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2018-04-03T06:07:11.078Z | 2014-02-01T00:00:00.000Z | 45630960 | s2ag/train | A phase 2 study of HQK‐1001, an oral fetal haemoglobin inducer, in β‐thalassaemia intermedia
The β-thalassaemia syndromes represent a World Health Organization-designated global health burden (Weatherall et al, 2010). Reactivation of fetal globin (HbF) expression is a rational therapeutic approach in inherited β-globindisorders, because the fetal HBG(γ-globin genes) are universally present and appropriately contextually integrated in the HBB(β-globin gene) locus in haematopoietic stem cells (Bauer et al, 2012). The defective production of β-globin chains in β-thalassaemia can be compensated for by an increase in γ-globin chains, which pair with α-globinchains to form HbF, thereby decreasing the α/non α-globin imbalance, the hallmark of β-thalassaemia. Several classes of HbF inducers have been investigated in β-thalassaemia, including cytotoxic agents, DNA methyl transferase inhibitors, histone deacetylase (HDAC) inhibitors including short chain fatty acids, thalidomide derivative, and erythropoietin, but no consistently effective agents have been identified (Musallam et al, 2013).
The short chain fatty acids arginine butyrate, sodium phenylbutyrate, and isobutyramide were shown to increase HbF in β-thalassaemia and sickle cell disease, but had to be administered intravenously or by large oral daily doses, which is not practical for widespread long-term use (Perrine et al, 1993; Collins et al, 1995; Capellini et al, 2000). The orally bio available butyrate derivative 2,2-dimethylbutyrate sodium salt (HQK-1001) does not exhibit HDAC2 inhibitory activity and stimulates HBG expression and erythropoiesis in animal models and in vitro at concentrations readily achievable in humans(Pace et al, 2002; Mankindy et al, 2006). In a proof-of-concept study, HQK-1001 at 10, 20, 30, and 40 mg/kg administered daily for eight weeks in 21 subjects with non-transfusion dependent β-thalassaemia was well-tolerated (Fuchareon et al, 2013). HQK-1001 at 20 mg/kg, which provided the best results, increased HbFin 8 of 9 subjects with a median increase of 6.6% and 4.4 g/l, and increased total haemoglobin in 4 of 9 subjects by a mean of 11 g/L. Here, a single-centre study was conducted to evaluate HQK-1001 at 20 mg/kg/day administered for a longer period (NCT01642758).
Adult patients with β-thalassaemia intermedia characterized by two β-globin mutations were eligible if their haemoglobin was between 60 and 90 g/l on two occasions during the 30-day screening period. Patients were excluded if they were transfused within the previous three months, received iron chelation agents within the previous seven days, another investigational agent within the previous 30 days, erythropoietic agents within the previous 90 days, or hydroxycarbamide within the previous six months, or had pulmonary hypertension requiring oxygen therapy, alanine aminotransferase (ALT) > 4 times the upper limit of normal, or serum creatinine > 135 μmol/l. HQK-1001 capsules (HemaQuest Pharmaceuticals, San Diego, CA) was administered at 20 mg/kg once daily for 24 weeks. Folic acid was given daily, and to prevent iron-deficient inefficient erythropoiesis, oral iron was given if serum ferritin was 2250 pmol/l. After signing an Ethics Committee approved informed consent form, subjects were assessed clinically and underwent laboratory tests twice during a 30-day screening period, every four weeks while receiving HQK-1001, and then four weeks after the end of dosing.
Ten subjects were enrolled, seven male and three female, with a mean age of 29.4 years (range 18-52 years). Eight subjects were splenectomized; two had palpable splenomegaly at 4 and 7 cm below the left costal margin. The mean (range) baseline values were: HbF26.6% (7.9–73.8%), absolute HbF 20.1 g/l (5.5–53.9 g/l), total haemoglobin 77.4 g/l (61.5–96.0 g/l), platelet count 782 × 109/l (486-1039 × 109/l), reticulocytes 10.9% (7.1–15.7%), and serum ferritin 3188 pmol/l (375–9772 pmol/l).
Nine subjects completed the study and one subject was discontinued at Week 16 because of worsening anaemia requiring a transfusion. Mean compliance with HQK-1001, calculated as the ratio of the number of HQK-1001 capsules taken divided by the number of capsules prescribed, was 92.5%; two subjects had compliance <90%. Treatment was generally well-tolerated. All adverse events, except one case of vertigo, were graded as mild or moderate, and were reversible. Fatigue was the most common adverse event, reported in 3 subjects. In contrast, 5 subjects reported increased activity and improved mood. Two subjects each reported nausea, epigastric pain, dyspepsia or fever. The most common laboratory abnormalities were mild and reversible increases in aspartate aminotransferase (AST) in five subjects and in ALT in four.
HbF increased in all subjects, with peak increase occurring after a mean of 14 weeks of therapy; the mean (range) increase from baseline was 4.8% (2.3–9.8%) for HbF % (p = 0.0006) and 3.19 g/l (0.5–6.6 g/l) for absolute HbF (p = 0.001). Total haemoglobin increased in 7 subjects, with a mean increase of 4.7 g/l (range 1.0–10.0 g/l). Figure 1 shows the baseline and peak value by subject for HbF and total haemoglobin. Table I presents each subject's thalassaemia mutations and polymorphisms for 3 quantitative trait loci (QTL) that were shown to strongly influence baseline HbF levels (Thein et al, 2009). Seven subjects were homozygous for the IVS I-6 (C-T) β+ thalassemia mutation and only 3 were heterozygous for a favourable genetic modifier.
Figure 1
Baseline and peak values for HbF and total haemoglobin
Table I
Baseline Characteristics
This study demonstrates that HQK-1001 at 20 mg/kg/day for 24 weeks was well tolerated, significantly increased HbF, and modestly increased total haemoglobin. An interim analysis of a recently completed study of HQK-1001 at 20 mg/kg/day for 26 weeks in 10 patients with Hb E-β-thalassaemia showed higher mean increase in HbF of 10% (range 4.3–20.9%), with an increase in total haemoglobin > 5 g/l in 3 subjects (Fuchareon et al, 2012). These patients all had a βO–thalassaemia mutation, and 9 had at least one favorable allele for the Xmn-I QTL, which is linked to the HBB:c.79G>A(βE globin) gene in that population. Three trials have now demonstrated that HQK-1001 increases HbF in β-thalassaemia. It remains to be determined whether the magnitude of increase in HbF is sufficient to reduce long-term complications of chronic haemolysis, ineffective erythropoiesis, anaemia, and transfusion requirements. Further studies of genetically characterized patients for longer periods appear warranted. | v2 |
2018-06-24T16:01:20.710Z | 2014-01-01T00:00:00.000Z | 49384650 | s2ag/train | Development and Evaluation of novel floating-osmotic capsule for zero order delivery of extract of Andrographis paniculata Nees
SUMMARY The present work was aimed at formulating a novel osmotic capsule for Andrographis paniculata (family: Acanthaceae) extract to maintain a constant extract level in the blood, avoid dose dumping and improve the therapeutic efficacy in liver disorders. It also encompasses the concept of floating dosage form to maintain prolonged gastric residence and drug release. INTRODUCTION Andrographis paniculata (AP) is an important medicinal plant found throughout Southeast Asia. It exhibits various pharmacological properties out of which its hepatoprotective activity is scientifically well documented.. Andrographaloids have been proved to be the main chemical molecules responsible for most of the activities of this herb. Pharmacokinetic studies showed that andrographolides are quickly absorbed and extensively metabolized in humans. Floating osmotic dosage forms are expected to be retained in the stomach which ensures continuous release at the site of absorption thereby improving therapeutic efficacy. Box-Behnken design was applied using Design Expert® 6.0.8 to optimize the process variables. EXPERIMENTAL METHODS Powder (40#) of entire herb of AP was extracted in 50% ethanol by heating in a Soxhlet apparatus. Dry extract was obtained by evaporating the filtered extract in a Rota evaporator at 60C under reduced pressure. Cross linking of capsules (size 000) was carried out for 24 hours in a desiccator saturated with formaldehyde vapor. Later they were air dried for 24 h at room temperature. Sample size for each batch was 20 capsules. Solubility of the capsules was checked in 0.1 N HCl for 24 h for their structural integrity. Table 1: Box-Behnken Design Batches Cetostearyl alcohol (CA) was selected as floating agent as it has low density. With the help of a syringe 150 mg melted CA was filled in each of the capsule bodies and cooled properly for rigidization. Osmogen (mixture of NaCl and Lactose) and 200 mg drug were precisely weighed as per the formula (Table 1), passed through sieve 40, mixed well and filled in the capsule body. Orifice was prepared with the help of standard needle gauge of appropriate size [22’, 24’ or 26’] in the cap. Body part was locked with cap and sealed with 10% gelatin solution. The capsules were evaluated for floating time (in B at ch es Real values (%w/w) Responses Pore size X1 Amt of osmogen X2 NaCl: Lactose Ratio X3 Q0.5 Q7 n of Korse meyer F1 22 250 75:25 4.78 81.16 1.057 F2 24 250 50:50 2.75 73.99 1.234 F3 26 250 75:25 0.8 64.23 1.486 F4 22 200 50:50 5.52 76.96 1.047 F5 24 200 25:75 3.63 64.54 1.113 F6 26 300 50:50 4.33 74.65 1.090 F7 24 250 50:50 2.51 75.03 1.244 F8 24 300 75:25 3.46 74.11 1.114 F9 24 300 25:75 4.57 68.12 1.060 F10 22 300 50:50 5.61 86.74 0.966 F11 24 250 50:50 2.62 73.65 1.282 F12 26 250 25:75 1.96 63.81 1.426 F13 24 200 75:25 0.77 58.55 1.710 F14 24 250 50:50 1.49 74.7 1.377 F15 26 200 50:50 0.5 55.13 1.874 F16 24 250 50:50 2.68 75.19 1.271 F17 22 250 25:75 5.28 79.05 0.995 dissolution apparatus-visual method) and the release of the drug was estimated as andrographalides on a HPLC system. RESULTS AND DISCUSSION There was no lag time in all 17 batches and floating time was found to be more than 14 h. Release at 0.5 h (Q 0.5), release at 7 h (Q7) and n value of Korsemeyer and Peppas equation were selected as dependent variables. The prepared formulations controlled the drug release for a period of 12 h. Multiple Regression analysis revealed significant differences among all the batches due to independent variables (p value less than 0.05). Q0.5 = 2.41+1.7X1 +0.944X2 –0.704X3 – 0.935X12 + 0.438X23 +0.165X13+0.84X11+0.74X22-0.0438X33 Q7 = 74.51+8.26X1+6.055X2+0.316X3–2.44X12 + 2.99X23+0.423X13+2.296X113.44X22– 4.744X33 n = 1.2820.227X1-0.189X2+ 0.097X3 + 0.176X12 0.136X23 0.023X11 0.015X22 – 0.018X33 As shown in figure 1 as the levels of X1 and X2 increase, there was increase in the andrographalides release at the initial time period. When the levels of X3 were increased there was slight decrease in the drug release at 30 mins. At Q7 increase in level of X3 resulted in increase in the release of andrographalides. The effect of the ratio of osmogen was found to be insignificant at the last phases of the drug release as depicted by the p value greater than 0.05. This may be because of complete exhaustion of the osmogen to form the solution inside the osmotic capsule. The value of n decreased with increase in the levels of X1 and X2, while it increased with the increase in the level of X3 though this effect is less prominent compared to that with X1 and X2. The selection of the optimized batch (F9) was based on the complete drug release at 12 hours and the zero order drug release as reflected by R value of zero order and n value of the Korsemeyer and Peppas. Figure 1 : Response Surface Plot of % drug released at 7 hrs (n=3) CONCLUSION It can thus be concluded that floating osmotic capsule could be used as a potential tool for delivering zero-order release for herbal extracts like AP. It was found to reduce the dose dumping; as is the case with most sustained release systems and can simultaneously reduce the dose frequency of the drug to twice a day; thus providing a better patient compliance. REFERENCES 1. Panossian, A.; Hovhannisyan, A. Phytomed. 2000, 7, 351-364. 2. Kapil, A.; Koul, I.; Banerjee, S.; Gupta, B. Biochem. Pharmacol. 1993, 46, 182–185. ACKNOWLEDGMENTS The authors are thankful to L J Institute of Pharmacy, Ahmedabad and B K Mody Government Pharmacy College, Rajkot for providing the needed support and lab facilities. The technical support from Dr. Shreeraj Shah, LJIP is gratefully acknowledged. | v2 |
2021-11-25T16:22:20.106Z | 2021-11-05T00:00:00.000Z | 244550800 | s2ag/train | A Prospective Phase I/II Trial to Jointly Optimize the Administration Schedule and Dose of Melphalan for Injection (Evomela) As a Preparative Regimen for Autologous Hematopoietic Stem Cell Transplantation in Newly Diagnosed Multiple Myeloma
Introduction: The most commonly used conditioning regimen for autologous hematopoietic cell transplantation (auto-HCT) in multiple myeloma (MM) is high-dose melphalan. However, conventional melphalan formulations can put patients at risk of potential propylene glycol (PG)-associated toxicities. In addition, the traditional melphalan formulations are unstable at room temperature, which prevents studying longer infusion schedules. The higher stability and potentially lower toxicity of PG-free (PGF) melphalan (Evomela) supports the evaluation of different doses and prolonged infusion schedules, in addition to the traditional 30-60 minute bolus doses.
Here, we report interim results of a trial designed to assess whether the characteristics of PGF melphalan allow for a higher dose or prolongation of infusion time, in order to increase the efficacy of melphalan in myeloma patients undergoing auto-HCT.
Methods: The primary objective of this two-stage phase I-II trial is to evaluate the optimal dose and schedule of PGF melphalan given as a single agent preparative regimen on day -2 before auto-HCT. The study enrolls adults with non-relapsed MM, a Karnofsky performance score ≥70%, who have received ≥2 cycles of initial systemic therapy and were within 2 to 12 months of their first induction. Participants are randomized (1:1) to two different infusion schedules (30-60 minute or 8-9 hour) using Evomela (2mg/ml) at one of two doses (200 or 225 mg/m 2). The first 3 patients in each schedule were treated at the dose of 200 mg/m 2. Since no DLT was observed, the dose was escalated to 225 mg/m 2. All patients will continue to receive 225 mg/m 2 in the absence of DLT. Disease response was assessed according to the International Myeloma Working Group uniform response criteria. Minimal residual disease (MRD) was measured by using multiparametric flow cytometry (10 -5) in the bone marrow at day-90 after transplant.
Secondary outcomes include incidence of treatment related mortality, rate of MRD, complete response at 90 days post auto-HCT, and progression-free and overall survival.
Results: To date (July 20,2021), 24 eligible patients have been randomized. Seventeen patients (47% female, mean age 59) are eligible for assessing response 90 days post-treatment, 11 (64.7%) in schedule 1 (30-60 mins) and 6 (35.3%) in schedule 2 (8-9 hrs). The overall response rate (partial response [PR] or better) is 100%, with 5(29.4%) stringent complete remissions (sCR), 5 (29.4%) complete remissions (CR), 4(23.5%) very good partial responses (VGPR), and 3(17.6%) partial remission (PR). The CR+sCR rate is 58.8%. Of the 15 patients eligible for MRD assessment, 11 (73.3%) in schedule 1 and 4 (26.7%) in schedule 2, 11/15 (73.3%) were MRD-negative and 8/15 (53.3%) were sCR/CR+MRD-negative 90 days post-treatment. The median follow-up is 11 months (95%CI:6.1-15.4) No patient has experienced disease progression or death.
Dose-limiting toxicity (DLT) is defined as grade 4 mucositis, or any grade 4 or 5 non-hematologic or non-infectious toxicity occurring within 30 days from the start of infusion. Twenty-one patients were evaluable for toxicity monitoring and no patient experienced >grade 3 adverse events with either schedule. Notably, no patient experienced ≥grade 3 esophagitis or oral mucositis. Diarrhea was the most frequent adverse event, and the incidence of grade 3 diarrhea was 18% in the short infusion arm and 43% with the longer infusion. No DLTs have been observed.
On pharmacokinetics analysis, the C max was highest in the short infusion arm (p<0.001). The area under the curve (AUC) 0-∞, including the dose-normalized AUC 0-∞ was lower in the short infusion arm; however, the differences were not statistically significant (p=0.815 and p=0.940, respectively).
Conclusions: Preliminary trial results have demonstrated that PGF melphalan, as a high-dose conditioning regimen for auto-HCT in patients with MM, has an acceptable safety profile (no >grade 3 events). The response rates, including the CR+MRD-negative rates are encouraging. The impact of bolus versus longer infusion schedule on outcomes will be assessed after the completion of the trial.
Figure 1 Figure 1.
Mehta: Kadmon: Research Funding; CSLBehring: Research Funding; Syndax: Research Funding; Incyte: Research Funding. Popat: Bayer: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Lee: Genentech: Consultancy; Legend Biotech: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Sanofi: Consultancy; Takeda Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Regeneron: Research Funding; Bristol Myers Squibb: Consultancy; Oncopetides: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy, Research Funding; Celgene: Consultancy. Thomas: Acerta Pharma: Research Funding; Ascentage Pharma: Research Funding; BMS: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; X4 Pharma: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding. Patel: Pfizer: Consultancy; Janssen: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Oncopeptides: Consultancy. Orlowski: Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Genzyme, GSK Biologicals, Janssen Biotech, Karyopharm Therapeutics, Inc., Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda P: Consultancy, Honoraria; CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Other: Clinical research funding; Asylia Therapeutics, Inc., BioTheryX, Inc., and Heidelberg Pharma, AG.: Other: Laboratory research funding; Asylia Therapeutics, Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, Forma Therapeutics, Genzyme, GSK Biologicals, Janssen Biotech, Juno Therapeutics, Karyopharm Therapeutics, Inc., Kite Pharma, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, I: Membership on an entity's Board of Directors or advisory committees. Shpall: Takeda: Patents & Royalties; Affimed: Patents & Royalties; Adaptimmune: Consultancy; Magenta: Consultancy; Novartis: Consultancy; Bayer HealthCare Pharmaceuticals: Honoraria; Axio: Consultancy; Navan: Consultancy; Novartis: Honoraria; Magenta: Honoraria. Qazilbash: Bristol-Myers Squibb: Other: Advisory Board; Amgen: Research Funding; Oncopeptides: Other: Advisory Board; Angiocrine: Research Funding; NexImmune: Research Funding; Janssen: Research Funding; Biolline: Research Funding.
| v2 |
2018-11-15T17:49:43.340Z | 2018-11-08T00:00:00.000Z | 53237220 | s2ag/train | Formyl-methionine as an N-degron of a eukaryotic N-end rule pathway
Another N-end rule to add Proteins that emerge from a ribosome bear the N-terminal methionine (Met) residue. In bacteria, Met is formylated before translation starts, whereas in eukaryotes, most nascent proteins seemed to start with unmodified Met. Working in yeast, Kim et al. found that the N-terminal formylation of eukaryotic proteins is detectable even under normal conditions and is greatly increased upon specific stresses, which cause some Fmt1 formyltransferase to be retained in the cytoplasm. The retention of this normally mitochondrial protein was found to require the Gcn2 kinase. In addition, the Psh1 ubiquitin ligase was shown to target N-terminally formylated eukaryotic proteins for proteasome-dependent degradation by the so-called fMet/N-end rule pathway. Science, this issue p. eaat0174 N-terminal formylation of proteins in yeast cytosol suggests the existence of an fMet/N-end rule pathway in eukaryotes. INTRODUCTION In both bacteria and eukaryotic mitochondria and chloroplasts, the ribosomal synthesis of proteins is initiated with the N-terminal (Nt) formyl-methionine (fMet) residue. Nt-fMet is produced pretranslationally by formyltransferases, which use 10-formyltetrahydrofolate as a cosubstrate. By contrast, proteins synthesized by cytosolic ribosomes of eukaryotes were always presumed to bear unformylated N-terminal Met (Nt-Met). The unformylated Nt-Met residue of eukaryotic proteins is often cotranslationally Nt-acetylated, a modification that creates specific degradation signals, Ac/N-degrons, which are targeted by the Ac/N-end rule pathway. The N-end rule pathways are a set of proteolytic systems whose unifying feature is their ability to recognize proteins containing N-degrons, thereby causing the degradation of these proteins by the proteasome or autophagy in eukaryotes and by the proteasome-like ClpAP protease in bacteria. The main determinant of an N‑degron is a destabilizing Nt-residue of a protein. Studies over the past three decades have shown that all 20 amino acids of the genetic code can act, in cognate sequence contexts, as destabilizing Nt‑residues. The previously known eukaryotic N-end rule pathways are the Arg/N-end rule pathway, the Ac/N-end rule pathway, and the Pro/N-end rule pathway. Regulated degradation of proteins and their natural fragments by the N-end rule pathways has been shown to mediate a broad range of biological processes. RATIONALE The chemical similarity of the formyl and acetyl groups and their identical locations in, respectively, Nt‑formylated and Nt-acetylated proteins led us to suggest, and later to show, that the Nt-fMet residues of nascent bacterial proteins can act as bacterial N-degrons, termed fMet/N-degrons. Here we wished to determine whether Nt-formylated proteins might also form in the cytosol of a eukaryote such as the yeast Saccharomyces cerevisiae and to determine the metabolic fates of Nt-formylated proteins if they could be produced outside mitochondria. Our approaches included molecular genetic techniques, mass spectrometric analyses of proteins’ N termini, and affinity-purified antibodies that selectively recognized Nt-formylated reporter proteins. RESULTS We discovered that the yeast formyltransferase Fmt1, which is imported from the cytosol into the mitochondria inner matrix, can generate Nt-formylated proteins in the cytosol, because the translocation of Fmt1 into mitochondria is not as efficacious, even under unstressful conditions, as had previously been assumed. We also found that Nt‑formylated proteins are greatly up-regulated in stationary phase or upon starvation for specific amino acids. The massive increase of Nt-formylated proteins strictly requires the Gcn2 kinase, which phosphorylates Fmt1 and mediates its retention in the cytosol. Notably, the ability of Gcn2 to retain a large fraction of Fmt1 in the cytosol of nutritionally stressed cells is confined to Fmt1, inasmuch as the Gcn2 kinase does not have such an effect, under the same conditions, on other examined nuclear DNA–encoded mitochondrial matrix proteins. The Gcn2-Fmt1 protein localization circuit is a previously unknown signal transduction pathway. A down-regulation of cytosolic Nt‑formylation was found to increase the sensitivity of cells to undernutrition stresses, to a prolonged cold stress, and to a toxic compound. We also discovered that the Nt-fMet residues of Nt‑formylated cytosolic proteins act as eukaryotic fMet/N-degrons and identified the Psh1 E3 ubiquitin ligase as the recognition component (fMet/N-recognin) of the previously unknown eukaryotic fMet/N-end rule pathway, which destroys Nt‑formylated proteins. CONCLUSION The Nt-formylation of proteins, a long-known pretranslational protein modification, is mediated by formyltransferases. Nt-formylation was thought to be confined to bacteria and bacteria-descended eukaryotic organelles but was found here to also occur at the start of translation by the cytosolic ribosomes of a eukaryote. The levels of Nt‑formylated eukaryotic proteins are greatly increased upon specific stresses, including undernutrition, and appear to be important for adaptation to these stresses. We also discovered that Nt-formylated cytosolic proteins are selectively destroyed by the eukaryotic fMet/N-end rule pathway, mediated by the Psh1 E3 ubiquitin ligase. This previously unknown proteolytic system is likely to be universal among eukaryotes, given strongly conserved mechanisms that mediate Nt‑formylation and degron recognition. The eukaryotic fMet/N-end rule pathway. (Top) Under undernutrition conditions, the Gcn2 kinase augments the cytosolic localization of the Fmt1 formyltransferase, and possibly also its enzymatic activity. Consequently, Fmt1 up-regulates the cytosolic fMet–tRNAi (initiator transfer RNA), and thereby increases the levels of cytosolic Nt-formylated proteins, which are required for the adaptation of cells to specific stressors. (Bottom) The Psh1 E3 ubiquitin ligase targets the N-terminal fMet-residues of eukaryotic cytosolic proteins, such as Cse4, Pgd1, and Rps22a, for the polyubiquitylation-mediated, proteasome-dependent degradation. In bacteria, nascent proteins bear the pretranslationally generated N-terminal (Nt) formyl-methionine (fMet) residue. Nt-fMet of bacterial proteins is a degradation signal, termed fMet/N-degron. By contrast, proteins synthesized by cytosolic ribosomes of eukaryotes were presumed to bear unformylated Nt-Met. Here we found that the yeast formyltransferase Fmt1, although imported into mitochondria, could also produce Nt-formylated proteins in the cytosol. Nt-formylated proteins were strongly up-regulated in stationary phase or upon starvation for specific amino acids. This up-regulation strictly required the Gcn2 kinase, which phosphorylates Fmt1 and mediates its retention in the cytosol. We also found that the Nt-fMet residues of Nt-formylated proteins act as fMet/N-degrons and identified the Psh1 ubiquitin ligase as the recognition component of the eukaryotic fMet/N-end rule pathway, which destroys Nt-formylated proteins. | v2 |
2020-11-05T09:10:17.254Z | 2020-11-05T00:00:00.000Z | 228841080 | s2ag/train | Predictive Biomarkers of Response to Venetoclax in Combination with Cobimetinib in Relapsed/Refractory Multiple Myeloma (RRMM)
Introduction: Both anti-apoptosis and pro-survival mechanisms promote myeloma cell growth and proliferation, and B-cell lymphoma-2 (BCL-2) is over-expressed in a subset of myeloma patients (pts). Venetoclax (V; orally administered BCL-2 inhibitor) monotherapy has demonstrated efficacy in RRMM pts with t(11;14) translocation, who represent 15-20% of the pt population. Given that the MAPK pathway is frequently dysregulated in myeloma, with NRAS/KRAS/BRAF mutations in >50% of RRMM cases (Xu et al. Oncogenesis 2017; Kortum et al. Blood 2016), we postulated that the combination of cobimetinib (C; orally administered MEK inhibitor) and V would not only shift the apoptotic balance towards cell death, thereby maximizing the effectiveness of V, but also boost CD8+ T-cell antigen recognition and immune-mediated tumor cell death when combined with atezolizumab (A; intravenously administered PD-L1 inhibitor), collectively improving responses in RRMM pts. Here, we present biomarker data from a Phase Ib/II study that was designed to assess safety, efficacy, and pharmacokinetics of C alone, C+V, and C+V+A in RRMM pts (NCT03312530).
Objective: Biomarker analyses were performed to identify potential predictors of response to the C+V combination.
Methods: t(11;14) status was determined by fluorescence in situ hybridization (FISH), and NRAS/KRAS/BRAF mutation status was assessed using Ion AmpliSeqTM Cancer Hotspot Panel v2. Immune monitoring was performed in longitudinal peripheral blood samples using multidimensional flow cytometry. RNA sequencing (RNAseq) was performed using CD138+ sorted cells.
Results: A total of 49 pts were enrolled and randomized 1:2:2 to receive either C alone (n=6), C+V (n=22), or C+V+A (n=21). Overall, 0/6 (0%) pts in the C arm, 6/22 (27%) pts in the C+V arm and 6/21 (29%) pts in the C+V+A arm achieved a response (1 complete response, 3 very good partial responses and 8 partial responses). In the C+V+A arm, only 3/17 pts studied showed the pharmacodynamic (PD) effects of A (increase in CD8+HLA-DR+Ki-67+ T cells), who also showed an increase in T cell exhaustion phenotype (CD8+PD1+TIGIT+TIM3+ T cells), in comparison with nearly all pts who showed PD effects when treated with A alone in an earlier Phase Ib study (Cho et al. EHA 2018). On-treatment decreases in T-cell counts in pts treated with C+V and C+V+A versus C alone suggest that the C+V combination could affect T-cell viability. These results could partially explain the limited efficacy of A. Downstream response analyses were performed in 37/43 pts with known t(11;14) and NRAS/KRAS/BRAF mutation status from pts in the C+V and C+V+A arms to identify the pt subsets most likely to respond to the C+V combination (Figure1). In total, 6/8 (77%) t(11;14) pts and 5/29 (15%) non-t(11;14) pts responded to the C+V combination, versus 40% (n=30) and 6% (n=36) of pts, respectively, who responded to V monotherapy (Kumar S et al. Blood 2017). Mutation screening showed that 5/7 (71%) pts with both t(11;14) and NRAS/KRAS/BRAF mutation were responders. To investigate the efficacy observed in non-t(11;14) pts, we studied the BCL2/BCL2L1 (BCL-XL) gene expression ratio. In 27/43 pts with known t(11;14) status, NRAS/KRAS/BRAF mutation status and BCL2/BCL2L1 ratio, we found that 4/14 (29%) non-t(11;14) pts with either NRAS/KRAS/BRAF mutation or high BCL2/BCL2L1 ratio (>2.3) had a response (Figure1 and2), of which 2 responders were mutant and had low BCL2/BCL2L1 ratio, while all pts with wild-type NRAS/KRAS/BRAF genes and low BCL2/BCL2L1 ratio (n=7) were non-responders.
Conclusions: The data presented, albeit from a small Phase Ib/II study with limited biomarker-evaluable pts, suggest that t(11;14) pts with MAPK pathway mutations demonstrated improved response to the C+V combination when compared with wild-type non-t(11;14) pts, suggesting that inhibition of the MAPK pathway could be contributing to the observed efficacy in these pts. In addition, selecting for non-t(11;14) pts with either NRAS/KRAS/BRAF mutation or high BCL2/BCL2L1 ratio, representing >52% of the pt population in this study (Figure3), could enrich for responders to the C+V combination. The inclusion of NRAS/KRAS/BRAF biomarkers may improve the response rate in the non-t(11:14) pt population and also increase the size of the pt population that could benefit from a V-based regimen. Further investigation is needed to understand the contribution of C to the observed clinical benefit.
Raval: F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Hamidi:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; University of Michigan: Ended employment in the past 24 months. Hwang:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Green:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company; Genentech, Inc: Current Employment. Onishi:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Rodriguez-Otero:Janssen, BMS, AbbVie, Sanofi, GSK, Oncopeptides, Kite, Amgen: Consultancy, Honoraria; Celgene-BMS: Consultancy, Honoraria; Mundipharma: Research Funding; Janssen, BMS: Other: Travel, accommodations, expenses; BMS, Janssen, Amgen: Honoraria. San-Miguel:Roche, AbbVie, GlaxoSmithKline, and Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb, Celgene, Novartis, Takeda, Amgen, MSD, Janssen, and Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gallo:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Paiva:Kite: Consultancy; SkylineDx: Consultancy; Takeda: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Adaptive: Honoraria; Amgen: Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding. Schjesvold:Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, Takeda: Consultancy; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, SkyliteDX, Takeda: Honoraria; Celgene, Amgen, Janssen, Oncopeptides: Research Funding.
| v2 |
2021-08-12T06:23:49.130Z | 2021-08-11T00:00:00.000Z | 236978490 | s2ag/train | Interventions for great saphenous vein incompetence.
BACKGROUND
Great saphenous vein (GSV) incompetence, causing varicose veins and venous insufficiency, makes up the majority of lower-limb superficial venous diseases. Treatment options for GSV incompetence include surgery (also known as high ligation and stripping), laser and radiofrequency ablation, and ultrasound-guided foam sclerotherapy. Newer treatments include cyanoacrylate glue, mechanochemical ablation, and endovenous steam ablation. These techniques avoid the need for a general anaesthetic, and may result in fewer complications and improved quality of life (QoL). These treatments should be compared to inform decisions on treatment for varicosities in the GSV. This is an update of a Cochrane Review first published in 2011.
OBJECTIVES
To assess the effects of endovenous laser ablation (EVLA), radiofrequency ablation (RFA), endovenous steam ablation (EVSA), ultrasound-guided foam sclerotherapy (UGFS), cyanoacrylate glue, mechanochemical ablation (MOCA) and high ligation and stripping (HL/S) for the treatment of varicosities of the great saphenous vein (GSV).
SEARCH METHODS
The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, and AMED databases, and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 2 November 2020. We undertook reference checking to identify additional studies.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) treating participants for varicosities of the GSV using EVLA, RFA, EVSA, UGFS, cyanoacrylate glue, MOCA or HL/S. Key outcomes of interest are technical success, recurrence, complications and QoL.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected trials, applied Cochrane's risk of bias tool, and extracted data. We calculated odds ratios (ORs) with 95% confidence intervals (CIs) and assessed the certainty of evidence using GRADE.
MAIN RESULTS
We identified 11 new RCTs for this update. Therefore, we included 24 RCTs with 5135 participants. Duration of follow-up ranged from five weeks to eight years. Five comparisons included single trials. For comparisons with more than one trial, we could only pool data for 'technical success' and 'recurrence' due to heterogeneity in outcome definitions and time points reported. All trials had some risk of bias concerns. Here we report the clinically most relevant comparisons. EVLA versus RFA Technical success was comparable up to five years (OR 0.98, 95% CI 0.41 to 2.38; 5 studies, 780 participants; moderate-certainty evidence); over five years, there was no evidence of a difference (OR 0.85, 95% CI 0.30 to 2.41; 1 study, 291 participants; low-certainty evidence). One study reported recurrence, showing no clear difference at three years (OR 1.53, 95% CI 0.78 to 2.99; 291 participants; low-certainty evidence), but a benefit for RFA may be seen at five years (OR 2.77, 95% CI 1.52 to 5.06; 291 participants; low-certainty evidence). EVLA versus UGFS Technical success may be better in EVLA participants up to five years (OR 6.13, 95% CI 0.98 to 38.27; 3 studies, 588 participants; low-certainty evidence), and over five years (OR 6.47, 95% CI 2.60 to 16.10; 3 studies, 534 participants; low-certainty evidence). There was no clear difference in recurrence up to three years and at five years (OR 0.68, 95% CI 0.20 to 2.36; 2 studies, 443 participants; and OR 1.08, 95% CI 0.40 to 2.87; 2 studies, 418 participants; very low-certainty evidence, respectively). EVLA versus HL/S Technical success may be better in EVLA participants up to five years (OR 2.31, 95% CI 1.27 to 4.23; 6 studies, 1051 participants; low-certainty evidence). No clear difference in technical success was seen at five years and beyond (OR 0.93, 95% CI 0.57 to 1.50; 5 studies, 874 participants; low-certainty evidence). Recurrence was comparable within three years and at 5 years (OR 0.78, 95% CI 0.47 to 1.29; 7 studies, 1459 participants; and OR 1.09, 95% CI 0.68 to 1.76; 7 studies, 1267 participants; moderate-certainty evidence, respectively). RFA versus MOCA There was no clear difference in technical success (OR 1.76, 95% CI 0.06 to 54.15; 3 studies, 435 participants; low-certainty evidence), or recurrence (OR 1.00, 95% CI 0.21 to 4.81; 3 studies, 389 participants; low-certainty evidence). Long-term data are not available. RFA versus HL/S No clear difference in technical success was detected up to five years (OR 5.71, 95% CI 0.64 to 50.81; 2 studies, 318 participants; low-certainty evidence); over five years, there was no evidence of a difference (OR 0.88, 95% CI 0.29 to 2.69; 1 study, 289 participants; low-certainty evidence). No clear difference in recurrence was detected up to three years (OR 0.93, 95% CI 0.58 to 1.51; 4 studies, 546 participants; moderate-certainty evidence); but a possible long-term benefit for RFA was seen (OR 0.41, 95% CI 0.22 to 0.75; 1 study, 289 participants; low-certainty evidence). UGFS versus HL/S Meta-analysis showed a possible benefit for HL/S compared with UGFS in technical success up to five years (OR 0.32, 95% CI 0.11 to 0.94; 4 studies, 954 participants; low-certainty evidence), and over five years (OR 0.09, 95% CI 0.03 to 0.30; 3 studies, 525 participants; moderate-certainty evidence). No clear difference was detected in recurrence up to three years (OR 1.81, 95% CI 0.87 to 3.77; 3 studies, 822 participants; low-certainty evidence), and after five years (OR 1.24, 95% CI 0.57 to 2.71; 3 studies, 639 participants; low-certainty evidence). Complications were generally low for all interventions, but due to different definitions and time points, we were unable to draw conclusions (very-low certainty evidence). Similarly, most studies evaluated QoL but used different questionnaires at variable time points. Rates of QoL improvement were comparable between interventions at follow-up (moderate-certainty evidence).
AUTHORS' CONCLUSIONS
Our conclusions are limited due to the relatively small number of studies for each comparison and differences in outcome definitions and time points reported. Technical success was comparable between most modalities. EVLA may offer improved technical success compared to UGFS or HL/S. HL/S may have improved technical success compared to UGFS. No evidence of a difference was detected in recurrence, except for a possible long-term benefit for RFA compared to EVLA or HL/S. Studies which provide more evidence on the breadth of treatments are needed. Future trials should seek to standardise clinical terminology of outcome measures and the time points at which they are measured. | v2 |
2019-04-19T13:11:46.054Z | 1996-01-18T00:00:00.000Z | 121745330 | s2ag/train | A Second Course in Statistics: Regression Analysis
1. A Review of Basic Concepts (Optional) 1.1 Statistics and Data 1.2 Populations, Samples and Random Sampling 1.3 Describing Qualitative Data 1.4 Describing Quantitative Data Graphically 1.5 Describing Quantitative Data Numerically 1.6 The Normal Probability Distribution 1.7 Sampling Distributions and the Central Limit Theorem 1.8 Estimating a Population Mean 1.9 Testing a Hypothesis about a Population mean 1.10 Inferences about the Difference Between Two Population Means 1.11 Comparing Two Population Variances 2. Introduction to Regression Analysis 2.1 Modeling a Response 2.2 overview of Regression Analysis 2.3 Regression Applications 2.4 Collecting the Data for Regression 3. Simple Linear Regression 3.1 Introduction 3.2 The Straight-Line Probabilistic Model 3.3 Fitting the Model: The Method of Least-Squares 3.4 Model Assumptions 3.5 An Estimator of s2 3.6 Assessing the Utility of the Model: Making Inferences About the Slope A A 1 3.7 The Coefficient of Correlation 3.8 The Coefficient of Determination 3.9 Using the Model for Estimation and Prediction 3.10 A Complete Example 3.11 Regression Through the Origin (Optional) 3.12 A Summary of the Steps to Follow in a Simple Linear Regression Analysis 4. Multiple Regression Models 4.1 General Form of a Multiple Regression Model 4.2 Model Assumptions 4.3 A First-Order Model with Quantitative Predictors 4.4 Fitting the Model: The Method of Least Squares 4.5 Estimation of s2 , the variance of e 4.6 Inferences about the A A parameters 4.7 The Multiple Coefficient of Determination, R2 4.8 Testing the Utility of a Model: The Analysis of Variance F test 4.9 An Interaction Model with Quantitative Predictors 4.10 A Quadratic (Second-Order) Model with a Quantitative Predictor 4.11 Using the model for Estimation and Prediction 4.12 More Complex Multiple Regression Models (Optional) 4.13 A Test for Comparing Nested Models 4.14 A Complete Example 4.15 A Summary of the Steps to Follow in a Multiple Regression Analysis 5. Model Building 5.1 Introduction: Why Model Building is Important 5.2 The Two Types of independent Variables: Quantitative and Qualitative 5.3 Models with a Single Quantitative Independent Variable 5.4 First-Order Models with Two or More Quantitative Independent Variables 5.5. Second-Order Models with Two or More Quantitative Independent Variables 5.6 Coding Quantitative Independent Variables (Optional) 5.7 Models with One Qualitative Independent Variable 5.8 Models with Two Qualitative Independent Variables 5.9 Models with Three or more Qualitative Independent Variables 5.10 Models with Both Quantitative and Qualitative Independent Variables 5.11 External Model Validation (Optional) 5.12 Model Building: An Example 6. Variable Screening Methods 6.1 Introduction: Why Use a Variable Screening Method? 6.2 Stepwise Regression 6.3 All-Posssible-Regressions Selection Procedure 6.4 Caveats 7. Some Regression Pitfalls 7.1 Introduction 7.2 Observational DataVersus Designed Experiments 7.3 Deviating from the Assumptions 7.4 Parameter Estimability and Interpretation 7.5 Multicollinearity 7.6 Extrapolation: Predicting Outside the Experimental Region 7.7 Data Transformations 8. Residual Analysis 8.1 Introduction 8.2 Plotting Residuals and Detecting Lack of Fit 8.3 Detecting Unequal Variances 8.4 Checking the Normality Assumption 8.5 Detecting Outliers and Identifying Influential Observations 8.6 Detecting Residual Correlation: The Durbin-Watson Test 9. Special Topics in Regression (Optional) 9.1 Introduction 9.2 Piecewise Linear Regression 9.3 Inverse Prediction 9.4 Weighted Least Squares 9.5 Modeling Qualitative Dependent Variable 9.6 Logistic Regression 9.7 Ridge Regression 9.8 Robust Regression 9.9 Nonparametric Regression Models 10. Introduction to Time Series Modeling and Forecasting 10.1 What is a Time Series? 10.2 Time Series Components 10.3 Forecasting using Smoothing Techniques (Optional) 10.4 Forecasting: The Regression Approach 10.5 Autocorrelation and Autoregressive Error Models 10.6 Other Models for Autocorrelated Errors (Optional) 10.7 Constructing Time Series Models 10.8 Fitting Time Series Models With Autoregressive Errors 10.9 Forecasting with Time Series Autoregressive Models 10.10 Seasonal Time Series Models: An Example 10.11 Forecasting Using Lagged Values of the Dependent Variable (Optional) 11. Principles of Experimental Design 11.1 Introduction 11.2 Experimental Design Terminology 11.3 Controlling the Information in an Experiment 11.4 Noise-Reducing Designs 11.5 Volume-Increasing Designs 11.6 Selecting the Sample Size 11.7 The Importance of Randomization 12. The Analysis of Variance for Designed Experiments 12.1 Introduction 12.2 The Logic Behind Analysis of Variance 12.3. One-Factor Completely Randomized Designs 12.4 Randomized Block Designs 12.5 Two-Factor Factorial Experiments 12.6 More Complex Factorial Designs (Optional) 12.7 Follow up Analysis: Tukey's Multiple Comparisons of Means 12.8 Other Multiple Comparisons Methods (Optional) 12.9 Checking ANOVA Assumptions 13. CASE STUDY: Modeling the Sale Prices of Residential Properties in Four Neighborhoods 13.1 The Problem 13.2 The Data 13.3 The Theoretical Model 13.4 The Hypothesized Regression Models 13.5 Model Comparisons 13.6 Interpreting the Prediction Equation 13.7 Predicting the Sale Price of a Property 13.8 Conclusions 14. CASE STUDY: An Analysis of Rain Levels in California 14.1 The Problem 14.2 The Data 14.3 A Model for Average Annual Precipitation 14.4 A Residual Analysis of the Model 14.5 Adjustments to the Model 14.6 Conclusions 15. CASE STUDY: Reluctance to Transmit Bad News: the MUM Effect 15.1 The Problem 15.2 The Design 15.3 Analysis of Variance Models and Results 15.4 Follow up Analysis 15.5 Conclusions 16. CASE STUDY: An Investigation of Factors Affecting the Sale Price of Condominium Units Sold at Public Auction 16.1 The Problem 16.2 The Data 16.3 The Models 16.4 The Regression Analyses 16.5 An Analysis of the Residuals form Model 3 16.6 What the Model 3 Regression Analysis Tells Us 16.7 Comparing the Mean Sale Price for Two Types of Units (Optional) 16.8 Conclusions 17. CASE STUDY: Modeling Daily Peak Electricity Demands 17.1 The Problem 17.2 The Data 17.3 The Models 17.4 The Regression and Autoregression Analyses 17.5 Forecasting Daily Peak Electricity Demand 17.6 Conclusions Appendix A: The Mechanics of a Multiple Regression Analysis. Appendix B: A Procedure for Inverting a Matrix. Appendix C: Statistical Tables. Appendix D: SAS for Windows Tutorial. Appendix E: SPSS for Windows Tutorial. Appendix F: MINITAB for Windows Tutorial. Appendix G: Sealed Bid Data for Fixed and Competitive Highway Construction Contracts. Appendix H: Real Estate Appraisals and Sales Data for Six Neighborhoods in Tampa, Florida. Appendix I: Condominium Sales Data. Answers to Odd-Numbered Exercises. Index. | v2 |
2018-04-03T03:45:53.433Z | 2014-09-23T00:00:00.000Z | 205172140 | s2ag/train | Types of indwelling urethral catheters for short-term catheterisation in hospitalised adults.
