivirals and vaccination against common pathogens including SARS-CoV-2, influenza, and S. pneumoniae." + } +} \ No newline at end of file diff --git a/37099340.json b/37099340.json new file mode 100644 index 0000000000000000000000000000000000000000..58907acdd72c5d7faa2094b36c32ddeec64abf09 --- /dev/null +++ b/37099340.json @@ -0,0 +1,8 @@ +{ + "id": "37099340", + "label": 0, + "article": { + "id": "37099340", + "text": "BACKGROUND:\n-rearranged acute lymphoblastic leukemia (ALL) in infants is an aggressive disease with 3-year event-free survival below 40%. Most relapses occur during treatment, with two thirds occurring within 1 year and 90% within 2 years after diagnosis. Outcomes have not improved in recent decades despite intensification of chemotherapy.\n\nMETHODS:\nWe studied the safety and efficacy of blinatumomab, a bispecific T-cell engager molecule targeting CD19, in infants with -rearranged ALL. Thirty patients younger than 1 year of age with newly diagnosed -rearranged ALL were given the chemotherapy used in the Interfant-06 trial with the addition of one postinduction course of blinatumomab (15 μg per square meter of body-surface area per day; 28-day continuous infusion). The primary end point was clinically relevant toxic effects, defined as any toxic effect that was possibly or definitely attributable to blinatumomab and resulted in permanent discontinuation of blinatumomab or death. Minimal residual disease (MRD) was measured by polymerase chain reaction. Data on adverse events were collected. Outcome data were compared with historical control data from the Interfant-06 trial.\n\nRESULTS:\nThe median follow-up was 26.3 months (range, 3.9 to 48.2). All 30 patients received the full course of blinatumomab. No toxic effects meeting the definition of the primary end point occurred. Ten serious adverse events were reported (fever [4 events], infection [4], hypertension [1], and vomiting [1]). The toxic-effects profile was consistent with that reported in older patients. A total of 28 patients (93%) either were MRD-negative (16 patients) or had low levels of MRD (\u003c5×10 [i.e., \u003c5 leukemic cells per 10,000 normal cells], 12 patients) after the blinatumomab infusion. All the patients who continued chemotherapy became MRD-negative during further treatment. Two-year disease-free survival was 81.6% in our study (95% confidence interval [CI], 60.8 to 92.0), as compared with 49.4% (95% CI, 42.5 to 56.0) in the Interfant-06 trial; the corresponding values for overall survival were 93.3% (95% CI, 75.9 to 98.3) and 65.8% (95% CI, 58.9 to 71.8).\n\nCONCLUSIONS:\nBlinatumomab added to Interfant-06 chemotherapy appeared to be safe and had a high level of efficacy in infants with newly diagnosed -rearranged ALL as compared with historical controls from the Interfant-06 trial. (Funded by the Princess Máxima Center Foundation and others; EudraCT number, 2016-004674-17.)." + } +} \ No newline at end of file diff --git a/37100016.json b/37100016.json new file mode 100644 index 0000000000000000000000000000000000000000..7e34a370d074d48face8ad5fcbeb6552fc61eb1e --- /dev/null +++ b/37100016.json @@ -0,0 +1,8 @@ +{ + "id": "37100016", + "label": 0, + "article": { + "id": "37100016", + "text": "SOX2 is a transcription factor belonging to the SOX gene family, whose activity has been associated with the maintenance of the stemness and self-renewal of embryonic stem cells (ESCs), as well as the induction of differentiated cells into induced pluripotent stem cells (iPSCs). Moreover, accumulating studies have shown that SOX2 is amplified in various cancers, notably in esophageal squamous cell carcinoma (ESCC). In addition, SOX2 expression is linked to multiple malignant processes, including proliferation, migration, invasion, and drug resistance. Taken together, targeting SOX2 might shed light on novel approaches for cancer therapy. In this review, we aim to summarize the current knowledge regarding SOX2 in the development of esophagus and ESCC. We also highlight several therapeutic strategies for targeting SOX2 in different cancer types, which can provide new tools to treat cancers possessing abnormal levels of SOX2 protein." + } +} \ No newline at end of file diff --git a/37100025.json b/37100025.json new file mode 100644 index 0000000000000000000000000000000000000000..825b2e8ca266b7d93947be3c8247a21cf33db18e --- /dev/null +++ b/37100025.json @@ -0,0 +1,8 @@ +{ + "id": "37100025", + "label": 0, + "article": { + "id": "37100025", + "text": "BACKGROUND:\nAcute myeloid leukemia (AML) is a hematological malignancy due to anomalous differentiation and proliferation of hematopoietic stem cells with myeloid blast buildup. Induction chemotherapy is considered the first line of treatment in most patients with AML. However, targeted therapy in the form of FLT-3, IDH, BCL-2, and immune checkpoint inhibitors, can be considered as the first line depending on their molecular profile, resistance to chemotherapy, comorbidities, etc. This review aims to assess the tolerability and efficacy of isocitrate dehydrogenase (IDH) inhibitors in AML.\n\nMETHODS:\nWe searched Medline, WOS, Embase, and clinicaltrials.gov. PRISMA guidelines were followed in this systematic review. 3327 articles were screened, and 9 clinical trials (N = 1119) were included.\n\nRESULTS:\nIn randomized clinical trials (RCTs), objective response (OR) was reported in 63-74% of the patients with IDH inhibitors + azacitidine as compared to 19-36 % of the patients with azacitidine monotherapy in newly diagnosed (ND) medically unfit patients. Survival rates were significantly improved with the use of ivosidenib. OR was reported in 39.1-46 % of the patients who relapsed/refractory to chemotherapy. ≥Grade 3 IDH differentiation syndrome and QT prolongation were reported in 3.9-10 % and 2-10 % of the patients, respectively.\n\nCONCLUSION:\nIDH inhibitors (ivosidenib for IDH-1 and enasidenib for IDH-2) are safe and effective in treating ND medically unfit or relapsed refractory patients with IDH mutation. However, no survival benefit was reported with enasidenib. More randomized multicenter double-blinded clinical studies are needed to confirm these results and compare them with other targeting agents." + } +} \ No newline at end of file diff --git a/37100242.json b/37100242.json new file mode 100644 index 0000000000000000000000000000000000000000..bc9960f9a189b85a5b42b9f12c0a6b5c3ade2c85 --- /dev/null +++ b/37100242.json @@ -0,0 +1,8 @@ +{ + "id": "37100242", + "label": 0, + "article": { + "id": "37100242", + "text": "\"Bacteroides denticanum\" is an anaerobic, non-spore-forming, gram-negative bacterium with a rod morphology typical of canine, ovine, and macropod oral flora. There is only one report of bloodstream infection caused by \"B. denticanum\" from a dog bite in human. Here, we report a case with no history of animal contact who developed an abscess caused by \"B. denticanum\" around a pharyngo-esophageal anastomosis after undergoing balloon dilatation procedure for stenosis following laryngectomy. The patient was a 73-year-old man with laryngeal cancer, esophageal cancer, hyperuricemia, dyslipidemia, and hypertension with a 4-week history of cervical pain, sore throat, and fever. Computed tomography showed fluid collection on the posterior pharyngeal wall. Matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) identified Bacteroides pyogenes, Lactobacillus salivarius, and Streptococcus anginosus from abscess aspiration. 16S ribosomal RNA sequencing re-identified the Bacteroides species as \"B. denticanum\". T2-weighted magnetic resonance images showed a high signal intensity adjacent to the anterior vertebral body of C3-C7. The diagnosis was peripharyngeal esophageal anastomotic abscess and acute vertebral osteomyelitis caused by \"B. denticanum\", L. salivarius, and S. anginosus. The patient was treated with sulbactam ampicillin intravenously for 14 days and then switched to oral amoxicillin with clavulanic acid for 6 weeks. To our knowledge, this is the first report of a human infection caused by \"B. denticanum\" without a history of animal contact. Despite remarkable advancements facilitated by MALDI-TOF MS in microbiological diagnosis, the accurate identification of novel, emerging, or uncommon microorganisms and comprehending their pathogenicity, suitable therapy, and follow up necessitate sophisticated molecular approaches." + } +} \ No newline at end of file diff --git a/37100486.json b/37100486.json new file mode 100644 index 0000000000000000000000000000000000000000..c00a3426a11cf0901ceb3ec2d12fb18f1d4800c0 --- /dev/null +++ b/37100486.json @@ -0,0 +1,8 @@ +{ + "id": "37100486", + "label": 0, + "article": { + "id": "37100486", + "text": "BACKGROUND:\nWhether initial invasive management in older vs younger adults with chronic coronary disease and moderate or severe ischemia improves health status or clinical outcomes is unknown.\n\nOBJECTIVES:\nThe goal of this study was to examine the impact of age on health status and clinical outcomes with invasive vs conservative management in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial.\n\nMETHODS:\nOne-year angina-specific health status was assessed with the 7-item Seattle Angina Questionnaire (SAQ) (score range 0-100; higher scores indicate better health status). Cox proportional hazards models estimated the treatment effect of invasive vs conservative management as a function of age on the composite clinical outcome of cardiovascular death, myocardial infarction, or hospitalization for resuscitated cardiac arrest, unstable angina, or heart failure.\n\nRESULTS:\nAmong 4,617 participants, 2,239 (48.5%) were aged \u003c65 years, 1,713 (37.1%) were aged 65 to 74 years, and 665 (14.4%) were aged ≥75 years. Baseline SAQ summary scores were lower in participants aged \u003c65 years. Fully adjusted differences in 1-year SAQ summary scores (invasive minus conservative) were 4.90 (95% CI: 3.56-6.24) at age 55 years, 3.48 (95% CI: 2.40-4.57) at age 65 years, and 2.13 (95% CI: 0.75-3.51) at age 75 years (P = 0.008). Improvement in SAQ Angina Frequency was less dependent on age (P = 0.08). There were no age differences between invasive vs conservative management on the composite clinical outcome (P = 0.29).\n\nCONCLUSIONS:\nOlder patients with chronic coronary disease and moderate or severe ischemia had consistent improvement in angina frequency but less improvement in angina-related health status with invasive management compared with younger patients. Invasive management was not associated with improved clinical outcomes in older or younger patients. (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches [ISCHEMIA]; NCT01471522)." + } +} \ No newline at end of file diff --git a/37100542.json b/37100542.json new file mode 100644 index 0000000000000000000000000000000000000000..47810908d610b3ceead37e9aeeb2aed6295f7b04 --- /dev/null +++ b/37100542.json @@ -0,0 +1,8 @@ +{ + "id": "37100542", + "label": 0, + "article": { + "id": "37100542", + "text": "BACKGROUND:\nOesophageal adenocarcinoma and adenocarcinoma of the oesophagogastric junction are among the most common malignant epithelial tumours. Most patients receive neoadjuvant therapy before complete tumour resection. Histological assessment after resection includes identification of residual tumour tissue and areas of regressive tumour, data which are used to calculate a clinically relevant regression score. We developed an artificial intelligence (AI) algorithm for tumour tissue detection and tumour regression grading in surgical specimens from patients with oesophageal adenocarcinoma or adenocarcinoma of the oesophagogastric junction.\n\nMETHODS:\nWe used one training cohort and four independent test cohorts to develop, train, and validate a deep learning tool. The material consisted of histological slides from surgically resected specimens from patients with oesophageal adenocarcinoma and adenocarcinoma of the oesophagogastric junction from three pathology institutes (two in Germany, one in Austria) and oesophageal cancer cohort of The Cancer Genome Atlas (TCGA). All slides were from neoadjuvantly treated patients except for those from the TCGA cohort, who were neoadjuvant-therapy naive. Data from training cohort and test cohort cases were extensively manually annotated for 11 tissue classes. A convolutional neural network was trained on the data using a supervised principle. First, the tool was formally validated using manually annotated test datasets. Next, tumour regression grading was assessed in a retrospective cohort of post-neoadjuvant therapy surgical specimens. The grading of the algorithm was compared with that of a group of 12 board-certified pathologists from one department. To further validate the tool, three pathologists processed whole resection cases with and without AI assistance.\n\nFINDINGS:\nOf the four test cohorts, one included 22 manually annotated histological slides (n=20 patients), one included 62 sides (n=15), one included 214 slides (n=69), and the final one included 22 manually annotated histological slides (n=22). In the independent test cohorts the AI tool had high patch-level accuracy for identifying both tumour and regression tissue. When we validated the concordance of the AI tool against analyses by a group of pathologists (n=12), agreement was 63·6% (quadratic kappa 0·749; p\u003c0·0001) at case level. The AI-based regression grading triggered true reclassification of resected tumour slides in seven cases (including six cases who had small tumour regions that were initially missed by pathologists). Use of the AI tool by three pathologists increased interobserver agreement and substantially reduced diagnostic time per case compared with working without AI assistance.\n\nINTERPRETATION:\nUse of our AI tool in the diagnostics of oesophageal adenocarcinoma resection specimens by pathologists increased diagnostic accuracy, interobserver concordance, and significantly reduced assessment time. Prospective validation of the tool is required.\n\nFUNDING:\nNorth Rhine-Westphalia state, Federal Ministry of Education and Research of Germany, and the Wilhelm Sander Foundation." + } +} \ No newline at end of file diff --git a/37100753.json b/37100753.json new file mode 100644 index 0000000000000000000000000000000000000000..d1e6c469c5237884793b09a825fad8be0fde5bf3 --- /dev/null +++ b/37100753.json @@ -0,0 +1,8 @@ +{ + "id": "37100753", + "label": 0, + "article": { + "id": "37100753", + "text": "To evaluate the efficacy of neoadjuvant chemotherapy (NACT) in the treatment of locally advanced olfactory neuroblastoma (ONB), and to explore the factors related to the efficacy of NACT. A total of 25 patients with ONB who underwent NACT in Beijing TongRen Hospital from April 2017 to July 2022 were retrospectively analyzed. There were 16 males and 9 females, with an average age of 44.9 years (ranged 26-72 years). There were 22 cases of Kadish stage C and 3 cases of stage D. After multiple disciplinary team(MDT) discussion, all patients were treated sequentially with NACT-surgery-radiotherapy. Among them, 17 cases were treated with taxol, cis-platinum and etoposide (TEP), 4 cases with taxol, nedaplatin and ifosfamide (TPI), 3 cases with TP, while 1 case with EP. SPSS 25.0 software was used for statistical analysis, and survival analyses were calculated based on the Kaplan-Meier method. The overall response rate of NACT was 32% (8/25). Subsequently, 21 patients underwent extended endoscopic surgery and 4 patients underwent combined cranial-nasal approach. Three patients with stage D disease underwent cervical lymph node dissection. All patients received postoperative radiotherapy. The mean follow-up time was 44.2 months (ranged 6-67 months). The 5-year overall survival rate was 100.0%, and the 5-year disease-free survival rates was 94.4%. Before NACT, Ki-67 index was 60% (50%, 90%), while Ki-67 index was 20% (3%, 30%) after chemotherapy [ (, )]. The change of Ki-67 before and after NACT was statistically significant (=-24.24, \u003c0.05). The effects of age, gender, history of surgery, Hyams grade, Ki-67 index and chemotherapy regimen to NACT were analyzed. Ki-67 index≥25% and high Hyams grade were related to the efficacy of NACT (all \u003c0.05). NACT could reduce Ki-67 index in ONBs. High Ki-67 index and Hyams grade are clinical indicators sensitive to the efficacy of NACT. NACT-surgery-radiotherapy is effective for patients with locally advanced ONB." + } +} \ No newline at end of file diff --git a/37100932.json b/37100932.json new file mode 100644 index 0000000000000000000000000000000000000000..a22871090bc958825cedf7953aed555975495c4b --- /dev/null +++ b/37100932.json @@ -0,0 +1,8 @@ +{ + "id": "37100932", + "label": 0, + "article": { + "id": "37100932", + "text": "Psychostimulants and alcohol are widely abused substances with the adverse effects on global public health. Substance abuse seriously harms people's health and causes various diseases, especially neurodegenerative diseases. Neurodegenerative diseases include Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). The pathogenesis of neurodegenerative diseases is complex and diverse, usually involving oxidative stress, mitochondrial dysfunction, metal homeostasis disorder, and neuro-inflammation. The precise molecular mechanisms underlying neurodegeneration remain unclear, which is a major obstacle to therapeutic approaches. Therefore, it is urgent to improve the understanding of the molecular mechanisms of neurodegenerative processes and to identify the therapeutic targets for treatment and prevention. Ferroptosis is a regulatory cell necrosis caused by iron ion catalysis and lipid peroxidation induced by reactive oxygen species (ROS), which is thought to be associated with nervous system diseases, particularly neurodegenerative diseases. This review overviewed the ferroptosis process and explored the relationship of ferroptosis with substance abuse and neurodegenerative diseases, which provides a new way to study the molecular mechanisms of neurodegenerative diseases induced by alcohol, cocaine, and methamphetamine (MA), and also provides the potential therapeutic targets for substance abuse-induced neurodegenerative diseases." + } +} \ No newline at end of file diff --git a/37100955.json b/37100955.json new file mode 100644 index 0000000000000000000000000000000000000000..ce84b4d810226c725bf2de899db5c79a7b15f734 --- /dev/null +++ b/37100955.json @@ -0,0 +1,8 @@ +{ + "id": "37100955", + "label": 0, + "article": { + "id": "37100955", + "text": "Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease." + } +} \ No newline at end of file diff --git a/37101158.json b/37101158.json new file mode 100644 index 0000000000000000000000000000000000000000..a12c371e4db0677a00b96305962cf6f081cfa9d9 --- /dev/null +++ b/37101158.json @@ -0,0 +1,8 @@ +{ + "id": "37101158", + "label": 0, + "article": { + "id": "37101158", + "text": "BACKGROUND:\nIntestinal parasitic infections are common in humans, especially among young children. These conditions are often asymptomatic and self-limiting, and diagnosis is mainly based on the search for ova and parasites in the stools since serology may be biased due to cross reactivity between parasites. Pinworm is common in children and is not usually associated with hypereosinophilia; adhesive-tape test is the gold standard testing for the microscopic detection of Enterobious vermicularis (Ev) eggs.\n\nCASE PRESENTATION:\nA 13-year-old boy was referred due to a self-resolving episode of vomiting and palpebral oedema after dinner, together with a history of chronic rhinitis, chronic cough, absolute IgA deficiency and Hashimoto's thyroiditis and hypereosinophilia (higher value = 3140/µl). On evaluation we detected only palpable thyroid and hypertrophic nasal turbinates. Food allergy was excluded, but skin prick tests showed sensitization to house dust mites and cat epithelium and spirometry showed a marked obstructive pattern with positive bronchodilation test prompting the diagnosis of asthma for which maintenance inhaled treatment was started. Chest x-ray and abdomen ultrasound were negative. Further blood testing showed positive IgG anti-Echinococcus spp. and Strongyloides stercoralis and positive IgE for Ascaris, while Ev were detected both by the adhesive tape test and stool examination, so that we made a final diagnosis of pinworm infection. Three months after adequate treatment with pyrantel pamoate the adhesive-tape test turned out negative and blood testing showed a normal eosinophil count. The child later developed also type 1 diabetes.\n\nCONCLUSIONS:\nWe suggest the need to investigate for enterobiasis in children with hypereosinophilia and to consider autoimmunity as a potential confounding factor when interpreting serology for helminths." + } +} \ No newline at end of file diff --git a/37101189.json b/37101189.json new file mode 100644 index 0000000000000000000000000000000000000000..70fe2778804b9421c539224d64646c3156a8495a --- /dev/null +++ b/37101189.json @@ -0,0 +1,8 @@ +{ + "id": "37101189", + "label": 0, + "article": { + "id": "37101189", + "text": "BACKGROUND:\nRenal cell carcinoma (RCC) survival has improved due to recent developments in RCC treatment. Therefore, other co-morbid conditions may have a more critical role. This study aims to explore the common causes of death in patients with RCC to improve the management and survival of RCC.\n\nMETHOD:\nWe used the Surveillance, Epidemiology, and End Results (SEER) (1992-2018) database to get patients with RCC. We calculated the percentage of total deaths of six kinds of the cause of death (COD) and the cumulative incidence of death for each selected cause over survival time. The joinpoint regression was utilized to present the trend of mortality rate by COD.\n\nRESULTS:\nWe enrolled 107,683 cases with RCC. RCC was the leading cause of death in patients with RCC [25376(48.3%)], followed by cardiovascular diseases [9023(17.2%)], other cancers [8003 (15.2%)], other non-cancer diseases [4195 (8%)], non-disease cause [4023 (7.7%)], and respiratory diseases [1934 (3.6%)]. The proportion of patients who died of RCC decreased gradually over survival time, and this value decreased from 69.71% in 1992-1996 to 38.96% in 2012-2018. The non-RCC cause mortality rate showed an increasing trend, whereas a slight decrease was observed in RCC specific mortality rate. The distribution of such conditions varied across different patient populations.\n\nCONCLUSION:\nRCC was still the primary COD of patients with RCC. However, non-RCC cause death was increasingly important among RCC patients in recent two decades. Cardiovascular disease and other cancers were crucial co-morbidities that required significant attention in the management of RCC patients." + } +} \ No newline at end of file diff --git a/37101551.json b/37101551.json new file mode 100644 index 0000000000000000000000000000000000000000..118c936417f98b65c93a3f1901909ce5b9c45fb3 --- /dev/null +++ b/37101551.json @@ -0,0 +1,8 @@ +{ + "id": "37101551", + "label": 0, + "article": { + "id": "37101551", + "text": "Chronic myeloid leukemia (CML) accounts for 2-3% of childhood leukemias. About 5% of cases present in a blastic phase of CML which clinically and morphologically mimics more common acute leukemias of childhood. We report a case of a 3-year-old male who presented with gradual onset swelling of the abdomen and extremities along with generalized weakness. Examination revealed massive splenomegaly, pallor, and pedal edema. Initial workup showed anemia, thrombocytopenia, and leukocytosis (120,000/uL) with a blast percentage of 35%. Blasts were positive for CD13, CD33, CD117, CD34 and HLA-DR, and stained negative for Myeloperoxidase and Periodic Acid Schiff. Fluorescence in situ hybridization was positive for b3a2/e14a2 junction BCR-ABL1 transcript and negative for RUNX1-RUNX1T1/t(8;21), clinching the diagnosis of CML in myeloid blast crisis. The patient expired within 17 days of diagnosis and initiation of therapy." + } +} \ No newline at end of file diff --git a/37101724.json b/37101724.json new file mode 100644 index 0000000000000000000000000000000000000000..1f22d0cbff8a8e7eb754ab0f92f83141979cf0e5 --- /dev/null +++ b/37101724.json @@ -0,0 +1,8 @@ +{ + "id": "37101724", + "label": 0, + "article": { + "id": "37101724", + "text": "Cell-based assays covering environmentally relevant modes of action are widely used for water quality monitoring. However, no high-throughput assays are available for testing developmental neurotoxicity of water samples. We implemented an assay that quantifies neurite outgrowth, which is one of the neurodevelopmental key events, and cell viability in human neuroblastoma SH-SY5Y cells using imaging techniques. We used this assay for testing of extracts of surface water collected in agricultural areas during rain events and effluents from wastewater treatment plants (WWTPs), where more than 200 chemicals had been quantified. Forty-one chemicals were tested individually that were suspected to contribute to the mixture effects among the detected chemicals in environmental samples. Sample sensitivity distributions indicated higher neurotoxicity for surface water samples than for effluents, and the endpoint of neurite outgrowth inhibition was six times more sensitive than cytotoxicity in the surface water samples and only three times more sensitive in the effluent samples. Eight environmental pollutants showed high specificity, and those ranged from pharmaceuticals (mebendazole and verapamil) to pesticides (methiocarb and clomazone), biocides (1,2-benzisothiazolin-3-one), and industrial chemicals (-methyl-2-pyrrolidone, 7-diethylamino-4-methylcoumarin, and 2-(4-morpholinyl)benzothiazole). Although neurotoxic effects were newly detected for some of our test chemicals, less than 1% of the measured effects were explained by the detected and toxicologically characterized chemicals. The neurotoxicity assay was benchmarked against other bioassays: activations of the aryl hydrocarbon receptor and the peroxisome proliferator-activated receptor were similar in sensitivity, highly sensitive and did not differ much between the two water types, with surface water having slightly higher effects than the WWTP effluent. Oxidative stress response mirrored neurotoxicity quite well but was caused by different chemicals in the two water types. Overall, the new cell-based neurotoxicity assay is a valuable complement to the existing battery of effect-based monitoring tools." + } +} \ No newline at end of file diff --git a/37102017.json b/37102017.json new file mode 100644 index 0000000000000000000000000000000000000000..e2a40893ff4d3b792fcdc8a0c32a7bf7ad359691 --- /dev/null +++ b/37102017.json @@ -0,0 +1,8 @@ +{ + "id": "37102017", + "label": 0, + "article": { + "id": "37102017", + "text": "Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults. It is an aggressive malignancy and requires a multidisciplinary approach with various modalities which include chemotherapy, radiotherapy as well as immunotherapy. A 63-year-old Malay male patient with underlying type 2 diabetes mellitus, hypertension, ischemic heart disease, and stage II chronic kidney disease presented with a one-month history of bilateral eye proptosis associated with lid swelling and red eye. He also complained of progressive right eye blurring of vision. Visual acuity was counting fingers on the right and 6/18 on the left. On examination, the relative afferent pupillary defect was negative. There was bilateral eye proptosis, conjunctival chemosis, and restricted extra-ocular movement in all gazes. There was also exposure keratopathy over the right eye, and intraocular pressure was raised. Bilateral cervical and axillary lymph nodes were palpable. A computerized tomography scan of the brain and orbit revealed bilateral orbital masses with no bony erosions. An incisional biopsy over the upper lid confirmed the diagnosis of diffuse large B-cell lymphoma with multiple myeloma-1 (MUM-1) positivity which defines the activated B-cell subtype (ABC). He was co-managed with a hematologist and was commenced on the rituximab-cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) chemotherapy regime. Bilateral eye proptosis, chemosis, and restriction of extra-ocular movement resolved after the completion of treatment. However, right eye vision remains poor as the patient developed central self-sealed corneal perforation with iris plugging which has healed with scarring. Diffuse large B-cell orbital lymphoma is a fast-growing and aggressive tumor, hence early diagnosis and prompt multi-disciplinary treatment are crucial for a good outcome." + } +} \ No newline at end of file diff --git a/37102222.json b/37102222.json new file mode 100644 index 0000000000000000000000000000000000000000..53a2b0a11a734f6073c3f5a5d6b20dde586938f6 --- /dev/null +++ b/37102222.json @@ -0,0 +1,8 @@ +{ + "id": "37102222", + "label": 0, + "article": { + "id": "37102222", + "text": "BACKGROUND:\nThe recently developed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine has a short history of use and further information is needed regarding its efficacy, especially in immunocompromised conditions, such as plasma cell dyscrasia (PCD).\n\nMETHODS:\nWe retrospectively measured serum SARS-CoV-2 antibodies against the spike protein (S-IgG) after the second and third mRNA vaccine doses (doses 2 and 3, respectively) in 109 patients with PCD. We evaluated the proportion of patients with an adequate humoral response (defined as S-IgG titers ≥300 antibody units/mL).\n\nRESULTS:\nAlthough active anti-myeloma treatments prior to vaccination had a significantly negative impact on adequate humoral response, specific drug subclasses including immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies were not negatively associated, except for B-cell maturation antigen-targeted therapy. Dose 3 (booster vaccination) led to significantly higher S-IgG titers and more patients acquired an adequate humoral response. Furthermore, evaluation of vaccine-induced cellular immune response in patients using T-spot Discovery SARS-CoV-2 kit, revealed an enhanced cellular immune response after Dose 3.\n\nCONCLUSIONS:\nThis study highlighted the significance of booster SARS-CoV-2 mRNA vaccination in patients with PCD with respect to humoral and cellular immunity. Moreover, this study highlighted the potential impact of certain drug subclasses on vaccine-induced humoral immune response." + } +} \ No newline at end of file diff --git a/37102302.json b/37102302.json new file mode 100644 index 0000000000000000000000000000000000000000..5dff5c74727ed964b4af3b92f24dd4af110c25d1 --- /dev/null +++ b/37102302.json @@ -0,0 +1,8 @@ +{ + "id": "37102302", + "label": 0, + "article": { + "id": "37102302", + "text": "Pediatric acute myeloid leukemia (AML) is a poor prognostic subtype of pediatric leukemia. However, the detailed characteristics of many genetic abnormalities are yet to be established in this disease. Although TP53 and RB1 are established as representative tumor suppressor genes in various cancers, alterations of these two genes, especially RB1, have not been characterized in pediatric AML. We performed next-generation sequencing in 328 pediatric AML patients from the Japanese AML-05 trial to ascertain TP53 and RB1 alterations, and their prognostic implications. We identified seven patients with TP53 alterations (2.1%) and six patients with RB1 alterations (1.8%). These alterations were found in only patients without RUNX1::RUNX1T1, CBFB::MYH11, or KMT2A rearrangements. TP53 and RB1 were frequently co-deleted with their neighboring genes PRPF8 and ELF1, respectively. Patients with TP53 alterations had significantly lower 5-year overall survival (OS; 14.3% vs. 71.4%, p \u003c 0.001) and lower 5-year event-free survival (EFS; 0% vs. 56.3%, p \u003c 0.001); similarly, patients with RB1 had significantly lower 5-year OS (0% vs. 71.8%, p \u003c 0.001) and lower 5-year EFS (0% vs. 56.0%, p \u003c 0.001) when compared to patients without these alterations. In gene expression analyses, oxidative phosphorylation, glycolysis, and protein secretion were upregulated in patients with TP53 and/or RB1 alterations. Additionally, Kaplan-Meier analysis revealed that high expressions of SLC2A5, KCNAB2, and CD300LF were related to poor OS of non-core-binding factor AML patients (p \u003c 0.001, p = 0.001, and p = 0.021, respectively). This study will contribute to the development of risk-stratified therapy and precision medicine in pediatric AML." + } +} \ No newline at end of file diff --git a/37102648.json b/37102648.json new file mode 100644 index 0000000000000000000000000000000000000000..8300ad3c9fcb1db7dab091d2f61250854d2fbfef --- /dev/null +++ b/37102648.json @@ -0,0 +1,8 @@ +{ + "id": "37102648", + "label": 0, + "article": { + "id": "37102648", + "text": "Toll-like receptors (TLRs) are a family of pattern-recognition receptors triggered by pathogen-derived and tissue-damage-related ligands. TLRs were previously believed to only be expressed in immune cells. However, it is now confirmed that they are ubiquitously expressed in cells within the body including neurons, astrocytes, and microglia of the central nervous system (CNS). Activation of TLRs is capable of inducing immunologic and inflammatory responses to injury or infection of CNS. This response is self-limiting that usually resolves once the infection has been eradicated or the tissue damage has been repaired. However, the persistence of inflammation-inducing insults or a failure in normal resolution mechanisms may result in overwhelming inflammation which may induce neurodegeneration. This implies that TLRs may play a role in mediating the link between inflammation and neurodegenerative diseases namely Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, and amyotrophic lateral sclerosis. So, new therapeutic approaches that specifically target TLRs may be developed by better understanding TLR expression mechanisms in the CNS and their connections to particular neurodegenerative disorders. Therefore, this review paper discussed the role of TLRs in neurodegenerative diseases." + } +} \ No newline at end of file diff --git a/37102707.json b/37102707.json new file mode 100644 index 0000000000000000000000000000000000000000..7ba38789621901cca5d050c70ee647aac103b7dd --- /dev/null +++ b/37102707.json @@ -0,0 +1,8 @@ +{ + "id": "37102707", + "label": 0, + "article": { + "id": "37102707", + "text": "OBJECTIVES:\nTo identify variables predicting inter fractional anatomical variationsmeasured with cone-beam CT (CBCT) throughout abdominal paediatric radiotherapy, and to assess the potential of surface-guided radiotherapy (SGRT) to monitor these changes.\n\nMETHODS:\nMetrics of variation in gastrointestinal (GI) gas volume andseparation of the body contour and abdominal wallwere calculated from 21 planning CTs and 77 weekly CBCTs for 21 abdominal neuroblastoma patients (median 4y, range: 2 -19y). Age, sex, feeding tubes, and general anaesthesia (GA) were explored as predictive variables for anatomical variation. Furthermore,GI gas variationwas correlated with changes in body and abdominal wall separation, as well as simulated SGRT metrics of translational and rotationalcorrections between CT/CBCT.\n\nRESULTS:\nGI gas volumes varied 74 ± 54 ml across all scans, while body and abdominal wall separationvaried 2.0 ± 0.7 mm and4.1±1.5mmfrom planning, respectively. Patients \u003c 3.5y ( = 0.04) and treated under GA ( \u003c 0.01) experienced greater GI gas variation; GA was the strongest predictor in multivariate analysis ( \u003c 0.01). Absence of feeding tubes was linked to greater body contour variation ( = 0.03). GI gas variation correlated with body ( = 0.53) and abdominal wall ( = 0.63) changes. The strongest correlations with SGRT metrics were found for anteroposterior translation ( = 0.65) androtation of the left-right axis ( = -0.36).\n\nCONCLUSIONS:\nYoung age, GA, and absence of feeding tubes were linked to stronger inter fractional anatomical variation and are likely indicative of patients benefiting from adaptive/robust planning pathways.Our data suggests a role for SGRT toinformthe need for CBCT at each treatment fractionin this patient group.\n\nADVANCES IN KNOWLEDGE:\nThis is the first study to suggest the potential role of SGRT for the management of internal inter fractional anatomical variation in paediatric abdominal radiotherapy." + } +} \ No newline at end of file diff --git a/37102951.json b/37102951.json new file mode 100644 index 0000000000000000000000000000000000000000..ac353ea3fd0b4aab8b7dbc6f56660195665ca98f --- /dev/null +++ b/37102951.json @@ -0,0 +1,8 @@ +{ + "id": "37102951", + "label": 0, + "article": { + "id": "37102951", + "text": ": Pre-surgical simulation-based training with three-dimensional (3D) models has been intensively developed in complex surgeries in recent years. This is also the case in liver surgery, although with fewer reported examples. The simulation-based training with 3D models represents an alternative to current surgical simulation methods based on animal or ex vivo models or virtual reality (VR), showing reported advantages, which makes the development of realistic 3D-printed models an option. This work presents an innovative, low-cost approach for producing patient-specific 3D anatomical models for hands-on simulation and training. : The article reports three paediatric cases presenting complex liver tumours that were transferred to a major paediatric referral centre for treatment: hepatoblastoma, hepatic hamartoma and biliary tract rhabdomyosarcoma. The complete process of the additively manufactured liver tumour simulators is described, and the different steps for the correct development of each case are explained: (1) medical image acquisition; (2) segmentation; (3) 3D printing; (4) quality control/validation; and (5) cost. A digital workflow for liver cancer surgical planning is proposed. : Three hepatic surgeries were planned, with 3D simulators built using 3D printing and silicone moulding techniques. The 3D physical models showed highly accurate replications of the actual condition. Additionally, they proved to be more cost-effective in comparison with other models. : It is demonstrated that it is possible to manufacture accurate and cost-effective 3D-printed soft surgical planning simulators for treating liver cancer. The 3D models allowed for proper pre-surgical planning and simulation training in the three cases reported, making it a valuable aid for surgeons." + } +} \ No newline at end of file diff --git a/37103086.json b/37103086.json new file mode 100644 index 0000000000000000000000000000000000000000..676b0fb3014307dde9e392f8e9a38f0c8327c3a8 --- /dev/null +++ b/37103086.json @@ -0,0 +1,8 @@ +{ + "id": "37103086", + "label": 0, + "article": { + "id": "37103086", + "text": "BACKGROUND/AIM:\nLacrimal sac tumors are rare tumor types, with a long time interval from disease onset to diagnosis. We aimed to investigate the characteristics and outcomes of patients with lacrimal sac tumors.