Context: Duchenne muscular dystrophy (DMD) results in loss of ambulation and premature death. Ultrasound provides real-time, safe, and cost-effective routine examinations. Deep learning allows the automatic generation of useful features for classification. This study utilized deep learning of ultrasound imaging for classifying patients with DMD based on their ambulatory function. A total of 85 individuals (including ambulatory and nonambulatory subjects) underwent ultrasound examinations of the gastrocnemius for deep learning of image data using LeNet, AlexNet, VGG-16, VGG-16, VGG-19, and VGG-19 models (the notation TL indicates fine-tuning pretrained models). Gradient-weighted class activation mapping (Grad-CAM) was used to visualize features recognized by the models. The classification performance was evaluated using the confusion matrix and receiver operating characteristic (ROC) curve analysis. The results show that each deep learning model endows muscle ultrasound imaging with the ability to enable DMD evaluations. The Grad-CAMs indicated that boundary visibility, muscular texture clarity, and posterior shadowing are relevant sonographic features recognized by the models for evaluating ambulatory function. Of the proposed models, VGG-19 provided satisfying classification performance (the area under the ROC curve: 0.98; accuracy: 94.18%) and feature recognition in terms of physical characteristics. Deep learning of muscle ultrasound is a potential strategy for DMD characterization.


Context: Ca2+ is a ubiquitous intracellular messenger responsible for controlling numerous cellular processes including fertilization, mitosis, neuronal transmission, contraction and relaxation of muscles, gene transcription, and cell death. At rest, the cytoplasmic Ca2+ concentration [Ca2+]i is approximately 100 nM, but this level rises to 500-1,000 nM upon activation. In osteoblasts, the elevation of [Ca2+]i is a result of an increase in the release of Ca2+ from endoplasmic reticulum and/or extracellular Ca2+ influx through voltage gated Ca2+ channels. Many of the cellular effects of Ca2+ are mediated by the Ca2+ binding protein, calmodulin (CaM). Upon binding up to four calcium ions, CaM undergoes a conformational change, which enables it to bind to specific proteins eliciting a specific response. Calmodulin kinase II (CaMKII) is a major target of the Ca(2+)/CaM second messenger system. Once bound to Ca(2+)/CaM, the multimeric CaMKII is released from its autoinhibitory status and maximally activated, which then leads to an intraholoenzyme autophosphorylation reaction. Calcineurin (Cn) is another major target protein that is activated by Ca(2+)/CaM. Cn is a serine-threonine phosphatase that consists of a heterodimeric protein complex composed of a catalytic subunit (CnA) and a regulatory subunit (CnB). Upon activation, Cn directly binds to, and dephosphorylates nuclear factor of activated T cells (NFAT) transcription factors within the cytoplasm allowing them to translocate to the nucleus and participate in the regulation of gene expression. This review will examine the potential mechanisms by which calcium, CaM, CaMKII, and Cn/NFAT control osteoblast proliferation and differentiation.


Context: A rare occurrence of an atypical case of multiple evanescent white dot syndrome (MEWDS) in a 75-year-old man without viral prodrome or white dots on fundus that presented with acute, severe left eye visual loss, which returned to baseline without treatment in several weeks. Multimodal imaging, including fluorescein angiography (FA), fundus autofluorescence (FAF), indocyanine green angiography (ICG), and optical coherence tomography (OCT) demonstrated classical presentation of MEWDS with wreath-like lesions and inflammatory foci in the retinal pigment epithelium that correlated among modalities. Possible underlying systemic disorders were ruled out through extended work up. To the best of our knowledge, this is the first report to show atypical MEWDS in an elderly man with classic changes on FA, FAF, ICG, and OCT.


Context: Paraneoplastic cerebellar degeneration may occur in association with Lambert-Eaton myasthenic syndrome (LEMS), but to our knowledge, the co-occurrence of paraneoplastic opsoclonus-myoclonus syndrome and LEMS has not been previously reported. A 67-year-old woman presented with a complex partial seizure and evolving ocular flutter, opsoclonus, myoclonus and 'cerebellar' signs, all of which improved spontaneously within 6 weeks. Approximately 8 weeks after symptom onset, the patient became encephalopathic, she had a further complex partial seizure, and she became areflexic with potentiation of deep tendon reflexes. Radiological, bronchoscopic and histological investigations revealed small-cell lung cancer, and neurophysiological investigations confirmed a diagnosis of LEMS. High-titre anti-P/Q-type voltage-gated calcium-channel antibodies were identified in the serum, which increased as the signs of opsoclonus and myoclonus resolved. The encephalopathy and clinical features of LEMS responded dramatically to chemotherapy and radiotherapy. Spontaneous improvement of paraneoplastic opsoclonus-myoclonus syndrome may occur, and this syndrome may occur in association with LEMS. Antivoltage-gated calcium-channel antibodies are not implicated in the pathogenesis of paraneoplastic opsoclonus-myoclonus syndrome.


Context: Alu and B1 repeats are mobile elements that originated in an initial duplication of the 7SL RNA gene prior to the primate-rodent split about 80 million years ago and currently account for a substantial fraction of the human and mouse genome, respectively. Following the primate-rodent split, Alu and B1 elements spread independently in each of the two genomes in a seemingly random manner, and, according to the prevailing hypothesis, negative selection shaped their final distribution in each genome by forcing the selective loss of certain Alu and B1 copies. In this paper, contrary to the prevailing hypothesis, we present evidence that Alu and B1 elements have been selectively retained in the upstream and intronic regions of genes belonging to specific functional classes. At the same time, we found no evidence for selective loss of these elements in any functional class. A subset of the functional links we discovered corresponds to functions where Alu involvement has actually been experimentally validated, whereas the majority of the functional links we report are novel. Finally, the unexpected finding that Alu and B1 elements show similar biases in their distribution across functional classes, despite having spread independently in their respective genomes, further supports our claim that the extant instances of Alu and B1 elements are the result of positive selection.


Context: Histone deacetylase (HDAC) inhibitors have received considerable attention as potential therapeutics for a variety of cancers and neurological disorders. Recent publications on a class of pimelic diphenylamide HDAC inhibitors have highlighted their promise in the treatment of the neurodegenerative diseases Friedreich's ataxia and Huntington's disease, based on efficacy in cell and mouse models. These studies' authors have proposed that the unique action of these compounds compared to hydroxamic acid-based HDAC inhibitors results from their unusual slow-on/slow-off kinetics of binding, preferentially to HDAC3, resulting in a distinctive pharmacological profile and reduced toxicity. Here, we evaluate the HDAC subtype selectivity, cellular activity, absorption, distribution, metabolism and excretion (ADME) properties, as well as the central pharmacodynamic profile of one such compound, HDACi 4b, previously described to show efficacy in vivo in the R6/2 mouse model of Huntington's disease. Based on our data reported here, we conclude that while the in vitro selectivity and binding mode are largely in agreement with previous reports, the physicochemical properties, metabolic and p-glycoprotein (Pgp) substrate liability of HDACi 4b render this compound suboptimal to investigate central Class I HDAC inhibition in vivo in mouse per oral administration. A drug administration regimen using HDACi 4b dissolved in drinking water was used in the previous proof of concept study, casting doubt on the validation of CNS HDAC3 inhibition as a target for the treatment of Huntington's disease. We highlight physicochemical stability and metabolic issues with 4b that are likely intrinsic liabilities of the benzamide chemotype in general.


Context: Administration to rats of a murine antibody preparation against ICAM-1, 1A29, elicits the production of host antibodies against the protein, activation of circulating neutrophils, complement activation, and sustained microvascular activation. These observations provide several possible mechanisms for central nervous system-related clinical deterioration that occurred when Enlimomab was given in acute ischemic stroke.


Context: Ichthyosis follicularis, atrichia, and photophobia (IFAP) are typical features of a rare neuroichthyosis termed IFAP syndrome. We demonstrate the ultrastructural findings of the eyes from a 33-year-old patient with IFAP syndrome. Clinically, eyebrows and eyelashes were absent from birth, and photophobia was noted at the age of 1 year. The globes measured 28 and 29 mm, respectively, and both eyes showed a posterior staphyloma. Histopathologically, bilateral centrally located subepithelial avascular corneal scarring with secondary corneal amyloid deposition was found. In addition to already described ocular abnormalities in IFAP syndrome we demonstrate ultrastructural anomalies of desmosomes and tonofilaments in corneal epithelium; defects of basement membrane, Bowman layer, and anchoring fibrils; secondary corneal amyloid deposition; and keratocyte degeneration. A defective tear film, recurrent atopic keratoconjunctival inflammations, or a primary anomaly of corneal epithelial adhesion are potential causes for the corneal defects. Photophobia is most likely due to corneal abnormalities.


Context: Our finding that minocycline has a harmful effect on patients with ALS has implications for trials of minocycline in patients with other neurological disorders, and for how potential neuroprotective agents are screened for use in patients with ALS.


Context: Low pressure headache typically occurs as a complication of dural puncture. "Spontaneous" low pressure headache is a relatively rare but under-recognised cause of intractable headache. Clinical suspicion of this condition warrants imaging of the brain to confirm the diagnosis; spinal imaging may be needed to identify the site of the leak. Epidural blood patching may be necessary to seal the leak - CT fluoroscopy may be helpful in delivering the patch directly to the site of the leak. Surgical intervention may be required in intractable cases. We describe a patient with spontaneous intracranial hypotension and review the clinical and radiological features of this syndrome.


Context: Belzutifan (Welireg™) is an oral small molecule inhibitor of hypoxia-inducible factor (HIF)-2α being developed by Peloton Therapeutics for the treatment of solid tumours, including renal cell carcinoma (RCC) with clear cell histology (ccRCC) and von Hippel-Lindau (VHL) disease-associated RCC. In August 2021, belzutifan received its first approval in the USA for the treatment of patients with VHL disease who require therapy for associated RCC, central nervous system (CNS) haemangioblastomas or pancreatic neuroendocrine tumours (pNET), not requiring immediate surgery. Clinical studies of belzutifan (as monotherapy or combination therapy) in other indications, including ccRCC, pNET and phaeochromocytoma/paraganglioma, are also underway in various countries. This article summarizes the milestones in the development of belzutifan leading to this first approval for certain VHL disease-associated tumours.