BACKGROUND
Urinary tract infection (UTI) is the most common hospital-acquired infection. The major associated cause is indwelling urethral catheters. Several measures have been introduced to reduce catheter-associated urinary tract infections (CAUTIs). One of these measures is the introduction of specialised urethral catheters that have been designed to reduce the risk of infection. These include antiseptic-coated and antimicrobial-impregnated catheters.
OBJECTIVES
The primary objective of this review was to compare the effectiveness of different types of indwelling urethral catheters in reducing the risk of UTI and to assess their impact on other outcomes in adults who require short-term urethral catheterisation in hospitals.
SEARCH METHODS
We searched the Cochrane Incontinence Group's Specialised Trials Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE in process, ClinicalTrials.gov, WHO ICTRP and handsearching of journals and conference proceedings (searched 9 September 2014). We also examined the bibliographies of relevant articles and contacted catheter manufacturer representatives for trials.
SELECTION CRITERIA
We included all randomised controlled trials (RCTs) and quasi-RCTs comparing types of indwelling urethral catheters for short-term catheterisation in hospitalised adults. 'Short-term' is defined as a duration of catheterisation which is intended to be less than or equal to 14 days.
DATA COLLECTION AND ANALYSIS
At least two review authors independently screened abstracts, extracted data and assessed risk of bias of the included trials. Any disagreement was resolved by discussion or consultation with a third party. We processed data as described in the Cochrane Handbook for Systematic Reviews of Interventions. We assessed the quality of evidence using the GRADE approach.
MAIN RESULTS
Twenty-six trials met the inclusion criteria involving 12,422 hospitalised adults in 25 parallel group trials, and 27,878 adults in one large cluster-randomised cross-over trial. No trials compared one antiseptic catheter versus another, nor an antimicrobial catheter versus another. Antiseptic-coated indwelling urethral catheters versus standard indwelling urethral cathetersThe primary outcome, symptomatic CAUTI was reported in one large trial with a low risk of bias, comparing silver alloy hydrogel-coated latex catheter (antiseptic-coated) against a standard polytetrafluoroethylene (PTFE)-coated latex catheter (control). The trial used a pragmatic, US Centers for Disease Control and Prevention (CDC)-based definition for symptomatic CAUTI. For the comparison between silver alloy-coated catheter versus standard catheter, there was no significant difference in symptomatic CAUTI incidence (RR 0.99, 95% CI 0.85 to 1.16).For secondary outcomes, the included trials reported on two types of antiseptic catheters (coated with either silver oxide or silver alloy). For the outcome of bacteriuria, silver oxide catheters were not associated with any statistically significant reduction (RR 0.90, 95% CI 0.72 to 1.13). These catheters are no longer manufactured. Silver alloy catheters achieved a slight but statistically significant reduction in bacteriuria (RR 0.82, 95% CI 0.73 to 0.92). However, the one large trial with a low risk of bias did not support this finding (RR 0.99, 95% CI 0.85 to 1.16). The randomised cross-over trial of silver alloy catheters versus standard catheters was excluded from the pooled results because data were not available prior to crossover. The results of this trial showed less bacteriuria in the silver alloy catheter group.For the outcome of discomfort whilst the catheter was in-situ, fewer patients with silver alloy catheters complained of discomfort compared with standard catheters (RR 0.84, 95% CI 0.74 to 0.96). Antimicrobial-impregnated indwelling urethral catheters versus standard indwelling urethral cathetersThe primary outcome measure, symptomatic CAUTI was reported in one large trial with a low risk of bias, comparing nitrofurazone-impregnated silicone catheter (antimicrobial-impregnated) against a standard PTFE-coated latex catheter (control). The nitrofurazone catheter achieved a reduction in symptomatic CAUTI incidence which was of borderline statistical significance (RR 0.84, 95% CI 0.71 to 0.99).For secondary outcomes, the included trials reported on two types of antimicrobial catheters (impregnated with either nitrofurazone or minocycline/rifampicin). Antimicrobial-impregnated catheters, compared with standard catheters, were found to lower the rate of bacteriuria in the antimicrobial group for both minocycline and rifampicin (RR 0.36, 95% CI 0.18 to 0.73), and nitrofurazone (RR 0.73, 95% CI 0.64 to 0.85). The minocycline and rifampicin catheter is no longer manufactured.For the outcome of discomfort whilst the catheter was in-situ, more patients with nitrofurazone catheters complained of pain whilst the catheter was in-situ compared with standard catheters (RR 1.26, 95% CI 1.12 to 1.41). For the period after catheter removal, more patients with nitrofurazone catheters complained of pain than standard catheters (RR 1.43, 95% CI 1.30 to 1.57). Antimicrobial-impregnated indwelling urethral catheters versus antiseptic-coated indwelling urethral cathetersOne large trial compared antimicrobial-impregnated (nitrofurazone) catheters versus silver alloy-coated (antiseptic-coated) catheters. The results showed people were less likely to have a symptomatic CAUTI with nitrofurazone-impregnated catheters (228/2153, 10.6%) compared with silver alloy-coated catheters (263/2097, 12.5%), but this was of borderline statistical significance (RR 0.84, 95% CI 0.71 to 1.00). They did, however, have significantly less bacteriuria (RR 0.78, 95% CI 0.67 to 0.91),While the catheter was in-situ (RR 1.50, 95% CI 1.32 to 1.70), and on removal (RR 1.32, 95% CI 1.20 to 1.45), nitrofurazone catheters were associated with more discomfort compared with silver-coated catheters. One type of standard indwelling urethral catheter versus another type of standard indwelling urethral catheterNone of the trials comparing standard catheters versus other types of standard catheters measured symptomatic CAUTI. In terms of reducing bacteriuria, individual trials were too small to show whether one type of standard catheter was superior to another type. For the outcome of urethral reactions, fully siliconised catheters appeared to be superior to latex-based catheters. However, the trials involved small numbers of participants. There were no statistically significant differences between the different catheters for all other outcomes.
AUTHORS' CONCLUSIONS
Silver alloy-coated catheters were not associated with a statistically significant reduction in symptomatic CAUTI, and are considerably more expensive. Nitrofurazone-impregnated catheters reduced the risk of symptomatic CAUTI and bacteriuria, although the magnitude of reduction was low and hence may not be clinically important. However, they are more expensive than standard catheters. They are also more likely to cause discomfort than standard catheters. | v2 |
2019-10-17T09:05:43.183Z | 2018-11-29T00:00:00.000Z | 239503790 | s2ag/train | Phase II Trial of Combination of Elotuzumab, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma
Background
This study aimed to determine the benefit of early therapeutic intervention with the combination of elotuzumab, Lenalidomide, and Dexamethasone in patients with high-risk smoldering multiple myeloma (SMM). ClinicalTrials.gov Identifier: NCT02279394.
Aims
The overarching objective of this trial is to determine progression free survival to symptomatic multiple myeloma (MM). Furthermore, the study examined whether genomic studies can help in determining patients who would benefit the most from this early therapeutic intervention.
Methods
Patients enrolled in this study met eligibility for high-risk SMM based on the newly defined criteria proposed by Rajkumar et al, Blood 2014. Patients were administered weekly elotuzumab (10 mg/kg) on days 1, 8, 15, and 22 for the first two 28-day cycles while receiving lenalidomide on days 1-21. For cycles 3-8, patients were administered elotuzumab infusions on days 1, 8, and 15. dexamethasone (40mg) was given on days 1, 8 and 15 to 40 of the 50 enrolled patients. After 8 cycles or best response, patients were given the option to mobilize with either cyclophosphamide or plerixafor and collect stem cells for future transplant. Patients were then allowed to continue on maintenance therapy where they were administered elotuzumab (20 mg/kg) on day 1, in combination with lenalidomide days 1-21 of a 28-day cycle. Bone marrow (BM) samples of 32 patients were obtained before starting therapy for baseline assessment and whole exome sequencing (WES) of plasma cells.
Results
In total, 50 patients were enrolled on this study from January 2015 and completed accrual in December 2016, with the participation of eight sites. The median age of enrolled patients was 62 years (range, 29-79) with 18 males (36%) and 32 females (64%). Interphase fluorescence in situ hybridization (iFISH) detected high-risk cytogenetics (defined by the presence of 17p deletion, t(4;14), and 1q gain) in 20 patients. The median time to response was 2.8 months (range, 1.8-4.6). The most common toxicities were fatigue (92%), followed by diarrhea (72%), and hyperglycemia (62%). The most common grade 3 or more adverse events were hypophosphatemia (34%), neutropenia (26%), and lymphocyte count decreased (22%). Three patients (6%) had grade 4 hypophosphatemia during treatment. Additionally, grade 4 cholecystitis, cataract, lymphocyte count increase, hyperglycemia, neutropenia, and thrombocytopenia occurred in one patient (2%). Diabetic Ketoacidosis and sepsis led to death in a patient (2%). Stem cell collection was successful in all mobilized patients to date. As of this abstract date, the overall response rate is 84% (41/49). There were 3 complete responses (6%), 18 very good partial responses (37%), 20 partial responses (41%), 5 minimal responses (10%), 3 stable disease (6%), and 2 unevaluable patients. All the study participants except for three have finished treatment and are currently under follow up. None of the patients showed progression to overt MM to date. We continue to collect data for progression free survival.
WES was performed on 32 samples at the time of initiation of therapy. Recurrent mutations in the MAPK pathway (KRAS, NRAS) and tumor suppressor gene, TP53, were detected in 40% of the cases (16% and 24%, respectively), while mutations in the NF-KB and plasma cell differentiation pathways were present in 13% of patients. Somatic copy number alterations (SCNAs) were called based on WES: 1q duplication, 13q, 17p, and 1p deletions were identified in 25, 31, 12, and 7% of cases, respectively. Interestingly, in 6 patients, high-risk SCNAs (1q gain and 17p deletion) were not reported in iFISH but were detected by WES. The analysis of these 32 samples showed that patients who are harboring mutations in the DNA repair pathway genes, had modest response to treatment. Finally, we are analyzing the transcriptomic profile of CD138 negative cells, which represent the BM microenvironment cells (immune and stromal cells) to characterize the BM microenvironment at baseline and end of treatment, and thus, elucidate the role of these cells in the differential response to therapy.
Conclusion
The combination of elotuzumab, lenalidomide, and dexamethasone is well tolerated and demonstrates a high response rate with no progression to overt MM to date. Correlation with genomic studies can help define patients who benefit the most from this early therapeutic intervention.
Ghobrial: Takeda: Consultancy; Janssen: Consultancy; BMS: Consultancy; Celgene: Consultancy. Bustoros:Dava Oncology: Honoraria. Badros:GSK: Research Funding; Celgene: Consultancy, Research Funding; Karyopharm: Research Funding. Matous:Celgene: Consultancy, Honoraria, Speakers Bureau. Rosenblatt:Merck: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Jakubowiak:Karyopharm: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Usmani:Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding. Zonder:Celgene: Consultancy, Honoraria; Pharmacyclics: Other: DSMC; Janssen: Honoraria; Takeda: Honoraria; Alnylam: Honoraria; Coelum: Honoraria; BMS: Research Funding. Munshi:OncoPep: Other: Board of director. Anderson:Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; C4 Therapeutics: Equity Ownership, Other: Scientific founder; OncoPep: Equity Ownership, Other: Scientific founder; Millennium Takeda: Consultancy; Celgene: Consultancy. Richardson:Amgen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.
| v2 |
2019-08-29T13:02:37.691Z | 1995-01-01T00:00:00.000Z | 201654250 | s2ag/train | Experimentally determined activity-composition relations for Ca-rich scapolite in the system CaAl2Si2O8-NaAlSi3O8-CaCO3 at 7 kbar
Equilibrium compositions of coexisting Ca-rich carbonate scapolite and plagioclase in the presence of calcite have been investigated experimentally at 7.0 kbar in the temperature range 775-850 °C. The CaO-AI203-Si02-C02 univariant reaction is 3CaAl2Si20s + CaC03 = Ca4A16Si6024C~03 (1) anorthite (An) calcite meionite (Me) in plagioclase in scapolite with NaSi(CaAl)_1 substitution in both plagioclase and scapolite in the Na20-CaO-AI203Si02-C02 divariant assemblage. The experiments were carried out in a 3/4in. diameter NaCI pressure cell with a hematite + magnetite buffer and a hydrous oxalic acid flux. Starting materials were a natural Cland S-free mizzonite (Me63), Baker reagent precipitated calcite, and synthetic meionite and plagioclases of composition AnlOOand Ann. Changes of compositions of the reactants were determined by microprobe analysis. The experimental results confirm the inferences based on obsc:~rvations in natural assemblages made by earlier workers that Na substitution greatly stabilizes scapolite relative to plagioclase. The marked stabilization of mizzonite to lower tenlperatures is largely a consequence of the large amounts of atomic mixing possible in the scapolite structure. An activity model for the meionite component in terms of its rnole fraction, XMe, which involves complete disordering of Ca and Na and, independently, Si and AI, has been derived from the experimental brackets. = (1 + XMe)6(3XMe)6(3XMe+ 1)4 [ -13450 v (1 _ v )2 ] aMe 410 exp T ./iMe AMe. This formula may lose validity in a lower temperature range if scapolite develops greater atomic ordering near the mizzonite composition. The disordered scapolite model is used to calculate apparent C02 activities for recrystallization of some Grenville granulites studied by Moecher and Essene (1991). We find close agreement with their predicted C02 activities based on scapolite + garnet + plagioclase + quartz equilibrium at 800 °C and 10 kbar, despite the different scapolite activity models used in the two sets of calculations. The simplest explanation of this coincidence is that their empirical scapolite model and the present experi]mentally based model are both valid, although the latter is restricted to high temperatures (above 750°C). INTRODUCTION somatic settings (e.g., the Idaho Batholith aureole; Hietanen, 1967), whtereas scapolite from high-grade metamorphic calc-silicates and mafic gneisses has a composition close~r to the meionite and sulfate meionite end-members, with many scapolite grains having close to two-thirds of the meionite component. This particular composition range is termed mizzonite (Shaw, 1960; Evans et aI., 1969; Moecher and Essene, 1991). Carbonate scapolite is unique in being a refractory CO2bearing phase that can coexist stably with common siliThe mineral scapolite can be chemically represented as a solid solution of four end-members: a calcium carbonate end-member, meionite, Ca4Al6Si6024C03 (Me); a sodium chloride end-member, marialite, Na4Al3Si9024CI (Ma); a hypothetical end-member Na3CaAl3Si9024C03 (Na-Me); and a calcium sulfate end-member, sulfate meionite, Ca4A16Si6024S04 (S04-Me). Scapolite rich in the marialite component occurs in high-temperature meta0003-004X/9 5/0708-0744$02.00 744 BAKER AND NEWTON: ACTIVITY RELATIONS FOR Ca-RICH SCAPOLITE cate minerals at elevated temperature conditions. Moecher and Essene (1990, 1991) showed that the reaction meionite quartz in scapolite anorthite in plagioclase in fluid grossular in garnet is useful for calculating C02 activities driving recrystallization of high-grade, deep-crustal metamorphic rocks containing the common assemblage scapolite + plagioclase + garnet + quartz, providing a new approach to debate about the role of C02 in the formation of granulite facies terranes (Newton et a!., 1980b; Valley et a!., 1990; Frost and Frost, 1987; Waters, 1988). JHowever, calculations involving carbonate scapolite require a knowledge of the activity-composition relations along the join from meionite to sodium meionite. The stability of the scapolite end-menlber meionite at crustal pressures is limited, at low temperatures, by Reaction 1. Goldsmith and Newton (1977) reported broad reversals of this univariant reaction, and these experiments suggested that meionite is stable relative to anorthite and calcite above 875 °C, almost independently of pressure. Huckenholz and Seiberl (1989) presented a second experimental study of this equilibrium and suggested markedly lower temperature limits for nleionite stability and a steep negative dPldT slope for th~~reaction. More recent experiments (Baker and Newton, 1994) favor the results of Goldsmith and Newton (1977) and require a steep positive dPldT slope for the univariant reaction. The incorporation of Na into meionite through a plagioclase substitution, NaSi(CaAI)_l' expands the range of conditions over which scapolite is stable:. Goldsmith and Newton (1977) found that carbonate scapolite ranging from pure meionite to compositions near Meso (or Eq Anso) were stable at temperatures above 850 °C. Orville (1975) and Ellis (1978) experimentally determined the stability of mizzonite with respect to plagioclase plus calcite, and both authors found that mizzonite is stable to temperatures at least 100 °C lower than pure meionite. Ellis (1978) found a relatively wide range~of solid solution from MeS3 to Me83 at 750 °C and 4 kbar, whereas Orville (1975) found a much narrower range of solid solution at identical conditions. Observations froml natural calcareous assemblages formed at temperatures of 600 °C or below indicate that mizzonite, Me67, cot~xisting with plagioclase of composition An44-48or An94__9s, is the lowesttemperature Na-free scapolite (Oterdoom and Gunter, 1983; Moecher and Essene, 1990). Estimates of mixing properties along the join from meionite to sodium meionite on the basis of paragenetic analysis have been made by Oterdoom and Gunter (1983) and Moecher and Essene (1990). However, no reversed experimental data describing the compositions of coexisting scapolite and plagioclase have been available here745 tofore. The data of Goldsmith and Newton (1977) indicate that the scapolite-plagioclase compositional tie lines are quite temperature dependent, as indicated also by the natural parageneses. They found that the sulfate to carbonate ratio of the synthetic scapolites has a marked effect on the tie lines. However, they were unable to reverse the coexisting compositions in their high-temperature dry experiments. It is the object of the present work to attempt to secure reversals of the temperature dependence of the composition of coexisting carbonate scapolite and plagioclase in the presence of calcite in order to define experimentally the activity-composition relations of calcic carbonate scapolite. EXPERIMENTAL METHODS | v2 |
2019-08-20T06:01:41.190Z | 2012-01-01T00:00:00.000Z | 219541050 | s2ag/train | Southern Abstracts Subject Index
Abdominal abscess, cause of, in child with VP shunt, 35 Academic medical center, modeling the potential impact of Health Care Reform on an, 556 Accessory cardiac bronchus (ACB), hemoptysis, 257 Acetaminophin, anaphylaxsis, 258 Achalasia, Kennedy disease (KD), 457 Acquired cytomegalovirus (CMV) infection, in premature infants less than 30 weeks’ gestational age, 231 Acquired immune deficiency syndrome (AIDS) HIV/AIDS patients, assisting in times of disaster, 185 nausea, vomiting, and diarrhea in a patient with, case report, 464 Acrolein, suppression of EPC levels in humans with CVD risk, 3 ACTH independent macronodular adrenal hyperplasia, Cushing’s syndrome due to bilateral, 139 Actinomycosis, case report on empyema caused by, 12 Acute agitation, abused a new type of intoxicant, 253 Acute bodily injury, presence of hypokalemia, hypomagnesemia and ionized hypocalcemia in patients hospitalized with, 98 Acute calcineurin inhibition, with tacrolimus increases phosphorylation of UT-A1 at serine 486, 271 Acute central nervous system injury, usefulness of serum procalcitonin in the workup of febrile patients, 366 Acute diarrhea, in a prednisone dependent, atopic patient, eosinophilic gastroenteritis, 349 Acute disseminated encephalomyelitis (ADEM), in a patient with acute hepatitis C virus infection, 386 Acute diverticulitis with eosinophilia, Strongyloides stercolaris, case report, 196 Acute exacerbations of COPD (AECOPD), factors predicting length of stay in patients with, 520 Acute HIV, challenge of timely diagnosis, and associated infectiousness due to high viral loads, 365 Acute interstitial nephritis (AIN), associated with the use of an antibiotic-impregated bone cement spacer (ABCS), 281 Acute kidney injury (AKI) acute interstitial nephritis associated with the use of an antibiotic-impregated bone cement spacer (ABCS), 281 after partial nephrectomy, 277 urinary biomarkers in predicting patient outcome and renal recovery, 275 Acute lung injury (ALI), endothelial cell PPAR-gamma knockout exacerbates sepsis, 403 Acute lymphoblastic leukemia L-arginine depletion by PEG-arginase I, 477 Acute myocardial infarction (AMI) before and after the storm, Hurricane Katrina, 330 high risk of, in patients with anterior precordial lead terminal T wave inversion, 117 Acute pontine infarction, case report on eight-and-a-half syndrome caused by, 17 Acute renal failure, diagnosis of LCAT, 129 Acute respiratory failure, chiari malformation type I (CM 1), 255 Acute stressor states, cation dyshomeostasis, prolonged myocardial repolarization with cardiac arrhythmias and necrosis, 333 Acutely ill patient, critical concepts, a unique approach to undergraduate education in the care, 381 Adenocarcinoma, detected by screening colonoscopy, case report, 463 Adenoma, toxic, papillary thyroid carcinoma in, 143 Adjuvant therapy, characteristics of de novo stage IV breast cancer presentation and comparison with stage IV disease relapse, 352 Admissions characteristics of minority applicants, analysis of, 538 Adolescents acceptance and compliance on HPV vaccination in inner-city indigent male and female, 58 case report on unusual presentation of Tinea pedis in, 44 the effect of BMI on endothelial function among, 56 medication adherence among, in pediatric renal clinic, 60 veno-arterial ECMO in, with mediastinal mass, 34 Adult bone marrow cell therapy, on cardiac parameters and outcomes, 334 Aerosols, assessing the safety of a mask designed for efficient delivery, 260 African-Americans body composition, glucoregulation and energy expenditure in healthy, 136 case report on TPP in males, 10 Albuminocytologic dissociation, and autoimmune disorder, pediatric idiopathic intracranial hypertension (IIH), 388 Aldosterone-mediated MAPK ERK1/2 signal pathway, in regulation of NCC protein expression in response to dietary salt change, 268 Aldosterone/salt treatment (ALDOST) in rats induces oxidative stress and impaired pancreatic beta cell function, 449 where cardiac pathology and muscle wasting simulate cachexia and whose origins relate to intracellular Ca overloading and oxidative stress, 295, 307 Aldosteronism and hypocalcemia, idiopathic intracranial hypertension (IIH), 389 in rats induces oxidative stress and impaired pancreatic beta cell function, 449 reverse remodeling and the recovery from cachexia in rats, 295, 307 salvaging myocardium in rats with, nebivolol a beta blocker for, 2 Alexia without agraphia, and the possible extended visual pathway, 385 Allogeneic stem cell infusion, acute hemolytic reaction during, 181 Alopecia, in mice with a novel parathyroid hormone fusion protein, prophylaxis vs. therapy, 443 Alpha-1-agonists, orthostatic hypotension in revascularized patient with CAD, 36 Ambulatory Care Clinic, new tool to evaluate internal medicine residents in the, 539 Ambulatory Care Sensitive Conditions (ACSC), are conditions that could be prevented with adequate access to primary care services, 299 American Academy of Pediatrics (AAP) guidelines, diagnosis and management of attention deficit/hyperactivity disorder (ADHD), 319 Amniotic fluid, prevents indomethacin & hydrocortisone mediated inhibition of intestinal epithelial cells, 397 Anaphylaxsis, acetaminophin, 258 Angioedema with eosinophilia, case report, 170 recurrent diffuse, Gleich’s syndrome in patients with, 71 Angiotensin converting enzyme 2 in blood pressure and oxidative stress, role of, 523 Angiotensin converting enzyme inhibitors (ACEI), case report on use of, as unexpected causes of hyponatremia, 84 Angiotensin II (ANG-II) dependent hypertension, dietary salt restriction on systolic blood pressure (SBP), urinary protein excretion, and urine flow in Cyp1a1-Ren2 rats, 267 dependent malignant hypertension, chronic direct renin, inhibition improves renal hemodynamics in CYP1A1-REN2 transgenic rats, 411 induced hypertension, lack of protein kinase C > leads to impaired urine concentrating ability and decreased aquaporin-2, 416 induced skeletal muscle wasting (cachexia) and blood pressure increase, differential requirement for NADPH oxidase-and mitochondria-derived superoxides, 336 induced transient receptor potential cation channel-6 activity in cultured podocytes, protein kinase g negatively regulates, 529 mediated increase, cyclooxygenase-2, expression in the rat renal inner medulla, activation of the (Pro)renin receptor, 413 neurohormonal mechanisms of, appetite suppression by altering orexigenic neuropeptide expression in mouse hypothalamus, 97 promotes papillogenesis during late metanephric development, 290 reduces satellite cells and suppresses muscle regeneration, 422 role of endothelin I and, in cardiomyopathy of diabetic patients, 81 TNF-> receptor type 2, but not type 1, is involved in the renal tissue injury response, 417 SOUTHERN ABSTRACTS SUBJECT INDEX | v2 |
2019-03-18T14:04:19.957Z | 2018-11-29T00:00:00.000Z | 81873720 | s2ag/train | Interim Analysis Results from an International, Multi-Centre, Non-Interventional Retrospective Study to Describe Treatment Pathways, Outcomes, and Resource Use in Patients with Classical Hodgkin Lymphoma: B-CD30+ Hodgkin Lymphoma International Multi-Centre Retrospective Study of Treatment Practices
Background: The cure rate for advanced classical Hodgkin lymphoma (cHL) is approximately 70%, which is calculated based on data from clinical trials performed in North American and/or European countries (Canellos GP, et al. N Engl J Med. 1992;327:1478-84; Carde P, et al. J Clin Oncol. 2016;34:2028-36; Gordon LI, et al. J Clin Oncol. 2013;31:684-91). However, there are limited outcome data available in other countries, apart from some small hospital-based studies (Ramirez P, et al. Rev Bras Hematol E Hemoter. 2015;37:184-9; Law MF, et al. Arch Med Sci. 2014;10:498-504; Jaime-Pérez JC, et al. Oncologist. 2015;20:386-92; Omer Al-Sayes FM, Sawan A. J Taibah Univ Med Sci. 2006;1:48-56).
The B-HOLISTIC retrospective chart review study seeks to address the paucity of data on cHL treatment patterns, clinical outcomes, and healthcare resource utilization in 13 countries across Latin America, Africa, Middle East, and the Asia-Pacific region.
Methods: The study will collect data from approximately 2,600 patients aged ≥18 years and newly diagnosed with stage IIB-IV cHL or relapsed/refractory cHL (RRHL) between 01 January 2010 and 31 December 2013, and will follow them until death or chart review, whichever occurs first. The primary objective is to describe progression-free survival (PFS) in patients with RRHL. Secondary objectives include describing demographic and clinical characteristics, clinical outcomes (overall survival, best clinical response after completion of treatment, response duration), key adverse events associated with each line of therapy, and cHL-related healthcare resource use.
Results: As of 14 May 2018, a total of 165 patients from 12 sites have been included in the interim analysis, predominantly from Turkey and South Korea. At this time, 150 patients had cHL and 24 patients had RRHL, including 9 patients who were enrolled in the cHL group and had a documented relapse/progression during the study period. Here, we report the results of the newly diagnosed cHL group; data from the RRHL group will be reported in subsequent publications.
At diagnosis, 64.7% of the cHL group were male, with a median age of 36.5 years (range, 18-89 years); 22.7% had stage IV disease, 30% had extranodal disease, 59.3% had 'B' symptoms, and 34.9% had an International Prognostic Score (IPS) of ≥4. Patients were classified as 13.3% in stage I-IIA; 24% in stage IIB; 53.3% in stage IIIA-IVB; and 9.3% as unknown. Patients classified as stage I-IIA are a deviation from the clinical study protocol and will be removed from the final study analysis. The proportion of patients alive was 94%, with the cause of death reported as either HL-related (44.4%), due to an adverse event (11.1%), or other (44.4%).
Positron emission tomography (PET) or PET-computed tomography (CT) imaging was performed in 58.5% of patients at baseline, 48% of patients at interim, and 36.6% at end-of-treatment; CT imaging was performed in 68.7% of patients at baseline, 83.6% of patients at interim, and 59.7% of patients at end-of-treatment.
At frontline treatment, 95.3% of patients received chemotherapy (mostly doxorubicin, bleomycin, vinblastine, dacarbazine [ABVD], 92.3% [median number of cycles, 6; range, 2-8]), 22.7% of patients received radiotherapy, with 22% of patients receiving radiotherapy and chemotherapy (median total dose, 34.5 Gy; range, 24-45 Gy). The majority of patients received involved-field radiotherapy (53.1%), with other modalities including involved-node (21.9%), involved-site (18.8%), whole body (3.1%), or other (3.1%).
The proportion of patients who achieved a complete or partial response to frontline treatment was 52.1% and 21.1%, respectively. The PFS for treatment in frontline cHL in the overall patient population at 48 months was 81% (95% CI, 73.1-86.7; Figure 1), with a median duration of follow-up of 58.9 months (range, 2.6-128.3 months). The PFS for treatment in frontline cHL excluding ineligible patients classified as stage I-IIA (13.3%) at 48 months was 78.9% (95% CI 69.7-85.6).
Due to the retrospective nature of this study, adverse events were under-reported and will be presented once the data are mature.
Conclusion: The B-HOLISTIC study is ongoing, with final patient enrolment anticipated in December 2018. These interim data provide real-world information on the incidence, treatment, and outcomes of cHL in countries where little is known about this patient population.
Ferhanoglu: Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Yeh:GNT Biotech & Medicals Crop.: Research Funding. Brittain:Takeda: Membership on an entity's Board of Directors or advisory committees. Karduss:Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Kwong:Bayer: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Song:Peking University Cancer Hospital (Beijing Cancer Hospital): Employment. Zerga:Bristol Myers Squibb: Other: Conference fees; Roche: Other: Conference fees; Janssen: Other: Conference fees; Takeda: Other: Conference fees. Blair:Takeda Pharmaceuticals International Co.: Employment. Dalal:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA: Employment, Equity Ownership. Wan:Takeda Pharmaceuticals International Co.: Employment. Hertzberg:Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees.
| v2 |
2021-01-10T18:07:12.409Z | 2021-01-01T00:00:00.000Z | 231547260 | s2ag/train | GASTRIC CANCER CELL MICRO ENVIRONMENT MODULATES THE NK CELL EFFICACY IN RAT SPLENOCYTES
44 Figure 1 Cytolytic activity of splenocytes against K562 cells at 24 h with various effect to target (E:T) ratio. (A), untreated splenocytes; (B), splenocytes were treated with 1% (v/v) SNU 484 supernatant for 1 day prior to the experiment, Abstracts A20 LUPUS 2017;4(Suppl 1):A1–A227 on Jauary 0, 2021 by gest. P rocted by coright. httpupus.bm jcom / Lpus S ci M d: frst pulished as 10.1136/l2017-000215.45 on 24 M arch 217. D ow nladed fom analyzed using flow cytometry. The PBMCs were incubated with anti-CD3/CD28 beads, supplemented with transforming growth factor-b and interleukin-2 to induce differentiation of Tregs, with or without tunicamycin for 36 hours. Results The percentage of Tregs in the PBMCs of SLE patients was lower than that in the HCs (1.8 ± 0.9 versus 2.6 ± 0.7%, p=0.02). The induced differentiation of Tregs increased in both groups, and the increased proportion was greater in the SLE group (600 ± 351 versus 252 ± 95%, p=0.01). Incubation with tunicamycin in the Treg differentiation process also increased the proportion of Tregs in both groups (385 ± 259 versus 166 ± 105%, p=0.006), and the increased proportion was higher in the SLE group. Conclusions The baseline percentage of Tregs was lower in SLE patients than in HCs. However, when Treg differentiation was induced, the differentiation of Tregs was more pronounced in the SLE group. This exaggerated differentiation may reflect the paradoxical response to the diminished suppressive capacity of Tregs in SLE patients. 46 CD11C+T-BET+ B CELL IS CRITICAL FOR ANTICHROMATINTIN IGG2A PRODUCTION IN THE DEVELOPMENT OF LUPUS D Dai*, Z Shiyu, S Nan. Renji HospitalSchool of MedicineShanghai Jiaotong University, Department of Rheumatology, Shanghai, China 10.1136/lupus-2017-000215.46 Background and aims A hallmark of systemic lupus erythematosus is high titers of circulating autoantibodies. Recently a novel CD11c+ B cell subset has been identified in aged female mice that is critical for the development of autoimmunity.Transfer of MHC II-mismatched splenocytes from Bm12 mice into B6 mice causes a chronic graft versus host reaction (cGVHD), which is characterised by the production of high titers of autoantibodies and immunopathology that closely resemble SLE. The aim of this study was to figure out the role of CD11c+ B cell in the production of autoantibodies during the development of lupus induced by cGVHD. Methods We developed and validated cGVHD model by splenocytes transfer of Bm12 mice into B6 mice and identified CD11c+ B cell by flow cytometry and examined anti-chromatin antibody by ELISA. We also identified CD11c+T-bet+ B cell of peripheral blood mononuclear cells obtained from SLE patients and healthy controls. Results CD11c+T-bet+ B cell was significantly increased in the development of lupus induced by cGVHD. CD138 +CD11c+ B cell produced large amounts of anti-chromatin IgG2a upon in vitro stimulation. Depletion of CD11c+ B cells significantly ameliorated anti-chromatin IgG2a production in vivo. T-bet deficiency impaired the expression of CD11c in B cells and anti-chromatin autoantibodies production in the process of cGVHD. The accumulation of T-bet+CD11+ B cell was found in lupus patients. Conclusions Our data demonstrated the aberrant activation and differentiation of CD11c+T-bet+ B cell, which produced large amounts of anti-chromatin IgG2a in lupus murine model and patients. 47 THE MEMBRANE-CYTOSKELETON LINKER EZRIN AND SRC FAMILY KINASE LYN COLLABORATE TO MAINTAIN OPTIMAL B CELL ACTIVATION AND PREVENT THE DEVELOPMENT OF AUTOIMMUNITY N Gupta*, D Pore, N Parameswaran, E Huang, D Dejanovic, M Upadhyay, N Desai. Cleveland Clinic Lerner Research Institute, Immunology, Cleveland, USA 10.1136/lupus-2017-000215.47 Background and aims Systemic lupus erythematosus (SLE) is characterised by hyperactive B cell antigen receptor (BCR) signalling, autoantibody production and glomerulonephritis. Human GWAS studies have shown a strong association between alterations in the Src family kinase Lyn and incidence of SLE. Mice with genetic deletion of Lyn lose peripheral B cell tolerance and display all the hallmark symptoms associated with human SLE. Therefore, Lyn mice represent a clinically relevant model to investigate the molecular regulation of B cell autoimmunity in SLE. We have previously reported that the membrane-cytoskeleton linker protein Ezrin regulates various facets of B cell function through its dynamic phosphorylation and dephosphorylation. Interestingly, we observed that Ezrin is hyperphosphorylated in Lyn B cells, leading to the hypothesis that Ezrin facilitates B cell autoimmunity in Lyn mice. Methods To test our hypothesis we generated double knockout mice (DKO) bearing systemic deletion of Lyn and conditional deletion of Ezrin in the B cell lineage. B cell activation, lupusassociated autoantibodies and kidney pathology were investigated. Results Compared to Lyn-deficient mice, the DKO mice displayed reduced germinal centre B cell and plasma cell differentiation, and decrease in autoantibody levels and glomerulonephritis. Further, an increase in BCR repertoire diversity and inhibition of BCR signalling pathways was observed in DKO B cells. Conclusions Investigation of proteins that drive B cell hyperactivation in SLE is important for the development of effective and novel therapies. Our data demonstrate that ezrin is an important regulator of B cell activation in the absence of Lyn, and thus a potential molecular target in SLE. 48 IXAZOMIB, AN ORAL PROTEASOME INHIBITOR, REDUCES ANTIBODY PRODUCTION BY DEPLETING PLASMA CELLS IN A T CELL DEPENDENT ANTIGEN RESPONSE MODEL Y Itomi*, T Tanaka, M Sagara, T Kawamura, T Sato. Takeda Pharmaceutical Company, Immunology Unit, FujisawaKanagawa, Japan; Takeda Pharmaceutical Company, Regenerative Medicine Unit, FujisawaKanagawa, Japan 10.1136/lupus-2017-000215.48 Background and aims Pathogenic auto-antibodies produced by plasma cells are key drivers of many auto-immune diseases such as Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), and Sjogren’s Syndrome (SS). In addition, solid organ transplant rejection is also mediated by antibodies produced against the donor organ. Plasma cells are highly metabolically active antibody factories and thus sensitive to depletion by proteasome inhibitors. Ixazomib, an oral Abstracts LUPUS 2017;4(Suppl 1):A1–A227 A21 on Jauary 0, 2021 by gest. P rocted by coright. httpupus.bm jcom / Lpus S ci M d: frst pulished as 10.1136/l2017-000215.45 on 24 M arch 217. D ow nladed fom | v2 |
2018-04-03T04:59:15.669Z | 2007-08-27T00:00:00.000Z | 41126660 | s2ag/train | Stereoselective synthesis of isoxazolidines through Pd-catalyzed carboetherification of N-butenylhydroxylamines.
Isoxazolidines are frequently used as intermediates in the synthesis of complex molecules,[1] and are found in several interesting biologically active compounds.[2] In addition, the isoxazolidine N-O bond can be easily cleaved under reducing conditions to afford 1,3-amino alcohols, which are also of synthetic utility.[3] The most commonly employed method for the construction of isoxazolidines involves 1,3-dipolar cycloaddition reactions between nitrones and alkenes,[4] which generates the O1-C5 bond and the C3-C4 bond in one step [Eq. (1)]. Although these transformations are very useful, many intermolecular cycloadditions of unactivated alkenes generate mixtures of regioisomers.[4] Moreover, the major stereoisomers typically result from endo-addition on the less hindered face of the alkene, and the selective preparation of stereoisomers resulting from exo-addition and/or addition to the more substituted alkene face cannot be achieved in a straightforward manner.[4]
In this communication, we describe a new approach to the construction of substituted isoxazolidines that involves palladium-catalyzed carboetherification reactions of N-butenyl hydroxylamine derivatives with aryl bromides [Eq. (2)]. This method represents a new strategy for construction of the isoxazolidine ring, in which the O1-C5 bond and a C5′-Ar bond are formed in one step.[5] These transformations also provide access to isoxazolidine stereoisomers that cannot be generated with currently available methods. The reactions appear to proceed via intramolecular alkene insertion into previously unprecedented palladium alkoxyamine intermediates, which may be of utility in other Pd-catalyzed carbon-heteroatom bond-forming processes.
(1)
(2)
In preliminary experiments, we examined Pd-catalyzed reactions of N-butenyl hydroxylamines 1-3 with 4-bromobiphenyl using conditions that were employed in our prior studies on Pd-catalyzed carboetherification reactions of γ-hydroxyalkenes.[6-8] As shown below (Table 1), attempts to cyclize unprotected hydroxylamine substrate 1 or N-boc-protected derivative 2 were unsuccessful.[9] However, we were gratified to find that treatment of N-benzyl-protected substrate 3 with 4-bromobiphenyl and NaOtBu in the presence of catalytic amounts of Pd(OAc)2 and DPE-Phos[10] afforded the desired product 4 in 80% isolated yield.
Table 1
Carboetherification of N-butenyl hydroxylamines[a]
With viable reaction conditions and a suitable nitrogen protecting group identified, we examined Pd-catalyzed carboetherification reactions between several different substituted hydroxylamines and a number of aryl bromides. As shown in Table 2, this method is effective with electron-rich (entry 10), electron-neutral (entries 4, 7, 8, and 12), electron-poor (entries 1, 2, 11, and 13), o-substituted (entry 8), and heterocyclic (entries 3, 5, 6, and 9) aryl bromides. In addition to the N-benzyl protected derivatives described above, hydroxylamine substrates bearing N-methyl or N-tert-butyl groups also undergo cyclization in good yield.
Table 2
Pd-catalyzed synthesis of substituted isoxazolidines[a]
The carboetherification reactions are also effective with substrates bearing substituents along the tether between the hydroxylamine moiety and the alkene. Transformations of these substrates provide access to disubstituted isoxazolidines with moderate to excellent stereocontrol. Importantly, in many cases these cyclizations provide a means to generate isoxazolidines that could not be prepared using 1,3-dipolar cycloaddition methods. For example, Pd-catalyzed reactions of 10 with 4-bromobiphenyl or 3-bromobenzotrifluoride provide 22 and 23 in 78% and 69% isolated yields, with >20:1 diastereoselectivity and regioselectivity (Table 2, entries 12-13). In contrast, a 1,3-dipolar cycloaddition reaction between a nitrone and a 3-arylcyclopentene would be expected to occur on the less hindered face of the alkene to afford a different stereoisomer, and would likely generate mixtures of regioisomers.[4] In addition, reactions of 8 with aryl bromides proceed in 82-85% yield and 10:1 dr to afford the 2R*,3aS*-hexahydropyrrolo[1,2b]isoxazole isomers 18-19 (entries 8-9). However, dipolar cycloadditions between 3,4-dihydropyrrole-1-oxide and allylbenzene derivatives instead generate stereoisomeric 2S*,3aS*-hexahydropyrrolo[1,2b]isoxazoles.[11] The hydroxylamine carboetherifications can also be used to prepare trans-4,5-disubstitued isoxazolidines 12-14 and cis-3,5-disubstituted isoxazolidines 15-17 in good yield with 3-5:1 diastereoselectivity.