\n\nPATIENTS AND METHODS:\nThe medical records of 25 patients with lacrimal sac tumors initially treated at the Kyushu university hospital from January 1996 to July 2020 were reviewed.\n\nRESULTS:\nOur analysis included 3 epithelial benign tumors (12.0%) and 22 malignant (88.0%) tumors (squamous cell carcinoma, n=6; adenoid cystic carcinoma, n=2; sebaceous adenocarcinoma, n=2; mucoepidermoid carcinoma, n=1; malignant lymphoma, n=10). The average time from symptom onset to diagnosis was 14.7 months (median=8 months; range=1-96 months). The analysis of patients revealed that lacrimal sac mass (22/25, 88.0%) was the most frequent symptom and a possible tumor marker. Most epithelial benign (n=3) and malignant epithelial (n=12) tumors were treated surgically (14/15, 93.3%). One malignant case was treated with heavy ion beam therapy. Eight patients were treated with postoperative (chemo)radiation therapy because of positive surgical margins (including one unanalyzed case). Local control was ultimately achieved in all but one case. The patient survived for 24 months with immune checkpoint inhibitors and subsequent chemotherapy for local and metastatic recurrence.\n\nCONCLUSION:\nWe report our experience in the diagnosis and treatment of lacrimal sac tumors and analyze the clinical trends in cases involving these tumors. Postoperative radiotherapy and pharmacotherapy, including immune checkpoint inhibitors, may be useful for recurrent cases." + } +} \ No newline at end of file diff --git a/37103089.json b/37103089.json new file mode 100644 index 0000000000000000000000000000000000000000..f3b468bb2d204d622a20aae16e0aa8a38d858fc7 --- /dev/null +++ b/37103089.json @@ -0,0 +1,8 @@ +{ + "id": "37103089", + "label": 0, + "article": { + "id": "37103089", + "text": "BACKGROUND/AIM:\nLenalidomide (LND) is an oral antineoplastic agent used in the treatment of various malignant hematologic diseases, including multiple myeloma. Major adverse events of LND include myelosuppression, pneumonia, and thromboembolism. Thromboembolism is an adverse drug reaction (ADR) associated with poor outcomes, therefore anticoagulants are administered prophylactically. However, LND-induced thromboembolism has not been clearly characterized from clinical trials. The purpose of this study was to evaluate the incidence, timing, and outcome details of thromboembolism caused by LND using the JADER (Japanese Adverse Drug Event Report) database.\n\nPATIENTS AND METHODS:\nADRs due to LND reported from April 2004 to March 2021 were selected. Data on thromboembolic adverse events were analyzed and relative risks were estimated using reported odds ratios (RORs) and 95% confidence intervals (CIs). In addition, the time of onset and outcome of thromboembolism were analyzed.\n\nRESULTS:\nThere were 11,681 adverse events attributed to LND. Of these, 306 were thromboembolisms. The most frequently reported thrombosis with the highest ROR was deep vein thrombosis (DVT) (165 cases, ROR=7.12, 95%CI=6.09-8.33). The median onset of DVT (quartiles, 25-75%) was 80 (28-155) days. The parameter value (β) was 0.87 (0.76-0.99), suggesting the onset of DVT early in treatment. The prognosis of DVT due to LND was recovery and remission in 34% and 43% of patients, respectively, but 7.9% did not recover.\n\nCONCLUSION:\nDVT is the most frequent thromboembolism in LND, and early treatment is important." + } +} \ No newline at end of file diff --git a/37103104.json b/37103104.json new file mode 100644 index 0000000000000000000000000000000000000000..323dd2a089271fb4db4df103c8e9970a02bf8fc0 --- /dev/null +++ b/37103104.json @@ -0,0 +1,8 @@ +{ + "id": "37103104", + "label": 0, + "article": { + "id": "37103104", + "text": "BACKGROUND/AIM:\nWe aimed to describe the impact of preoperative sarcopenia on the oncological outcome of non-metastatic renal cell carcinoma (RCC) after surgical treatment.\n\nPATIENTS AND METHODS:\nData on 299 Japanese patients with non-metastatic RCC who underwent radical treatment at Kanazawa University Hospital between October 2007 and December 2018 were extracted. Clinicopathological features and survival prognosis of patients stratified by the presence or absence of sarcopenia as indicated by the psoas muscle mass index (PMI) were retrospectively analyzed. PMI \u003c516.8 and \u003c235.1 mm/m at the L3 level for male and female were defined as the cutoff values for sarcopenia, respectively.\n\nRESULTS:\nOf 299 patients, 113 (37.8%) were classified as sarcopenic. The sarcopenia group showed a larger tumor size, worse pathological tumor stage and histological grade, and more frequent lymphovascular invasion than the non-sarcopenia group. According to Kaplan-Meier curves, sarcopenia was associated with a shorter overall survival (OS) and metastasis-free survival (p=0.0174 and 0.0306, respectively). Multivariate analysis identified sarcopenia as a significant and independent prognostic factor for poor OS (hazard ratio, 2.58; 95% confidence interval=1.09-6.08; p=0.030).\n\nCONCLUSION:\nSarcopenia is a significant factor indicating worse pathological outcomes and poor survival prognosis in surgically treated non-metastatic RCC." + } +} \ No newline at end of file diff --git a/37103106.json b/37103106.json new file mode 100644 index 0000000000000000000000000000000000000000..294f874dd6e2eef506ae28610d5e2d0a4f49ae55 --- /dev/null +++ b/37103106.json @@ -0,0 +1,8 @@ +{ + "id": "37103106", + "label": 0, + "article": { + "id": "37103106", + "text": "BACKGROUND/AIM:\nMucinous tubular and spindle cell carcinoma (MTSCC) of the kidney is a rare histological type of renal cell carcinoma (RCC). There are few reports of MTSCC occurring in renal transplant recipients (RTRs). The aim of this study was to report a case of long-term survival of a RTR with metastatic MTSCC of the kidney with sarcomatoid changes.\n\nCASE REPORT:\nA 53-year-old male with a left retroperitoneal tumor was referred to our department. He had been receiving hemodialysis since 1991 and underwent kidney transplantation in 2015. Computed tomography (CT) revealed suspected RCC, and a radical nephrectomy was performed in June 2020. Pathological findings revealed MTSCC with sarcomatoid changes. After the surgery, multiple metastases appeared in the bilateral adrenals, skin, para-aortic lymph nodes, muscles, mesocolon, and liver. We treated the patient with metastasectomy, radiation therapy, and sequential systemic therapy with tyrosine kinase inhibitors (TKI). Two years after the initial surgery, the patient died of cancer while controlling its progression.\n\nCONCLUSION:\nWe report a RTR with aggressive and metastatic MTSCC with sarcomatoid changes, resulting in a longer survival time relative to multimodal therapy." + } +} \ No newline at end of file diff --git a/37103111.json b/37103111.json new file mode 100644 index 0000000000000000000000000000000000000000..e0c66c9b706674ea4625d4b83bcdfea3232043b2 --- /dev/null +++ b/37103111.json @@ -0,0 +1,8 @@ +{ + "id": "37103111", + "label": 0, + "article": { + "id": "37103111", + "text": "BACKGROUND/AIM:\nRadiotherapy is a salvage therapy type for postoperative recurrence of esophageal cancer. Compared to conventional photon-based radiotherapy, proton beam therapy can reduce the irradiated dose to the surrounding organs, facilitating the management of patients who are unfit for radiotherapy. In this study, the outcomes and toxicity of proton beam therapy for postoperative lymph node oligorecurrence of esophageal cancer were investigated.\n\nPATIENTS AND METHODS:\nWe retrospectively evaluated the clinical outcomes and toxicity of 13 sites in 11 patients treated with proton beam therapy for postoperative lymph node oligorecurrence of esophageal cancer. In total, eight men and three women with a median age of 68 years (range=46-83 years) were included.\n\nRESULTS:\nThe median follow-up period was 20.2 months. During the follow-up period, four patients died of esophageal cancer. Eight of the 11 patients developed recurrence; of these, seven patients had recurrence outside the irradiated field, and one had recurrence inside and outside the irradiated field. The 2-year overall survival, progression-free survival, and local control rates were 48.0%, 27.3%, and 84.6%, respectively. The median survival time was 22.4 months. There were no severe acute or late adverse events.\n\nCONCLUSION:\nProton beam therapy could be a safe and effective treatment method for postoperative lymph node oligorecurrence of esophageal cancer. It may be beneficial even in cases where conventional photon-based radiotherapy is difficult to administer in combination with increased doses or with chemotherapy." + } +} \ No newline at end of file diff --git a/37103532.json b/37103532.json new file mode 100644 index 0000000000000000000000000000000000000000..3ec1dbb7d92fa174fdf66b8a8ef88c1f7a5a25f1 --- /dev/null +++ b/37103532.json @@ -0,0 +1,8 @@ +{ + "id": "37103532", + "label": 0, + "article": { + "id": "37103532", + "text": "Uterine leiomyomas are common hormone-responsive neoplasms that frequently cause heavy menstrual bleeding, anemia, pelvic pressure, pain, and adverse reproductive outcomes. In this overview, the efficacy and safety of oral gonadotropin-releasing hormone (GnRH) antagonists, co-administered with menopausal replacement-level steroid hormones or used at doses to avoid complete hypothalamic suppression, are reviewed for the management of uterine leiomyomas. Oral GnRH antagonists provide rapid suppression of sex steroids and avoid the initial steroidal flare and resultant temporary worsening of symptoms typically seen with parenteral GnRH agonists. Oral GnRH antagonists are effective in reducing leiomyoma-associated heavy menstrual bleeding, with high rates of amenorrhea and improved anemia and leiomyoma-associated pain, and providing modest reduction in uterine volume when used in combination with menopausal replacement-level steroid hormones. This add-back therapy can reduce hypogonadal side effects, including hot flushes and bone mineral density loss, close to levels seen with placebo therapy. Currently, both elagolix 300 mg twice daily with once-daily estradiol (1 mg) and norethindrone (0.5 mg) and relugolix 40 mg once daily with estradiol (1 mg) and norethindrone (0.5 mg) combination therapy are approved for leiomyoma treatment by the U.S. Food and Drug Administration. Linzagolix is under investigation in the United States but approved at two does with and without steroid hormones in the European Union. The efficacy of these agents appears to be robust over a wide spectrum of clinical presentations, demonstrating that worse disease parameters at baseline do not appear to inhibit efficacy. Across clinical trials, participants largely reflected the population of individuals affected by uterine leiomyomas." + } +} \ No newline at end of file diff --git a/37103551.json b/37103551.json new file mode 100644 index 0000000000000000000000000000000000000000..aa52ee823122f2c3819c82fef621f32dddfb293b --- /dev/null +++ b/37103551.json @@ -0,0 +1,8 @@ +{ + "id": "37103551", + "label": 0, + "article": { + "id": "37103551", + "text": "INTRODUCTION:\nMultidisciplinary tumor board (MDTB) meetings are useful sources of insight and collaboration when establishing treatment approaches for oncologic cases. However, such meetings can be time intensive and inconvenient. We implemented a Virtual Tumor Board (VTB) within Michigan Urological Surgery Improvement Collaborative (MUSIC) to discuss and improve the management of complicated renal masses (RMs).\n\nMETHODS:\nUrologists were invited to discuss decision-making for RMs through voluntary engagement. Communication was performed exclusively through email. Case details were collected and responses were tabulated. All participants were surveyed about their perceptions of the VTB.\n\nRESULTS:\n50 RM cases were reviewed in a VTB that included 53 urologists. Patients ranged from 20-90 years old and 94% had localized RM. The cases generated 355 messages, ranging from 2-16 (median 7) per case; 144 responses (40.6%) were sent via smart-phone. All urologists (100%) who submitted to the VTB had their questions answered. The VTB provided suggestions to those with no stated treatment plan in 42% of cases, confirmed the physician's initial approach to their case in 36%, and offered alternative approaches in 16% of cases. 83% of survey respondents felt the experience was \"Beneficial\" or \"Very Beneficial\" and 93% stated increased confidence in their case management.\n\nCONCLUSIONS:\nMUSIC's initial experience with a VTB showed good engagement. The format reduced barriers to multi-institutional and multi-disciplinary discussions and improved the quality of care for selected patients with complex RMs." + } +} \ No newline at end of file diff --git a/37104058.json b/37104058.json new file mode 100644 index 0000000000000000000000000000000000000000..612bcdaa4a5f76b25c677b82a2cb604a06361c4d --- /dev/null +++ b/37104058.json @@ -0,0 +1,8 @@ +{ + "id": "37104058", + "label": 0, + "article": { + "id": "37104058", + "text": "Although venetoclax-based lower-intensity regimens have greatly improved outcomes for older adults with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy, the optimal induction for older patients with newly diagnosed AML who are suitable candidates for hematopoietic stem cell transplant (HSCT) is controversial. We retrospectively analyzed post-HSCT outcomes of 127 patients ≥60 years of age who received induction therapy at our institution with intensive chemotherapy (IC, n=44), lower-intensity therapy (LIT) without venetoclax (n=29) or LIT with venetoclax (n=54) and who underwent allogeneic HSCT in first remission. The 2-year relapse-free survival with LIT with venetoclax was 60%, versus 54% with IC and 41% with LIT without venetoclax, and 2-year overall survival for LIT with venetoclax was 72%, versus 58% with IC and 41% with LIT without venetoclax. The benefit to LIT with venetoclax induction was greatest in patients with adverse-risk AML (2-year OS 74%, 46%, and 29%, respectively). Induction with LIT, with or without venetoclax, was associated with the lowest rate of non-relapse mortality (NRM) (2-year NRM 17% versus 27% with IC; P=0.04). By multivariate analysis, type of induction therapy did not significantly impact any of the post-HSCT outcomes evaluated; hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was the only factor that independently predicted for RFS and OS. LIT plus venetoclax followed by HSCT is feasible treatment strategy in older, fit, and HSCT-eligible patients with newly diagnosed AML and may be particularly beneficial in those with adverse-risk disease." + } +} \ No newline at end of file diff --git a/37104170.json b/37104170.json new file mode 100644 index 0000000000000000000000000000000000000000..1a4325894f527e737d60d6e6b17a4bf176387b7c --- /dev/null +++ b/37104170.json @@ -0,0 +1,8 @@ +{ + "id": "37104170", + "label": 0, + "article": { + "id": "37104170", + "text": "Prion diseases, also known as transmissible spongiform encephalopathies, are rare, progressive, and fatal neurodegenerative disorders, which are caused by the accumulation of the misfolded cellular prion protein (PrPC). The resulting cytotoxic prion species, referred to as the scrapie prion isoform (PrPSc), assemble in aggregates and interfere with neuronal pathways, ultimately rendering neurons dysfunctional. As the prion protein physiologically interacts with redox-active metals, an altered redox balance within the cell can impact these interactions, which may lead to and facilitate further misfolding and aggregation. The initiation of misfolding and the aggregation processes will, in turn, induce microglial activation and neuroinflammation, which leads to an imbalance in cellular redox homeostasis and enhanced redox stress. Potential approaches for therapeutics target redox signalling, and this review illustrates the pathways involved in the above processes." + } +} \ No newline at end of file diff --git a/37104478.json b/37104478.json new file mode 100644 index 0000000000000000000000000000000000000000..5be923107a728344f104df5108c9896a24f107f1 --- /dev/null +++ b/37104478.json @@ -0,0 +1,8 @@ +{ + "id": "37104478", + "label": 0, + "article": { + "id": "37104478", + "text": "Alzheimer's disease (AD) is a neurodegenerative disorder considered as a global public health threat influencing many people. Despite the concerning rise in the affected population, there is still a shortage of potent and safe therapeutic agents. The aim of this research is to discover novel natural source molecules with high therapeutic effects, stability and less toxicity for the treatment of AD, specifically targeting acetylcholinesterase (AChE). This research can be divided into two steps: in silico search for molecules by systematic simulations and in vitro experimental validations. We identified five leading compounds, namely Queuine, Etoperidone, Thiamine, Ademetionine and Tetrahydrofolic acid by screening natural molecule database, conducting molecular docking and druggability evaluations. Stability of the complexes were investigated by Molecular Dynamics simulations and free energy calculations were conducted by Molecular Mechanics Generalized Born Surface Area method. All five complexes were stable within the binding catalytic site (CAS) of AChE, with the exception of Queuine which remains stable on the peripheral site (PAS). On the other hand Etoperidone both interacts with CAS and PAS sites showing dual binding properties. Binding free energy values of Queuine and Etoperidone were -71.9 and -91.0 kcal/mol respectively, being comparable to control molecules Galantamine (-71.3 kcal/mol) and Donepezil (-80.9 kcal/mol). Computational results were validated through in vitro experiments using the SH-SY5Y(neuroblastoma) cell line with Real Time Cell Analysis (RTCA) and cell viability assays. The results showed that the selected doses were effective with half inhibitory concentrations estimated to be: Queuine (IC50 = 70,90 μM), Etoperidone (IC50 = 712,80 μM), Thiamine (IC50 = 18780,34 μM), Galantamine (IC50 = 556,01 μM) and Donepezil (IC50 = 222,23 μM), respectively. The promising results for these molecules suggest the development of the next step in vivo animal testing and provide hope for natural therapeutic aids in the treatment of AD." + } +} \ No newline at end of file diff --git a/37104672.json b/37104672.json new file mode 100644 index 0000000000000000000000000000000000000000..68ea53c5527538497ee171ba638b000186dc8586 --- /dev/null +++ b/37104672.json @@ -0,0 +1,8 @@ +{ + "id": "37104672", + "label": 0, + "article": { + "id": "37104672", + "text": "BACKGROUND:\nSex hormones may influence the development of gastrointestinal cancer, but evidence is inconsistent.\n\nMETHODS:\nWe systematically searched MEDLINE and Embase databases to identify prospective studies examining associations between prediagnostic circulating levels of sex hormones and risk of five gastrointestinal cancers: esophageal, gastric, liver, pancreatic, and colorectal cancer. Pooled odds ratios (ORs) and 95% confidence intervals (95%CIs) were calculated using random-effects models.\n\nRESULTS:\nAmong 16,879 identified studies, 29 were included (11 cohort, 15 nested case-control, and 3 case-cohort studies). Comparing the highest versus lowest tertiles, levels of most sex hormones were not associated with the studied tumors. Higher levels of sex hormone-binding globulin (SHBG) were associated with increased risk of gastric cancer (OR=1.35; 95%CI, 1.06-1.72), but such associations were restricted in men only (OR=1.43; 95%CI, 1.10-1.85) when stratified by sex. Higher SHBG levels were associated with increased risk of liver cancer (OR=2.07; 95%CI, 1.40-3.06). Higher testosterone levels were associated with increased risk of liver cancer overall (OR=2.10; 95%CI, 1.48-2.96), particularly in men (OR=2.63; 95%CI, 1.65-4.18), Asian populations (OR=3.27; 95%CI, 1.57-6.83) and in hepatitis B surface antigen-positive individuals (OR=3.90; 95%CI, 1.43-10.64). Higher levels of SHBG and testosterone were associated with decreased risk of colorectal cancer in men (OR=0.89; 95%CI, 0.80-0.98 and OR=0.88; 95%CI, 0.80-0.97, respectively) but not in women.\n\nCONCLUSIONS:\nCirculating levels of sex hormone-binding globulin and testosterone may influence the risk of gastric, liver, and colorectal cancer.\n\nIMPACT:\nFurther clarifying the role of sex hormones in the development of gastrointestinal cancer may unravel future novel targets for prevention and treatment." + } +} \ No newline at end of file diff --git a/37104677.json b/37104677.json new file mode 100644 index 0000000000000000000000000000000000000000..b66e76dd7bf7d29b00c26c7a01b0cac2a0b7cc8e --- /dev/null +++ b/37104677.json @@ -0,0 +1,8 @@ +{ + "id": "37104677", + "label": 0, + "article": { + "id": "37104677", + "text": "OBJECTIVES:\nTo determine the impact of pretransplant measurable residual disease (pre-MRD) and the efficacy of maintenance therapy in t(8;21) acute myeloid leukemia (AML) patients after allogeneic hematopoietic cell transplantation (allo-HCT).\n\nMETHODS:\nWe retrospectively analyzed 100 t(8;21) AML patients who underwent allo-HCT between 2013 and 2022. 40 patients received pre-emptive therapy including immunosuppressant adjustment, azacitidine, and donor lymphocyte infusion (DLI) combined with chemotherapy. 23 patients received prophylactic therapy, including azacitidine or chidamide.\n\nRESULTS:\nPatients with a positive pre-MRD (pre-MRDpos) had a higher 3-year cumulative incidence of relapse (CIR) (25.90% [95% CI, 13.87%-39.70%] vs 5.00% [95% CI, 0.88%-15.01%]; = 0.008). Pre-MRDpos patients were less likely to have a superior 3-year disease-free survival (DFS) (40.83% [95% CI, 20.80%-80.16%]) if their MRD was still positive at 28 days after transplantation (post-MRDpos). The 3-year DFS and CIR were 53.17% (95% CI, 38.31% - 73.80%) and 34.87% (95% CI, 18.84% - 51.44%), respectively, for patients receiving pre-emptive interventions after molecular relapse. The 3-year DFS and CIR were 90.00% (95%CI, 77.77% - 100%) and 5.00% (95%CI, 0.31% - 21.10%), respectively, for high-risk patients receiving prophylactic therapy. In most patients, epigenetic-drug-induced adverse events were reversible with dose adjustment or temporary discontinuation.\n\nCONCLUSION:\nPatients with pre-MRDpos and post-MRDpos were more likely to have higher rates of relapse and inferior DFS, even after receiving pre-emptive interventions. Prophylactic therapy may be a better option for high-risk t(8;21) AML patients; however, this warrants further investigation." + } +} \ No newline at end of file diff --git a/37104757.json b/37104757.json new file mode 100644 index 0000000000000000000000000000000000000000..cf41869d75aec9c4d1404ca07b6e8f7da40b4768 --- /dev/null +++ b/37104757.json @@ -0,0 +1,8 @@ +{ + "id": "37104757", + "label": 0, + "article": { + "id": "37104757", + "text": "The treatment of patients with relapsed and refractory multiple myeloma has become increasingly complex due to the rising number of available therapies. Patients are also increasingly exposed to, and refractory to, multiple classes of therapy at the time of progression. Patients who are at an early point in their myeloma disease course are likely to have several effective options, but choices and prognosis are limited for relapsing patients who are more heavily pretreated, particularly if they are at least triple-class refractory. When selecting the next line of therapy, it remains essential to consider patient comorbidities and frailty as well as treatment history and disease risk. Fortunately, the myeloma treatment landscape continues to evolve with the development of therapies directed toward new biologic targets, such as B-cell maturation antigen. These new agents, including bispecific T-cell engagers and chimeric antigen receptor T-cell therapy, have shown unprecedented efficacy in late-line myeloma and will be increasingly used at earlier time points. Novel combinations of currently approved treatments, including quadruplets and salvage transplantation, also remain important options for consideration." + } +} \ No newline at end of file diff --git a/37104870.json b/37104870.json new file mode 100644 index 0000000000000000000000000000000000000000..b296f0d6036ad78275b2f168f524e2d1170c81d9 --- /dev/null +++ b/37104870.json @@ -0,0 +1,8 @@ +{ + "id": "37104870", + "label": 0, + "article": { + "id": "37104870", + "text": "BACKGROUND:\nPatients with advanced esophageal cancer carry poor prognoses; limited data exist to guide second-line therapy in the metastatic setting. Paclitaxel has been used yet is associated with limited efficacy. There is preclinical evidence of synergy between paclitaxel and cixutumumab, a monoclonal antibody targeting insulin-like growth factor-1 receptor. We conducted a randomized phase II trial of paclitaxel (arm A) versus paclitaxel plus cixutumumab (arm B) in the second-line for patients with metastatic esophageal or gastroesophageal junction (GEJ) cancers.\n\nMETHODS:\nThe primary endpoint was progression-free survival (PFS); 87 patients (43 in arm A, 44 in arm B) were treated.\n\nRESULTS:\nMedian PFS was 2.6 months in arm A [90% CL 1.8-3.5] and 2.3 months in arm B [90% 2.0-3.5], P = .86. Stable disease was observed in 29 (33%) patients. Objective response rates for Arms A and B were 12% [90% CI, 5-23%] and 14% [90% CI, 6-25%]. Median overall survival was 6.7 months [90% CL 4.9-9.5] in arm A and 7.2 months [90% CL 4.9-8.1] in arm B, P = 56.\n\nCONCLUSION:\nThe addition of cixutumumab to paclitaxel in second-line therapy of metastatic esophageal/GEJ cancer was well tolerated but did not improve clinical outcomes relative to standard of care (ClinicalTrials.gov Identifier: NCT01142388)." + } +} \ No newline at end of file diff --git a/37104931.json b/37104931.json new file mode 100644 index 0000000000000000000000000000000000000000..7b89bb374f22e5d8528131364a534539f159a6cb --- /dev/null +++ b/37104931.json @@ -0,0 +1,8 @@ +{ + "id": "37104931", + "label": 0, + "article": { + "id": "37104931", + "text": "BACKGROUND:\nWe report updated data for avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma from the third interim analysis of the phase III JAVELIN Renal 101 trial.\n\nPATIENTS AND METHODS:\nProgression-free survival (PFS), objective response rate (ORR), and duration of response per investigator assessment (RECIST version 1.1) and overall survival (OS) were evaluated in the overall population and in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups; safety was also assessed.\n\nRESULTS:\nOverall, median OS [95% confidence interval (CI)] was not reached [42.2 months-not estimable (NE)] with avelumab plus axitinib versus 37.8 months (31.4-NE) with sunitinib [hazard ratio (HR) 0.79, 95% CI 0.643-0.969; one-sided P = 0.0116], and median PFS (95% CI) was 13.9 months (11.1-16.6 months) versus 8.5 months (8.2-9.7 months), respectively (HR 0.67, 95% CI 0.568-0.785; one-sided P \u003c 0.0001). In patients with IMDC favorable-, intermediate-, poor-, or intermediate plus poor-risk disease, respectively, HRs (95% CI) for OS with avelumab plus axitinib versus sunitinib were 0.66 (0.356-1.223), 0.84 (0.649-1.084), 0.60 (0.399-0.912), and 0.79 (0.636-0.983), and HRs (95% CIs) for PFS were 0.71 (0.490-1.016), 0.71 (0.578-0.866), 0.45 (0.304-0.678), and 0.66 (0.550-0.787), respectively. ORRs, complete response rates, and durations of response favored avelumab plus axitinib overall and across all risk groups. In the avelumab plus axitinib arm, 81.1% had a grade ≥3 treatment-emergent adverse event (TEAE), and incidences of TEAEs and immune-related AEs were highest \u003c6 months after randomization.\n\nCONCLUSIONS:\nAvelumab plus axitinib continues to show improved efficacy versus sunitinib and a tolerable safety profile overall and across IMDC risk groups. The OS trend favors avelumab plus axitinib versus sunitinib, but data remain immature; follow-up is ongoing.\n\nTRIAL REGISTRATION:\nClinicalTrials.govNCT02684006; https://clinicaltrials.gov/ct2/show/NCT02684006." + } +} \ No newline at end of file diff --git a/37105077.json b/37105077.json new file mode 100644 index 0000000000000000000000000000000000000000..51fc6463eb360054d582242aad5076806d5927d9 --- /dev/null +++ b/37105077.json @@ -0,0 +1,8 @@ +{ + "id": "37105077", + "label": 0, + "article": { + "id": "37105077", + "text": "The clinical treatment of AML is dominated by \"7 + 3\" therapy, but it often shows great toxicity and limited therapeutic efficacy in application. Therefore, it is urgent to develop novel therapeutic strategies to achieve safe and efficient treatment of AML. Small-molecule inhibitors have the characteristics of high specificity, low off-target toxicity and remarkable therapeutic effect, and are receiving more and more attention in tumor therapy. In this study, we screened a library of 1972 FDA-approved small molecular compounds for those that induced the inflammatory death of AML cells, among which the TLR8 agonist Motolimod (MTL) showed stronger anti-AML activity in the animal model but slight affection on normal lymphocytes in control mice. In terms of mechanism, cellular experiments in AML cell lines proved that TLR8 and LKB1/AMPK are the key distinct mechanisms for MTL triggered caspase-3-dependent cell death and the expression of a large number of inflammatory factors. In conclusion, our findings identified the immunoactivator MTL as a single agent exerting significant anti-AML activity in vitro and in vivo, with strong potential for clinical translation." + } +} \ No newline at end of file diff --git a/37105172.json b/37105172.json new file mode 100644 index 0000000000000000000000000000000000000000..4b0aa13daf9e57c2d543a63b92278073dad8c1ce --- /dev/null +++ b/37105172.json @@ -0,0 +1,8 @@ +{ + "id": "37105172", + "label": 0, + "article": { + "id": "37105172", + "text": "In neurodegenerative diseases, microglia switch to an activated state, which results in excessive secretion of pro-inflammatory factors. Our work aims to investigate how this paracrine signaling affects neuronal function. Here, we show that activated microglia mediate non-cell-autonomous inhibition of neuronal autophagy, a degradative pathway critical for the removal of toxic, aggregate-prone proteins accumulating in neurodegenerative diseases. We found that the microglial-derived CCL-3/-4/-5 bind and activate neuronal CCR5, which in turn promotes mTORC1 activation and disrupts autophagy and aggregate-prone protein clearance. CCR5 and its cognate chemokines are upregulated in the brains of pre-manifesting mouse models for Huntington's disease (HD) and tauopathy, suggesting a pathological role of this microglia-neuronal axis in the early phases of these diseases. CCR5 upregulation is self-sustaining, as CCL5-CCR5 autophagy inhibition impairs CCR5 degradation itself. Finally, pharmacological or genetic inhibition of CCR5 rescues mTORC1 hyperactivation and autophagy dysfunction, which ameliorates HD and tau pathologies in mouse models." + } +} \ No newline at end of file diff --git a/37105303.json b/37105303.json new file mode 100644 index 0000000000000000000000000000000000000000..20620151caa3b68cf309b63a90ddb9e92827f57d --- /dev/null +++ b/37105303.json @@ -0,0 +1,8 @@ +{ + "id": "37105303", + "label": 0, + "article": { + "id": "37105303", + "text": "BACKGROUND AND PURPOSE:\nCardiac arrhythmia is a recognised potential complication of thoracic radiotherapy, but the responsible cardiac substructures for arrhythmogenesis have not been identified. Arrhythmogenic tissue is commonly located in the pulmonary veins (PVs) of cardiology patients with arrhythmia, however these structures are not currently considered organs-at-risk during radiotherapy planning. A standardised approach to their delineation was developed and evaluated.\n\nMATERIALS AND METHODS:\nThe gross and radiological anatomy relevant to atrial fibrillation was derived from cardiology and radiology literature by a multidisciplinary team. A region of interest and contouring instructions for radiotherapy computed tomography scans were iteratively developed and subsequently evaluated. Radiation oncologists (n=5) and radiation technologists (n=2) contoured the PVs on the four-dimensional planning datasets of five patients with locally advanced lung cancer treated with 1.8-2.75 Gy fractions. Contours were compared to reference contours agreed by the researchers using geometric and dosimetric parameters.\n\nRESULTS:\nThe mean dose to the PVs was 35% prescription dose. Geometric and dosimetric similarity of the observer contours with reference contours was fair, with an overall mean Dice of 0.80 ± 0.02. The right superior PV (mean DSC 0.83 ± 0.02) had better overlap than the left (mean DSC 0.80 ± 0.03), but the inferior PVs were equivalent (mean DSC of 0.78). The mean difference in mean dose was 0.79 Gy ± 0.71 (1.46% ± 1.25).\n\nCONCLUSION:\nA PV atlas with multidisciplinary approval led to reproducible delineation for radiotherapy planning, supporting the utility of the atlas in future clinical radiotherapy cardiotoxicity research encompassing arrhythmia endpoints." + } +} \ No newline at end of file diff --git a/37105563.json b/37105563.json new file mode 100644 index 0000000000000000000000000000000000000000..a46e3178658d8b63c18dba133dcb4d53e1bed9eb --- /dev/null +++ b/37105563.json @@ -0,0 +1,8 @@ +{ + "id": "37105563", + "label": 0, + "article": { + "id": "37105563", + "text": "Plasmacytoid dendritic cells (pDCs) are type I interferon-producing cells that modulate immune responses. There are two types of pDC neoplasms: 1) mature pDC proliferation (MPDCP) associated with myeloid neoplasm and 2) blastic pDC neoplasm (BPDCN). MPDCP is a clonal expansion of mature pDCs that is predominantly associated with chronic myelomonocytic leukemia. In contrast, BPDCN is a clinically aggressive myeloid malignancy involving the skin, bone marrow, lymphatic organs, and central nervous system. There are various types of skin lesions, ranging from solitary brown or violaceous to disseminated cutaneous lesions, which often spread throughout the body. The expression of CD4, CD56, CD123, and pDC markers (TCL-1, TCF4, CD303, and CD304, etc.) are typical immunophenotype of BPDCN. Historically, BPDCN treatment has been based on acute leukemia regimens and allogeneic hematopoietic cell transplantation in selected patients. Recent advances in molecular biology and genetics have led to the development of targeted agents, such as tagraxofusp (a recombinant fusion protein targeting CD123), anti-CD123 CAR-T cells, XmAb14045, and IMGN632. Lastly, this review provides a comprehensive overview of pDC neoplasms." + } +} \ No newline at end of file diff --git a/37105803.json b/37105803.json new file mode 100644 index 0000000000000000000000000000000000000000..1766eef5fb3f9d153ae86cd107fb15c93e485e28 --- /dev/null +++ b/37105803.json @@ -0,0 +1,8 @@ +{ + "id": "37105803", + "label": 0, + "article": { + "id": "37105803", + "text": "RATIONALE AND OBJECTIVES:\nTo evaluate single-institution outcomes of drug-eluting bead transarterial chemoembolization (DEB-TACE) in the treatment of locally advanced neuroendocrine tumor (NET) hepatic metastases with a focus on safety and efficacy of treatment.\n\nMATERIALS AND METHODS:\nA single-center retrospective cohort study of the outcomes of consecutive patients with NELM who underwent DEB-TACE between 2014 and 2019 was performed. Clinicopathologic characteristics, radiologic response (modified Response Evaluation Criteria in Solid Tumors) at 1-month follow-up, adverse events, progression-free survival (PFS), and overall survival were calculated.\n\nRESULTS:\nAmong 287 patients (mean age of 62 years; 39% male: 61% female), disease burden was bilobar (90.2%) with mean largest tumor diameter measuring 4.9 ± 2.8 cm. Of these patients, 14.6% had no evidence of tumor in other organs or lymph nodes. Complete response occurred in 60 (20.9%) patients while 133 (46.3%) had partial responses. Major complication occurred in 2.4%. Liver function tests including total bilirubin and AST were overall stable at the 1-month follow-up, with only a small increase in the ALT at +8.9% (p \u003c 0.01). Overall survival was 80.1% at 1 year, 49.1% at 3 years, and 12.3% at 5 years with a mean PFS of 14.4 ± 12.5 months.