Context: The transcriptional imbalance due to the difference in the number of X chromosomes between male and female mammals is remedied through X-chromosome inactivation, the epigenetic transcriptional silencing of one of the two X chromosomes in females. The X-linked Xist long non-coding RNA functions as an X inactivation master regulator; Xist is selectively upregulated from the prospective inactive X chromosome and is required in cis for X inactivation. Here we discover an Xist antisense long non-coding RNA, XistAR (Xist Activating RNA), which is encoded within exon 1 of the mouse Xist gene and is transcribed only from the inactive X chromosome. Selective truncation of XistAR, while sparing the overlapping Xist RNA, leads to a deficiency in Xist RNA expression in cis during the initiation of X inactivation. Thus, the Xist gene carries within its coding sequence an antisense RNA that drives Xist expression.


Context: Charcot-Marie-Tooth (CMT) diseases include a group of clinically heterogeneous inherited neuropathies subdivided into demyelinating (CMT1), axonal (CMT2) and intermediate CMT forms. CMTs are associated with different genes, although mutations in some of these genes may cause both clinical pictures. To date, more than 50 CMT genes have been identified, but more than half of the cases are due to mutations in MFN2, MPZ, GJB1 and PMP22. The aim of this study was to estimate the frequency of disease mutations of these four genes in the axonal form of CMT in order to evaluate their effectiveness in the molecular diagnosis of CMT2 patients. A cohort of 38 CMT2 Italian subjects was screened for mutations in the MFN2, MPZ and GJB1 genes by direct sequencing and for PMP22 rearrangements using the MLPA technique. Overall, we identified 15 mutations, 8 of which were novel: 11 mutations (28.9 %) were in the MFN2 gene, 2 (5.3 %) in MPZ and 2 (5.3 %) in PMP22. No mutations were found in GJB1. Two patients showed rearrangements in the PMP22 gene, which is commonly associated with CMT1 or HNPP phenotypes thus usually not tested in CMT2 patients. By including this gene in the analysis, we reached a molecular diagnosis rate of 39.5 %, which is one of the highest reported in the literature. Our findings confirm the MFN2 gene as the most common cause of CMT2 and suggest that PMP22 rearrangements should be considered in the molecular diagnosis of CMT2 patients.


Context: Achondrogenesis type II is an autosomal-dominant disease leading to severe micromelic dwarfism. Here, we report on the postmortem identification of a de novo heterozygous mutation in the COL2A1 gene (c.1529G>A, p.Gly510Asp) in a fetus who presented with generalized hydrops fetalis and severe micromelia during prenatal sonographic examinations. Initially, a reciprocal translocation t(4;17)(q31;p13) was detected in this fetus by chorionic villus sampling. Subsequent chromosomal analysis of maternal and paternal blood showed that the patient's mother was carrier of the same reciprocal translocation. SNP array analysis of the fetus did not provide evidence for chromosomal imbalances or CNVs that could be associated with the fetal phenotype. The coexistence of a cytogenetic (reciprocal translocation) and a molecular genetic (COL2A1 mutation) abnormality in the fetus carries important implications for genetic counseling.


Context: The N-end rule pathway is a ubiquitin-dependent proteolytic system, in which destabilizing N-terminal residues of short-lived proteins function as an essential determinant of an N-terminal degradation signal (N-degron). An N-degron can be created from a pre-N-degron through specific N-terminal modifications, providing a means conditionally to destabilize otherwise stable polypeptides. The pathway has been found in all organisms examined, from prokaryotes to eukaryotes. Recent biochemical and proteomic studies identified many components of the mammalian N-end rule pathway, including a family of substrate recognition ubiquitin ligases and their substrates. The genetic dissection in animals and humans revealed its essential role in various vital physiological processes, ranging from cardiovascular development and meiosis to the pathogenesis of human genetic diseases. These discoveries have provided new insights into the components, functions and mechanics of this unique proteolytic system.


Context: Chronic myelogenous leukemia is characterized by the Philadelphia-chromosome, a shortened chromosome 22 which is the result of a reciprocal translocation between chromosome 9 and 22. The fusion gene is called BCR-ABL. After transcription and translation the constitutively activated p210 BCR-ABL oncoprotein is formed. This leads to uncontrolled activation of the ABL tyrosin kinase. Deregulated cellular proliferation and diminished apoptosis of BCR-ABL transformed cells is the result. Expression of the BCR-ABL oncoprotein is sufficient and necessary for the development of a CML phenotype. Imatinib mesylate (Glivec) is a small molecule that binds to the ATP pocket of ABL and blocks downstream signalling events. Imatinib is very effective in the treatment of CML in all stages of the disease. Patients with newly diagnosed chronic phase CML were randomized to imatinib or to interferon plus cytarabine in the IRIS trial. Imatinib showed significantly superior tolerability, hematologic and cytogenetic resposes and increased time to progression. In patients with advanced phase CML, imatinib is less effective and response duration is short. Median overall survival of blast crisis patients is 6.9 months only. Additional BCR-ABL independent chromosomal abnormalities are common in advanced phase CML and result in resistance to imatinib. BCR-ABL kinase-domaine mutations are frequently found in imatinib resistant patients and confer diminished sensitivity to imatinib. Second generation, more powerful ABL kinase inhibitors, which are effective against most of the known mutations are currently tested in clinical trials.


Context: We describe an assay for transposase-accessible chromatin using sequencing (ATAC-seq), based on direct in vitro transposition of sequencing adaptors into native chromatin, as a rapid and sensitive method for integrative epigenomic analysis. ATAC-seq captures open chromatin sites using a simple two-step protocol with 500-50,000 cells and reveals the interplay between genomic locations of open chromatin, DNA-binding proteins, individual nucleosomes and chromatin compaction at nucleotide resolution. We discovered classes of DNA-binding factors that strictly avoided, could tolerate or tended to overlap with nucleosomes. Using ATAC-seq maps of human CD4(+) T cells from a proband obtained on consecutive days, we demonstrated the feasibility of analyzing an individual's epigenome on a timescale compatible with clinical decision-making.


Context: The vertebrate nuclear pore complex (NPC) is a macromolecular assembly of protein subcomplexes forming a structure of eightfold radial symmetry. The NPC core consists of globular subunits sandwiched between two coaxial ring-like structures of which the ring facing the nuclear interior is capped by a fibrous structure called the nuclear basket. By postembedding immunoelectron microscopy, we have mapped the positions of several human NPC proteins relative to the NPC core and its associated basket, including Nup93, Nup96, Nup98, Nup107, Nup153, Nup205, and the coiled coil-dominated 267-kDa protein Tpr. To further assess their contributions to NPC and basket architecture, the genes encoding Nup93, Nup96, Nup107, and Nup205 were posttranscriptionally silenced by RNA interference (RNAi) in HeLa cells, complementing recent RNAi experiments on Nup153 and Tpr. We show that Nup96 and Nup107 are core elements of the NPC proper that are essential for NPC assembly and docking of Nup153 and Tpr to the NPC. Nup93 and Nup205 are other NPC core elements that are important for long-term maintenance of NPCs but initially dispensable for the anchoring of Nup153 and Tpr. Immunogold-labeling for Nup98 also results in preferential labeling of NPC core regions, whereas Nup153 is shown to bind via its amino-terminal domain to the nuclear coaxial ring linking the NPC core structures and Tpr. The position of Tpr in turn is shown to coincide with that of the nuclear basket, with different Tpr protein domains corresponding to distinct basket segments. We propose a model in which Tpr constitutes the central architectural element that forms the scaffold of the nuclear basket.


Context: Apolipoprotein E (apoE) is a ligand for clearance of lipoprotein remnants such as chylomicrons and very low-density lipoproteins. It has anti-atherogenic and anti-inflammatory properties. Therefore, there is extensive ongoing research to create peptides that can mimic properties of apoE. A number of synthetic peptides that encompass different regions of apoE have been studied for inhibiting inflammatory states, including Alzheimer disease. However, peptides that clear atherogenic lipoproteins, analogous to apoE, via enhanced hepatic uptake have not been previously reviewed. Toward this end, we describe the design and studies of a dual-domain apoE mimetic peptide, Ac-hE18A-NH(2). This peptide consists of residues 141-150, the putative receptor-binding region of human apoE, covalently linked to a well characterized class A amphipathic helix, 18A, which has no sequence homology to any other exchangeable apolipoprotein sequences. It demonstrates dramatic effects in reducing plasma cholesterol levels in dyslipidemic mouse and rabbit models. We discuss the scientific rationale and review the literature for the design and efficacy of the peptide. Analogous to apoE, this peptide bypasses the low-density lipoprotein receptor for the hepatic uptake of atherogenic lipoproteins via heparan sulfate proteoglycan (HSPG). ApoE mimetics such as Ac-hE18A-NH(2) may therefore restore or replace ligands in genetically induced hyperlipidemias to enable reduction in atherogenic lipoproteins via HSPG even in the absence of functional low-density lipoprotein receptors. Therefore, this and similar peptides may be useful in the treatment of dyslipidemic disorders such as familial hyperlipidemia and atherosclerosis.


Context: In angiosperms the strictly light-dependent reduction of protochlorophyllide to chlorophyllide is catalyzed by NADPH:protochlorophyllide oxidoreductase (POR). The Arabidopsis thaliana genome encodes three structurally related but differentially regulated POR genes, PORA, PORB and PORC. PORA is expressed primarily early in development-during etiolation, germination and greening. In contrast, PORB and PORC are not only expressed during seedling development but also throughout the later life of the plant, during which they are responsible for bulk chlorophyll synthesis. The Arabidopsis porB-1 porC-1 mutant displays a severe xantha (highly chlorophyll-deficient) phenotype characterized by smaller prolamellar bodies in etioplasts and decreased thylakoid stacking in chloroplasts. Here we have demonstrated the ability of an ectopic PORA overexpression construct to restore prolamellar body formation in the porB-1 porC-1 double mutant background. In response to illumination, light-dependent chlorophyll production, thylakoid stacking and photomorphogenesis are also restored in PORA-overexpressing porB-1 porC-1 seedlings and adult plants. An Arabidopsis porB-1 porC-1 double mutant can therefore be functionally rescued by the addition of ectopically expressed PORA, which suffices in the absence of either PORB or PORC to direct bulk chlorophyll synthesis and normal plant development.