A plausible mechanism for the isoxazolidine-forming reactions is shown in Scheme 1. These transformations appear to be mechanistically related to Pd-catalyzed carboetherification reactions of γ-hydroxy alkenes with aryl bromides,[6] and are likely initiated by oxidative addition of the aryl bromide to Pd(0) to afford 24. The LnPd(Ar)(Br) complex can then be transformed to intermediate 25 via reaction with the hydroxylamine substrate and NaOtBu. Intramolecular syn-oxypalladation[6,12] of the tethered alkene moiety of 25 would generate 26, which can undergo C-C bond-forming reductive elimination[13] to afford the observed isoxazolidine products. The conversion of 10 to syn-addition products 22 and 23 is consistent with this hypothesis. Moreover, this model also accounts for the observed stereochemistry of 12-21, as the syn-oxypalladation likely occurs from an organized cyclic transition state in which nonbonding interactions are minimized by pseudoequatorial orientation of the substrate R1 and R2 groups. This transition state arrangement would provide cis-3,5-disubstituted products (R2 = H) and trans-4,5-disubstituted compounds (R1 = H).
Although palladium(aryl)alkoxides have been shown to be important intermediates in a number of catalytic processes,[6,14-15] the analogous complexes derived from hydroxylamines (e.g. 25) are unknown. The reactions described in this paper represent the first examples of catalytic transformations involving Pd(Ar)(ONRR’) species. These previously unknown intermediates will likely find additional applications in other metal-catalyzed carbon-heteroatom bond-forming reactions.[15]
In conclusion, we have developed a new stereoselective method for the construction of substituted isoxazolidines via Pd-catalyzed carboetherification reactions of unsaturated hydroxylamine substrates. In many cases the stereochemical outcome of these transformations is complementary to nitrone cycloadditions, and this method provides a new strategic disconnection that can be used for retrosynthetic analysis of substituted isoxazolidines. | v2 |
2019-11-22T01:12:59.165Z | 2019-11-13T00:00:00.000Z | 209262140 | s2ag/train | Mitochondrial Oxphos As Survival Mechanism of Minimal Residual AML Cells after Induction Chemotherapy : Survival Benefit By Complex I Inhibition with Iacs-010759
Acute myeloid leukemia (AML) is initiated and maintained by a relatively rare leukemia stem cells (LSCs) capable of self-renewal and proliferation. Recent data showed that LSCs (Lagadinou et al. Cell Stem Cell 2013) and residual cytarabine (Ara-C)-resistant AML cells (representing minimal residual disease, MRD) (Farge et al. Cancer Discovery 2017) are highly dependent on mitochondrial function for survival. This unique metabolic biology makes chemoresistant LSCs and AML cells vulnerable to pharmacological blockade of the oxidative phosphorylation (OXPHOS). We have reported that a novel OXPHOS inhibitor IACS-010759 potently inhibits mitochondrial complex I, suppresses OXPHOS and selectively inhibits the growth of AML cells in vitro and in vivo (Molina et al. Nat Med 2018). In this study, we aimed to determine the effects of OXPHOS inhibition with IACS-010759 on residual AML cells surviving standard chemotherapy (Doxorubicin/Ara-C, DA) in cell line and patient-derived xenograft (PDX) AML models.
Consistent with our hypothesis, OCI-AML3 cells treated with DA in vitro induced elevated levels of reactive oxygen species, higher mitochondrial mass and membrane potential (Fig. 1A), indicating reliance on the mitochondrial metabolism. Further, Ara-C treatment resulted in significantly increased basal and maximal oxygen consumption rates (OCR) (36%±8%, p=0.03; 36%±3%, p=0.003, respectively) compared to control. In turn, targeting OXPHOS with IACS-010759 at 30 nM fully inhibited basal and Ara-C-induced OCR. These findings indicate that chemotherapy fosters mitochondrial respiration in AML, which could be abrogated by OXPHOS inhibitor.
To test the efficacy of combining IACS-010759 (5 mg/kg) and standard chemotherapy (Doxorubicin: 1.5 mg/kg; Ara-C: 50 mg/kg) in vivo, we injected NRG mice with genetically engineered OCI-AML3/Luc/GFP cells. Bioluminescent imaging demonstrated significantly reduced leukemia burden in DA/IACS-010759 combination group compared to vehicle on days 15 and 42 (p<0.01) (Fig. 1B). DA/IACS-010759 combination significantly extended survival, compared to the vehicle or single-agent treatment arms (Fig. 1C). Mouse body weight monitoring indicated that therapy was well tolerated
We next examined the efficacy of IACS-010759 on leukemia cells surviving chemotherapy in a chemosensitive PDX AML model of minimal residual disease (Fig. 1D). Treatment of mice inoculated with a human AML PDX harboring FLT3-ITD mutation with DA reduced circulating leukemia burden (0.8 ± 0.6% vs 45.8 ± 8.2% blasts in vehicle-treated mice, p=0.001). The residual AML cells in DA-treated mice expanded and caused rapidly progressive leukemia (78.2 ± 6.2% vs 95.3 ± 1.0% in vehicle-treated mice, p=0.047) on week 6 post DA. Daily oral treatment of mice with IACS-010759 (7.5 mg/kg) as a single agent reduced leukemia burden, and delayed leukemia recurrence when administered post completion of DA (Fig. 1E). A SPADE tree was built based on 13 surface markers and colored by expression intensity of CD34 using CyTOF mass cytometry data (Fig. 1F). The data demonstrated reduced frequency of CD34+CD38lowCD123+ AML LSCs and increase in CD11c+ differentiated cells in both IACS and IACS/DA groups (Fig. 1G&H). In contrast, chemotherapy alone failed to significantly reduce fractions of LSCs or induce differentiation. Proliferation measured by Ki67 was greatly reduced by IACS/DA combination in all populations including LSCs (1.4 ± 0.3% vs 5.5 ± 0.4% in vehicle group, p<0.01). The expression of Hypoxia-Inducible Factor 1α (HIF-1α) was downregulated, consistent with the decreased oxygen consumption induced by IACS-010759 (not shown).
In conclusion, minimal residual AML cells surviving chemotherapy depend on OXPHOS for survival. OXPHOS inhibition with complex I inhibitor IACS-010759 is effective in reducing LSCs and MRD, alone and in combination with chemotherapy in vivo. Our data advocate for combining IACS-010759 with chemotherapy for improved control of MRD upon identification of a recommended Phase II dose in a clinical trial of IACS-010759 in AML (NCT02882321).
Zhang: The University of Texas M.D.Anderson Cancer Center: Employment. Kuruvilla:The University of Texas M.D.Anderson Cancer Center: Employment. Kantarjian:Pfizer: Honoraria, Research Funding; Cyclacel: Research Funding; AbbVie: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Immunogen: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Ariad: Research Funding; Novartis: Research Funding; Agios: Honoraria, Research Funding; BMS: Research Funding; Astex: Research Funding; Amgen: Honoraria, Research Funding; Jazz Pharma: Research Funding. Daver:Jazz: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Agios: Consultancy; Immunogen: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Celgene: Consultancy; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Forty-Seven: Consultancy; Novartis: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Astellas: Consultancy; Servier: Research Funding; NOHLA: Research Funding; Glycomimetics: Research Funding; Otsuka: Consultancy. Andreeff:BiolineRx: Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; NIH/NCI: Research Funding; CPRIT: Research Funding; Breast Cancer Research Foundation: Research Funding; Oncolyze: Equity Ownership; Oncoceutics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eutropics: Equity Ownership; Aptose: Equity Ownership; Reata: Equity Ownership; 6 Dimensions Capital: Consultancy; AstaZeneca: Consultancy; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy; Amgen: Consultancy. Konopleva:Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding.
| v2 |
2021-09-28T15:21:40.722Z | 2021-07-22T00:00:00.000Z | 241488850 | s2ag/train | How reduced can post-impact terrestrial atmospheres be?
<p><strong>Abstract</strong></p><p>Giant impacts have been suggested as promising scenarios under which reduced species important to prebiotic chemistry can form (e.g., CH<sub>4</sub>, NH<sub>3</sub>, HCN, PH<sub>3</sub>). This scenario relies on the ability of the impactor iron core to chemically reduce the planet's H<sub>2</sub>O inventory, producing significant quantities of H<sub>2</sub> gas. Previous studies have focussed solely on the internal atmospheric chemistry of this process [1, 2]. The influence of the impact-generated melt phase on the atmospheric composition has been neglected. Further, the impactor’s iron inventory has been assumed to be fully available to reduce the atmosphere. Here, we examine the effects of these two assumptions, and hence the ability of giant impacts to produce atmospheres suitable for subsequent prebiotic chemistry.</p><p><strong>Method</strong></p><p>We evolve our systems, comprised of a target and impactor, from their pre-impact states to a post-impact state prior to interactions between the melt and atmosphere (Figure 1). Impactors have a mass ratio of iron core to silicate mantle of approximately 30:70. A range of impactor masses are considered, although a typical mass of 2x10<sup>22</sup> kg can be defined based off of Earth’s mantle excesses in highly siderophilic elements [3]. The target has a pre-impact atmosphere of 100 bars CO<sub>2</sub> and 2 bars N<sub>2</sub>, and a surface ocean of 1.85 Earth Oceans, considering estimates for early Earth. The target mantle oxygen fugacity is at the fayalite-magnetite-quartz buffer. As a result of the impact, the target’s initial atmosphere is eroded, its oceans are vaporised, and its surface is partially melted. The iron core of the impactor breaks up [4], and is either accreted by the target or escapes the system. Iron made available to the atmosphere during this accretion acts to reduce the vaporised oceans and form H<sub>2</sub>.</p><p>To calculate the silicate melt mass produced from impact, we use the iSALE shock physics code [5, and references therin]. Impact melt masses are determined and parametrised as a function of specific impact energy (Figure 2). To calculate the distribution of impactor iron, we use the GADGET2 smooth particle hydrodynamics code [6]. The distribution of the impactor iron (between the atmosphere, the mantle, and escaping the system) is determined and parametrised as a function of impactor mass, impact velocity, and impact angle (Figure 3, see also [7]).</p><p>After impact processing, we evolve our system to equilibrium via melt-atmosphere interactions. We define equilibrium as when both the oxygen fugacities of the atmosphere and melt phase, and simultaneously the partial pressure of H<sub>2</sub>O in each phase, are equal. Melt-atmosphere interactions include redox chemistry in an H<sub>2</sub>-H<sub>2</sub>O-Fe<sub>2</sub>O<sub>3</sub>-FeO-Fe system, and water partitioning between the atmosphere and the melt phase.</p><p><strong>Results</strong></p><p>We find that for larger impactor masses, both the inclusion of the impact-generated melt phase and the iron distribution individually act to decrease the abundance of H<sub>2</sub> in the post-impact atmosphere. Together, their effects compound one another to produce a large decrease in H<sub>2</sub> compared to the fiducial case without either effect. This change holds over a range of initial conditions.</p><p>We find that the greatest change is caused by the presence of the melt phase. Interactions between the atmosphere and melt phase alone (i.e., following previous models’ assumptions of all impactor iron being available to reduce the atmosphere [1]) can decrease the atmospheric H<sub>2</sub> abundance by up to an order of magnitude, with greater change at greater impactor masses (Figure 4, left).</p><p>The distribution of the impactor's iron affects results in 2 ways. Firstly, some of the reducing power of the impactor is lost, either through iron being buried in regions of the mantle not able to take part in melt-atmosphere interactions (e.g., solid mantle or rapidly solidifying melt), or through iron escaping the system during breakup of the impactor. Secondly, at large impactor masses, the reduction of the atmosphere by the impactor iron leads to a mass loss from the atmosphere that decreases atmospheric pressure. The decreased system pressure then influences the oxygen fugacity of the melt phase and affects the partitioning of H<sub>2</sub>O, both of which affect the H<sub>2</sub> abundance of the atmosphere at equilibrium. These effects can further decrease the atmospheric H<sub>2</sub> by up to a factor of 3 (Figure 4, right).</p><p><strong>Conclusions</strong></p><p>Including equilibration between the impact-processed atmosphere and the impact-generated melt phase, as well as distribution of the impactor’s iron inventory, can decrease atmospheric H<sub>2</sub> by up to an order of magnitude compared to the fiducial model not considering these effects. Overestimated H<sub>2</sub> abundances can produce atmospheres suitable for subsequent formation of reduced species important for prebiotic chemistry. However, these atmospheres are also problematic for prebiotic chemistry in terms of surface temperatures and the blocking of Solar UV radiation by reduced carbon species in the atmosphere.</p><p>Atmospheres that are in equilibrium with the impact-generated melt phases below them, and that have been formed under distribution of the impactor iron inventory, are more oxidised and less massive than the fiducial case without either effect. These atmospheres are thus less likely to encounter issues surrounding surface temperature and UV blocking. Importantly, despite the decreases in H<sub>2</sub> from the fiducial case, these atmospheres still host H<sub>2</sub> abundances sufficient for subsequent prebiotic chemistry to take place.</p><p><strong>References </strong></p><p>[1] Zahnle K. J., Lupu R., Catling D. C., Wogan N., 2020, The Planetary Science Journal, 1, 11</p><p>[2] Benner S. A., et al., 2019, ChemSystemsChem, 2</p><p>[3] Bottke W. F., Walker R. J., Day J. M., Nesvorny D., Elkins-Tanton L., 2010, Science, 330, 1527</p><p>[4] Genda H., Brasser R. and Mojzsis S. J., 2017, Earth and Planetary Science Letters, 480, p.25-32.</p><p>[5] Wünnemann K., Collins G. S., Melosh H. J., 2006, Icarus, 180, 514</p><p>[6] Springel V., 2005, Monthly Notices of the Royal Astronomical Society, 364, 1105</p><p>[7] Citron R. I., Stewart S.T., 2021, Lunar Planet. Sci., No. 2548, p. 1621</p><p><img src="https://contentmanager.copernicus.org/fileStorageProxy.php?f=gnp.bd2ac4361ea064861202261/sdaolpUECMynit/1202CSPE&app=m&a=0&c=3d02d6f68a99358155f23f366f19488a&ct=x&pn=gnp.elif&d=1" alt=""></p><p><img src="https://contentmanager.copernicus.org/fileStorageProxy.php?f=gnp.488d7a361ea060961202261/sdaolpUECMynit/1202CSPE&app=m&a=0&c=fbae221ba88b7e1f2c2b1c4c67c79781&ct=x&pn=gnp.elif&d=1" alt=""></p><p><img src="https://contentmanager.copernicus.org/fileStorageProxy.php?f=gnp.ef8b70461ea066961202261/sdaolpUECMynit/1202CSPE&app=m&a=0&c=7130958eec1e8a96960e6b7c70c1eef3&ct=x&pn=gnp.elif&d=1" alt=""></p><p><img src="https://contentmanager.copernicus.org/fileStorageProxy.php?f=gnp.327fb7461ea063071202261/sdaolpUECMynit/1202CSPE&app=m&a=0&c=bfab9e1f9f80ce196664aaf25e65649b&ct=x&pn=gnp.elif&d=1" alt=""></p> | v2 |
2019-03-17T13:08:49.148Z | 2017-11-21T00:00:00.000Z | 212667010 | s2ag/train | Alcoholics Anonymous and other 12-step programs for alcohol use disorder.
BACKGROUND
Alcohol use disorder (AUD) confers a prodigious burden of disease, disability, premature mortality, and high economic costs from lost productivity, accidents, violence, incarceration, and increased healthcare utilization. For over 80 years, Alcoholics Anonymous (AA) has been a widespread AUD recovery organization, with millions of members and treatment free at the point of access, but it is only recently that rigorous research on its effectiveness has been conducted.
OBJECTIVES
To evaluate whether peer-led AA and professionally-delivered treatments that facilitate AA involvement (Twelve-Step Facilitation (TSF) interventions) achieve important outcomes, specifically: abstinence, reduced drinking intensity, reduced alcohol-related consequences, alcohol addiction severity, and healthcare cost offsets.
SEARCH METHODS
We searched the Cochrane Drugs and Alcohol Group Specialized Register, Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, CINAHL and PsycINFO from inception to 2 August 2019. We searched for ongoing and unpublished studies via ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) on 15 November 2018. All searches included non-English language literature. We handsearched references of topic-related systematic reviews and bibliographies of included studies.
SELECTION CRITERIA
We included randomized controlled trials (RCTs), quasi-RCTs and non-randomized studies that compared AA or TSF (AA/TSF) with other interventions, such as motivational enhancement therapy (MET) or cognitive behavioral therapy (CBT), TSF treatment variants, or no treatment. We also included healthcare cost offset studies. Participants were non-coerced adults with AUD.
DATA COLLECTION AND ANALYSIS
We categorized studies by: study design (RCT/quasi-RCT; non-randomized; economic); degree of standardized manualization (all interventions manualized versus some/none); and comparison intervention type (i.e. whether AA/TSF was compared to an intervention with a different theoretical orientation or an AA/TSF intervention that varied in style or intensity). For analyses, we followed Cochrane methodology calculating the standard mean difference (SMD) for continuous variables (e.g. percent days abstinent (PDA)) or the relative risk (risk ratios (RRs)) for dichotomous variables. We conducted random-effects meta-analyses to pool effects wherever possible.
MAIN RESULTS
We included 27 studies containing 10,565 participants (21 RCTs/quasi-RCTs, 5 non-randomized, and 1 purely economic study). The average age of participants within studies ranged from 34.2 to 51.0 years. AA/TSF was compared with psychological clinical interventions, such as MET and CBT, and other 12-step program variants. We rated selection bias as being at high risk in 11 of the 27 included studies, unclear in three, and as low risk in 13. We rated risk of attrition bias as high risk in nine studies, unclear in 14, and low in four, due to moderate (> 20%) attrition rates in the study overall (8 studies), or in study treatment group (1 study). Risk of bias due to inadequate researcher blinding was high in one study, unclear in 22, and low in four. Risks of bias arising from the remaining domains were predominantly low or unclear. AA/TSF (manualized) compared to treatments with a different theoretical orientation (e.g. CBT) (randomized/quasi-randomized evidence) RCTs comparing manualized AA/TSF to other clinical interventions (e.g. CBT), showed AA/TSF improves rates of continuous abstinence at 12 months (risk ratio (RR) 1.21, 95% confidence interval (CI) 1.03 to 1.42; 2 studies, 1936 participants; high-certainty evidence). This effect remained consistent at both 24 and 36 months. For percentage days abstinent (PDA), AA/TSF appears to perform as well as other clinical interventions at 12 months (mean difference (MD) 3.03, 95% CI -4.36 to 10.43; 4 studies, 1999 participants; very low-certainty evidence), and better at 24 months (MD 12.91, 95% CI 7.55 to 18.29; 2 studies, 302 participants; low-certainty evidence) and 36 months (MD 6.64, 95% CI 1.54 to 11.75; 1 study, 806 participants; low-certainty evidence). For longest period of abstinence (LPA), AA/TSF may perform as well as comparison interventions at six months (MD 0.60, 95% CI -0.30 to 1.50; 2 studies, 136 participants; low-certainty evidence). For drinking intensity, AA/TSF may perform as well as other clinical interventions at 12 months, as measured by drinks per drinking day (DDD) (MD -0.17, 95% CI -1.11 to 0.77; 1 study, 1516 participants; moderate-certainty evidence) and percentage days heavy drinking (PDHD) (MD -5.51, 95% CI -14.15 to 3.13; 1 study, 91 participants; low-certainty evidence). For alcohol-related consequences, AA/TSF probably performs as well as other clinical interventions at 12 months (MD -2.88, 95% CI -6.81 to 1.04; 3 studies, 1762 participants; moderate-certainty evidence). For alcohol addiction severity, one study found evidence of a difference in favor of AA/TSF at 12 months (P < 0.05; low-certainty evidence). AA/TSF (non-manualized) compared to treatments with a different theoretical orientation (e.g. CBT) (randomized/quasi-randomized evidence) For the proportion of participants completely abstinent, non-manualized AA/TSF may perform as well as other clinical interventions at three to nine months follow-up (RR 1.71, 95% CI 0.70 to 4.18; 1 study, 93 participants; low-certainty evidence). Non-manualized AA/TSF may also perform slightly better than other clinical interventions for PDA (MD 3.00, 95% CI 0.31 to 5.69; 1 study, 93 participants; low-certainty evidence). For drinking intensity, AA/TSF may perform as well as other clinical interventions at nine months, as measured by DDD (MD -1.76, 95% CI -2.23 to -1.29; 1 study, 93 participants; very low-certainty evidence) and PDHD (MD 2.09, 95% CI -1.24 to 5.42; 1 study, 286 participants; low-certainty evidence). None of the RCTs comparing non-manualized AA/TSF to other clinical interventions assessed LPA, alcohol-related consequences, or alcohol addiction severity. Cost-effectiveness studies In three studies, AA/TSF had higher healthcare cost savings than outpatient treatment, CBT, and no AA/TSF treatment. The fourth study found that total medical care costs decreased for participants attending CBT, MET, and AA/TSF treatment, but that among participants with worse prognostic characteristics AA/TSF had higher potential cost savings than MET (moderate-certainty evidence).
AUTHORS' CONCLUSIONS
There is high quality evidence that manualized AA/TSF interventions are more effective than other established treatments, such as CBT, for increasing abstinence. Non-manualized AA/TSF may perform as well as these other established treatments. AA/TSF interventions, both manualized and non-manualized, may be at least as effective as other treatments for other alcohol-related outcomes. AA/TSF probably produces substantial healthcare cost savings among people with alcohol use disorder. | v2 |
2022-08-07T18:45:19.344Z | 2021-01-01T00:00:00.000Z | 251395870 | s2ag/train | Zn 2+ Intoxication of Mycobacterium marinum during Dictyostelium discoideum Infection Is Counteracted by Induction of the Pathogen Zn 2+ Exporter CtpC
: Macrophages use diverse strategies to restrict intracellular pathogens, including either depriving the bacteria of (micro)nutrients such as transition metals or intoxicating them via metal accumulation. Little is known about the chemical warfare between Mycobacterium marinum, a close relative of Mycobacterium tuberculosis (Mtb), and its hosts. We use the professional phagocyte Dictyostelium discoideum to investigate the role of Zn2+ during M. marinum infection. We show that M. marinum senses toxic levels of Zn2+ and responds by upregulating one of its isoforms of the Zn2+ efflux transporter CtpC. Deletion of ctpC (MMAR 1 271) leadstogrowthinhibitioninbrothsupplementedwithZn 2 + aswellasreducedintracellulargrowth.BothphenotypeswerefullyrescuedbyconstitutiveectopicexpressionoftheMtbCtpCoreffluxtransporterinM.marinumInfectionleadstotheaccumulationofZn 2+ insidetheMycobacterium − containingvacuole ( MCV ) , achievedbytheinductionandrecruitmentoftheD.discoideumZn 2+ effluxpumpsZntAandZntB intotheMCV, carriedoutbyZntB, themainZn 2+ transporterinendosomesandphagosomes.Counterintuitively, bacterialg thaninwild − typecells, suggestingrestrictionbyotherZn 2+ − mediatedmechanisms.AbsenceofCtpCfurtherepistaticallyattenuatestheintr IMPORTANCEMicroelementsareessentialforthefunctionoftheinnateimmunesystem.Adeficiencyinzincorcopperresulservesasanimportantcatalyticandstructuralcofactorforavarietyofenzymesincludingtranscriptionfactorsandenzymesinvistoxicathighconcentrationsandrepresentsacell − autonomousimmunitystrategythatensureskillingofintracellularbacter concentrationsresultfromthebalanceofimportintothecytosolviaZIPinfluxtransportersandeffluxviaZnTtransporters.HpoisoningisinvolvedinrestrictingMycobacteriummarinuminfections.OurstudyextendsobservationsduringMycobacterhomeostasis.Keywords ABSTRACT Macrophages use diverse strategies to restrict intracellular pathogens, including either depriving the bacteria of (micro)nutrients such as transition metals or intoxicating them via metal accumulation. Little is known about the chemical warfare between Mycobacterium marinum , a close relative of Mycobacterium tuberculosis (Mtb), and its hosts. We use the professional phagocyte Dictyostelium discoideum to investigate the role of Zn 2 1 during M. marinum infection. We show that M. marinum senses toxic levels of Zn 2 1 and responds by upregulating one of its isoforms of the Zn 2 1 ef fl ux transporter CtpC. Deletion of ctpC (MMAR_1271) leads to growth inhibition in broth supplemented with Zn 2 1 as well as reduced intracellular growth. Both phenotypes were fully rescued by constitutive ectopic expression of the Mtb CtpC orthologue demonstrating that MMAR_1271 is the functional CtpC Zn 2 1 ef fl ux transporter in M. marinum . Infection leads to the accumulation of Zn 2 1 inside the Mycobacterium -containing vacuole (MCV), achieved by the induction and recruitment of the D. discoideum Zn 2 1 ef fl ux pumps ZntA and ZntB. In cells lacking ZntA, there is further attenuation of M. marinum growth, presumably due to a compensatory ef fl ux of Zn 2 1 into the MCV, carried out by ZntB, the main Zn 2 1 transporter in endosomes and phagosomes. Counterintuitively, bacterial growth is also impaired in zntB KO cells, in which MCVs appear to accumulate less Zn 2 1 than in wild-type cells, suggesting restriction by other Zn 2 1 -mediated mechanisms. Absence of CtpC further epistatically attenuates the intracellular proliferation of M. marinum in zntA and zntB KO cells, con fi rming that mycobacteria face noxious levels of Zn 2 1 . IMPORTANCE Microelements are essential for the function of the innate immune system. A de fi ciency in zinc or copper results in an increased susceptibility to bacterial infections. Zn 2 1 serves as an important catalytic and structural cofactor for a variety of enzymes including transcription factors and enzymes involved in cell signaling. But Zn 2 1 is toxic at high concentrations and represents a cell-autonomous immunity strategy that ensures killing of intracellular bacteria in a process called zinc poisoning. The cytosolic and lumenal Zn 2 1 concentrations result from the balance of import into the cytosol via ZIP in fl ux transporters and ef fl ux via ZnT transporters. Here, we show that Zn 2 1 poisoning is involved in restricting Mycobacterium marinum infections. Our study extends observations during Mycobacterium tuberculosis infection and explores for the fi rst time how the interplay of ZnT transporters affects mycobacterial infection by impacting Zn 2 1 homeostasis. MicroWell plates (Nunc) or black 96-well plates (Perkin Elmer) covered with a gas-permeable mois- ture barrier seal (BioConcept). The course of infection was monitored by measuring either luminescence or fl uorescence (at 509 and 646nm) as a proxy of bacterial growth using a Synergy Mx microplate reader (BioTek) at a constant temperature of 25°C for around 70 h with 1-h intervals. The growth of the D ctpC (GFP) and D ctpC :: ctpC (E2-Crimson) strains was normalized to M. marinum wt strains expressing GFP and E2-Crimson, respectively. Phagocytic plaque assay. Phagocytic plaque assays in the presence of nonpathogenic bacteria as food source were performed as described previously (43). Brie fl y, 50 m l of an overnight culture of various nonpathogenic bacteria was added to the wells of a 24-well plate containing 2ml SM-agar. Then, 10, 100, 1,000, or 10,000 D. discoideum cells were added to the bacterial lawn and plates were incubated at 22°C for 4 to 7days until plaques were visible. Quanti fi cation was performed by scoring the appearance of plaques in at least three independent experiments. The logarithmic plaquing score was de fi ned as fol-lows: plaque formation in wells with 10 amoebae yielded a score of 1,000; in the cases where cells did not grow at lower dilutions, they obtained the corresponding lower scores of 100, 10, and 1. The ability of D. discoideum Ax2(Ka), zntA KO, Ax4, and zntB KO to form plaques on M. marinum wt and D ctpC was assessed as described previously (43, 65). Brie fl y, 5 (cid:1) 10 8 mycobacteria were harvested and resuspended in 1.2ml of 7H9-OADC-glycerol-Tween containing a 1:10 5 dilution of an overnight culture of Klebsiella pneumoniae . Fifty microliters of the suspension was added to the wells of a 24-well plate containing 2ml of 7H11-OADC-glycerol-Tween. | v2 |
2019-12-12T08:03:34.785Z | 2019-11-13T00:00:00.000Z | 209275670 | s2ag/train | Weekly Carfilzomib, Lenalidomide, Dexamethasone and Daratumumab (wKRd-D) Combination Therapy Provides Unprecedented MRD Negativity Rates in Newly Diagnosed Multiple Myeloma: A Clinical and Correlative Phase 2 Study
INTRODUCTION. Bortezomib, lenalidomide and dexamethasone (VRd) is considered a standard of care combination therapy for newly diagnosed multiple myeloma patients. Prior studies show that ~25% of patients treated with 8 cycles of VRd achieve minimal residual disease (MRD) negativity. Recently, 42% stringent complete response (sCR) rates were reported with the use of VRd combined with the CD38-targeted monoclonal antibody daratumumab (VRd-D). Prior studies using 8 cycles of bi-weekly carfilzomib 36 mg/m2 with lenalidomide and dexamethasone (bKRd) combination therapy in newly diagnosed multiple myeloma show ~40% MRD negativity rates. We were motivated to develop a phase 2 study (total N=82) using weekly dosing of carfilzomib 56 mg/m2 with lenalidomide and dexamethasone (wKRd) in combination with daratumumab (wKRd-D). Our study also included a parallel cohort of bi-weekly dosing of carfilzomib 36 mg/m2 with lenalidomide and dexamethasone (bKRd) in combination with daratumumab (bKRd-D). Primary end-point of our study was to rule out 60% and to target up to 80% MRD negativity rate.
METHODS. This is a two-arm, Phase II clinical trial based on Simon's optimal two-stage design. The once-a-week carfilzomib (wKRd) (N=41) has the following treatment schedule: 8 cycles of treatment; 28-day cycles with carfilzomib 20/56 mg/m2 days 1, 8, and 15; lenalidomide 25 mg days 1-21; dexamethasone 40 mg weekly cycles 1-4, 20 mg after cycle 4; and daratumumab 16 mg/kg days 1, 8, 15, and 22 cycles 1-2, days 1 and 15 cycles 3-6, and day 1 cycles 7-8. The bi-weekly carfilzomib (bKRd) (N=41): 8 cycles of treatment; 28-day cycles with carfilzomib 20/36 mg/m2 days 1, 2, 8, 9, 15 and 16; lenalidomide, dexamethasone, and daratumumab are given at the same doses/schedules as the weekly cohort. For fit patients, stem cell collection is recommended after 4 to 6 cycles of therapy; DKRd therapy is resumed after collection to a total of 8 cycles DKRd. Treatment response is being assessed with parallel bone marrow-based MRD assays (10-color single tube flowcytometry and invivoscribe IGHV sequencing); per IMWG guidelines both MRD assays allow detection of 1 myeloma cell in 100,000 bone marrow cells (10^-5). Baseline bone marrow samples are evaluated with targeted DNA sequencing for FISH-Seq and somatic mutational characteristics (myTYPE).
RESULTS. The first stage of the weekly cohort (wKRd-D) is fully enrolled (N=28) and the second stage of the cohort (N=13) is anticipated to complete enrollment shortly (total N=41). Currently, 29 patients meeting eligibility criteria were enrolled (14 males, 15 females) between October 2018 and August 2019. Baseline characteristics include; median age 59 years (range 36-70 years); 12 (41%) patients had high-risk FISH/SNP signature defined as one or more of the following: 1q+, t(4;14), t(14;16), t(14;20), and 17p-. At the submission of this abstract, 28 patients have completed one or more cycles wKRd-D; among these, 10 patients have completed therapy. The median number of cycles delivered is currently 6 (range 1-8). Seven of the 10 patients who have completed study treatment are MRD negative. So far, additional 8 patients have become MRD negative while on therapy. Thus, among patients treated on the weekly cohort (wKRd-D) and who were evaluable for the MRD primary end-point at this analysis, we found 15/18 (83%) to be MRD negative. We further show no added major clinical toxicities with wKRd-D compared to our institution standard of care bKRd. The bi-weekly carfilzomib cohort (bKRd-D) shows similar results to the weekly cohort (wKRd-D). With a comparable efficacy and safety profile coupled with a substantial reduction of the number of infusions (total of 51 vs 27 infusions with bKRd-D vs wKRd-D, respectively), we conclude that the weekly dosing (wKRd-D) may offer an attractive treatment modality for newly diagnosed multiple myeloma patients.
CONCLUSIONS. Among patients evaluable for the MRD primary end-point, in the absence of an autologous bone marrow transplant, we show an unprecedented 15/18 (83%) MRD negativity rate among newly diagnosed multiple myeloma patients treated on the weekly cohort (wKRd-D) using carfilzomib 56 mg/m2 dosing. Our promising results have prompted the development of a large randomized multi-center study ("ADVANCE") evaluating wKRd-D in relation to established standard of care, which is anticipated to start enrollment in Q3/Q4 of 2019.
Landgren: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Theradex: Other: IDMC; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Lesokhin:GenMab: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Janssen: Research Funding; Genentech: Research Funding; Takeda: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Hassoun:Novartis: Consultancy; Celgene: Research Funding; Janssen: Research Funding. Smith:Fate Therapeutics and Precision Biosciences: Consultancy; Celgene: Consultancy, Patents & Royalties, Research Funding. Shah:Physicians' Education Resource: Honoraria. Landau:Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Karyopharm: Consultancy, Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Arcila:Invivoscribe, Inc.: Consultancy, Honoraria. Ho:Invivoscribe, Inc.: Honoraria. Roshal:Auron Therapeutics: Equity Ownership, Other: Provision of services; Physicians' Education Resource: Other: Provision of services; Celgene: Other: Provision of Services. Dogan:Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Roche: Consultancy, Research Funding.
Dara-KRd is not an FDA approved combination therapy for newly diagnosed multiple myeloma.
| v2 |
2021-11-26T16:14:53.524Z | 2021-11-05T00:00:00.000Z | 244648000 | s2ag/train | Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone (Dara-KRd), Autologous Transplantation and MRD Response-Adapted Consolidation and Treatment Cessation. Final Primary Endpoint Analysis of the Master Trial
Background: Minimal/measurable residual disease (MRD) post initial therapy is prognostic of long term outcomes in patients (pts) with newly diagnosed MM (NDMM), but has not been used to modify therapy. We hypothesized that the combination of daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd) would be safe and highly active in pts with NDMM. In addition, we employed MRD by next generation sequencing (NGS) to inform the use and duration of Dara-KRd post-autologous transplant (AHCT) and treatment cessation in pts with confirmed MRD negativity.
Methods: Eligible pts had NDMM requiring treatment, CrCl ≥40 ml/min, adequate liver and heart function, ECOG performance status 0-2 with no age limit. There was a planned enrichment for pts with high-risk cytogenetic abnormalities (HRCA). Treatment cycles consisted of daratumumab 16 mg/kg IV days 1,8,15,22 (with typical reduction in frequency with subsequent cycles), carfilzomib 56 mg/m 2 IV days 1,8,15, lenalidomide 25 mg PO days 1-21 and dexamethasone 40 mg PO/IV days 1,8,15,22 repeated every 28 days. Pts received 4 cycles of Dara-KRd as induction, AHCT, and received 0, 4 or 8 cycles of Dara-KRd consolidation, according to MRD status. MRD was evaluated by NGS (ClonoSEQ®) in all pts at end of induction, post-AHCT, and during each 4-cycle block of Dara-KRd consolidation. Primary endpoint was achievement of MRD negativity (<10 -5 as defined by IMWG) in the intent-to-treat population. Other endpoints included MRD <10 -6 and complete response (CR) by IMWG criteria. Pts received therapy until achievement of two consecutive MRD <10 -5 (confirmed MRD-negativity, i.e., post-induction and post-AHCT or post-AHCT and during consolidation). Confirmed MRD-negative pts entered treatment-free observation and MRD surveillance ("MRD-SURE" phase) with surveillance for MRD resurgence 6 months after treatment cessation and yearly thereafter. Pts completing consolidation without confirmed MRD-negativity received lenalidomide maintenance.
Results: The study accrued 123 participants between 03/2018 and 09/2020. Fifty-three patients (43%) had no HRCA, 46 (37%) had 1 and 24 (20%) had 2+ HRCA [gain 1q, t(4;14), t(14;16), t(14;20) or del(17p)]. Median age was 60 y (36-79) and 20% were 70 or older. Twenty-three percent of pts were non-white, 20% had ECOG 2, 21% had high LDH, and 20% R-ISS3. Disease was trackable by NGS-MRD in 118 (95.9%) of pts. Median follow up is 25.1 mo. Four pts remain on protocol treatment, 20 transitioned to lenalidomide maintenance and 84 (71.2%) have reached confirmed MRD negativity and entered MRD-SURE. For those patients, median follow up post treatment cessation is 14.2 mo. Most common severe adverse events were pneumonia (N=8), and venous thromboembolism (N=3) and 3 patients died during treatment. Overall, 80% of pts have achieved MRD negativity and 66 % MRD < 10 -6. Depth of response improved with each phase of therapy and became similar in patients with 0, 1 or 2+ HR abnormalities as assessed post-AHCT and with MRD-guided consolidation (Figure 1). A similar proportion of patients with 0, 1 and 2+ HRCA reached MRD negativity (78. % vs. 82% vs 79 %) and MRD<10 -6 (64% vs. 73% vs. 58%). Response ≥CR was obtained in 86% of pts. Two-year progression-free survival (PFS) was 87% (91%, 97%, 58% for patients with 0, 1 and 2+ HRCA respectively) and 2-year overall survival (OS) was 94% (96%, 100%, and 75% for patients with 0, 1 and 2+ HRCA respectively, Figure 2). None of the pts reaching MRD-SURE has died from MM recurrence. Cumulative incidence of MRD resurgence or IMWG progression 12 months after cessation of therapy was 4%, 0% and 27% for patients with 0, 1 or 2+ HR abnormalities respectively.
Conclusion: Monoclonal antibody-based quadruplet therapy, AHCT and MRD response-adapted consolidation therapy leads to the highest rate of MRD negativity reported in NDMM. Near all patients with 0 or 1 HRCA and confirmed MRD negativity remain free of IMWG progression or MRD resurgence despite cessation of treatment. While most patients with ultra-high risk MM reach deep responses with this approach, novel consolidative strategies are needed. For most patients with NDMM, this strategy creates the opportunity of MRD surveillance as an experimental alternative to the burden of indefinite maintenance.
Figure 1 Figure 1.
Costa: Janssen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau. Chhabra: GSK: Honoraria. Dholaria: Janssen: Research Funding; Jazz: Speakers Bureau; MEI: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Angiocrine: Research Funding; Poseida: Research Funding; Celgene: Speakers Bureau. Silbermann: Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Giri: CareVive: Honoraria, Research Funding; PackHealth: Research Funding. Hari: GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy; Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau.