\n\nCONCLUSION:\nBased on this institutional experience, DEB-TACE is an acceptable locoregional therapy choice for hepatic metastases of NET due to its tolerable safety profile and relative efficacy." + } +} \ No newline at end of file diff --git a/37105869.json b/37105869.json new file mode 100644 index 0000000000000000000000000000000000000000..b68de118da0fa7b7aaa90d7fe5adafe9b031e298 --- /dev/null +++ b/37105869.json @@ -0,0 +1,8 @@ +{ + "id": "37105869", + "label": 0, + "article": { + "id": "37105869", + "text": "INTRODUCTION:\nEsophagectomy is the mainstay of esophageal cancer treatment, but anastomotic insufficiency related morbidity and mortality remain challenging for patient outcome. Therefore, the objective of this work was to optimize anastomotic technique and gastric conduit perfusion with hyperspectral imaging (HSI) for total minimally invasive esophagectomy (MIE) with linear stapled anastomosis.\n\nMATERIAL AND METHODS:\nA live porcine model (n = 58) for MIE was used with gastric conduit formation and simulation of linear stapled side-to-side esophagogastrostomy. Four main experimental groups differed in stapling length (3 vs. 6 cm) and simulation of anastomotic position on the conduit (cranial vs. caudal). Tissue oxygenation around the anastomotic simulation site was evaluated using HSI and was validated with histopathology.\n\nRESULTS:\nThe tissue oxygenation (ΔStO) after the anastomotic simulation remained constant only for the short stapler in caudal position (-0.4 ± 4.4%, n.s.) while it was impaired markedly in the other groups (short-cranial: -15.6 ± 11.5%, p = 0.0002; long-cranial: -20.4 ± 7.6%, p = 0.0126; long-caudal: -16.1 ± 9.4%, p \u003c 0.0001). Tissue samples from avascular stomach as measured by HSI showed correspondent eosinophilic pre-necrotic changes in 35.7 ± 9.7% of the surface area.\n\nCONCLUSION:\nTissue oxygenation at the site of anastomotic simulation of the gastric conduit during MIE is influenced by stapling technique. Optimal oxygenation was achieved with a short stapler (3 cm) and sufficient distance of the simulated anastomosis to the cranial end of the gastric conduit. HSI tissue deoxygenation corresponded to histopathologic necrotic tissue changes. The experimental model with HSI and ML allow for systematic optimization of gastric conduit perfusion and anastomotic technique while clinical translation will have to be proven." + } +} \ No newline at end of file diff --git a/37105980.json b/37105980.json new file mode 100644 index 0000000000000000000000000000000000000000..8f1d069297d154804ab9234603f23acb7c638850 --- /dev/null +++ b/37105980.json @@ -0,0 +1,8 @@ +{ + "id": "37105980", + "label": 0, + "article": { + "id": "37105980", + "text": "Myeloid-derived suppressor cells (MDSCs) were found to gradually accumulate in the orthotopic esophageal cancer mouse model during tumor progression. Although the roles of MDSCs in promoting tumor growth and inhibiting immune response have been extensively explored, currently, there are still no effective means for targeting MDSCs clinically. The deficiency of specific markers of MDSCs was responsible for the limited strategy to eliminating in clinic. This study identified that GPR84 was exclusively overexpressed on MDSCs. It was further found that GPR84 was prominently expressed on MDSCs in clinical samples and tumor mouse models, which drives the immunosuppression on CD8T cells by inhibiting PD-L1 degradation in lysosomes. Furthermore, G-CSF and GM-CSF were found to induce GPR84 expression through the STAT3/C/EBPβ signaling pathway. In addition, GPR84MDSCs and PD-L1MDSCs were highly accumulated in anti-PD-1 therapy-resistant patients with esophageal cancer, and high GPR84 signature risk was verified as a negative factor for the overall survival of patients with anti-PD-1 treatment. Finally, GPR84 antagonism combined with an anti-PD-1 antibody enhanced the antitumor responses. Therefore, targeting GPR84 enhanced anti-PD-1 efficacy in esophageal cancer and other malignant tumors. This combination therapy has the potential for tumor therapy in clinics." + } +} \ No newline at end of file diff --git a/37106163.json b/37106163.json new file mode 100644 index 0000000000000000000000000000000000000000..0cced07942d477b029892eb614c49b109450311a --- /dev/null +++ b/37106163.json @@ -0,0 +1,8 @@ +{ + "id": "37106163", + "label": 0, + "article": { + "id": "37106163", + "text": "Although the landscape for treating acute myeloid leukemia (AML) patients has changed substantially in recent years, the majority of patients will eventually relapse and succumb to their disease. Allogeneic stem cell transplantation provides the best anti-AML treatment strategy, but is only suitable in a minority of patients. In contrast to B-cell neoplasias, chimeric antigen receptor (CAR) T-cell therapy in AML has encountered challenges in target antigen heterogeneity, safety, and T-cell dysfunction. We established a Fab-based adapter CAR (AdCAR) T-cell platform with flexibility of targeting and control of AdCAR T-cell activation. Utilizing AML cell lines and a long-term culture assay for primary AML cells, we were able to demonstrate AML-specific cytotoxicity using anti-CD33, anti-CD123, and anti-CLL1 adapter molecules in vitro and in vivo. Notably, we show for the first time the feasibility of sequential application of adapter molecules of different specificity in primary AML co-cultures. Importantly, using the AML platform, we were able to demonstrate that chronic T-cell stimulation and exhaustion can be counteracted through introduction of treatment-free intervals. As T-cell exhaustion and target antigen heterogeneity are well-known causes of resistance, the AdCAR platform might offer effective strategies to ameliorate these limitations." + } +} \ No newline at end of file diff --git a/37106446.json b/37106446.json new file mode 100644 index 0000000000000000000000000000000000000000..7c2531a1e9ccdb23cf5cab44ed829c662f4155f9 --- /dev/null +++ b/37106446.json @@ -0,0 +1,8 @@ +{ + "id": "37106446", + "label": 0, + "article": { + "id": "37106446", + "text": "CircZBTB44 (hsa_circ_0002484) has been identified to be upregulated in renal cell carcinoma (RCC) tissues, while its role and contribution in RCC remain elusive. We confirmed the overexpression of circZBTB44 in RCC cells compared to normal kidney cell HK-2. CircZBTB44 knockdown suppressed the viability, proliferation, and migration of RCC cells and inhibited tumorigenesis in xenograft mouse models. Heterogeneous Nuclear Ribonucleoprotein C (HNRNPC) and Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) are two RNA binding proteins of circZBTB44. HNRNPC facilitated the translocation of circZBTB44 from nuclei to cytoplasm via m6A modification, facilitating the interaction of IGF2BP3 and circZBTB44 in the cytoplasm of RCC cells. Furthermore, circZBTB44 upregulated Hexokinase 3 (HK3) expression by binding to IGF2BP3 in RCC cells. HK3 exerted oncogenic effects on RCC cell malignant behaviors and tumor growth. In the co-culture of RCC cells with macrophages, circZBTB44 promoted M2 polarization of macrophages by up-regulating HK3. In summary, HNRNPC mediated circZBTB44 interaction with IGF2BP3 to up-regulate HK3, promoting the proliferation and migration of RCC cells in vitro and tumorigenesis in vivo. The results of the study shed new light on the targeted therapy of RCC." + } +} \ No newline at end of file diff --git a/37106694.json b/37106694.json new file mode 100644 index 0000000000000000000000000000000000000000..ff9d619fe0508985e11cbaded864afe64fe9cd8b --- /dev/null +++ b/37106694.json @@ -0,0 +1,8 @@ +{ + "id": "37106694", + "label": 0, + "article": { + "id": "37106694", + "text": "circRNAs constitute a novel class of RNA, generally considered as non-coding RNAs; nonetheless, their coding potential has been under scrutiny. In this work, we systematically explored the predicted proteins of more than 160,000 circRNAs detected by exome capture RNA-sequencing and collected in the MiOncoCirc pan-cancer compendium, including normal and cancer samples from different types of tissues. For the functional evaluation, we compared their primary structure and domain composition with those derived from the same linear mRNAs. Among the 4362 circRNAs potentially encoding proteins with a unique primary structure and 1179 encoding proteins with a novel domain composition, 183 were differentially expressed in cancer. In particular, eight were associated with prognosis in acute myeloid leukemia. The functional classification of the dysregulated circRNA-encoded polypeptides showed an enrichment in the heme and cancer signaling, DNA-binding, and phosphorylation processes, and disclosed the roles of some circRNA-based effectors in cancer." + } +} \ No newline at end of file diff --git a/37106759.json b/37106759.json new file mode 100644 index 0000000000000000000000000000000000000000..63b6862430847956dbfede129c3fddcaf59785f4 --- /dev/null +++ b/37106759.json @@ -0,0 +1,8 @@ +{ + "id": "37106759", + "label": 0, + "article": { + "id": "37106759", + "text": "Adenosine is a nucleoside that is widely distributed in the central nervous system and acts as a central excitatory and inhibitory neurotransmitter in the brain. The protective role of adenosine in different pathological conditions and neurodegenerative diseases is mainly mediated by adenosine receptors. However, its potential role in mitigating the deleterious effects of oxidative stress in Friedreich's ataxia (FRDA) remains poorly understood. We aimed to investigate the protective effects of adenosine against mitochondrial dysfunction and impaired mitochondrial biogenesis in L-buthionine sulfoximine (BSO)-induced oxidative stress in dermal fibroblasts derived from an FRDA patient. The FRDA fibroblasts were pre-treated with adenosine for 2 h, followed by 12.50 mM BSO to induce oxidative stress. Cells in medium without any treatments or pre-treated with 5 µM idebenone served as the negative and positive controls, respectively. Cell viability, mitochondrial membrane potential (MMP), aconitase activity, adenosine triphosphate (ATP) level, mitochondrial biogenesis, and associated gene expressions were assessed. We observed disruption of mitochondrial function and biogenesis and alteration in gene expression patterns in BSO-treated FRDA fibroblasts. Pre-treatment with adenosine ranging from 0-600 µM restored MMP, promoted ATP production and mitochondrial biogenesis, and modulated the expression of key metabolic genes, namely nuclear respiratory factor 1 (), transcription factor A, mitochondrial (), and NFE2-like bZIP transcription factor 2 (). Our study demonstrated that adenosine targeted mitochondrial defects in FRDA, contributing to improved mitochondrial function and biogenesis, leading to cellular iron homeostasis. Therefore, we suggest a possible therapeutic role for adenosine in FRDA." + } +} \ No newline at end of file diff --git a/37106830.json b/37106830.json new file mode 100644 index 0000000000000000000000000000000000000000..5a5a9666e935f8e8e8bed01c960a3d48a7f126e6 --- /dev/null +++ b/37106830.json @@ -0,0 +1,8 @@ +{ + "id": "37106830", + "label": 0, + "article": { + "id": "37106830", + "text": "Microglial activation and failure of the antioxidant defense mechanisms are major hallmarks in different brain injuries, particularly traumatic brain injury (TBI). Cofilin is a cytoskeleton-associated protein involved in actin binding and severing. In our previous studies, we identified the putative role of cofilin in mediating microglial activation and apoptosis in ischemic and hemorrhagic conditions. Others have highlighted the involvement of cofilin in ROS production and the resultant neuronal death; however, more studies are needed to delineate the role of cofilin in oxidative stress conditions. The present study aims to investigate the cellular and molecular effects of cofilin in TBI using both in vitro and in vivo models as well as the first-in-class small-molecule cofilin inhibitor (CI). An in vitro HO-induced oxidative stress model was used in two different types of cells, human neuroblastoma (SH-SY5Y) and microglia (HMC3), along with an in vivo controlled cortical impact model of TBI. Our results show that treatment with HO increases the expression of cofilin and slingshot-1 (SSH-1), an upstream regulator of cofilin, in microglial cells, which was significantly reduced in the CI-treated group. Cofilin inhibition significantly attenuated HO-induced microglial activation by reducing the release of proinflammatory mediators. Furthermore, we demonstrate that CI protects against HO-induced ROS accumulation and neuronal cytotoxicity, activates the AKT signaling pathway by increasing its phosphorylation, and modulates mitochondrial-related apoptogenic factors. The expression of NF-E2-related factor 2 (Nrf2) and its associated antioxidant enzymes were also increased in CI-treated SY-SY5Y. In the mice model of TBI, CI significantly activated the Nrf2 and reduced the expression of oxidative/nitrosative stress markers at the protein and gene levels. Together, our data suggest that cofilin inhibition provides a neuroprotective effect in in vitro and in vivo TBI mice models by inhibiting oxidative stress and inflammatory responses, the pivotal mechanisms involved in TBI-induced brain damage." + } +} \ No newline at end of file diff --git a/37107353.json b/37107353.json new file mode 100644 index 0000000000000000000000000000000000000000..77e4a6b6287f8f7b006f3dd1bb1cdd091c3fb2ec --- /dev/null +++ b/37107353.json @@ -0,0 +1,8 @@ +{ + "id": "37107353", + "label": 0, + "article": { + "id": "37107353", + "text": "In light of the known neuroprotective properties of indole compounds and the promising potential of hydrazone derivatives, two series of aldehyde-heterocyclic hybrids combining those pharmacophores were synthesized as new multifunctional neuroprotectors. The obtained derivatives of indole-3-propionic acid (IPA) and 5-methoxy-indole carboxylic acid (5MICA) had good safety profiles: Hemolytic effects \u003c 5% (200 μM) and IC \u003e 150 µM were found in the majority of the SH-SY5Y and bEnd3 cell lines. The 2,3-dihydroxy, 2-hydroxy-4-methoxy, and syringaldehyde derivatives of 5MICA exhibited the strongest neuroprotection against HO-induced oxidative stress in SH-SY5Y cells and 6-OHDA-induced neurotoxicity in rat-brain synaptosomes. All the compounds suppressed the iron-induced lipid peroxidation. The hydroxyl derivatives were also the most active in terms of deoxyribose-degradation inhibition, whereas the 3,4-dihydroxy derivatives were able to decrease the superoxide-anion generation. Both series of compounds showed an increased inhibition of hMAO-B, with greater expression detected in the 5MICA hybrids. The in vitro BBB model with the bEnd3 cell line showed that some compounds increased the permeability of the endothelial monolayer while maintaining the tight junctions. The combined results demonstrated that the derivatives of IPA and 5MICA showed strong neuroprotective, antioxidant, MAO-B inhibitory activity and could be considered as prospective multifunctional compounds for the treatment of neurodegenerative disorders." + } +} \ No newline at end of file diff --git a/37108151.json b/37108151.json new file mode 100644 index 0000000000000000000000000000000000000000..aca18567586b773f744796f3fdc120c627931579 --- /dev/null +++ b/37108151.json @@ -0,0 +1,8 @@ +{ + "id": "37108151", + "label": 0, + "article": { + "id": "37108151", + "text": "Amyotrophic lateral sclerosis (ALS) is a major life-threatening disease caused by motor neuron degeneration. More effective treatments through drug discovery are urgently needed. Here, we established an effective high-throughput screening system using induced pluripotent stem cells (iPSCs). Using a Tet-On-dependent transcription factor expression system carried on the vector, motor neurons were efficiently and rapidly generated from iPSCs by a single-step induction method. Induced iPSC transcripts displayed characteristics similar to those of spinal cord neurons. iPSC-generated motor neurons carried a mutation in () and () genes and had abnormal protein accumulation corresponding to each mutation. Calcium imaging and multiple electrode array (MEA) recordings demonstrated that ALS neurons were abnormally hyperexcitable. Noticeably, protein accumulation and hyperexcitability were ameliorated by treatment with rapamycin (mTOR inhibitor) and retigabine (Kv7 channel activator), respectively. Furthermore, rapamycin suppressed ALS neuronal death and hyperexcitability, suggesting that protein aggregate clearance through the activation of autophagy effectively normalized activity and improved neuronal survival. Our culture system reproduced several ALS phenotypes, including protein accumulation, hyperexcitability, and neuronal death. This rapid and robust phenotypic screening system will likely facilitate the discovery of novel ALS therapeutics and stratified and personalized medicine for sporadic motor neuron diseases." + } +} \ No newline at end of file diff --git a/37108308.json b/37108308.json new file mode 100644 index 0000000000000000000000000000000000000000..65f0a3be200249ec95c8362777f95a60dcc5217e --- /dev/null +++ b/37108308.json @@ -0,0 +1,8 @@ +{ + "id": "37108308", + "label": 0, + "article": { + "id": "37108308", + "text": "Despite recent advances, prognosis of acute myeloid leukemia (AML) remains unsatisfactory due to poor response to therapy or relapse. Among causes of resistance, over-expression of multidrug resistance (MDR) proteins represents a pivotal mechanism. ABCG2 is an efflux transporter responsible for inducing MDR in leukemic cells; through its ability to extrude many antineoplastic drugs, it leads to AML resistance and/or relapse, even if conflicting data have been reported to date. Moreover, ABCG2 may be co-expressed with other MDR-related proteins and is finely regulated by epigenetic mechanisms. Here, we review the main issues regarding ABCG2 activity and regulation in the AML clinical scenario, focusing on its expression and the role of polymorphisms, as well as on the potential ways to inhibit its function to counteract drug resistance to, eventually, improve outcomes in AML patients." + } +} \ No newline at end of file diff --git a/37108344.json b/37108344.json new file mode 100644 index 0000000000000000000000000000000000000000..6408889fd51e576ddbd57dd06574f9a8b5a47d16 --- /dev/null +++ b/37108344.json @@ -0,0 +1,8 @@ +{ + "id": "37108344", + "label": 0, + "article": { + "id": "37108344", + "text": "Acute myeloid leukemia (AML) is a hematological malignancy characterized by excessive proliferation of abnormal myeloid precursors accompanied by a differentiation block and inhibition of apoptosis. Increased expression of an anti-apoptotic MCL-1 protein was shown to be critical for the sustained survival and expansion of AML cells. Therefore, herein, we examined the pro-apoptotic and pro-differentiating effects of S63845, a specific inhibitor of MCL-1, in a single-agent treatment and in combination with BCL-2/BCL-XL inhibitor, ABT-737, in two AML cell lines: HL-60 and ML-1. Additionally, we determined whether inhibition of the MAPK pathway had an impact on the sensitivity of AML cells to S63845. To assess AML cells' apoptosis and differentiation, in vitro studies were performed using PrestoBlue assay, Coulter electrical impedance method, flow cytometry, light microscopy and Western blot techniques. S63845 caused a concentration-dependent decrease in the viability of HL-60 and ML-1 cells and increased the percentage of apoptotic cells. Combined treatment with S63845 and ABT-737 or MAPK pathway inhibitor enhanced apoptosis but also induced differentiation of tested cells, as well as altering the expression of the MCL-1 protein. Taken together, our data provide the rationale for further studies regarding the use of MCL-1 inhibitor in combination with other pro-survival protein inhibitors." + } +} \ No newline at end of file diff --git a/37108359.json b/37108359.json new file mode 100644 index 0000000000000000000000000000000000000000..441bec46a14b4c031c9e1ac8a32d4508ca489fe5 --- /dev/null +++ b/37108359.json @@ -0,0 +1,8 @@ +{ + "id": "37108359", + "label": 0, + "article": { + "id": "37108359", + "text": "Current therapies for T-cell acute leukemia are based on risk stratification and have greatly improved the survival rate for patients, but mortality rates remain high owing to relapsed disease, therapy resistance, or treatment-related toxicities/infection. Patients with relapsed disease continue to have poor outcomes. In the past few years, newer agents have been investigated to optimize upfront therapies for higher-risk patients in the hopes of decreasing relapse rates. This review summarizes the progress of chemo/targeted therapies using Nelarabine/Bortezomib/CDK4/6 inhibitors for T-ALL in clinical trials and novel strategies to target NOTCH-induced T-ALL. We also outline immunotherapy clinical trials using monoclonal/bispecific T-cell engaging antibodies, anti-PD1/anti-PDL1 checkpoint inhibitors, and CAR-T for T-ALL therapy. Overall, pre-clinical studies and clinical trials showed that applying monoclonal antibodies or CAR-T for relapsed/refractory T-ALL therapy is promising. The combination of target therapy and immunotherapy may be a novel strategy for T-ALL treatment." + } +} \ No newline at end of file diff --git a/37108366.json b/37108366.json new file mode 100644 index 0000000000000000000000000000000000000000..3779bb6fbdefd143fd7a270492506d8a04639375 --- /dev/null +++ b/37108366.json @@ -0,0 +1,8 @@ +{ + "id": "37108366", + "label": 0, + "article": { + "id": "37108366", + "text": "Parkinson's disease (PD) is a multifactorial disorder involving both motor and non-motor symptoms caused by the progressive death of distinct neuronal populations, including dopaminergic neurons in the substantia nigra. The deposition of aggregated α-synuclein protein into Lewy body inclusions is a hallmark of the disorder, and α-synuclein pathology has been found in the enteric nervous system (ENS) of PD patients up to two decades prior to diagnosis. In combination with the high occurrence of gastrointestinal dysfunction in early stages of PD, current evidence strongly suggests that some forms of PD may originate in the gut. In this review, we discuss human studies that support ENS Lewy pathology as a characteristic feature of PD, and present evidence from humans and animal model systems that α-synuclein aggregation may follow a prion-like spreading cascade from enteric neurons, through the vagal nerve, and into the brain. Given the accessibility of the human gut to pharmacologic and dietary interventions, therapeutic strategies aimed at reducing pathological α-synuclein in the gastrointestinal tract hold significant promise for PD treatment." + } +} \ No newline at end of file diff --git a/37108384.json b/37108384.json new file mode 100644 index 0000000000000000000000000000000000000000..543fbd4c0d9366eb6a15dc542cbc3d149821a2c2 --- /dev/null +++ b/37108384.json @@ -0,0 +1,8 @@ +{ + "id": "37108384", + "label": 0, + "article": { + "id": "37108384", + "text": "Ginsenoside is the primary active substance of ginseng and has many pharmacological effects, such as anti-cancer, immune, regulating sugar and lipid metabolism, and antioxidant effects. It also protects the nervous and cardiovascular systems. This study analyzes the effects of thermal processing on the bioactivities of crude ginseng saponin. Heat treatment increased the contents of minor ginsenosides in crude saponins, such as Rg3, and heat-treated crude ginseng saponin (HGS) had better neuroprotective effects than non-treated crude saponin (NGS). HGS reduced glutamate-induced apoptosis and reactive oxygen species generation in pheochromocytoma 12 (PC12) cells, significantly more than NGS. HGS protected PC12 cells against glutamate-induced oxidative stress by upregulating Nrf2-mediated antioxidant signaling and downregulating MAPK-mediated apoptotic signaling. HGS has the potential for the prevention and treatment of neurodegenerative disorders, such as Alzheimer's and Parkinson's disease." + } +} \ No newline at end of file diff --git a/37108474.json b/37108474.json new file mode 100644 index 0000000000000000000000000000000000000000..ee145410e8237d60a84e4ae69ab6b8c1bcd889f8 --- /dev/null +++ b/37108474.json @@ -0,0 +1,8 @@ +{ + "id": "37108474", + "label": 0, + "article": { + "id": "37108474", + "text": "Patients with advanced esophageal squamous cell carcinoma (SCC) have a poor prognosis when treated with standard chemotherapy. Programmed death ligand 1 (PD-L1) expression in esophageal cancer has been associated with poor survival and more advanced stage. Immune checkpoint inhibitors, such as PD-1 inhibitors, showed benefits in advanced esophageal cancer in clinical trials. We analyzed the prognosis of patients with unresectable esophageal SCC who received nivolumab with chemotherapy, dual immunotherapy (nivolumab and ipilimumab), or chemotherapy with or without radiotherapy. Patients who received nivolumab with chemotherapy had a better overall response rate (ORR) (72% vs. 66.67%, = 0.038) and longer overall survival (OS) (median OS: 609 days vs. 392 days, = 0.04) than those who received chemotherapy with or without radiotherapy. In patients receiving nivolumab with chemotherapy, the duration of the treatment response was similar regardless of the treatment line they received. According to clinical parameters, liver and distant lymph nodes metastasis showed a trend of negative and positive impacts, respectively, on treatment response in the whole cohort and in the immunotherapy-containing regimen cohort. Nivolumab add-on treatment showed less gastrointestinal and hematological adverse effects, compare with chemotherapy. Here, we showed that nivolumab combined with chemotherapy is a better choice for patients with unresectable esophageal SCC." + } +} \ No newline at end of file diff --git a/37108561.json b/37108561.json new file mode 100644 index 0000000000000000000000000000000000000000..d0a4c5b40793e5ea6684345d1b4b4fd6819257e0 --- /dev/null +++ b/37108561.json @@ -0,0 +1,8 @@ +{ + "id": "37108561", + "label": 0, + "article": { + "id": "37108561", + "text": "This multicenter retrospective study aimed to clarify the prognostic factors for mortality and changes in treatment modalities and disease activities after the onset of pneumonia (PCP) in patients with rheumatoid arthritis (RA). Data regarding the clinical background, treatment modalities, and disease activity indicators of RA at the onset of PCP (baseline), and 6 months and 12 months after treatment were extracted. Of the 37 patients with RA-PCP (median age, 69 years; 73% female), chemical prophylaxis was administered to 8.1%. Six patients died during PCP treatment. The serum C-reactive protein (CRP) levels and the prednisolone (PDN) dose at baseline in the PCP death group were significantly higher than those in the survivor group. Multivariate analysis using a Cox regression model showed that PDN dose at baseline was a predictor of death from PCP in patients with RA. During the 12 months from baseline, the RA disease activity significantly decreased. A high dose of corticosteroids for RA may result in a poor prognosis when PCP is complicated. In the future, preventive administration techniques must be established for patients with RA who need PCP prevention." + } +} \ No newline at end of file diff --git a/37108567.json b/37108567.json new file mode 100644 index 0000000000000000000000000000000000000000..fbb344472c0fa3bacc38ee93d51b9368730d508c --- /dev/null +++ b/37108567.json @@ -0,0 +1,8 @@ +{ + "id": "37108567", + "label": 0, + "article": { + "id": "37108567", + "text": "Human mitochondria contain a circular genome that encodes 13 subunits of the oxidative phosphorylation system. In addition to their role as powerhouses of the cells, mitochondria are also involved in innate immunity as the mitochondrial genome generates long double-stranded RNAs (dsRNAs) that can activate the dsRNA-sensing pattern recognition receptors. Recent evidence shows that these mitochondrial dsRNAs (mt-dsRNAs) are closely associated with the pathogenesis of human diseases that accompany inflammation and aberrant immune activation, such as Huntington's disease, osteoarthritis, and autoimmune Sjögren's syndrome. Yet, small chemicals that can protect cells from a mt-dsRNA-mediated immune response remain largely unexplored. Here, we investigate the potential of resveratrol (RES), a plant-derived polyphenol with antioxidant properties, on suppressing mt-dsRNA-mediated immune activation. We show that RES can revert the downstream response to immunogenic stressors that elevate mitochondrial RNA expressions, such as stimulation by exogenous dsRNAs or inhibition of ATP synthase. Through high-throughput sequencing, we find that RES can regulate mt-dsRNA expression, interferon response, and other cellular responses induced by these stressors. Notably, RES treatment fails to counter the effect of an endoplasmic reticulum stressor that does not affect the expression of mitochondrial RNAs. Overall, our study demonstrates the potential usage of RES to alleviate the mt-dsRNA-mediated immunogenic stress response." + } +} \ No newline at end of file diff --git a/37108572.json b/37108572.json new file mode 100644 index 0000000000000000000000000000000000000000..13deb841d3215014c4889a1d20c63e9a9bafb81b --- /dev/null +++ b/37108572.json @@ -0,0 +1,8 @@ +{ + "id": "37108572", + "label": 0, + "article": { + "id": "37108572", + "text": "DJ-1 (also known as PARK7) is a multifunctional enzyme in human beings that is highly conserved and that has also been discovered in diverse species (ranging from prokaryotes to eukaryotes). Its complex enzymatic and non-enzymatic activities (such as anti-oxidation, anti-glycation, and protein quality control), as well as its role as a transcriptional coactivator, enable DJ-1 to serve as an essential regulator in multiple cellular processes (e.g., epigenetic regulations) and make it a promising therapeutic target for diverse diseases (especially cancer and Parkinson's disease). Due to its nature as a Swiss army knife enzyme with various functions, DJ-1 has attracted a large amount of research interest, from different perspectives. In this review, we give a brief summary of the recent advances with respect to DJ-1 research in biomedicine and psychology, as well as the progress made in attempts to develop DJ-1 into a druggable target for therapy." + } +} \ No newline at end of file diff --git a/37108666.json b/37108666.json new file mode 100644 index 0000000000000000000000000000000000000000..9fda879201d62d5ac5434c300d446728278736dc --- /dev/null +++ b/37108666.json @@ -0,0 +1,8 @@ +{ + "id": "37108666", + "label": 0, + "article": { + "id": "37108666", + "text": "The tumor microenvironment (TME) plays an important part in the initiation and development of clear cell renal cell carcinoma (ccRCC). However, an understanding of the immune infiltration in TME is still unknown. Our study aims to explore the correlation between the TME and the clinical features, as well as the prognosis of ccRCC. In the present study, ESTIMATE and CIBERSORT computational methods were applied to calculate the proportion of tumor-infiltrating immune cells (TICs) and the amount of immune and stromal fractions in the ccRCC form The Cancer Genome Atlas (TCGA) database. Then, we sought to find out those immune cell types and genes which may play a significant role and validated them in the GEO database. Furthermore, an immunohistochemical analysis of our external validation dataset was used to detect SAA1 and PDL1 expression in the ccRCC cancer tissues and corresponding normal tissues. Statistical analysis was performed to study the relationship between SAA1 and clinical characteristics, as well as PDL1 expression. Furthermore, a ccRCC cell model with SAA1 knockdown was constructed, which was used for cell proliferation and the migration test. The intersection analysis of the univariate COX and PPI analysis were performed to imply Serum Amyloid A1 (SAA1) as a predictive factor. The expression of SAA1 was significantly negatively correlated to OS and positively correlated to the clinical TMN stage system. The genes in the high-expression SAA1 group were basically enriched in immune-related activities. The proportion of mast cells resting was negatively correlated with SAA1 expression, indicating that SAA1 may be involved in the maintenance of the immune status for the TME. Moreover, the PDL1 expression was positively related to the SAA1 expression and negatively correlated with the patients' prognosis. Further experiments revealed that the knockdown of SAA1 inhibited ccRCC development through suppressing cell proliferation and migration. SAA1 may be a novel marker for the prognosis prediction of ccRCC patients and may play a vital role in the TME by mast cell resting and PDL1 expression. SAA1 has the potential to become a therapeutic target and indicator for immune target therapy in ccRCC treatment." + } +} \ No newline at end of file diff --git a/37109003.json b/37109003.json new file mode 100644 index 0000000000000000000000000000000000000000..86a58dbf59d4450f10c8027609bfce730f686cd9 --- /dev/null +++ b/37109003.json @@ -0,0 +1,8 @@ +{ + "id": "37109003", + "label": 0, + "article": { + "id": "37109003", + "text": "In the last 20 years, growing interest in chronic rhinosinusitis (CRS) has become evident in medical literature; nevertheless, it is still difficult to identify the real prevalence of the disease. Epidemiological studies are few and focused on heterogeneous populations and diagnostic methods. Recent research has contributed to identifying CRS as a disease characterized by heterogeneous clinical scenarios, high impact on quality of life, and elevated social costs. Patient stratification with phenotypes and identification of the pathobiological mechanism at the origin of the disease (endotype) and its comorbidities are pivotal in the diagnostic process, and they should be addressed in order to properly tailor treatment. A multidisciplinary approach, shared diagnostic and therapeutic data, and follow-up processes are therefore necessary. Oncological multidisciplinary boards offer models to imitate in accordance with the principles of precision medicine: tracing a diagnostic pathway with the purpose of identifying the patient's immunological profile, monitoring therapeutical processes, abstaining from having only a single specialist involved in treatment, and placing the patient at the center of the therapeutic plan. Awareness and participation from the patient's perspective are fundamental steps to optimize the clinical course, improve quality of life, and reduce the socioeconomic burden." + } +} \ No newline at end of file diff --git a/37109033.json b/37109033.json new file mode 100644 index 0000000000000000000000000000000000000000..d334850f8fb63533710979fd4473c548924397da --- /dev/null +++ b/37109033.json @@ -0,0 +1,8 @@ +{ + "id": "37109033", + "label": 0, + "article": { + "id": "37109033", + "text": "PURPOSE:\nIn the era of precision medicine, target-therapy with monoclonal antibodies (mAb) has enabled new treatment options in patients affected by eosinophilic granulomatosis with polyangiitis (EGPA). Nevertheless, sometimes unsatisfactory results at a nasal level may be observed. The aim of this study is to describe reboot surgery as a potential adjuvant strategy in multi-operated, yet uncontrolled EGPA patients treated with Mepolizumab.\n\nMETHODS:\nWe performed reboot surgery on EGPA patients with refractory CRSwNP. We obtained clinical data, nasal endoscopy, nasal biopsy, and symptom severity scores two months before surgery and 12 months after it. Computed tomography (CT) prior to surgery was also obtained.\n\nRESULTS:\nTwo patients were included in the study. Baseline sinonasal disease was severe. Systemic EGPA manifestations were under control, and the patients received previous mepolizumab treatment and previous surgery with no permanent benefits on sinonasal symptoms. Twelve months after surgery, nasal symptoms were markedly improved; endoscopy showed an absence of nasal polyps and there were fewer eosinophils at histology.