Context: Many thousands of Circular RNAs (circRNAs) have recently been identified in metazoan genomes by transcriptome-wide sequencing. Most circRNAs are generated by back-splicing events from exons of protein-coding genes. A great deal of progress has recently been made in understanding the genome-wide expression patterns, biogenesis, and regulation of circRNAs. To date, however, few functions of circRNAs have been identified. CircRNAs are preferentially expressed in neural tissues and some are found at synapses, suggesting possible functions in the nervous system. Several circRNAs have been shown to function as microRNA "sponges" to counteract microRNA mediated repression of mRNA. New functions for circRNAs are arising, including protein sequestration, transcriptional regulation, and potential functions in cancer. Here, we highlight the recent progress made in understanding the biogenesis and regulation of circRNAs, discuss newly uncovered circRNA functions, and explain the methodological approaches that could reveal more exciting and unexpected roles for these RNAs.


Context: The Tal1 oncogene is a class II basic helix-loop-helix (bHLH) transcription factor, overexpressed in as much as 60% of T cell acute lymphoblastic leukemia cases. Like other class II bHLH proteins, Tal1 can heterodimerize with the class I bHLH proteins, such as E47, and bind to a DNA recognition sequence termed E box. Therefore, it is believed that the oncogenic capacity of Tal1 lies in its ability, as a heterodimer with E47, to activate aberrantly a set of "leukemogenic" genes in T cells. However, compared with E47 homodimers, Tal1/E47 heterodimers are very poor transactivators. Thus the effect of Tal1 is actually to inhibit E47 homodimer activity. Here we propose that the transforming properties of Tal1 are the result of its ability to inhibit E47 activity. We address the mechanism of Tal1 inhibition and demonstrate that Tal1/E47 heterodimers cannot activate transcription because their respective activation domains are incompatible. Furthermore, we present data showing that Tal1 can inhibit E47-mediated activation of the CIP1 gene. Finally, we demonstrate that Tal1 inhibits E47 activity in leukemic T cells.


Context: The normal human chromosome complement consists of 46 chromosomes comprising 22 morphologically different pairs of autosomes and one pair of sex chromosomes. Variations in either chromosome number and/or structure frequently result in significant mental impairment and/or a variety of other clinical problems, among them, altered bone mass and strength. Chromosomal syndromes associated with specific chromosomal abnormalities are classified as either numerical or structural and may involve more than one chromosome. Aneuploidy refers to the presence of an extra copy of a specific chromosome, or trisomy, as seen in Down's syndrome (trisomy 21), or the absence of a single chromosome, or monosomy, as seen in Turner syndrome (a single X chromosome in females: 45, X). Aneuploidies have diverse phenotypic consequences, ranging from severe mental retardation and developmental abnormalities to increased susceptibility to various neoplasms and premature death. In fact, trisomy 21 is the prototypical aneuploidy in humans, is the most common genetic abnormality associated with longevity, and is one of the most widespread genetic causes of intellectual disability. In this review, the impact of trisomy 21 on the bone mass, architecture, skeletal health, and quality of life of people with Down syndrome will be discussed.


Context: Chromatin structural states and their remodelling, including higher-order chromatin folding and three-dimensional (3D) genome organisation, play an important role in the control of gene expression. The role of 3D genome organisation in the control and execution of lineage-specific transcription programmes during the development and differentiation of multipotent stem cells into specialised cell types remains poorly understood. Here, we show that substantial remodelling of the higher-order chromatin structure of the epidermal differentiation complex (EDC), a keratinocyte lineage-specific gene locus on mouse chromosome 3, occurs during epidermal morphogenesis. During epidermal development, the locus relocates away from the nuclear periphery towards the nuclear interior into a compartment enriched in SC35-positive nuclear speckles. Relocation of the EDC locus occurs prior to the full activation of EDC genes involved in controlling terminal keratinocyte differentiation and is a lineage-specific, developmentally regulated event controlled by transcription factor p63, a master regulator of epidermal development. We also show that, in epidermal progenitor cells, p63 directly regulates the expression of the ATP-dependent chromatin remodeller Brg1, which binds to distinct domains within the EDC and is required for relocation of the EDC towards the nuclear interior. Furthermore, Brg1 also regulates gene expression within the EDC locus during epidermal morphogenesis. Thus, p63 and its direct target Brg1 play an essential role in remodelling the higher-order chromatin structure of the EDC and in the specific positioning of this locus within the landscape of the 3D nuclear space, as required for the efficient expression of EDC genes in epidermal progenitor cells during skin development.


Context: Scurvy, a disease of dietary deficiency of vitamin C, is uncommon today. Among diseases, scurvy has a rich history and an ancient past. The Renaissance (14th to 16th centuries) witnessed several epidemics of scurvy among sea voyagers. In 1747, James Lind, a British Naval surgeon, performed a carefully designed clinical trial and concluded that oranges and lemons had the most antiscorbutic effect. Eventually, with the provision of lemon juice to the sea voyagers, scurvy became rare at sea. Infantile scurvy appeared almost as a new disease toward the end of the 19th century. The increased incidence of infantile scurvy during that period was attributed to the usage of heated milk and proprietary foods. Thomas Barlow described the classic clinical and pathologic features of infantile scurvy in 1883. Between 1907 and 1912, Holst and Frolich induced and cured scurvy in guinea pigs by dietary modification. In 1914, Alfred Hess established that pasteurization reduced the antiscorbutic value of milk and recommended supplementation of fresh fruit and vegetable juices to prevent scurvy. Such pioneering efforts led to the eradication of infantile scurvy in the United States. A brief history of infantile scurvy is provided.


Context: Health care workers (HCW) are particularly at risk of acquiring tuberculosis (TB), even in countries with low TB incidence. Therefore, TB screening in HCW is a useful prevention strategy in countries with both low and high TB incidence. Tuberculin skin test (TST) is widely used although it suffers of low specificity; on the contrary, the in vitro enzyme immunoassay tests (IGRA) show superior specificity and sensitivity but are more expensive. The present study reports the results of a three-year TB surveillance among HCW in a large teaching hospital in Rome, using TST (by standard Mantoux technique) and IGRA (by QuantiFERON-TB) as first- and second-level screening tests, respectively. Out of 2290 HCW enrolled, 141 (6.1%) had a positive TST; among them, 99 (70.2%) underwent the IGRA and 16 tested positive (16.1%). The frequency of HCW tested positive for TB seems not far from other experiences in low incidence countries. Our results confirm the higher specificity of IGRA, but, due to its higher cost, TST can be considered a good first level screening test, whose positive results should be further confirmed by IGRA before the patients undergo X-ray diagnosis and/or chemotherapy.


Context: Imatinib mesylate was designed as an inhibitor targeting the BCR-ABL tyrosine kinase, the molecular counterpart of the Philadelphia translocation t(9;22)(q34;q11). We report on a patient with chronic myeloid leukemia (CML) undergoing acceleration during imatinib treatment. Cytogenetic analysis revealed four different cell populations: 46,XX,t(9;22)(q34;q11),der(18)t(2;18)(p11;p11)[1]/47,idem,i(17)(q10),-der(18)t(2;18),+der(22)t(9;22)[1]/46,idem,-t(9;22),der(9)t(9;22),ider(22)t(9;22)[12]/ 47,idem,-t(9;22),der(9)t(9;22),+22,ider(22)t(9;22)x2[1]. FISH analysis confirmed the presence of these four clones. Moreover, 49% of the interphase nuclei contained either one or two clustered fusion signals, indicating a low-level amplification of the BCR-ABL fusion gene. With quantitative real-time RT-PCR, a BCR-ABL/G6PDH ratio of 0.8 was determined, which is comparable to that measured in the K562 cell line with a known BCR-ABL amplification and which is increased by more than about 60-fold compared to a CML at diagnosis with >80% Philadelphia-positive cells. We give further evidence that the genomic BCR-ABL amplification results in an increased level of BCR-ABL transcript linking two potent mechanisms of resistance against imatinib treatment.


Context: Antibodies are administered parenterally because oral absorption is limited by gastrointestinal degradation and inefficient diffusion through the epithelium. The systemic absorption of antibodies following intramuscular or subcutaneous administration most likely occurs via convective transport through lymphatic vessels into blood. The majority of antibody elimination occurs via intracellular catabolism into peptides and amino acids following endocytosis. Binding of ligand to an antibody reduces the free ligand that is available to interact with the receptor and efficacy is driven by the magnitude and duration of the reduction in free ligand concentration. A galcanezumab pharmacokinetic/pharmacodynamic model shows that galcanezumab decreases free calcitonin gene-related peptide concentrations in a dose- and time-dependent manner and continues to suppress free calcitonin gene-related peptide with repeated dosing. The model provides evidence for a mechanistic linkage to galcanezumab therapeutic effects for the preventive treatment of migraine.


Context: The first data from the phase III CheckMate-227 trial of ipilimumab plus nivolumab for the treatment of non-small cell lung cancer suggests that the two drugs boost progression-free survival in patients with a high tumor mutation burden. After 1 year, progression-free survival was 43% for patients treated with the checkpoint inhibitor combination, compared with 13% for patients treated with chemotherapy.


Context: Regorafenib (BAY 73-4506, Stivarga®) is an oral diphenylurea multikinase inhibitor that targets angiogenic (VEGFR1-3, TIE2), stromal (PDGFR-β, FGFR), and oncogenic receptor tyrosine kinases (KIT, RET, and RAF). Regorafenib is the first small-molecule multikinase inhibitor to achieve survival benefits in metastatic colorectal cancer that has progressed after all standard therapies. Consequently, regorafenib was FDA approved for this indication. In addition, regorafenib treatment resulted in a significant improvement in progression-free survival (PFS) compared with placebo in patients with metastatic gastrointestinal stromal tumors (GIST) after progression on standard treatments and is also an FDA approved indication. Currently, regorafenib is examined in several clinical trials (mostly phase II) in different tumor entities, including renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and soft tissue sarcoma (STS).