Carfilzomib for newly diagnosed multiple myeloma
| v2 |
2019-03-17T13:02:37.451Z | 2004-01-01T00:00:00.000Z | 79816780 | s2ag/train | PET in the management of bone metastases
Dr. Cook receives grants/research support from Philips Medical Systems and is a consultant to Alliance Medical Ltd. T he skeleton is one of the most common metastatic sites in patients with malignancy. It has been estimated that approximately 70% of patients with breast and prostate cancer have skeletal metastases during the late stages of the disease. Other cancers commonly associated with bone metastases include lung, renal, thyroid, and primary bone sarcomas. Survival with bone metastases may be prolonged in some cancers, including breast and prostate, where the median survival is as long as two years. In comparison, the median survival in lung cancer with skeletal disease is only three months. Skeletal metastases are predominantly lytic in nature in most cancers, but in some patients, such as those with prostate cancer, skeletal disease tends to be predominantly sclerotic. Lytic metastases are generally associated with an increase in morbidity and reduction in survival compared with sclerotic disease. Skeletal metastases are associated with significant morbidity, including pain, hypercalcemia, pathological fracture, and spinal cord compression, as well as bone marrow suppression. Due to the relatively long survival in some patients with skeletal metastases, the management of this problem and its complications represents a major demand on healthcare resources. Accurate noninvasive staging and follow-up of treatment effects of the skeleton by imaging is therefore an important part of clinical oncological management. PET imaging of the skeleton is possible with two different radiopharmaceuticals: F-18 fluoride ion as a skeletal tracer and F-18 fluoReferences 1. Galasko CSB. The anatomy and pathways of skeletal metastases. In Weiss L, Gilbert AH, eds. Bone metastases. Boston, MA: GK Hall, 1981:49-63. 2. Rubens RD. Bone metastases—incidence and complications. In Rubens RD, Mundy GR, eds. Cancer and the skeleton. London: Martin Dunitz, 2000:33-42. 3. Blau M, Nagler W, Bender MA. A new isotope for bone scanning. J Nucl Med 1962;3:332-334. 4. Piert M, Zittel TT, Machulla HJ, et al. Blood flow measurements with [15O]H2O and [18F]fluoride ion PET in porcine vertebrae. J Bone Miner Res 1998;13:1328-1336. 5. Galasko B, Samuel C, eds. Radionuclide scintigraphy in orthopaedics. London: Churchill Livingstone, 1984. 6. Blau M, Ganatra R, Bender MA. 18F-fluoride for bone imaging. Semin Nucl Med 1972;2:3137. 7. Schirrmeister H, Buck A, Guhlmann A, Reske SN. Anatomical distribution and sclerotic activity of bone metastases from thyroid cancer assessed with F-18 sodium fluoride PET. Thyroid 2001;11:677-683. 8. Schirrmeister H, Glatting G, Hetzel J, et al. Prospective evaluation of the clinical value of planar bone scans, SPECT and (18)F-labeled NaF PET in newly diagnosed lung cancer. J Nucl Med 2001;42:1800-1804. 9. Schirrmeister H, Guhlmann A, Elsner K, et al. Sensitivity in detecting osseous lesions depends on anatomic localization: planar bone scintigraphy versus 18F PET. J Nucl Med 1999;40:16231629. 10. Hetzel M, Arslandemir C, Konig HH, et al. F18 NaF PET for detection of bone metastases in lung cancer: accuracy, cost-effectiveness and impact on patient management. J Bone Miner Res 2003;18:2206-2214. 11. Schirrmeister H, Guhlmann A, Kotzerke J, et al. Early detection and accurate description of extent of metastatic bone disease in breast cancer with fluoride ion and PET. J Clin Oncol 1999;17:2381-2389. 12. Schirrmeisier H, Buck AK, Bergmann L, et al. PET for staging of solitary plasmacytoma. Cancer Biother Radiopharm 2003;18:841-845. 13. Wu HC, Yen RF, Shen YY, et al. Comparing whole body 18F-2-deoxyglucose PET and 99mTc MDP bone scan to detect bone metastases in patients with renal cell carcinomas— a preliminary report. J Cancer Res Clin Oncol 2002;128:503-506. 14. Cook GJR, Houston S, Rubens R, et al. Detection of bone metastases in breast cancer by 18 FDG PET: differing metabolic activity in osteoblastic and osteolytic lesions. J Clin Oncol 1998;16:3375-3379. 15. Franzius C, Sciuk J, Daldrup-Link HE, et al. FDG PET for detection of osseous metastases from malignant primary bone tumours: comparison with bone scintigraphy. Eur J Nucl Med 2000;27:1305-1311. 16. Moog F, Bangerter M, Kotzerke J, et al. 18F-fluorodeoxyglucose-positron emission tomography as a new approach to detect lymphomatous bone marrow. J Clin Oncol 1998;16:603609. 17. Sugawara Y, Fisher SJ, Zasadny KR, et al. Preclinical and clinical studies of bone marrow uptake of fluorine-1-fluorodeoxyglucose with or without granulocyte colony-stimulating factor during chemotherapy. J Clin Oncol 1998;16:173-180. 18. Jadvar H, Pinski JK, Conti PS. FDG PET in suspected recurrent and metastatic prostate cancer. Oncol Rep 2003;10:1485-1488. 19. Gayed I, Vu T, Johnson M, et al. Comparison of bone and 2-deoxy-2-[18F]fluoro-D-glucose PET in the evaluation of bony metastases in lung cancer. Mol Imaging Biol 2003;5:26-31. 20. Ohta M, Tokuda Y, Suzuki Y, et al. Whole body PET for the evaluation of bony metastases in patients with breast cancer: comparison with 99mTc-MDP bone scintigraphy. Nucl Med Commun 2001;22:875-879. 21. Bury T, Barreto A, Daenen F, et al. FDG PET for the detection of bone metastases in patients with non-small cell lung cancer. J Nucl Med 1998;25:1244-1247. 22. Stafford SE, Gralow JR, Schubert EK, et al. Use of serial FDG PET to measure the response of bone-dominant breast cancer to therapy. Acad Radiol 2002;9:913-921. 23. Zhuang H, Sam JW, Chacko TK, et al. Rapid normalisation of osseous FDG uptake following traumatic or surgical fractures. Eur J Nucl Med 2003;30:1096-1103. 24. Ho-Shon I, Fogelman I. F-18 FDG PET and benign fractures. Clin Nucl Med 2003;28:171175. P E T I N T H E M A N A G E M E N T O F B O N E M E T A S T A S E S | v2 |
2019-12-12T08:03:22.696Z | 2019-11-13T00:00:00.000Z | 209289350 | s2ag/train | Concomitant Treatment with Ruxolitinib and Deferasirox in the Management of Iron Overload in Patients with Myelofibrosis: A Multicenter Italian Experience
Introduction: Deferasirox (DFX) is the currently available iron-chelation therapy (ICT) for the management of iron overload (IOL), mainly in myelodysplastic syndromes; recently, two retrospective independent studies (Di Veroli, 2018; Elli, 2019) demonstrated that a treatment with DFX is feasible and effective also in the setting of myelofibrosis (MF). However, no data are still available regarding the concomitant use of DFX in patients (pts) treated with Ruxolitinib (Rux).
Aims and Methods: We retrospectively collected in 16 Italian Centers 59 pts (M: 37; F: 22) with primary MF (n=41) or post-Polycythemia Vera (n=9) and post-Essential Thrombocythemia (n=9) MF, treated with Rux and DFX for the management of IOL secondary to transfusion-dependent anemia. Primary endpoint of the study was to evaluate the efficacy of DFX in terms of reduction of ferritin levels and hematological improvement (HI). Additional endpoints were the safety of DFX associated to Rux treatment and the impact on survival and leukemic evolution.
Results: The main features of pts at diagnosis and at baseline of DFX treatment are reported in Table 1 (column A). Pts started DFX after a median time from MF diagnosis of 26.7 months [Interquartile range (IR) 2.6-240.9] and from transfusion dependency of 13.5 months (IR 1.5 - 145.3). Forty-eight pts started DFX when already under Rux treatment, while 11 pts before Rux treatment. The median ferritin level (FL) at baseline was 1675 ng/mL (IR 646-6447). The median starting dose of DFX was 1000 mg/day (12.5 mg/kg/day).
All pts were evaluable for DFX response (> 3 months of DFX), with a median time of DFX and Rux exposure of 14.5 months (IR 3.2-73.3) and 40 months (2.1-88.6), respectively; the median period of concomitant DFX-Rux treatment was 11.1 months (3.7-58.4). As to ICT efficacy, 24 pts (40.7%) obtained an iron chelation response (ICR), defined as a stable reduction of FL < 1.000 ng/mL or a reduction ≥ 50% of FL respect to baseline. The main variables analyzed in pts with ICR or no ICR were reported in Table 1 (Column B and C, respectively). At univariate analysis, pts who obtained ICR did not presented significant differences compared to pts without ICR, except for a significantly lower median FL at diagnosis (251 vs 496 mcg/l, p=0.008). As expected, ICR pts showed a progressive significant reduction of FL at 3, 6, 12 and 18 months, respect to baseline, in contrast to pts without ICR (p < 0.0001). The median time of exposure to DFX was higher in ICR vs no ICR group (22.0 vs 12.9 months, p=0.03), as well as the median time of concomitant DFX-Rux treatment (14.2 vs 9.7 months, p=0.019).
The International Working Group criteria (Cheson, 2006) were applied to assess HI during ICT. Erythroid response (ER) was defined as complete (CR: achievement of transfusion independency), partial (PR: reduction in the transfusion requirement ≥ 50% and/or increase of haemoglobin levels) or no response (NR). ER was observed in 25 pts (42.4%) with ten (17%) obtaining CR, 15 (25.4%) PR and 34 (57.6%) NR. Obtainment of ICR predicted for the achievement of ER: 17 (70.8%) pts with ICR achieved CR or PR compared to 8 (22.8%) without ICR (p =0.0007). DFX-related toxicities occurred in 30 pts (50.8%) and consisted mainly in renal impairment (32.2%), liver enzymes alterations (6.7%) or epigastric pain (8.4%): however, only in one case was observed a grade 3 toxicity. Overall, a dose reduction/temporary discontinuation related to DFX-toxicity was reported in 14 (23.7%) pts; however only 5 (8.4%) pts completely discontinued ICT because of grade ≥ 2 toxicity. After a median follow-up from diagnosis of 58.6 months (IR 7.1-282.9), 19 pts (32.2%) died [13 of them (22%) for leukemic evolution or disease progression]. The 3-year cumulative overall survival (Figure 1) and the 3-year cumulative incidence of leukemic evolution (Figure 2) from DFX initiation were 75.1% (95%CI 55.6 - 94.6) and 20.2% (95%CI 2.1 - 38.3) in pts who obtained ICR compared to 54.5% (95%CI 31.9 - 77.1) and 36.1% (95%CI 13.1 - 59.1) in pts without ICR, respectively (p=0.13 and p=0.153).
Conclusions: The present multicenter study showed that ICT with DFX is effective and safe also in this setting of pts receiving concomitant Rux treatment. HI with ER seems occur in a significant proportion of pts and correlates with the achievement of ICR. Further larger and prospective investigations are required in order to evaluate the impact on survival and leukemic evolution of this combination.
Elli: Novartis: Membership on an entity's Board of Directors or advisory committees. Iurlo:Novartis: Other: Speaker Honoraria; Incyte: Other: Speaker Honoraria; Pfizer: Other: Speaker Honoraria. Benevolo:Novartis Pharmaceuticals: Consultancy. Abruzzese:BMS: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Bonifacio:Novartis: Honoraria; Amgen: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Incyte: Honoraria. Cilloni:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Tiribelli:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Trawinska:Novartis: Consultancy, Honoraria. Breccia:BMS: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Gambacorti-Passerini:Bristol-Meyers Squibb: Consultancy; Pfizer: Honoraria, Research Funding. Palumbo:Janssen: Honoraria; Celgene: Honoraria; Teva: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Hospira: Honoraria. Latagliata:Celgene: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Pfizer: Honoraria.
| v2 |
2020-11-05T09:10:27.516Z | 2020-11-05T00:00:00.000Z | 228911510 | s2ag/train | The Prognostic Significance of Acquired 1q22 Gain in Multiple Myeloma
Background: Within the heterogeneous genomic landscape of multiple myeloma (MM), clonal evolution including the acquisition of risk-defining mutations and chromosomal abnormalities is a recurrent event and can be detected by fluorescence in situ hybridization (FISH). The effects of acquired abnormalities on clinical outcomes have not been well defined. We previously reported that patients who acquired 17p deletion [del(17p)] during the course of their disease had a significantly reduced overall survival (OS) by 38 months compared to patients who did not acquire del17p (Lakshman et al 2019). Similarly, while de novo gain of the long arm of chromosome 1 (1q22 gain) is a known high-risk aberration associated with significantly shorter OS and progression-free survival (PFS) in MM, the prognostic significance of acquired 1q22 gain has not been described. The primary objective of this study was to analyze factors predictive for acquired 1q22 gain and determine its impact on survival.
Methods: We identified MM patients from the Mayo Clinic Dysproteinemia Database who had at least one follow up FISH performed ≥6 months from diagnosis. The clinical characteristics, concomitant cytogenetic abnormalities, first line treatments administered, and OS were compared between patients with acquired 1q22 gain and patients who did not acquire this abnormality. The Mayo Clinic IRB approved this study.
Results: A total of 1041 MM patients met the inclusion criteria. Of these, 63 patients (6.1%) had acquired 1q22 gain, defined as being negative for 1q22 gain on initial FISH at diagnosis and having this abnormality detected on subsequent FISH. Median age at diagnosis was 59 years and 56% were male. Median time to acquisition of 1q22 gain was 60 months (range 8-140 months). We identified one control patient for each case who was diagnosed within one year of the case and had a subsequent FISH performed at a similar duration from diagnosis. Patients with acquired 1q22 gain had similar baseline characteristics except for a higher proportion of high-risk (HR) FISH at diagnosis [t(4;14), t(14;16), t(14;20), and del(17p13)] when compared to controls (27% HR FISH versus 6% HR FISH; P<0.01). 1q22 gain was concomitantly present with trisomies in 33 patients (54%), monosomy 13 in 24 patients (39%), t(4;14) in 8 patients (13%), and del(17p13) in 7 patients (12%). All patients received treatment prior to acquisition of 1q22 gain. Of the 63 patients, first line induction therapy consisted of proteasome inhibitor (PI) with steroid in 43%, immunomodulatory drugs (IMiD) with steroid in 40%, and PI + IMiD with steroid in 17% of patients. 54 patients (85%) received upfront stem cell transplant (SCT) (median 5.9 months to SCT), compared to 50 patients (79%) in the control group who received SCT.
The median follow up of all 126 patients was 6.8 years. There was a statistically significant reduction in median OS from diagnosis in patients with acquired 1q22 gain compared to the control group (10.8 years versus 13.0 years; P = 0.02; Figure 1). Predictors of acquisition of 1q22 gain were identified using a case-control method. Age ≥70 at diagnosis and presence of HR FISH at baseline appeared to increase the risk of acquiring 1q22 gain.
Conclusion: Acquisition of 1q22 gain is a relatively uncommon occurrence, but notably reduced OS by 2.2 years compared to patients who did not acquire 1q22 during the course of their disease (P = 0.02). Older age and the presence of HR FISH at diagnosis increased the risk of acquisition of 1q22 gain. The presence of high-risk translocations at baseline suggests that acquisition of 1q22 gain occurs in the context of more aggressive disease biology.
Kapoor: Cellectar: Consultancy; Celgene: Honoraria; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding. Dispenzieri:Alnylam: Research Funding; Pfizer: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Intellia: Research Funding; Janssen: Research Funding. Gertz:Prothena: Consultancy; Celgene: Consultancy; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Advisory Board for Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Advisory Board for Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Consultancy; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding; NCI SPORE MM: Research Funding; Ionis/Akcea: Consultancy; Physicians Education Resource: Consultancy; Medscape: Consultancy, Speakers Bureau; Amgen: Consultancy; Appellis: Consultancy; Annexon: Consultancy; Spectrum: Consultancy, Research Funding; Janssen: Consultancy; Sanofi: Consultancy; Data Safety Monitoring board from Abbvie: Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy. Dingli:Apellis: Consultancy; Rigel: Consultancy; Millenium: Consultancy; Bristol Myers Squibb: Research Funding; Karyopharm Therapeutics: Research Funding; Sanofi-Genzyme: Consultancy; Alexion: Consultancy; Janssen: Consultancy. Lin:Novartis: Consultancy; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy; Merck: Research Funding; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vineti: Consultancy; Legend BioTech: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding. Kumar:Cellectar: Other; Genecentrix: Consultancy; Dr. Reddy's Laboratories: Honoraria; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Sanofi: Research Funding; Karyopharm: Consultancy; MedImmune: Research Funding; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; Kite Pharma: Consultancy, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Adaptive Biotechnologies: Consultancy; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Merck: Consultancy, Research Funding; Carsgen: Other, Research Funding; Tenebio: Other, Research Funding.
| v2 |
2019-05-29T13:10:54.772Z | 2019-05-28T00:00:00.000Z | 167221020 | s2ag/train | Pneumococcal conjugate vaccines for preventing acute otitis media in children.
BACKGROUND
Prior to introducing pneumococcal conjugate vaccines (PCVs), Streptococcus pneumoniae was most commonly isolated from middle ear fluid of children with acute otitis media (AOM). Reducing nasopharyngeal colonisation of this bacterium by PCVs may lead to a decline in AOM. The effects of PCVs deserve ongoing monitoring since studies from the post-PCV era report a shift in causative otopathogens towards non-vaccine serotypes and other bacteria. This updated Cochrane Review was first published in 2002 and updated in 2004, 2009, and 2014. The review title was changed (to include the population, i.e. children) for this update.
OBJECTIVES
To assess the effect of PCVs in preventing AOM in children up to 12 years of age.
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, Web of Science, and trials registers (ClinicalTrials.gov and WHO ICTRP) to 29 March 2019.
SELECTION CRITERIA
Randomised controlled trials of PCV versus placebo or control vaccine.
DATA COLLECTION AND ANALYSIS
We used the standard methodological procedures expected by Cochrane. The primary outcomes were frequency of all-cause AOM and adverse effects. Secondary outcomes included frequency of pneumococcal AOM and frequency of recurrent AOM (defined as three or more AOM episodes in six months or four or more in one year). We used GRADE to assess the quality of the evidence.
MAIN RESULTS
We included 14 publications of 11 trials (60,733 children, range 74 to 37,868 per trial) of 7- to 11-valent PCVs versus control vaccines (meningococcus type C vaccine in three trials, and hepatitis A or B vaccine in eight trials). We included two additional trials for this update. We did not find any relevant trials with the newer 13-valent PCV. Most studies were funded by pharmaceutical companies. Overall, risk of bias was low. In seven trials (59,415 children) PCVs were administered in early infancy, while four trials (1318 children) included children aged one year and over who were either healthy or had a history of respiratory illness. There was considerable clinical heterogeneity across studies, therefore we did not perform meta-analyses.Adverse eventsNine trials reported on adverse effects (77,389 children; high-quality evidence). Mild local reactions and fever were common in both groups, and occurred more frequently in PCV than in control vaccine groups: redness (< 2.5 cm): 5% to 20% versus 0% to 16%; swelling (< 2.5 cm): 5% to 12% versus 0% to 8%; and fever (< 39 °C): 15% to 44% versus 8% to 25%. More severe redness (> 2.5 cm), swelling (> 2.5 cm), and fever (> 39 °C) occurred less frequently (0% to 0.9%, 0.1% to 1.3%, and 0.4% to 2.5%, respectively in children receiving PCV) and did not differ significantly between PCV and control vaccine groups. Pain or tenderness, or both was reported more frequently in PCV than in control vaccine groups: 3% to 38% versus 0% to 8%. Serious adverse events judged causally related to vaccination were rare and did not differ significantly between groups, and no fatal serious adverse event judged causally related to vaccination was reported.PCV administered in early infancyPCV7The effect of a licenced 7-valent PCV with CRM197 as carrier protein (CRM197-PCV7) on all-cause AOM varied from -5% (95% confidence interval (CI) -25% to 12%) relative risk reduction (RRR) in high-risk infants (1 trial; 944 children; moderate-quality evidence) to 6% (95% CI -4% to 16%; 1 trial; 1662 children) and 6% (95% CI 4% to 9%; 1 trial; 37,868 children) RRR in low-risk infants (high-quality evidence). PCV7 with the outer membrane protein complex of Neisseria meningitidis serogroup B as carrier protein (OMPC-PCV7), was not associated with a reduction in all-cause AOM (RRR -1%, 95% CI -12% to 10%; 1 trial; 1666 children; high-quality evidence).CRM197-PCV7 and OMPC-PCV7 were associated with 20% (95% CI 7% to 31%) and 25% (95% CI 11% to 37%) RRR in pneumococcal AOM, respectively (2 trials; 3328 children; high-quality evidence) and CRM197-PCV7 with 9% (95% CI -12% to 27%) to 10% (95% CI 7% to 13%) RRR in recurrent AOM (2 trials; 39,530 children; high-quality evidence).PHiD-CV10/11The effect of a licenced 10-valent PCV conjugated to protein D, a surface lipoprotein of Haemophilus influenzae, (PHiD-CV10) on all-cause AOM varied from 6% (95% CI -6% to 17%; 1 trial; 5095 children) to 15% (95% CI -1% to 28%; 1 trial; 7359 children) RRR in healthy infants (moderate-quality evidence). PHiD-CV11 was associated with 34% (95% CI 21% to 44%) RRR in all-cause AOM (1 trial; 4968 children; high-quality evidence).PHiD-CV10 and PHiD-CV11 were associated with 53% (95% CI 16% to 74%) and 52% (95% CI 37% to 63%) RRR in pneumococcal AOM (2 trials; 12,327 children; high-quality evidence) and PHiD-CV11 with 56% (95% CI -2% to 80%) RRR in recurrent AOM (1 trial; 4968 children; moderate-quality evidence).PCV administered at later agePCV7We found no evidence of a beneficial effect on all-cause AOM of administering CRM197-PCV7 in children aged 1 to 7 years with a history of respiratory illness or frequent AOM (2 trials; 457 children; high-quality evidence) and CRM197-PCV7 combined with a trivalent influenza vaccine in children aged 18 to 72 months with a history of respiratory tract infections (1 trial; 597 children; high-quality evidence).CRM197-PCV9In 1 trial including 264 healthy day-care attendees aged 1 to 3 years, CRM197-PCV9 was associated with 17% (95% CI -2% to 33%) RRR in parent-reported all-cause OM (low-quality evidence).
AUTHORS' CONCLUSIONS
Administration of the licenced CRM197-PCV7 and PHiD-CV10 during early infancy is associated with large relative risk reductions in pneumococcal AOM. However, the effects of these vaccines on all-cause AOM is far more uncertain. We found no evidence of a beneficial effect on all-cause AOM of administering PCVs in high-risk infants, after early infancy (i.e. in children one year and above), and in older children with a history of respiratory illness. Compared to control vaccines, PCVs were associated with an increase in mild local reactions (redness, swelling), fever, and pain and/or tenderness. We found no evidence of a difference in more severe local reactions, fever, or serious adverse events judged causally related to vaccination. | v2 |
2020-10-28T19:10:26.650Z | 2020-08-04T00:00:00.000Z | 229041930 | s2ag/train | The long-term tidal dynamics of differentiated rocky exoplanets
<p><strong>Overview</strong></p><p>Tidal interaction plays a unique role in coupling the thermal, orbital, and rotational evolution of close-in moons and exoplanets. The reaction of a planetary body subjected to tidal loading is determined by its interior structure, rheological properties, and orbital parameters. The interior and orbital dynamics are, conversely, affected by the tidal dissipation. In this study, we address the parameter dependence of stable spin states and tidal heating, as well as the long-term coupled thermal-orbital evolution of rocky exoplanets. Special attention is paid to the consistent evolution of spin rate and to the role of an emerging subsurface magma ocean in the secular maintenance of nonzero orbital eccentricity.</p><p> </p><p><strong>Model and Methods</strong></p><p>Our model consists of several modules and relies on the semi-analytical description of the thermal and orbital dynamics. All processes are interconnected through the tidal dissipation, which drains the energy from the orbit and presents an additional heat source for the planetary interior. The tidal heat rate (e.g., Segatz 1988; Efroimsky and Makarov, 2014) as well as the evolution equations for the orbital parameters and the spin rate are calculated using the Darwin-Kaula expansion into modes corresponding to different tidal frequencies (Kaula, 1964). To quantify the deformation and the additional potential of the deformed planet, we calculate the complex tidal Love numbers <em>k<sub>2</sub><sup>*</sup>(ω)</em> (e.g., Castillo-Rogez et al., 2011) using the equations of the normal mode theory (e.g., Sabadini and Vermeersen, 2004). This approach permits us to account for a differentiated interior of the planet.</p><p>The thermal evolution of the model planets is described by a parametrized model of stagnant lid convection (e.g., Grott and Breuer, 2008) with basal and volumetric heating, where the major heat source is provided by the tidal dissipation.  The internal dynamics are coupled to the rest of the model through the temperature dependence of mantle viscosity, the evolution of the stagnant lid thickness and the emergence of a stable subsurface magma ocean. All changes in the interior structure and rheological properties are reflected by the tidal Love number, which determines the tidal response and the rate of energy dissipation.</p><p> </p><p><strong>Results</strong></p><p>The first goal of this study is to explore the parametric dependence of the tidal dissipation and the spin-orbit locking. We study the effect of different rheological parameters, the planet size, the interior structure, and the eccentricity. As a result of the viscoelastic rheology, the model planet can get locked into higher than synchronous spin-orbit resonances, which provide an important source of dissipation especially in the case of relatively low orbital eccentricities. We also find that planets with smaller radii are more likely to get locked into higher resonances than larger or more massive planets. In addition to a parametric study of a generic terrestrial exoplanet, we also apply the model on three currently known low-mass exoplanet candidates: Proxima Centauri b, GJ 411 b, and GJ 625 b.</p><p>The second goal is the assessment of the mutual interconnection between the secular thermal and orbital evolution. We investigate the evolution paths of the three mentioned exoplanets and observe that the thermal evolution proceeds as a sequence of thermal equilibria. The equilibrium temperature profiles of the tidally evolving exoplanets are governed primarily by the stable spin-orbit ratio, which is determined by the mantle viscosity and eccentricity. The temperature-driven changes in the interior and the transitions between different spin-orbit resonances also affect the rate of orbital evolution. Specifically, the final despinning of a planet to the synchronous rotation may slow down the circularization of the planetary orbit and help to maintain nonzero orbital eccentricity for a considerable time. Using the coupled model, we also study the effect of different initial eccentricities and mantle viscosities on the current thermal and rotational state of the three exoplanets and compare the resulting eccentricities with their current, empirically given values (Figure 1).</p><p> </p><p><img src="https://contentmanager.copernicus.org/fileStorageProxy.php?f=gnp.715338c070fe56185182951/sdaolpUECMynit/0202CSPE&app=m&a=0&c=53360f89feee32411268e362d629142a&ct=x&pn=gnp.elif" alt=""></p><p>Figure 1: Orbital and thermal characteristics of Proxima Centauri b after 5 Gyr of coupled thermal-orbital evolution; adapted from Walterova and Behounkova (2020). Depending on the initial orbital eccentricity (<em>x-axis</em>) and the reference viscosity at temperature <em>T<sub>0</sub></em>=1600 K (<em>y-axis</em>), the individual panels depict the evolved eccentricity (<em>left</em>), the spin-orbit ratio (<em>middle</em>) and the surface tidal heat flux (<em>right</em>). Light blue areas correspond to the model parameters for which the evolved eccentricity complies with observation (Jenkins et al., 2019). The range of the empirically given values is also indicated by a red line in the first colorbar.</p><p> </p><p><strong>Conclusion</strong></p><p>The orbital evolution of strongly tidally loaded exoplanets, whose thermal state is shaped by the tidal heating, is naturally interconnected with their internal dynamics. The changes in the interior, namely the partial melting and the formation of a subsurface magma ocean, translate into the decrease in the rate of orbital evolution and in the tidal heat generation. The understanding of this complex feedback may help us to better constrain the conditions on extrasolar worlds and to address their hypothetical habitability.</p><p> </p><p><strong>Acknowledgements</strong></p><p>The research leading to these results received funding from the Czech Science Foundation through project No. 19-10809S and from Charles University through project SVV 115-09/260581.</p><p> </p><p><strong>References</strong></p><p>[1] M. Segatz, T. Spohn, M. N. Ross, and G. Schubert. <em>Icarus</em>, 75(2):187–206,1988.</p><p>[2] M. Efroimsky and V. V. Makarov. <em>The Astrophysical Journal</em>, 795(1):19, 2014.</p><p>[3] W. M. Kaula. <em>Reviews of Geophysics</em>, 2(4):661–685, 1964.</p><p>[4] J. C. Castillo-Rogez, M. Efroimsky, and V. Lainey. <em>Journal of Geophysical Research</em>, 116(E09008), 2011.</p><p>[5] R. Sabadini and B. Vermeersen. <em>Global Dynamics of the Earth: Applications of Normal Mode Relaxation Theory to Solid-Earth Geophysics.</em> Kluwer Academic Publishers, Dordrecht, the Netherlands, 2004.</p><p>[6] M. Grott and D. Breuer. <em>Icarus</em>, 193(2):503–515, 2008.</p><p>[7] M. Walterova and M. Behounkova. Submitted to <em>The Astrophysical Journal.</em></p><p>[8] J. S. Jenkins, J. Harrington, R. C. Challener, et al. <em>Monthly Notices of the Royal Astronomical Society</em>, 487(1):268–274, 2019.</p><!-- COMO-HTML-CONTENT-END -->
<p class="co_mto_htmlabstract-citationHeader">
<strong class="co_mto_htmlabstract-citationHeader-intro">How to cite:</strong>
Walterova, M. and Behounkova, M.: The long-term tidal dynamics of differentiated rocky exoplanets, Europlanet Science Congress 2020, online, 21 September–9 Oct 2020, EPSC2020-86, 2020
</p> | v2 |
2020-11-05T09:07:52.182Z | 2020-11-05T00:00:00.000Z | 228906980 | s2ag/train | Zella 201: A Biomarker-Guided Phase II Study of Alvocidib Followed By Cytarabine and Mitoxantrone in MCL-1 Dependent Acute Myeloid Leukemia (AML): Results of Newly Diagnosed High-Risk Exploratory Arm
Background:
Alvocidib is an investigational cyclin-dependent kinase-9 (CDK9) inhibitor that can suppress RNA polymerase II-mediated transcription of genes implicated in leukemia cell survival, including myeloid leukemia cell-1 (MCL-1). MCL-1 is an anti-apoptotic BCL-2 family member that is a key mediator of apoptosis in AML. Alvocidib combined in a timed-sequential regimen with cytarabine and mitoxantrone (ACM) has shown clinical activity in newly diagnosed and relapsed/refractory (R/R) AML through Phase I and II clinical trials. Analysis of bone marrow samples from newly diagnosed AML patients (pts) treated with ACM showed an association of complete remission (CR) with MCL-1 dependence by a BH3 profiling biomarker assay. Zella 201 was initiated based on the hypothesis that ACM may have preferential clinical activity in pts with MCL-1 dependence. We report the findings from an exploratory cohort of newly diagnosed high-risk (NDHR) AML pts with MCL-1 dependence treated with ACM.
Methods:
Zella 201 is a biomarker-driven Phase II study of ACM in R/R AML patients with MCL-1 dependence. Stage 1 included a cohort of R/R AML pts with various levels of MCL-1 dependence and an exploratory cohort of NDHR AML with MCL-1 dependence >40%, as determined by a BH3 profiling assay. Eligibility criteria for the NDHR cohort included pts 18-65 years with high-risk AML defined as one of the following: A) treatment-related AML, B) AML from preexisting MDS/MPN, C) adverse-risk by ELN 2017 criteria. Induction therapy consisted of alvocidib 30 mg/m2 as a 30 minute IV bolus followed by 60 mg/m2 over 4 hours on Days (D) 1-3, cytarabine 667 mg/m2/D by continuous IV infusion D6-8, and mitoxantrone 40 mg/m2 IV on D9. Up to 3 additional cycles of the same regimen (with or without mitoxantrone) were permitted in responders. The primary endpoint was CR/CRi. Key secondary endpoints were overall survival (OS), relapse-free survival (RFS), overall response rate and safety.
Results:
Thirteen NDHR pts were treated and evaluable in this cohort (Table 1). One pt received alvocidib on days 1-3 and withdrew from the study on day 6 due to grade 4 diarrhea, cytokine release syndrome, and acute kidney injury. This pt was excluded from the efficacy analysis. Median MCL-1 score was 56% (Range: 42-70%). This cohort was influenced by the following poor risk categories: secondary AML (n= 9; 69%), adverse-risk by ELN (n=8; 62%) and TP53 mutations (n=6; 46%). The most common ≥Grade 3 treatment-emergent non-hematologic AEs (n=14) were diarrhea (29%); TLS, hypocalcemia, sepsis, hypotension (21%), pneumonia, colitis, hyperglycemia, anorectal infection, dyspnea, and left ventricular dysfunction (all 14%).
Overall, CR/CRi was 62% with 7 (54%) pts responding following 1 cycle of therapy and another pt achieving CR after a second cycle. Two of six pts with TP53 mutation achieved CR. Although all pts included in this cohort were determined to be MCL-1 dependent, there was no association of CR with increasing MCL-1 dependence. Six (46%) pts went on to an allogeneic stem cell transplant (SCT). Sixty-day mortality was 0%. Median follow-up, OS, and RFS were 8.0, 8.5, and 6.1 months, respectively. Five of 8 (68%) CR/CRi pts have relapsed, and 10 pts (77%) have expired to date. The three pts still alive all received a post-study SCT.
Conclusion:
ACM has clinical activity in a limited cohort of NDHR AML pts with MCL-1 dependence scores >40% in a biomarker assay. Despite observed CR rates, duration of CR was modest and overall outcomes were poor. These results are comparable to historical controls with conventional chemotherapy regimens given the high-risk subset (62% of pts had adverse-risk and 46% had TP53 mutations). Further study is warranted to better define subgroups of ND AML pts who may benefit from alvocidib-containing induction regimens.
Zeidner: AsystBio Laboratories: Consultancy; AROG: Research Funding; Forty-Seven: Other: Travel Reimbursement, Research Funding; Merck: Research Funding; Sumitomo Dainippon Pharma Oncology, Inc.: Research Funding; Daiichi Sankyo: Honoraria; Genentech: Honoraria; Pfizer: Honoraria; Takeda: Consultancy, Honoraria, Other: Travel Reimbursement, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Other: Independent Review Committee; Agios: Honoraria. Lee:Sumitomo Dainippon Pharma Oncology, Inc.: Research Funding; Novartis: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Bayer: Research Funding; AbbVie: Research Funding; Celgene: Consultancy. Fine:Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Wang:Bristol Meyers Squibb (Celgene): Consultancy; Jazz Pharmaceuticals: Consultancy; Abbvie: Consultancy; Pfizer: Speakers Bureau; Genentech: Consultancy; Stemline: Speakers Bureau; PTC Therapeutics: Consultancy; Macrogenics: Consultancy; Astellas: Consultancy. Bhatt:Incyte: Consultancy, Research Funding; Oncoceutics: Other; National Marrow Donor Program: Research Funding; Jazz: Research Funding; Partnership for health analytic research: Consultancy; Takeda: Consultancy; Omeros: Consultancy; Agios: Consultancy; Rigel: Consultancy; Tolero: Research Funding; Pfizer: Research Funding; Abbvie: Consultancy, Research Funding. Kolibaba:Verastem: Honoraria; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Compass Oncology: Ended employment in the past 24 months; Seattle Genetics: Research Funding; Atara Biotech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sumitomo Dainippon Pharma Oncology, Inc.: Consultancy, Other: Travel, Accommodations, Expenses Paid; Genentech: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Celgene: Research Funding; AbbVie: Research Funding; Acerta: Research Funding; McKesson Life Sciences: Consultancy; Cell Therapeutics: Research Funding; Pharmacyclics: Research Funding. Anthony:Sumitomo Dainippon Pharma Oncology, Inc.: Current Employment; Exact Sciences: Consultancy. Bearss:Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Smith:Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.
| v2 |
2019-11-22T00:53:09.239Z | 2019-11-13T00:00:00.000Z | 209275730 | s2ag/train | Efficacy Proof of Concept for Allogeneic CD123 Targeting CAR T-Cells Against Primary Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN): Efficient Control of Tumor Progression in PDX Model and Potential Loss of CD123 Expression in Relapsed Disease
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy with historically poor outcomes and no established standard of care. Nearly 100% of patients with BPDCN overexpress CD123, and targeting CD123 has therefore emerged as an attractive therapeutic target.
UCART123v1 is an allogeneic "off the shelf" product composed of genetically modified T-cells expressing an anti-CD123 CAR and a RQR8 depletion ligand, which confers susceptibility to rituximab. The expression of the T-cell receptor αβ (TCRαβ) is abrogated through the inactivation of the TRAC gene, using Cellectis' TALEN® gene-editing technology.
We have previously reported the selective in vitro anti-tumor activity of UCART123v1 cells against primary BPDCN samples using cytotoxicity and T-cell degranulation assays, as well as the secretion of IFNγ and other cytokines (IL2, IL5, IL6, IL-13 and TNF-α) by UCART123v1 cells when cultured in the presence of BPDCN cells (Cai et al, 2017 ASH).
To evaluate anti-tumor activity of UCART123v1 cells in vivo, we established two relapsed BPDCN patient-derived xenografts (PDX1 and 2) in NSG-SGM3 mice. In PDX-1 model, mice were randomized upon tumour engraftment (D21 after primary BPDCN injection) into 4 groups and received an IV injection of either vehicle, 10×106 TCRαβ KO control T-cells, or UCART123v1 cells (3×106 or 10×106 cells). Mice from vehicle group died by D53 after BPDCN injection with high tumor burden in PB, spleen and BM. 3 out of 9 (33%) mice treated with 3×106 and 6 out of 9 (67%) mice treated with 10×106 UCART123v1 were alive and disease-free at the end of the study (D299 after primary BPDCN injection).
In PDX-2 model, which received the same treatment as PDX-1 (at D19 after primary BPDCN cell injection), all vehicle-treated mice died by D49. UCART123v1 therapy extended survival of treated mice to 104-241 days, but tumors relapsed at 90-155 days (Fig. 1A). The relapses in UCART123v1 treated mice were associated with the emergence of CD123-, CD56+CD45+ BPDCN cells infiltrating spleens and BMs (Fig. 1B).
To understand the molecular basis for CD123 loss, we isolated RNA from CD123+ cells from two of the vehicle-treated mice and CD123- cells from four of the UCART123v1-treated mice and performed RT-PCR and RNA-sequencing. The cells from all samples were hCD45+ and hCD56+, indicating leukemic origin. These analyses detected the presence of full-length transcripts (exons 2-12) in both CD123+ control samples (Sample 1 and 2in Fig. 1C). In 2 of the 4 CD123- samples, CD123 transcripts were absent, as were transcripts of neighbouring genes (samples 3 and 9 in Fig. 1C). RNA-sequencing reads aligned to Genome Browser tracks for CD123 and housekeeping gene GPI showed no reads present for CD123 but reads present for GPI in the two samples with CD123 loss. The aCGH (Array‐Based Comparative Genomic Hybridization) results showed that samples 3 and 9 (CD123-) had large regional deletions on chromosome X, which includes the CD123 gene. In another sample (sample 5), the splicing analysis algorithm MAJIQ detected CD123 transcripts containing only exons 2-9, indicating premature transcription termination. If translated, this truncated transcript would produce a protein isoform lacking the transmembrane domain in exon 10. Finally, MAJIQ also revealed canonical splicing of exon 2 to exon 3 in all CD123+ samples but a sharp increase in skipping from exon 2 to exon 5 in sample 16 (Fig. 1D). This exon-skipping event preserves the open-reading frame and yields the previously reported transcript variant 2. Per UniProt, the resultant protein will retain the ligand-binding domain but lack several glycosylation sites and two beta sheets in the extracellular domain, potentially compromising recognition by UCART123v1 cells. The aCGH and FISH results further showed that this patient sample harbored TP53 deletion, which could have contributed to DNA instability observed in different mice engrafted with these tumor cells.
In summary, allogeneic anti-CD123 CAR T therapy resulted in eradication of BPDCN in vitro and in increased disease-free survival in primary BPDCN PDX models. However, CD123 loss was observed in one PDX model harboring a TP53 deletion. These results provide preclinical proof-of-principle that UCART123v1 cells have potent anti-BPDCN activity, and indicate potential mechanisms leading to antigen loss and disease relapse.
Galetto: Cellectis Inc: Employment. Gouble:Cellectis: Employment. Zhang:The University of Texas M.D.Anderson Cancer Center: Employment. Kuruvilla:The University of Texas M.D.Anderson Cancer Center: Employment. Neelapu:Cellectis: Research Funding; Celgene: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; BMS: Research Funding; Poseida: Research Funding; Novartis: Consultancy; Karus: Research Funding; Acerta: Research Funding; Incyte: Consultancy; Pfizer: Consultancy; Merck: Consultancy, Research Funding; Unum Therapeutics: Consultancy, Research Funding; Precision Biosciences: Consultancy; Cell Medica: Consultancy; Allogene: Consultancy. Lane:AbbVie: Research Funding; Stemline Therapeutics: Research Funding; N-of-One: Consultancy. Kantarjian:BMS: Research Funding; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; Agios: Honoraria, Research Funding; Novartis: Research Funding; Immunogen: Research Funding; Jazz Pharma: Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Takeda: Honoraria; Astex: Research Funding; Daiichi-Sankyo: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding. Guzman:Cellectis: Research Funding; Samus Therapeutics: Patents & Royalties: intellectual rights to the PU-FITC assay; SeqRx: Consultancy. Pemmaraju:Stemline Therapeutics: Consultancy, Honoraria, Research Funding; samus: Research Funding; plexxikon: Research Funding; incyte: Consultancy, Research Funding; affymetrix: Research Funding; sagerstrong: Research Funding; Daiichi-Sankyo: Research Funding; cellectis: Research Funding; celgene: Consultancy, Honoraria; abbvie: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; mustangbio: Consultancy, Research Funding. Konopleva:Genentech: Honoraria, Research Funding; Ablynx: Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties.
| v2 |
2018-04-03T00:37:12.606Z | 2016-10-12T00:00:00.000Z | 13437470 | s2ag/train | Short-term and long-term effects of tibolone in postmenopausal women.
BACKGROUND
Tibolone is a synthetic steroid used for the treatment of menopausal symptoms, on the basis of short-term data suggesting its efficacy. We considered the balance between the benefits and risks of tibolone.
OBJECTIVES
To evaluate the effectiveness and safety of tibolone for treatment of postmenopausal and perimenopausal women.
SEARCH METHODS
In October 2015, we searched the Gynaecology and Fertility Group (CGF) Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and PsycINFO (from inception), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and clinicaltrials.gov. We checked the reference lists in articles retrieved.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) comparing tibolone versus placebo, oestrogens and/or combined hormone therapy (HT) in postmenopausal and perimenopausal women.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures of The Cochrane Collaboration. Primary outcomes were vasomotor symptoms, unscheduled vaginal bleeding and long-term adverse events. We evaluated safety outcomes and bleeding in studies including women either with or without menopausal symptoms.
MAIN RESULTS
We included 46 RCTs (19,976 women). Most RCTs evaluated tibolone for treating menopausal vasomotor symptoms. Some had other objectives, such as assessment of bleeding patterns, endometrial safety, bone health, sexuality and safety in women with a history of breast cancer. Two included women with uterine leiomyoma or lupus erythematosus. Tibolone versus placebo Vasomotor symptomsTibolone was more effective than placebo (standard mean difference (SMD) -0.99, 95% confidence interval (CI) -1.10 to -0.89; seven RCTs; 1657 women; moderate-quality evidence), but removing trials at high risk of attrition bias attenuated this effect (SMD -0.61, 95% CI -0.73 to -0.49; odds ratio (OR) 0.33, 85% CI 0.27 to 0.41). This suggests that if 67% of women taking placebo experience vasomotor symptoms, between 35% and 45% of women taking tibolone will do so. Unscheduled bleedingTibolone was associated with greater likelihood of bleeding (OR 2.79, 95% CI 2.10 to 3.70; nine RCTs; 7814 women; I2 = 43%; moderate-quality evidence). This suggests that if 18% of women taking placebo experience unscheduled bleeding, between 31% and 44% of women taking tibolone will do so. Long-term adverse eventsMost of the studies reporting these outcomes provided follow-up of two to three years (range three months to three years). Breast cancerWe found no evidence of differences between groups among women with no history of breast cancer (OR 0.52, 95% CI 0.21 to 1.25; four RCTs; 5500 women; I2= 17%; very low-quality evidence). Among women with a history of breast cancer, tibolone was associated with increased risk (OR 1.5, 95% CI 1.21 to 1.85; two RCTs; 3165 women; moderate-quality evidence). Cerebrovascular eventsWe found no conclusive evidence of differences between groups in cerebrovascular events (OR 1.74, 95% CI 0.99 to 3.04; four RCTs; 7930 women; I2 = 0%; very low-quality evidence). We obtained most data from a single RCT (n = 4506) of osteoporotic women aged 60 to 85 years, which was stopped prematurely for increased risk of stroke. Other outcomesEvidence on other outcomes was of low or very low quality, with no clear evidence of any differences between the groups. Effect estimates were as follows:• Endometrial cancer: OR 2.04, 95% CI 0.79 to 5.24; nine RCTs; 8504 women; I2 = 0%.• Cardiovascular events: OR 1.38, 95% CI 0.84 to 2.27; four RCTs; 8401 women; I2 = 0%.• Venous thromboembolic events: OR 0.85, 95% CI 0.37 to 1.97; 9176 women; I2 = 0%.• Mortality from any cause: OR 1.06, 95% CI 0.79 to 1.41; four RCTs; 8242 women; I2 = 0%. Tibolone versus combined HT Vasomotor symptomsCombined HT was more effective than tibolone (SMD 0.17, 95% CI 0.06 to 0.28; OR 1.36, 95% CI 1.11 to 1.66; nine studies; 1336 women; moderate-quality evidence). This result was robust to a sensitivity analysis that excluded trials with high risk of attrition bias, suggesting a slightly greater disadvantage of tibolone (SMD 0.25, 95% CI 0.09 to 0.41; OR 1.57, 95% CI 1.18 to 2.10). This suggests that if 7% of women taking combined HT experience vasomotor symptoms, between 8% and 14% of women taking tibolone will do so. Unscheduled bleedingTibolone was associated with a lower rate of bleeding (OR 0.32, 95% CI 0.24 to 0.41; 16 RCTs; 6438 women; I2 = 72%; moderate-quality evidence). This suggests that if 47% of women taking combined HT experience unscheduled bleeding, between 18% and 27% of women taking tibolone will do so. Long-term adverse eventsMost studies reporting these outcomes provided follow-up of two to three years (range three months to three years). Evidence was of very low quality, with no clear evidence of any differences between the groups. Effect estimates were as follows:• Endometrial cancer: OR 1.47, 95% CI 0.23 to 9.33; five RCTs; 3689 women; I2 = 0%.• Breast cancer: OR 1.69, 95% CI 0.78 to 3.67; five RCTs; 4835 women; I2 = 0%.• Venous thromboembolic events: OR 0.44, 95% CI 0.09 to 2.14; four RCTs; 4529 women; I2 = 0%.• Cardiovascular events: OR 0.63, 95% CI 0.24 to 1.66; two RCTs; 3794 women; I2 = 0%.• Cerebrovascular events: OR 0.76, 95% CI 0.16 to 3.66; four RCTs; 4562 women; I2 = 0%.• Mortality from any cause: only one event reported (two RCTs; 970 women).