\n\nCONCLUSIONS:\nWe presented the first experience of two EGPA patients with refractory CRSwNP who underwent non-mucosa sparing (reboot) sinus surgery; our results support the possible adjuvant role of reboot surgery in this particular subset of patients." + } +} \ No newline at end of file diff --git a/37109054.json b/37109054.json new file mode 100644 index 0000000000000000000000000000000000000000..9ea90c0955adb80e8131089763a173e1c0c38520 --- /dev/null +++ b/37109054.json @@ -0,0 +1,8 @@ +{ + "id": "37109054", + "label": 0, + "article": { + "id": "37109054", + "text": "Twelve Asian patients with sarcoma received interval-compressed (ic-) chemotherapy scheduled every 14 days with a regimen of vincristine (2 mg/m), doxorubicin (75 mg/m), and cyclophosphamide (1200-2200 mg/m) (VDC) alternating with a regimen of ifosfamide (9000 mg/m) and etoposide (500 mg/m) (IE), with filgrastim (5-10 mcg/kg/day) between cycles. Carboplatin (800 mg/m) was added for CIC-rearranged sarcoma. The patients were treated with 129 cycles of ic-VDC/IE with a median interval of 19 days (interquartile range [IQR], 15-24 days. Median nadirs (IQR) were neutrophil count, 134 (30-396) × 10/L at day 11 (10-12), recovery by day 15 (14-17) and platelet count, 35 (23-83) × 10/L at day 11 (10-13), recovery by day 17 (14-21). Fever and bacteremia were observed in 36% and 8% of cycles, respectively. The diagnoses were Ewing sarcoma (6), rhabdomyosarcoma (3), myoepithelial carcinoma (1), malignant peripheral nerve sheath tumor (1), and Sarcoma (1). Seven of the nine patients with measurable tumors responded (one CR and six PR). Interval-compressed chemotherapy is feasible in the treatment of Asian children and young adults with sarcomas." + } +} \ No newline at end of file diff --git a/37109063.json b/37109063.json new file mode 100644 index 0000000000000000000000000000000000000000..9a3d755ccd207e45a755acc0bbca1c381bb14012 --- /dev/null +++ b/37109063.json @@ -0,0 +1,8 @@ +{ + "id": "37109063", + "label": 0, + "article": { + "id": "37109063", + "text": "Asthma and COPD have characteristic symptoms, yet patients with both are prevalent. Despite this, there is currently no globally accepted definition for the overlap between asthma and COPD, commonly referred to as asthma-COPD overlap (ACO). Generally, ACO is not considered a distinct disease or symptom from either clinical or mechanistic perspectives. However, identifying patients who present with both conditions is crucial for guiding clinical therapy. Similar to asthma and COPD, ACO patients are heterogeneous and presumably have multiple underlying disease processes. The variability of ACO patients led to the establishment of multiple definitions describing the condition's essential clinical, physiological, and molecular characteristics. ACO comprises numerous phenotypes, which affects the optimal medication choice and can serve as a predictor of disease prognosis. Various phenotypes of ACO have been suggested based on host factors including but not limited to demographics, symptoms, spirometric findings, smoking history, and underlying airway inflammation. This review provides a comprehensive clinical guide for ACO patients to be used in clinical practice based on the available limited data. Future longitudinal studies must evaluate the stability of ACO phenotypes over time and explore their predictive powers to facilitate a more precise and effective management approach." + } +} \ No newline at end of file diff --git a/37109078.json b/37109078.json new file mode 100644 index 0000000000000000000000000000000000000000..244280cc1afa9d59bf39ef8895c11f2a188c21ac --- /dev/null +++ b/37109078.json @@ -0,0 +1,8 @@ +{ + "id": "37109078", + "label": 0, + "article": { + "id": "37109078", + "text": "PURPOSE:\nTo investigate the incidence of central nervous system (CNS) diseases in adult patients with voiding dysfunction and videourodynamics (VUDS) proven urethral sphincter dysfunction.\n\nMETHODS:\nThis retrospective analysis reviewed the medical charts of patients aged \u003e 60 years who underwent VUDS for non-prostatic voiding dysfunction from 2006 to 2021. A chart review was performed to search for the occurrence and treatment of CNS diseases after the VUDS examination up to 2022. The diagnosis of CNS disease, such as cerebrovascular accidents (CVA), Parkinson's disease (PD), and dementia, by neurologists was also retrieved from the charts. Based on the VUDS findings, patients were divided into the following subgroups: dysfunctional voiding (DV), poor relaxation of the external sphincter (PRES), and hypersensitive bladder (HSB) and coordinated sphincter subgroups. The incidence of CVA, PD, and dementia in each subgroup was recorded and compared among them using one-way analysis of variance (ANOVA).\n\nRESULTS:\nA total of 306 patients were included. VUDS examinations revealed DV in 87 patients, PRES in 108, and HSB in 111. Among them, 36 (11.8%) patients had CNS disease, including CVA in 23 (7.5%), PD in 4 (1.3%), and dementia in 9 (2.9%). Among the three subgroups, the DV group had the highest incidence rate of CNS disease ( = 16, 18.4%), followed by PRES ( = 12, 11.1%) and HSB ( = 8, 7.2%). However, no significant difference was noted in the incidence of CNS disease across the three subgroups. Nevertheless, the incidence of CNS disease was higher in patients with DV and PRES than that in the general population.\n\nCONCLUSIONS:\nThe incidence of CNS diseases was high in patients aged \u003e 60 years with voiding dysfunction due to urethral sphincter dysfunction. Patients with VUDS-confirmed DV had the highest incidence of CNS disease among the three subgroups." + } +} \ No newline at end of file diff --git a/37109081.json b/37109081.json new file mode 100644 index 0000000000000000000000000000000000000000..5fba7bebbfc8db6cd46400b832f284fe6481e41f --- /dev/null +++ b/37109081.json @@ -0,0 +1,8 @@ +{ + "id": "37109081", + "label": 0, + "article": { + "id": "37109081", + "text": "Multiple myeloma (MM) is a hematological neoplasm for which different chemotherapy treatments are used with several drugs in combination. One of the most frequently used drugs for the treatment of MM is the proteasome inhibitor bortezomib. Patients treated with bortezomib are at increased risk for thrombocytopenia, neutropenia, gastrointestinal toxicities, peripheral neuropathy, infection, and fatigue. This drug is almost entirely metabolized by cytochrome CYP450 isoenzymes and transported by the efflux pump P-glycoprotein. Genes encoding both enzymes and transporters involved in the bortezomib pharmacokinetic pathway are highly polymorphic. The response to bortezomib and the incidence of adverse drug reactions (ADRs) vary among patients, which could be due to interindividual variations in these possible pharmacogenetic biomarkers. In this review, we compiled all pharmacogenetic information relevant to the treatment of MM with bortezomib. In addition, we discuss possible future perspectives and the analysis of potential pharmacogenetic markers that could influence the incidence of ADR and the toxicity of bortezomib. It would be a milestone in the field of targeted therapy for MM to relate potential biomarkers to the various effects of bortezomib on patients." + } +} \ No newline at end of file diff --git a/37109183.json b/37109183.json new file mode 100644 index 0000000000000000000000000000000000000000..ce8b675cc6a97c2b57f8c5cef31c8f44121b1c8c --- /dev/null +++ b/37109183.json @@ -0,0 +1,8 @@ +{ + "id": "37109183", + "label": 0, + "article": { + "id": "37109183", + "text": "Emerging evidence is increasingly supporting the use of transcranial photobiomodulation (tPBM) to improve symptoms of neurodegenerative diseases, including Parkinson's disease (PD). The objective of this study was to analyse the safety and efficacy of tPBM for PD motor symptoms. The study was a triple blind, randomized placebo-controlled trial with 40 idiopathic PD patients receiving either active tPBM (635 nm plus 810 nm LEDs) or sham tPBM for 24 min per day (56.88J), six days per week, for 12 weeks. The primary outcome measures were treatment safety and a 37-item MDS-UPDRS-III (motor domain) assessed at baseline and 12 weeks. Individual MDS-UPDRS-III items were clustered into sub-score domains (facial, upper-limb, lower-limb, gait, and tremor). The treatment produced no safety concerns or adverse events, apart from occasional temporary and minor dizziness. There was no significant difference in total MDS-UPDRS-III scores between groups, presumably due to the placebo effect. Additional analyses demonstrated that facial and lower-limb sub-scores significantly improved with active treatment, while gait and lower-limb sub-scores significantly improved with sham treatment. Approximately 70% of participants responded to active treatment (≥5 decrease in MDS-UPDRS-III score) and improved in all sub-scores, while sham responders improved in lower-limb sub-scores only. tPBM appears to be a safe treatment and improved several PD motor symptoms in patients that responded to treatment. tPBM is proving to be increasingly attractive as a possible non-pharmaceutical adjunct therapy." + } +} \ No newline at end of file diff --git a/37109194.json b/37109194.json new file mode 100644 index 0000000000000000000000000000000000000000..98d0ccfb8f1b72a1469353cd5038b3c0b052b78d --- /dev/null +++ b/37109194.json @@ -0,0 +1,8 @@ +{ + "id": "37109194", + "label": 0, + "article": { + "id": "37109194", + "text": "Emergency care for asthma is provided by general practitioners, pulmonologists, and emergency departments (EDs). Although it is known that patients presenting to EDs with acute asthma exacerbations are a vulnerable population and that this mode of presentation is a risk marker for more severe complications, research on this population is scarce. We conducted a retrospective study on patients with asthma exacerbations who presented to the ED of the University Hospital Basel, Switzerland, during 2017-2020. Of the last 200 presentations, 100 were selected and analyzed to assess demographic information, the use of previous and ED-prescribed asthma medication, and clinical outcomes after a mean period of time of 18 months. Of these 100 asthma patients, 96 were self-presenters, and 43 had the second highest degree of acuity (emergency severity index 2). Global Initiative for Asthma (GINA) step 1 and step 3 were the most common among patients with known GINA levels, accounting for 22 and 18 patients, respectively. A total of 4 patients were undergoing treatment with oral corticosteroids at presentation, and 34 were at discharge. At presentation, 38 patients used the combination therapy of inhaled corticosteroid/long-acting β-agonist (ICS/LABA), and 6 patients underwent ICS monotherapy. At discharge, 68 patients were prescribed with ICS/LABA. At entry to the ED, about one-third of patients did not use any asthma medication. In total, 10 patients were hospitalized. None of them needed invasive or non-invasive ventilation. A follow-up for the study was precluded by the majority of patients. This group of asthma patients seemed particularly vulnerable as their asthma medication at presentation was often not according to guidelines or even lacking, and almost all the patients had self-presented to the ED without any reference from a physician. The majority of patients did not give consent to the collection of any follow-up information. These medical shortcomings reflect an urgent medical need to improve care for patients at high risk of asthma exacerbations." + } +} \ No newline at end of file diff --git a/37109269.json b/37109269.json new file mode 100644 index 0000000000000000000000000000000000000000..3e9d789a70a2eb4ce78b38528a6abbb06cc1cca4 --- /dev/null +++ b/37109269.json @@ -0,0 +1,8 @@ +{ + "id": "37109269", + "label": 0, + "article": { + "id": "37109269", + "text": "Chiari 1 Malformation (CM1) is classically defined as a caudal displacement of the cerebellar tonsils through the foramen magnum into the spinal cord. Modern imaging techniques and experimental studies disclose a different etiology for the development of CM1, but the main etiology factor is a structural defect in the skull as a deformity or partial reduction, which push down the lower part of the brain and cause the cerebellum to compress into the spinal canal. CM1 is classified as a rare disease. CM1 can present with a wide variety of symptoms, also non-specific, with consequent controversies on diagnosis and surgical decision-making, particularly in asymptomatic or minimally symptomatic. Other disorders, such as syringomyelia (Syr), hydrocephalus, and craniocervical instability can be associated at the time of the diagnosis or appear secondarily. Therefore, CM1-related Syr is defined as a single or multiple fluid-filled cavities within the spinal cord and/or the bulb. A rare CM1-related disorder is syndrome of lateral amyotrophic sclerosis (ALS mimic syndrome). We present a unique clinical case of ALS mimic syndrome in a young man with CM1 and a huge singular syringomyelic cyst with a length from segment C2 to Th12. At the same time, the clinical picture showed upper hypotonic-atrophic paraparesis in the absence of motor disorders in the lower extremities. Interestingly, this patient did not have a disorder of superficial and deep types of sensitivity. This made it difficult to diagnose CM1. For a long time, the patient's symptoms were regarded as a manifestation of ALS, as an independent neurological disease, and not as a related disorder of CM1. Surgical treatment for CM1 was not effective, but it allowed to stabilize the course of CM1-related ALS mimic syndrome over the next two years." + } +} \ No newline at end of file diff --git a/37109309.json b/37109309.json new file mode 100644 index 0000000000000000000000000000000000000000..e7ad9c02a7039ad165a86d0e8b8cd2d7d98e4e1c --- /dev/null +++ b/37109309.json @@ -0,0 +1,8 @@ +{ + "id": "37109309", + "label": 0, + "article": { + "id": "37109309", + "text": "Claudins (CLDNs) are a multigene family of proteins and the principal components of tight junctions (TJs), which normally mediate cell-cell adhesion and selectively allow the paracellular flux of ions and small molecules between cells. Downregulation of claudin proteins increases the paracellular permeability of nutrients and growth stimuli to malignant cells, which aids the epithelial transition. Claudin 18.2 (CLDN18.2) was identified as a promising target for the treatment of advanced gastroesophageal adenocarcinoma (GEAC), with high levels found in almost 30% of metastatic cases. CLDN18.2 aberrations, enriched in the genomically stable subgroup of GEAC and the diffuse histological subtype, are ideal candidates for monoclonal antibodies and CAR-T cells. Zolbetuximab, a highly specific anti-CLDN18.2 monoclonal antibody, demonstrated efficacy in phase II studies and, more recently, in the phase III SPOTLIGHT trial, with improvements in both PFS and OS with respect to standard chemotherapy. Anti-CLDN18.2 chimeric antigen receptor (CAR)-T cells showed a safety profile with a prevalence of hematologic toxicity in early phase clinical trials. The aim of this review is to present new findings in the treatment of CLDN18.2-positive GEAC, with a particular focus on the monoclonal antibody zolbetuximab and on the use of engineered anti-CLDN18.2 CAR-T cells." + } +} \ No newline at end of file diff --git a/37109571.json b/37109571.json new file mode 100644 index 0000000000000000000000000000000000000000..69d45db98719b0a87f2897da6a0b35d445cb0d4e --- /dev/null +++ b/37109571.json @@ -0,0 +1,8 @@ +{ + "id": "37109571", + "label": 0, + "article": { + "id": "37109571", + "text": "BACKGROUND:\nPramipexole is a dopamine full agonist approved for the treatment of Parkinson's disease and restless legs syndrome. Its high affinity for the D3 receptor and neuroprotective, antioxidant, and anti-inflammatory activity provides a rationale for the treatment of depression. In this paper, we review studies on the effectiveness and safety of antidepressant pramipexole augmentation in treatment-resistant depression.\n\nMETHODS:\nThis comprehensive systematic review and meta-analysis of observational studies on pramipexole-antidepressant augmentation included patients with resistant unipolar and bipolar depression. The primary outcome measure was the treatment response, measured at the study endpoint.\n\nRESULTS:\nWe identified 8 studies including 281 patients overall, 57% women and 39.5% with bipolar disorder and 60.5% with major depressive disorder. The mean follow-up duration was 27.3 weeks (range 8-69). The pooled estimate of treatment response was 62.5%, without significant differences between unipolar and bipolar depression. Safety was good, with nausea and somnolence the most frequent side effects.\n\nCONCLUSIONS:\nThe findings of this systematic review, needing further confirmation, show that off-label use of pramipexole as augmentation of antidepressant treatment could be a useful and safe strategy for unipolar and bipolar treatment-resistant depression." + } +} \ No newline at end of file diff --git a/37109674.json b/37109674.json new file mode 100644 index 0000000000000000000000000000000000000000..cdc215355a1eb2899c5fff4ecbb4139046c11478 --- /dev/null +++ b/37109674.json @@ -0,0 +1,8 @@ +{ + "id": "37109674", + "label": 0, + "article": { + "id": "37109674", + "text": ": Calcium-binding protein 39-like (CAB39L) has been reported to be downregulated and possessed diagnostic and prognostic values in several types of cancer. However, the clinical value and mechanism of CAB39L in kidney renal clear cell carcinoma (KIRC) remain unclear. : Bioinformatics analysis was conducted using different databases including TCGA, UALCAN, GEPIA, LinkedOmics, STRING, and TIMER. One-way variance analysis and -test were chosen to investigate the statistical differences of CAB39L expression in KIRC tissues with different clinical characteristics. The receiver operating characteristic (ROC) curve was chosen to assess the discriminatory capacity of CAB39L. Kaplan-Meier curves were employed for assessing the influence of CAB39L on the progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS) of KIRC patients. The independent prognostic significance of clinical parameters for OS such as CAB39L expression in KIRC patients was estimated by Cox analysis. A series of in vitro functional experiments and Western blot (WB) and immunohistochemistry (IHC) were used to validate the relative protein expression and function of CAB39L. : The mRNA and protein levels of CAB39L were relatively downregulated in KIRC samples. Meanwhile, hypermethylation of the CAB39L promoter region was possibly associated with its low expression in KIRC. The ROC curve showed that the mRNA expression of CAB39L had a strong diagnostic value for both early and late KIRC. Kaplan-Meier survival curves indicated that a higher mRNA level of CAB39L predicted good PFS, DSS, and OS. The mRNA expression of CAB39L was an independent prognostic factor (hazard ratio = 0.6, = 0.034) identified by multivariate Cox regression analysis. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis exhibited that CAB39L was mainly associated with substance and energy metabolism. Finally, overexpression of CAB39L impaired the proliferation and metastasis of KIRC cells in vitro. : CAB39L possesses prognostic and diagnostic capacity in KIRC." + } +} \ No newline at end of file diff --git a/37109715.json b/37109715.json new file mode 100644 index 0000000000000000000000000000000000000000..ac7e1bb4badea2241b7c9b66c66ab978b23fa45f --- /dev/null +++ b/37109715.json @@ -0,0 +1,8 @@ +{ + "id": "37109715", + "label": 0, + "article": { + "id": "37109715", + "text": "In 15-20% of cases, Graves' disease (GD) shifts to Hashimoto's thyroiditis (HT), while the shift from HT to GD is rare. We present a case of a patient in whom HT shifted to GD, along with a literature review. A 50-year-old woman with myxedema was diagnosed with Hashimoto's disease due to hypothyroidism and the presence of antibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TgAb); she also had thyroid stimulating antibodies (TSAb) without any signs of GD. Although thyroid hormone replacement therapy improved her thyroid function, 2 months later, hyperthyroidism appeared and did not improve after discontinuation of the replacement therapy. The patient was diagnosed with GD, which improved with antithyroid agent administration. To date, only 50 cases regarding conversion from HT to GD have been reported. The median age is 44 years (range, 23-82 years), and the median time of conversion is 7 years (range, 0.1-27 years). The male-to-female ratio of HT conversion to GD is 1:9, closer to that of regular GD (1:10) than that of general HT (1:18). All patients received thyroid hormone replacement therapy for hypothyroidism due to HT. Continuous evaluation of TSAb levels is recommended in HT, particularly in cases of TSAb-positive and those under replacement, since it may help predict conversion to GD. Evaluating the clinical characteristics of patients with HT preceding GD is crucial to ensure appropriate treatment and reduce the risk of adverse events." + } +} \ No newline at end of file diff --git a/37109725.json b/37109725.json new file mode 100644 index 0000000000000000000000000000000000000000..c0f74a4989a5b5505fb274602a4ff8343e7d9579 --- /dev/null +++ b/37109725.json @@ -0,0 +1,8 @@ +{ + "id": "37109725", + "label": 0, + "article": { + "id": "37109725", + "text": "In the past decades, several treatments have been proposed for the management of metastatic renal cell carcinoma (mRCC). Among these, cytoreductive nephrectomy (CN) represents a controversial and open issue in the era of targeted therapy and novel immunotherapy with immune checkpoint inhibitors. Two important studies, CARMENA and SURTIME, analyzed therapy with sunitinib with or without CN, and immediate CN followed by sunitinib versus a deferred CN after three cycles of sunitinib, respectively. CARMENA showed the non-inferiority of sunitinib alone versus sunitinib plus CN, whereas SURTIME showed no difference in progression-free survival (PFS), but a better median OS among patients with deferred CN. Therefore, more prospective clinical trials and appropriate patient identification are necessary to support CN in this new scenario. This review provides a snapshot of the current evidence for CN in mRCC, discusses the management strategies, and offers perspectives on the direction of future research." + } +} \ No newline at end of file diff --git a/37110126.json b/37110126.json new file mode 100644 index 0000000000000000000000000000000000000000..cd8ed9eb016eec3c213c238641bb22c68a27cd4b --- /dev/null +++ b/37110126.json @@ -0,0 +1,8 @@ +{ + "id": "37110126", + "label": 0, + "article": { + "id": "37110126", + "text": "Recent advances in targeting leukemic stem cells (LSCs) using venetoclax with azacitidine (ven + aza) has significantly improved outcomes for de novo acute myeloid leukemia (AML) patients. However, patients who relapse after traditional chemotherapy are often venetoclax-resistant and exhibit poor clinical outcomes. We previously described that fatty acid metabolism drives oxidative phosphorylation (OXPHOS) and acts as a mechanism of LSC survival in relapsed/refractory AML. Here, we report that chemotherapy-relapsed primary AML displays aberrant fatty acid and lipid metabolism, as well as increased fatty acid desaturation through the activity of fatty acid desaturases 1 and 2, and that fatty acid desaturases function as a mechanism of recycling NAD+ to drive relapsed LSC survival. When combined with ven + aza, the genetic and pharmacologic inhibition of fatty acid desaturation results in decreased primary AML viability in relapsed AML. This study includes the largest lipidomic profile of LSC-enriched primary AML patient cells to date and indicates that inhibition of fatty acid desaturation is a promising therapeutic target for relapsed AML." + } +} \ No newline at end of file diff --git a/37110139.json b/37110139.json new file mode 100644 index 0000000000000000000000000000000000000000..375d3a4e5b1881b16930e7ca681dc8dc713e0b2b --- /dev/null +++ b/37110139.json @@ -0,0 +1,8 @@ +{ + "id": "37110139", + "label": 0, + "article": { + "id": "37110139", + "text": "The Wnt signaling pathway is reported to be associated with lung cancer progression, metastasis and drug resistance, and thus it is an important therapeutic target for lung cancer. Plants have been shown as reservoirs of multiple potential anticancer agents. In the present investigation, the ethanolic leaf extract of (-EtOH) was initially analyzed by means of gas chromatography-mass spectrometry (GC-MS) to identify the important phytochemical constituents. The GC-MS analysis of -EtOH exhibited 48 peaks of various secondary metabolites such as terpenoids, flavonoids, carbohydrates, coumarins, amino acids, steroids, proteins, phytosterols, and diterpenes. It was found that the treatment with increasing doses of -EtOH suppressed the proliferation and migration of lung cancer cells. Furthermore, -EtOH induced prominent nuclear alteration along with a reduction in mitochondrial membrane potential and increased ROS (reactive oxygen species) generation in lung cancer cells. Moreover, -EtOH-treated cells exhibited increased apoptosis, demonstrated by the activation of caspase cascade. -EtOH also induced downregulation of Wnt3 and β-catenin expression along with cell cycle protein cyclin D1. Thus, the results of our study elucidated the potential of bioactive components of in the therapeutic management of lung cancer cells." + } +} \ No newline at end of file diff --git a/37110201.json b/37110201.json new file mode 100644 index 0000000000000000000000000000000000000000..1c72ad3101cfb7b5738240548d176fb2a6ba4bfd --- /dev/null +++ b/37110201.json @@ -0,0 +1,8 @@ +{ + "id": "37110201", + "label": 0, + "article": { + "id": "37110201", + "text": "Glioblastoma is the most common malignant primary brain tumor in adults. Thalidomide is a vascular endothelial growth factor inhibitor that demonstrates antiangiogenic activity, and may provide additive or synergistic anti-tumor effects when co-administered with other antiangiogenic medications. This study is a comprehensive review that highlights the potential benefits of using thalidomide, in combination with other medications, to treat glioblastoma and its associated inflammatory conditions. Additionally, the review examines the mechanism of action of thalidomide in different types of tumors, which may be beneficial in treating glioblastoma. To our knowledge, a similar study has not been conducted. We found that thalidomide, when used in combination with other medications, has been shown to produce better outcomes in several conditions or symptoms, such as myelodysplastic syndromes, multiple myeloma, Crohn's disease, colorectal cancer, renal failure carcinoma, breast cancer, glioblastoma, and hepatocellular carcinoma. However, challenges may persist for newly diagnosed or previously treated patients, with moderate side effects being reported, particularly with the various mechanisms of action observed for thalidomide. Therefore, thalidomide, used alone, may not receive significant attention for use in treating glioblastoma in the future. Conducting further research by replicating current studies that show improved outcomes when thalidomide is combined with other medications, using larger sample sizes, different demographic groups and ethnicities, and implementing enhanced therapeutic protocol management, may benefit these patients. A meta-analysis of the combinations of thalidomide with other medications in treating glioblastoma is also needed to investigate its potential benefits further." + } +} \ No newline at end of file diff --git a/37110204.json b/37110204.json new file mode 100644 index 0000000000000000000000000000000000000000..e9ad0e74decceb9c43c72291145f207763a1c405 --- /dev/null +++ b/37110204.json @@ -0,0 +1,8 @@ +{ + "id": "37110204", + "label": 0, + "article": { + "id": "37110204", + "text": "Menopause-associated asthma impacts a subset of women, tends to be more severe, and is less responsive to current treatments. We recently developed a model of menopause-associated asthma using 4-Vinylcyclohexene Diepoxide (VCD) and house dust mites (HDM). The goal of this study was to uncover potential biomarkers and drivers of menopause-onset asthma by assessing serum and bronchoalveolar lavage fluid (BALF) samples from mice with and without menopause and HDM challenge by large-scale targeted metabolomics. Female mice were treated with VCD/HDM to model menopause-associated asthma, and serum and BALF samples were processed for large-scale targeted metabolomic assessment. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to examine metabolites of potential biological significance. We identified over 50 individual metabolites, impacting 46 metabolic pathways, in the serum and BALF that were significantly different across the four study groups. In particular, glutamate, GABA, phosphocreatine, and pyroglutamic acid, which are involved in glutamate/glutamine, glutathione, and arginine and proline metabolisms, were significantly impacted in the menopausal HDM-challenged mice. Additionally, several metabolites had significant correlations with total airway resistance including glutamic acid, histamine, uridine, cytosine, cytidine, and acetamide. Using metabolic profiling, we identified metabolites and metabolic pathways that may aid in discriminating potential biomarkers for and drivers of menopause-associated asthma." + } +} \ No newline at end of file diff --git a/37110362.json b/37110362.json new file mode 100644 index 0000000000000000000000000000000000000000..4174f9e47c0634c09f446a62bdb6623a23a8e48c --- /dev/null +++ b/37110362.json @@ -0,0 +1,8 @@ +{ + "id": "37110362", + "label": 0, + "article": { + "id": "37110362", + "text": "Evidence from the literature suggests an association between the microbiome and asthma development. Here, we aimed to identify the current evidence for the association between asthma and the upper airway, lower airway and/or the gut microbiome. An electronic systemic search of PubMed, EBSCO, Science Direct and Web of Science was conducted until February 2022 to identify the eligible studies. The Newcastle-Ottawa Scale and the Systematic Review Centre for Laboratory Animal Experimentation risk of the bias tools were used to assess quality of included studies. Twenty-five studies met the inclusion criteria. Proteobacteria and Firmicutes were identified as being significantly higher in the asthmatic children compared with the healthy controls. The high relative abundance of , and in the microbiome of the upper airway in early infancy was associated with a higher risk of asthma development later in life. The gut microbiome analyses indicated that a high relative abundance of in early childhood might be associated with asthma development later in life. The findings reported here serve as potential microbiome signatures associated with the increased risk of asthma development. There is a need for large longitudinal studies to further identify high-risk infants, which will help in design strategies and prevention mechanisms to avoid asthma early in life." + } +} \ No newline at end of file diff --git a/37110590.json b/37110590.json new file mode 100644 index 0000000000000000000000000000000000000000..3c5e9ba1790062596c026ec9e340d2a13ad6bddb --- /dev/null +++ b/37110590.json @@ -0,0 +1,8 @@ +{ + "id": "37110590", + "label": 0, + "article": { + "id": "37110590", + "text": "Recent scientific data recognize the B7-H3 checkpoint molecule as a potential target for immunotherapy of pediatric solid tumors (PSTs). B7-H3 is highly expressed in extracranial PSTs such as neuroblastoma, rhabdomyosarcoma, nephroblastoma, osteosarcoma, and Ewing sarcoma, whereas its expression is absent or very low in normal tissues and organs. The influence of B7-H3 on the biological behavior of malignant solid neoplasms of childhood is expressed through different molecular mechanisms, including stimulation of immune evasion and tumor invasion, and cell-cycle disruption. It has been shown that B7-H3 knockdown decreased tumor cell proliferation and migration, suppressed tumor growth, and enhanced anti-tumor immune response in some pediatric solid cancers. Antibody-drug conjugates targeting B7-H3 exhibited profound anti-tumor effects against preclinical models of pediatric solid malignancies. Moreover, B7-H3-targeting chimeric antigen receptor (CAR)-T cells demonstrated significant in vivo activity against different xenograft models of neuroblastoma, Ewing sarcoma, and osteosarcoma. Finally, clinical studies demonstrated the potent anti-tumor activity of B7-H3-targeting antibody-radioimmunoconjugates in metastatic neuroblastoma. This review summarizes the established data from various PST-related studies, including in vitro, in vivo, and clinical research, and explains all the benefits and potential obstacles of targeting B7-H3 by novel immunotherapeutic agents designed to treat malignant extracranial solid tumors of childhood." + } +} \ No newline at end of file diff --git a/37110620.json b/37110620.json new file mode 100644 index 0000000000000000000000000000000000000000..8537a160be96ab0416755ba67b8ff80cb536084f --- /dev/null +++ b/37110620.json @@ -0,0 +1,8 @@ +{ + "id": "37110620", + "label": 0, + "article": { + "id": "37110620", + "text": "The Lion's mane mushroom (Hericium erinaceus, HE) is a traditional medical mushroom with high nutritional and economic value. HE possesses anticancer, antimicrobial, antioxidant, immunomodulating, neurotrophic, and neuroprotective activities. The present study evaluated the protection and antioxidative activities of micronized mycelium of HE (HEM) in mice treated with 1-methyl-4-phenylpyridinium (MPTP). HEM was cultivated via solid-state fermentation and micronized using cell wall-breaking technology to increase its bioavailability when ingested. Erinacine A, the bioactive compound in the HEM, played a pivotal role in antioxidant defense. We found that micronized HEM could recover the dopamine level in the mice striatum in a dose-dependent manner that had been greatly reduced during MPTP treatment. Moreover, the malondialdehyde (MDA) and carbonyl levels were reduced in the livers and brains of the MPTP + HEM-treated groups compared with the MPTP group. Additionally, antioxidant enzyme activities, including catalase, superoxide dismutase (SOD), glucose-6-phosphate dehydrogenase (G6PDH), and glutathione reductase (GRd), were elevated after the administration of HEM in MPTP-treated mice in a dose-dependent manner. Taken together, our data indicate that HEM cultivated via solid-state fermentation and processed with cell wall-breaking technology showed an excellent antioxidant efficacy." + } +} \ No newline at end of file diff --git a/37110707.json b/37110707.json new file mode 100644 index 0000000000000000000000000000000000000000..2b1ae171b9ba32e66b3a89f7384795aa1a3f2d3f --- /dev/null +++ b/37110707.json @@ -0,0 +1,8 @@ +{ + "id": "37110707", + "label": 0, + "article": { + "id": "37110707", + "text": "We hypothesized that (ES) induces apoptosis by inhibiting the expression of c-Myc in colon cancer cells, and this study proved that the methanol extract of ES has anticancer effects in colon cancer cells. ES belongs to the Celastraceae family and is well known for its medicinal properties. Extracts of species belonging to this family have been used to treat diverse diseases, including rheumatoid arthritis, chronic nephritis, allergic conjunctivitis, rhinitis, and asthma. However, ES has been targeted because there are currently few studies on the efficacy of ES for various diseases, including cancer. ES lowers cell viability in colon cancer cells and reduces the expression of c-Myc protein. We confirm that the protein level of apoptotic factors such as PARP and Caspase 3 decrease when ES is treated with Western blot, and confirm that DNA fragments occur through TUNEL assay. In addition, it is confirmed that the protein level of oncogenes CNOT2 and MID1IP1 decrease when ES is treated. We have also found that ES enhances the chemo-sensitivity of 5-FU in 5-FU-resistant cells. Therefore, we confirm that ES has anticancer effects by inducing apoptotic cell death and regulating the oncogenes CNOT2 and MID1IP1, suggesting its potential for use in the treatment of colon cancer." + } +} \ No newline at end of file diff --git a/37110852.json b/37110852.json new file mode 100644 index 0000000000000000000000000000000000000000..39482d1b68076adb33e6875b1f5327d2fe3ecd8b --- /dev/null +++ b/37110852.json @@ -0,0 +1,8 @@ +{ + "id": "37110852", + "label": 0, + "article": { + "id": "37110852", + "text": "Kaposi's sarcoma, an AIDS-defining illness, is caused by Kaposi's sarcoma-associated herpesvirus (KSHV), an oncogenic virus. In this study, we engineered ribozymes derived from ribonuclease P (RNase P) catalytic RNA with targeting against the mRNA encoding KSHV immediate early replication and transcription activator (RTA), which is vital for KSHV gene expression. The functional ribozyme F-RTA efficiently sliced the RTA mRNA sequence in vitro. In cells, KSHV production was suppressed with ribozyme F-RTA expression by 250-fold, and RTA expression was suppressed by 92-94%. In contrast, expression of control ribozymes hardly affected RTA expression or viral production. Further studies revealed both overall KSHV early and late gene expression and viral growth decreased because of F-RTA-facilitated suppression of RTA expression. Our results indicate the first instance of RNase P ribozymes having potential for use in anti-KSHV therapy." + } +} \ No newline at end of file diff --git a/37110891.json b/37110891.json new file mode 100644 index 0000000000000000000000000000000000000000..7fd7c12d333d43d3b31ecce34a821fe7b52837e8 --- /dev/null +++ b/37110891.json @@ -0,0 +1,8 @@ +{ + "id": "37110891", + "label": 0, + "article": { + "id": "37110891", + "text": "The citrus canker pathogen has caused severe damage to citrus crops worldwide, resulting in significant economic losses for the citrus industry. To address this, a green synthesis method was used to develop silver nanoparticles with the leaf extract of (GS-AgNP-LEPN). This method replaces the need for toxic reagents, as the LEPN acts as a reducing and capping agent. To further enhance their effectiveness, the GS-AgNP-LEPN were encapsulated in extracellular vesicles (EVs), nanovesicles with a diameter of approximately 30-1000 nm naturally released from different sources, including plant and mammalian cells, and found in the apoplastic fluid (APF) of leaves. When compared to a regular antibiotic (ampicillin), the delivery of APF-EV-GS-AgNP-LEPN and GS-AgNP-LEPN to pv. was shown to have more significant antimicrobial activity. Our analysis showed the presence of phyllanthin and nirurinetin in the LEPN and found evidence that both could be responsible for antimicrobial activity against pv. Ferredoxin-NADP reductase (FAD-FNR) and the effector protein XopAI play a crucial role in the survival and virulence of pv. Our molecular docking studies showed that nirurinetin could bind to FAD-FNR and XopAI with high binding energies (-10.32 kcal/mol and -6.13 kcal/mol, respectively) as compared to phyllanthin (-6.42 kcal/mol and -2.93 kcal/mol, respectively), which was also supported by the western blot experiment. We conclude that (a) the hybrid of APF-EV and GS-NP could be an effective treatment for citrus canker, and (b) it works via the nirurinetin-dependent inhibition of FAD-FNR and XopAI in pv." + } +} \ No newline at end of file diff --git a/37111040.json b/37111040.json new file mode 100644 index 