Context: Pregnancy, with or without additional complications, constitutes a high-risk condition for complications of influenza infection and warrants early intervention with neuraminidase inhibitors such as oseltamivir, if influenza is suspected. Treatment should not be delayed for laboratory confirmation. In South Africa, the high burden of HIV infection is a further complication.


Context: Hedgehog proteins exert critical roles in embryogenesis and require heparan sulfate proteoglycans (HS-PGs) for action. Indian hedgehog (Ihh) is produced by prehypertrophic chondrocytes in developing long bones and regulates chondrocyte proliferation and other events, but it is not known whether it requires HS-PGs for function. Because the HS-PG syndecan-3 is preferentially expressed by proliferating chondrocytes, we tested whether it mediates Ihh action. Primary chick chondrocyte cultures were treated with recombinant Ihh (rIhh-N) in absence or presence of heparinase I or syndecan-3 neutralizing antibodies. While rIhh-N stimulated proliferation in control cultures, it failed to do so in heparinase- or antibody-treated cultures. In reciprocal gain-of-function studies, chondrocytes were made to overexpress syndecan-3 by an RCAS viral vector. Cells became more responsive to rIhh-N, but even this response was counteracted by heparinase or antibody treatment. To complement the in vitro data, RCAS viral particles were microinjected in day 4-5 chick wing buds and effects of syndecan-3 misexpression were monitored over time. Syndecan-3 misexpression led to widespread chondrocyte proliferation and, interestingly, broader expression and distribution of Ihh. In addition, the syndecan-3 misexpressing skeletal elements were short, remained cartilaginous, lacked osteogenesis, and exhibited a markedly reduced expression of collagen X and osteopontin, products characteristic of hypertrophic chondrocytes and bone cells. The data are the first to indicate that Ihh action in chondrocyte proliferation involves syndecan-3 and to identify a specific member of the syndecan family as mediator of hedgehog function.


Context: This study does not support the conception that patients with reflux oesophagitis should be screened vigorously for coeliac disease. The association between these two conditions is, at most, weak, but a gluten-free diet may still bring symptomatic relief for reflux symptoms in coeliac disease.


Context: Inhibition of proteasome, a proteolytic complex responsible for the degradation of ubiquitinated proteins, has emerged as a powerful strategy for treatment of multiple myeloma (MM), a plasma cell malignancy. First-in-class agent, bortezomib, has demonstrated great positive therapeutic efficacy in MM, both in pre-clinical and in clinical studies. However, despite its high efficiency, a large proportion of patients do not achieve sufficient clinical response. Therefore, the development of a second-generation of proteasome inhibitors (PIs) with improved pharmacological properties was needed. Recently, several of these new agents have been introduced into clinics including carfilzomib, marizomib and ixazomib. Further, new orally administered second-generation PI oprozomib is being investigated. This review provides an overview of main mechanisms of action of PIs in MM, focusing on the ongoing development and progress of novel anti-proteasome therapeutics.


Context: Anticitrullinated protein antibodies (ACPAs) constitute a class of autoantibodies found in 60-70% of patients with rheumatoid arthritis (RA). The most common test for ACPA positivity is based on the occurrence of antibodies that bind to circular citrullinated peptides, so-called CCP, some of which are derived from endogenously citrullinated proteins, like filaggrin. Several lines of evidence suggest that these autoantibodies may confer pathological reactions. They appear years before onset of clinical disease and are associated with worse prognosis and a more erosive disease. Their presence correlates with the most prominent genetic risk factors for RA development, and they were recently described to mediate relevant biological functions such as activation of complement system and induction of osteoclastogenesis. The development of new drugs that specifically target these autoantibodies is an appealing and novel approach. Herein, we briefly review the autoimmune condition of RA, characterized by the presence of ACPA, and we describe how the neutralization of autoantibodies might become a novel pharmacological principle.


Context: Chromatin regions with different states usually harbor distinct epigenetic information, through which gene expression is regulated. Recent studies using mammalian cells showed that a chromatin state signature is associated with active developmental enhancers, defined by high levels of histone H3 lysine 27 acetylation (H3K27ac) and strong depletion of H3K27 trimethylation (H3K27me3). These findings also imply that active enhancers may play a role in creating a chromatin state by changing histone modification markers, which in turn affects gene expression. To explore whether an active enhancer in plants affect histone modifications, we investigated the cauliflower mosaic virus 35S enhancer (35Senh) for understanding its action model in Arabidopsis. We report that the 35Senh has a function to change the histone modification pattern at its presenting loci, by characterization of the 35Senh activated BREVIPEDICELLUS (BP) silencing lines and the randomly selected 35Senh activation tagging lines. By analyzing histone modification markers reflecting the plant chromatin state, we show that the 35Senh is generally correlated with the reduced level of H3K27me3 and the increased level of H3K4me3 at the insertion loci. Our data are consistent with those in mammals and suggest that the enhancer sequence correlating with the active chromatin state signature may be generally present in the eukaryotic kingdom.


Context: End tidal carbon dioxide tension (P(ET,CO(2))) is a surrogate for dead space ventilation which may be useful in the evaluation of pulmonary embolism (PE). We aimed to define the optimal P(ET,CO(2)) level to exclude PE in patients evaluated for possible thromboembolism. 298 patients were enrolled over 6 months at a single academic centre. P(ET,CO(2)) was measured within 24 h of contrast-enhanced helical computed tomography, lower extremity duplex or ventilation/perfusion scan. Performance characteristics were measured by comparing test results with clinical diagnosis of PE. PE was diagnosed in 39 (13%) patients. Mean P( ET,CO(2)) in healthy volunteers did not differ from P( ET,CO(2)) in patients without PE (36.3+/-2.8 versus 35.5+/-6.8 mmHg). P(ET,CO(2 )) in patients with PE was 30.5+/-5.5 mmHg (p<0.001 versus patients without PE). A P(ET,CO(2)) of >or=36 mmHg had optimal sensitivity and specificity (87.2 and 53.0%, respectively) with a negative predictive value of 96.6% (95% CI 92.3-98.5). This increased to 97.6% (95% CI 93.2-99.) when combined with Wells score <4. A P(ET,CO(2)) of >or=36 mmHg may reliably exclude PE. Accuracy is augmented by combination with Wells score. P( ET,CO(2)) should be prospectively compared to D-dimer in accuracy and simplicity to exclude PE.


Context: Differentiation between abacavir hypersensitivity and viral respiratory infections is problematic. Fifteen cases of abacavir hypersensitivity were matched to 30 controls with culture proven influenza A with no abacavir exposure. Rash was associated with hypersensitivity (odds ratio [OR] = 13.1, P = 0.02) as was the presence of nausea (OR = 30, P < 0.001), vomiting (OR = 17.1, P = 0.001) or diarrhoea (OR = 22, P < 0.001). The number of gastrointestinal symptoms was also predictive of hypersensitivity reaction (P < 0.001). Respiratory symptoms (cough, sore throat, or dyspnoea) were not associated with abacavir hypersensitivity (OR = 0.08, P = 0.001). Multivariate analysis confirmed the following associations for abacavir hypersensitivity: the number of gastrointestinal symptoms (OR = 8.6, P = 0.0032), cough (OR = 0.039, P = 0.02) and rash (OR = 16.9, P = 0.07). Abacavir hypersensitivity is strongly associated with gastrointestinal (GI) symptoms. Cough without GI symptoms is associated with influenza.


Context: We report two cases of x-linked dominant hypophosphatemic rickets involving a man and his daughter. The family tree consists of 44 members with 13 of them having short stature and bowing of the lower limbs. The study of this family tree strongly suggests an x-linked dominant inheritance.


Context: Viliuisk encephalomyelitis is an acute, often fatal, meningoencephalitis that tends to develop into a prolonged chronically progressive panencephalitis. Clinical, neuropathologic, and epidemiologic data argue for an infectious cause, although multiple attempts at pathogen isolation have been unsuccessful. To assess mechanisms of disease transmission and spread, we studied 6 multiplex families. Secondary cases occurred among genetically related and unrelated persons in a setting of prolonged intrahousehold contact with a patient manifesting the disease. Transmission to unrelated persons was documented in a densely populated region around the city of Yakutsk in which Viliuisk encephalomyelitis had not been previously known. Initially identified in a small Yakut-Evenk population on the Viliui River of eastern Siberia, the disease subsequently spread through human contacts to new geographic areas, thus characterizing Viliuisk encephalomyelitis as an emerging infectious disease.


Context: A large body of clinical and nonclinical evidence supports the role of neurotoxic soluble beta amyloid (amyloid, Aβ) oligomers as upstream pathogenic drivers of Alzheimer's disease (AD). Recent late-stage trials in AD that have evaluated agents targeting distinct species of Aβ provide compelling evidence that inhibition of Aβ oligomer toxicity represents an effective approach to slow or stop disease progression: (1) only agents that target soluble Aβ oligomers show clinical efficacy in AD patients; (2) clearance of amyloid plaque does not correlate with clinical improvements; (3) agents that predominantly target amyloid monomers or plaque failed to show clinical effects; and (4) in positive trials, efficacy is greater in carriers of the ε4 allele of apolipoprotein E (APOE4), who are known to have higher brain concentrations of Aβ oligomers. These trials also show that inhibiting Aβ neurotoxicity leads to a reduction in tau pathology, suggesting a pathogenic sequence of events where amyloid toxicity drives an increase in tau formation and deposition. The late-stage agents with positive clinical or biomarker data include four antibodies that engage Aβ oligomers (aducanumab, lecanemab, gantenerumab, and donanemab) and ALZ-801, an oral agent that fully blocks the formation of Aβ oligomers at the clinical dose.