AUTHORS' CONCLUSIONS
Moderate-quality evidence suggests that tibolone is more effective than placebo but less effective than HT in reducing menopausal vasomotor symptoms, and that tibolone is associated with a higher rate of unscheduled bleeding than placebo but with a lower rate than HT.Compared with placebo, tibolone increases recurrent breast cancer rates in women with a history of breast cancer, and may increase stroke rates in women over 60 years of age. No evidence indicates that tibolone increases the risk of other long-term adverse events, or that it differs from HT with respect to long-term safety.Much of the evidence was of low or very low quality. Limitations included high risk of bias and imprecision. Most studies were financed by drug manufacturers or failed to disclose their funding source. | v2 |
2019-03-17T13:02:57.016Z | 2016-12-02T00:00:00.000Z | 80395510 | s2ag/train | Lentiglobin Gene Therapy for Transfusion-Dependent β-Thalassemia: Update from the Northstar Hgb-204 Phase 1/2 Clinical Study
BACKGROUND
Allogeneic hematopoietic stem cell (HSC) transplant is potentially curative for patients with β-thalassemia major or, as more broadly defined, transfusion dependent β-thalassemia (TDT). However, HSC transplant is generally restricted to younger patients with matched sibling donors. Gene therapy could provide a transformative treatment for a broader population of patients with TDT, including those who are older or lack an appropriate donor.
HGB-204 is an international, multi-center Phase 1/2 clinical study investigating the safety and efficacy of LentiGlobin Drug Product (DP), a gene therapy product containing autologous HSCs transduced ex vivowith the BB305 lentiviral vector, in patients with TDT. We previously reported initial data in 13 treated patients with 0 to 19 months follow-up. Study enrollment is complete, and all 18 patients have undergone DP infusion. Here, we report new results on the study's full cohort of 18 patients, 14 of whom have ≥ 6 months of follow-up, including 1 who has completed the primary 24-month analysis period.
METHODS
Patients (12 to 35 years of age) with TDT were enrolled at participating sites in the U.S., Australia, and Thailand. HSC mobilization was accomplished with granulocyte colony stimulating factor (G-CSF) and plerixafor, and HSCs were harvested by apheresis. In a centralized manufacturing facility, CD34+-selected stem cells were transduced with the BB305 lentiviral vector, which encodes the human β-globin gene engineered to contain a single point mutation (AT87Q) and is regulated by the β-globin locus control region. Patients underwent myeloablation with intravenous busulfan, followed by infusion of transduced CD34+ cells (LentiGlobin DP). Patients were monitored for hematologic engraftment, vector copy number (VCN), hemoglobin AT87Q (HbAT87Q) expression, and transfusion requirements. Safety assessments including adverse clinical events (AEs), integration site analysis (ISA) and surveillance for replication competent lentivirus (RCL) were evaluated post-infusion.
RESULTS
Eighteen patients with TDT (β0/β0 [n=8], β0/βE [n=6], β0/β+ [n=1], β0/βx [n=1] and β+/β+ [n=2] genotypes) have received LentiGlobin DP. The median age of the 13 female and 5 male patients treated was 20 years (range: 12-35 years). The median DP VCN was 0.7 (range: 0.3-1.5 copies/diploid genome) and the median cell dose was 8.1 x 106 CD34+ cells/kg (range: 5.2-18.1 x 106 cells/kg). Patients engrafted with a median time of 18.5 days (range: 14-30 days) to neutrophil recovery. The toxicity profile observed was typical of myeloablative conditioning with single agent busulfan. There have been no ≥ Grade 3 DP-related AEs and no evidence of clonal dominance or RCL during a median follow-up of 14.4 months post-infusion (range: 3.7-27.0 months; cut-off date: 27 June 2016). To date, patients with at least 6 months of follow-up achieved a median HbAT87Q level of 4.7 g/dL at 6 months (range: 1.8-8.9 g/dL; n=14), with a median VCN in peripheral blood of 0.4 (range: 0.2−1.0; n=13). Of these, all patients with non-β0/β0 genotypes and ≥12 months of follow-up (n=5) have remained free of transfusions (median 19.4 months without transfusion; range: 15.3 to 24.0 months) with a median total Hb of 11.6g/dL (range: 9.0-11.9 g/dL) at the most recent follow-up visit. While patients with β0/β0genotypes and ≥12 months of follow-up (n=5) have continued to require transfusions, annual median transfusion volumes have decreased 60% (from median 171.9 ml/kg/year at baseline [range: 168.1-223.2ml/kg/year] to 67.8 ml/kg/year post-treatment [range: 14.8-123.7 ml/kg/year]).
CONCLUSIONS
In the largest TDT gene therapy trial to date, all patients have demonstrated therapeutic Hb expression without ≥ Grade 3 DP-related AEs. The levels of HbAT87Q in patients with at least 6 months of follow-up have exceeded the study primary endpoint (≥ 2g/dL) in 13/14 (93%) patients and are sustained in the 10 patients with ≥12 months of follow up. Compared to their baseline, all patients with β0/β0 genotypes have considerably reduced transfusion requirements. Notably, following a single infusion of LentiGlobin DP, patients with genotypes other than β0/β0 have discontinued transfusions and remain free of transfusions to date. These early results support the continued development of LentiGlobin DP as a treatment for TDT.
Thompson: Amgen: Research Funding; bluebird bio: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Mast: Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eli Lily: Research Funding; Baxalta (now part of Shire): Research Funding. Kwiatkowski:Luitpold Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Apopharma: Research Funding; Ionis pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Sideris Pharmaceuticals: Consultancy; Shire Pharmaceuticals: Consultancy. Rasko:GSK: Honoraria; IMAGO BioSciences: Consultancy, Equity Ownership; Genea: Consultancy, Equity Ownership; Rarecyte: Consultancy, Equity Ownership; Australian government and philanthropic foundations: Research Funding; Cure The Future Foundation: Other: Voluntary non-executive Board Member; Royal College of Pathologists of Australasia Foundation: Other: Voluntary non-executive Board Member; Office of the Gene Technology Regulator (OGTR) Australian Government: Membership on an entity's Board of Directors or advisory committees. Schiller:Incyte Corporation: Research Funding. Ho:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. von Kalle:bluebird bio: Consultancy; GeneWerk: Equity Ownership. Leboulch:bluebird bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Petrusich:bluebird bio: Employment, Equity Ownership. Asmal:bluebird bio: Employment, Equity Ownership. Walters:Kiadis Pharma: Honoraria; Bayer HealthCare: Honoraria; Leerink Partners, LLC: Consultancy; ViaCord Processing Laboratory: Other: Medical Director ; AllCells, Inc./LeukoLab: Other: Medical Director ; bluebirdBio, Inc: Honoraria.
| v2 |
2019-12-14T14:02:22.373Z | 2019-12-13T00:00:00.000Z | 209340860 | s2ag/train | Interventions for female drug-using offenders.
BACKGROUND
This review represents one in a family of three reviews focusing on the effectiveness of interventions in reducing drug use and criminal activity for offenders.
OBJECTIVES
To assess the effectiveness of interventions for female drug-using offenders in reducing criminal activity, or drug use, or both.
SEARCH METHODS
We searched 12 electronic bibliographic databases up to February 2019.
SELECTION CRITERIA
We included randomised controlled trials (RCTs).
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane.
MAIN RESULTS
We included 13 trials with 2560 participants. Interventions were delivered in prison (7/13 studies, 53%) and community (6/13 studies, 47%) settings. The rating of bias was affected by the lack of clear reporting by authors, and we rated many items as 'unclear'. In two studies (190 participants) collaborative case management in comparison to treatment as usual did not reduce drug use (risk ratio (RR) 0.65, 95% confidence interval (CI) 0.20 to 2.12; 1 study, 77 participants; low-certainty evidence), reincarceration at nine months (RR 0.71, 95% CI 0.32 to 1.57; 1 study, 77 participants; low-certainty evidence), and number of subsequent arrests at 12 months (RR 1.11, 95% CI 0.83 to 1.49; 1 study, 113 participants; low-certainty evidence). One study (36 participants) comparing buprenorphine to placebo showed no significant reduction in self-reported drug use at end of treatment (RR 0.57, 95% CI 0.27 to 1.20) and three months (RR 0.58, 95% CI 0.25 to 1.35); very low-certainty evidence. No adverse events were reported. One study (38 participants) comparing interpersonal psychotherapy to a psychoeducational intervention did not find reduction in drug use at three months (RR 0.67, 95% CI 0.30 to 1.50; low-certainty evidence). One study (31 participants) comparing acceptance and commitment therapy (ACT) to a waiting list showed no significant reduction in self-reported drug use using the Addiction Severity Index (mean difference (MD) -0.04, 95% CI -0.37 to 0.29) and abstinence from drug use at six months (RR 2.89, 95% CI 0.73 to 11.43); low-certainty evidence. One study (314 participants) comparing cognitive behavioural skills to a therapeutic community programme and aftercare showed no significant reduction in self-reported drug use (RR 0.86, 95% CI 0.58 to 1.27), re-arrest for any type of crime (RR 0.73, 95% CI 0.52 to 1.03); criminal activity (RR 0.80, 95% CI 0.63 to 1.03), or drug-related crime (RR 0.95, 95% CI 0.68 to 1.32). A significant reduction for arrested (not for parole) violations at six months follow-up was significantly in favour of cognitive behavioural skills (RR 0.43, 95% CI 0.25 to 0.77; very low-certainty evidence). A second study with 115 participants comparing cognitive behavioural skills to an alternative substance abuse treatment showed no significant reduction in reincarceration at 12 months (RR 0.70, 95% CI 0.43 to 1.12; low certainty-evidence. One study (44 participants) comparing cognitive behavioural skills and standard therapy versus treatment as usual showed no significant reduction in Addiction Severity Index (ASI) drug score at three months (MD 0.02, 95% CI -0.05 to 0.09) and six months (MD -0.02, 95% CI -0.09 to 0.05), and incarceration at three months (RR 0.46, 95% CI 0.04 to 4.68) and six months (RR 0.51, 95% CI 0.20 to 1.27); very low-certainty evidence. One study (171 participants) comparing a single computerised intervention versus case management showed no significant reduction in the number of days not using drugs at three months (MD -0.89, 95% CI -4.83 to 3.05; low certainty-evidence). One study (116 participants) comparing dialectic behavioural therapy and case management (DBT-CM) versus a health promotion intervention showed no significant reduction at six months follow-up in positive drug testing (RR 0.67, 95% CI 0.43 to 1.03), number of people not using marijuana (RR 1.23, 95% CI 0.95 to 1.59), crack (RR 1.00, 95% CI 0.87 to 1.14), cocaine (RR 1.02, 95% CI 0.93 to 1.12), heroin (RR 1.05, 95% CI 0.98 to 1.13), methamphetamine (RR 1.02, 95% CI 0.87 to 1.20), and self-reported drug use for any drug (RR 1.20, 95% CI 0.92 to 1.56); very low-certainty evidence. One study (211 participants) comparing a therapeutic community programme versus work release showed no significant reduction in marijuana use at six months (RR 1.03, 95% CI 0.19 to 5.65), nor 18 months (RR 1.00, 95% CI 0.07 to 14.45), heroin use at six months (RR 1.59, 95% CI 0.49 to 5.14), nor 18 months (RR 1.92, 95% CI 0.24 to 15.37), crack use at six months (RR 2.07, 95% CI 0.41 to 10.41), nor 18 months (RR 1.64, 95% CI 0.19 to 14.06), cocaine use at six months (RR 1.09, 95% CI 0.79 to 1.50), nor 18 months (RR 0.93, 95% CI 0.64 to 1.35). It also showed no significant reduction in incarceration for drug offences at 18 months (RR 1.45, 95% CI 0.87 to 2.42); with overall very low- to low-certainty evidence. One study (511 participants) comparing intensive discharge planning and case management versus prison only showed no significant reduction in use of marijuana (RR 0.79, 95% CI 0.53 to 1.16), hard drugs (RR 1.12, 95% CI 0.88 to 1.43), crack cocaine (RR 1.08, 95% CI 0.75 to 1.54), nor positive hair testing for marijuana (RR 0.75, 95% CI 0.55 to 1.03); it found a significant reduction in arrests (RR 0.19, 95% CI 0.04 to 0.87), but no significant reduction in drug charges (RR 1.07, 95% CI 0.75 to 1.53) nor incarceration (RR 1.09, 95% CI 0.86 to 1.39); moderate-certainty evidence. One narrative study summary (211 participants) comparing buprenorphine pre- and post-release from prison showed no significant reduction in drug use at 12 months post-release; low certainty-evidence. No adverse effects were reported.
AUTHORS' CONCLUSIONS
The studies showed a high degree of heterogeneity for types of comparisons, outcome measures and small samples. Descriptions of treatment modalities are required. On one outcome of arrest (no parole violations), we identified a significant reduction when cognitive behavioural therapy (CBT) was compared to a therapeutic community programme. But for all other outcomes, none of the interventions were effective. Larger trials are required to increase the precision of confidence about the certainty of evidence. | v2 |
2019-03-18T14:06:39.114Z | 2018-11-29T00:00:00.000Z | 80797920 | s2ag/train | Carfilzomib in Relapsed or Refractory Multiple Myeloma Patients with Early or Late Relapse Following Prior Therapy: An Analysis of Overall Survival in Subgroups from the Randomized Phase 3 Aspire and Endeavor Trials
Introduction: Carfilzomib is an irreversible proteasome inhibitor with proven efficacy as a single agent and in doublet and triplet combinations (Siegel et al, Blood. 2012;120:2817-25; Dimopoulos et al, Lancet Oncol. 2017;18:1327-37; Siegel et al, J Clin Oncol. 2018;36:728-34). The phase 3 ASPIRE and ENDEAVOR trials demonstrated that treatment with carfilzomib-based regimens led to superior efficacy outcomes (progression-free survival [PFS], overall survival [OS], and overall response rate [ORR]) compared with standard regimens in patients (pts) with relapsed or refractory multiple myeloma (RRMM) (ASPIRE: carfilzomib-lenalidomide-dexamethasone [KRd] vs lenalidomide-dexamethasone [Rd]; ENDEAVOR: carfilzomib-dexamethasone [Kd] vs bortezomib-dexamethasone [Vd]). A previous subanalysis of these trials found that carfilzomib improved PFS and ORR, regardless of whether pts experienced an early or late relapse following the immediate prior therapy (Mateos et al, ASH 2017). Here we performed post hoc analyses of ASPIRE and ENDEAVOR to examine OS and updated safety in the ASPIRE and ENDEAVOR early or late relapse subgroups.
Methods: ASPIRE and ENDEAVOR enrolled pts with RRMM (1-3 prior lines of therapy). Pts in both studies received carfilzomib twice weekly in 28-day cycles. In ASPIRE, pts were randomized to KRd or Rd, and those in the KRd arm received carfilzomib 27 mg/m2, which was discontinued after cycle 18. In ENDEAVOR, pts were randomized to Kd or Vd. The Kd group received carfilzomib 56 mg/m2; the Vd group received 21-day bortezomib cycles (1.3 mg/m2). In ENDEAVOR, treatment was continued until progression or unacceptable toxicity. Early relapsers were defined as pts who relapsed ≤1 year after initiating the most recent prior line of therapy (as assessed by investigator), while late relapsers were those who relapsed after >1 year. OS was summarized via Kaplan-Meier methods. In this post hoc analysis, P values were calculated for exploratory purposes. Data cutoff dates used here were April 28, 2017 for ASPIRE and July 19, 2017 for ENDEAVOR.
Results: In ASPIRE, median OS for early relapsers was 36.0 months for KRd vs 27.7 months for Rd (hazard ratio [HR]: 0.807; 95% confidence interval [CI]: 0.586-1.110; P=0.0935) (Figure 1). For late relapsers in ASPIRE, median OS was 53.2 months for KRd vs 41.2 months for Rd (HR: 0.752; 95% CI: 0.606-0.932; P=0.0046). Rates of grade ≥3 treatment-emergent adverse events (TEAEs) in ASPIRE were similar for early and late relapsers (KRd vs Rd, 89.3% vs 82.0% for early relapsers and 86.9% vs 83.0% for late relapsers). In ENDEAVOR, early relapsers had a median OS of 28.6 months for Kd vs 21.7 months for Vd (HR: 0.807; 95% CI: 0.587-1.109; P=0.0920) (Figure 2). For late relapsers in ENDEAVOR, median OS was not evaluable (NE) for Kd vs 42.3 months for Vd (HR: 0.722; 95% CI: 0.576-0.905; P=0.0023). Grade ≥3 TEAEs (Kd vs Vd) in ENDEAVOR occurred in 77.0% vs 77.0% of early relapsers and 83.6% vs 69.0% of late relapsers.
Conclusions: RRMM pts who received KRd and Kd had longer OS compared with those who received Rd and Vd, regardless of whether they had an early or late relapse following the most recent prior line of therapy. Late relapsers had a numerically greater magnitude of OS benefit with KRd and Kd compared with control arms than early relapsers. Rates of grade ≥3 AEs were consistent with those previously reported in ASPIRE and ENDEAVOR for the overall population. In conclusion, these findings underscore the impressive efficacy of carfilzomib-based therapy for the treatment of pts with RRMM.
Figure 1. Figure 1.
Mateos: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Goldschmidt:Sanofi: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; ArtTempi: Honoraria; Chugai: Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Adaptive Biotechnology: Consultancy. San-Miguel:Amgen: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; BMS: Honoraria; Celgene: Honoraria; Roche: Honoraria. Blaedel:Amgen: Employment, Equity Ownership. Obreja:Amgen: Employment, Equity Ownership. Yang:Amgen Inc.: Employment, Equity Ownership. Szabo:Amgen: Employment, Equity Ownership. Leleu:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.
| v2 |
2018-04-03T05:10:57.882Z | 2016-06-01T00:00:00.000Z | 3707520 | s2ag/train | Risk of severe ovarian hyperstimulation syndrome in GnRH antagonist versus GnRH agonist protocol: RCT including 1050 first IVF/ICSI cycles.
STUDY QUESTION
Is the risk of severe ovarian hyperstimulation syndrome (OHSS) similar in a short GnRH antagonist and long GnRH agonist protocol in first cycle IVF/ICSI patients less than 40 years of age?.
SUMMARY ANSWER
There is an increased risk of severe OHSS in the long GnRH agonist group compared with the short GnRH antagonist protocol. WHAT IS KNOWN ALREADY?: In the most recent Cochrane review, the GnRH antagonist protocol was associated with a similar live birth rate (LBR), a similar on-going pregnancy rate (OPR), and a lower incidence of OHSS (odds ratio (OR) = 0.43 95% confidence interval (CI): 0.33-0.57) compared with the traditional GnRH agonist protocol. Previous trials comparing the two protocols mainly included selected patient populations, a limited number of patients and the applied OHSS criteria differed, making direct comparisons difficult. In two recent large meta-analyses, no significant differences in LBR (OR = 0.86; 95% CI: 0.72-1.02) or in the incidence of severe OHSS were reported, while others found a lower LBR (OR = 0.82; 95% CI: 0.68-0.97) and a reduced risk of severe OHSS using the GnRH antagonist protocol (OR = 0.60; 95% CI: 0.40-0.88).
STUDY DESIGN, SIZE, DURATION
Phase IV, dual-centre, open-label, RCT including 1050 women allocated to either short GnRH antagonist or long GnRH agonist protocol in a 1:1 ratio and enrolled over a 5-year period using a web-based concealed randomization code. This is a superiority study designed to detect a difference in severe OHSS, the primary outcome, between the two groups with a power of 80% and stratified for age, assisted reproductive technology (ART) clinic and planned fertilization procedure (IVF/ICSI). The secondary aims were to compare rates of mild and moderate OHSS, positive plasma (p)-hCG, on-going pregnancy and live birth between the two arms. None of the women had undergone previous ART treatment.
PARTICIPANTS/MATERIALS, SETTING, METHODS
All infertile women referred for their first IVF/ICSI at two public fertility clinics, less than 40 years of age and with no uterine malformations were asked to participate. A total of 1099 subjects were randomized, including women with poor ovarian reserve, polycystic ovary syndrome and irregular cycles. A total of 49 women withdrew their consent, thus 1050 subjects were allocated to the GnRH antagonist (n = 534) and agonist protocol (n = 516), respectively. In total 1023 women started recombinant human follitropin-β (rFSH) stimulation, 528 in the GnRH antagonist group and 495 in the GnRH agonist group. All subjects were given a fixed rFSH dose of 150 IU or 225 IU according to age ≤36 years or >36 years, with the option to adjust dose at stimulation day 6. Clinical OHSS parameters were collected at oocyte retrieval, and Days 3 and 14 post-transfer. On-going pregnancy was determined by transvaginal ultrasonography at gestational weeks 7-9. In the intention-to-treat (ITT) analysis for reproductive outcomes, 1050 subjects were included. For the ITT analyses on OHSS 1023 subjects who started gonadotrophin stimulation were included.
MAIN RESULTS AND THE ROLE OF CHANCE
The incidence of severe OHSS [5.1% (27/528) versus 8.9% (44/495) (difference in proportion percentage point (Δpp) = -3.8pp; 95% CI: -7.1 to -0.4; P = 0.02)] and moderate OHSS [10.2% (54/528) versus 15.6% (77/495) (Δpp = -5.3pp; 95% CI: -9.6 to -1.0; P = 0.01) ] was significantly lower in the GnRH antagonist group compared with the agonist group, respectively. In the GnRH antagonist and agonist group, respectively, 4.7% (25/528) versus 8.5% (42/495) women were seen by a physician due to OHSS (P = 0.01), and 1.7% (9/528) versus 3.6% (18/495) were admitted to hospital due to OHSS (P = 0.06). No women had ascites-puncture in the GnRH antagonist group versus 2.0% (10/495) in the GnRH agonist group (P < 0.01). LBRs were 22.8% (122/534) versus 23.8% (123/516) (Δpp = -1.0pp; 95% CI: -6.3 to 4.3; P = 0.70) and OPRs were 24.9% (133/528) versus 26.2% (135/516) (Δpp = -1.3pp; 95% CI: -6.7 to 4.2; P = 0.64) per randomized subject in the GnRH antagonist versus agonist group, with a mean number of 1.1 versus 1.2 embryos transferred in the two groups. Pregnancy rates (PR) per randomized subject, per started gonadotrophin stimulation and per embryo transfer were all similar in the two groups.
LIMITATIONS, REASONS FOR CAUTION
A possible limitation is the duration of the trial, with new methods, such as 'freeze all' and 'GnRH agonist triggering', being developed during the trial, the new methods were sought avoided, however a total number of 32 women had 'freeze all' and 'GnRH agonist triggering' was performed in three cases. Ultrasonic measurements were performed by different physicians and inter-observer bias may be present. Measures of anti-Mullerian hormone and antral follicle count, to estimate ovarian reserve and thus predict risk of OHSS, were not performed. Finally, the physicians were not blinded to GnRH treatment group after randomization.
WIDER IMPLICATIONS OF THE FINDINGS
The short GnRH antagonist protocol should be the protocol of choice for patients undergoing their first ART cycle in females <40 years of age including both low and high responders when an age-dependent initially fixed gonadotrophin dose is used, as an increased risk of severe OHSS and the associated complications is seen in the long GnRH agonist group and as PRs and LBRs are similar in the two groups. Patients at risk of OHSS particularly benefit from the short GnRH antagonist treatment as GnRH agonist triggering can be used.
STUDY FUNDING/COMPETING INTERESTS
An unrestricted research grant is funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD). The funders had no influence on the data collection, analyses or conclusions of the study. No conflict of interests to declare.
TRIAL REGISTRATION NUMBER
EudraCT #: 2008-005452-24. ClinicalTrial.gov: NCT00756028. Trial registration date: 18 September 2008. Date of first patient's enrolment: 14 January 2009. | v2 |
2021-11-25T16:10:00.624Z | 2021-11-05T00:00:00.000Z | 244535950 | s2ag/train | Real-World Efficacy of Venetoclax-Based Regimens in Patients with Chronic Lymphocytic Leukemia in Israel: A Multicenter Prospective Study
Background: The BCL-2 inhibitor venetoclax in combination with an anti-CD20 monoclonal antibody (rituximab or obinutuzumab) has demonstrated superior outcomes and manageable safety as compared to chemo-immunotherapy in phase III clinical trials for chronic lymphocytic leukemia (CLL). Moreover, venetoclax-based regimens induced high rates of undetectable minimal residual disease (uMRD). Prospective data on the effectiveness of venetoclax-based regimens specifically with regard to achieving uMRD in a real-world setting are still lacking. Here we report the first interim analysis for efficacy and safety of an ongoing nationwide real-world study of venetoclax based therapy for CLL/small lymphocytic lymphoma (SLL).
Method: A prospective observational nationwide multicenter study. Treatment-naïve (TN) and relapsed/refractory (R/R) CLL/SLL patients were enrolled in 13 medical centers in Israel. The primary endpoint was clinical response, per physician assessment 12-months after the initiation of venetoclax treatment. Key secondary endpoints included progression free survival (PFS), overall survival (OS) and uMRD as assessed at a central laboratory by 8-color flow-cytometry.
Results: Between February 10, 2019, and Jun 17, 2021 (data cut), 199 CLL/SLL patients were enrolled from 13 medical centers in Israel to receive venetoclax based therapy. The study included 83 TN and 116 R/R evaluable CLL/SLL patients with a median age of 69 years (range, 34-85) and 70.5 years (range, 25-91), respectively (Table 1). R/R patients had received a median of one prior therapy with a range up to 8, of these patients 60 (51.7%) were previously treated with a B-cell receptor inhibitor (BCRi) including ibrutinib in 52 (44.8%) and idelalisib in combination with rituximab in 6 (5.2%). TN patients had been treated with venetoclax in combination with obinutuzumab (92.8%) or rituximab (4.8%) and R/R patients received either venetoclax with rituximab (60.3%) or obinutuzumab (9.5%), venetoclax monotherapy (25.8%) or triple therapy with venetoclax, rituximab and ibrutinib in 5 (4.3%).
Dose escalation of venetoclax to the recommended dose of 400 mg daily was achieved in 80.7% (n=67) of TN and 81% (n=94) of R/R patients. The median duration of ramp-up was 38 and 42 days in TN and R\R patients, respectively. Prior to therapy, tumor lysis syndrome (TLS) risk was considered high in 12% and 29.3% of TN and R/R patients, respectively (Table 1). Laboratory TLS occurred in one TN patient and 4 R/R patients, whereas 3 of the R/R patients experienced clinical TLS.
Nineteen TN and 75 R/R patients had a follow-up of at least 12 months or discontinued study prematurely. The 12-month overall response rate (ORR) for TN and R/R patients was 89.5% [complete response (CR) 13 (68.4%), partial response (PR) 4 (21.1%)] and 73.3% [CR 37 (49.3%), PR 18 (24%)], respectively. In the R/R cohort, the 12-month ORR among assessed patients was 67.6% (25/37) in BCRi-exposed versus 85.7% (30/35) in BCRi-naïve patients. At 12 months, peripheral blood uMRD (<0.01%) was achieved in 12 out of 14 (85.7%) TN and 26 out of 38 (68.4%) R/R evaluated patients. At a median follow-up of 5.1 months (range, 0.5-15.6) for TN and 10.1 months (range, 0-25.7) for R/R patients, the median PFS and OS, for both cohorts have not been reached. The estimated 12-month PFS was 90.9% for TN and 81.1% for R/R patients. For R/R patients with prior exposure to BCRi, the estimated 12-month PFS was 69.6% versus 94.8% in BCRi-naïve patients (figure 1).
Grade ≥3 adverse events (AEs) were reported in 34.9% of TN patients and 43.9% R/R patients. The most frequent grade ≥3 AEs documented were neutropenia (TN: 19.2% and R/R 17.2%), infections (TN: 4.8% and R/R: 21.5%) and febrile neutropenia (TN: 2.4% and in R/R: 2.6%). COVID-19 occurred in 7 patients including one death. At the time of data cut, 10 deaths occurred, one TN and 9 R/R patients. Causes for death included infections (5 patients), disease progression (2 patients), acute myeloid leukemia/ myelodysplastic syndrome (2 patients) and a soft-tissue sarcoma (1 patient).
Conclusions: This first interim analysis of our ongoing prospective real-world study of venetoclax-based treatment for TN and R/R CLL/SLL, demonstrates high efficacy together with a high proportion of undetectable MRD levels and a favorable toxicity profile. These efficacy results are comparable to those reported in previous Phase III clinical trials for CLL, with no new safety signals.
Figure 1 Figure 1.
Herishanu: AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Roche: Honoraria; AstraZeneca: Honoraria. Goldschmidt: AbbVie: Consultancy, Research Funding. Itchaki: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Levi: AbbVie: Consultancy, Research Funding. Aviv: AbbVie: Honoraria, Research Funding. Fineman: AbbVie: Research Funding. Dally: AbbVie: Honoraria, Research Funding. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Ruchlemer: AbbVie: Consultancy, Honoraria, Research Funding. Abadi: AbbVie: Honoraria, Research Funding. Shvidel: AbbVie: Honoraria, Research Funding. Braester: AbbVie: Honoraria, Research Funding. Cohen: AbbVie: Current Employment, Current equity holder in publicly-traded company. Frankel: AbbVie: Current Employment, Current equity holder in publicly-traded company. Ofek: AbbVie: Current Employment, Current equity holder in publicly-traded company. Berelovich: AbbVie: Current Employment, Current equity holder in publicly-traded company. Grunspan: AbbVie: Current Employment, Other: May hold equity. Benjamini: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding.
| v2 |
2018-05-08T18:02:33.386Z | 2006-01-01T00:00:00.000Z | 16117440 | s2ag/train | Killer Cells and Low-Dose Interleukin 2 following Adoptive Immunotherapy with Lymphokine-activated Cytolytic Potential of Peripheral Blood T-Lymphocytes Updated
In this study, we investigated the cytolytic activity of peripheral blood T-cells ll'lil i obtained from nine patients with primary lung cancer treated by surgical adjuvant adoptive immunothcrapy (AIT) with lymphokine-activated killer cells and low-dose recombinant interleukin 2 at the time of rebound lymphocytosis (24-48 h after AIT). In eight of nine patients, nonspecific cytotoxicity of peripheral blood lymphocytes signif icantly increased as compared with that of pre-AIT peripheral blood lymphocytes. However, purified PBT showed much less activity to kill tumor cells although they increased in number and were activated well in terms of increases in the expression of HLA-DR and interleukin 2 receptor. The cytolytic activity of post-AIT PBT was significantly en hanced when they were targeted to Fc receptor-bearing tumor cells (K562 or Daudi) with anti-CD3 (NL-T3) or anti-T-cell receptor (TCR)a/3 (\VT31) monoclonal antibody in all five patients examined. Phenotypically, the targeted cytotoxicity was predominantly mediated by CD8+ cells. The results indicated that in v/ro-activated I'll I by AIT could not exhibit direct cytotoxicity, but they acquired cytolytic potential, the effect of which was expressed by targeting to tumor cells. INTRODUCTION Since the discovery of the LAK4 phenomenon (1), IL-2 has been used for cancer therapy, either alone or in combination with ex r/vo-generated LAK cells (2-5). Several investigators reported that LAK activity is successfully induced in PBL by IL-2/LAK therapy (4, 6). Recently, CD56+ NK cells have been proposed as a circulating in vivo cytotoxic effector because most of in v/Yo-induced LAK activity is mediated by CD56+ NK cells while PBT acquire hardly substantial cytotoxicity (7-11) and become hyporesponsive to exogenous antigens and mitogens (12, 13), following IL-2 administration. However, there are several reports (14, 15) showing that LAK activity is also induced in T-cells by stimulation with IL-2 for several days in vitro. For improvement of efficacy of AIT, it is important to clarify whether in m'o-activated PBT can acquire cytolytic activity or not.This study showed that most in vivo LAK activity following AIT using ex v/i'o-induced LAK cells and s.c. injection of IL-2 (16-18) is mediated by a non-T-cell population. PBT do not show direct cytotoxicity although they are surely acti vated and increased in number after AIT. as reported by Lotze Received 9/20/90; accepted 12/13/90. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 l;.S.C. Section 1734 solely lo indicate this fact. 1This work was partially supported by Grant 02557049 from the Ministry of Education. Science and Culture and by a Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare. Japan. 2To whom requests for reprints should be addressed. ' On leave of absence from Japan Synthetic Rubber Co.. Ltd. * The abbreviations used are: LAK, lymphokine-activated killer; AIT, adoptive immunothcrapy; 11.-2. inlcrleukin 2; IL-2R, interleukin 2 receptor; CM. complete culture medium; mAb. monoclonal antibody: PBL. peripheral blood lymphocytes; PBT, peripheral blood T-cells; NK. natural killer; TCR. T-cell receptor; FcR. Fc receptor; ['H]dThd. tritiutcd thymidine; PFP. pore-forming protein; JRU, Japan reference units: FITC, fluorescein ¡sothiocyanate:PE. phycoerythrin. et al. (19). Recently. Smyth et al. (20) demonstrated that CD8+ T-cells activated by IL-2 acquire targeted cytotoxicity accom panied with expression of PFP (21. 22), although they cannot exert direct antitumor cytotoxicity. In the present study, we also examined targeted cytotoxicity of post-AIT PBT by using a system of anti-CD3 or TCR mAb and FcR+ tumor targets. MATERIALS AND METHODS Culture Medium. CM consisted of RPMI 1640 (Nissui Seiyaku Co., Ltd., Tokyo. Japan) supplemented with 20 m.M ,V-2-hydro\yethylpiperazine-A"-2-ethanesulfonic acid. 100 units/ml penicillin G, 100 ¿ig/mlstreptomycin sulfate, and 10ci heat-inactivated (56°Cfor 30 min) pooled human AB-type serum. IL-2. Human rccombinant IL-2 was kindly provided by Takeda Chemical Industries, Ltd.. Osaka, Japan (23). The specific activity of IL-2 was 1.4 x IO7 JRU/mg protein. When the Biological Response Modifiers Program Standard was used, it corresponded to 1.2 x IO7 units/mg protein. Patients. Nine patients (7 males and 2 females; mean age, 65 years, ranging from 56 to 74 years) with primary lung cancer were included in this study, who underwent surgery (pulmonary lobcctomy or pncumonectomy) at the Kyushu University Hospital. According to the tumor-nodes-metastasis classification of the International Union Against Cancer (1982) 5 adenocarcinomas and 4 squamous cell carci nomas were classified into 8 cases of stage I and 1 case of stage HI. Treatment. Fourteen to 20 days after surgery, the patients received immunotherapy. according to the regimen which we reported previously (18). Briefly, IL-2 was administered s.c. at a dose of 2 x 10" JRU/day with a half of each daily dose for 6 consecutive days. Lymph node lymphocytes were ascptically prepared from regional lymph nodes at the time of surgery and used as a source of LAK cells (16). The lymph node lymphocytes were subsequently cultured using a dialysis-pcrfusion culture device, which we have recently developed ( 17). and infused back to patients on the second day of administration of IL-2. Numbers of infused LAK cells ranged from 3 x IO9to 1.1 x 10"'/patiem (mean, 7 x 10"). Preparation of PBL. Heparinized peripheral blood samples were obtained just before the start of AIT and 2 days after the finish. PBL were isolated from each blood sample by centrifugation on FicollHypaque gradients (LSM; Organon Teknika. Durham. NC) and by subsequent removal of plastic-adherent monocy tes. Antibodies. FITC-conjugated and/or FITC-unconjugated NU series of murine niAbs were kindly provided by Nichirei Co., Tokyo. Japan. The mAbs used were: NU-T3 (anti-CD3), NU-Tpan (anti-CD5), NUTH/I (anti-CD4), NU-TS/C (anti-CD8) and NU-B2 (anti-CD20). FITCconjugated and FITC-unconjugated Leu-Ila (anti-CD 16) and Leu-19 (anti-CD56). phycoerythrin-conjugated Leu-3b (anti-CD4). anti-IL2R (anti-Tac) and anti-HLA-DR. and both FITC-conjugated and FITCunconjugated WT31 (anti-TCRit(i) were purchased from Becton-Dickinson. Mountain View, CA. Goat anti-mouse IgG + IgM were pur chased from Tago. Inc., Burlingame, CA. Isolation of Lymphocyte Subsets. Subpopulations of PBL were iso lated by a panning method (24). Briefly. PBL were incubated with mAb for 40 min at 4°C. After 3 washings with Hanks' balanced salt solution. | v2 |
2020-07-04T13:05:46.849Z | 2020-07-01T00:00:00.000Z | 220326380 | s2ag/train | Techniques for preventing hypotension during spinal anaesthesia for caesarean section.
BACKGROUND
Maternal hypotension is the most frequent complication of spinal anaesthesia for caesarean section. It can be associated with nausea or vomiting and may pose serious risks to the mother (unconsciousness, pulmonary aspiration) and baby (hypoxia, acidosis, neurological injury).
OBJECTIVES
To assess the effects of prophylactic interventions for hypotension following spinal anaesthesia for caesarean section.
SEARCH METHODS
We searched Cochrane Pregnancy and Childbirth's Trials Register (9 August 2016) and reference lists of retrieved studies.
SELECTION CRITERIA
Randomised controlled trials, including full texts and abstracts, comparing interventions to prevent hypotension with placebo or alternative treatment in women having spinal anaesthesia for caesarean section. We excluded studies if hypotension was not an outcome measure.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed study quality and extracted data from eligible studies. We report 'Summary of findings' tables using GRADE.
MAIN RESULTS
We included 125 studies involving 9469 women. Interventions were to prevent maternal hypotension following spinal anaesthesia only, and we excluded any interventions considered active treatment. All the included studies reported the review's primary outcome. Across 49 comparisons, we identified three intervention groups: intravenous fluids, pharmacological interventions, and physical interventions. Authors reported no serious adverse effects with any of the interventions investigated. Most trials reported hypotension requiring intervention and Apgar score of less than 8 at five minutes as the only outcomes. None of the trials included in the comparisons we describe reported admission to neonatal intensive care unit. Crystalloid versus control (no fluids) Fewer women experienced hypotension in the crystalloid group compared with no fluids (average risk ratio (RR) 0.84, 95% confidence interval (CI) 0.72 to 0.98; 370 women; 5 studies; low-quality evidence). There was no clear difference between groups in numbers of women with nausea and vomiting (average RR 0.19, 95% CI 0.01 to 3.91; 1 study; 69 women; very low-quality evidence). No baby had an Apgar score of less than 8 at five minutes in either group (60 babies, low-quality evidence). Colloid versus crystalloid Fewer women experienced hypotension in the colloid group compared with the crystalloid group (average RR 0.69, 95% CI 0.58 to 0.81; 2009 women; 27 studies; very low-quality evidence). There were no clear differences between groups for maternal hypertension requiring intervention (average RR 0.64, 95% CI 0.09 to 4.46, 3 studies, 327 women; very low-quality evidence), maternal bradycardia requiring intervention (average RR 0.98, 95% CI 0.54 to 1.78, 5 studies, 413 women; very low-quality evidence), nausea and/or vomiting (average RR 0.89, 95% CI 0.66 to 1.19, 14 studies, 1058 women, I² = 29%; very low-quality evidence), neonatal acidosis (average RR 0.83, 95% CI 0.15 to 4.52, 6 studies, 678 babies; very low-quality evidence), or Apgar score of less than 8 at five minutes (average RR 0.24, 95% CI 0.03 to 2.05, 10 studies, 730 babies; very low-quality evidence). Ephedrine versus phenylephrine There were no clear differences between ephedrine and phenylephrine groups for preventing maternal hypotension (average RR 0.92, 95% CI 0.71 to 1.18; 401 women; 8 studies; very low-quality evidence) or hypertension (average RR 1.72, 95% CI 0.71 to 4.16, 2 studies, 118 women, low-quality evidence). Rates of bradycardia were lower in the ephedrine group (average RR 0.37, 95% CI 0.21 to 0.64, 5 studies, 304 women, low-quality evidence). There was no clear difference in the number of women with nausea and/or vomiting (average RR 0.76, 95% CI 0.39 to 1.49, 4 studies, 204 women, I² = 37%, very low-quality evidence), or babies with neonatal acidosis (average RR 0.89, 95% CI 0.07 to 12.00, 3 studies, 175 babies, low-quality evidence). No baby had an Apgar score of less than 8 at five minutes in either group (321 babies; low-quality evidence). Ondansetron versus control Ondansetron administration was more effective than control (placebo saline) for preventing hypotension requiring treatment (average RR 0.67, 95% CI 0.54 to 0.83; 740 women, 8 studies, low-quality evidence), bradycardia requiring treatment (average RR 0.49, 95% CI 0.28 to 0.87; 740 women, 8 studies, low-quality evidence), and nausea and/or vomiting (average RR 0.35, 95% CI 0.24 to 0.51; 653 women, 7 studies, low-quality evidence). There was no clear difference between the groups in rates of neonatal acidosis (average RR 0.48, 95% CI 0.05 to 5.09; 134 babies; 2 studies, low-quality evidence) or Apgar scores of less than 8 at five minutes (284 babies, low-quality evidence). Lower limb compression versus control Lower limb compression was more effective than control for preventing hypotension (average RR 0.61, 95% CI 0.47 to 0.78, 11 studies, 705 women, I² = 65%, very low-quality evidence). There was no clear difference between the groups in rates of bradycardia (RR 0.63, 95% CI 0.11 to 3.56, 1 study, 74 women, very low-quality evidence) or nausea and/or vomiting (average RR 0.42, 95% CI 0.14 to 1.27, 4 studies, 276 women, I² = 32%, very-low quality evidence). No baby had an Apgar score of less than 8 at five minutes in either group (130 babies, very low-quality evidence). Walking versus lying There was no clear difference between the groups for women with hypotension requiring treatment (RR 0.71, 95% CI 0.41 to 1.21, 1 study, 37 women, very low-quality evidence). Many included studies reported little to no information that would allow an assessment of their risk of bias, limiting our ability to draw meaningful conclusions. GRADE assessments of the quality of evidence ranged from very low to low. We downgraded evidence for limitations in study design, imprecision, and indirectness; most studies assessed only women scheduled for elective caesarean sections. External validity also needs consideration. Readers should question the use of colloids in this context given the serious potential side effects such as allergy and renal failure associated with their administration.