0000000000000000000000000000000000000000..d2a7d793748a33814cd92ea559e659c155e9a914 --- /dev/null +++ b/37111040.json @@ -0,0 +1,8 @@ +{ + "id": "37111040", + "label": 0, + "article": { + "id": "37111040", + "text": "Amyotrophic lateral sclerosis (ALS) is a progressive disease of neuronal degeneration in the motor cortex, brainstem, and spinal cord, resulting in impaired motor function and premature demise as a result of insufficient respiratory drive. ALS is associated with dysfunctions in neurons, neuroglia, muscle cells, energy metabolism, and glutamate balance. Currently, there is not a widely accepted, effective treatment for this condition. Prior work from our lab has demonstrated the efficacy of supplemental nutrition with the Deanna Protocol (DP). In the present study, we tested the effects of three different treatments in a mouse model of ALS. These treatments were the DP alone, a glutamate scavenging protocol (GSP) alone, and a combination of the two treatments. Outcome measures included body weight, food intake, behavioral assessments, neurological score, and lifespan. Compared to the control group, DP had a significantly slower decline in neurological score, strength, endurance, and coordination, with a trend toward increased lifespan despite a greater loss of weight. GSP had a significantly slower decline in neurological score, strength, endurance, and coordination, with a trend toward increased lifespan. DP+GSP had a significantly slower decline in neurological score with a trend toward increased lifespan, despite a greater loss of weight. While each of the treatment groups fared better than the control group, the combination of the DP+GSP was not better than either of the individual treatments. We conclude that the beneficial effects of the DP and the GSP in this ALS mouse model are distinct, and appear to offer no additional benefit when combined." + } +} \ No newline at end of file diff --git a/37111280.json b/37111280.json new file mode 100644 index 0000000000000000000000000000000000000000..4b7e10fb21c340c17199e52e5890d99ee85dfd9a --- /dev/null +++ b/37111280.json @@ -0,0 +1,8 @@ +{ + "id": "37111280", + "label": 0, + "article": { + "id": "37111280", + "text": "The COVID-19 pandemic has posed a significant challenge to global public health. In response, the search for specific antiviral drugs that can effectively treat the disease caused by the SARS-CoV-2 virus has become a priority. While significant progress has been made in this regard, much work remains to address this ongoing crisis effectively. Favipiravir is an antiviral drug initially developed for the treatment of influenza and has received approval for emergency use for COVID-19 in many countries. A better understanding of the biodistribution and pharmacokinetics of Favipiravir in vivo would facilitate the development and translation of clinical antiviral drugs for COVID-19. Herein, we report the evaluation of [F]Favipiravir in naive mice, transgenic mice models of Alzheimer's disease, and nonhuman primates (NHP) with positron emission tomography (PET). The [F]Favipiravir was obtained in an overall decay-corrected radiochemical yield of 29% with a molar activity of 25 GBq/µmol at the end of synthesis (EOS). PET imaging in naive mice, transgenic mice models of Alzheimer's disease, and nonhuman primates revealed a low initial brain uptake, followed by a slow washout of [F]Favipiravir in vivo. The [F]Favipiravir was eliminated by a combination of hepatobiliary and urinary excretion. The low brain uptake was probably attributed to the low lipophilicity and low passive permeability of the drug. We hope this proof-of-concept study will provide a unique feature to study antiviral drugs using their corresponding isotopologues by PET." + } +} \ No newline at end of file diff --git a/37111289.json b/37111289.json new file mode 100644 index 0000000000000000000000000000000000000000..a9e41e1b3b4cebf3d66ebe61a1eaf592dd63a67d --- /dev/null +++ b/37111289.json @@ -0,0 +1,8 @@ +{ + "id": "37111289", + "label": 0, + "article": { + "id": "37111289", + "text": "MicroRNAs (miRNAs) are non-coding RNAs that play a major role in gene regulation in several diseases. MicroRNA-502-3p (MiR-502-3p) has been previously characterized in a variety of human diseases such as osteoporosis, diabetes, tuberculosis, cancers, and neurological disorders. Our studies recently explored the new role of miR-502-3p in regulating synapse function in Alzheimer's disease (AD). AD is the most common cause of dementia in elderly individuals. Synapse is the initial target that is hit during AD progression. The most common causes of synapse dysfunction in AD are amyloid beta, hyperphosphorylated tau, and microglia activation. MiR-502-3p was found to be localized and overexpressed in the AD synapses. Overexpression of miR-502-3p was correlated with AD severity in terms of Braak stages. Studies have shown that miR-502-3p modulates the glutaminergic and GABAergic synapse function in AD. The current study's emphasis is to discuss the in-depth roles of miR-502-3p in human diseases and AD and the future possibilities concerning miR-502-3p as a therapeutic for AD treatment." + } +} \ No newline at end of file diff --git a/37111311.json b/37111311.json new file mode 100644 index 0000000000000000000000000000000000000000..0c996355f2ec90737d9ee8b80c06587251022d68 --- /dev/null +++ b/37111311.json @@ -0,0 +1,8 @@ +{ + "id": "37111311", + "label": 0, + "article": { + "id": "37111311", + "text": "KRAS is one of the most common mutations detected in non-small cell lung cancer (NSCLC) patients, and it is a marker of poor prognosis. The first FDA-approved KRAS inhibitors, sotorasib and adagrasib, have been an enormous breakthrough for patients with KRAS mutant NSCLC; however, resistance to therapy is emerging. The transcriptional coactivators YAP1/TAZ and the family of transcription factors TEAD1-4 are the downstream effectors of the Hippo pathway and regulate essential cellular processes such as cell proliferation and cell survival. YAP1/TAZ-TEAD activity has further been implicated as a mechanism of resistance to targeted therapies. Here, we investigate the effect of combining TEAD inhibitors with KRAS inhibitors in KRAS mutant NSCLC tumor models. We show that TEAD inhibitors, while being inactive as single agents in KRAS-driven NSCLC cells, enhance KRAS inhibitor-mediated anti-tumor efficacy in vitro and in vivo. Mechanistically, the dual inhibition of KRAS and TEAD results in the downregulation of MYC and E2F signatures and in the alteration of the G2/M checkpoint, converging in an increase in G1 and a decrease in G2/M cell cycle phases. Our data suggest that the co-inhibition of KRAS and TEAD leads to a specific dual cell cycle arrest in KRAS NSCLC cells." + } +} \ No newline at end of file diff --git a/37111314.json b/37111314.json new file mode 100644 index 0000000000000000000000000000000000000000..737dc9c509ac27a72ff0658b39150c59b52c00ad --- /dev/null +++ b/37111314.json @@ -0,0 +1,8 @@ +{ + "id": "37111314", + "label": 0, + "article": { + "id": "37111314", + "text": "Over the past decade, the treatment of metastatic melanoma has improved significantly due to the development of innovative therapies, such as drugs that target the BRAF/MAPK kinase pathway and the PD-1 pathway. However, these therapies do not work for all patients, highlighting the need for additional research on the pathophysiology of melanoma. Paclitaxel is a chemotherapeutic agent used when first-line treatments are unsuccessful; however, its efficacy is limited. Since Krüppel-like factor 9 (KLF9) (antioxidant repressor) is downregulated in melanoma, we propose that restoring KLF9 levels may sensitize malignant melanoma to chemotherapeutic agents, such as paclitaxel. We used adenovirus overexpression and siRNA technologies to assess the role of KLF9 in mediating the response of malignant melanoma-derived cell lines RPMI-7951 and A375 to paclitaxel treatment. We found that increasing KLF9 levels potentiates the effectiveness of paclitaxel, as shown by apoptotic parameters such as decreased cell viability, pro-caspase-3 activation, increased number of annexin V-positive cells, and reduction in nuclear proliferation marker (KI67). These results suggest that KLF9 may be a potential target for improving chemotherapeutic response in melanoma." + } +} \ No newline at end of file diff --git a/37111337.json b/37111337.json new file mode 100644 index 0000000000000000000000000000000000000000..9c0bcf0f4dfca6d55f84d606bf3937a8660a8936 --- /dev/null +++ b/37111337.json @@ -0,0 +1,8 @@ +{ + "id": "37111337", + "label": 0, + "article": { + "id": "37111337", + "text": "Alzheimer's disease (AD) is the most common form of dementia. It increases the risk of other serious diseases and causes a huge impact on individuals, families, and socioeconomics. AD is a complex multifactorial disease, and current pharmacological therapies are largely based on the inhibition of enzymes involved in the pathogenesis of AD. Natural enzyme inhibitors are the potential sources for targeting AD treatment and are mainly collected from plants, marine organisms, or microorganisms. In particular, microbial sources have many advantages compared to other sources. While several reviews on AD have been reported, most of these previous reviews focused on presenting and discussing the general theory of AD or overviewing enzyme inhibitors from various sources, such as chemical synthesis, plants, and marine organisms, while only a few reviews regarding microbial sources of enzyme inhibitors against AD are available. Currently, multi-targeted drug investigation is a new trend for the potential treatment of AD. However, there is no review that has comprehensively discussed the various kinds of enzyme inhibitors from the microbial source. This review extensively addresses the above-mentioned aspect and simultaneously updates and provides a more comprehensive view of the enzyme targets involved in the pathogenesis of AD. The emerging trend of using in silico studies to discover drugs concerning AD inhibitors from microorganisms and perspectives for further experimental studies are also covered here." + } +} \ No newline at end of file diff --git a/37111341.json b/37111341.json new file mode 100644 index 0000000000000000000000000000000000000000..02745b45849c6072d87e4c41b027059c1c42cdc2 --- /dev/null +++ b/37111341.json @@ -0,0 +1,8 @@ +{ + "id": "37111341", + "label": 0, + "article": { + "id": "37111341", + "text": "Unfractionated heparin has multiple pharmacological activities beyond anticoagulation. These anti-inflammatory, anti-microbial, and mucoactive activities are shared in part by low molecular weight and non-anticoagulant heparin derivatives. Anti-inflammatory activities include inhibition of chemokine activity and cytokine synthesis, inhibitory effects on the mechanisms of adhesion and diapedesis involved in neutrophil recruitment, inhibition of heparanase activity, inhibition of the proteases of the coagulation and complement cascades, inhibition of neutrophil elastase activity, neutralisation of toxic basic histones, and inhibition of HMGB1 activity. This review considers the potential for heparin and its derivatives to treat inflammatory lung disease, including COVID-19, ALI, ARDS, cystic fibrosis, asthma, and COPD via the inhaled route." + } +} \ No newline at end of file diff --git a/37111346.json b/37111346.json new file mode 100644 index 0000000000000000000000000000000000000000..7e8efa2e990f8b9878413e50eeccd6e024007907 --- /dev/null +++ b/37111346.json @@ -0,0 +1,8 @@ +{ + "id": "37111346", + "label": 0, + "article": { + "id": "37111346", + "text": "Multiple myeloma is a malignancy of immunoglobulin-secreting plasma cells that is now often treated in the newly diagnosed and relapsed and/or refractory settings with monoclonal antibodies targeting lineage-specific markers used either alone or in rationally designed combination regimens. Among these are the anti-CD38 antibodies daratumumab and isatuximab, and the anti-Signaling lymphocytic activation molecule family member 7 antibody elotuzumab, all of which are used in their unconjugated formats. Single-chain variable fragments from antibodies also form a key element of the chimeric antigen receptors (CARs) in the B-cell maturation antigen (BCMA)-targeted CAR T-cell products idecabtagene vicleucel and ciltacabtagene autoleucel, which are approved in the advanced setting. Most recently, the bispecific anti-BCMA and T-cell-engaging antibody teclistamab has become available, again for patients with relapsed/refractory disease. Another format into which antibodies can be converted to exert anti-tumor efficacy is as antibody-drug conjugates (ADCs), and belantamab mafodotin, which also targets BCMA, represented the first such agent that gained a foothold in myeloma. Negative results from a recent Phase III study have prompted the initiation of a process for withdrawal of its marketing authorization. However, belantamab remains a drug with some promise, and many other ADCs targeting either BCMA or other plasma cell surface markers are in development and showing potential. This contribution will provide an overview of some of the current data supporting the possibility that ADCs will remain a part of our chemotherapeutic armamentarium against myeloma moving forward, and also highlight areas for future development." + } +} \ No newline at end of file diff --git a/37111355.json b/37111355.json new file mode 100644 index 0000000000000000000000000000000000000000..81cffb7b5a17e2be6f2a75fd987a97d3f341c3bc --- /dev/null +++ b/37111355.json @@ -0,0 +1,8 @@ +{ + "id": "37111355", + "label": 0, + "article": { + "id": "37111355", + "text": "Uveal melanoma (UM) is a rare malignant cancer of the eye, with up to 50% of patients dying from metastasis, for which no effective treatment is available. Due to the rarity of the disease, there is a great need to harness the limited material available from primary tumors and metastases for advanced research and preclinical drug screening. We established a platform to isolate, preserve, and transiently recover viable tissues, followed by the generation of spheroid cultures derived from primary UM. All assessed tumor-derived samples formed spheroids in culture within 24 h and stained positive for melanocyte-specific markers, indicating the retention of their melanocytic origin. These short-lived spheroids were only maintained for the duration of the experiment (7 days) or re-established from frozen tumor tissue acquired from the same patient. Intravenous injection of fluorescently labeled UM cells derived from these spheroids into zebrafish yielded a reproducible metastatic phenotype and recapitulated molecular features of the disseminating UM. This approach allowed for the experimental replications required for reliable drug screening (at least 2 individual biological experiments, with \u003e 20). Drug treatments with navitoclax and everolimus validated the zebrafish patient-derived model as a versatile preclinical tool for screening anti-UM drugs and as a preclinical platform to predict personalized drug responses." + } +} \ No newline at end of file diff --git a/37111374.json b/37111374.json new file mode 100644 index 0000000000000000000000000000000000000000..666bc876567cfdca4656082f9d0258e98b905740 --- /dev/null +++ b/37111374.json @@ -0,0 +1,8 @@ +{ + "id": "37111374", + "label": 0, + "article": { + "id": "37111374", + "text": "Exposure of many cancer cells, including multiple myeloma cells, to cytotoxic concentrations of natural products celastrol and withaferin A or synthetic compounds of the IHSF series resulted in denaturation of a luciferase reporter protein. Proteomic analysis of detergent-insoluble extract fractions from HeLa-derived cells revealed that withaferin A, IHSF058 and IHSF115 caused denaturation of 915, 722 and 991 of 5132 detected cellular proteins, respectively, of which 440 were targeted by all three compounds. Western blots showed that important fractions of these proteins, in some cases approaching half of total protein amounts, unfolded. Relatively indiscriminate covalent modification of target proteins was observed; 1178 different proteins were modified by IHSF058. Further illustrating the depth of the induced proteostasis crisis, only 13% of these proteins detectably aggregated, and 79% of the proteins that aggregated were not targets of covalent modification. Numerous proteostasis network components were modified and/or found in aggregates. Proteostasis disruption caused by the study compounds may be more profound than that mediated by proteasome inhibitors. The compounds act by a different mechanism that may be less susceptible to resistance development. Multiple myeloma cells were particularly sensitive to the compounds. Development of an additional proteostasis-disrupting therapy of multiple myeloma is suggested." + } +} \ No newline at end of file diff --git a/37111540.json b/37111540.json new file mode 100644 index 0000000000000000000000000000000000000000..a390e2fc28415a490f2033f6cba25b6e35740987 --- /dev/null +++ b/37111540.json @@ -0,0 +1,8 @@ +{ + "id": "37111540", + "label": 0, + "article": { + "id": "37111540", + "text": "Alzheimer's disease (AD) is the most prevalent form of dementia. It affects more than 30 million people worldwide and costs over US$ 1.3 trillion annually. AD is characterized by the brain accumulation of amyloid β peptide in fibrillar structures and the accumulation of hyperphosphorylated tau aggregates in neurons, both leading to toxicity and neuronal death. At present, there are only seven drugs approved for the treatment of AD, of which only two can slow down cognitive decline. Moreover, their use is only recommended for the early stages of AD, meaning that the major portion of AD patients still have no disease-modifying treatment options. Therefore, there is an urgent need to develop efficient therapies for AD. In this context, nanobiomaterials, and dendrimers in particular, offer the possibility of developing multifunctional and multitargeted therapies. Due to their intrinsic characteristics, dendrimers are first-in-class macromolecules for drug delivery. They have a globular, well-defined, and hyperbranched structure, controllable nanosize and multivalency, which allows them to act as efficient and versatile nanocarriers of different therapeutic molecules. In addition, different types of dendrimers display antioxidant, anti-inflammatory, anti-bacterial, anti-viral, anti-prion, and most importantly for the AD field, anti-amyloidogenic properties. Therefore, dendrimers can not only be excellent nanocarriers, but also be used as drugs per se. Here, the outstanding properties of dendrimers and derivatives that make them excellent AD nanotherapeutics are reviewed and critically discussed. The biological properties of several dendritic structures (dendrimers, derivatives, and dendrimer-like polymers) that enable them to be used as drugs for AD treatment will be pointed out and the chemical and structural characteristics behind those properties will be analysed. The reported use of these nanomaterials as nanocarriers in AD preclinical research is also presented. Finally, future perspectives and challenges that need to be overcome to make their use in the clinic a reality are discussed." + } +} \ No newline at end of file diff --git a/37111580.json b/37111580.json new file mode 100644 index 0000000000000000000000000000000000000000..62c7f08ccf1371cf3293d08d9a5e4d737aef4f6c --- /dev/null +++ b/37111580.json @@ -0,0 +1,8 @@ +{ + "id": "37111580", + "label": 0, + "article": { + "id": "37111580", + "text": "Amyotrophic lateral sclerosis (ALS) is the most prevalent motor neuron disorder in adults, which is associated with a highly disabling condition. To date, ALS remains incurable, and the only drugs approved by the FDA for its treatment confer a limited survival benefit. Recently, SOD1 binding ligand 1 (SBL-1) was shown to inhibit in vitro the oxidation of a critical residue for SOD1 aggregation, which is a central event in ALS-related neurodegeneration. In this work, we investigated the interactions between SOD1 wild-type and its most frequent variants, i.e., A4V (NP_000445.1:p.Ala5Val) and D90A (NP_000445.1:p.Asp91Val), with SBL-1 using molecular dynamics (MD) simulations. The pharmacokinetics and toxicological profile of SBL-1 were also characterized in silico. The MD results suggest that the complex SOD1-SBL-1 remains relatively stable and interacts within a close distance during the simulations. This analysis also suggests that the mechanism of action proposed by SBL-1 and its binding affinity to SOD1 may be preserved upon mutations A4V and D90A. The pharmacokinetics and toxicological assessments suggest that SBL-1 has drug-likeness characteristics with low toxicity. Our findings, therefore, suggested that SBL-1 may be a promising strategy to treat ALS based on an unprecedented mechanism, including for patients with these frequent mutations." + } +} \ No newline at end of file diff --git a/37111585.json b/37111585.json new file mode 100644 index 0000000000000000000000000000000000000000..57dc996050b5af11d42829c560ed9a32620547de --- /dev/null +++ b/37111585.json @@ -0,0 +1,8 @@ +{ + "id": "37111585", + "label": 0, + "article": { + "id": "37111585", + "text": "Chemically crosslinked hydrogels based on poly(-vinylcaprolactam) (PNVCL) were synthetized by a photoinitiated chemical method. A galactose-based monomer, 2-lactobionamidoethyl methacrylate (LAMA), and -vinylpyrrolidone (NVP) were added with the aim to improve the physical and chemical properties of hydrogels. The effects of both comonomers on the swelling ratio (Q), volume phase transition temperature (VPTT), glass transition temperature (T), and Young's moduli by mechanical compression below and above the VPTT were studied. Gold nanorods (GNRDs) and 5-fluorouracil (5FU) were embedded into the hydrogels, to study the drug release profiles with and without the excitation of GNRDs by irradiation in the near-infrared region (NIR). Results showed that the addition of LAMA and NVP increased the hydrogels' hydrophilicity, elasticity, and VPTT. The loading of GNRDs in the hydrogels changed the release rate of 5FU when irradiated intermittently with an NIR laser. The present study reports on the preparation of a hydrogel-based platform of PNVCL-GNRDs-5FU as a potential hybrid anticancer hydrogel for chemo/photothermal therapy that could be applied against skin cancer for topical 5FU delivery." + } +} \ No newline at end of file diff --git a/37111608.json b/37111608.json new file mode 100644 index 0000000000000000000000000000000000000000..f441a3f49aa690d89220281d41909c38fd49be60 --- /dev/null +++ b/37111608.json @@ -0,0 +1,8 @@ +{ + "id": "37111608", + "label": 0, + "article": { + "id": "37111608", + "text": "In recent years, gold nanoparticles (AuNPs) have aroused the interest of many researchers due to their unique physicochemical and optical properties. AuNPs are being explored in a variety of biomedical fields, either in diagnostics or therapy, particularly for localized thermal ablation of cancer cells after light irradiation. Besides the promising therapeutic potential of AuNPs, their safety constitutes a highly important issue for any medicine or medical device. For this reason, in the present work, the production and characterization of physicochemical properties and morphology of AuNPs coated with two different materials (hyaluronic and oleic acids (HAOA) and bovine serum albumin (BSA)) were firstly performed. Based on the above importantly referred issue, the in vitro safety of developed AuNPs was evaluated in healthy keratinocytes, human melanoma, breast, pancreatic and glioblastoma cancer cells, as well as in a three-dimensional human skin model. Ex vivo and in vivo biosafety assays using, respectively, human red blood cells and were also carried out. HAOA-AuNPs were selected for in vivo acute toxicity and biodistribution studies in healthy Balb/c mice. Histopathological analysis showed no significant signs of toxicity for the tested formulations. Overall, several techniques were developed in order to characterize the AuNPs and evaluate their safety. All these results support their use for biomedical applications." + } +} \ No newline at end of file diff --git a/37111618.json b/37111618.json new file mode 100644 index 0000000000000000000000000000000000000000..315a3ed00e3c9de7f12c7b2f611c5689114b00b7 --- /dev/null +++ b/37111618.json @@ -0,0 +1,8 @@ +{ + "id": "37111618", + "label": 0, + "article": { + "id": "37111618", + "text": "Alzheimer's disease (AD), the most common type of dementia, is characterized by senile plaques composed of amyloid β protein (Aβ) and neurofilament tangles derived from the hyperphosphorylation of tau protein. However, the developed medicines targeting Aβ and tau have not obtained ideal clinical efficacy, which raises a challenge to the hypothesis that AD is Aβ cascade-induced. A critical problem of AD pathogenesis is which endogenous factor induces Aβ aggregation and tau phosphorylation. Recently, age-associated endogenous formaldehyde has been suggested to be a direct trigger for Aβ- and tau-related pathology. Another key issue is whether or not AD drugs are successfully delivered to the damaged neurons. Both the blood-brain barrier (BBB) and extracellular space (ECS) are the barriers for drug delivery. Unexpectedly, Aβ-related SP deposition in ECS slows down or stops interstitial fluid drainage in AD, which is the direct reason for drug delivery failure. Here, we propose a new pathogenesis and perspectives on the direction of AD drug development and drug delivery: (1) aging-related formaldehyde is a direct trigger for Aβ assembly and tau hyperphosphorylation, and the new target for AD therapy is formaldehyde; (2) nano-packaging and physical therapy may be the promising strategy for increasing BBB permeability and accelerating interstitial fluid drainage." + } +} \ No newline at end of file diff --git a/37111629.json b/37111629.json new file mode 100644 index 0000000000000000000000000000000000000000..c467cffe39c767ff8cf90f7b6c1cc9b2e9ff1fad --- /dev/null +++ b/37111629.json @@ -0,0 +1,8 @@ +{ + "id": "37111629", + "label": 0, + "article": { + "id": "37111629", + "text": "Cancer immunotherapy is a type of treatment that harnesses the power of the immune systems of patients to target cancer cells with better precision compared to traditional chemotherapy. Several lines of treatment have been approved by the US Food and Drug Administration (FDA) and have led to remarkable success in the treatment of solid tumors, such as melanoma and small-cell lung cancer. These immunotherapies include checkpoint inhibitors, cytokines, and vaccines, while the chimeric antigen receptor (CAR) T-cell treatment has shown better responses in hematological malignancies. Despite these breakthrough achievements, the response to treatment has been variable among patients, and only a small percentage of cancer patients gained from this treatment, depending on the histological type of tumor and other host factors. Cancer cells develop mechanisms to avoid interacting with immune cells in these circumstances, which has an adverse effect on how effectively they react to therapy. These mechanisms arise either due to intrinsic factors within cancer cells or due other cells within the tumor microenvironment (TME). When this scenario is used in a therapeutic setting, the term \"resistance to immunotherapy\" is applied; \"primary resistance\" denotes a failure to respond to treatment from the start, and \"secondary resistance\" denotes a relapse following the initial response to immunotherapy. Here, we provide a thorough summary of the internal and external mechanisms underlying tumor resistance to immunotherapy. Furthermore, a variety of immunotherapies are briefly discussed, along with recent developments that have been employed to prevent relapses following treatment, with a focus on upcoming initiatives to improve the efficacy of immunotherapy for cancer patients." + } +} \ No newline at end of file diff --git a/37111634.json b/37111634.json new file mode 100644 index 0000000000000000000000000000000000000000..04a244327dbfead28649cad476b3b577de780074 --- /dev/null +++ b/37111634.json @@ -0,0 +1,8 @@ +{ + "id": "37111634", + "label": 0, + "article": { + "id": "37111634", + "text": "The ROR1 receptor tyrosine kinase is expressed in embryonic tissues but is absent in normal adult tissues. ROR1 is of importance in oncogenesis and is overexpressed in several cancers, such as NSCLC. In this study, we evaluated ROR1 expression in NSCLC patients (N = 287) and the cytotoxic effects of a small molecule ROR1 inhibitor (KAN0441571C) in NSCLC cell lines. ROR1 expression in tumor cells was more frequent in non-squamous (87%) than in squamous (57%) carcinomas patients, while 21% of neuroendocrine tumors expressed ROR1 ( = 0.0001). A significantly higher proportion of p53 negative patients in the ROR1 group than in the p53 positive non-squamous NSCLC patients ( = 0.03) was noted. KAN0441571C dephosphorylated ROR1 and induced apoptosis (Annexin V/PI) in a time- and dose-dependent manner in five ROR1 NSCLC cell lines and was superior compared to erlotinib (EGFR inhibitor). Apoptosis was confirmed by the downregulation of MCL-1 and BCL-2, as well as PARP and caspase 3 cleavage. The non-canonical Wnt pathway was involved. The combination of KAN0441571C and erlotinib showed a synergistic apoptotic effect. KAN0441571C also inhibited proliferative (cell cycle analyses, colony formation assay) and migratory (scratch wound healing assay) functions. Targeting NSCLC cells by a combination of ROR1 and EGFR inhibitors may represent a novel promising approach for the treatment of NSCLC patients." + } +} \ No newline at end of file diff --git a/37111678.json b/37111678.json new file mode 100644 index 0000000000000000000000000000000000000000..41e42395451eccf56d5a870587102de2500f2524 --- /dev/null +++ b/37111678.json @@ -0,0 +1,8 @@ +{ + "id": "37111678", + "label": 0, + "article": { + "id": "37111678", + "text": "The combination of TiO nanoparticles (NPs) and photosensitizers (PS) may offer significant advantages in photodynamic therapy (PDT) of melanoma, such as improved cell penetration, enhanced ROS production, and cancer selectivity. In this study, we aimed to investigate the photodynamic effect of 5,10,15,20-(Tetra-N-methyl-4-pyridyl)porphyrin tetratosylate (TMPyP4) complexes with TiO NPs on human cutaneous melanoma cells by irradiation with 1 mW/cm blue light. The porphyrin conjugation with the NPs was analyzed by absorption and FTIR spectroscopy. The morphological characterization of the complexes was performed by Scanning Electron Microscopy and Dynamic Light Scattering. The singlet oxygen generation was analyzed by phosphorescence at 1270 nm. Our predictions indicated that the non-irradiated investigated porphyrin has a low degree of toxicity. The photodynamic activity of the TMPyP4/TiO complex was assessed on the human melanoma Mel-Juso cell line and non-tumor skin CCD-1070Sk cell line treated with various concentrations of the PS and subjected to dark conditions and visible light-irradiation. The tested complexes of TiO NPs with TMPyP4 presented cytotoxicity only after activation by blue light (405 nm) mediated by the intracellular production of ROS in a dose-dependent manner. The photodynamic effect observed in this evaluation was higher in melanoma cells than the effect observed in the non-tumor cell line, demonstrating a promising potential for cancer-selectivity in PDT of melanoma." + } +} \ No newline at end of file diff --git a/37111680.json b/37111680.json new file mode 100644 index 0000000000000000000000000000000000000000..3de9b9ef2a6001cb6982b941526dc423f750cbd8 --- /dev/null +++ b/37111680.json @@ -0,0 +1,8 @@ +{ + "id": "37111680", + "label": 0, + "article": { + "id": "37111680", + "text": "is an evergreen coniferous species that has been widely used for treating pulmonary diseases and colds. Previous research has demonstrated the anti-inflammatory effect of species and the anti-asthmatic activities of leaf essential oil (AEO). As asthma and allergic rhinitis (AR) share pathophysiology and pharmacotherapeutic interventions, AEO inhalation can also ameliorate upper respiratory allergic diseases. This study explored the protective effects of AEO on AR with network pharmacological pathway prediction. The potential target pathways of AEO were analyzed by a network pharmacological approach. The BALB/c mice were sensitized by ovalbumin (OVA) and 10 μm particular matter (PM) to induce allergic rhinitis. Aerosolized AEO 0.0003% and 0.03% were delivered by nebulizer for 5 min a day, 3 times a week for 7 weeks. Nasal symptoms (sneezing and rubbing), histopathological changes in nasal tissues, serum IgE, and zonula occludens-1 (ZO-1) expressions on nasal tissues were analyzed. After AR induction with OVA+PM and inhalation of AEO 0.0003% and 0.03% treatment, AEO significantly decreased allergic symptoms (sneezing and rubbing), hyperplasia of nasal epithelial thickness, goblet cell counts, and serum IgE level. The network analysis demonstrated that the possible molecular mechanism of AEO is highly associated with the IL-17 signaling pathway and tight junction. The target pathway of AEO was investigated in RPMI 2650 nasal epithelial cells. Treatment of AEO on PM-treated nasal epithelial cells significantly reduced the production of inflammatory mediators related to the IL-17 signaling pathway, NF-κB, and the MAPK signaling pathway and prevented the reduction in TJ-related factors. When taken together, AEO inhalation may be considered as a potential treatment for AR by alleviating nasal inflammation and recovering the tight junction." + } +} \ No newline at end of file diff --git a/37111717.json b/37111717.json new file mode 100644 index 0000000000000000000000000000000000000000..4eeb848621519fd5f4ac17c5f5163a41a7c33db9 --- /dev/null +++ b/37111717.json @@ -0,0 +1,8 @@ +{ + "id": "37111717", + "label": 0, + "article": { + "id": "37111717", + "text": "The development of effective disease-modifying therapies to halt Parkinson's disease (PD) progression is required. In a subtype of PD patients, alpha-synuclein pathology may start in the enteric nervous system (ENS) or autonomic peripheral nervous system. Consequently, strategies to decrease the expression of alpha-synuclein in the ENS will be an approach to prevent PD progression at pre-clinical stages in these patients. In the present study, we aimed to assess if anti-alpha-synuclein shRNA-minicircles (MC) delivered by RVG-extracellular vesicles (RVG-EV) could downregulate alpha-synuclein expression in the intestine and spinal cord. RVG-EV containing shRNA-MC were injected intravenously in a PD mouse model, and alpha-synuclein downregulation was evaluated by qPCR and Western blot in the cord and distal intestine. Our results confirmed the downregulation of alpha-synuclein in the intestine and spinal cord of mice treated with the therapy. We demonstrated that the treatment with anti-alpha-synuclein shRNA-MC RVG-EV after the development of pathology is effective to downregulate alpha-synuclein expression in the brain as well as in the intestine and spinal cord. Moreover, we confirmed that a multidose treatment is necessary to maintain downregulation for long-term treatments. Our results support the potential use of anti-alpha-synuclein shRNA-MC RVG-EV as a therapy to delay or halt PD pathology progression." + } +} \ No newline at end of file diff --git a/37111728.json b/37111728.json new file mode 100644 index 0000000000000000000000000000000000000000..cdbe06d9aef87c511857cba57b6752c09acced62 --- /dev/null +++ b/37111728.json @@ -0,0 +1,8 @@ +{ + "id": "37111728", + "label": 0, + "article": { + "id": "37111728", + "text": "Skin cancer (SC) is affecting an increasing number of people worldwide. Its lesions affect mainly the most exposed regions of the skin. SC is classified into to main categories: non-melanoma (basal cell carcinoma of the epidermis and squamous cell carcinoma) and melanoma (the abnormal proliferation of melanocytes, which is rarer, more hazardous, and more deadly). Prevention and early diagnosis are important actions, and surgery is often considered. After the removal of cancerous lesions, the local administration of medicine can guarantee anticancer therapeutic action, rapid healing and the recovery of tissue, ensuring the absence of recurrence. Magnetic gels (MGs) have attracted increased attention regarding their pharmaceutical and biomedical applications. They are magnetic nanoparticles (e.g., iron oxide nanoparticles) dispersed in a polymeric matrix, which constitute adaptive systems under a magnetic field. MGs can combine magnetic susceptibility, high elasticity, and softness, and are thus useful platforms for diagnostics, drug delivery, and also for hyperthermia. This manuscript reviews MGs as a technological strategy for the treatment of SC. An overview of SC and the treatment, types, and methods of preparing MGs are discussed. Moreover, the applications of MGs in SC and their future perspectives are considered. The combination of polymeric gels and magnetic nanoparticles continues to be investigated, and new products must hit the market. Clinical trials and new products are expected, due to the important advantages of MGs." + } +} \ No newline at end of file diff --git a/37111733.json b/37111733.json new file mode 100644 index 0000000000000000000000000000000000000000..71c08b090d8d5a53f43735a7c37320f2eba56b7b --- /dev/null +++ b/37111733.json @@ -0,0 +1,8 @@ +{ + "id": "37111733", + "label": 0, + "article": { + "id": "37111733", + "text": "Inhaled corticosteroids are the mainstay in the management of lung inflammation associated to chronic lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Nonetheless, available