Context: Deficiency of 5,10-methylenetetrahydrofolate reductase (MTHFR) leads to deficient remethylation of homocysteine and is one of the causes of homocystinuria. Only 28 patients have been reported so far. A 15-year-old boy with mild mental retardation was admitted in our hospital because of progressive difficulty in walking. He is the second child. The paternal grandparents are first cousins. On admission, clinical examination revealed mild disturbance of consciousness, left hemiparesis, truncal ataxia, pyramidal tract signs in the lower limbs and sensory disturbance in his feet. There was no marfanoid symptoms nor ectopia lentis. EEGs showed slow activity with sporadic spike and wave complexes. Peak latencies of N20 of median nerves SEPs, the third and 5th wave of ABR and P100 of VEP were delayed. The CT scan showed mild cortical atrophy and MRI revealed increased intensity on T2-weighted images in the cerebral white matter. Biochemical studies revealed homocystinuria with homocystinemia. Both plasma methionine and serum folic acid were low. Serum vitamin B12 and methylmalonic acid in urine were normal. The lymphoblastoid cell line, transformed by Epstein-Barr virus of lymphocytes of the patient, could not grow when homocysteine was substituted in the culture medium for methionine. The normal control cell line grew naturally under the same condition. A diagnosis of homocystinuria due to MTHFR deficiency was made. The patient was on various therapeutic regimens for about 70 days. Treatment with high doses of folic acid (400 mg/day) resulted in disappearance of homocysteine in plasma, remarkable decrease of homocysteine in urine and increase of methionine in plasma of the patient.(ABSTRACT TRUNCATED AT 250 WORDS)


Context: Ex vivo skin preservation is important for skin banks, burn centers, and in research; however, the optimal preservation solution is not known. Human amniotic fluid (HAF), in addition to its role in fetal wound healing, has promise as an effective and readily available preservation solution. The purpose of this study was to compare the efficacy of several solutions, including HAF, in full-thickness skin preservation. Human amniotic fluid was obtained from patients undergoing amniocentesis. Full-thickness skin obtained during abdominoplasty was divided into 1-cm(2) samples. These specimens were preserved in either saline, HAF from a single patient, pooled HAF, University of Wisconsin solution, or custodial histidine-tryptophan-ketoglutarate solution at 4°C. There were 5 samples in each group. Specimens were examined for keratinocyte survival at 7, 14, 21, 28, and 35 days using the trypan blue assay. The first 200 cells identified were counted to calculate the degree of cell death. Comparisons were made between the groups, and a multivariable repeated-measures analysis was performed to determine statistical significance, which was defined as P < 0.05. The individual and pooled HAF showed greater keratinocyte survival than the other solutions, at each time point. The difference was statistically significant (P < 0.05) when compared to saline and custodial solution but not statistically significant when compared to University of Wisconsin solution. When used as a tissue preservation solution, HAF produces superior keratinocyte survival than several commercially available solutions. Amniotic fluid, nature's tissue preservation solution, may be an inexpensive, readily available alternative for use in skin banks, burn centers, and research.


Context: The sequencing of the complete genome of the nematode Caenorhabditis elegans was a landmark achievement and ushered in a new era of whole-organism, systems analyses of the biology of this powerful model organism. The success of the C. elegans genome sequencing project also inspired communities working on other organisms to approach genome sequencing of their species. The phylum Nematoda is rich and diverse and of interest to a wide range of research fields from basic biology through ecology and parasitic disease. For all these communities, it is now clear that access to genome scale data will be key to advancing understanding, and in the case of parasites, developing new ways to control or cure diseases. The advent of second-generation sequencing technologies, improvements in computing algorithms and infrastructure and growth in bioinformatics and genomics literacy is making the addition of genome sequencing to the research goals of any nematode research program a less daunting prospect. To inspire, promote and coordinate genomic sequencing across the diversity of the phylum, we have launched a community wiki and the 959 Nematode Genomes initiative (www.nematodegenomes.org/). Just as the deciphering of the developmental lineage of the 959 cells of the adult hermaphrodite C. elegans was the gateway to broad advances in biomedical science, we hope that a nematode phylogeny with (at least) 959 sequenced species will underpin further advances in understanding the origins of parasitism, the dynamics of genomic change and the adaptations that have made Nematoda one of the most successful animal phyla.


Context: We report the whole-genome sequence of the common marmoset (Callithrix jacchus). The 2.26-Gb genome of a female marmoset was assembled using Sanger read data (6×) and a whole-genome shotgun strategy. A first analysis has permitted comparison with the genomes of apes and Old World monkeys and the identification of specific features that might contribute to the unique biology of this diminutive primate, including genetic changes that may influence body size, frequent twinning and chimerism. We observed positive selection in growth hormone/insulin-like growth factor genes (growth pathways), respiratory complex I genes (metabolic pathways), and genes encoding immunobiological factors and proteases (reproductive and immunity pathways). In addition, both protein-coding and microRNA genes related to reproduction exhibited evidence of rapid sequence evolution. This genome sequence for a New World monkey enables increased power for comparative analyses among available primate genomes and facilitates biomedical research application.


Context: FLT3 mutations are one of the most common findings in acute myeloid leukemia (AML). FLT3 inhibitors have been in active clinical development. Midostaurin as the first-in-class FLT3 inhibitor has been approved for treatment of patients with FLT3-mutated AML. In this review, we summarized the preclinical and clinical studies on new FLT3 inhibitors, including sorafenib, lestaurtinib, sunitinib, tandutinib, quizartinib, midostaurin, gilteritinib, crenolanib, cabozantinib, Sel24-B489, G-749, AMG 925, TTT-3002, and FF-10101. New generation FLT3 inhibitors and combination therapies may overcome resistance to first-generation agents.


Context: Cirsoid aneurysms are rare arteriovenous malformations of the scalp, which are usually of congenital etiology. We describe the case of a young Sri Lankan farmer who presented with a progressively enlarging scalp mass of interesting character, yielding unique images on plain radiography before more advanced imaging and subsequent definitive treatment were performed. The utility of this simple imaging technique in underdeveloped settings is highlighted, and further diagnostic and treatment options are discussed in brief.


Context: Macroautophagy is a catabolic process by which cytosolic components are sequestered by double membrane vesicles called autophagosomes and sorted to the lysosomes/vacuoles to be degraded. Saccharomyces cerevisiae has adapted this mechanism for constitutive transport of the specific vacuolar hydrolases aminopeptidase I (Ape1) and α-mannosidase (Ams1); this process is called the cytoplasm to vacuole targeting (Cvt) pathway. The precursor form of Ape1 self-assembles into an aggregate-like structure in the cytosol that is then recognized by Atg19 in a propeptide-dependent manner. The interaction between Atg19 and autophagosome-forming machineries allows selective packaging of the Ape1-Atg19 complex by the autophagosome-like Cvt vesicle. Ams1 also forms oligomers and utilizes the Ape1 transport system by interacting with Atg19. Although the mechanism of selective transport of the Cvt cargoes has been well studied, it is unclear whether proteins other than Ape1 and Ams1 are transported via the Cvt pathway. We describe here that aspartyl aminopeptidase (Yhr113w/Ape4) is the third Cvt cargo, which is similar in primary structure and subunit organization to Ape1. Ape4 has no propeptide, and it does not self-assemble into aggregates. However, it binds to Atg19 in a site distinct from the Ape1- and Ams1-binding sites, allowing it to "piggyback" on the Ape1 transport system. In growing conditions, a small portion of Ape4 localizes in the vacuole, but its vacuolar transport is accelerated by nutrient starvation, and it stably resides in the vacuole lumen. We propose that the cytosolic Ape4 is redistributed to the vacuole when yeast cells need more active vacuolar degradation.


Context: Darolutamide is a novel, nonsteroidal androgen receptor (AR)-signaling inhibitor. It serves as a second-generation antiandrogen and is currently indicated for the treatment of patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). The product was approved by the United States Food and Drug Administration (FDA) in July 2019 and by the Japanese Ministry of Health, Labour and Welfare (MHLW) in January 2020 for the treatment of men with nmCRPC, and is awaiting approval in the E.U. for the same indication. This review will cover the background, preclinical development, safety, pharmacokinetics, pharmacodynamics and clinical studies that led to the approval of darolutamide. The key clinical data, ongoing trials and future directions for darolutamide are also discussed herein.


Context: Blood gene expression profiling has led to major advances in the field of rheumatology over the last few decades. Specifically, DNA microarray technology has been integral in increasing our knowledge of key players in the pathogenesis of some rare pediatric rheumatic diseases. Our group, using microarray analysis, identified the interferon (IFN) gene signature in pediatric systemic lupus erythematosus (SLE) and has published data that suggest high doses of intravenous corticosteroid treatment may have benefit over strictly oral regimens. Additionally, DNA microarray technology led to our discovery that the interleukin (IL)-1 gene signature is associated with systemic juvenile idiopathic arthritis (sJIA) and to the use of IL-1 blockade with anakinra in this disease. We also reported the biologic rationale for use of anakinra early in the disease course. Anakinra is now being used as first-line treatment in sJIA in multiple centers. Herein, we review how information obtained from blood gene expression profiling has changed our clinical practice.


Context: Kearns-Sayre syndrome (KSS) is a sporadic multisystem disorder due to rearrangements in mitochondrial DNA (mtDNA). To gain further insight into the pathogenesis of cerebellar dysfunction in KSS, antibodies against synaptophysin (SY) were used to identify presynaptic terminals and antibodies to calbindin D (CB) to identify Purkinje cells in the cerebellar cortex and in the dentate nucleus from two autopsied cases of KSS. By conventional neuropathology we found marked spongiform degeneration and by immunohistochemistry a disruption of presynaptic terminals and of the terminal arborizations of Purkinje cell axons on multipolar neurons of the dentate nucleus in the KSS patients. We suggest that a disconnection of Purkinje cells at the dentate nucleus may play a role in the pathogenesis of cerebellar ataxia in KSS.


Context: Laboratory strains of rats are a commonly used subject to study play behavior. Recent research has shown that play in one laboratory strain of rat (e.g., Long-Evans hooded) differs in a number of ways from its wild counterparts. These findings suggest that domestication affects some aspects of play behavior. However, there are multiple strains of laboratory rats, which have been domesticated through different lineages all derived from wild rats and it cannot be assumed that all domestic strains are identical in their play. Therefore, the aim of this study was to compare the play behavior of three other strains of laboratory rats (e.g., Wistar, Sprague-Dawley, and Brown Norway). All strains were similar to each other as they all engaged in high frequencies of play, tolerated similar interanimal distances before initiating playful defense and displayed similar acrobatic capacities, suggesting domestication produces some common changes in play and other factors that influence play. However, strains differed significantly from one another in the use of tactics that promote bodily contact during play. Indeed, in this regard, some strains were more similar to wild rats than others, suggesting that some domestication-induced changes are either unique or more prominent in some laboratory strains than others. Such a mosaic pattern of transformation not only offers the possibility of using strain differences to characterize the genetic factors contributing to different facets of play, but also cautions researchers from making rat-general conclusions from studies on any one strain.