AUTHORS' CONCLUSIONS
While interventions such as crystalloids, colloids, ephedrine, phenylephrine, ondansetron, or lower leg compression can reduce the incidence of hypotension, none have been shown to eliminate the need to treat maternal hypotension in some women. We cannot draw any conclusions regarding rare adverse effects associated with use of the interventions (for example colloids) due to the relatively small numbers of women studied. | v2 |
2019-04-24T13:10:23.452Z | 2003-12-24T00:00:00.000Z | 129584280 | s2ag/train | THE BASICRANIAL MORPHOLOGY OF MADTSOIID SNAKES (SQUAMATA, OPHIDIA) AND THE EARLIEST ALETHINOPHIDIA (SERPENTES)
JOHN D. SCANLON*, School of Biological Sciences, University of New South Wales, UNSW Sydney 2052, AustraliaSnakes of the extinct family Madtsoiidae are known from early LateCretaceous to Eocene deposits in Madagascar, western and northernAfrica, southwestern Europe (Spain and possibly France), and SouthAmerica (reviewed by Rage, 1998; Rage and Werner, 1999). Two gen-era occur in both the Campanian or Maastrichtian of Argentina and theearly Eocene of Australia (Patagoniophis and Alamitophis, Albino,1986; Scanlon, 1993; see Boles, 1999, for recent discussion and con-firmation of the Eocene date), and Australia is the only region in whichmadtsoiids are known later than the Eocene. Wonambi naracoortensisSmith, 1976, occurs in Pleistocene and Pliocene deposits (Scanlon andLee, 2000), and large species of Yurlunggur Scanlon, 1992, also rangefrom late Oligocene to late Pleistocene (Mackness and Scanlon, 1999).The highest known diversity and some of the best-preserved materialof madtsoiids are from the late Oligocene and Miocene of Riversleigh,northwestern Queensland, including Wonambi barriei, one or more un-named species of Yurlunggur, two small species of Nanowana, and atleast one additional new taxon (Scanlon, 1996, 1997; Scanlon and Lee,2000).Cranial remains of Wonambi naracoortensis from Naracoorte, SouthAustralia (Barrie, 1990; Scanlon and Lee, 2000), provide the best evi-dence of the morphology and affinities of any madtsoiid (though thefamily as currently recognized may not be monophyletic; see below).These specimens were originally interpreted as supporting the inclusionof Madtsoiidae in Alethinophidia (Barrie, 1990; Scanlon, 1992), butreinterpretation of the morphology and more comprehensive phyloge-netic analyses placed this lineage outside a clade including all livingsnakes, including scolecophidians as well as alethinophidians (Scanlon,1996; Scanlon and Lee, 2000; Lee and Scanlon, 2002). These resultsconfirm the interpretations of Hoffstetter (1961:155) and McDowell(1987) regarding the primitive features of madtsoiid vertebrae relativeto those of all living snakes, and conflict with the widespread assump-tions that scolecophidians are basal snakes and that all known fossilsnakes are either scolecophidians or alethinophidians (e.g., Underwood,1967; Rage, 1984, 1987; Rieppel, 1988; Zaher and Rieppel, 1999;Tchernov et al., 2000).Part of the braincase of a second Australian madtsoiid, similar to thatof Wonambi but differing conspicuously in proportions, has been rec-ognized from a late Oligocene or early Miocene deposit at Riversleigh,northwestern Queensland. This deposit contains vertebrae, ribs, and jawelements representing several taxa of madtsoiids including Nanowanagodthelpi, N. schrenki, and Wonambi barriei (Scanlon, 1996, 1997;Scanlon and Lee, 2000). However, the only vertebrae consistent in sizewith the braincase fragment are similar to those of Yurlunggur cam-fieldensisScanlon, 1992, allowing the braincase fragment to be referredto the same genus (Scanlon, 1996). All Yurlunggur vertebrae knownfrom Riversleigh have relatively higher neural spines than the somewhatlater Y. camfieldensis, so are considered specifically distinct, but taxo-nomic treatment of vertebrae is deferred pending study of recently dis-covered articulated remains.As well as Wonambi, comparisons are made with extant snakes ofsome basal lineages (anilioids and booids) and with Dinilysia patagon-* Present address: Department of Environmental Biology, Univer-sity of Adelaide, and Department of Palaeontology, South AustralianMuseum North Terrace, Adelaide SA 5000, Australia, e-mail: [email protected] Woodward, 1901 (?Coniacian, Late Cretaceous; Estes et al., 1970;Caldwell and Albino, 2001), which has been interpreted as a basal al-ethinophidian or a pre-alethinophidian snake of similar grade to madt-soiids (reviewed by Scanlon and Lee, 2000). I also make some com-parisons with a putative madtsoiid braincase fragment from the Ceno-manian of Wadi Abu Hashim, Sudan (Rage and Werner, 1999), andcomment on its significance.Comparisons with recent taxa are based on collections of the Queens-land Museum, Australian Museum, Macleay Museum, South AustralianMuseum, M. Archer, D. J. Barrie, and the author (details available onrequest).Riversleigh fossils are prepared using acetic acid (e.g., Archer et al.,1991) and the specimen described here is completely free of carbonatematrix. The course of canals and foramina was determined visuallyunder a binocular microscope, using a hair as a probe.Terminology for cranial anatomy either follows that in Rieppel’s(1979) review of snake basicranial evolution, or Rieppel’s terms arenoted parenthetically when different ones are preferred.Institutional Abbreviations QM F, Queensland Museum (Pa-laeontology), Brisbane.SYSTEMATIC PALEONTOLOGYREPTILIASQUAMATAOPHIDIAYURLUNGGUR Scanlon, 1992YURLUNGGUR sp.Material QM F23041.Locality Mike’s Menagerie Site (Mike’s Menagerie Local Fauna),Godthelp Hill, Riversleigh World Heritage Fossil Property, northwesternQueensland.Age The deposit forms part of ‘Tertiary System B,’ interpreted tobe late Oligocene or early Miocene in age (Archer et al., 1989, 1997).Description A fragment 22.0 mm in length comprises most of theco-ossified basisphenoid and parasphenoid (Fig. 1), here referred to as‘sphenoid’ for brevity; the width of the cultriform process immediatelyanterior to the basipterygoid processes is 7.3 mm; the same, immedi-ately anterior to ossified portions of trabeculae is 5.0 mm; the maximumwidth across the basipterygoid processes is 10.7 mm; the length of thecanal for the abducens nerve is 6.4 mm; the length of the articulatorysurface of the basipterygoid process (right) is 7.5 mm; the length of thevidian canal is greater than 6.6 mm.The dorsal surface (Fig. 1A) bears an oval, bowl-like hypophysial pit(sella turcica) centered just anterior to a line joining the posterior endsof the basipterygoid processes. It is not recessed below the posteriordorsum sellae (crista sellaris); the posterior and lateral walls are nearlyvertical, while the anterior wall is more oblique but demarcated ante-riorly by a shallowly overhanging crest approximately 2 mm across.This crest is interrupted by three small troughs probably accommodatingblood vessels (one to the left of the midline, two smaller ones to theright). A similar pattern of three anterior troughs is seen in Calabariareinhardti, and a slightly less similar condition in Xenopeltis unicolorand Loxocemus bicolor (Rieppel, 1979:figs. 5, 7), where they representthe anterior course of the ramus cranialis of the cerebral carotid.In the midline within the hypophysial pit, 0.7 mm posterior to thetransverse anterior crest, is a small foramen opening posteriorly, re- | v2 |
2019-03-11T13:08:08.213Z | 2012-07-24T00:00:00.000Z | 72963900 | s2ag/train | Correlation between anxiety in labor and duration as well as outcome
Abstract Background and aim: Delivery is a stressful event. It seems that the cervix of an anxious woman does not dilate easily. The purpose of this study was determine the correlation between anxiety during labor and duration as well as outcome of delivery in women referring to hospitals affiliated to Shahid Behshti Medical University and Shahid Akbar Abadi Hospital . Materials and Methods: A descriptive correlational design was used. 200 women were selected via a multistage quota sampling in each hospital. A demographic and obstetrical questionnaire, Spielberg's State Trait Anxiety Inventory, and a checklist regarding the condition of the parturient women during hospitalization, duration of labor as well as delivery and Apgar score of the neonate were used for data collection.Data were analysed using SPSS 16 statistical software. Findings: Most women experienced moderate anxiety (%53/5).Mean of total time of delivery was 250/87±150/34 minutes, %94/5 was normal delivery and the mean of apgar score in first minute was 9 and in 5 minute was10. No significant correlation was found between anxiety in labor room and duration (first, second and third stage) as well as outcome (type and Apgar score) of delivery. Conclusion: Since most women experienced moderate anxiety, midwives and other healthcare workers should consider psychological aspects of mothers in labor rooms and make the atmosphere of these placed favorable addition, preparative educational courses during pregnancy is needed . Keywords: Anxiety, labor, delivery REFERENCES -Anderson L Poromaa IS Wulff M Astrom M Bixo M (2004). Implications of antenatal depression and anxiety for obstetric outcome. Obstetrics and Gynecology. 104 (3) 467-476. -Carson VB (2000). Mental Health Nursing. 2nd edition, Philadelphia: W.B. Saunders Company. -Chang MY Wang SY Chen C H (2002). Effects of massage on pain and anxiety during labour: A randomized controlled trial in Taiwan. Journal of Advanced Nursing. 38 (1) 68- 73. -Coad J Dunstal M (2001). Anatomy and Physiology for Midwives. Edinburgh, New York: Mosby. -Cunningham FG Williams JW (2010).Williams Obstetrics. 23 rd edition New York: Mc Graw- Hill Company. -Decherney HA Nathan L (2003) Current Obstetric & Gynecologic, 9th edition, New York, Mc Graw- Hill. -Gagnon A Waghorn K (1999).One to one nurse labor support of nuliparous women stimulated with oxytocin. Journal of Obstetric. Gynecologic&Neonatal Nursing. 28 (4) 371- 376. -Johnson RC SLADE P (2003). Obstetric complications and anxiety during pregnancy: is there a relationship? Journal of Psychosomatic Obstetrics and Gynecologic. 24 (1) 1-14 -Johnson C R Slade P (2002).Does fear of childbirth during pregnancy predicts emergency caesarean section. An International Journal of Obstetrics' and Gynecology. 109 (11) 1213- 1221. -Kaviany H Ahmady Abhary A etal (2002). Prevalance of anxiety disorder in Tehran city. Thinking and Behavior Journal.8 (31) 4-11 -Keogh E Hughes S Ellery D Daniel C Psy C Holdcroft A (2006). Psychosocial influences on women's experience of planned elective cesarean section. Psychomatic Medicine. 68 (1) 167-174. -Lang AJ Sorrell JT Rodgers CS Lebeck M (2006). Anxiety sensitivity as a predictor of labor pain. European Journal of Pain, 10 (3) 263-270. -Langer A Campero L Garcia C Reynoso S (1998). Effects of psychosocial support during labour and childbirth on breastfeeding, medical interventions, and mother's wellbing in a Mexican public hospital: a randomized clinical trial. British Journal of Obstetries and Gynaecology. 105 (10) 1056 – 1063 -Littleton HL Breikopf CR Berenson AB (2007). Correlates of anxiety symptoms during pregnancy and association with perinatal outcomes: A meta – analysis. American Journal of Obstetrics & Gynecology. 196 (5) 424- 432. -Motevally E Feizy Z Gangy T Haganny H (2003). [Does viewing of videotape effect on childbirth anxiety level of primigravida mothers?].Iran Journal of Nursing.16 (33) 100-104 (Persian). -Moslemabadi Farahani A Malekzadegan R Mohammadi F Hosseini (2005). [Effect of the one to one midwifery care during labor on modes of delivery Iran journal of nursing].18 (43) 71-82 (Persian). -Mallekpour Afshary F Salary P etal (2005). [Effect of childbiirth preparation of training on anxiety during pregnancy and parturition in primiparous women reffered to health centers in Mashhad city 2000] . Journal of Shaheed Sadoghy University of Medical Sciences. 13 (2) 39-44(Persian). -Nasiri Amiri F. Salmalian H, Hajiahmadi M (2009). [Association between Prenatal Anxiety and Spontaneous Preterm Birth]. Journal of Babol University of Medical Sciences.11 (4) 42-48. (Persian) -Nasiry,M.(2000).[Psychcological Health During Pregnancy and Parturition]. Tehran Boshra Publication.(Persian). -Mirzaei F,Keshtgar S Kaviani M etal (2009).The Effect of Lavender essence smelling during labor on cortisol and serotonin plasma levels and anxiety reduction in nulliparous woman. Journal of Kerman University of Medical Sciences.16 (3) 245-254 (Persian). -Masoomi R Lamiyan M Ghaedi S (2008). [Role of oxytocin in anxiety in the normal Parturition].Journal of Zahedan university of Medcial sciences. 10 (1) 53-58(Persian) -Pirdel M Pirdel L (2009). Perceived Environmental Stressors and Pain Perception During Labor Among Primiparous and Multiparous Women. Journal of Reproduction and Infertility. 10 (3) 224-217. -Sadock J Sadock VA Kaplan HI (2000).Comprehensive Textbook of Psychiatry. 7 th edition, Philadelphia: Lippincott Williams & Wilkins. -Shamaeian Razavi N Bahri Binabaj N Hoseiny Shahidy L PourHeidar M (2006). [The effect of maternal position on labor pain]. Journal of Ofogh-E-Danesh.12 (2) 16-21 (Persian) -Sadok B Sadok V (2005). [Abstract of Psychiatry] translated by .Pourafkary NVol (1,2).2 nd Edition .Tehran. Shahrab pub. (Persian) -Sedaghat S (1999). [Factors causing anxiety before and after delivery in primiparous women reffered to health centers and hospitals of Tehran and Shaheed Beheshty University of Medical Sciences in 1999]. Tesis for MS degree in Shaheed Beheshty University of Medical Sciences. (Persian) -Shamloo S (1994). [Mental Health].Tehran .Chehr pub. (Persian) -Wijma k (2003). Why focus" on fear of childbirth".Journal of Psychoso Obstetrics and Gyneocology. 24 (3)141-143. -World Health organization (2001). htt://www.emro.int/mnh/PublicInformation Part 6. htm. | v2 |
2020-11-05T09:07:48.720Z | 2020-11-05T00:00:00.000Z | 228922680 | s2ag/train | Patient-Reported Outcomes Among Patients with High-Risk Untreated Follicular Lymphoma (FL) Randomized to Bendamustine/Rituximab (BR) or Bendamustine/Rituximab with Bortezomib (BVR) Therapy: Results from the ECOG-ACRIN E2408 Study
Introduction: FL is the most common indolent non-Hodgkin lymphoma in the Western world. FL may cause disease-related symptoms, and patients with high-risk disease usually require systemic therapy. BR is commonly used as first-line therapy for high-risk FL, and the addition of bortezomib to a BR backbone has been studied (Evens A et al. Clin Can Res 2020). Little is known about how these therapeutic options impact patients' health-related quality of life (HRQL). To fill this gap, patient-reported outcomes (PROs) were administered to patients enrolled on E2408 to quantify symptom burden and effects of BR versus BVR induction on HRQL.
Methods: Patients (n=258) randomized to receive 6 cycles of BR or BVR induction completed PROs assessing neurotoxicity (FACT/GOG-Ntx) at the beginning of each treatment cycle. Additional PROs measuring fatigue (FACT-F), lymphoma-specific concerns (FACT-Lym) and HRQL (Functional Assessment of Cancer Therapy-General; FACT-G) were completed at baseline, mid-treatment (MT; cycle 3/4) and end of induction (EOI; cycle 6). Paired t-test was used to assess PRO score changes from baseline to MT and EOI within BR or BVR group. Two-sample t-test was used to compare change scores between groups at MT and EOI, respectively. Univariate analyses with a linear model identified patient baseline characteristics and clinical factors (age, sex, stage, performance status, # extra nodal sites, FLIPI, GELF, bone marrow involvement, elevated LDH, palpable splenomegaly, B-symptoms, CRIS) associated with PRO change scores from baseline to EOI, adjusting for treatment group. A multivariate model was built with backward variable selection approach for each of the PROs.
Results: As shown in Figure 1, compared with baseline, patients randomized to BVR reported significantly worse FACT/GOG-Ntx scores at cycle 4, which continued to end of induction (FACT/GOG-Ntx change scores -2.91 to -3.73; p < 0.001). Neurotoxicity remained stable for patients treated with BR (Ntx change scores -0.02 to -0.55). FACT-Fatigue scores indicated worse fatigue at MT compared to baseline for patients receiving BVR (-2.7, p<0.05), yet they remained stable for BR. FACT-Lym scores were significantly higher at MT (BR: 2.69, p<0.001; BVR: 2.71, p=0.007) and end of induction (BR: 3.32, p<0.001; BVR: 3.55, p<0.001) compared to baseline, signifying a reduction in lymphoma-related symptoms in both arms. FACT-G scores were comparable between treatment arms at each time-point and did not change significantly from baseline to end of induction.
Univariate analyses among all patients identified older age and the absence of palpable splenomegaly at baseline as associated with worse FACT-Lym, FACT-Fatigue, and FACT-G change scores, signifying less improvement in lymphoma-related symptoms, fatigue and HRQL from baseline to end of induction (p<0.01). The presence of B-symptoms at baseline was associated with a greater reduction in lymphoma-related symptoms and fatigue from baseline to end of induction (p<0.01). Higher ECOG performance status was only associated with higher FACT-Fatigue change score, suggesting more improvement in fatigue for those with worse performance status at baseline. A multivariate model generated similar results.
Conclusions: Despite worse treatment-related symptoms throughout induction, the addition of bortezomib was associated with comparable overall HRQL to those treated with BR. Both treatments were associated with a reduction in lymphoma-related symptoms from baseline to end of induction, likely contributing to stable HRQL throughout treatment despite treatment-related symptoms. Findings also suggest that a subgroup of patients, particularly those who are older, may experience fewer improvements in lymphoma-related symptoms. This underscores the potential need for closer monitoring and clinical management of these patients. Collectively, results are likely to be encouraging for patients experiencing lymphoma-related symptoms, for whom the symptom burden associated with treatment may be worth the trade-off given the potential for improved disease-related symptom control.
Evens: Merck: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Research To Practice: Honoraria, Speakers Bureau; Epizyme: Consultancy, Honoraria, Research Funding; Mylteni: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Advani:Celgene, Forty Seven, Inc., Genentech/Roche, Janssen Pharmaceutical, Kura, Merck, Millenium, Pharmacyclics, Regeneron, Seattle Genetics: Research Funding; Astra Zeneca, Bayer Healthcare Pharmaceuticals, Cell Medica, Celgene, Genentech/Roche, Gilead, KitePharma, Kyowa, Portola Pharmaceuticals, Sanofi, Seattle Genetics, Takeda: Consultancy. Ansell:Trillium: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; AI Therapeutics: Research Funding; Takeda: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; ADC Therapeutics: Research Funding. Winter:Norvartis: Consultancy, Other: DSMB; Ariad/Takeda: Consultancy; CVS/Caremark: Consultancy; Delta Fly Pharma: Consultancy; Amgen: Consultancy; Epizyme: Other: DSMB; Merck: Membership on an entity's Board of Directors or advisory committees, Other: advisory board; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: advisory board. Cella:FACIT.org: Membership on an entity's Board of Directors or advisory committees, Other: President; Astellas: Consultancy, Honoraria; Pled Pharma: Research Funding; Janssen: Research Funding; Clovis: Research Funding; Alexion: Research Funding; Apellis: Consultancy; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Kiniksa: Consultancy; IDDI: Consultancy; BMS: Consultancy, Research Funding; ASAHI KASEI PHARMA CORP.: Consultancy; Oncoquest: Consultancy; Mei Pharma: Consultancy; Ipsen: Consultancy, Research Funding; Evidera: Consultancy; DSI: Consultancy, Research Funding; BlueNote: Consultancy; Abbvie: Consultancy, Research Funding; PROMIS Health Org: Membership on an entity's Board of Directors or advisory committees, Other. Kahl:ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Laboratories Inc: Consultancy; Pharmacyclics LLC: Consultancy; Genentech: Consultancy; Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Acerta: Consultancy, Research Funding. Wagner:Celgene Inc.: Membership on an entity's Board of Directors or advisory committees; Connect Multiple Myeloma Registry: Membership on an entity's Board of Directors or advisory committees.
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2019-04-03T13:09:46.021Z | 2018-11-29T00:00:00.000Z | 92667400 | s2ag/train | Molecular Spectrum of CSF3R variants Correlate with Specific Myeloid Malignancies and Secondary Mutations
Different CSF3R mutations (CSF3RMT) result in aberrant G-CSF signaling pathways and are linked to a wide range of myeloid disorders. Loss-of-function mutations in its extracellular domain cause severe congenital neutropenia (SCN). Activating mutations in the juxtamembrane region have been associated with a variety of myeloid malignancies. Truncating mutations in the cytoplasmic domain are associated with SCN cases that progress to MDS or AML. In this study, we evaluate the extent to which different CSF3RMT associate with disease onset, progression to leukemia and neutrophil counts in patients (pts) diagnosed with myeloid malignancies.
We identified CSF3RMT cases in a cohort of 1400 pts [median age 71 years (yrs)]. We analyzed somatic and germline mutational patterns, and cross-sectional correlation with other gene mutations in CSF3RMT. A stringent algorithm based on conserved amino acid residues and alterations of protein features was used to predict the pathogenic significance of CSF3RMT. We identified 44 CSF3RMT: 33 germline (CSF3RGL) and 11 somatic (CSF3RS) variants.
Most CSF3RGL were found in pts (median age 63 yrs) with MDS or related conditions (87% of all mutant cases), conversely these mutations were present in 5% (n= 22/424) of MDS, 3% (n= 7/244) MDS/MPN and <1% (n= 3/392) of AML and in 1 out of 3 pts with aCML tested. Mutations were mostly missense and located between the cytoplasmic (58%: M696T, R698C (isoform III), D732N, P733T, S744F, Y752*, E808K), and extracellular (42%: C131Y, E149Q, A208V, Q216H, D320N, E405K, S413L, Y562H) domains. No mutations were detected in the juxtamembrane domain. Variants were grouped in Tier-1 (61%: C131Y, E149Q, A208V, Q216H, D320N, E405K, S413L, Y562H Y752*, E808K) and Tier-2 (variants with uncertain significance, 39%: S413L, M696T, R689C, D732N, P733T, S744F). E808K and R698C were the most common amino acid changes in Tier-1 (53%) and Tier-2 (44%), respectively. A total of 4/7 pts with E808K progressed to AML (but none with R698C), supporting previous observations that E808K (or E785K) represents a pathogenic variant predisposing to leukemia. A total of 46% (n=14) of pts with CSF3RGL had neutropenia [median 0.9x109/L (0.02-1.22x109/L)] at the time of sampling. Two pts diagnosed with a prior cancer manifested sustained neutropenia before the diagnosis of MDS and MDS/MPN. G-CSF was administered in 21% of pts. Alterations in -7/7q- were common (21%). Some pts also harbored other somatic mutations in NF1 (15%), DNMT3A (12%), SETBP1 (12%), or U2AF1 (12%). Of note, 1 patient carried mutations in WAS and GATA2 and another carried a mutation in VPS45, which have been previously associated with SCN/MDS. The patient with aCML harbored also a CSF3RS (T615A).
Overall combined allelic burden in pts cohort was 2% vs. 1.6% expected allelic burden in control populations for the same variants (P=.02).
CSF3R S were found in 11 pts (median age 71 yrs) with AML or MDS related conditions (73% of all mutant cases), conversely these mutations were present in 1.4% (n= 6/424) of AML, <1% in MDS (n= 2/244) and MDS/MPN (n= 1/392) and in 2/3 pts with aCML tested. Mutations were missense in 63% of pts, T618I being most recurrent (n=5/11; 45%). Frameshifts accounted for 36% of the mutations and were localized in the cytoplasmic domain (Q741*, Q749*, Y752*, Q768*). All mutations were heterozygous. At the time of sampling 3/11 pts had leukocytosis and 3/11 had neutropenia. Mutations were distributed between the juxtamembrane domain (55%) and the cytoplasmic domain (45%). Mutations in the extracellular domain were not detected. Pts with sAML mostly carried mutations in the juxtamembrane domain (67%), those with MDS carried only in cytoplasmic domain, and those with MDS/MPN or aCML carried mutations in both the juxtamembrane and extracellular domains. There was one somatic and one RUNX1GL mutation. The cytogenetic abnormalities -7/7q- were detected in 18% (2/11) of cases. Interestingly, T618I was found solely in pts with sAML.
Focusing on associations between CSF3RMT and mutations in the class III receptor tyrosine kinases CSF1R, FLT3, and KIT we identified only FLT3 to be co-mutated with CSF3RMT. All 3 pts (2 CSF3RGL and 1 CSF3RS) with such co-mutations evolved to AML.
In sum, we found that CSF3RGL do not commonly co-occur with CSF3RS, suggesting that the neutropenia observed at the sampling time most likely is causative of undetected GL variants and/or is representative of a long unrecognized disease.
Nazha: MEI: Consultancy. Carraway:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Balaxa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Speakers Bureau; FibroGen: Consultancy. Santini:Otsuka: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
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2019-11-22T00:52:34.316Z | 2019-11-13T00:00:00.000Z | 209252600 | s2ag/train | Results of a First in Human, Dose Ascending, Phase I Study Examining the Safety and Tolerability of KA2237, an Oral PI3K p110β/δ Inhibitor in Patients with Relapsed/Refractory (R/R) B-Cell Lymphoma
Introduction: Despite therapeutic advances, there remains a considerable need for novel therapies for B-cell lymphomas. Although a high proportion of patients (pts) show response to initial therapy, many fail to achieve durable remissions and experience recurrent disease. Agents that target molecular pathways associated with the development and progression of lymphoma are likely to be highly effective and are desirable. The p110δ isoform of the PI3K enzyme is mainly expressed in lymphocytes and has been an attractive therapeutic target, with several PI3Kδ inhibitors demonstrating meaningful efficacy in B-cell lymphomas. Targeting the p110β isoform may further overcome tumor growth and escape mechanisms by mitigating the upregulation of the PI3K/AKT pathway, particularly in PTEN-deficient lymphomas. KA2237 is an oral, potent and selective inhibitor of the PI3K β and δ isoforms. The aim of this first in human, phase I, open-label, single arm study (NCT02679196) was to investigate the safety, tolerability, pharmacokinetic properties and pharmacodynamic effects of KA2237, in order to determine the maximum tolerated dose based on dose limiting toxicity and assess preliminary anti-tumor activity in pts with R/R B-cell lymphoma.
Methods: Pts ≥ 18 years (yrs) of age, ECOG ≤ 2, with B-cell lymphoma R/R or intolerant of established therapies (including rituximab) were enrolled using a 3+3 dose escalation (50-400mg) design. KA2237 was given orally on a once daily continuous schedule until progression or unacceptable toxicity. Anti-tumor activity was evaluated by computed tomography and, when available, integrating 18F-FDG positron emission tomography response assessment, at 8, 16 and 24 weeks. Response was assessed according to Lugano 2014 criteria. Pts received PJP prophylaxis.
Results: 21 pts with B-cell lymphoma were enrolled (8 DLBCL [diffuse large B-cell], 5 FL [follicular], 3 MCL [mantle cell], 3 CLL/SLL [chronic lymphocytic leukemia/small lymphocytic lymphoma], 1 MZL [marginal zone], 1 WM [Waldenstrom]). Pts received KA2237 at 4 dose levels: 50mg (n=6), 100mg (n=3), 200mg (n=7) and 400mg (n=5) daily; 21 pts were evaluable for safety assessment. Pharmacokinetic profiles were favorable with mean plasma half-life of 17-33 hours, compatible with once daily oral dosing. Median age was 69 yrs (range 48-84) with 76% males; median number of prior therapies was 3 (range 1-6). Median follow up duration was 8.5 months (range 6.9-24.6). Median duration of drug exposure was 82 days (range 10-714 days). 86% of pts experienced treatment-related adverse events (TRAE). 43% of pts experienced a grade ≥ 3 TRAE, with rash (n=3), transaminitis (n=2) and pneumonitis (n=2) occurring in more than 1 pt. 29% discontinued treatment due to a TRAE with pneumonitis (n=2) occurring in more than 1 pt. One grade 5 TEAE (multifocal pneumonia) was observed. 19/21 pts were evaluable for response, ORR was 37% (4 CR, 3 PR). Responses were observed across lymphoma subtypes including DLBCL, FL, CLL and MCL. Responses were often durable (see Figure) and in 2 pts with DLBCL who achieved CR permitted consolidation by autologous stem cell transplantation.
Conclusions: KA2237 is an oral, once a day, selective dual inhibitor of PI3K β/δ with a manageable toxicity profile and promising single-agent clinical activity in heavily pretreated R/R B-cell lymphoma. The recommended phase II dose is 200mg daily. The findings of this study support the further evaluation of KA2237.
Figure.
Nastoupil: Novartis: Honoraria; Spectrum: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding. Neelapu:Acerta: Research Funding; Merck: Consultancy, Research Funding; Poseida: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Karus: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Incyte: Consultancy; Precision Biosciences: Consultancy; BMS: Research Funding; Allogene: Consultancy; Pfizer: Consultancy; Cellectis: Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Cell Medica: Consultancy. Fowler:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ABBVIE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Westin:Janssen: Other: Advisory Board, Research Funding; Genentech: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Unum: Research Funding; Kite: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; MorphoSys: Other: Advisory Board. Wang:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Acerta Pharma: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; MoreHealth: Consultancy, Equity Ownership; BioInvent: Consultancy, Research Funding; Aviara: Research Funding; BeiGene: Research Funding; Loxo Oncology: Research Funding; VelosBio: Research Funding; Pulse Biosciences: Consultancy; Juno Therapeutics: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Dava Oncology: Honoraria; Kite Pharma: Consultancy, Research Funding. Beer:Karus therapeutics Ltd.: Employment. Cecil:Karus Therapeutics: Employment. Dow:Karus Therapeutics: Employment. McHale:Karus Therapeutics: Employment. Silva:Karus Therapeutics: Employment. Ward:Karus Therapeutics: Employment. Yavari:Karus Therapeutics: Employment. Shuttleworth:Karus Therapeutics: Employment.
| v2 |
2017-11-13T20:31:28.685Z | 1970-05-16T00:00:00.000Z | 32264820 | s2ag/train | Presumed plasmacytoma of clivus producing isolated hypoglossal nerve palsy.
CASE HISTORY A 44-year-old housewife presented in December 1966 with a two-month history of neck pain accentuated by coughing and sneezing. The neck was short and movements were painful, but there were no other abnormal signs. X-ray pictures of the cervical spine and chest were normal. The haemoglobin was 10-8 g./100 ml.; white cell count 6,000/cu. mm.; E.S.R. 44 mm. in the 1st hour; M.C.H.C. 32%; and a blood film showed some anisocytosis and mncrocytosis. Two months later the pain was unaltered and wasting and weakness of the left half of the tongue were noted. She was admitted to the Wessex Neurological Centre under the care of Dr. G. S. Graveson for investigation. Dysarthria was obvious and she stated that since September 1966 friends had commented that she spoke as if "her plate was loose." E.N.T. examination excluded clinical 9th or 10th nerve involvement. Skull x-ray films showed the basisphenoid and body of the sphenoid to be extensively eroded, with early basilar invagination. Tomographic cuts of the midline structures failed to show any part of the clivus intact. The anterior end, floor, and dorsum of the pituitary fossa were normal, but the bone was completely missing from the level of the posterior clinoid processes to the anterior rim of the foramen magnum. The basilar impression was presumed secondary to the clivus erosion. Air encephalography and tomography were normal except for the pontine cistern, which showed an abnormal convex configuration to the upper part of the clivus. Chest x-ray examination was negative. Haemoglobin 12 g./100 ml.; white cell count 6,300/cu. mm.; E.S.R. 132 mm. in the 1st hour; and albumin 2.5 g. and globulin 5-6 g./100 ml. Electrophoresis showed reduced albumin and alphaand betaglobulins, with a compact band in gammaglobulin. Sia's test was negative. Sternal marrow produced a dilute specimen with plasma cells comprising 5% of all nucleated cells. Urine protein was less than 10 mg./100 ml. and Bence Jones proteinuria was not detected. Reiter's protein complement fixation test was twice and the Wassermann reaction three times anti-complementary, and Price's precipitin reaction was negative three times. C.S.F. contained 16 lymphocytes/cu. mm.; protein 35 mg./100 ml.; no excess globulin; and glucose 48 mg./100 ml. Serum calcium was 8.8 mg./100 ml.; phosphate 2-7 mg./100 ml.; alkaline phosphatase 10 K.A. units; fasting glucose 76 mg./100 ml.; and cortisol (9-35 a.m.) 9 tig./100 ml. Total urinary neutral 17-oxosteroids 4-2 mg./24 hours, total urinary neutral 17-oxogenic steroids 8-6 mg./24 hours, and total urinary free cortisol 765 ,ug./24 hours. A diagnosis at that time was made of a solitary plasmacytoma destroying the skull base and directly involving the left hypoglossal nerve. She was given 4,500 r tumour dose of radiation to the skull base. Pain was reduced but the physical signs were unaltered. In June 1967 she was admitted to St. Mary's Hospital, Portsmouth, with a one-week history of fever and vomiting. She was drowsy, confused, disorientated, and incontinent. There was neck stiffness and Kernig's sign was positive. Lumbar puncture produced cloudy fluid at 140 mm. pressure containing 1,200 white cells/cu. mm. (950' polymorphs, 5%' lymphocytes); protein 300 mg./100 ml.; and sugar 66 mg./100 ml. but no organisms or acid-fast bacilli. Haemoglobin was 80%, white cell count 9,800/cu. mm., and E.S.R. 53 mm. in the 1st hour. A diagnosis was made of "chemical meningitis," possibly due to tumour irritation of the meninges, and treatment was instituted with sulphadiazine, chloramphenicol, and penicillin. She made a good recovery and was discharged 11 days after admission. In June 1968 she was readmitted with a four-day history of headache, vomiting, fever, confusion, and incontinence. She had photophobia and neck stiffness, and the middle lobe of the right lung was collapsed and consolidated. Lumbar puncture produced fluid at 260 mm. pressure containing pus cells and Gram-positive cocci, and later pneumococci were grown. She was treated with penicillin and sulphadiazine. Haemoglobin was 70%; white cell count 7,100/cu. mm. (neutrophils 4,828, lymphocytes 2,130, and monocytes 142/cu. mm.); E.S.R. 12 mm. in the 1st hour; albumin 3-38 g./100 ml.; alpha1 globulin 1-25 g./100 ml.; alpha-2 globulin 2-00 g./100 mL; beta-globulin 1-25 g./100 ml.; gammaglobulin 4.62 g./100 ml.; calcium 8-9 mg./100 ml.; phosphate 2-0 mg./100 ml.; sodium 124mEq/l.; potassium 3-7 mEq/l.; chloride 99 mEq/l.; bicarbonate 22 mEq/l.; and urea 24 mg./100 ml.; serum aspartate aminotransferase was 20 and serum alanine aminotransferase 24 units; bilirubin 0-3 mg./100 ml.; alkaline phosphatase 4 K.A. units; thymol turbidity 0; and zinc turbidity 0. Immunoelectrophoresis showed the M protein to be of Ig.G specificity with some IgA present, but IgM was not detected. Sternal marrow was highly cellular. Granulopoiesis showed greatly increased activity at all stages of maturation and was normal in morphology. The myeloid-erythroid ratio was about 8:1. Erythropoiesis was normoblastic in maturation and morphology. About 6%' of marrow cells were atypical pleomorphic plasma cells 1 5-30,u diameter. Several giant multinuclear forms and an occasional plasmacytoblast were seen. Megakaryocytes were present in apparently normal numbers. Urine contained no Bence Jones protein. Ten days after admission repeat lumbar puncture produced fluid containing 15 white cells/cu. mm., 25 red cells/cu. mm., protein 45mg./100 ml., and no organisms. Two days later when bending she developed severe central back pain of sudden onset without radiation. The only additional physical sign was tenderness in the dorsolumbar spine. X-ray examination showed deposits, presumably myeloma, in D 12 and possibly D 8, and further pictures eight days later showed collapse of D 12 and L 2. She was given cyclophosphamide 100 mg./day, but this was soon discontinued owing to leucopenia, and stilboestrol 20 mg./day was substituted. She continued to take this after leaving hospital. In January 1969 melphalan 2 mg./day was added but discontinued after one month owing to leucopenia. The neurological signs remained unaltered throughout. | v2 |
2020-10-28T19:11:58.350Z | 2020-08-04T00:00:00.000Z | 229041900 | s2ag/train | Temporal link between impact events and biotic crises – The case of the Puchezh-Katunki impact structure (Russia)
<div>
<ol>
<li><strong> Introduction</strong></li>
</ol>
<p>Geochemical evidence for a collision between a large (~10 km) extraterrestrial body and Earth at the end of the Cretaceous, ca. 66 million years ago, and the conclusion that this event was the cause for the global Cretaceous-Paleogene boundary extinction event [1], triggered an intense worldwide search for evidence of other impact events that could be temporally correlated to other extinction events [2, 3]. To date, no convincing links to any other extinction events have been presented [2].</p>
<p>                      Connecting extinction events with a specific impact event/crater is complicated by the fact that the inventory of terrestrial impact craters remains largely incomplete, due to, e.g., erosion and sedimentary cover. In addition, our understanding of impact diagnostic markers in sedimentary strata is far from complete, especially in the case of target rocks that lack quartz or when dealing with extraterrestrial projectiles with “not so distinctive” geochemical signature, such as achondrites. On top of these considerations, the ages of a large number of the known terrestrial impact structures are poorly constrained. A precise, and most importantly accurate, age for an impact event is crucial when attempting to tie a specific impact event to a biosphere episode recorded in the stratigraphic record.</p>
<p>The 40-km-diameter Puchezh-Katunki impact structure [4], located ~400 km northeast of Moscow (Russia), with an estimated age ranging from ~164 to 203 Ma [5, 6], has been discussed as a possible trigger for four different biotic crises (Fig. 1; [7-12]).</p>
<p>Here we present new <sup>40</sup>Ar/<sup>39</sup>Ar data on impact melt rock samples from the Vorotilovo Deep Well drill core, retrieved from the center of the Puchezh-Katunki impact structure [4,6]. The new age obtained for the structure provides valuable data regarding relationships between impact events and extinction events in general and specifically the proposed relationship with some Mesozoic extinction/biotic events, and also contributes to the improvement of the age database of terrestrial impact structures.</p>
<p> </p>
<ol start="2">
<li><strong> Results and Discussion</strong></li>
</ol>
<p>Laser step-heating of four whole-rock samples of impact melt rock from the Puchezh-Katunki impact structure were run in duplicate (Fig. 1). The samples (V1018, V1144, and V1251) come from the upper parts of the drill core. The new <sup>40</sup>Ar/<sup>39</sup>Ar data allow us to precisely and accurately date the formation of the Puchezh-Katunki impact structure to 195.8 ± 1.0 Ma (2σ; mean square of weighted deviates (MSWD) = 2.0; P = 0.11). This new age makes Puchezh-Katunki one of the most precisely dated impact structures on Earth (2σ relative error: 0.51%).</p>
<p>As previously noted, only one global mass extinction has been confirmed to be the direct result of an impact event. The possible relation between impact events and global mass extinctions has been extensively discussed in the literature [2, 3], and lower limits on crater sizes that cause global effects have been debated as well (op.cit.). For example, there is little evidence that the late Eocene impact events (e.g., the Popigai and Chesapeake Bay impact events) have caused any global biotic effects. It is of course possible that less severe, perhaps regional, biotic events have also played an important role in the evolution of life (e.g., [13]). Understanding these events can yield important insights into e.g., the relationship between environmental changes and extinctions (i.e., causality), and how life recovers after such sudden events. Despite not causing global mass extinction, impact events of significant magnitude to cause regional havoc (e.g., resulting in impact craters equivalent to the size of Puchezh-Katunki) will have an impact on life (e.g., [14]) at least on a regional to continent-wide scale, and could possibly have caused both yet undetected biotic events as well as some of the (minor) extinction events that are recognized in the stratigraphic succession. However, since the geological timescale is continuously refined and ages updated, connecting even a well-dated impact structure with an event in the stratigraphic record is by no means straight-forward.</p>
<p>Our new age of 195.8 ± 1.0 Ma for the formation of Puchezh-Katunki excludes any relationship with the previously mentioned biotic/extinction events, and clearly illustrates that connecting poorly constrained crater ages with extinction events is troublesome. Therefore, we stress that using poorly constrained or outdated ages leads to erroneous or problematic conclusions (see also e.g., [15, 16]). We also want to emphasize that proving synchronicity between an impact event and a biotic event is not the same thing as proving causality.</p>
<br />
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2020-02-20T09:09:35.635Z | 2019-11-13T00:00:00.000Z | 213321040 | s2ag/train | APR-246 Combined with Azacitidine (AZA) in TP53 Mutated Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML). a Phase 2 Study By the Groupe Francophone Des Myélodysplasies (GFM)
Introduction : TP53 mutated (TP53m) MDS and AML have very poor outcome irrespective of the treatment received, including 40% responses (20% CR) with azacitidine (AZA) with short response duration and a median overall survival (OS) of about 8 months (Bejar, Blood 2014). APR-246 is a prodrug spontaneously converted to methylene quinuclidinone (MQ), a Michael acceptor that binds covalently to cysteines in mutant p53, leading to protein reconformation that reactivates its pro apoptotic and cell cycle arrest functions. The combination of AZA and APR 246 showed promising results in a phase Ib study in TP53m MDS (Sallman, ASH 2018). We report interim results of a GFM phase 2 study of AZA+ APR-246 in TP53m MDS and AML, conducted in parallel with a similar US MDS consortium study.