inhalation products are mostly short-acting formulations that require frequent administrations and do not always produce the desired anti-inflammatory effects. In this work, the production of inhalable beclomethasone dipropionate (BDP) dry powders based on polymeric particles was attempted. As starting material, the PHEA-g-RhB-g-PLA-g-PEG copolymer was chosen, obtained by grafting 0.6, 2.4 and 3.0 mol%, respectively, of rhodamine (RhB), polylactic acid (PLA) and polyethylene glycol 5000 (PEG) on alpha,beta-poly(N-2-hydroxyethyl)DL-aspartamide (PHEA). The drug was loaded into the polymeric particles (MP) as an inclusion complex (CI) with hydroxypropyl-cyclodextrin (HP-β-Cyd) (at a stoichiometric ratio of 1:1) or as free form. The spray-drying (SD) process to produce MPs was optimized by keeping the polymer concentration (0.6 wt/vol%) constant in the liquid feed and by varying other parameters such as the drug concentration. The theoretical aerodynamic diameter (d) values among the MPs are comparable and potentially suitable for inhalation, as confirmed also through evaluation of the experimental mass median aerodynamic diameter (MMAD). BDP shows a controlled release profile from MPs that is significantly higher (more than tripled) than from Clenil. In vitro tests on bronchial epithelial cells (16HBE) and adenocarcinomic human alveolar basal epithelial cells (A549) showed that all the MP samples (empty or drug-loaded) were highly biocompatible. None of the systems used induced apoptosis or necrosis. Moreover, the BDP loaded into the particles (BDP-Micro and CI-Micro) was more efficient than free BDP to counteract the effects of cigarette smoke and LPS on release of IL-6 and IL-8." + } +} \ No newline at end of file diff --git a/37111758.json b/37111758.json new file mode 100644 index 0000000000000000000000000000000000000000..079db8ef6823d4cb377aa2248760071506c407b8 --- /dev/null +++ b/37111758.json @@ -0,0 +1,8 @@ +{ + "id": "37111758", + "label": 0, + "article": { + "id": "37111758", + "text": "Lung cancer is the leading cause of cancer-related death worldwide. Its late diagnosis and consequently poor survival make necessary the search for new therapeutic targets. The mitogen-activated protein kinase (MAPK)-interacting kinase 1 (MNK1) is overexpressed in lung cancer and correlates with poor overall survival in non-small cell lung cancer (NSCLC) patients. The previously identified and optimized aptamer from our laboratory against MNK1, apMNKQ2, showed promising results as an antitumor drug in breast cancer in vitro and in vivo. Thus, the present study shows the antitumor potential of apMNKQ2 in another type of cancer where MNK1 plays a significant role, such as NSCLC. The effect of apMNKQ2 in lung cancer was studied with viability, toxicity, clonogenic, migration, invasion, and in vivo efficacy assays. Our results show that apMNKQ2 arrests the cell cycle and reduces viability, colony formation, migration, invasion, and epithelial-mesenchymal transition (EMT) processes in NSCLC cells. In addition, apMNKQ2 reduces tumor growth in an A549-cell line NSCLC xenograft model. In summary, targeting MNK1 with a specific aptamer may provide an innovative strategy for lung cancer treatment." + } +} \ No newline at end of file diff --git a/37111761.json b/37111761.json new file mode 100644 index 0000000000000000000000000000000000000000..6376df06a8805b17d723ce87d322248535a11aa3 --- /dev/null +++ b/37111761.json @@ -0,0 +1,8 @@ +{ + "id": "37111761", + "label": 0, + "article": { + "id": "37111761", + "text": "Although the anticancer role of curcumin has been extensively addressed in preclinical research, only a few studies were carried out in humans, with conflicting results. The aim of this systematic review is to collate together the results of the therapeutic effect of curcumin in cancer patients. A literature search was carried out in Pubmed, Scopus, and the Cochrane Central Register of Controlled Trials up to 29 January 2023. Only randomized controlled trials (RCTs) designed to evaluate the effects of curcumin on cancer progression, patient survival, or surgical/histological response were included. Seven out of 114 articles, published between 2016 and 2022, were analyzed. They evaluated patients with locally advanced and/or metastatic prostate, colorectal, and breast cancers, as well as multiple myeloma and oral leucoplakia. Curcumin was given as an add-on therapy in five studies. Cancer response was the most investigated primary endpoint and curcumin issued some positive results. On the contrary, curcumin was ineffective in improving overall or progression-free survival. The curcumin safety profile was favorable. In conclusion, available clinical evidence is not strong enough to support the therapeutic use of curcumin in cancer. New RCTs exploring the effects of different curcumin formulations in early-stage cancers would be welcome." + } +} \ No newline at end of file diff --git a/37111814.json b/37111814.json new file mode 100644 index 0000000000000000000000000000000000000000..7a66658c1c488dfa55fbcbf486b838246accd4cb --- /dev/null +++ b/37111814.json @@ -0,0 +1,8 @@ +{ + "id": "37111814", + "label": 0, + "article": { + "id": "37111814", + "text": "Malignant melanoma is an aggressive type of skin cancer characterised by high metastatic capacity and mortality rate. On the other hand, is known for its medicinal properties, including its anticancer potency. In this context, we aimed to (i) isolate various extracts of , (ii) characterize their phytochemical content, and (iii) determine their cytotoxic potential in an in vitro model of human malignant melanoma. To these ends, we utilized various spectrophotometric and chromatographic (UPLC-MS/MS) approaches to document the higher content of the methanolic extract in polyphenols, soluble sugars, proteins, condensed tannins, and chlorophylls -a and -b as opposed to those of dichloromethane and petroleum. In addition, the cytotoxicity profiling of all extracts was assessed through a colorimetric-based Alamar Blue assay in human malignant melanoma (A375 and COLO-679) as well as non-tumorigenic immortalized keratinocyte (HaCaT) cells. Overall, the methanolic extract was shown to exert significant cytotoxicity, in a time- and concentration-dependent manner, as opposed to the other extracts. The observed cytotoxicity was confined only to human malignant melanoma cells, whereas non-tumorigenic keratinocyte cells remained relatively unaffected. Finally, the expression levels of various apoptotic genes were assessed by qRT-PCR, indicating the activation of both intrinsic and extrinsic apoptotic cascades." + } +} \ No newline at end of file diff --git a/37111938.json b/37111938.json new file mode 100644 index 0000000000000000000000000000000000000000..3a9aba2be0ef4e807aa6744740222acb8c8544d8 --- /dev/null +++ b/37111938.json @@ -0,0 +1,8 @@ +{ + "id": "37111938", + "label": 0, + "article": { + "id": "37111938", + "text": "Alzheimer's disease (AD) is the most prevalent neurodegenerative condition, primarily affecting seniors. Despite the significant time and money spent over the past few decades, no therapy has been developed yet. In recent years, the research has focused on ameliorating the cytotoxic amyloid beta (Aβ) peptide aggregates and the increased elevated oxidative stress, two interconnected main AD hallmarks. Medicinal plants constitute a large pool for identifying bioactive compounds or mixtures with a therapeutic effect. (SS) has been previously characterized as neuroprotective toward AD. We investigated this ability of SS by generating eight distinct solvent fractions, which were chemically characterized and assessed for their antioxidant and neuroprotective potential. The majority of the fractions were rich in phenolics and flavonoids, and all except one showed significant antioxidant activity. Additionally, four SS extracts partly rescued the viability in Aβ-treated SH-SY5Y human neuroblastoma cells, with the initial aqueous extract being the most potent and demonstrating similar activity in retinoic-acid-differentiated cells as well. These extracts were rich in neuroprotective substances, such as apigenin, myricetin-3-galactoside, and ellagic acid. Our findings indicate that specific SS mixtures can benefit the pharmaceutical industry to develop herbal drugs and functional food products that may alleviate AD." + } +} \ No newline at end of file diff --git a/37112243.json b/37112243.json new file mode 100644 index 0000000000000000000000000000000000000000..ed207e436b6f33446fbff9fc25ff9ed9eeb9f316 --- /dev/null +++ b/37112243.json @@ -0,0 +1,8 @@ +{ + "id": "37112243", + "label": 0, + "article": { + "id": "37112243", + "text": "Parkinson's disease (PD) is characterized by a variety of motor and non-motor symptoms, some of them pertaining to gait and balance. The use of sensors for the monitoring of patients' mobility and the extraction of gait parameters, has emerged as an objective method for assessing the efficacy of their treatment and the progression of the disease. To that end, two popular solutions are pressure insoles and body-worn IMU-based devices, which have been used for precise, continuous, remote, and passive gait assessment. In this work, insole and IMU-based solutions were evaluated for assessing gait impairment, and were subsequently compared, producing evidence to support the use of instrumentation in everyday clinical practice. The evaluation was conducted using two datasets, generated during a clinical study, in which patients with PD wore, simultaneously, a pair of instrumented insoles and a set of wearable IMU-based devices. The data from the study were used to extract and compare gait features, independently, from the two aforementioned systems. Subsequently, subsets comprised of the extracted features, were used by machine learning algorithms for gait impairment assessment. The results indicated that insole gait kinematic features were highly correlated with those extracted from IMU-based devices. Moreover, both had the capacity to train accurate machine learning models for the detection of PD gait impairment." + } +} \ No newline at end of file diff --git a/37112313.json b/37112313.json new file mode 100644 index 0000000000000000000000000000000000000000..eca86944c4509f007c8c422f82a62ba74450770e --- /dev/null +++ b/37112313.json @@ -0,0 +1,8 @@ +{ + "id": "37112313", + "label": 0, + "article": { + "id": "37112313", + "text": "We used the first enzyme-free synthesis and stabilization of soluble melanochrome (MC) and 5,6-indolequinone (IQ) derived from levodopa (LD), dopamine (DA), and norepinephrine (NE) oxidation to develop a simple colorimetric assay for catecholamine detection in human urine, also elucidating the time-dependent formation and molecular weight of MC and IQ using UV-Vis spectroscopy and mass spectrometry. The quantitative detection of LD and DA was achieved in human urine using MC as a selective colorimetric reporter to demonstrate the potential assay applicability in a matrix of interest in therapeutic drug monitoring (TDM) and in clinical chemistry. The assay showed a linear dynamic range between 5.0 mg L and 50.0 mg L, covering the concentration range of DA and LD found in urine samples from, e.g., Parkinson's patients undergoing LD-based pharmacological therapy. The data reproducibility in the real matrix was very good within this concentration range (RSD% 3.7% and 6.1% for DA and LD, respectively), also showing very good analytical performances with the limits of detection of 3.69 ± 0.17 mg L and 2.51 ± 0.08 mg L for DA and LD, respectively, thus paving the way for the effective and non-invasive monitoring of dopamine and levodopa in urine from patients during TDM in Parkinson's disease." + } +} \ No newline at end of file diff --git a/37112493.json b/37112493.json new file mode 100644 index 0000000000000000000000000000000000000000..5356c9da081b5a04ad9c7e7925a7cea52495d4a5 --- /dev/null +++ b/37112493.json @@ -0,0 +1,8 @@ +{ + "id": "37112493", + "label": 0, + "article": { + "id": "37112493", + "text": "This study characterized person-specific rates of change of total daily physical activity (TDPA) and identified correlates of this change. TDPA metrics were extracted from multiday wrist-sensor recordings from 1083 older adults (average age 81 years; 76% female). Thirty-two covariates were collected at baseline. A series of linear mixed-effect models were used to identify covariates independently associated with the level and annual rate of change of TDPA. Though, person-specific rates of change varied during a mean follow-up of 5 years, 1079 of 1083 showed declining TDPA. The average decline was 16%/year, with a 4% increased rate of decline for every 10 years of age older at baseline. Following variable selection using multivariate modeling with forward and then backward elimination, age, sex, education, and 3 of 27 non-demographic covariates including motor abilities, a fractal metric, and IADL disability remained significantly associated with declining TDPA accounting for 21% of its variance (9% non-demographic and 12% demographics covariates). These results show that declining TDPA occurs in many very old adults. Few covariates remained correlated with this decline and the majority of its variance remained unexplained. Further work is needed to elucidate the biology underlying TDPA and to identify other factors that account for its decline." + } +} \ No newline at end of file diff --git a/37112496.json b/37112496.json new file mode 100644 index 0000000000000000000000000000000000000000..f9c057f36b6b3b922eca4ad7397f1a1afee4f1e1 --- /dev/null +++ b/37112496.json @@ -0,0 +1,8 @@ +{ + "id": "37112496", + "label": 0, + "article": { + "id": "37112496", + "text": "Maintaining physical activity is an important clinical goal for people with Parkinson's disease (PwPD). We investigated the validity of two commercial activity trackers (ATs) to measure daily step counts. We compared a wrist- and a hip-worn commercial AT against the research-grade Dynaport Movemonitor (DAM) during 14 days of daily use. Criterion validity was assessed in 28 PwPD and 30 healthy controls (HCs) by a 2 × 3 ANOVA and intraclass correlation coefficients (ICC). The ability to measure daily step fluctuations compared to the DAM was studied by a 2 × 3 ANOVA and Kendall correlations. We also explored compliance and user-friendliness. Both the ATs and the DAM measured significantly fewer steps/day in PwPD compared to HCs ( \u003c 0.01). Step counts derived from the ATs showed good to excellent agreement with the DAM in both groups (ICC \u003e 0.83). Daily fluctuations were detected adequately by the ATs, showing moderate associations with DAM-rankings. While compliance was high overall, 22% of PwPD were disinclined to use the ATs after the study. Overall, we conclude that the ATs had sufficient agreement with the DAM for the purpose of promoting physical activity in mildly affected PwPD. However, further validation is needed before clinical use can be widely recommended." + } +} \ No newline at end of file diff --git a/37112766.json b/37112766.json new file mode 100644 index 0000000000000000000000000000000000000000..ac5f787d2fa72b6d17c6ec566a8d51f4296adaee --- /dev/null +++ b/37112766.json @@ -0,0 +1,8 @@ +{ + "id": "37112766", + "label": 0, + "article": { + "id": "37112766", + "text": "T-cell acute lymphoblastic leukemia (T-ALL) is a hematologic malignancy derived from T cells. Numerous CAR T therapies have been successfully applied to treat hematologic malignancies in the clinic. Nevertheless, there remain several challenges to the extensive application of CAR T cell therapy in T cell malignancies, especially in T-ALL. The main reason for CAR T therapy limitations is that T-ALL cells and normal T cells share antigens, which improves the difficulty of sorting pure T cells, resulting in product contamination, and would lead to CAR T cell fratricide. Thus, we considered creating a CAR on T-ALL tumor cells (CAR T-ALL) to prevent fratricide and eliminate tumor cells. We found that T-ALL cells transduced with CAR would actually commit fratricide. However, CAR T-ALL could kill only tumor cells on T-ALL cell lines, and other types of tumor cells had no killing function after being transferred with CAR. Furthermore, we created CD99 CAR with expression controlled by the Tet-On system on Jurkat cells, which could avoid the fratricide of CAR T-ALL during proliferation, ensuring the controllability of the killing time and effect. Jurkat transduced with a CAR-targeting antigen, which was expressed on other cancer cells, could kill other cancer cell lines, demonstrating that T-ALL cells could be used as tool cells for cancer therapy. Our study supplied a new feasible treatment regimen for cancer treatment in the clinic." + } +} \ No newline at end of file diff --git a/37112810.json b/37112810.json new file mode 100644 index 0000000000000000000000000000000000000000..aa811897d77cda4a582161d0b176089cda33ebe8 --- /dev/null +++ b/37112810.json @@ -0,0 +1,8 @@ +{ + "id": "37112810", + "label": 0, + "article": { + "id": "37112810", + "text": "Oncolytic viral therapy is a promising novel approach to cancer treatment. Oncolytic viruses cause tumor regression through direct cytolysis on the one hand and recruiting and activating immune cells on the other. In this study, to enhance the antitumor efficacy of the thymidine kinase-deficient vaccinia virus (VV, Lister strain), recombinant variants encoding bacterial flagellin (subunit B) of (LIVP-FlaB-RFP), firefly luciferase (LIVP-Fluc-RFP) or red fluorescent protein (LIVP-RFP) were developed. The LIVP-FLuc-RFP strain demonstrated exceptional onco-specificity in tumor-bearing mice, detected by the in vivo imaging system (IVIS). The antitumor efficacy of these variants was explored in syngeneic murine tumor models (B16 melanoma, CT26 colon cancer and 4T1 breast cancer). After intravenous treatment with LIVP-FlaB-RFP or LIVP-RFP, all mice tumor models exhibited tumor regression, with a prolonged survival rate in comparison with the control mice. However, superior oncolytic activity was observed in the B16 melanoma models treated with LIVP-FlaB-RFP. Tumor-infiltrated lymphocytes and the cytokine analysis of the serum and tumor samples from the melanoma-xenografted mice treated with these virus variants demonstrated activation of the host's immune response. Thus, the expression of bacterial flagellin by VV can enhance its oncolytic efficacy against immunosuppressive solid tumors." + } +} \ No newline at end of file diff --git a/37112906.json b/37112906.json new file mode 100644 index 0000000000000000000000000000000000000000..ab39d03e1944d8634b95407bc68c3aa527ff0d70 --- /dev/null +++ b/37112906.json @@ -0,0 +1,8 @@ +{ + "id": "37112906", + "label": 0, + "article": { + "id": "37112906", + "text": "Endogenous retroviruses (ERVs) account for 8% of our genome, and, although they are usually silent in healthy tissues, they become reactivated and expressed in pathological conditions such as cancer. Several studies support a functional role of ERVs in tumour development and progression, specifically through their envelope (Env) protein, which contains a region described as an immunosuppressive domain (ISD). We have previously shown that targeting of the murine ERV (MelARV) Env using virus-like vaccine (VLV) technology, consisting of an adenoviral vector encoding virus-like particles (VLPs), induces protection against small tumours in mice. Here, we investigate the potency and efficacy of a novel MelARV VLV with a mutated ISD (ISDmut) that can modify the properties of the adenoviral vaccine-encoded Env protein. We show that the modification of the vaccine's ISD significantly enhanced T-cell immunogenicity in both prime and prime-boost vaccination regimens. The modified VLV in combination with an α-PD1 checkpoint inhibitor (CPI) exhibited excellent curative efficacy against large established colorectal CT26 tumours in mice. Furthermore, only ISDmut-vaccinated mice that survived CT26 challenge were additionally protected against rechallenge with a triple-negative breast cancer cell line (4T1), showing that our modified VLV provides cross-protection against different tumour types expressing ERV-derived antigens. We envision that translating these findings and technology into human ERVs (HERVs) could provide new treatment opportunities for cancer patients with unmet medical needs." + } +} \ No newline at end of file diff --git a/37112976.json b/37112976.json new file mode 100644 index 0000000000000000000000000000000000000000..9241cf904f18dd7e8ea8ba6227de5b45abeaf46b --- /dev/null +++ b/37112976.json @@ -0,0 +1,8 @@ +{ + "id": "37112976", + "label": 0, + "article": { + "id": "37112976", + "text": "Chronic hepatitis B (CHB) is the most common cause of hepatocellular carcinoma (HCC) worldwide. Antiviral treatment reduces the risk of HCC and mortality; nonetheless, globally in 2019, only 2.2% of CHB patients received treatment. Current international CHB guidelines recommend antiviral treatment only in subsets of patients with clear evidence of liver damage. This contrasts with hepatitis C or HIV where early treatment is recommended in all infected patients, regardless of end-organ damage. This narrative review aims to provide an overview of data on the early initiation of antiviral treatment and its related potential economic impact. Literature searches were performed using PubMed and abstracts from international liver congresses (2019-2021). Data on risk of disease progression and HCC and the impact of antiviral treatment in currently ineligible patients were summarized. Cost-effectiveness data on early antiviral treatment initiation were also collated. Accumulating molecular, clinical, and economic data suggest that early initiation of antiviral treatment could save many lives through HCC prevention in a highly cost-effective manner. In light of these data, we consider several alternative expanded treatment strategies that might further a simplified 'treatment as prevention' approach." + } +} \ No newline at end of file diff --git a/37112983.json b/37112983.json new file mode 100644 index 0000000000000000000000000000000000000000..12282ecda5726e5f638ff4e1486b0bd4112809c8 --- /dev/null +++ b/37112983.json @@ -0,0 +1,8 @@ +{ + "id": "37112983", + "label": 0, + "article": { + "id": "37112983", + "text": "Rhinoviruses (RVs) are the major cause of common cold, a respiratory disease that generally takes a mild course. However, occasionally, RV infection can lead to serious complications in patients debilitated by other ailments, e.g., asthma. Colds are a huge socioeconomic burden as neither vaccines nor other treatments are available. The many existing drug candidates either stabilize the capsid or inhibit the viral RNA polymerase, the viral proteinases, or the functions of other non-structural viral proteins; however, none has been approved by the FDA. Focusing on the genomic RNA as a possible target for antivirals, we asked whether stabilizing RNA secondary structures might inhibit the viral replication cycle. These secondary structures include G-quadruplexes (GQs), which are guanine-rich sequence stretches forming planar guanine tetrads via Hoogsteen base pairing with two or more of them stacking on top of each other; a number of small molecular drug candidates increase the energy required for their unfolding. The propensity of G-quadruplex formation can be predicted with bioinformatics tools and is expressed as a GQ score. Synthetic RNA oligonucleotides derived from the RV-A2 genome with sequences corresponding to the highest and lowest GQ scores indeed exhibited characteristics of GQs. In vivo, the GQ-stabilizing compounds, pyridostatin and PhenDC3, interfered with viral uncoating in Na but not in K-containing phosphate buffers. The thermostability studies and ultrastructural imaging of protein-free viral RNA cores suggest that Na keeps the encapsulated genome more open, allowing PDS and PhenDC3 to diffuse into the quasi-crystalline RNA and promote the formation and/or stabilization of GQs; the resulting conformational changes impair RNA unraveling and release from the virion. Preliminary reports have been published." + } +} \ No newline at end of file diff --git a/37112991.json b/37112991.json new file mode 100644 index 0000000000000000000000000000000000000000..e28a032fbe38fd4ba6d7bb53d826e44de8c55e9b --- /dev/null +++ b/37112991.json @@ -0,0 +1,8 @@ +{ + "id": "37112991", + "label": 0, + "article": { + "id": "37112991", + "text": "Although Kaposi's sarcoma-associated herpesvirus (KSHV) has been reported to cause several human cancers including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL), the mechanisms of KSHV-induced tumorigenesis, especially virus-host interaction network, are still not completely understood, which therefore hinders the development of effective therapies. Histamine, together with its receptors, plays an important role in various allergic diseases by regulating different inflammation and immune responses. Our previous data showed that antagonists targeting histamine receptors effectively repressed KSHV lytic replication. In the current study, we determined that histamine treatment increased cell proliferation and anchorage-independent growth abilities of KSHV-infected cells. Furthermore, histamine treatment affected the expression of some inflammatory factors from KSHV-infected cells. For clinical relevance, several histamine receptors were highly expressed in AIDS-KS tissues when compared to normal skin tissues. We determined that histamine treatment promoted KSHV-infected lymphoma progression in immunocompromised mice models. Therefore, besides viral replication, our data indicate that the histamine and related signaling are also involved in other functions of KSHV pathogenesis and oncogenesis." + } +} \ No newline at end of file diff --git a/37113037.json b/37113037.json new file mode 100644 index 0000000000000000000000000000000000000000..5954ec6424e27f0eadd45ef44849f5c63983a28f --- /dev/null +++ b/37113037.json @@ -0,0 +1,8 @@ +{ + "id": "37113037", + "label": 0, + "article": { + "id": "37113037", + "text": "BACKGROUND:\nPatients with food allergy may be advised to introduce specific foods into their diets, both to increase tolerance gradually and as next steps after completing oral immunotherapy or other therapeutic interventions. However, the safe use of retail foods depends on the ability to establish the specific allergen protein content of these foods.\n\nOBJECTIVE:\nTo develop a systematic approach to estimate the protein content of peanut, milk, egg, wheat, cashew, hazelnut, and walnut in a variety of retail food equivalents for each allergen and associated patient education materials.\n\nMETHOD:\nWe created an algorithm that used a multistep process with information from product food labels, nutrient databases, independent weighing and measuring of foods, and information provided by manufacturers, including certificates of analysis, and e-mail communication to estimate the allergen protein content of multiple retail foods for each of seven allergens. Once a variety of retail food equivalents for each allergen and allergen serving size was determined, we developed participant education handouts, which were reviewed by study teams at 10 food allergy centers, the National Institute of Allergy and Infectious Diseases, and the Consortium for Food Allergy Research coordinating center. After 1 year of use, multiple queries were addressed and the retail food equivalents and educational materials were reviewed and edited.\n\nRESULTS:\nWe identified a variety of retail food equivalents for seven allergens at six serving sizes, and created 48 unique patient education materials.\n\nCONCLUSION:\nOur results provide extensive guidance on a variety of retail equivalents for seven foods, and a method to estimate retail food protein equivalents systematically with ongoing reassessment." + } +} \ No newline at end of file diff --git a/37113132.json b/37113132.json new file mode 100644 index 0000000000000000000000000000000000000000..b9d0d8c116c2f6fae4add71669034f41bc36a448 --- /dev/null +++ b/37113132.json @@ -0,0 +1,8 @@ +{ + "id": "37113132", + "label": 0, + "article": { + "id": "37113132", + "text": "BACKGROUND:\nRecent studies have reported that gut microbiota is closely associated with cognitive fuction. Fecal microbiota transplantation (FMT) may be a potential treatment for cognitive impairment, but its efficacy in patients with cognitive impairment is unknown.\n\nOBJECTIVES:\nThis study aimed to investigate the safety and efficacy of FMT for cognitive impairment treatment.\n\nMETHODS:\nFive patients aged 54-80 years (three women) were enrolled in this single-arm clinical trial from July 2021 to May 2022. The Montreal Cognitive Assessment-B (MoCA-B), Activities of Daily Living (ADL), and the cognitive section of the Alzheimer's Disease Assessment Scale (ADAS-Cog) were assessed at days 0, 30, 60, 90, and 180. Additionally, stool and serum samples were obtained twice before FMT was administered and six months after the treatment. The structure of fecal microbiota was analyzed by 16S RNA gene sequencing. Serum samples were analyzed for metabolomics and lipopolysaccharide (LPS)-binding proteins by liquid chromatography-mass spectrometry and enzyme-linked immunosorbent assay, respectively. Safety was assessed based on adverse events, vital signs, and laboratory parameters during FMT and the follow-up period.\n\nRESULTS:\nThe MoCA, ADL, and ADAS-Cog scores of patients with mild cognitive impairment (patients C and E) after FMT were improved or maintained compared with those before transplantation. However, patients with severe cognitive impairment (patients A, B, and D) had no worsening of cognitive scores. Fecal microbiota analysis showed that FMT changed the structure of gut microbiota. The results of serum metabolomics analysis suggested that there were significant changes in the serum metabolomics of patients after FMT, with 7 up-regulated and 28 down-regulated metabolites. 3b,12a-dihydroxy-5a-cholanoic acid, 25-acetylvulgaroside, deoxycholic acid, 2(R)-hydroxydocosanoic acid, and P-anisic acid increased, while bilirubin and other metabolites decreased. KEFF pathway analysis indicated that the main metabolic pathways were bile secretion and choline metabolism in cancer. No adverse effects were reported throughout the study.\n\nCONCLUSIONS:\nIn this pilot study, FMT could maintain and improve cognitive function in mild cognitive impairment by changing gut microbiota structure and affecting serum metabolomics. Fecal bacteria capsules were safe. However, further studies are needed to evaluate the safety and efficacy of fecal microbiota transplantation. ClinicalTrials.gov Identifier: CHiCTR2100043548." + } +} \ No newline at end of file diff --git a/37113145.json b/37113145.json new file mode 100644 index 0000000000000000000000000000000000000000..1162ecff217e572a3418e2784e7cdfcda1900c38 --- /dev/null +++ b/37113145.json @@ -0,0 +1,8 @@ +{ + "id": "37113145", + "label": 0, + "article": { + "id": "37113145", + "text": "Alzheimer's disease (AD) is a progressive neurodegenerative condition characterized by tau pathology and accumulations of neurofibrillary tangles (NFTs) along with amyloid-beta (Aβ). It has been associated with neuronal damage, synaptic dysfunction, and cognitive deficits. The current review explained the molecular mechanisms behind the implications of Aβ aggregation in AD multiple events. Beta (β) and gamma (γ) secretases hydrolyzed amyloid precursor protein (APP) to produce Aβ, which then clumps together to form Aβ fibrils. The fibrils increase oxidative stress, inflammatory cascade, and caspase activation to cause hyperphosphorylation of tau protein into neurofibrillary tangles (NFTs), which ultimately lead to neuronal damage. Acetylcholine (Ach) degradation is accelerated by upstream regulation of the acetylcholinesterase (AChE) enzyme, which leads to a deficiency in neurotransmitters and cognitive impairment. There are presently no efficient or disease-modifying medications for AD. It is necessary to advance AD research to suggest novel compounds for treatment and prevention. Prospectively, it might be reasonable to conduct clinical trials with unclean medicines that have a range of effects, including anti-amyloid and anti-tau, neurotransmitter modulation, anti-neuroinflammatory, neuroprotective, and cognitive enhancement." + } +} \ No newline at end of file diff --git a/37113150.json b/37113150.json new file mode 100644 index 0000000000000000000000000000000000000000..7a1cf31b7a072dad93e9544e40a7889105e59c82 --- /dev/null +++ b/37113150.json @@ -0,0 +1,8 @@ +{ + "id": "37113150", + "label": 0, + "article": { + "id": "37113150", + "text": "Alzheimer's disease (AD) is a devastating neurodegenerative disorder for which there is no cure. Recently, several studies have reported a significant reduction in the incidence and progression of dementia among some patients receiving antihypertensive medications such as angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs). Why these drugs are beneficial in some AD patients and not others is unclear although it has been shown to be independent of their role in regulating blood pressure. Given the enormous and immediate potential of ACE-Is and ARBs for AD therapeutics it is imperative that we understand how they function. Recently, studies have shown that ACE-Is and ARBs, which target the renin angiotensin system in mammals, are also effective in suppressing neuronal cell death and memory defects in models of AD despite the fact that this pathway is not conserved in flies. This suggests that the beneficial effects of these drugs may be mediated by distinct and as yet, identified mechanisms. Here, we discuss how the short lifespan and ease of genetic manipulations available in provide us with a unique and unparalleled opportunity to rapidly identify the targets of ACE-Is and ARBs and evaluate their therapeutic effectiveness in robust models of AD." + } +} \ No newline at end of file diff --git a/37113354.json b/37113354.json new file mode 100644 index 0000000000000000000000000000000000000000..cb217aa70a1ca594a1569ef34564105efe0539de --- /dev/null +++ b/37113354.json @@ -0,0 +1,8 @@ +{ + "id": "37113354", + "label": 0, + "article": { + "id": "37113354", + "text": "In single-fraction (sf) stereotactic radiosurgery (SRS) for brain metastases (BM) from lung adenocarcinoma (LAC), a marginal dose of ≥22-24 Gy is generally deemed desirable for achieving long-term local tumor control, whereas symptomatic brain radionecrosis significantly increases when the surrounding brain volume receiving ≥12 Gy (V) exceeds \u003e5-10 cm, especially in a deep location. Here, we describe a 75-year-old male with a single LAC-BM of 20 mm in diameter, with a deep eloquent location, which was treated with sfSRS followed by erlotinib, resulting in sustained local complete remission (CR) with minimal adverse radiation effect at nearly five years after sfSRS. The LAC harbored epidermal growth factor receptor (EGFR) mutation. The gross tumor volume (GTV) was defined based on contrast-enhanced computed tomography (CECT) alone. sfSRS was implemented 11 days after planning CECT acquisition. The original GTV had some under- and over-coverage of the enhancing lesion. The D values of corrected GTV (cGTV) (3.08 cm) and 2-mm outside the cGTV were 18.0 Gy with 55% isodose and 14.8 Gy, respectively. The irradiated isodose volumes, including the GTV, receiving ≥22 Gy and ≥12 Gy were 2.18 cm and 14.32 cm, respectively. Erlotinib was administered 13 days after sfSRS with subsequent dose adjustments over 22 months. There was a remarkable tumor response and subsequent nearly CR of the BM were observed at 2.7 and 6.3 months, respectively, with the tumor remnant being visible as a tiny cavitary lesion located in the cortex of the post-central gyrus at 56.4 months. The present case suggests the existence of: (i) extremely radio- and tyrosine kinase inhibitor (TKI)-sensitive LAC-BM for which sfSRS of ≤18 Gy combined with EGFR-TKI is sufficient for attaining long-term CR; and (ii) long-term brain tolerance following sfSRS despite high 12 Gy volume and deep eloquent location in the late 70s The moderate marginal dose of the GTV, the main location of the BM in the cerebral cortex, and the excellent tumor responses with sufficient extrication from the mass effect may render the BM immune to late adverse radiation effect." + } +} \ No newline at end of file diff --git a/37113357.json b/37113357.json new file mode 100644 index 0000000000000000000000000000000000000000..996bba9de46ac84096ec4d9302a0316db2b95fa8 --- /dev/null +++ b/37113357.json @@ -0,0 +1,8 @@ +{ + "id": "37113357", + "label": 0, + "article": { + "id": "37113357", + "text": "Multiple cancers are a common occurrence, and the choice of treatment can be a challenging decision. The current case report describes a 71-year-old woman with overlapping anaplastic lymphoma kinase (ALK)-rearranged lung adenocarcinoma and HER2-mutant breast cancer, who achieved improvement with concurrent use of the molecularly targeted agents Alectinib, Trastuzumab, and Pertuzumab. A 71-year-old woman was diagnosed with lung adenocarcinoma and brain metastases, and invasive ductal carcinoma of the right breast, HER2-mutant type. In March 2021, a biopsy confirmed the presence of the ALK fusion gene in lung cancer. In April 2021, he started Alectinib and showed shrinkage of lung cancer; in December 2021, a metastatic liver tumor was found, and a liver biopsy diagnosed liver metastasis of breast cancer. Therefore, Alectinib was discontinued in February 2022, and Trastuzumab, Pertuzumab, and Docetaxel were started as chemotherapy for breast cancer. She continued treatment with Trastuzumab and Pertuzumab, but in July 2022, she developed an increase in lung cancer. Her metastatic liver tumor continued shrinking, and she was started on Trastuzumab, Pertuzumab, and Alectinib. After six months of treatment, the patient showed a sustained reduction in both lung cancer, breast cancer, and brain metastases with no adverse events. ALK rearrangement lung cancer often develops in young women, and similarly, breast cancer often develops in women. Therefore, those cancers may occur simultaneously. In such cases, the choice of treatment can be difficult, as both cancers require different approaches. Alectinib has been shown to have a high response rate and prolonged progression-free survival in ALK-rearranged non-small cell lung cancer (NSCLC). Trastuzumab and Pertuzumab are commonly used for the treatment of HER2-mutant breast cancer and have been shown to significantly improve progression-free survival and overall survival. This case report provides evidence that the concurrent use of Alectinib, Trastuzumab, and Pertuzumab can be an effective treatment for patients with overlapping ALK-rearranged NSCLC and HER2-mutant breast cancer. It is important to consider concurrent treatment in patients with multiple cancers to optimize treatment outcomes and improve quality of life. However, further studies are needed to establish the safety and efficacy of this combination of drugs for the treatment of overlapping cancers." + } +} \ No newline at end of file diff --git a/37113386.json b/37113386.json new file mode 100644 index 0000000000000000000000000000000000000000..a25fa279f85538bbeedca05350fbf63e5a352409 --- /dev/null +++ b/37113386.json @@ -0,0 +1,8 @@ +{ + "id": "37113386", + "label": 0, + "article": { + "id": "37113386", + "text": "The aim of the present study was to investigate the protective effect of Blume (GEB) against () in Alzheimer's disease (AD) through network pharmacology. Firstly, the active constituents of GEB through ETCM and BATMAN-TCM databases were collected and its potential AD-related targets in Swiss Target Prediction were predicted. The potential targets related to AD were collected from the GeneCards, OMIM, CTD and DisGeNET databases, and the differential genes (DEGs) between the normal population and the AD patient population in GSE5281 chip of the Gene Expression Omnibus database were collected at the same time. The intersection of the three targets yielded 59 key targets of GEB for the treatment of AD. The drug-active ingredient-target-AD network diagram was constructed and visualized with Cytoscape software to obtain the core components. Subsequently, protein-protein interaction analysis (PPI) was performed on 59 key targets through STRING database, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses was performed on 59 key targets. Finally, molecular docking was conducted between core components and core targets using AutoDock software, and the AD model was used for experimental verification to explore the regulatory paralysis effect of core components on the model, β-amyloid (Aβ) plaque deposition, and quantitative polymerase chain reaction verification of the regulatory effect of components on targets. The GEB components 4,4'-dihydroxydiphenyl methane (DM) and protocatechuic aldehyde (PA) were found to be most strongly associated with AD, and five core targets were identified in the PPI network, including GAPDH, EP300, HSP90AB1, KDM6B, and CREBBP. In addition to GAPDH, the other four targets were successfully docked with DM and PA using AutoDock software. Compared with the control group, 0.5 mM DM and 0.25 mM PA significantly delayed paralysis (P\u003c0.01), and inhibited the aggregation of Aβ plaques in . Both DM and PA could upregulate the expression level of core target gene HSP90AB1 (P\u003c0.01), and DM upregulated the expression of KDM6B (P\u003c0.01), suggesting that DM and PA may be potential active components of GEB in the treatment of AD." + } +} \ No newline at end of file diff --git a/37113492.json b/37113492.json new file mode 100644 index 0000000000000000000000000000000000000000..c760aa2799ae5385b6f8a4f36e501697083d1d07 --- /dev/null +++ b/37113492.json @@ -0,0 +1,8 @@ +{ + "id": "37113492", + "label": 0, + "article": { + "id": "37113492", + "text": "INTRODUCTION:\nImmune checkpoint inhibitor (ICPI) therapy is used to treat various malignancies; however, it can be associated with off-target effects including kidney injury. Acute tubulointerstitial nephritis is the most commonly described renal pathology associated with ICPIs, although less frequently, glomerulopathies may be identified when a kidney biopsy is performed in the work-up of acute kidney injury (AKI).