Context: Anhedonia was independently associated with a 1.5-fold increased risk for all-cause mortality in patients who survived the first 6 months post-PCI. Enhancing positive emotions, in addition to reducing negative emotions, may constitute an important target for future psychological intervention trials in CAD patients.


Context: Super-enhancers are large clusters of transcriptional enhancers regarded as having essential roles in driving the expression of genes that control cell identity during development and tumorigenesis. The construction of a genome-wide super-enhancer database is urgently needed to better understand super-enhancer-directed gene expression regulation for a given biology process. Here, we present a specifically designed web-accessible database, Super-Enhancer Archive (SEA, http://sea.edbc.org). SEA focuses on integrating super-enhancers in multiple species and annotating their potential roles in the regulation of cell identity gene expression. The current release of SEA incorporates 83 996 super-enhancers computationally or experimentally identified in 134 cell types/tissues/diseases, including human (75 439, three of which were experimentally identified), mouse (5879, five of which were experimentally identified), Drosophila melanogaster (1774) and Caenorhabditis elegans (904). To facilitate data extraction, SEA supports multiple search options, including species, genome location, gene name, cell type/tissue and super-enhancer name. The response provides detailed (epi)genetic information, incorporating cell type specificity, nearby genes, transcriptional factor binding sites, CRISPR/Cas9 target sites, evolutionary conservation, SNPs, H3K27ac, DNA methylation, gene expression and TF ChIP-seq data. Moreover, analytical tools and a genome browser were developed for users to explore super-enhancers and their roles in defining cell identity and disease processes in depth.


Context: Previous work has demonstrated that fusion of a luciferase to an opsin, to create a luminescent opsin or luminopsin, provides a genetically encoded means of manipulating neuronal activity via both chemogenetic and optogenetic approaches. Here we have expanded and refined the versatility of luminopsin tools by fusing an alternative luciferase variant with high light emission, Gaussia luciferase mutant GLucM23, to depolarizing and hyperpolarizing channelrhodopsins with increased light sensitivity. The combination of GLucM23 with Volvox channelrhodopsin-1 produced LMO4, while combining GLucM23 with the anion channelrhodopsin iChloC yielded iLMO4. We found efficient activation of these channelrhodopsins in the presence of the luciferase substrate, as indicated by responses measured in both single neurons and in neuronal populations of mice and rats, as well as by changes in male rat behavior during amphetamine-induced rotations. We conclude that these new luminopsins will be useful for bimodal opto- and chemogenetic analyses of brain function.


Context: Quality control mechanisms in the endoplasmic reticulum prevent deployment of aberrant or unwanted proteins to distal destinations and target them to degradation by a process known as endoplasmic reticulum-associated degradation, or ERAD. Attempts to characterize ERAD by identifying a specific component have revealed that the most general characteristic of ERAD is that the protein substrates are initially translocated to the ER and eventually eliminated in the cytosol by the ubiquitin-proteasome pathway. Hence, dislocation from the ER back to the cytosol is a hallmark in ERAD and p97/Cdc48p, a cytosolic AAA-ATPase that is essential for ERAD, appears to provide the driving force for this process. Moreover, unlike many ERAD components that participate in degradation of either lumenal or membrane substrates, p97/Cdc48p has a more general role in that it is required for ERAD of both types of substrates. Although p97/Cdc48p is not dedicated exclusively to ERAD, its ability to physically associate with ERAD substrates, with VIMP and with the E3 gp78 suggest that the p97/Cdc48Ufdl/Npl4 complex acts as a coordinator that maintains coupling between the different steps in ERAD.


Context: (131)I, when released in a radiological or nuclear accident as happened recently in Fukushima, Japan, may cause thyroid cancer as a long-term consequence. Iodine thyroid blocking (ITB) is known to reduce the risk of developing thyroid cancer. Potential adverse effects of ITB have not been systematically investigated so far. This article summarises the results of a review on adverse effects of ITB based on a systematic literature search in scientific medical databases. A meta-analysis was not performed as identified studies displayed major heterogeneity. The search resulted in 14 articles relevant to the topic, reporting mostly on surveys, ecological and intervention studies. Only one study from Poland focused on effects (both desired and adverse) of an ITB intervention following the Chernobyl accident. All other studies reported on iodine administration in a different context. Overall, the studies did not reveal severe adverse reactions to potassium iodide in the general public. Since ITB is a protective measure only applied in very specific circumstances, scientifically sound studies of adverse effects are scarce and consequently the evidence base is weak. The assessment of adverse effects of ITB relies on indirect evidence from related areas. This study may contribute to ongoing developments in pharmacoepidemiology aiming to better quantify adverse effects of medications and health care interventions including ITB.


Context: Adipose tissue is central to the regulation of lipid metabolism. Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2), one of the most severe lipodystrophy diseases, is caused by mutation of the Seipin gene. Seipin plays an important role in adipocyte differentiation and lipid homeostasis, but its exact molecular functions are still unknown. Here, we show that Seipin physically interacts with the sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) in both Drosophila and man. SERCA, an endoplasmic reticulum (ER) calcium pump, is solely responsible for transporting cytosolic calcium into the ER lumen. Like dSeipin, dSERCA cell-autonomously promotes lipid storage in Drosophila fat cells. dSeipin affects dSERCA activity and modulates intracellular calcium homeostasis. Adipose tissue-specific knockdown of the ER-to-cytosol calcium release channel ryanodine receptor (RyR) partially restores fat storage in dSeipin mutants. Our results reveal that Seipin promotes adipose tissue fat storage by regulating intracellular calcium homeostasis.


Context: Verubecestat did not reduce cognitive or functional decline in patients with mild-to-moderate Alzheimer's disease and was associated with treatment-related adverse events. (Funded by Merck; ClinicalTrials.gov number, NCT01739348 .).


Context: The ASCTs (alanine, serine, and cysteine transporters) belong to the solute carrier family 1 (SLC1), which also includes the human glutamate transporters (excitatory amino acid transporters, EAATs) and the prokaryotic aspartate transporter GltPh. Despite the high degree of amino acid sequence identity between family members, ASCTs function quite differently from the EAATs and GltPh. The aim of this study was to mutate ASCT1 to generate a transporter with functional properties of the EAATs and GltPh, to further our understanding of the structural basis for the different transport mechanisms of the SLC1 family. We have identified three key residues involved in determining differences between ASCT1, the EAATs and GltPh. ASCT1 transporters containing the mutations A382T, T459R, and Q386E were expressed in Xenopus laevis oocytes, and their transport and anion channel functions were investigated. A382T and T459R altered the substrate selectivity of ASCT1 to allow the transport of acidic amino acids, particularly l-aspartate. The combination of A382T and T459R within ASCT1 generates a transporter with a similar profile to that of GltPh, with preference for l-aspartate over l-glutamate. Interestingly, the amplitude of the anion conductance activated by the acidic amino acids does not correlate with rates of transport, highlighting the distinction between these two processes. Q386E impaired the ability of ASCT1 to bind acidic amino acids at pH 5.5; however, this was reversed by the additional mutation A382T. We propose that these residues differences in TM7 and TM8 combine to determine differences in substrate selectivity between members of the SLC1 family.


Context: Gleevec (imatinib mesylate), a highly promising new drug for the treatment of chronic myelogenous leukemia in blast crisis, in accelerated phase, and in chronic phase after interferon failure or intolerance, received orphan drug status from the U.S. Food and Drug Administration (FDA) Office of Orphan Products Development on January 31, 2001, and accelerated approval from the FDA for the above three indications on May 10, 2001. The purpose of this report is to summarize FDA regulatory mechanisms, i.e., accelerated approval and orphan drug regulations, that have permitted patients to receive this drug as rapidly as possible.


Context: Clostridium difficile is the etiologic agent of nosocomial and community-acquired diarrhea associated with exposure to antibiotics that disrupt the normal colonic flora. As antibacterials currently used for primary C. difficile infections favor recurrences, new methods able to neutralize the bacterium without affecting the gut microbiota are badly needed. Complementary treatment with probiotic agents to reconstitute the physiologicaL intestinal flora does not yield any consistent benefit. In recent years, fecal transplantation has been used in the English-speaking countries with cure rates of about 87%. Fecal microbiota transplantation (FMT) holds considerable promise as a therapy for recurrent Clostridium difficile infection, but well-designed, randomized-controlled trials and Long-term follow-up registries are stilt required. These are needed to identify the right patient, efficacy and safety profile of FMT before this approach can be widely advocated. Another aspect of bad/good parasites are the use of helminth or helminth ova for treating autoimmune diseases, especially those affecting the gut.


Context: CTCF is a transcription factor and a candidate tumor suppressor that contains a DNA-binding domain composed of 11 zinc fingers. We reported previously that CTCF is differentially regulated during differentiation of human myeloid leukemia cells. In this study we aimed to investigate the role of CTCF in myeloid cell differentiation. A human cell line, K562, that can be chemically induced to differentiate into various hematopoietic lineages was chosen as a model system for this study. Several K562 cell lines with constitutive and conditional expression of CTCF have been generated. By using these model systems we demonstrated that: (i) ectopic expression of CTCF in K562 cells led to growth retardation and promotion of differentiation into the erythroid lineage; (ii) CTCF knock-down significantly inhibited differentiation of K562 cells into erythroid lineage; (iii) differentiation of K562 into the megakaryocytic lineage was not significantly affected; and (iv) down-regulation of MYC has been identified as one of the mechanisms by which CTCF promotes erythroid differentiation. Taken together our results demonstrate that CTCF is involved in the control of myeloid cell growth and differentiation.