Patients and Methods : The study included hypomethylating agent (HMA) naïve and not previously allografted intermediate, high or very high IPSS-R TP53m MDS and AML adult patients. Patients received APR-246 4500 mg IV /d (6 hour infusions) (days 1-4) followed by AZA 75 mg/m²/d (days 4-10) in 28 day cycles. Response (primary endpoint, assessed by IWG 2006 for MDS and ELN criteria for AML) was evaluated after 3 and 6 cycles in the intent to treat (ITT) population, ie all patients who had received any protocol treatment, and in patients who had at least a blood and bone marrow evaluation after cycle 3 (evaluable population). Allo-SCT, when possible, was proposed after 3 to 6 cycles, and treatment with reduced APR 246 and AZA doses could be continued after allo-SCT.
Results : 53 patients were enrolled between Sept 2018 and July 2019 in 7 GFM centers, with a median age of 73 years (range 44-87), and M/F: 28/25. 34 patients had MDS (including 74% very high IPSS-R) and 19 had AML. IPSS-R cytogenetic risk was very poor in 30/34 MDS, and unfavorable in 18/19 AML, complex in 89% of the patients. Median baseline mutated TP53 VAF was 21% (range 3-76).
Nineteen of the 53 patients had been included at least 7 months before date of analysis (25 July 2019), had received protocol treatment and were thus potentially evaluable for response after 6 treatment cycles (ITT population). One of them died after only one cycle from an unrelated cause (cerebral ischemic stroke), and 2 during the third cycle (from bleeding and sepsis, respectively). In the remaining 16 patients (evaluable population per protocol), the response rate was 75% including 9 (56%) CR, 3 (19%) marrow CR or stable disease with hematological improvement (HI), and 4 treatment resistance. In the ITT population, the response rate was 63%, including 47% CR, and 16% stable or marrow CR+ HI. Among CR patients, complete cytogenetic CR and negative NGS for TP53 mutation (VAF cutoff of 2%) were achieved in 7/9 (78%) and 8/8 (100%), respectively. So far, 1 patient has undergone allo-SCT.
All 53 patients had received at least one treatment cycle, and no increased myelosuppression, compared with AZA alone, was apparent. Treatment related AEs observed in ≥ 20% of patients were febrile neutropenia in 19 (36%) and neurological AEs in 21 (40%) of the patients. The latter, reviewed with a neurological team, were mainly grade 1 or 2 and consisted of ataxia (n=13), sometimes associated with cognitive impairment (n=4), suggesting a cerebellar origin. Other patients experienced acute confusion (n=4), isolated dizziness (n=3) and facial paresthesia (n=1). Neurological AEs reached grade III in 3 cases (1 acute confusion, 2 ataxia). Occurrence of neurological AEs was correlated with lower glomerular filtration rate at treatment onset (p<0.01) and higher age (p=0.05). Neurological symptoms spontaneously regressed within 5 days of drug discontinuation (after a median of 1 day). They did not recur in the following cycles after per protocol APR 246 dose reductions.
Conclusion : In this very high-risk elderly population of TP53m MDS and AML, generally with complex karyotype, a promising 56% CR rate at 6 cycles was reached in the evaluable population with AZA+ APR 246 combination, with deep molecular remission in all CR patients. We observed manageable neurologic AEs, mainly in elderly patients with reduced renal function, who therefore require close monitoring and dose reduction if necessary. An update regarding safety and efficacy in the 53 patients, including survival data, will be available at the meeting. A phase III international trial comparing AZA alone and AZA+ APR 246 in TP53m MDS is ongoing.
Cluzeau: Abbvie: Consultancy; Jazz Pharma: Consultancy; Menarini: Consultancy. Peterlin:AbbVie Inc: Consultancy; Astellas: Consultancy; Jazz Pharma: Consultancy; Daiichi-Sankyo: Consultancy. Recher:Daiichi-Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; chugai: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stamatoullas:Celgene: Honoraria; Takeda: Consultancy. Berthon:JAZZPHARMACEUTICAL: Other: DISCLOSURE BOARD; CELGEN: Other: DISCLOSURE BOARD; PFIZER: Other: DISCLOSURE BOARD. Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Ades:Amgen: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Fenaux:Celgene Corporation: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Aprea: Research Funding.
| v2 |
2021-11-25T16:13:50.558Z | 2021-11-05T00:00:00.000Z | 244551890 | s2ag/train | Evaluation of International Working Group 2006 Response Criteria in Patients with Higher-Risk Myelodysplastic Syndromes (HR-MDS) Treated with Hypomethylating Agent Monotherapy in the Frontline Setting
Introduction: Monotherapy with hypomethylating agents (HMA) remains the standard of care for patients (pts) with myelodysplastic syndromes (MDS). Response in MDS is based on the modified International Working Group (IWG) 2006 criteria. Prior studies focusing on unselected MDS pts showed that achieving a complete remission (CR) was associated with favorable overall survival (OS). However, the association of other outcomes with OS was less clear and only 20% of HMA-treated MDS pts achieve a CR. For example, pts who achieved <5% bone marrow (BM) blasts are currently classified as marrow CR (mCR), which has not been associated with OS improvement. Therefore, interpreting the significance of mCR reported in various clinical trials is challenging. Clinically meaningful reduction in bleeding or infectious complications can occur at improvements in absolute neutrophil count (ANC) and platelet counts that do not meet the current thresholds used for CR (ANC ≥1.0 × 10 9/L, platelets ≥100 × 10 9/L, and Hb >11 g/dL). To avoid missing clinically meaningful benefits when studying new drugs in clinical trials, a clearly defined response criterion that is less stringent than CR but still captures clinically meaningful hematologic improvement (HI) is needed. Here we sought to evaluate the impact of current IWG 2006 response criteria as well as CRh on OS of pts with HR-MDS treated with frontline HMA monotherapy.
Methods: We included all adult (≥18 years) MDS pts treated with frontline HMA (azacitidine [AZA], decitabine [DEC], or ASTX727) monotherapy between 1/1/2012 and 12/31/2020 at Yale University. We decided to use HMA monotherapy as it is the standard care for HR-MDS and to minimize the impact of therapy choice confounding the association of achieved response with OS. Pts were excluded if they received prior treatments for MDS aside from erythropoiesis-stimulating agents and if no baseline with at least one follow-up BM study were available for response assessment. We collected patient and disease characteristics (transfusion burden, IPSS/IPSS-R score, cytogenetics, molecular studies) at baseline. Best responses were assessed based on IWG 2006 criteria for MDS. We defined CRh as <5% BM blasts, platelets ≥50 × 10 9/L, ANC ≥0.5 × 10 9/L and no peripheral blood blasts. We followed pts until death or last follow-up and recorded dates of allogeneic hematopoietic cell transplant (HCT) if applicable. Date of data cut-off for survival status was 5/31/2021.
We performed Kaplan-Meier analysis to estimate the duration of overall survival and we used log rank test to test the difference in OS between subgroups of pts. Multiple comparisons were adjusted using the Bonferroni method.
Results: A total of 100 pts was included in this analysis (Table 1). Median age was 68 years (yrs; range, 23 - 86), 60% were males, and 79% and 18% of pts received AZA and DEC, respectively. Median number of HMA cycles was 6 (interquartile range [IQR]: 4-10), and 33 pts (33%) underwent HCT. During follow-up, 46 pts (48%) progressed to AML. At a median follow-up of 1.5 yrs (IQR: 0.9 - 2.3 yrs), median OS for the entire pt cohort was 1.9 yrs (Figure 1). OS by response category is shown in Table 2. Median OS was not reached for patients who achieved a CR (95% CI: not reached [NR] - NR) as compared to 1.9 yrs (95% CI: 1.5 yrs - NR) and 2.0 yrs (95% CI: 1.2 yrs - NR) among pts with mCR + HI and mCR without HI, respectively. Median OS among patients with stable disease (SD) was similar (2.0 yrs [95% CI: 1.5 yrs - NR]). Finally, we explored the prognostic value of CRh and found a median OS of 1.9 yrs (95% CI: 1.5 yrs - NR), which appeared comparable to mCR +/- HI or SD. Similar results were found with censoring at time of HCT (Figure 2).
Discussion: In this retrospective analysis of MDS pts treated with HMA monotherapy in the frontline setting, achieving CR as best response was associated with improved OS compared with mCR +/- HI and SD. However, as the numbers were small these results should be interpreted with caution, and other clinically relevant outcomes such as freedom of transfusion, infectious or bleeding complications, and patient-reported outcomes were not captured in the current analysis. Our results also apply only to MDS pts treated with HMA monotherapy in the frontline setting. The prognostic implications of CRh need to be evaluated in larger patient cohorts. To overcome these limitations, we are currently in the process of expanding the study to a much larger multi-center, international analysis.
Figure 1 Figure 1.
Neparidze: Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding; Janssen: Research Funding. Shallis: Curis: Divested equity in a private or publicly-traded company in the past 24 months. Podoltsev: PharmaEssentia: Honoraria; Pfizer: Honoraria; CTI BioPharma: Honoraria; Blueprint Medicines: Honoraria; Incyte: Honoraria; Bristol-Myers Squib: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Brunner: GSK: Research Funding; Aprea: Research Funding; Keros Therapeutics: Consultancy; Agios: Consultancy; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Acceleron: Consultancy; Takeda: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; Janssen: Research Funding. Zeidan: AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; Epizyme: Consultancy; Amgen: Consultancy, Research Funding; BioCryst: Other: Clinical Trial Committees; Incyte: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Acceleron: Consultancy, Research Funding; Agios: Consultancy; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Genentech: Consultancy; Jasper: Consultancy; ADC Therapeutics: Research Funding; Jazz: Consultancy; Astex: Research Funding; Daiichi Sankyo: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Aprea: Consultancy, Research Funding; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Geron: Other: Clinical Trial Committees; AstraZeneca: Consultancy; Pfizer: Other: Travel support, Research Funding; BeyondSpring: Consultancy; Ionis: Consultancy; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Janssen: Consultancy; Astellas: Consultancy.
| v2 |
2019-08-17T13:58:46.304Z | 2006-07-15T00:00:00.000Z | 220557290 | s2ag/train | CALCINEURIN INHIBITOR (CNI) AVOIDANCE VS STEROID AVOIDANCE FOLLOWING KIDNEY TRANSPLANTATION: POSTOPERATIVE COMPLICATIONS.
Abstract# 1257 Poster Board #-Session: P52-I 1257 Poster Board #-Session: P52-I CALCINEURIN INHIBITOR (CNI) AVOIDANCE VS STEROID AVOIDANCE FOLLOWING KIDNEY TRANSPLANTATION: POSTOPERATIVE COMPLICATIONS. David Shaffer, A Tarik Kizilisik, J Harold Helderman, Anthony J Langone, William A Nylander, Irene Feurer, Heidi M Schaefer. Division of Kidney and Pancreas Transplantation, Vanderbilt University Medical Center, Nashville, TN; Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN; Vanderbilt Transplant Center, Vanderbilt University Medical Center, Nashville, TN. Aim: Calcineurin inhibitors (CNI) and steroids have been the cornerstone of immunosuppression post-kidney transplant. Both however have numerous shortand long-term adverse effects. We compared post-operative complications following kidney transplantation with a CNI-free versus a steroid-free maintenance protocol. Methods: We compared two prospective, sequential but non-randomized groups of primary cadaver or non-HLA identical kidney transplant recipients treated with either: CNI avoidance (SRL 5 mg QD beginning POD#3 (target level 8-12 ng/ml), MMF 1 gm BID, and prednisone tapered to 10 mg QD at 3 mos) or steroid avoidance (3-day Solumedrol taper then no steroids, TAC 0.075 mg/kg BID (target level 8-12 ng/ml), MMF 1 gm BID). All patients received Thymoglobulin induction 6 mg/kg total dose. Results: 41 pts (16 CAD, 25 LD) received CNI avoidance and 39 (17 CAD, 22 LD) steroid avoidance. Age, race, gender, transplant type, CMV status, BMI, and CIT were not different between groups. HLA Ag MM was lower in steroid avoidance group (2.7 vs 3.4, p=0.005). Results CNI avoidance Steroid avoidance p value (n=41) (n=39) F/U d, mean (range) 422 (683-194) 167 (248-99) Patient survival 95% 100% Graft survival 92% 100% BPAR 5 (12%) 2 (5%) ns Lymphocele 0 0 Ureteral stenosis/leak 0 1 Wound dehiscence (operative) 1 0 Wound seroma (non-operative) 6 6 PTDM 6 (21%) 0 0.025 Viral infections (BK, CMV) 0 0 Discontinue study med 7 (17%) 3 (8%) ns 7 pts were switched from SRL to CNI [rejection (3), anemia (1), pulmonary toxicity (2), leukopenia (1)]. 3 pts resumed prednisone in steroid avoidance group. There was 1 post-biopsy bleed leading to graft loss and 2 deaths with functioning grafts due to malignancy in CNI avoidance group. 1 pt in steroid avoidance group had a pulmonary embolus requiring warfarin. Conclusions: Both groups had comparable BPAR and surgical and wound complications. SRL-based CNI avoidance pts had significantly more PTDM and a trend toward more drug-related toxicity resulting in discontinuation compared to steroid avoidance pts. Whether either regimen improves long-term graft or patient outcomes awaits longer follow-up. Abstract# 1258 Poster Board #-Session: P53-I 1258 Poster Board #-Session: P53-I PARADOXICAL RESPONSE TO TACROLIMUS ASSESSED BY IL2 GENE EXPRESSION. Enas A El-Safa, Salim Fredericks, Iain MacPhee, Atholl Johnston, David W Holt. Clinical Pharmacology, Barts and The London, London, United Kingdom; The Analytical Unit, St George’sUniversity of London, London, United Kingdom; Renal Medicine, St George’s-University of London, London, United Kingdom. New immunosuppressant drugs have improved efficacy and reduced side effects but have not been matched by improvements in methods of monitoring. The calcineurin inhibitors (CNIs), ciclosporin and tacrolimus are potent immunosuppressant drugs used following organ transplantation to prevent rejection. Inhibition of the production of IL-2 is one of the main actions of CNIs. In this study we attempted to demonstrate the interindividual variation in the response to tacrolimus by assessing IL-2 mRNA expression in healthy volunteers and renal transplant patients. Whole blood samples from 16 healthy volunteers were cultured. Samples were incubated for 24 hours , in the presence of 1mg/L anti CD3 and anti CD28 monoclonal antibodies to stimulate in vitro lymphocyte proliferation. Each sample was split into 2 aliquots and pre-incubated for 2 hours with and without tacrolimus (25μg/L). An identical procedure was performed on 7 blood samples from renal transplant patients before transplantation. Total RNA was isolated and IL-2 mRNA was quantified using RT-PCR. In the healthy volunteer samples, the copy number of IL-2 mRNA was suppressed by the presence of tacrolimus in most of the cases. 11of the 16samples treated with tacrolimus demonstrated attenuation of IL-2 mRNA expression ranging from 27 to 83% compared with control. A paradoxical increase, ranging from 157 to 265% was observed in the remaining 5 samples. In patient samples, there was up regulation ranging from 155 to 375% of IL-2 mRNA in 2 samples and after transplantation these patients developed acute rejection. One of the 5 remaining samples showed minimal reduction of IL-2 mRNA of 10% while the other 4 showed marked inhibition ranging from 32 to 77 %. These 5 patients had no rejection episodes. In this study we have noted an up-regulation of IL-2 mRNA in some samples incubated with tacrolimus. This paradoxical effect of CNIs could contribute to inter-individual variation in efficacy and demonstrate that individuals differ with respect to their sensitivity to CNIs. The variable in vitro response to tacrolimus has important implications for immunosuppressive therapy. Patients who are less responsive or resistant to this drug may be at risk of graft rejection. The approach described here could be used to assess a patient’s response to CNIs prior to transplantation. Abstract# 1259 Poster Board #-Session: P54-I 1259 Poster Board #-Session: P54-I RAPAMYCIN-INDUCED PROTEINURIA: INCIDENCE, OUTCOME AND THERAPEUTIC HANDLING. Helady S Pinheiro, Adriano M Braga, Thalita A Amaro, Marcus G Bastos. NIEPEN – Nephrology Division, Federal University of Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil. We performed a retrospective and cross-sectional study to evaluate the incidence, outcome, and management of proteinuria in 31 renal transplant recipients converted to Rapamycin (RAPA). All patients received RAPA immediately after stopping either the calcineurin inhibitor or the antiproliferative medication. We did not observe any acute rejection episodes after this “stop and go” regimen. Chronic glomerulonephrites (74.1%) was the most frequent etiology of chronic kidney disease. Most patients (87.1%) were previously biopsied and chronic allograft nephropathy (58.1%) and calcineurin inhibitors toxicity (51.6%) were the mean reasons for the conversion. RAPA-induced proteinuria (RIP) was defined as the occurrence of urinary protein ≥ 300mg/day or any further increase in protein loss in those patients who had already previously showed this level of proteinuria. | v2 |
2020-02-20T09:09:35.974Z | 2019-11-13T00:00:00.000Z | 214342060 | s2ag/train | Resistance to Acalabrutinib in CLL Is Mediated Primarily By BTK Mutations
Introduction
Acalabrutinib (A) is a selective, second-generation irreversible Bruton's Tyrosine Kinase inhibitor (BTKi) that has shown outstanding clinical activity in chronic lymphocytic leukemia (CLL) and other hematologic malignancies. Acquired resistance to the first-generation BTKi, ibrutinib (I), is mediated most commonly by C481S mutations in BTK, which decrease binding affinity and change binding from irreversible to reversible. The mechanism of resistance to A has not been investigated.
Patients and Methods
All patients (pts) treated at The Ohio State University and enrolled on an IRB approved phase 1b/2 study in CLL were included in this analysis. Beginning 12 months (mos) after the initiation of A, pts underwent deep sequencing every 3-6 cycles using a digital droplet PCR assay for BTK C481S or Ion Torrent Sequencing for any BTK or PLCG2 mutations. At relapse, samples from each pt underwent full BTK and PLCG2 sequencing. Correlation between baseline characteristics and relapse was assessed using proportional sub-distribution hazards model, pts who were still on treatment were censored at last follow-up.
Results
105 pts were included in this analysis. 38 (36%) were treatment-naïve (TN), 50 (48%) were relapsed/refractory (RR), and 17 (16%) were previously intolerant of I (intol). The median age was 62 (range 33-84) and median number of prior therapies was 1 (range 0-11). The pts were generally high-risk, with 66% having unmutated IGHV, 24% with del(11)(q22.3), 15% with del(17)(p13.1), and 28% with complex karyotype (≥ 3 abnormalities). With a median follow-up of 47.5 mos (range 37.7-58.5) 30% of pts (n=31) have discontinued therapy, 17 for progression of disease (CLL in 16 pts, Richter's transformation in 1), and 14 for other reasons.
Cumulative incidence rate (CIR) of progression varied significantly by cohort. At 12 mos, CIR of progression ranged from 0% in both the TN and RR cohorts to 11.8% (95% CI 1.8-32%) in those who were intol. By 36 mos, CIR of progression was 5.3% (95% CI 0.9-15.7%) in TN cohort, 6% (95% CI 1.5-15%) in the RR cohort, and 35.3% (95% CI 13.7-58%) in the intol cohort (Figure 1).
In univariable analysis, higher risk of progression was associated with del(17)(p13.1) on baseline FISH (p<0.0001), number of prior therapies (p=0.009), female sex (P=0.01), increased baseline LDH (p=0.02), and presence of Myc abnormality on baseline FISH (p=0.05). Treatment status was associated with risk of progression as well, where TN pts had a similar risk to RR, but intol pts had a higher risk of progression (p=0.02). In multivariable analysis, del(17)(p13.1) (p=0.01) and sex (p=0.03) remained significantly associated with risk of progression after accounting for other variables. When taking into account total time of BTKi exposure, there was no statistically significant increased risk of progression for intol pts (p=0.13), however, at 48 mos of BTKi exposure, those who were only treated with A had a CIR of progression of 17.3% (95% CI: 7.9-29.6%), while those who switched BTKi had a CIR of 36% (95% CI 13.8-59.1%).
All 16 pts with CLL relapse had a sample evaluated for BTK C481S at relapse, and 14 had samples evaluated for full BTK and PLCG2 mutations using Ion Torrent deep sequencing. BTK C481 mutations were found in 11/16 (69%; C481S in 10, C481R and C481Y in 1). One pt with a BTK C481S mutation also had a BTK T474I gatekeeper mutation, and one had co-existing C481R mutation. Two pts with BTK C481S mutations had co-existing PLCG2 mutations previously associated with I resistance at <3% VAF.
103/105 pts were screened every 3-6 cycles for BTK mutations. 22 pts have had mutations detected at a median of 31.6 mos from A initiation. TN and RR pts had median time to mutation of 38.8 and 32.9 mo, respectively. For intol pts median time to mutation detection was 24.8 mos from start of A, 33.8 mos from start of any BTKi. Median time from BTK mutation detection to clinical relapse is 12 mos (95% CI: 4.8-not reached), with no significant difference among cohorts in time from mutation to disease progression.
Conclusions
Here we show for the first time that CLL relapse on A is mediated predominantly by mutations in BTK similar to I. While not unexpected, this is significant as resistant patterns could be different given the more selective nature of A as well as potentially higher BTK occupancy over time due to twice daily dosing. Monitoring for BTK resistance offers the opportunity to intervene clinically before symptomatic disease.
Woyach: Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Rogers:AbbVie: Research Funding; Acerta Pharma: Consultancy; Genentech: Research Funding; Janssen: Research Funding. Bhat:Janssen: Consultancy; Pharmacyclics: Consultancy. Grever:Acerta Pharma, LLC: Membership on an entity's Board of Directors or advisory committees. Lozanski:Boehringer Ingelheim: Research Funding; Beckman Coulter: Research Funding; Stemline Therapeutics Inc.: Research Funding; Genentec: Research Funding. Byrd:Ohio State University: Patents & Royalties: OSU-2S; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Genentech: Research Funding; Genentech: Research Funding; Acerta: Research Funding; Acerta: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; BeiGene: Research Funding.
| v2 |
2018-04-03T02:23:39.527Z | 2012-04-01T00:00:00.000Z | 33396360 | s2ag/train | 2012 integrative healthcare symposium: treating the pain of lyme disease and adopting lifestyle change as therapy.
Chronic Lyme disease is a symptom complex of borrelial organisms and multiple co-infections with bacteria involving Borrelia burgdorferi, Anaplasma phagocytophilium, Ehrlichia chaffeensis, Babesia, piroplasms and other parasites, Bartonella, Mycoplasma, and Rickettsia. Additional sources of infection include other bacteria and viruses that are now widespread in ticks. In the mid-1990s, Krause et al. noted that multiple co-infections may suppress the immune system or may cause a nonspecific stimulation of the immune system, leading to inflammation, pain, and immune dysfunction.1
In 2009, Dr. Horowitz suggested that the term multiple chronic infectious disease syndrome (MCIDS) would more precisely describe patients with longstanding borrelial infection and co-infections who are experiencing chronic fatigue, muscle and joint pain, neuropathy, and neuropsychiatric abnormalities. In these patients, he said, multiple overlapping etiologic factors are responsible for their symptoms.
After commenting that his typical patient has already been seen by 15 to 20 specialists, Dr. Horowitz outlined an integrative approach, based on addressing “the 3 I’s” (infection, immunity, and inflammation) and on using a differential diagnosis model including evaluation of neurotoxicity; allergies; nutritional and enzyme deficiencies; psychological factors; viruses; and endocrine and gastrointestinal disorders.
First among the remedial steps, treating infection demands a strategy for combatting all three subtypes of B. burgdorferi infection, including cell wall, cystic, and intracellular forms.
“If you treat all three forms, you’ll generally have much better results than using one drug at a time,” Dr. Horowitz commented.
Both acute and chronic pain may be manifestations of chronic Lyme disease and MCIDS. Lyme disease, its co-infections, viruses, and opportunistic infections, such as Candida, may be responsible for driving chronic pain syndromes.
“Chronic Lyme disease and MCIDS,” Dr. Horowitz said, is the “great imitator.2–5 Under its commodious umbrella lies a host of pain syndromes, including symptoms of chronic fatigue and fibromyalgia, autoimmune disease, neurological pain (headache, migraine, trigeminal neuralgia, radiculopathy, encephalopathy, cranial nerve palsies, carpal tunnel/ulnar neuropathy), gastrointestinal disorders (irritable bowel syndrome, inflammatory bowel disease), genitourinary disorders (interstitial cystitis), gynecological disorders (dyspareunia, neuralgia), cardiac disorders (costochondritis, pericarditis, palpitations), psychogenic disorders (depression, psychosis, obsessive–compulsive disorder, anxiety-related pain), endocrine disorders (early andropause, irregular menses, low growth hormone levels, pituitary failure), and ophthalmological disorders (conjunctivitis, uveitis, retinitis, optic neuritis).
The infecting agents cause inflammation through various pathways such as interleukin-1 (IL-1), IL-6, tumor necrosis factor–alpha (TNF-α), nitric oxide, and its metabolites, thereby creating free radicals and oxidative stress, which damage cell membranes, mitochondria, and nerve cells. Autoimmunity may also result when antibodies cross-react with tissue antigens. Mitigating these effects requires multiple strategies, including:
treating infection, immunity, and inflammation (the 3 I’s).
supporting detoxification pathways in the liver, skin, kidneys, and lymph system.
balancing hormones.
addressing nutritional deficiencies, food allergies, and sleep disorders.
eliminating environmental triggers, such as heavy metals (a further source of inflammation).
Dr. Horowitz summarized the pain-relieving strategies that he developed while treating more than 12,000 patients with Lyme disease with overlapping chronic fatigue and fibro-myalgia syndromes.
“It is the cytokines that are really driving the pain,” he said.
In attempts to identify the source of the patient’s pain, a multifaceted approach with the 15-point model works best.
“Usually, the sickest patients require a combined approach using pharmaceuticals and nutraceuticals,” he added.
Referring to some classical treatment recommendations, Dr. Horowitz said that nonsteroidal anti-inflammatory drugs (NSAIDs) might be effective for muscle and neuropathic pain. Antidepressants that block norepinephrine uptake are usually more effective than those that inhibit serotonin. Combinations of tricyclic antidepressants and gabapentin (Neurontin, Pfizer), with or without opioids, improve analgesia at lower doses compared with single analgesics alone. Intravenous (IV) immunoglobulin is the treatment of choice for small-fiber neuropathy. Minimally invasive, often successful techniques for refractory pain include electronic stimulators, pulsed radio-frequency, and botulinum toxin A.
As for integrative pain therapies, Dr. Horowitz said that low-dose naltrexone (ReVia, Duramed) has proved effective in Crohn’s disease, multiple sclerosis, and fibromyalgia. In his open-label study of 500 patients with Lyme disease and MCIDS, approximately 75% of patients experienced less fatigue, myalgia, and arthralgia when the naltrexone dose was titrated to 4.5 mg at bedtime.
For the patient with a stimulated immune system that produces inflammatory cytokines, alpha-lipoic acid (ALA), glutathione, the phenol resveratrol, and curcumin have been found to relieve pain, fatigue, and “brain fog.” When cytokine levels are too high, IV or oral glutathione—a therapy that is often underused—is very safe. Compounding pharmacies, Dr. Horowitz offered, could combine resveratrol, curcumin, and ALA to decrease cytokine levels. To avoid systemic effects in patients needing therapy for localized pain, he suggested that dimethyl sulfoxide (DMSO), along with these agents and others (e.g., low-dose naltrexone, glutathione, and anti-inflammatories) could be absorbed into creams.
Angiotensin-receptor blockers (ARBs) reduce TNF-α levels and may be useful for persistent inflammation, especially if the inflammation is associated with uncontrolled hypertension.
Anti-inflammatory foods, such as those in the Mediterranean diet (fruits, vegetables, fish, and whole grains), or very-low-carbohydrate diets with small, frequent meals may be helpful in reducing inflammatory responses for patients with metabolic syndrome and insulin resistance.
The herbs Andrographis paniculata, Polygonum cuspidatum (resveratrol extract), Stephania tetranda root, and Smilax rotundifolia (common greenbriar) all have strong scientific backing in patients with ongoing symptoms and inflammation, Dr. Horowitz said.
Nuclear factor (erythroid-derived 2)-like 2 induces the expression of genes for several antioxidant enzymes and may help to regulate oxidative stress. Because acute and chronic episodes of psychological stress can induce inflammatory processes,6 stress reduction through meditation, yoga, or Tai Chi is also recommended.
Dr. Horowitz concluded that treating the three forms of B. burgdorferi, co-infections, hormonal abnormalities, heavy metals, neurotoxins, sleep disorders, psychiatric problems, and nutritional deficiencies is the best way for patients to regain their health and to decrease pain.
“Most conventional practitioners don’t believe that Lyme disease exists in chronic form, because they think the blood tests are reliable when they come up negative. But ELISA [enzyme-linked immunosorbent assay] is unreliable; you need a Western blot looking at the Lyme-specific bands from a good lab,” Dr. Horowitz said. | v2 |
2020-12-10T09:08:08.159Z | 2020-12-02T00:00:00.000Z | 236821260 | s2ag/train | Chemotherapy De-Escalation Using an 18F-FDG PET/CT–Based, Pathologic Response–Adapted Strategy in HER2-Positive Early Breast Cancer: The PHERGain Trial
Background: Several de-escalation approaches are under investigation in patients with HER2-positive early breast cancer (EBC). We assessed early metabolic responses to neoadjuvant trastuzumab and pertuzumab (HP) using 18F-FDG PET/CT (FDG-PET) and the possibility of chemotherapy de-escalation using a response–adapted strategy.
Methods: PHERGain is a randomised, open-label phase 2 trial conducted in 45 centres from seven European countries. Patients aged ≥18 years with FDG-PET–evaluable, centrally confirmed HER2-positive EBC were randomly allocated (1:4) to receive docetaxel (T), carboplatin (C), and HP (arm A) or HP±endocrine therapy (arm B). Randomisation was stratified by hormone receptor status. Centrally reviewed FDG-PET was performed with pre-randomisation and after two treatment cycles. Arm A patients completed six cycles regardless of FDG-PET results. Arm B/FDG-PET–responders continued HP±endocrine therapy for six cycles; arm B/FDG-PET–nonresponders switched to six cycles of TCHP. Co-primary endpoints were the percentage of arm B/FDG-PET–responders with pathologic complete response (pCR) in the breast and axilla (ypT0/is ypN0) and 3-year invasive disease-free survival (iDFS) of arm B patients.
Findings: Between 26 June 2017 and 24 April 2019, 356 patients were randomly assigned to arm A (n=71) or arm B (n=285). pCR occurred in 41 patients in arm A (57.7%, 95% Confidence Interval (CI) 47.4–69.4%) and 101 in arm B (35.4%, 95% CI 29.9–41.3%). Among arm B patients, 227 (79.6%) were FDG-PET–responders, 86 (37.9%, 95% CI 31.6–44.5%) of whom obtained pCR. No new safety signals were identified. Global health status declined ≥10% in 65.0% and 35.5% of patients in arms A and B, respectively.
Interpretation: FDG-PET identified HER2-positive EBC patients likely to benefit from chemotherapy-free dual HER2 blockade with HP and a reduced impact on global health status. Depending on iDFS results, this strategy could select patients not requiring chemotherapy.
Trial Registration: This trial is registered with EudraCT (2016-002676-27) and ClinicalTrials.gov (NCT03161353).
Funding Statement: The study was conceived and designed by Medica Scientia Innovation Research (MEDSIR) in collaboration with F. Hoffmann-La Roche Ltd, which funded the study and provided the study drugs. MEDSIR, as legal sponsor of the study, is responsible for compliance with all clinical and regulatory procedures and adherence to the study protocol.
Declaration of Interests: JMP-G reports to have a consulting role for Roche and Lilly, and travel expenses from Roche. GG reports research funding to the Institution from Roche and that an immediate family member received personal fees from Roche outside the submitted work. MRB reports to have a consulting role for Novartis, Pfizer, MSD, and to be part of speaker bureau for Pfizer, Novartis, Roche, Lilly, Astrazeneca. AS reports to have a consulting role for Roche and EISAI, to be part of speaker bureau for Roche and EISAI, expert testimony for ESIAI and Roche, and travel expenses from Roche and Pfizer. BB reports to have a consulting role for Genentech and MSD, to be part of speaker bureau for Genentech, and travel expenses from Pfizer. SE-de-R reports to have a consulting role for Roche, Pierre-Fabre, Eisai, research funding from Synthon and Roche, and travel expenses from Roche, Pierre-Fabre, and Daiichi Sankyo. AP reports honoraria from Pfizer, Novartis, Roche, MSD Oncology, Lilly, Daiichi Sankyo, Amgen, to have a consulting role for Amgen, Roche, Novartis, Pfizer, Brystol-Myers Squibb, Boehringer, PUMA Biotechnology, Oncolytics Biotech, Daiichi Sankyo, Abbvie, NanoString Technologies, research funding to the Institution from Roche, Novartis, Incyte, PUMA Biotechnology, to have intellectual property (PCT/EP2016/080056: HER2 AS A PREDICTOR OF RESPONSE TO DUAL HER2 BLOCKADE IN THE ABSENCE OF CYTOTOXIC THERAPY; WO/2018/096191. Chemoendocrine score (CES) Based on PAM50 for breast cancer with positive hormone receptors with an intermediate risk of recurrence), travel expenses from Daiichi Sankyo, other relationship with Oncolytics, Peptomyc S.L., and that an immediate family member is an employee of Novartis. MC reports to have a consulting role for Pierre-Fabre, Pfizer, OBI Pharma, Celldex, AstraZeneca, and honoraria from Novartis. NA reports to have a consulting role for Pfizer, Novartis, Roche, AstraZeneca, and Lilly, and travel expenses from Pfizer, Novartis, Roche, and AstraZeneca. MS-C reports honoraria from MEDSIR, Syntax for Science, and Nestle, to have a consulting role for MEDSIR, Syntax for Science, and Nestle, to be part of speaker bureau for MEDSIR, Syntax for Science, Roche, research funding from MEDSIR, Syntax for Science, and Roche, and travel expenses from MEDSIR, Syntax for Science, and Roche. AM is a full-time employee of MEDSIR. JC reports to have a consulting role for Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, Merck Sharp&Dohme, GSK, Leuko, Bioasis, and Clovis Oncology, honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp&Dohme, and Daiichi Sankyo, research funding to the Institution from Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman-La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, and Queen Mary University of London, and intellectual property for MEDSIR. AL-C reports leadership for Eisai, Celgene, Lilly, Pfizer, Roche, Novartis, and MSD, intellectual property for MEDSIR and Initia-Research, to have a consulting role for Lilly, Roche, Pfizer, Novartis, Pierre-Fabre, GenomicHealth, and GSK, to be part of speaker bureau for Lilly, AstraZeneca, and MSD, research funding from Roche, Foundation Medicine, and Pierre-Fabre, Agendia, and travel expenses from Roche, Lilly, Novartis, Pfizer, and AstraZeneca. LC, NR, NM, CA, FD, and KK have nothing to declare.