\n\nCASE PRESENTATION:\nTwo patients with small cell carcinoma of the lung were treated with etoposide, carboplatin, and the ICPI atezolizumab. During 2 and 1.5 months of atezolizumab therapy, respectively, patients developed AKI, hematuria, and proteinuria, and kidney biopsies were performed. Both biopsies showed fibrillary glomerulonephritis with focal crescentic features. One patient died 5 days after the kidney biopsy, while the second showed improvement of renal function after discontinuation of atezolizumab and initiation of corticosteroid therapy.\n\nDISCUSSION:\nWe describe two cases of fibrillary glomerulonephritis with crescents after administration of atezolizumab. Development of impaired kidney function following initiation of ICPI therapy in both cases raises the possibility that ICPI therapy may potentiate the development of endocapillary proliferation and crescents (i.e., an \"active\" glomerulitis) immune modulation. Thus, exacerbation of underlying glomerulonephritis should be kept in the differential diagnosis of patients who develop AKI, proteinuria, and hematuria following ICPI therapy." + } +} \ No newline at end of file diff --git a/37113570.json b/37113570.json new file mode 100644 index 0000000000000000000000000000000000000000..ae421e86ee9e999c82cdd8af4116f76d8338214c --- /dev/null +++ b/37113570.json @@ -0,0 +1,8 @@ +{ + "id": "37113570", + "label": 0, + "article": { + "id": "37113570", + "text": "BACKGROUND:\nDrug efficacy generally varies with different durations. There is no systematic review analyzing the effect of selegiline for Parkinson's disease (PD) on different treatment duration. This study aims to analyze how the efficacy and safety of selegiline changes for PD over time.\n\nMETHODS:\nPubMed, the Cochrane Library, Embase, China National Knowledge Infrastructure and Wanfang Database were systematically retrieved for randomized controlled trials (RCTs) and observational studies of selegiline for PD. The search period was from inception to January 18th, 2022. The efficacy outcomes were measured by the mean change from baseline in the total and sub Unified Parkinson's Disease Rating Scale (UPDRS), Hamilton Depression Rating Scale (HAMD) and Webster Rating Scale (WRS) scores. The safety outcomes were measured by the proportion of participants having any adverse events overall and that in different system organ classes.\n\nRESULTS:\nAmong the 3,786 studies obtained, 27 RCTs and 11 observational studies met the inclusion criteria. Twenty-three studies reported an outcome which was also reported in at least one other study, and were included in meta-analyses. Compared with placebo, selegiline was found with a stronger reduction of total UPDRS score with increasing treatment duration [mean difference and 95% CIs in 1 month: -3.56 (-6.67, -0.45); 3 months: -3.32 (-3.75, -2.89); 6 months: -7.46 (-12.60, -2.32); 12 months: -5.07 (-6.74, -3.41); 48 months: -8.78 (-13.75, -3.80); 60 months: -11.06 (-16.19, -5.94)]. A similar trend was also found from the point estimates in UPDRS I, II, III, HAMD and WRS score. The results of observational studies on efficacy were not entirely consistent. As for safety, compared with placebo, selegiline had higher risk of incurring any adverse events [rate: 54.7% vs. 62.1%; odd ratio and 95% CIs: 1.58 (1.02, 2.44)], with the excess adverse events mainly manifested as neuropsychiatric disorders [26.7% vs. 31.6%; 1.36 (1.06, 1.75)] and no significant change over time. The statistically difference in overall adverse event between selegiline and active controls was not found.\n\nCONCLUSION:\nSelegiline was effective in improving total UPDRS score with increasing treatment duration, and had a higher risk of incurring adverse events, especially the adverse events in the neuropsychiatric system.\n\nSYSTEMATIC REVIEW REGISTRATION:\nhttps://www.crd.york.ac.uk/prospero/, identifier: PROSPERO CRD42021233145." + } +} \ No newline at end of file diff --git a/37113573.json b/37113573.json new file mode 100644 index 0000000000000000000000000000000000000000..ce6616f6d3ddc74d1cc7dabf99b54eeb57ea6095 --- /dev/null +++ b/37113573.json @@ -0,0 +1,8 @@ +{ + "id": "37113573", + "label": 0, + "article": { + "id": "37113573", + "text": "INTRODUCTION:\nEarly detection of mild cognitive impairment (MCI), a pre-clinical stage of Alzheimer's disease (AD), has been highlighted as it could be beneficial to prevent progression to AD. Although prior studies on MCI screening have been conducted, the optimized detection way remain unclear yet. Recently, the potential of biomarker for MCI has gained a lot of attention due to a relatively low discriminant power of clinical screening tools.\n\nMETHODS:\nThis study evaluated biomarkers for screening MCI by performing a verbal digit span task (VDST) using functional near-infrared spectroscopy (fNIRS) to measure signals from the prefrontal cortex (PFC) from a group of 84 healthy controls and 52 subjects with MCI. The concentration changes of oxy-hemoglobin (HbO) were explored during the task in subject groups.\n\nRESULTS:\nFindings revealed that significant reductions in HbO concentration were observed in the PFC in the MCI group. Specially, the mean of HbO (mHbO) in the left PFC showed the highest discriminant power for MCI, which was higher than that of the Korean version of montreal cognitive assessment (MoCA-K) widely used as a screening tool for MCI. Furthermore, the mHbO in the PFC during the VDST was identified to be significantly correlated to the MoCA-K scores.\n\nDISCUSSION:\nThese findings shed new light on the feasibility and superiority of fNIRS-derived neural biomarker for screening MCI." + } +} \ No newline at end of file diff --git a/37113657.json b/37113657.json new file mode 100644 index 0000000000000000000000000000000000000000..379059e16ca452eac3f81e504ce11378647fbe50 --- /dev/null +++ b/37113657.json @@ -0,0 +1,8 @@ +{ + "id": "37113657", + "label": 0, + "article": { + "id": "37113657", + "text": "Radiomics and artificial intelligence (AI) may increase the differentiation of benign from malignant kidney lesions, differentiation of angiomyolipoma (AML) from renal cell carcinoma (RCC), differentiation of oncocytoma from RCC, differentiation of different subtypes of RCC, to predict Fuhrman grade, to predict gene mutation through molecular biomarkers and to predict treatment response in metastatic RCC undergoing immunotherapy. Neural networks analyze imaging data. Statistical, geometrical, textural features derived are giving quantitative data of contour, internal heterogeneity and gray zone features of lesions. A comprehensive literature review was performed, until July 2022. Studies investigating the diagnostic value of radiomics in differentiation of renal lesions, grade prediction, gene alterations, molecular biomarkers and ongoing clinical trials have been analyzed. The application of AI and radiomics could lead to improved sensitivity, specificity, accuracy in detecting and differentiating between renal lesions. Standardization of scanner protocols will improve preoperative differentiation between benign, low-risk cancers and clinically significant renal cancers and holds the premises to enhance the diagnostic ability of imaging tools to characterize renal lesions." + } +} \ No newline at end of file diff --git a/37113687.json b/37113687.json new file mode 100644 index 0000000000000000000000000000000000000000..4148e8f64f3c8140d9597672e680eb0bbf9f4990 --- /dev/null +++ b/37113687.json @@ -0,0 +1,8 @@ +{ + "id": "37113687", + "label": 0, + "article": { + "id": "37113687", + "text": "In leukemia, resistance to therapy is a major concern for survival. MAPK-interacting kinases (MNKs) have been identified as important activators of oncogenic-related signaling and may be mediators of resistance. Recent studies in leukemia models, especially acute myeloid leukemia (AML), have focused on targeting MNKs together with other inhibitors or treating chemotherapy-resistant cells with MNK inhibitors. The preclinical demonstrations of the efficacy of MNK inhibitors in these combination formats would suggest a promising potential for use in clinical trials. Optimizing MNK inhibitors and testing in leukemia models is actively being pursued and may have important implications for the future. These studies are furthering the understanding of the mechanisms of MNKs in cancer which could translate to clinical studies." + } +} \ No newline at end of file diff --git a/37113721.json b/37113721.json new file mode 100644 index 0000000000000000000000000000000000000000..153f3ac26c69739937380e0bdf5030c007794bb2 --- /dev/null +++ b/37113721.json @@ -0,0 +1,8 @@ +{ + "id": "37113721", + "label": 0, + "article": { + "id": "37113721", + "text": "BACKGROUND:\nWorldwide, renal cell carcinoma comprises 2.2% and 1.8% of global cancer incidence and mortality, respectively. Studies of epidemiology, treatment modalities and outcomes of renal cell carcinoma (RCC) in Sudan are scarce. To address this shortcoming, we evaluated baseline information on the epidemiology, types of treatment and outcomes of RCC at Gezira Hospital for Renal Diseases and Surgery (GHRDS) and the National Cancer Institute (NCI).\n\nMETHODS:\nWe performed a retrospective, descriptive study of all patients with RCC, who were treated in GHRDS and NCI from January 2000 to December 2015.\n\nRESULTS:\nA total of 189 patients with RCC were identified over the study period. Tumours were more common among male patients (56%) and involved the left kidney in 52% of cases. The median age at diagnosis was 57 years (range: 21-90 years). Loin pain was the most frequent symptom ( = 103 patients) followed by weight loss ( = 103 patients) and haematuria ( = 65 patients). The most common histopathologic type of RCC was clear cell (73.5%), followed by papillary (13.8%) and chromophobe (1.6%). The relative frequencies of stages I-IV were 3.2%, 14.3%, 29.1% and 53.4%, respectively. The overall median survival rate was 24 months, and the 5-year survival rate was 40%. The 5-year survival rate in stages I-IV was 95%, 83%, 39%, and 17%, respectively. Advanced stages and higher-grade tumour were associated with worse survival. The median survival of stage IV patients was better for patients who underwent nephrectomy (11.0 months) compared to those who did not undergo nephrectomy (4.0 months) ( value = 0.28).\n\nCONCLUSION:\nOur findings reveal poor outcomes for patients with RCC in Sudan, which is most likely due to the high proportion of patients presenting with advanced stages at the time of initial presentation." + } +} \ No newline at end of file diff --git a/37113733.json b/37113733.json new file mode 100644 index 0000000000000000000000000000000000000000..f4139cbc6c0c55d2ccdcd5e913874bfd6e769a85 --- /dev/null +++ b/37113733.json @@ -0,0 +1,8 @@ +{ + "id": "37113733", + "label": 0, + "article": { + "id": "37113733", + "text": "BACKGROUND:\nCirculating tumor cells (CTCs) are prognostic biomarker in non-small-cell lung cancer (NSCLC). CTCs could also be used as predictor of efficacy of systemic treatments in advanced NSCLC.\n\nOBJECTIVES:\nWe described the dynamic changes of CTCs during first-line platinum-based chemotherapy in advanced NSCLC and clarified the correlation between CTC counts and efficacy of chemotherapy.\n\nDESIGN:\nChemotherapy is administered and blood specimens are collected at four time points from baseline to disease progression for CTC detection.\n\nMETHODS:\nThis multicenter prospective study enrolled patients with previously untreated stage III or IV NSCLC fit for standard platinum-based chemotherapy. Bloods were sampled as per standard operating procedures at baseline, cycle 1 and cycle 4 of chemotherapy, and at disease progression for CTC analysis using the CellSearch system.\n\nRESULTS:\nAmong 150 patients enrolled, median overall survival (OS) was 13.8, 8.4, and 7.9 months in patients with CTC, KITCTC, and KITCTC at baseline ( = 0.002). Patients with persistent negative CTC (46.0%) had longer progression-free survival [5.7 months, 95% confidence interval (CI): 5.0-6.5 3.0 months, 0.6-5.4; hazard ratio (HR): 0.34, 95% CI: 0.18-0.67) and OS (13.1 months, 10.9-15.3 5.6 months, 4.1-7.1; HR: 0.17, 0.08-0.36) compared with patients with persistent positive CTC (10.7%), which was not impacted by chemotherapy. Chemotherapy decreased CTC from 36.0% (54/150) to 13.7% (13/95).\n\nCONCLUSIONS:\nCTC persistent presence during treatment represents poor prognosis and resistance to chemotherapy in advanced NSCLC. Chemotherapy could effectively eliminate CTCs. Molecular characterization and the functionalization of CTC will be warranted for further intensive investigation.\n\nTRIAL REGISTRATION:\nNCT01740804." + } +} \ No newline at end of file diff --git a/37113744.json b/37113744.json new file mode 100644 index 0000000000000000000000000000000000000000..d6d958ab43fcf0934a4f79179527a6645690a4aa --- /dev/null +++ b/37113744.json @@ -0,0 +1,8 @@ +{ + "id": "37113744", + "label": 0, + "article": { + "id": "37113744", + "text": "The accumulation and aggregation of -synuclein is a pathognomonic sign of Parkinson's disease (PD). Maneb (MB) exposure has also been reported as one environmental triggering factor of this multifactorial neurodegenerative disease. In our laboratory, we have previously reported that mild overexpression of -synuclein (200% increase with respect to endogenous neuronal levels) can confer neuroprotection against several insults. Here, we tested the hypothesis that -synuclein can modulate the neuronal response against MB-induced neurotoxicity. When exposed to MB, cells with endogenous -synuclein expression displayed increased reactive oxygen species (ROS) associated with diminished glutamate-cysteine ligase catalytic subunit () and hemeoxygenase-1 () mRNA expressions and upregulation of the nuclear factor erythroid 2-related factor 2 (NRF2) repressor, BTB domain and CNC homolog 1 (BACH1). We found that -synuclein overexpression (wt -syn cells) attenuated MB-induced neuronal damage by reducing oxidative stress. Decreased ROS found in MB-treated wt -syn cells was associated with unaltered and mRNA expressions and decreased BACH1 expression. In addition, the increased SOD2 expression and catalase activity were associated with forkhead box O 3a (FOXO3a) nuclear compartmentalization. Cytoprotective effects observed in wt -syn cells were also associated with the upregulation of silent information regulator 1 (SIRT1). In control cells, MB-treatment downregulated glutathione peroxidase 4 mRNA levels, which was coincident with increased ROS content, lipid peroxidation, and mitochondrial alterations. These deleterious effects were prevented by ferrostatin-1, an inhibitor of ferroptosis, under conditions of endogenous -synuclein expression. The overexpression of -synuclein attenuated MB toxicity by the activation of the same mechanisms as ferrostatin-1. Overall, our findings suggest that mild overexpression of -synuclein attenuates MB-induced neurotoxicity through the modulation of NRF2 and FOXO3a transcription factors and prevents cell death probably by intervening in mechanisms associated with ferroptosis. Thus, we postulate that early stages of -synuclein overexpression could be potentially neuroprotective against MB neurotoxicity." + } +} \ No newline at end of file diff --git a/37113841.json b/37113841.json new file mode 100644 index 0000000000000000000000000000000000000000..e822bf10b12ae5a989fb294d751005224c628e03 --- /dev/null +++ b/37113841.json @@ -0,0 +1,8 @@ +{ + "id": "37113841", + "label": 0, + "article": { + "id": "37113841", + "text": "UNLABELLED:\nLeukemoid reaction (increase in leucocyte count \u003e50 ×10 cell/l) occurs due to reactive causes of bone marrow and is diagnosed after excluding the malignant haematological disorder. Leukemoid reaction is a rare clinical presentation in metastatic renal cell carcinoma and is said to have a rare prognosis. This case has had been reported in the line of SCARE criteria.\n\nCASE PRESENTATION:\nA case of a 35-year-old female with no known previous co-morbidities presented with a history of abdominal pain in the right flank region for 2 months, fever and cough for 2 months. Physical examination showed palpable mass and tenderness in the right flank and investigations showed leukemoid reaction in peripheral blood smear. The patient was initially treated with strong intravenous antibiotics with suspicion of pyelonephritis in another centre, despite which the patient still had elevated leucocyte count and referred to our centre, where the patient was evaluated for elevated leucocyte count and with further investigations, ruled out any malignant haematological disorder. Final diagnosis of renal cell carcinoma was made by renal mass biopsy. The patient underwent targeted therapy with sunitinib. The patient expired and further investigation and follow-up were not possible.\n\nCONCLUSION:\nThe lack of data and evidence of extensive diagnostic tests is the reason we are unable to assume leukemoid reaction as a poor prognostic factor in case of metastatic renal cell carcinoma. The presence of other paraneoplastic syndromes with renal cell carcinoma might have resulted in the poor prognosis that cannot be excluded." + } +} \ No newline at end of file diff --git a/37113860.json b/37113860.json new file mode 100644 index 0000000000000000000000000000000000000000..b7e58a7bc9bfa2786ef28a2d3c3859e746883403 --- /dev/null +++ b/37113860.json @@ -0,0 +1,8 @@ +{ + "id": "37113860", + "label": 0, + "article": { + "id": "37113860", + "text": "UNLABELLED:\nAbout 2% of all lung malignancies are pulmonary carcinoid tumors, a family of neuroendocrine tumors. Rarely does a typical tracheal carcinoid of the trachea manifest as an endoluminal polypoidal tumor.\n\nCASE PRESENTATION:\nThe author describe a 61-year-old nonsmoker who complained of growing nonexertional shortness of breath 5 years ago. She also had a wheezy chest and a dry cough. The results of the chest radiography and electrocardiogram revealed no noteworthy abnormalities. The results of the pulmonary function test supported the diagnosis of bronchial asthma. A patient's treatment has not advanced. After performing a bronchoscopy, a biopsy was taken and sent for pathological analysis. The endobronchial lining was found to have a subepithelial tumor infiltrate made up of nests of homogeneous bland cells with central nuclei and mild granular cytoplasm, according to histopathologic analysis. Considering all of these findings, the patient was diagnosed with a primary tracheal carcinoid tumor, which was misdiagnosed and treated as bronchial asthma.\n\nDISCUSSION AND CONCLUSION:\nPeople with stridor or trepopnea symptoms should undergo a computed tomography scan since central airway tumors can mimic the symptoms of bronchial asthma while a chest radiograph may be normal. Tracheal carcinoid that has not progressed to the mediastinum can be successfully removed with flexible bronchoscopy and electrocautery, but the excision site needs to be continuously watched for recurrence." + } +} \ No newline at end of file diff --git a/37113866.json b/37113866.json new file mode 100644 index 0000000000000000000000000000000000000000..eec0191966db94f6d7793d95f88ed77b7e4f0c9a --- /dev/null +++ b/37113866.json @@ -0,0 +1,8 @@ +{ + "id": "37113866", + "label": 0, + "article": { + "id": "37113866", + "text": "UNLABELLED:\nOrbital rhabdomyosarcoma (RMS) is a highly malignant, mesenchymal orbital tumor of childhood with a predilection in children less than 20 years of age. It presents as a space-occupying lesion in the orbit, most commonly over the superior nasal quadrant of the orbit. The patient usually presents with rapid onset unilateral proptosis and eyelid edema.\n\nCASE PPRESENTATION:\nIn this article, a 14-year-old male presented with rapidly progressive swelling of the right orbit. On ocular examination, there was nonaxial inferolateral proptosis of the right eye. Computed tomography revealed a large soft tissue density tissue lesion in the right nasal cavity and meati measuring at least 3.2×2.7×5.4 cm in size with the erosion of the right orbit along with extension of the lesion in the extraconal compartment of the orbit. An MRI of the brain with contrast showed a heterogeneously enhancing altered signal intensity lesion. Debulking was planned, and a biopsy of the mass was sent that gave an impression of alveolar RMS. He also received radiotherapy and chemotherapy at one of the cancer hospitals in Nepal. Postsurgical follow-up showed gradual improvement in the visual acuity of the right eye. No evidence of metastasis and recurrence was found upon subsequent follow-up.\n\nCONCLUSION:\nThus, early diagnosis and prompt treatment is most for a favorable prognosis in the case of RMS. The main aim of this article was to briefly overview a rare case of RMS, its clinical presentation, diagnosis, treatment modalities, and its prognosis." + } +} \ No newline at end of file diff --git a/37113924.json b/37113924.json new file mode 100644 index 0000000000000000000000000000000000000000..654c606604c9b0fe65cd465ef521def06a5fca44 --- /dev/null +++ b/37113924.json @@ -0,0 +1,8 @@ +{ + "id": "37113924", + "label": 0, + "article": { + "id": "37113924", + "text": "UNLABELLED:\nIn 2020, renal cell carcinoma (RCC) had an incidence of 73 750 new cases. This cancer is well known for its ability to give early and late metastases to some usual and unusual sites. The term 'late recurrence' is widely used to indicate a period exceeding 10 years from curative nephrectomy. This not-understood behaviour is almost specific to RCC, and it happens in a range between 4.3 and 11% of cases of RCC.\n\nCASE PRESENTATION:\nWe report a case of a 67-year-old nonalcoholic smoker Syrian male presented with a 2-month painful mass located at the left upper posterolateral abdominal wall's region. He has had a history of left chromophobe cell RCC treated with radical nephrectomy with adjuvant radiotherapy for 12 years. In light of computed tomography's findings, a surgical biopsy was performed, and a pathological and immunohistochemical examination confirmed the diagnosis of chromophobe RCC.\n\nCLINICAL DISCUSSION:\nMalignant cells seeding the surgical cut path and staying dormant for 12 years is the best theory of many to explain our case.\n\nCONCLUSION:\nWe reported evidence for the potential of a relatively indolent histologic type of RCC (i.e. chromophobe cell carcinoma) to cause late recurrence after 12 years to a very rare site (i.e. abdominal wall's superficial muscles). Research should focus on addressing late recurrence to determine the best surveillance protocols; investigating malignant cells seeding during surgery to improve surgical oncology's outcomes; and studying late recurrence's genetics to boost our targeted therapy options." + } +} \ No newline at end of file diff --git a/37113964.json b/37113964.json new file mode 100644 index 0000000000000000000000000000000000000000..ccea98cf0ff9b24296c1b6d1d2bcad1eca51f85b --- /dev/null +++ b/37113964.json @@ -0,0 +1,8 @@ +{ + "id": "37113964", + "label": 0, + "article": { + "id": "37113964", + "text": "UNLABELLED:\nGastrointestinal metastasis of pleomorphic lung cancer presents with nonspecific manifestations, leading to delayed diagnosis. Herein, the authors report the case of a 56-year-old patient who presented with gastrointestinal bleeding due to pleomorphic lung carcinoma.\n\nCASE PRESENTATION:\nA 56-year-old patient presented to the emergency department with melena. On examination, he was hemodynamically stable. He had a sensitive and mobile mass in the periumbilical region. A thoracoabdominal computed tomography scan showed a mass of the right apical superior lobe measuring 4 cm and a lobulated jejunal mass measuring 10 cm. A percutaneous biopsy of the lung tumor revealed primary pleomorphic lung carcinoma. The authors performed a midline laparotomy and made a bowel resection with an end-to-end anastomosis. The postoperative course was marked by severe nosocomial pneumonia, leading to septic shock and death. The histopathologic examination concluded with a metastatic lesion of pleomorphic lung carcinoma.\n\nCLINICAL DISCUSSION:\nThe authors reported a rare case of jejunal metastasis of pleomorphic lung cancer. Pleomorphic carcinoma of the lung is a rare pathology that accounts for 0.1-0.4% of nonsmall-cell lung cancer. The prognosis is poor. In the presence of gastrointestinal bleeding caused by small bowel metastases of pleomorphic lung cancer, surgery is the treatment of choice.\n\nCONCLUSIONS:\nSmall bowel metastasis of pleomorphic lung cancer is rare. Surgical treatment is the treatment of choice. The authors highlight the importance of suspecting gastrointestinal metastases in patients with pleomorphic lung cancer in the presence of nonspecific digestive symptoms." + } +} \ No newline at end of file diff --git a/37113975.json b/37113975.json new file mode 100644 index 0000000000000000000000000000000000000000..067c064946029ae4200d7ebd398e5b6ec57090c9 --- /dev/null +++ b/37113975.json @@ -0,0 +1,8 @@ +{ + "id": "37113975", + "label": 0, + "article": { + "id": "37113975", + "text": "UNLABELLED:\nEsophageal cancer is the eighth most prevalent cancer globally. Previously, several biomarkers have been used to predict the prognosis, although with variable reliability. Interestingly, it is noted that changes in liver function tests levels before and after neoadjuvant treatment are predictive in terms of cancer recurrence.\n\nOBJECTIVES:\nThe objectives of the current study were to associate novel markers, including aspartate aminotransferase-to-platelet ratio (APRI) and aspartate aminotransferase-to-alanine aminotransferase ratio (AAR) with survival in esophageal malignancy.\n\nMATERIALS AND METHODS:\nA retrospective study in a tertiary care hospital (single-center) included 951 patients having diagnosed esophageal carcinoma of any age group.\n\nRESULTS:\nThe median (interquartile range) age of study participants were 50 (38-60) years, including 43% males and 57% female patients, while the median (interquartile range) levels of AAR and APRI were 0.97 (0.81-1.25) and 0.19 (0.13-0.29), respectively. AAR was found to be higher in dysphagia for solids only and dysphagia for both liquids and solids rather than liquids only (=0.002), while other associations included well-differentiated tumor grade (=0.011), finding of esophageal stricture on esophagogastroduodenoscopy (=0.015), and characteristic of mass on computerized tomography scan being both circumferential and mural (=0.005). APRI was found to be higher in adenocarcinoma (=0.038), and finding of circumferential±ulcerated mass on esophagogastroduodenoscopy (\u003c0.001). On survival analysis, adenocarcinoma (\u003c0.001), luminal narrowing (=0.002), AAR greater than 1.0 (=0.006), and APRI greater than 0.2 (=0.007) were found to be poor survival predictors. On Cox proportional hazards regression, APRI was found to be more associated with poor survival than AAR (Hazard ratio: 1.682, 1.208-2.340, =0.002).\n\nCONCLUSION:\nThis study correlated clinical and pathological features of esophageal malignancy with noninvasive markers of hepatic function." + } +} \ No newline at end of file diff --git a/37114014.json b/37114014.json new file mode 100644 index 0000000000000000000000000000000000000000..607e8e83fffae7d1e39dc7d5b1243771ab036a9d --- /dev/null +++ b/37114014.json @@ -0,0 +1,8 @@ +{ + "id": "37114014", + "label": 0, + "article": { + "id": "37114014", + "text": "INTRODUCTION:\nWe evaluated determinants associated with care partner outcomes along the Alzheimer's disease (AD) stages.\n\nMETHODS:\nWe included = 270 care partners of amyloid-positive patients in the pre-dementia and dementia stages of AD. Using linear regression analysis, we examined determinants of four care partner outcomes: informal care time, caregiver distress, depression, and quality of life (QoL).\n\nRESULTS:\nMore behavioral symptoms and functional impairment in patients were associated with more informal care time and depressive symptoms in care partners. More behavioral symptoms were related with more caregiver distress. Spouse care partners spent more time on informal care and QoL was lower in female care partners. Behavioral problems and subtle functional impairment of the patient predisposed for worse care partner outcomes already in the pre-dementia stages.\n\nDISCUSSION:\nBoth patient and care partner determinants contribute to the care partner outcomes, already in early disease stages. This study provides red flags for high care partner burden." + } +} \ No newline at end of file diff --git a/37114054.json b/37114054.json new file mode 100644 index 0000000000000000000000000000000000000000..c27f19c0887e8532a820417e2275fc35b6c72c3e --- /dev/null +++ b/37114054.json @@ -0,0 +1,8 @@ +{ + "id": "37114054", + "label": 0, + "article": { + "id": "37114054", + "text": "BACKGROUND:\nProgrammed cell death-ligand 1 (PD-L1) inhibitors plus chemotherapy have made substantial progress in extensive-stage small-cell lung cancer (ES-SCLC), but the survival benefit is still limited. This study aimed to evaluate the preliminary efficacy and safety of camrelizumab plus platinum-irinotecan (IP/IC) followed by maintenance camrelizumab plus apatinib in patients with untreated ES-SCLC.\n\nMETHODS:\nIn this non-randomized clinical trial (NCT04453930), eligible patients with untreated ES-SCLC received 4-6 cycles of camrelizumab plus IP/IC, followed by maintenance with camrelizumab plus apatinib until disease progression or unmanageable toxicity. The primary endpoint was progression-free survival (PFS). Patients who received PD-L1 inhibitors (atezolizumab or durvalumab) plus platinum-etoposide (EP/EC) were selected as the historical control.\n\nRESULTS:\nNineteen patients received IP/IC plus camrelizumab and 34 patients received EP/EC plus PD-L1 inhibitor. At a median follow-up time of 12.1 months, the median PFS was 10.25 months (95% CI: 9.40-NA) in the IP/IC plus camrelizumab group and 7.10 months (95% CI 5.79-8.40) in the EP/EC plus PD-L1 inhibitor group, respectively (HR=0.58, 95% CI 0.42-0.81). The objective response rate of IP/IC plus camrelizumab and EP/EC plus PD-L1 inhibitor was 89.6% and 82.4%, respectively. The most common treatment-related adverse events in the IP/IC plus camrelizumab group was neutropenia, followed by reactive cutaneous capillary endothelial proliferation (RCCEP) and diarrhea. The occurrence of immune-related adverse event was found to be associated with a prolonged PFS (HR=4.64, 95% CI 1.92-11.18).\n\nCONCLUSIONS:\nIP/IC plus camrelizumab followed by maintenance camrelizumab plus apatinib showed preliminary efficacy and acceptable safety profile in patients with untreated ES-SCLC." + } +} \ No newline at end of file diff --git a/37114057.json b/37114057.json new file mode 100644 index 0000000000000000000000000000000000000000..3f50d7b17ea5e91e3b8592947e0ea7111ba23561 --- /dev/null +++ b/37114057.json @@ -0,0 +1,8 @@ +{ + "id": "37114057", + "label": 0, + "article": { + "id": "37114057", + "text": "BACKGROUND:\nAnti-type 2 inflammation therapy has been proposed as a treatment strategy for eosinophil-associated chronic airway disorders that could reduce exacerbations and improve lung function. We performed a meta-analysis of randomized controlled trials to assess the effectiveness of type 2 monoclonal antibodies (anti-T2s) for eosinophil-associated chronic airway disorders.\n\nMETHODS:\nPubMed, Embase, Web of Science, and Cochrane Library were searched from their inception to 21 August 2022. Randomized clinical trials evaluating the effectiveness of anti-T2s versus placebo in the treatment of chronic airway diseases were selected. The outcomes were exacerbation rate and change in pre-bronchodilator forced expiratory volume in 1 s (FEV1) from baseline. The Cochrane Risk of Bias Assessment Tool 1.0 was used to evaluate the risk of bias, and the random-effects or fixed-effect model were used to pool the data.\n\nRESULTS:\nThirty-eight articles concerning forty-one randomized clinical trials with 17,115 patients were included. Compared with placebo, anti-T2s therapy yielded a significant reduction in exacerbation rate in COPD and asthma (Rate Ratio (RR)=0.89, 95%CI, 0.83-0.95, I 29.4%; RR= 0.59, 95%CI, 0.52-0.68, I 83.9%, respectively) and improvement in FEV1 in asthma (Standard Mean Difference (SMD)=0.09, 95%CI, 0.08-0.11, I 42.6%). Anti-T2s therapy had no effect on FEV1 improvement in COPD (SMD=0.05, 95%CI, -0.01-0.10, I 69.8%).\n\nCONCLUSION:\nDespite inconsistent findings across trials, anti-T2s had a positive overall impact on patients' exacerbation rate in asthma and COPD and FEV1 in asthma. Anti-T2s may be effective in treating chronic airway illnesses related to eosinophils.