Context: To evaluate the value of improved Mallampati grading combined with NoSAS questionnaire in screening for obstructive sleep apnea （OSA）. A total of 344 patients admitted to our hospital for sleep disorders were studied. All patients were measured for their height, weight, neck circumference and other parameters. NoSAS scores, improved Mallampati grading and polysomnography （PSG） were performed in these patients. According to AHI in PSG monitoring results, patients were divided into non-osa group （AHI<5） 93 cases and OSA group 251 cases. The OSA group were divided into mild （AHI 5-15）, moderate（AHI 16-30） and severe OSA group（AHI>30） according to the PSG result. The ROC curve was plotted to evaluate the screening value of NoSAS and improved Mallampati grading combined with NoSAS for OSA. With the NoSAS score of 8 or 9 as cutoffs for analysis, the sensitivity for OSA was 0.733 and 0.701; the specificity for OSA was 0.538 and 0.624, respectively. The sensitivity and specificity of NoSAS combined with improved Mallampati grading for screening OSA were 0.813 and 0.710, respectively. As a new screening tool, NoSAS questionnaire is simple and convenient, and has certain screening value to OSA. The improved Mallampati grading combined with NoSAS questionnaire can obviously improve the screening sensitivity and specificity of Osa, and has higher application value.


Context: Anthrax is a highly contagious and potentially fatal human disease caused by Bacillus anthracis, an aerobic, Gram-positive, spore-forming rod-shaped bacterium with worldwide distribution as a zoonotic infection in herbivore animals. Bioterrorist attacks with inhalational anthrax have prompted the development of more effective treatments. Antibodies against anthrax toxin have been shown to decrease mortality in animal studies. Raxibacumab is a recombinant human monoclonal antibody developed against inhalational anthrax. The drug received approval after human studies showed its safety and animal studies demonstrated its efficacy for treatment as well as prophylaxis against inhalational anthrax. It works by preventing binding of the protective antigen component of the anthrax toxin to its receptors in host cells, thereby blocking the toxin's deleterious effects. Recently updated therapy guidelines for Bacillus anthracis recommend the use of antitoxin treatment. Raxibacumab is the first monoclonal antitoxin antibody made available that can be used with the antibiotics recommended for treatment of the disease. When exposure is suspected, raxibacumab should be given with anthrax vaccination to augment immunity. Raxibacumab provides additional protection against inhalational anthrax via a mechanism different from that of either antibiotics or active immunization. In combination with currently available and recommended therapies, raxibacumab should reduce the morbidity and mortality of inhalational anthrax.


Context: We report a case with an unusual manifestation of autoerythrocyte sensitization syndrome (Gardner-Diamond syndrome). The patient had the clinical signs of compartment syndrome of the forearm requiring fasciotomy. Dermatological signs identical to Gardner-Diamond syndrome should alert the physician to avoid unnecessary fasciotomy, as these patients respond well to psychiatric treatment as in the present case.


Context: Despite being benign CNS tumours, meningiomas are not always curable and the likelihood of recurrence depends upon the completeness of initial removal. Adjuvant therapy for incompletely resected meningiomas is generally unsatisfactory and such lesions continue to pose difficult management problems. Photodynamic therapy (PDT) has been employed in the management of recurrent cerebral gliomas but its activity against meningiomas has not been specifically studied. An in vitro study of the effects of PDT against a variety of meningiomas was therefore conducted. It was found that PDT using haematoporphyrin derivative as a photosensitizing drug showed dose-dependent activity against a variety of histological subtypes of meningioma. The activity of PDT against meningiomas should be investigated further and may eventually provide a useful form of adjuvant therapy for incompletely resected lesions.


Context: Nondystrophic myotonias are characterized by muscle stiffness triggered by voluntary movement. They are caused by mutations in either the CLCN1 gene in myotonia congenita or in the SCN4A gene in paramyotonia congenita and sodium channel myotonias. Clinical and electrophysiological phenotypes of these disorders have been well described. No concomitant mutations in both genes have been reported yet. We report five patients from three families showing myotonia with both chloride and sodium channel mutations. Their clinical and electrophysiological phenotypes did not fit with the phenotype known to be associated with the mutation initially found in SCN4A gene, which led us to screen and find an additional mutation in CLCN1 gene. Our electrophysiological and clinical observations suggest that heterozygous CLCN1 mutations can modify the clinical and electrophysiological expression of SCN4A mutation.


Context: Colorectal cancer (CRC) is a worldwide public health problem, with nearly 800,000 new cases diagnosed each year, resulting in approximately 500,000 deaths. When advanced metastatic disease is diagnosed, CRC is associated with a poor prognosis, and 5-year survival rates are in the range of 5%-8%. Chemotherapy has been the mainstay approach for patients with advanced CRC. For nearly 40 years, the main drug used for this disease was the fluoropyrimidine 5-fluorouracil (5-FU). Significant advances have been made in chemotherapy treatment options for patients with metastatic disease, such that improvements in 2-year survival are now being reported with median survival rates of 21 months to 24 months. Over the past 10 years, 3 new cytotoxic chemotherapy agents have been approved by the FDA for metastatic CRC. These compounds include the topoisomerase I inhibitor irinotecan, the third-generation platinum analogue oxaliplatin, and the oral fluoropyrimidine capecitabine. Since 2004, 3 novel biologic agents have been approved by the FDA, and they include the anti-epidermal growth factor receptor antibodies cetuximab and panitumumab and the anti-vascular endothelial growth factor bevacizumab. The oral fluoropyrimidine capecitabine has been effectively and safely combined with irinotecan (CAPIRI) and/or oxaliplatin (CAPOX). Three randomized phase III studies have now shown that CAPOX is equivalent to FOLFOX (5-FU/leucovorin/oxaliplatin)-based regimens. Significant interest has centered around combining capecitabine-based cytotoxic regimens with the biologic agents, and specifically, bevacizumab and cetuximab. This review will update the current status of these capecitabine-based combination regimens.


Context: Fusobacterium species is known for being a causative agent for Lemierre's syndrome, which is characterized by thrombophlebitis of the jugular vein. However, Fusobacterium species causing Lemierre's variant gastrointestinal syndrome has only been reported in case reports. We present a case of Fusobacterium causing hepatic vein pylephlebitis, multiple brain abscesses, and hepatic abscess. To the best of our knowledge, there have only been four other case reports of Fusobacterium causing hepatic abscesses with associated septic pylephlebitis in the literature.


Context: The Waardenburg syndrome (WS) consists of at least two distinct autosomal dominant hereditary disorders. WS Type I has been mapped to the distal part of chromosome 2q and the gene identified as PAX3. Other gene(s) are responsible for WS Type II. Mapping WS Type II requires accurate diagnosis within affected families. To establish diagnostic criteria for WS Type II, 81 individuals from 21 families with Type II WS were personally studied, and compared with 60 personally studied patients from 8 families with Type I and 253 cases of WS (Type I or II) from the literature. Sensorineural hearing loss (77%) and heterochromia iridum (47%) were the two most important diagnostic indicators for WS Type II. Both were more common in Type II than in Type I. Other clinical manifestations, such as white forelock and skin patches, were more frequent in Type I. We estimate the frequency of phenotypic traits and propose diagnostic criteria for WS Type II. In practice, a diagnosis of WS Type II can be made with confidence given a family history of congenital hearing loss and pigmentary disorders, where individuals have been accurately measured for ocular distances to exclude dystopia canthorum.


Context: Apremilast is an effective and well-tolerated option in treating moderate-to-severe plaque psoriasis. Its safety profile and the oral administration offer significant advantages in prescribing apremilast for the treatment of psoriasis, particularly in some subsets of patients.


Context: Potocki-Shaffer syndrome is a rare contiguous gene deletion syndrome due to haploinsufficiency of the 11p11.2p12 region and is characterized by craniofacial abnormalities, developmental delay, intellectual disability, multiple exostoses, and biparietal foramina. In this study, six patients with the Potocki-Shaffer syndrome were identified and evaluated using a multidisciplinary protocol that included assessments by a geneticist, ophthalmologist, otolaryngologist, orthopedist, nephrologist, audiologist, and neuropsychologist. Diagnostic studies included skeletal survey, magnetic resonance imaging of the brain, renal ultrasound, complete blood count, comprehensive metabolic panel, thyroid studies, and urinalysis. Using array comparative genomic hybridization, we further characterized the deletion in five of these patients. The results of these evaluations were combined with a comprehensive review of reported cases. Our data highlight the characteristic facial features, biparietal foramina, moderate-to-severe developmental delay and intellectual disability, myopia and strabismus, and multiple exostoses seen with this disorder. We also identify for the first time an association of Potocki-Shaffer syndrome with sensorineural hearing loss and autistic behaviors. Finally, we provide recommendations for the health maintenance of patients with Potocki-Shaffer syndrome.


Context: The p38 Mitogen-Activated Protein (MAP) kinase, a serine/threonine kinase, is one of the best characterized kinases in the inflammatory process. Among the four identified p38 isoforms (p38α, p38β, p38γ, and p38δ), the α-form is the most fully studied and plays a central role in the biosynthesis of the proinflammatory cytokines i.e. IL-1β and TNF-α at the translational and transcriptional levels. Antagonism of these proinflammatory cytokines has been recognized as an effective possibility for the development of new drug candidates. The characterization of the pharmacological profile displayed by the selective p38 inhibitor prototype SB203580, proved its disease-modifying activity in the adjuvantinduced arthritis model. This strongly suggests that adequate modulation of production of these cytokines can bring significant benefits to the therapy of chronic inflammatory diseases. In addition to its important role for the secretion of proinflammatory cytokines, p38 is also involved in the activation of matrix metalloproteinases and the induction of COX- 2 transcription, proteins that are involved in the process of tissue destruction and inflammation. Because of its multiple functions in modulating the inflammatory response, it is expected that p38 inhibiting drugs will treat the underlying cause of chronic inflammatory diseases and stop their progression. The archetypal small molecule p38 inhibitors are the pyridinylimidazoles and these structures formed the basis for much of the early research. More recently a number of nonimidazole based p38 inhibitors such as the ureas, pyrazoles, pyrazoloheteroaryls, pyridazines, indoles, amides, pyridines, triazolopyridines, etc containing a variety of functionality have been reported to inhibit cytokine activity. This article provides a critical account of these different heterocycles reported for p38 MAPK inhibition and covers the recent research in the development of anti inflammatory agents.


Context: The combination of the T variant of the 1858 polymorphism of the PTPN22 gene in combination with the presence of anti-CCP antibodies, preferentially in a SE-positive individual, is associated with the development of RA.


Context: Carpal tunnel syndrome (CTS) is the most common median nerve neuropathy, accounting for 90% of all neuropathies. Carpal tunnel syndrome presents in 3.8% of the general population, with a higher prevalence among women. There are several risk factors associated with CTS, including both medical and non medical factors. The pathophysiologic mechanisms involved in the median nerve compression and traction are thought to be complex, and as yet are not fully understood. The present review aimed to provide an overview of the pathophysiology of median nerve neuropathy in the carpal tunnel, and subsequent development of CTS.


Context: Epigenetics refers to the study of heritable changes in the pattern of gene expression that is controlled by a mechanism specifically not due to changes the primary DNA sequence. Well-known epigenetic mechanisms include DNA methylation, post-translational histone modifications and RNA-based mechanisms including those controlled by small non-coding RNAs (miRNAs). Recent studies have shown that epigenetic modifications orchestrate the hepatic stellate cell (HSC) activation and liver fibrosis. In this review we focus on the aberrant methylation of CpG island promoters of select genes is the prominent epigenetic mechanism to effectively silence gene transcription facilitating HSC activation and liver fibrosis. Furthermore, we also discuss epigenetic dysregulation of tumor-suppressor miRNA genes by promoter DNA methylation and the interaction of DNA methylation with miRNAs involved in the regulation of HSC activation and liver fibrosis. Recent advances in epigenetics alterations in the pathogenesis of liver fibrosis and their possible use as new therapeutic targets and biomarkers.


Context: In metazoans transcriptional enhancers and their more complex relatives, locus control regions, are often located at great linear distances from their target genes. In addition, these elements frequently activate different members of gene families in temporal sequence or in different tissues. These issues have complicated understanding the mechanisms underlying long-range gene activation. Advances in primarily technical approaches, such as chromosome conformation capture (3C) and its derivatives have now solidified the idea that distant regulatory elements achieve proximity with their target genes when they are activating them. Furthermore, these approaches are now allowing genome-wide views of chromosome interactions that are likely to include regulatory, structural, and organization aspects from which we will be able to understand more about nuclear structure. At the base of these advances are experimental approaches to localize protein-binding sites in chromatin, to assess remodeling of chromatin and to measure interaction frequency between distant sites. Examples of these approaches comprise this review.


Context: The 2014-2015 outbreak of Ebola virus disease is the largest epidemic to date in terms of the number of cases, deaths, and affected areas. In October 2015, no antiviral agents had proven antiviral efficacy in patients. However, in September 2014, the World Health Organization inventoried and has since regularly updated a list of potential drug candidates with demonstrated antiviral efficacy in in vitro or animal models. This includes agents belonging to various therapeutic classes, namely direct antiviral agents (favipiravir and BCX4430), a combination of antibodies (ZMapp), type I interferons, RNA interference-based drugs (TKM-Ebola and AVI-7537), and anticoagulant drugs (rNAPc2). Here, we review the pharmacokinetic and pharmacodynamic information presently available for these drugs, using data obtained in healthy volunteers for pharmacokinetics and data obtained in human clinical trials or animal models for pharmacodynamics. Future studies evaluating these drugs in clinical trials are critical to confirm their efficacy in humans, propose appropriate doses, and evaluate the possibility of treatment combinations.


Context: In colorectal cancer (CRC) oncogenic mutations such as KRAS alterations, are considered standard molecular biomarkers that predict the clinical benefit for targeted intervention with epidermal growth factor receptor (EGFR) inhibitors. In addition, these mutations are associated with specific anatomical area in colon tumor development, as BRAF mutations with the microsatellite instability (MSI). In this translational study, we aimed to assess the mutation frequencies of the EGFR (hotspot area and polyadenine deletions A13_del), KRAS, BRAF(V600E), and PIK3CA oncogenes in a series of 280 CRC patients. MSI phenotypes are also considered in this series. All patients' clinicopathological data were assessed for statistical analysis and its associations were validated. We verified multiple associations between oncogenic mutations and determined clinicopathological tumor features (1) EGFR A13_deletions are associated with right colon carcinoma (P<0.005), mucinous histotype (P=0.042), G3 grading (P=0.024), and MSI status (P<0.005); (2) PIK3CA mutations are related mucinous histotype (P=0.021); (3) KRAS(G12) and KRAS(G13) mutations are correlated, respectively, with the left and right colon cancer development (P<0.005), and finally (4) MSI is associated with right colon tumors (P<0.005). Mostly, we verified a higher frequency rate of the KRAS(G13) and EGFR A13_del oncogene mutations in right colon cancer; whereas KRAS(G12) codon mutation occurs more frequently in left colon cancers. In particular, we assessed that right vs left colon cancer are associated with specific molecular characteristics. These evidences, in association with clinicopathological data, can delineate novel approaches for the CRC classification and targeted intervention.


Context: PARP-family ADP-ribosyltransferases (PARPs) and sirtuin deacetylases all use NAD(+) as cosubstrate for ADP-ribosyl transfer. PARP inhibitors are important research tools and several are being evaluated in cancer treatment. With the exception of a few tankyrase inhibitors, all current PARP inhibitors mimic the nicotinamide moiety in NAD(+) and block the nicotinamide binding pocket. We report here that while the activities of the four human sirtuin isoforms SIRT1, SIRT2, SIRT3 and SIRT6 are blocked by sirtuin inhibitor Ex527 in vitro, they are unaffected by the seven clinical and commonly used PARP inhibitors niraparib, olaparib, rucaparib, talazoparib, veliparib, PJ34, and XAV939. These findings indicate that PARP inhibitors containing planar nicotinamide mimetics do not bind to sirtuin cofactor sites. In conclusion, a simple commercially available assay can be used to rule out interference of novel PARP inhibitors with sirtuin NAD(+) binding.


Context: The Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signaling pathway is utilized by numerous cytokines and interferons, and is essential for the development and function of both innate and adaptive immunity. Aberrant activation of the JAK/STAT pathway is evident in neuroinflammatory diseases such as Multiple Sclerosis and Parkinson's Disease. Innate immunity is the front line defender of the immune system and is composed of various cell types, including microglia, macrophages and neutrophils. Innate immune responses have both pathogenic and protective roles in neuroinflammation, depending on disease context and the microenvironment in the central nervous system. In this review, we discuss the role of innate immunity in the pathogenesis of neuroinflammatory diseases, how the JAK/STAT signaling pathway regulates the innate immune response, and finally, the potential for ameliorating neuroinflammation by utilization of JAK/STAT inhibitors.


Context: Enhancer activation is a critical step for gene activation. Here we report an epigenetic crosstalk at enhancers between the UTX (H3K27 demethylase)-MLL4 (H3K4 methyltransferase) complex and the histone acetyltransferase p300. We demonstrate that UTX, in a demethylase activity-independent manner, facilitates conversion of inactive enhancers in embryonic stem cells to an active (H3K4me1/H3K27ac) state by recruiting and coupling the enzymatic functions of MLL4 and p300. Loss of UTX leads to attenuated enhancer activity, characterized by reduced levels of H3K4me1 and H3K27ac as well as impaired transcription. The UTX-MLL4 complex enhances p300-dependent H3K27 acetylation through UTX-dependent stimulation of p300 recruitment, while MLL4-mediated H3K4 monomethylation, reciprocally, requires p300 function. Importantly, MLL4-generated H3K4me1 further enhances p300-dependent transcription. This work reveals a previously unrecognized cooperativity among enhancer-associated chromatin modulators, including a unique function for UTX, in establishing an "active enhancer landscape" and defines a detailed mechanism for the joint deposition of H3K4me1 and H3K27ac.


Context: Analysis of 501 melanoma exomes identified RASA2, encoding a RasGAP, as a tumor-suppressor gene mutated in 5% of melanomas. Recurrent loss-of-function mutations in RASA2 were found to increase RAS activation, melanoma cell growth and migration. RASA2 expression was lost in ≥30% of human melanomas and was associated with reduced patient survival. These findings identify RASA2 inactivation as a melanoma driver and highlight the importance of RasGAPs in cancer.


Context: Viliuisk encephalomyelitis (VE) is a unique disease occurring in the Yakut (Sakha) population of Eastern Siberia. VE is always fatal, with some patients dying during the acute encephalitic phase of illness; those surviving the acute phase develop progressive dementia, rigidity and spastic quadriparesis as part of a more prolonged pan-encephalitic syndrome. The disease is characterized neuropathologically by multiple widespread micronecrotic foci with marked inflammatory reactions and subsequent gliosis throughout the cerebral cortex, basal ganglia, cerebellum and brain stem. The acute febrile onset with cerebrospinal fluid pleocytosis and increased protein and neuropathology showing inflammatory reactions suggest that VE is an infectious disease, but the causative agent has not been identified. Initially detected in a small mixed Yakut-Evenk population of the mid-Viliui region, the disease subsequently spread south to densely populated areas around the capital city of Yakutsk. The occurrence of secondary VE cases in households and the introduction of the disease by migrants into new populations indicate that the disease is horizontally transmitted in a setting of a long intra-household contact. Although there has been a recent decline in the number of cases, increasing travel may result in further spread of this fatal disease to susceptible individuals in other regions of the world.


Context: Duchenne muscular dystrophy (DMD) is a progressive muscle disease caused by loss of dystrophin protein, encoded by the DMD gene. DMD manifests early in childhood as difficulty walking, progresses to loss of ambulation by the teens, and leads to death in early adulthood. Adeno-associated virus-vectorized gene therapies to restore dystrophin protein expression using gene replacement or antisense oligonucleotide-mediated pre-mRNA splicing modulation have emerged, making great strides in uncovering barriers to gene therapies for DMD and other genetic diseases. While this first-generation of DMD therapies are being evaluated in ongoing clinical trials, uncertainties regarding durability and therapeutic efficacy prompted the development of new experimental therapies for DMD that take advantage of somatic cell gene editing. These experimental therapies continue to advance toward clinic trials, but questions remain unanswered regarding safety and translatable efficacy. Here we review the advancements toward treatment of DMD using gene editing and modulation therapies, with an emphasis on those nearest to clinical applications.