\n\nSYSTEMATIC REVIEW REGISTRATION:\nhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022362280." + } +} \ No newline at end of file diff --git a/37114074.json b/37114074.json new file mode 100644 index 0000000000000000000000000000000000000000..1f00b13af16a469620c5f7259986ff4fb7368e38 --- /dev/null +++ b/37114074.json @@ -0,0 +1,8 @@ +{ + "id": "37114074", + "label": 0, + "article": { + "id": "37114074", + "text": "Longstanding evidence implicate glioma stem-like cells as the main drivers contributing toward glioblastoma (GBM) therapy resistance and tumor recurrence. Although oncolytic herpes simplex virus (oHSV) viral therapy is a promising biological therapy recently approved for melanoma (in the United States and Europe) and GBM (in Japan); however, the impact of this therapy on GBM stem-like cells (GSCs) is understudied. Here we show that post-oHSV virotherapy activated AKT signaling results in an enrichment of GSC signatures in glioma, which mimics the enrichment in GSC observed after radiation treatment. We also uncovered that a second-generation oncolytic virus armed with PTEN-L (oHSV-P10) decreases this by moderating IL6/JAK/STAT3 signaling. This ability was retained in the presence of radiation treatment and oHSV-P10-sensitized intracranial GBM to radiotherapy. Collectively, our findings uncover potential mechanisms to overcome GSC-mediated radiation resistance via oHSV-P10." + } +} \ No newline at end of file diff --git a/37114121.json b/37114121.json new file mode 100644 index 0000000000000000000000000000000000000000..dbc17ae27d11fb03cb9ea91a3e02244aa8b29fb1 --- /dev/null +++ b/37114121.json @@ -0,0 +1,8 @@ +{ + "id": "37114121", + "label": 0, + "article": { + "id": "37114121", + "text": "The presence of anaplastic lymphoma kinase ( rearrangement is reported to be related to the lack of efficacy of immune checkpoint inhibitors (ICIs). High levels of microsatellite instability (MSI-high) are important biomarkers of ICIs, particularly in colorectal cancer. The therapeutic effect of ICIs for MSI-high NSCLC is uncertain because of the rarity of these tumors. Here we report a case of rearranged NSCLC with MSI-high. A 48-year-old male was diagnosed with lung adenocarcinoma, cT4N3M1a, stage IVA with rearrangement, high PD-L1 expression with a tumor proportion score (TPS) of 100%, and MSI-high. The patient was treated with alectinib as the first-line therapy but progressed at five months with left atrial invasion re-expansion. The patient discontinued alectinib and was switched to pembrolizumab monotherapy. After two months, left atrial invasion significantly decreased. The patient continued pembrolizumab for a year without noticeable adverse events, and tumor shrinkage persisted. This case supports the efficacy of ICIs for MSI-high NSCLC, even in the presence of rearrangement." + } +} \ No newline at end of file diff --git a/37114126.json b/37114126.json new file mode 100644 index 0000000000000000000000000000000000000000..e3a2aa6a9906e7b40ad36cf45fd6a282a853b144 --- /dev/null +++ b/37114126.json @@ -0,0 +1,8 @@ +{ + "id": "37114126", + "label": 0, + "article": { + "id": "37114126", + "text": "INTRODUCTION:\nMalignant melanoma with gastric metastasis is extremely rare. We report a case of gastric metastasis caused by malignant melanoma of the lower limb.\n\nCASE PRESENTATION:\nA 60-year-old woman was hospitalized for left plantar pain. The patient found a black maculopapular eruption on the left sole of her left foot, which caused pain when pressed, and the pain was aggravated by walking, so she went to our hospital for treatment. On the second day of admission, the lesion of the left foot was removed under local anesthesia, and the removed tissue was sent for pathological examination. Combined with immunohistochemistry, it was consistent with malignant melanoma. During hospitalization, the patient developed abdominal pain and asked for gastroscopy. Gastroscopy revealed two 0.5 cm × 0.6 cm spots that can be seen arising from the stomach mucosa which were slightly swollen, slightly black in the center, and without erosion, and no abnormality was found in the other parts. At the same time, a biopsy was taken under a gastroscope and pathology suggests malignant melanoma. The patient could not undergo subsequent treatment due to cost. The patient was followed up until February 2022 and was within the survival period.\n\nCONCLUSION:\nMalignant melanoma gastric metastasis is extremely rare. When a patient has a previous history of melanoma surgery, this needs to be considered when gastrointestinal symptoms are present, and regular endoscopic screening is recommended. Early surgical treatment and postoperative chemotherapy or combined targeted therapy may improve the prognosis of patients." + } +} \ No newline at end of file diff --git a/37114131.json b/37114131.json new file mode 100644 index 0000000000000000000000000000000000000000..cd84aefad82b9674a33ea186b5298106b7d70169 --- /dev/null +++ b/37114131.json @@ -0,0 +1,8 @@ +{ + "id": "37114131", + "label": 0, + "article": { + "id": "37114131", + "text": "Acute promyelocytic leukemia (APL) is a unique, highly curable subtype of acute myeloid leukemia, owing to the therapeutic advances of the last decades which led to high complete remission rates and excellent long-term survival. Nevertheless, it remains associated with high early mortality rates. Early death is the major cause of treatment failure in APL and is mainly attributed to coagulopathy, differentiation syndrome, and less commonly, infectious events. Timely recognition of each complication plays a crucial role in the management of patients diagnosed with APL. Coronavirus Infectious Disease 2019 (COVID-19) has shown great heterogeneity in patient presentation. Clinical manifestations range from asymptomatic disease to severe forms, mainly characterized by a hyperinflammatory syndrome leading to acute respiratory distress and multiorgan failure. Patients with acute leukemia and concomitant COVID-19-related hyperinflammatory syndrome have particularly poor outcomes. We hereby report the case of a 28-year-old male patient who was diagnosed with high-risk APL, with severe associated coagulopathy at presentation. He was treated with chemotherapy according to the AIDA regimen. The first week of induction therapy was complicated by a differentiation syndrome manifesting as fever not attributable to infection and respiratory distress with pulmonary infiltrates, resolved after ATRA discontinuation and corticotherapy. On the fourth week of treatment, he tested positive for acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with minor pulmonary involvement. Clinical manifestations over the following days included tachycardia and hypotension, associated with elevated inflammatory markers and cardiac biomarkers (troponin I x58 upper NV). Cardiovascular magnetic resonance imaging was consistent with myocarditis. COVID-19-associated myocarditis was successfully treated with methylprednisolone, intravenous immunoglobulins and Anakinra. Differentiation syndrome and COVID-19-associated myocarditis are two life-threatening complications that adversely impact survival. However, early recognition and prompt treatment initiation can improve clinical outcomes, as was the case of our patient." + } +} \ No newline at end of file diff --git a/37114136.json b/37114136.json new file mode 100644 index 0000000000000000000000000000000000000000..a15000b9a4d74fab5e7763e149d705c801752cad --- /dev/null +++ b/37114136.json @@ -0,0 +1,8 @@ +{ + "id": "37114136", + "label": 0, + "article": { + "id": "37114136", + "text": "BACKGROUND:\nThere is increasing evidence that immunotherapy (programmed cell death-1 (PD-1) inhibitor) combined with chemotherapy is superior to chemotherapy alone in neoadjuvant therapy for patients with previously untreated, unresectable advanced, or metastatic esophageal adenocarcinoma (EAC)/gastric/gastroesophageal junction adenocarcinoma (GEA). However, the results of recent studies have been contradictory. Therefore, the aim of this article is to evaluate the efficacy and safety of PD-1 inhibitors combined with chemotherapy in neoadjuvant therapy through meta-analysis.\n\nMETHOD:\nWe comprehensively reviewed the literature and clinical randomized controlled trials (RCTs) by February 2022 by searching Medical Subject Headings (MeSH) and keywords such as \"esophageal adenocarcinoma\" or \"immunotherapy\" in several databases, including the Embase, Cochrane, PubMed, and ClinicalTrials.gov websites. Two authors independently selected studies, extracted data, and assessed the risk of bias and quality of evidence by using standardized Cochrane Methods procedures. The primary outcomes were 1-year overall survival (OS) and 1-year progression-free survival (PFS), estimated by calculating the 95% confidence interval (CI) for the combined odds ratio (OR) and hazard ratio (HR). Secondary outcomes estimated using OR were disease objective response rate (DORR) and incidence of adverse events.\n\nRESULTS:\nFour RCTs with a total of 3,013 patients researching the efficacy of immunotherapy plus chemotherapy versus chemotherapy alone on gastrointestinal cancer were included in this meta-analysis. The results showed that immune checkpoint inhibitor plus chemotherapy treatment was associated with an increased risk of PFS (HR = 0.76 [95% CI: 0.70-0.83]; p \u003c 0.001), OS (HR = 0.81 [95% CI: 0.74-0.89]; p \u003c 0.001), and DORR (relative ratio (RR) = 1.31 [95% CI: 1.19-1.44]; p \u003c 0.0001) when compared with chemotherapy alone in advanced, unresectable, and metastatic EAC/GEA. However, immunotherapy combined with chemotherapy increased the incidence of adverse reactions such as alanine aminotransferase elevation (OR = 1.55 [95% CI: 1.17-2.07]; p = 0.003) and palmar-plantar erythrodysesthesia (PPE) syndrome (OR = 1.30 [95% CI: 1.05-1.63]; p = 0.02). Nausea (OR = 1.24 [95% CI: 1.07-1.44]; p = 0.005) and white blood cell count decreased (OR = 1.40 [95% CI: 1.13-1.73]; p = 0.002), and so on. Fortunately, toxicities were within acceptable limits. Meanwhile, for patients with a combined positive score (CPS) ≥1, compared with chemotherapy alone, immunotherapy combined with chemotherapy had a better overall survival rate (HR = 0.81 [95% CI: 0.73-0.90]; p = 0.0001).\n\nCONCLUSION:\nOur study shows that immunotherapy plus chemotherapy has an obvious benefit for patients with previously untreated, unresectable advanced, or metastatic EAC/GEA when compared with chemotherapy alone. However, a high risk of adverse reactions may occur during immunotherapy plus chemotherapy, and more studies focusing on the treatment strategies of untreated, unresectable advanced, or metastatic EAC/GEA are warranted.\n\nSYSTEMATIC REVIEW REGISTRATION:\nwww.crd.york.ac.uk, identifier CRD42022319434." + } +} \ No newline at end of file diff --git a/37114141.json b/37114141.json new file mode 100644 index 0000000000000000000000000000000000000000..b7702c8ed33f315287969a35c7d12c21568fa84e --- /dev/null +++ b/37114141.json @@ -0,0 +1,8 @@ +{ + "id": "37114141", + "label": 0, + "article": { + "id": "37114141", + "text": "BACKGROUND:\nMeningioma is a common type of intracranial tumor in adults. It rarely arises in the chest, with only a few case reports in the English literature. Here, we report the case of a patient with a primary ectopic meningioma (PEM) located in the thoracic cavity.\n\nCASE PRESENTATION:\nA 55-year-old woman presented with exercise-induced asthma, chest tightness, intermittent dry cough and fatigue for several months. Computed tomography revealed the presence of a huge mass in the thoracic cavity, with no connection to the spinal canal. Lung cancer and mesothelioma were suspected, and surgery was performed. Grossly, the mass was a grayish-white solid 9.5 cm × 8.4 cm × 5.3 cm in size. The microscopic morphology of the lesion was consistent with that of typical central nervous system meningioma. The pathological subtype was transitional meningioma. The tumor cells were arranged in a fascicular, whorled, storiform and meningithelial pattern, with occasional intranuclear pseudo-inclusions and psammoma bodies. In focal areas tumor cells were considerably dense, and the cells were round or irregular in shape, with less cytoplasm, uniform nuclear chromatin, and visible nucleoli and mitoses (2/10 HPF). By immunohistochemistry, the neoplastic cells showed strong and diffuse staining with vimentin, epithelial membrane antigen and SSTR2 with variable expression of PR, ALK and S100 protein. However, the cells were negative for GFAP, SOX-10, inhibin, CD34, STAT6, smooth muscle actin, desmin, CKpan, D2-40, WT-1, CK5/6 and CD45. The highest proliferation index by Ki-67 was 15%. The abnormal expression of ALK led to the initial misdiagnosis of an inflammatory myofibroblastic tumor. After 12 months of follow-up, no disease progression was observed.\n\nCONCLUSION:\nThe presence of primary ectopic meningiomas in the thoracic cavity is extremely rare, and this tumor is easily misdiagnosed clinically. Imaging is suggested to determine the location and possible differential diagnosis, while the final diagnosis should be pathological examination. Immunohistochemistry is crucial for disease diagnosis. Owing to our limited knowledge of PEM, its pathogenesis and tissue of origin remain unclear. Clinicians should pay close attention to such potential patients. The present case report may provide insights into the diagnosis and therapy of patients with this tumor." + } +} \ No newline at end of file diff --git a/37114153.json b/37114153.json new file mode 100644 index 0000000000000000000000000000000000000000..c107169bb1df293689509e05ce5e3465e1e25af4 --- /dev/null +++ b/37114153.json @@ -0,0 +1,8 @@ +{ + "id": "37114153", + "label": 0, + "article": { + "id": "37114153", + "text": "OBJECTIVE:\nTo explore the influences of total intravenous anesthesia (TIVA) and inhaled-intravenous anesthesia on the prognosis of patients with lung, breast, or esophageal cancer.\n\nMETHODS:\nIn this retrospective cohort study, patients with lung, breast, or esophageal cancer who underwent surgical treatments at Beijing Shijitan Hospital between January 2010 and December 2019 were included. The patients were categorized into the TIVA group and inhaled-intravenous anesthesia group, according to the anesthesia methods used for the patients for surgery of the primary cancer. The primary outcome of this study included overall survival (OS) and recurrence/metastasis.\n\nRESULTS:\nTotally, 336 patients were included in this study, 119 in the TIVA group and 217 in the inhaled-intravenous anesthesia group. The OS of patients in the TIVA group was higher than in the inhaled-intravenous anesthesia group (= 0.042). There were no significant differences in the recurrence/metastasis-free survival between the two groups (= 0.296). Inhaled-intravenous anesthesia (HR = 1.88, 95%CI: 1.15-3.07, = 0.012), stage III cancer (HR = 5.88, 95%CI: 2.57-13.43, \u003c 0.001), and stage IV cancer (HR = 22.60, 95%CI: 8.97-56.95, \u003c 0.001) were independently associated with recurrence/ metastasis. Comorbidities (HR = 1.75, 95%CI: 1.05-2.92, = 0.033), the use of ephedrine, noradrenaline or phenylephrine during surgery (HR = 2.12, 95%CI: 1.11-4.06, = 0.024), stage II cancer (HR = 3.24, 95%CI: 1.08-9.68, = 0.035), stage III cancer (HR = 7.60, 95%CI: 2.64-21.86, \u003c 0.001), and stage IV cancer (HR = 26.61, 95%CI: 8.57-82.64, \u003c 0.001) were independently associated with OS.\n\nCONCLUSION:\nIn patients with breast, lung, or esophageal cancer, TIVA is preferable than inhaled-intravenous anesthesia group for longer OS,, but TIVA was not associated with the recurrence/metastasis-free survival of patients." + } +} \ No newline at end of file diff --git a/37114179.json b/37114179.json new file mode 100644 index 0000000000000000000000000000000000000000..67731c0ae768ab217272c28a89c98d1d80014f68 --- /dev/null +++ b/37114179.json @@ -0,0 +1,8 @@ +{ + "id": "37114179", + "label": 0, + "article": { + "id": "37114179", + "text": "We previously demonstrated that a transforming growth factor β type II receptor () mutation can predict resistance to immune checkpoint inhibitors (ICIs) in patients with advanced non-small cell lung cancer (NSCLC), based on publicly available immunotherapeutic cohorts. However, the efficacy of ICI-based regimens in patients with advanced NSCLC harboring mutations in the real-world setting is rarely reported. The present study describes the case of a patient with advanced NSCLC who harbors a mutation. The patient was treated with ICI monotherapy and experienced hyperprogressive disease (HPD). The clinical information was retrospectively collected. The progression-free survival (PFS) was only 1.3 months. In conclusion, HPD occurred in a patient with advanced NSCLC with a mutation who received an ICI monotherapy regimen. The findings suggested that caution may be required regarding the clinical delivery of ICI monotherapy to patients with NSCLC and mutations; ICIs combined with chemotherapy may be an alternative treatment option." + } +} \ No newline at end of file diff --git a/37114291.json b/37114291.json new file mode 100644 index 0000000000000000000000000000000000000000..31780c28754138108023c799493cb48078bd96c2 --- /dev/null +++ b/37114291.json @@ -0,0 +1,8 @@ +{ + "id": "37114291", + "label": 0, + "article": { + "id": "37114291", + "text": "BACKGROUND:\nLentigo maligna (LM) is a melanocytic proliferation occurring on photo-exposed skin that may progress to LM melanoma. Surgery is recommended as first-line treatment. Excision margins of 5 to 10 mm remain, without international consensus. Several studies have shown that imiquimod, an immunomodulator, induces LM regression. This study investigated the effect of imiquimod versus placebo in neoadjuvant settings.\n\nPATIENTS AND METHODS:\nWe performed a prospective, randomized, multicentre, phase III clinical study. Patients were randomly assigned in 1:1 ratio to receive imiquimod or placebo for 4 weeks, followed by LM excision 4 weeks after the last application of imiquimod or placebo. The primary endpoint was extra-lesional excision, with a 5 mm margin from the residual pigmentation after imiquimod or vehicle. Secondary endpoints included the gain on the surface removed between the two groups; number of revision surgeries to obtain extra-lesional excisions; relapse-free time; and number of complete remissions after treatment.\n\nRESULTS:\nA total of 283 patients participated in this study; 247 patients, 121 patients in the placebo group and 126 in the imiquimod group, accounted for the modified ITT population. The first extralesional extirpation was performed in 116 (92%) imiquimod patients and in 102 (84%) placebo patients; the difference was not significant (p = 0.0743). Regarding the surface of LM, imiquimod reduced the LM surface (4.6 cm to 3.1 cm ) significantly (p\u003c0.001) more compared to the placebo (3.9 cm to 4.1 cm ).\n\nCONCLUSION:\nImiquimod reduces the lentigo maligna surface after one month of treatment, without a higher risk of intralesional excision and with a positive aesthetic outcome." + } +} \ No newline at end of file diff --git a/37114302.json b/37114302.json new file mode 100644 index 0000000000000000000000000000000000000000..dfb4f7b0abaac862b4f1750c82c63c68c5a45d1c --- /dev/null +++ b/37114302.json @@ -0,0 +1,8 @@ +{ + "id": "37114302", + "label": 0, + "article": { + "id": "37114302", + "text": "PKP1 has been crucially involved in enhancing the MYC translation leading to lung carcinogenesis via evading numerous tumour-suppressing checkpoint systems. Plakophilin 1(PKP1) is the part of armadillo and plakophilin gene families and it is a necessary component of desmosomes. Several researches reported PKP1 protein as one of the most overexpressed proteins in human lung cancer. Therefore, we have designed our research towards elucidating better plant-based compounds as drug candidates for the management of lung cancer with minimal adverse effects over other chemotherapeutic drugs such as afatinib. This study comprises forty-six flavonoids for targeting PKP1 using in silico approaches that were not used earlier as an anti-cancerous agent targeting PKP1 in lung cancer treatment. Flavonoids are plant-derived natural compounds that exhibited enormous anti-cancerous potential against several human cancers. NPACT database was used to screen potent flavonoids that have not been used to target the PKP1 protein in lung cancer. Patch Dock and CB Dock were employed to elucidate the PKP1 (1XM9) inhibitory potential of selected flavonoids. Analysis with both the docking tools has revealed that calyxins I showed maximum affinity in comparison to the standard drug, afatinib. Further PASS and BAS analyses were performed using SWISS ADME and molinspiration to investigate the pharmacokinetic profiling of potent flavonoids having significant binding energy. Visualization of complexes was done by using UCSF chimera. However, further detailed in vitro studies are needed to validate the candidature of calyxinsI for being developed as an anticancer drug for the management of lung cancer." + } +} \ No newline at end of file diff --git a/37114353.json b/37114353.json new file mode 100644 index 0000000000000000000000000000000000000000..98bea1dc60a528d0847d459a59bc407a415a1cea --- /dev/null +++ b/37114353.json @@ -0,0 +1,8 @@ +{ + "id": "37114353", + "label": 0, + "article": { + "id": "37114353", + "text": "To determine the physician's perspective and perception on walking exercise as well as barriers in guideline-directed best medical treatment of patients with lower extremity peripheral arterial disease (PAD). All members of the German Society for Vascular Surgery and Vascular Medicine and of the German Society for Angiology - Society for Vascular Medicine with valid email address were invited to participate in an electronic survey on walking exercise for treatment of intermittent claudication that was developed by the authors. Amongst 3910 invited participants, 743 (19%) provided valid responses (33% females, 84% vascular surgery, 15% angiology). Thereof, 65% were employed by non-university hospitals, 16% by university institutions, and 18% by outpatient facilities. A mean of 14 minutes were spent per patient to counsel and educate, while only 53% responded they had enough time in everyday clinical practice. While 98% were aware of the beneficial impact of structured exercise training (SET) on pain free walking distance and 90% advise their patients to adhere to SET, only 44% provided useful guidance to patients to find local SET programmes and merely 42% knew how to prescribe SET as service that can be reimbursed by medical insurances. Approximately 35% knew a local SET programme and appropriate contact person. Health-related quality of life was assessed in a structured way by only 11%. Forty-seven percent responded that medical insurances should be responsible to implement and maintain SET programmes, while only 4% held hospital physicians responsible to achieve this task. This nationwide survey study amongst vascular specialists illustrates the current insufficient utilisation of SET as an evidence-based therapeutic cornerstone in patients with lower extremity PAD in Germany. The study also identified several barriers and flaws from the physician's perspectives which should be addressed collectively by all health care providers aiming to increase the SET use and eventually its' impact on patients with PAD." + } +} \ No newline at end of file diff --git a/37114375.json b/37114375.json new file mode 100644 index 0000000000000000000000000000000000000000..27b0a41b634ea2911084ddcbad19f68f7a5f6ee0 --- /dev/null +++ b/37114375.json @@ -0,0 +1,8 @@ +{ + "id": "37114375", + "label": 0, + "article": { + "id": "37114375", + "text": "Rho proteins are part of the Ras superfamily, which function to modulate cytoskeletal dynamics including cell adhesion and motility. Recently, an activating mutation in Cdc42, a Rho family GTPase, was found in a patient sample of melanoma. Previously, our work had shown the PI3K was important downstream of mutationally active Cdc42. Our present study sought to determine whether PI3K was a crucial downstream partner for Cdc42 in a melanoma cells line with a BRAF mutation, which is the most common mutation in cutaneous melanoma. In this work we were able to show that Cdc42 contributes to proliferation, anchorage-independent growth, cell motility and invasion. Treatment with a pan-PI3K inhibitor was able to effectively ameliorate all these cancer phenotypes. These data suggest that PI3K may be an important target downstream of Cdc42 in melanoma." + } +} \ No newline at end of file diff --git a/37114423.json b/37114423.json new file mode 100644 index 0000000000000000000000000000000000000000..4438391f73add54c02c29202f6b37d6b96a5e1f2 --- /dev/null +++ b/37114423.json @@ -0,0 +1,8 @@ +{ + "id": "37114423", + "label": 0, + "article": { + "id": "37114423", + "text": "Alzheimer's disease (AD) is a multifactorial neurological disorder characterized by memory loss and cognitive impairment. The currently available single-targeting drugs have miserably failed in the treatment of AD, and multi-target directed ligands (MTDLs) are being explored as an alternative treatment strategy. Cholinesterase and monoamine oxidase enzymes are reported to play a crucial role in the pathology of AD, and multipotent ligands targeting these two enzymes simultaneously are under various phases of design and development. Recent studies have revealed that computational approaches are robust and trusted tools for identifying novel therapeutics. The current research work is focused on the development of potential multi-target directed ligands that simultaneously inhibit acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) enzymes employing a structure-based virtual screening (SBVS) approach. The ASINEX database was screened after applying pan assay interference and drug-likeness filter to identify novel molecules using three docking precision criteria; High Throughput Virtual Screening (HTVS), Standard Precision (SP), and Extra Precision (XP). Additionally, binding free energy calculations, ADME, and molecular dynamic simulations were employed to get structural insights into the mechanism of protein-ligand binding and pharmacokinetic properties. Three lead molecules viz. AOP19078710, BAS00314308 and BDD26909696 were successfully identified with binding scores of -10.565, -10.543 \u0026 -8.066 kcal/mol against AChE and -11.019, -12.357 \u0026 -10.068 kcal/mol against MAO-B, better score as compared to the standard inhibitors. In the near future, these molecules will be synthesized and evaluated through and assays for their inhibition potential against AChE and MAO-B enzymes." + } +} \ No newline at end of file diff --git a/37114426.json b/37114426.json new file mode 100644 index 0000000000000000000000000000000000000000..daecf65a4196d62490ccdfd9965072c834ab5c3d --- /dev/null +++ b/37114426.json @@ -0,0 +1,8 @@ +{ + "id": "37114426", + "label": 0, + "article": { + "id": "37114426", + "text": "We compared the effectiveness of teclistamab versus real-world physician's choice of therapy (RWPC) in triple-class exposed relapsed/refractory multiple myeloma. MajesTEC-1 eligibility criteria were applied to the RWPC cohort. Baseline covariate imbalances were adjusted using inverse probability of treatment weighting. Overall survival, progression-free survival and time to next treatment were compared. After inverse probability of treatment weighting, baseline characteristics were similar between cohorts (teclistamab, n = 165; RWPC, n = 364 [766 observations]). Teclistamab treated patients had numerically better overall survival (hazard ratio [HR]: 0.82 [95% CI: 0.59-1.14]; p = 0.233) and significantly greater progression-free survival (HR: 0.43 [0.33-0.56]; p \u003c 0.0001) and time to next treatment (HR: 0.36 [0.27-0.49]; p \u003c 0.0001) versus the RWPC cohort. Teclistamab offered clinical benefit over RWPC in triple-class exposed relapsed/refractory multiple myeloma." + } +} \ No newline at end of file diff --git a/37114448.json b/37114448.json new file mode 100644 index 0000000000000000000000000000000000000000..8df03bea3f2f26db6cc71a6141fa2c3b8986b6d6 --- /dev/null +++ b/37114448.json @@ -0,0 +1,8 @@ +{ + "id": "37114448", + "label": 0, + "article": { + "id": "37114448", + "text": "Oral spindle cell/sclerosing rhabdomyosarcoma (SCRMS) with anaplastic lymphoma kinase (ALK) expression is extremely rare, and its diagnosis is very challenging in the absence of clinical or pathological indicators. This case presented with gingival swelling and alveolar bone resorption and was suspected clinically to be periodontitis. A biopsy was performed and, due to immunoreactivity with ALK, the patient was misdiagnosed with inflammatory myofibroblastic tumor. However, based on the combined histological and immunohistochemical features, a revised diagnosis of SCRMS with ALK expression was finally concluded. We believe that this report makes a significant contribution to the precise diagnosis of this rare disease for proper treatment." + } +} \ No newline at end of file diff --git a/37114465.json b/37114465.json new file mode 100644 index 0000000000000000000000000000000000000000..ff1e886cf0fd7c05a46d4e71b631fc0f289fc515 --- /dev/null +++ b/37114465.json @@ -0,0 +1,8 @@ +{ + "id": "37114465", + "label": 0, + "article": { + "id": "37114465", + "text": "BACKGROUND:\nPatients with resectable noncardia gastric cancer may be subjected to perioperative chemotherapy (PEC), postoperative chemoradiation (POCR), or postoperative chemotherapy (POC). We analyzed these treatment strategies to determine optimal therapy based on nodal status.\n\nMETHOD:\nThe National Cancer Database was used to identify patients with resected noncardia gastric cancer (2004-2016). Patients were stratified based on clinical nodal status-negative (cLN-), positive (cLN+) and pathological nodal status (pLN-, pLN+). In cLN- patients who underwent upfront resection and were upstaged to pLN+, POC, and POCR were compared. Overall survival (OS) with PEC, POCR, and POC were compared in cLN- and cLN+.\n\nRESULTS:\nWe identified 6142 patients (cLN-: 3831; cLN+: 2311). In cLN- patients who underwent upfront resection (N = 3423), 69% were upstaged to pLN+ disease (N = 2499; POCR = 1796, POC = 703). On MVA, POCR was associated with significantly improved OS when compared to POC (hazard ratio [HR]: 0.75; p \u003c 0.001). In patients with cLN- disease (PEC = 408; POCR = 2439; POC = 984), PEC(HR: 0.77; p = 0.01) and POCR(HR: 0.81; p \u003c 0.001) were associated with improved OS compared with POC. In cLN+ group (PEC = 452; POCR = 1284; POC = 575), POCR was associated with improved OS compared with POC (HR: 0.81; p \u003c 0.01), and trend towards improved OS was noted when PEC(HR: 0.83; p = 0.055) was compared with POC.\n\nCONCLUSION:\nPostoperative chemoradiation may be the preferred treatment strategy over postoperative chemotherapy in non-cardia gastric cancer patients who receive upfront resection and are upstaged from clinically node negative to pathologically node positive disease." + } +} \ No newline at end of file diff --git a/37114475.json b/37114475.json new file mode 100644 index 0000000000000000000000000000000000000000..83cf5f0f8294a09d7916c1d86085d2a0c4af3f6f --- /dev/null +++ b/37114475.json @@ -0,0 +1,8 @@ +{ + "id": "37114475", + "label": 0, + "article": { + "id": "37114475", + "text": "PURPOSE:\nThis study aimed to investigate the efficacy of adjuvant chemotherapy after neoadjuvant chemoradiotherapy (CCRTx) followed by surgery in patients with esophageal squamous cell carcinoma (ESCC).\n\nMATERIALS AND METHODS:\nWe retrospectively analyzed the data from 382 patients who received neoadjuvant CCRTx and esophagectomy for ESCC between 2003 and 2018.\n\nRESULTS:\nThis study included 357 (93.4%) men, and the years median patient age was 63 (range 40~84 years). Overall, 69 (18.1%) patients received adjuvant chemotherapy, whereas 313 (81.9%) patients did not. The median follow-up period was 28.07 (interquartile range: 15.50-62.59) months. The 5-year overall survival (OS) and disease-free survival were 47.1% and 42.6%, respectively. Adjuvant chemotherapy did not improve OS in all patients, but subgroup analysis revealed that adjuvant chemotherapy improved the 5-year OS in patients with ypT+N+ (24.8% vs. 29.9%, p=0.048), whereas the survival benefit of adjuvant chemotherapy was not observed in patients with ypT0N0, ypT+N0, or ypT0N+. Multivariable analysis revealed that ypStage and adjuvant chemotherapy (hazard ratio=0.601, p=0.046) were associated with OS in patients with ypT+N+. Freedom from distant metastasis was marginally different according to the adjuvant chemotherapy (48.3% vs. 41.3%, p=0.141).\n\nCONCLUSION:\nAdjuvant chemotherapy after neoadjuvant therapy followed by surgery reduces the distant metastasis in ypT+N+ ESCC patients, thereby improving the OS. The consideration could be given to administration of adjuvant chemotherapy to ypT+N+ ESCC patients with tolerable conditions." + } +} \ No newline at end of file diff --git a/37114477.json b/37114477.json new file mode 100644 index 0000000000000000000000000000000000000000..641f2bd4d6571fab503ead519107df5c0b648deb --- /dev/null +++ b/37114477.json @@ -0,0 +1,8 @@ +{ + "id": "37114477", + "label": 0, + "article": { + "id": "37114477", + "text": "BACKGROUND:\nA meta-analysis method was used to investigate the prognostic value of CD8+ tumor-infiltrating lymphocytes (TILs) in non-small cell lung cancer (NSCLC) patients treated with PD-1/PD-L1 inhibitors.\n\nMETHODS:\nA database search of PubMed, Embase, Web of Science and Cochrane Library up until February 7th, 2023. A clinical study on the relationship between CD8+ TILs and PD-1/PD-L1 inhibitors in the therapeutics of NSCLC. RevMan 5.3 and StataMP 17.0 software were used for meta-analysis. The outcome indicators incorporated overall survival (OS), progression-free survival (PFS) and objective response rate (ORR).\n\nRESULTS:\nNineteen articles with 1488 patients were included. The analysis results showed that high CD8+ TILs were associated with better OS (HR=0.60, 95% CI: 0.46-0.77; P\u003c0.0001), PFS (HR=0.68, 95% CI: 0.53-0.88; P=0.003) and ORR (OR=2.26, 95% CI: 1.52-3.36; P\u003c0.0001) in NSCLC patients treated with PD-1/PD-L1 inhibitors. Subgroup analysis indicated that patients with high CD8+ TILs had good clinical prognostic benefits whether the location of CD8+ TILs was intratumoral or stromal, and compared with East Asian, high CD8+ TILs in Caucasians showed a better prognosis. High CD8+ TILs in peripheral blood did not improve OS (HR=0.83, 95% CI: 0.69-1.01; P=0.06) and PFS (HR=0.93, 95% CI: 0.61-1.14; P=0.76) in NSCLC patients receiving PD-1/PD-L1 inhibitors.\n\nCONCLUSION:\nIn spite of the location of CD8+ TILs, high densities of CD8+ TILs were predictive of treatment outcomes in NSCLC patients treated with PD-1/PD-L1 inhibitors. However, high CD8+ TILs in peripheral blood had no predictive effect." + } +} \ No newline at end of file diff --git a/37114585.json b/37114585.json new file mode 100644 index 0000000000000000000000000000000000000000..22a119a272efa01b27b959b74bb6888dcd44a5c8 --- /dev/null +++ b/37114585.json @@ -0,0 +1,8 @@ +{ + "id": "37114585", + "label": 0, + "article": { + "id": "37114585", + "text": "BACKGROUND:\nNational Cancer Institute cancer centers (NCICCs) provide specialized cancer care including precision oncology and clinical treatment trials. While these centers can offer novel therapeutic options, less is known about when patients access these centers or at what timepoint in their disease course they receive specialized care. This is especially important since precision diagnostics and receipt of the optimal therapy upfront can impact patient outcomes and previous research suggests that access to these centers may vary by demographic characteristics. Here, we examine the timing of patients' presentation at Moffitt Cancer Center (MCC) relative to their initial diagnosis across several demographic characteristics.\n\nMETHODS:\nA retrospective cohort study was conducted among patients who presented to MCC with breast, colon, lung, melanoma, and prostate cancers between December 2008 and April 2020. Patient demographic and clinical characteristics were obtained from the Moffitt Cancer Registry. The association between patient characteristics and the timing of patient presentation to MCC relative to the patient's cancer diagnosis was examined using logistic regression.\n\nRESULTS:\nBlack patients (median days = 510) had a longer time between diagnosis and presentation to MCC compared to Whites (median days = 368). Black patients were also more likely to have received their initial cancer care outside of MCC compared to White patients (odds ratio [OR] and 95% confidence interval [CI] = 1.45 [1.32-1.60]). Furthermore, Hispanics were more likely to present to MCC at an advanced stage compared to non-Hispanic patients (OR [95% CI] = 1.28 [1.05-1.55]).\n\nCONCLUSIONS:\nWe observed racial and ethnic differences in timing of receipt of care at MCC. Future studies should aim to identify contributing factors for the development of novel mitigation strategies and assess whether timing differences in referral to an NCICC correlate with long-term patient outcomes." + } +} \ No newline at end of file diff --git a/8919279.json b/8919279.json new file mode 100644 index 0000000000000000000000000000000000000000..43ed34396ad5c4fc646b9975146530c3d71863ef --- /dev/null +++ b/8919279.json @@ -0,0 +1,8 @@ +{ + "id": "8919279", + "label": 1, + "article": { + "id": "8919279", + "text": "Bile acid composition was assessed in 50 patients with colorectal cancer as compared to that in a control group of 50 subjects. The two groups were age- and sex-matched. The overall bile acid values were similar in both groups, while the relative concentrations of primary and secondary bile acids were different, a significant increase in the patients with colorectal cancer being observed. This finding thus seems to confirm the existence of a link between colorectal cancer and cholelithiasis. Both conditions share common risk factors, such as alterations in cholesterol metabolism and bile acid composition." + } +} \ No newline at end of file