Ethics Approval Statement: This study was performed in accordance with guidelines of the International Conference on 205 Harmonization and ethical principles outlined in the Declaration of Helsinki. Written informed 206 consent was obtained before enrolment, and all participants agreed to study-specific procedures. 207 Approvals from appropriate regulatory authorities and ethics committees were obtained. | v2 |
2018-12-18T08:43:19.052Z | 1999-01-01T00:00:00.000Z | 56399570 | s2ag/train | PLANKTONIC FORAMINIFERS FROM THE SUBPOLAR NORTH ATLANTIC AND NORDIC SEAS : SITES 980 – 987 AND 9071
During Ocean Drilling Program (ODP) Leg 162, five sites were drilled in the subpolar North Atlantic (Sites 980–984), three sites in the Nordic Seas (Sites 985–987), and two holes at Iceland Sea Site 907 (first drilled during ODP Leg 151). Carbonate sediments at the subpolar sites have generally common to abundant and well-preserved planktonic foraminifers, especially at Feni Drift Sites 980/981 and Rockall Plateau Site 982. Gardar Drift Site 983 and Bjorn Drift Site 984 featured greater concentrations of clay material and ice-rafted debris, diluting carbonate material in some intervals (particularly before ~1.8 Ma at Site 984). Nordic Seas Sites 907 and 985–987 feature generally rare to common and moderately well-preserved planktonic foraminifers only within the past 1 m.y., although Pliocene taxa are sparsely recorded at Site 986 on the Svalbard margin. Planktonic foraminifer datum levels are located to the section level where possible for the subpolar North Atlantic sites. Comparison to an integrated magnetostratigraphy and calcareous nannofossil stratigraphy shows that several datum levels are synchronous to within 5% of their published ages. In particular, the start of the Neogloboquadrina pachyderma (sinistral) Acme Zone (1.8 Ma), the first occurrence (FO) of Globorotalia inflata (2.09 Ma), the last occurrence (LO) of Globorotalia cf. crassula (3.3 Ma), and the FO of Globorotalia puncticulata (4.5 Ma) are judged synchronous in eastern sections of the subpolar North Atlantic. The LO of Neogloboquadrina atlantica (sinistral) occurs ~100–200 k.y. later relative to its mid-latitude North Atlantic age (2.41 Ma). t of the ore, enproene .g., anof iment gian r and reserer the ion s in nic one ne and 85) the und edare roore, and olar 84, dic 985– INTRODUCTION AND PREVIOUS WORK The subpolar North Atlantic is an important region in which to study late Neogene paleoceanographic and climatic change. The region is among the most sensitive to glacial–interglacial sea-surf temperature variations (e.g., CLIMAP, 1981) and has a major in ence on conversion of surface waters to deep waters and, hence global thermohaline circulation (e.g., Broecker and Denton, 198 Documenting tectonicto millennial-scale paleoceanographic cha es in this region associated with the late Neogene evolution of No ern Hemisphere glaciation is a major goal of Ocean Drilling Progr (ODP) Leg 162. The North Atlantic and Nordic Seas region sampled during L 162 ranges from temperate to polar waters. A southeast-northw transect of subpolar North Atlantic sites (Jansen, Raymo, Blum al., 1996) includes high sedimentation-rate locations on Feni D Bjorn Drift, and Gardar Drift (Fig. 1; Table 1). These high sedime tation-rate sites (drilled with the advanced hydraulic piston corer) low for detailed comparison of geographic synchroneity and as chroneity among planktonic foraminifer datum levels. Site 982 on Rockall Plateau reached lower Miocene sediments, providing a n ly complete Neogene sediment sequence for the subpolar North lantic. Together with sites from the Nordic Seas, these sites prov insights on subpolar North Atlantic paleobiogeography during t Neogene and the (a)synchroneity of planktonic foraminifer dat levels across the subpolar North Atlantic. Previous work in this region includes sites drilled on Deep S Drilling Project (DSDP) Leg 12 (Hayes, Pimm, et al., 1972), Leg (Talwani, Udintsev, et al., 1976), Leg 81 (Roberts, Schnitker, et 1984), and Leg 94 (Ruddiman, Kidd, Thomas, et al., 1987). Neog planktonic foraminifer paleobiogeography of the subpolar North A 1Raymo, M.E., Jansen, E., Blum, P., and Herbert, T.D. (Eds.), 1999. Proc. ODP, Sci. Results, 162: College Station, TX (Ocean Drilling Program). 2Department of Marine Science, University of South Florida, St. Petersburg, FL 33701, U.S.A. [email protected] ace flu, the 9). ngrtham eg est , et rift, nalynthe earAtide he um ea 38 al., ene tlantic shows progressive reduction in diversity and developmen endemic subpolar faunas in the late Miocene and continuing in late Pliocene (Berggren, 1972; Poore and Berggren, 1975; Po 1979; Huddlestun, 1984; Weaver, 1987; Raymo et al., 1987; Sp cer-Cervato et al., 1994). These changes are associated with the gressive cooling of the high northern latitudes during the Neog and the development of Northern Hemisphere glaciations (e Shackleton et al., 1984; Ruddiman, Kidd, Thomas, et al., 1987; J sen et al., 1988; Raymo et al., 1990). Whereas the subpolar North Atlantic featured the accumulation calcareous sediments throughout the Neogene, calcareous sed preservation in the Nordic Seas (Greenland, Iceland, and Norwe Seas) began much later, by ~1 Ma (Jansen et al., 1988; Spiegle Jansen, 1989; Spiegler, 1996). Because calcareous sediment p vation commenced within the Quaternary, planktonic foraminif faunas are dominated by Neogloboquadrina pachyderma (sinistral), although rare incursion of warmer water species is documented in Pliocene sediments of the Nordic Seas and Arctic Gateway reg (Spiegler and Jansen, 1989; Spiegler, 1996). The progressive development of cold surface-water condition the high-latitude North Atlantic has led to the need for two plankto foraminifer zonation schemes for the late Miocene to Holocene, for the subpolar North Atlantic (Weaver and Clement, 1986) and o for the Nordic Seas (Spiegler and Jansen, 1989). The tropical subtropical zonations (Blow, 1969, 1979; Bolli and Saunders, 19 have limited value in middle to high latitudes because many of warm-water forms on which these zonations are based are not fo at higher latitudes. Zonations for the upper Miocene to Holocene s iment sequence in the subpolar North Atlantic and Nordic Seas based mainly on species within the neogloboquadrinid and globo talid groups (Berggren, 1972; Poore and Berggren, 1975; Po 1979; Weaver and Clement, 1986, 1987; Weaver, 1987; Hooper Weaver, 1987; Spiegler and Jansen, 1989). In this study, the subp zonation of Weaver and Clement (1986) is used for Sites 980–9 including the upper Miocene to Holocene at Site 982. The Nor Seas zonation of Spiegler and Jansen (1989) is used for Sites 987 and 907. | v2 |
2018-12-15T05:05:30.747Z | 2007-01-01T00:00:00.000Z | 81627771 | s2ag/train | STUDIES ON PATHOLOGY OF SHEEP LUNG
In a developing agriculture based country like ours more than 70 crores of people are solely depend on agriculture and livestock and contributing more than 20% of G.D.P. annually. India ranks 6" among the countries of world with a population of 138.50 million sheep and Andrapradesh ranks IS' place in India with a sheep population of 21.37 millions. Lung infections are common in sheep, causing a great threat to the sheep rearing community. As disease problems severely cripples the production, a sound knowledge of common contagious or infectious diseases that accounts for morbidity and mortality in sheep become necessity. Keeping this in view, the present study on 'Studies on pathology of sheep lung' was undertaken to investigate various lung infections and isolation of bacteria those cause pneumonia in sheep and to know the ultra structural changes of pulmonary adenomatosis. Incidence of various types of pneumonia encountered were due bronchopneumonia (28%), pulmonary adenomatosis (9.8%), suppurative pneumonia (8.3%), interstial pneumonia (7.8%), fibrinous pneumonia (7.3%), Maedi (5.3%), pleuropneumonia (2.2%), hydatid cyst (1.26%), Sheep pox (1.0%), Tuberculosis (1 .OO/o), and neoplasm's like hemangioma and adenocarcinoma, noticed in two cases with an incidence of (0.5%) Bronchopneumonia was characterized by presence of moderate to severe infiltration of inflammatory cells, neutrophils and mononuclear cells in and around bronchioles and alveoli. Inter alveolar hemorrhages with mild edema of alveoli and peribronchial hemorrhages were seen. Pulmonary adenomatosis was characterized by papillary projections of epithelium into alveolar/ bronchiolar lumen. Fibrous tissue proliferation was seen. Metaplasia of alveolar epithelium leading to formation of glandular structures in alveoli was also evident. Suppurative pneumonia was characterized by areas of congestion, necrosis with calcification and presence of diffuse infiltration of inflammatory cells, mostly neutrophils and alveolar macrophages. Fibrous tissue proliferation was also evident. Interstitial pneumonia was characterized by thickened alveolar septa due to accumulation of serous and fibrinous exudates with infiltration of inflammatory cells like lymphocytes, macrophages and mononuclear cells in alveolar septa. In fibrinous pneumonia alveoli, bronchioles and bronchi were filled with sero fibrinous exudate. Infiltration of inflammatory cells like neutrophils and macrophages were seen along with edema, congestion and hemorrhages. Edema and widening of inter lobular septa was noticed in almost all cases with thickening of pleura. Maedi was characterized by hypertrophy and hyperplasia of bronchiolar epithelium. Peribronchiolar and perivascular infiltration with lymphocytes was most predominantly seen. Alveolar lumen contained desquamated epithelial cells. A thickened alveolar wall with interalveolar hemorrhages were also evident. xix Pleuro pneumonia was characterized by active hyperemia edema, congestion and hemorrhages with mild serous exudates along with mild infiltration of inflammatory cells like rnacrophages, lymphocytes and epitheloid cells. The pleura was thickened with fibrous tissue proliferation. Infiltration was very mild with neutrophiis and lymphocytes Tuberculosis was characterized by a granuloma with a central caseation and calcification surrounded by macrophages, epitheloid cells, lymphocytes, and Langhan's giant cells surrounded by fibrous covering. Other changes noticed were thickened pleura, sub pleural hemorrhages, pleural fibrosis and congestion. Hydatidosis was characterized by presence of mononuclear cells, eosinophils and plasma cell infiltration around the cystic space and surrounded by focal areas of fibrous tissue proliferation along with hemorrhages and congestion. Sheep pox was characterized by coagulative necrosis of the lobular tissue and infiltrated with the inflammatory cells mainly 'sheep pox' cells and macrophages and presence of serous exudate. The adjacent lung tissue showed congestion and infiltration with lymphocytes, neutrophils and macrophages. Neoplasms like hemangioma and adenocarcinoma were noticed in one case each. XX General pathological conditions encountered were pleuritis 2 (0.5%), bronchitis and bronchiolitis 15 (3.7%), bronchiectasis 2 (0.5%), bronchiolitis fibrosa oblitrans 2 (0.5%), pulmonary congestion and hemorrhages 17 (4.2%), pulmonary emphysema and atelectasis 16 (4.5%), pulmonary edema 16 (4.5%), pulmonary infarction 1 (0.2%), and anthracosis 1 (0.2%). Pleuritis was characterized by infiltration of inflammatory cells like neutophils and lymphocytes in the pleura and thickening of the pleura by edematous fluid. Bronchitis and bronchiolitis were characterized by presence of inflammatory cells like neutrophils, mononuclear cells and erythrocytes in the bronchi and bronchioles and these conditions were usually associated with bronchopneumonia. Widened lumen of bronchi contained mucus, large number of inflammatory cells, few erythrocytes. Bronchiolar wall was very thin and surrounded by fibrous tissue proliferation in bronchiectasis cases. Bronchiolitis fibrosa oblitranse was characterized by polypoid projections of bronchiolar epithelial and fibroblastic tissue, which was partially or completely, obliterated the lumen of bronchioles. H e m o m e s in the alveolar and bronchial spaces were noticed in pulmonary congestion and hemorrhages. Pulmonary emphysema was characterized by distended alveoli, widened interalveolar septa; few ruptured alveoli and atelectatic areas were characterized by cleft like alveoli with narrow lumen. Pulmonary edema was characterized by presence of edema fluid in the alveoli, interstitial tissue, interlobular septa and sub pleural zones and presence of compensatory emphysema and atelectatic changes. Pulmonary infarction revealed wedge or cone shaped hemorrhagic areas and presence of congestion, edema and atelectasis. Anthracosis was characterized by presence of black granules mostly in the alveolar walls and connective tissue septa of lung. In the present study 44 bacteria were isolated fiom 57 pneumonic ovine lungs. Pasteurella sps 10 (22.7%), E.coli 7 (1 5.9%), Corynebacterium sps 6 (13.6%), and Staphylococcus sps 6 (13.6%), were the major bacteria isolated. Stray cases of isolates were Streptococcus 3 (6.8%), Bacillus sps 2 (4.5%), Klebsiella sps 2 (4.5%), Proteus sps 2 (4.5%), Mjcobacterium 4 (9.0%), and Pseudomomis sps 2 (4.5%) cases. Major bacteria isolated fkom bronchopneumonia were Pastewella sps, followed by E-coli, Corynebacterium, and StaphyIococcal sps and from suppurative and fibrinous pneumonia cases, PasteureZla, E-coli. Corynebacterium were isolated. From pulmonary carcinoma, E. coli, Staphylococcus, Streptococcus was isolated and mycobacterium was identified in tuberculosis lung. Ultrastructurally, in all the cases of pulmonary adenomatosis proliferation of type I1 pneumocytes having microvilli, well-developed junctional complexes were noticed prominently. Mitochondria and endoplasmic reticulum were more numerous in type I1 penumocytes. In most of the cases mitochondria were well preserved with prominent cristae. Ciliated bronchiolar (Clara) cells with electron dense cytoplasmic granules without any surrounding membrane and microvilli were noticed. | v2 |
2021-11-25T16:07:14.862Z | 2021-11-05T00:00:00.000Z | 244539321 | s2ag/train | Utilization of a Targeted Next Generation Sequencing Assay to Identify Copy Number Alterations in Chronic Lymphocytic Leukemia and Monoclonal B-Cell Lymphocytosis
Introduction: Chronic lymphocytic leukemia (CLL) is characterized by multiple copy number alterations (CNA) and mutations that are central to disease pathogenesis, prognosis, risk-stratification, and identification of response or resistance to therapies. Fluorescence in situ hybridization (FISH) is gold standard in the clinical laboratory for detecting prognostic CNAs in CLL (e.g. deletion 17p13 (del(17p), deletion 11q23 (del(11q), deletion 13q14 (del(13q), and trisomy 12). Most clinical FISH assays have high specificity and sensitivity, but the technique can detect a limited number of alterations per assay. Importantly, next-generation sequencing (NGS) techniques have become more readily available for clinical applications and are increasingly being used for screening not only mutations, but also copy number abnormalities in multiple genes and chromosomal regions of interest in hematologic malignancies. Here, we evaluated the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) using a custom targeted NGS assay for detecting common prognostic chromosomal alterations in CLL and high-count monoclonal B-cell lymphocytosis (MBL), the precursor to CLL.
Methods : We designed a SureSelect DNA targeted sequencing panel, covering all exons of 59 recurrently CLL mutated genes and additional amplicons across regions affected by clinically relevant CNAs. All CLL (N=534) and MBL (N=162) patients had pre-treatment peripheral blood mononuclear cells (PBMC) collected within two years of diagnosis. DNA was extracted in cases with purity >80% of CD5+/CD19+ cells. Clinical FISH data was available within 100 days of NGS in all untreated CLL and MBL cases. PatternCNV was used to detect clinically relevant CNAs in chromosomes 11, 12, 13 and 17. We performed a principal component analysis on the CNA calls, excluding chromosomes 11, 12, 13, and 17 to identify clusters of samples. Each cluster was then independently rerun with PatternCNV and the results from chromosomes 11, 12, 13, and 17 were extracted and further analyzed. We excluded samples with low tumor metrics identified by FISH (less than 20% of cells with del(17p), del(11q), trisomy 12 and del(13q)).
Results: We sequenced a total of 696 patients of whom 162 were MBL and 534 were untreated CLL. The most commonly mutated genes were NOTCH1 (11.0%), TP53 (8.7%), SF3B1 (7.7%), ATM (4.1%), and CHD2 (3.8%). Based on CNA analyses from the NGS data, we identified 59 (9.1%) individuals with del(17p), 88 (13.4%) individuals with del(11q), 128 (20.0%) individuals with trisomy 12, and 329 (53.0%) individuals with del(13q). All 696 individuals had FISH panels conducted, with 39 (5.6%) individuals with del(17p), 68 (9.8%) individuals with (11q), 119 (17.1%) with trisomy 12, and 295 (42.4%) with del(13q). When we compared our CNA analyses with the FISH data, we found high concordance 95.0% for del(17p), 92.7% del(11p), 94.3% for trisomy 12, and 88.2% for del(13q). For del(17p) we found a sensitivity of 93.9%, specificity of 95.4%, PPV of 52.5%, and NPV of 99.7%. Del(11q) revealed a sensitivity of 88.1%, specificity of 94.0%, PPV of 59.1%, and NPV 98.8%. We found a sensitivity of 93.8%, specificity of 95.6%, PPV 82.0%, and NPV of 98.6% for trisomy 12 and for del(13q) we found a sensitivity of 92.6%, specificity of 90.9%, PPV of 91.7%, and NPV of 93.8%. We found lower PPVs in del(17p) and del(11q) likely due to lower prevalence of these chromosomal abnormalities.
Conclusion: Here we show a high sensitivity, specificity, and NPV when comparing targeted sequencing with FISH. FISH panel testing is widely used in clinical practice to characterize highly prognostic chromosomal abnormalities in CLL. Comprehensive genetic profiling with NGS has become increasingly important in the work up of hematologic malignancies and provides additional prognostic and predictive information, including clinically relevant mutations such as TP53, SF3B1, and NOTCH1, tumor mutation load and mutations associated with resistance to chemo-immunotherapy and targeted therapies, such as BTK or BCL2 inhibitors, that FISH cannot offer. We show that NGS can infer clinically relevant CNA in cases without FISH testing while also providing additional clinically relevant information.
Figure 1 Figure 1.
Cerhan: Regeneron Genetics Center: Other: Research Collaboration; Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; NanoString: Research Funding; Genentech: Research Funding. Parikh: Pharmacyclics, MorphoSys, Janssen, AstraZeneca, TG Therapeutics, Bristol Myers Squibb, Merck, AbbVie, and Ascentage Pharma: Research Funding; Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie: Membership on an entity's Board of Directors or advisory committees. Kay: Genentech: Research Funding; MEI Pharma: Research Funding; Sunesis: Research Funding; Acerta Pharma: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; CytomX Therapeutics: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Targeted Oncology: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Behring: Membership on an entity's Board of Directors or advisory committees.
| v2 |
2019-03-18T13:57:57.108Z | 2018-01-11T00:00:00.000Z | 80632001 | s2ag/train | Predictive Value of a Rapid Immunometric NycoCard D-dimer Assay for Acute Pulmonary Embolism (คุณค่าทางการพยากรณ์ของชุดตรวจสารโมเลกุลคู่ชนิดดี สำหรับการวินิจฉัยภาวะลิ่มเลือดอุดตันในหลอดเลือดแดงปอดเฉียบพลัน)
Background: The reported diagnostic performance of D-dimer assay for excluding pulmonary embolism (PE) vary widely. This study was carried out to assess the diagnostic performance of NycoCard D-dimer assay in suspected PE patients. Objective: To determine if a D-dimer assay can reliably exclude PE in patients with suspected PE. Methods: The patients evaluated for PE with a CT pulmonary angiography (CTPA) and D-dimer assay were eligible for inclusion. The electronic medical records of the patients were reviewed to analyze the diagnostic performance of NycoCard D-dimer assay for excluding acute PE. Collected data included the presence or absence of PE, D-dimer result and patient demographics. Results: A total of 229 consecutive patients underwent CTPA for acute PE and had a D-dimer measurement performed. Pulmonary embolisms were reported for 86/229 (37%) CTPAs. Overall, the D-dimer assay was found to have a sensitivity and specificity of 96.5% and 29.4%, respectively, for the diagnosis of PE, with a positive predictive value (PPV) and negative predictive value (NPV) of 45.1% and 93.3%, respectively. The negative predictive value in low or moderate clinical probability of PE is 95.5% (95% CI, 84.5% to 99.4%). The likelihood ratio associated with a negative D-dimer test result was 0.09 (CI, 0.02-0.38) Conclusions: A normal NycoCard D-dimer test result is useful in excluding PE when the clinical probability of the presence of PE is low or intermediate. An understanding of the physiological basis and limitations of D-dimer value may contribute to reduce its inappropriate use. ภมหลง : รายงานเกยวกบสมรรถภาพในการวนจฉยของการตรวจสารโมเลกลคชนดดในการวนจฉยภาวะลมเลอดอดตนในหลอดเลอดแดงปอดเฉยบพลน มความแตกตางกนมาก และชดตรวจสำเรจรปทใชในแตละสถานพยาบาลมความหลากหลายทงชนด และหลกการของชดตรวจแตละสถานพยาบาลควรประเมนสมรรถภาพในการวนจฉยของชดตรวจทใชในสถานพยาบาลตนเอง วตถประสงค : เพอประเมนสมรรถภาพในการวนจฉยของการตรวจสารโมเลกลคชนดดทใชในโรงพยาบาลมหาราชนครราชสมา ในการวนจฉยภาวะลมเลอดอดตนในหลอดเลอดแดงปอดเฉยบพลน วธการศกษา : ศกษาขอมลผปวยทไดรบการสงตรวจเอกซเรยคอมพวเตอรหลอดเลอดแดงปอดเพอการวนจฉยภาวะลมเลอดอดตนในหลอดเลอดแดงปอดเฉยบพลน และมผลการตรวจสารโมเลกลคชนดด ในโรงพยาบาลมหาราชนครราชสมา และนำมาวเคราะหทางสถต เพอประเมนสมรรถภาพในการวนจฉยของการตรวจสารโมเลกลคชนดดเพอการแยกโรคภาวะลมเลอดอดตนในหลอด เลอดแดงปอดเฉยบพลน ผลการศกษา : ศกษาผปวยจำนวน 229 ราย ทไดรบการสงตรวจเอกซเรยคอมพวเตอรหลอดเลอดแดงปอดเพอการวนจฉยภาวะลมเลอดอดตนในหลอดเลอดแดงปอดเฉยบพลน และมผลการตรวจสารโมเลกลคชนดดในโรงพยาบาลมหาราชนครราชสมา พบมผปวยทมภาวะลมเลอดอดตนในหลอดเลอดแดงปอดเฉยบพลนจำนวน86 ราย (รอยละ 37) ความไวและความจำเพาะของการตรวจสารโมเลกลคชนดด ในการวนจฉยภาวะลมเลอดอดตนในหลอดเลอดแดงปอดเฉยบพลนเทากบ รอยละ 96.5 และรอยละ 29.4 ตามลำดบ และมคาการพยากรณผลบวกและคาการพยากรณผลลบเทากบ รอยละ 45.1 และรอยละ 93.3 ตามลำดบอตราสวน ภาวะนาจะเปนเมอผลการการตรวจสารโมเลกลคชนดดเปนลบ เทากบ 0.09 สรป: การตรวจสารโมเลกลคชนดด โดยใชชดตรวจสำเรจรปทใชในโรงพยาบาลมหาราชนครราชสมา มประโยชนในการวนจฉยแยกโรคผปวยภาวะลมเลอดอดตนในหลอดเลอดแดงปอดเฉยบพลนกลมทมโอกาสเปนโรคจากการประเมนทางคลนกตำ หรอปานกลาง | v2 |
2020-02-20T09:09:36.471Z | 2019-11-13T00:00:00.000Z | 212889991 | s2ag/train | Ixazomib or Lenalidomide Maintenance Following Autologous Stem Cell Transplantation and Ixazomib, Lenalidomide, and Dexamethasone (IRD) Consolidation in Patients with Newly Diagnosed Multiple Myeloma: Results from a Large Multi-Center Randomized Phase II Trial
Background: Maintenance therapy with lenalidomide post-autologous stem cell transplantation (ASCT) has shown to improve progression-free survival (PFS) in multiple myeloma (MM), and has largely become the standard of care. However, toxicity leads to early discontinuation in nearly one-third of patients and additional options are needed (McCarthy, et al, JCO, 2017). Ixazomib is another maintenance option that has been shown to improve PFS; however, studies comparing lenalidomide and ixazomib are lacking. In this randomized phase 2 study, we analyzed the safety and efficacy of using lenalidomide and ixazomib as part of consolidation and maintenance therapies after ASCT (NCT02253316).
Methods: Eligible patients, age 18-70 with newly diagnosed MM undergoing ASCT during first-line treatment, were consented prior to ASCT. Approximately 4 months following ASCT, patients received 4 cycles of consolidation therapy with IRd [ixazomib 4 mg on days 1, 8 and 15 of a 28-day cycle, lenalidomide 15 mg on days 1 through 21, and dexamethasone 40 mg on days 1, 8 and 15]. Primary data on IRd consolidation were presented at ASH 2018 (Abstract 109920).
One month after the last consolidation cycle, patients were randomized (1:1) to maintenance therapy with single-agent ixazomib (4 mg on days 1, 8 and 15 of a 28-day cycle) or lenalidomide (10 mg daily months 1-3 followed by 15 mg for months 4+). The arms were stratified based on MRD-status post-consolidation. In total, 237 patients were enrolled from 10 US centers. This abstract coincides with planned interim analysis 3 which is the first comparison of ixazomib and lenalidomide maintenance. While the study was not powered to compare PFS between the two arms, the sample will provide a reasonable power to estimate non-inferiority. There is a planned stopping rule for non-inferiority set at a hazard ratio of >1.3 in favor of lenalidomide. Secondary end-points include MRD-negativity following 12 cycles and toxicity.
Results: At time of abstract submission, 215 patients had completed IRd consolidation and 191 had begun maintenance. 90 were randomized to ixazomib and 94 to lenalidomide. 7 patients were not randomized due to toxicity during consolidation; data from these patients are not included in the analyses. The characteristics of the two arms are summarized in Table 1.
Hematologic toxicity has been infrequent with ixazomib with neutropenia and thrombocytopenia occurring in 11% and 23% of patients. In comparison, neutropenia and thrombocytopenia occurred in 45% and 35% of patients on lenalidomide. The most common non-hematologic toxicities in both arms have been GI-related and infections, both expected events. 16% of patients on ixazomib have experienced Grade 3-4 non-hematologic toxicity compared to 34% on lenalidomide. No grade 3 or higher peripheral neuropathy has been reported in either arm.
11% of patients on ixazomib have discontinued due to toxicity and another 9% have required a dose reduction to 3mg. Lenalidomide toxicity has led to discontinuation in 15% of patients and another 12% were dose reduced to 5mg. Only 45% of patients receiving 4+ cycles of lenalidomide were able to titrate to the 15mg dose.
After a median follow-up of 11.2 months from randomization (19.7 months post-ASCT), 30% of patients on ixazomib have discontinued treatment due to disease progression. After a median follow-up of 12.3 months from randomization (20.2 months post-ASCT), 18% patients on lenalidomide have discontinued treatment due to disease progression.
Conclusion: Ixazomib and lenalidomide maintenance have been well tolerated to date. A comparison of PFS is currently being conducted as part of interim analysis 3 and final results will be presented, representing the first report directly comparing lenalidomide and ixazomib maintenance.
Table 1:
Vij: Genentech: Honoraria; Karyopharm: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria; Sanofi: Honoraria. Martin:Amgen, Sanofi, Seattle Genetics: Research Funding; Roche and Juno: Consultancy. Fiala:Incyte: Research Funding. Deol:Novartis: Other: Advisory board; Kite: Other: Advisory board; Agios: Other: Advisory board. Kaufman:Celgene: Consultancy; Winship Cancer Institute of Emory University: Employment; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Janssen: Honoraria; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; Takeda: Consultancy. Hofmeister:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Nektar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Imbrium: Membership on an entity's Board of Directors or advisory committees. Gregory:Poseida: Research Funding; Celgene: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau. Berdeja:AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding; Poseida: Research Funding; Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy. Chari:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Research Funding; GlaxoSmithKline: Research Funding; Novartis Pharmaceuticals: Research Funding; Oncoceutics: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Rosko:Vyxeos: Other: Travel support.
| v2 |
2019-07-18T20:35:19.000Z | 2010-01-01T00:00:00.000Z | 198156241 | s2ag/train | 100 Years Ago in the American Ornithologists' Union
The Auk, Vol. , Number , page . ISSN -, electronic ISSN -. by The American Ornithologists’ Union. All rights reserved. Please direct all requests for permission to photocopy or reproduce article content through the University of California Press’s Rights and Permissions website, http://www.ucpressjournals. com/reprintInfo.asp. DOI: ./auk.... In , just over General Notes were published in The Auk, and they were mostly a paragraph or less in length. Only dealt with something other than distributions of birds. New information was reported on birds from a total of states and three provinces, with Massachusetts having the most reports (), followed by Michigan (), New York (), Illinois (), Maine (), and New Jersey, Pennsylvania, North Carolina, Georgia, and Florida ( each). There was only one report from outside Canada and the United States: Charles T. Ramsden reported seeing three Bluewinged Teal (Anas discors) in Cuba on June (Auk :). A naturalist with wide-ranging interests, he would co-author the classic Herpetology of Cuba with Thomas Barbour in . Probably the most exotic report (:–) was of a Fork-tailed Flycatcher (Tyrannus savanna) collected in Marion, Maine, on December . Ora Willis Knight (–) authored the note, opining that “The statements of taxidermists are naturally open to suspicion where pecuniary matters are concerned, so it is always desirable to have confirmatory evidence where obtainable. The evidence in the present case seems entirely satisfactory.” A chemist by trade, Knight wrote The Birds of Maine (), was an accomplished botanist, and was what today would be an Elected Member of the AOU. A first for New England was the Mississippi Kite (Ictinia mississippiensis) observed by S. Prescott Fay (–) on the island of Martha’s Vineyard off the coast of Cape Cod during May and June . He and C. E. Brown watched the bird forage for quite a while and were able to relocate it several weeks later. However, Fay concluded that “it can only be regarded as a very rare straggler, scarcely deserving a place on our New England list.” Having graduated from Harvard University in , Fay published notes in The Auk between and on birds of Massachusetts, but that was the end of his publications. He led the famous expedition across the Northern Rockies, from Jasper, Alberta, to Hudson’s Hope, British Columbia, and his journal of that trip has recently been published (Helm and Murtha ). Fay was an ambulance driver during World War I in France and went on to have a career in the American Field Service, an organization that was started by World War I ambulance drivers. A strange report was made by Henry K. Coale (–), who joined the AOU in , concerning a Magnificent Frigatebird (Fregata magnificens) first seen flying on the Illinois side of the Mississippi River in (:). It was shot at but flew across the river to Burlington, Iowa, where it was electrocuted by a light wire. It was mounted and Coale saw it in a store window, stating that the specimen was the first state record for both Illinois and Iowa. Albinism was still of interest, and there were reports of a white-crowned, splotchy brown and white Fox Sparrow (Passerella iliaca) and a Red-winged Blackbird (Agelaius phoeniceus) with some white primaries in the left wing (:–) and a whiteheaded White-throated Sparrow (Zonotrichia albicollis) (:). A mostly white male Barn Swallow was shot on the flats of Monomy Island off the coast of Cape Cod, Massachusetts (:). The strangest report was made by Albert W. Honywill, Jr., of an albino duck shot in Minnesota (:) that had “no trace of a colored feather anywhere.” Because of the condition of the specimen, he was unable to say with any certainty what species it was, but he suggested that it was a Gadwall (Anas strepera), or perhaps an American Widgeon (A. americana). Honywill was a stalwart of the New Haven (Connecticut) Bird Club but apparently spent summers in Minnesota, as he published two articles in The Auk on summer birds he observed there (:–, :–). Wells W. Cooke (–) presented evidence that the type locality of Bell’s Vireo (Vireo bellii) was actually St. Joseph, Missouri, not “Fort Union (?)” as listed on the specimen tag (:– ). Using notes and journals of J. J. Audubon, who described Bell’s Vireo, Cooke was able to establish that the type specimen had been collected by J. G. Bell on May . Audubon had stated that Bell’s Vireo probably occurred as far north as Fort Union, but Cooke thought that he was in error. In fact, the actual location of Fort Union was in dispute, so Cooke had E. A. Preble look for it in . Preble discovered that the current state line between North Dakota and Montana went through the site of the fort. Cooke concluded that “as most of the buildings were in on the Dakota side, it seems best to consider that Old Fort Union was in North Dakota.” Cooke was the first luminary in the study of bird migration in North America. He envisioned cooperative observations of bird movements, and in –, he invited ornithologists in Iowa to send him lists of winter birds and dates of first arrival of migrants. This quickly spread to the whole Mississippi River Valley, and results were published on an annual basis. After stints in Vermont, Colorado, and Pennsylvania, he took a position with the Biological Survey in Washington, D.C., in , where the remaining years of his career were spent studying migration and distribution of birds. He kept file cards on each migratory record, learning to write with both his right and left hands to avoid writer’s cramp, and announced in that he had surpassed his millionth card. He died in March after a short bout with pneumonia.—Kimberly G. Smith, Department of Biological Sciences, University of Arkansas, Fayetteville, Arkansas, USA. E-mail: [email protected] | v2 |
2019-04-03T13:09:06.131Z | 2018-11-29T00:00:00.000Z | 91493831 | s2ag/train | Resource Utilization Early after Chimeric Antigen Receptor (CAR) T Cell Infusion for Hematologic Malignancies
Background: Chimeric antigen receptor-modified (CAR) T cells have the potential to provide durable clinical benefit in patients with several relapsed or refractory hematologic malignancies. We aimed to characterize institutional resources utilized (other than T cell collection and CAR T cell manufacturing and infusion) around the time of CAR T cell administration.
Methods: Adult patients treated on selected investigator-initiated clinical trials of CAR T cell therapy at Memorial Sloan Kettering Cancer Center were identified from the institutional database. Utilization data was collected from the start of admission for CAR T cell infusion through the end of the initial admission for infusion or through 30 days following initial CAR T cell infusion, whichever was longer. The data were sorted by disease type and into the categories of encounters, lab work, radiology, medications, and other diagnostic testing. Descriptive statistics were used to analyze the data.
Results: We identified 106 patients on 4 clinical trials receiving inpatient CAR T cell infusions between 6/2007 to 4/2018, with 56 patients (53%) having B-cell acute lymphoblastic leukemia (ALL), 37 (35%) chronic lymphocytic leukemia (CLL) or B-cell non-Hodgkin lymphoma (NHL), and 13 (12%) multiple myeloma (MM). The median age was 53 years (range 22-77), 45 years (range 22-74), 64 years (range 35-77), and 58 years (range 43-68) for the total population, and the ALL, CLL/NHL, and MM groups, respectively, and 65%, 75%, 41%, and 31% were male, respectively.
The median length of stay for the admission during which CAR T cells was given was 23 days (range 4 -133), with ALL patients admitted longer (Figure 1). Intensive care unit (ICU) days were limited with a range of 0-43 days, though 43 (41%) spent at least one day in the ICU. Of note, some protocols required infusion of the CAR T cells to be in the ICU. ICU admissions for ALL patients were than for other histologies longer (median 9 days vs 4 days). Outpatient clinic visits through day 30 post CAR T cell infusion occurred in 57 (53%) patients, with more of these in the CLL/NHL patients (median of 2 visits, range 1-4).
As expected, laboratory and radiology studies accounted for a large portion of resource utilization with a total of 62,953 laboratory panels and 1,190 radiology studies done during the study time frame. Fourteen percent of the labs were complete blood counts, basic or comprehensive metabolic panels, or liver function tests. For the total population, ALL, CLL/NHL, MM, there were a median of 63.5 (range 13-368), 91.5 (21-368), 47 (13-167), and 51 (range 38-113) of these panels done per patient during the time frame, respectively. Blood cultures accounted for 1.3% of the total laboratory tests. Among the radiology studies, 25% were CT scans, 10% MRIs, 7% PET scans, 5% ultrasounds, and 53% x-rays, with differences in patterns of use by disease type (Figure 2). Cardiac testing (echocardiographs & electrocardiograms) was done in 104 (98%, total 634 tests). Electroencephalogram was performed in 18 patients (17%, total 18 tests). There were 173 bone marrow aspirations/biopsies in 88 patients (83%) and 71 lumbar punctures in 38 patients (36%), many of which were potentially done for disease assessment rather than toxicity management.
Finally, 41,331 units of medications were given in this time frame, of which chemotherapy was 328 units (0.8%). The median medication units per patient was 255 (range 35-2091), 423 (range 35-2091), 200 (range 41-1190), and 207 (range 90-666) for the total population, and the ALL, CLL/NHL, and MM patients groups, respectively. Thirty-two doses of tocilizumab were given to 25 patients (24%), with ALL patients receiving 23 of those doses (72%).
Conclusion: While providing potential clinical benefit, CAR T cell therapy utilizes resources across the therapeutic spectrum, and increasing use of this therapeutic modality can create challenges in institutional resource capacity. Identifying these resources will allow for better care delivery and allocation of funds. Further refinement of CAR T cell products and improvements in CAR T cell-related toxicity management may permit safer delivery of this therapy and reduce costs per patient. Additional analysis of resource utilization among patients treated with commercial CAR T cell products, as well as comparison with alternative therapies and cost-effectiveness analysis, is warranted.
Shah: Amgen: Research Funding; Janssen: Research Funding. Park:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy; Shire: Consultancy; AstraZeneca: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; Juno Therapeutics: Consultancy, Research Funding. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. Palomba:Pharmacyclics: Consultancy; Celgene: Consultancy. Younes:Genentech: Research Funding; BMS: Honoraria, Research Funding; Pharmacyclics: Research Funding; Abbvie: Honoraria; Merck: Honoraria; Takeda: Honoraria; J&J: Research Funding; Incyte: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Honoraria; Roche: Honoraria, Research Funding; Curis: Research Funding; Astra Zeneca: Research Funding; Novartis: Research Funding; Bayer: Honoraria; Seattle Genetics: Honoraria; Sanofi: Honoraria. Geyer:Dava Oncology: Honoraria. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding. Mailankody:Physician Education Resource: Honoraria; Janssen: Research Funding; Juno: Research Funding; Takeda: Research Funding. Perales:Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Merck: Other: Personal fees; Takeda: Other: Personal fees; Abbvie: Other: Personal fees; Novartis: Other: Personal fees. Brentjens:Juno Therapeutics, a Celgene Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Bach:Vizient: Other: Personal Fees; Hematology Oncology Pharmacy Assoc: Other: Personal Fees; Excellus Health Plan: Other: Personal Fees; Gilead: Other: Personal Fees; Foundation Medicine: Other: Personal Fees; JMP Securities: Other: Personal Fees; Janssen: Other: Personal Fees; Grail: Other: Personal Fees; American Society for Hospital Pharmacy: Other: Personal Fees; Kaiser Permanente: Research Funding; Third Rock Ventures: Other: Personal Fees; WebMD: Other: Personal Fees; Anthem: Other: Personal Fees; Goldman Sachs: Other: Personal Fees; Novartis: Other: Personal Fees; Defined Health: Other: Personal Fees.
| v2 |
2018-04-03T01:44:18.407Z | 2015-03-03T00:00:00.000Z | 23580911 | s2ag/train | Cholinesterase inhibitors for rarer dementias associated with neurological conditions.
BACKGROUND
Rarer dementias include Huntington's disease (HD), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), frontotemporal dementia (FTD), dementia in multiple sclerosis (MS) and progressive supranuclear palsy (PSP). Cholinesterase inhibitors, including donepezil, galantamine and rivastigmine, are considered to be the first-line medicines for Alzheimer's disease and some other dementias, such as dementia in Parkinson's disease. Cholinesterase inhibitors are hypothesised to work by inhibiting the enzyme acetylcholinesterase (AChE) which breaks down the neurotransmitter acetylcholine. Cholinesterase inhibitors may also lead to clinical improvement for rarer dementias associated with neurological conditions.
OBJECTIVES
To assess the efficacy and safety of cholinesterase inhibitors for cognitive impairment or dementia associated with neurological conditions.
SEARCH METHODS
We searched the Cochrane Dementia and Cognitive Improvement Group's Specialised Register, CENTRAL, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS, several trial registries and grey literature sources in August 2013.
SELECTION CRITERIA
We included randomised, double-blind, controlled trials assessing the efficacy of treatment of rarer dementias associated with neurological conditions with currently marketed cholinesterase inhibitors.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed eligibility and quality of trials, and extracted data. We used the standard methodological procedures of the Cochrane Collaboration.
MAIN RESULTS
We included eight RCTs involving 567 participants. Six studies used a simple parallel-group design; the other two consisted of an open-label treatment period followed by a randomised phase. All trials were well concealed for allocation and double-blind, however the sample sizes of most trials were small. All trials used placebo as control. We performed meta-analyses for some outcomes in patients with MS. For all other conditions, results are presented narratively.Two trials included patients with HD; one found that cholinesterase inhibitor use in the short-term had no statistically significant impact on the cognitive portion of the Alzheimer Disease Assessment Scale (ADAS-Cog; 1 study, WMD 1.00, 95% CI -1.66 to 3.66, P = 0.46; low quality evidence), Unified Huntington's Disease Rating Scale (UHDRS) Verbal Fluency Test (1 study, WMD -1.20, 95% CI -7.97 to 5.57, P = 0.73; low quality evidence), UHDRS Symbol Digit Modalities Test (SDMT; 1 study, WMD 2.70, 95% CI -0.95 to 6.35, P = 0.15; low quality evidence) and other psychometric tests. The other study found that cholinesterase inhibitor use in the medium-term improved the results of the verbal fluency test (1 study, WMD 6.43, 95% CI 0.66 to 12.20, P = 0.03; moderate quality evidence) and California Verbal Learning Test - Second Edition (CVLT-II) Recognition Task (1 study, WMD 2.42, 95% CI 0.17 to 4.67, P = 0.04; moderate quality evidence). There was no statistically significant difference between groups on the SDMT (1 study, WMD -0.31, 95% CI -7.77 to 7.15, P = 0.94; moderate quality evidence), CVLT-II trials 1-5 (1 study, WMD -2.09, 95% CI -11.65 to 7.47, P = 0.67; moderate quality evidence), short-delay recall (1 study, WMD 0.35, 95% CI -2.87 to 3.57, P = 0.83; moderate quality evidence), or long-delay recall (1 study, WMD -0.14, 95% CI -3.08 to 2.80, P = 0.93; moderate quality evidence), and other psychometric tests.Four trials included patients with MS; one found no differences between the cholinesterase inhibitors (short-term) and placebo groups on the Wechsler Memory Scales general memory score (1 study, WMD 0.90, 95% CI -0.52 to 2.32, P = 0.22; low quality evidence). The three other trials found that, in the medium-term - cholinesterase inhibitors improved the clinician's impression of cognitive change (2 studies, OR 1.96, 95% CI 1.06 to 3.62, P = 0.03; high quality evidence). However, the treatment effect on other aspects of cognitive change were unclear, measured by the Selective Reminding Test (3 studies, WMD 1.47, 95% CI -0.39 to 3.32, P = 0.12; high quality evidence), patient's self-reported impression of memory change (2 studies, OR 1.67, 95% CI 0.93 to 3.00, P = 0.08; high quality evidence) and cognitive change (1 study, OR 0.95, 95% CI 0.45 to 1.98, P = 0.89; high quality evidence), clinician's impression of memory change (1 study, OR 1.50, 95% CI 0.59 to 3.84, P = 0.39; moderate quality evidence), other psychometric tests, and activities of daily living - patient reported impact of multiple sclerosis activities (1 study, WMD -1.18, 95% CI -3.02 to 0.66, P = 0.21; low quality evidence).One study on patients with CADASIL found a beneficial effect of cholinesterase inhibitors on the Executive interview, and Trail Making Test parts A and B. The impact of cholinesterase inhibitors on the Vascular ADAS-Cog score (1 study, WMD 0.04, 95% CI -1.57 to 1.65, P = 0.96; high quality evidence), the Clinical Dementia Rating Scale Sum of Boxes (1 study, WMD -0.09, 95% CI -0.48 to 0.03, P = 0.65; high quality evidence) Disability Assessment for Dementia scale (1 study, WMD 0.58, 95% CI -2.72 to 3.88, P = 0.73; moderate quality evidence), and other measures was unclearOne study included patients with FTD. This trial consisted of an open-label treatment period followed by a randomised, double-blind, placebo-controlled phase. No data of primary outcomes were reported in this study.In the included studies, the most common side effect was gastrointestinal symptoms. For all conditions, compared to the treatment group, the placebo group experienced significantly less nausea (6 studies, 44/257 vs. 22/246, OR 2.10, 95% CI 1.22 to 3.62, P = 0.007; high quality evidence), diarrhoea (6 studies, 40/257 vs. 13/246, OR 3.26, 95% CI 1.72 to 6.19, P = 0.0003; moderate quality evidence) and vomiting (3 studies, 17/192 vs. 3/182, OR 5.76, 95% CI 1.67 to 19.87, P = 0.006; moderate quality evidence).
AUTHORS' CONCLUSIONS
The sample sizes of most included trials were small, and some of the results were extracted from only one study. There were no poolable data for HD, CADASIL and FTD patients and there were no results for patients with PSP. Current evidence shows that the efficacy on cognitive function and activities of daily living of cholinesterase inhibitors in people with HD, CADASIL, MS, PSP or FTD is unclear, although cholinesterase inhibitors are associated with more gastrointestinal side effects compared with placebo. | v2 |
2020-11-05T09:05:48.994Z | 2020-11-05T00:00:00.000Z | 228809201 | s2ag/train | Pain and Opioid Use in Patients with FLT3 Mutation-Positive Relapsed/Refractory AML: A Subanalysis of Patient-Reported Outcomes from the Admiral Trial
Background: Despite widespread interest in pain management and opioid use across the United States, information on pain and opioid utilization in patients with relapsed or refractory acute myeloid leukemia (R/R AML) is lacking. Better understanding of patient-reported outcomes (PROs) specific to pain could be used to identify strategies to improve the quality of life in patients with R/R AML.
Aim/Objective: To describe pain and opioid use in patients with FLT3 mutation-positive (FLT3mut+)R/R AML receiving either gilteritinib or salvage chemotherapy (SC) using PRO data collected from the ADMIRAL study (NCT02421939).
Methods: ADMIRAL was a phase 3, open-label, multicenter, active-controlled randomized study comparing the efficacy and safety of gilteritinib to SC in patients with FLT3mut+ R/R AML. Pain was assessed using selected items from the Functional Assessment of Cancer Therapy - Leukemia (FACT-Leu; GP4 item: "I have pain") and the EuroQol 5-Dimension 5-Level Questionnaire (EQ-5D-5L; Pain/Discomfort domain). Data for these instruments were collected at baseline (BL), Day 1 of every treatment cycle, and end of treatment (EOT). A modified EOT (mEOT) was defined as the last PRO assessment before patient discontinuation, study data cut-off date, or patient death. Patients on high-intensity chemotherapy (HIC) were treated for up to two cycles depending on treatment response; as such, only changes from BL to Cycle 2 were evaluated. Opioid utilization, including percentage of patients using any opioid medication, specific medications, duration of use, and use by transfusion dependence, was also described. Analyses of the intention-to-treat population using analysis of covariance, including BL score, response to first-line AML therapy, and investigator-preselected SC as covariates, were conducted to estimate least squares mean (LSM) and compare the differences in pain question responses between treatment arms. Descriptive statistics were used to describe opioid utilization.
Results: Of 371 eligible patients, 247 were randomized to gilteritinib and 124 to SC. The median age for both groups was 62 years and slightly more patients were female (gilteritinib, 53.0%; SC, 56.5%). Improvements at the mEOT from BL in the Fact-Leu GP4 item were observed in both gilteritinib (LSM -0.3) and SC (LSM -0.1). Scores also changed on the EQ-5D-5L at the mEOT from BL for both groups (gilteritinib, LSM 0.2; SC, LSM 0.3). No treatment differences were observed between gilteritinib vs SC on the change from BL to Cycle 2 or mEOT on the Fact-Leu GP4 item (LSM [95% CI] of -0.1 [-0.65, 0.38]; P=0.6016 and -0.2 [-0.53, 0.21]; P=0.3902, respectively) or on the EQ-5D-5L Pain/Discomfort domain (LSM [95% CI] of 0.2 [-0.21, 0.62]; P=0.3255 and -0.1 [-0.38, 0.23]; P=0.6288, respectively).
During Cycles 1 and 2, no differences were identified between gilteritinib or SC on the percentage of patients using opioids (Cycle 1: 49.8% vs 55.6%; Cycle 2: 58.9% vs 62.7%, respectively) or the time-averaged duration of use (Cycle 1: 12.4 days vs 14.1 days; Cycle 2: 15.0 days vs 17.2 days, respectively). Patients on gilteritinib were less likely to use opioids during the first two cycles compared with patients on HIC, when stratified by chemotherapy intensity (Cycle 1: 49.0% vs 72.0%, P<0.05; Cycle 2: 58.2% vs 74.1%, P<0.05). Conversely, patients on gilteritinib were more likely to use opioids compared with patients on low-intensity chemotherapy during the first two cycles (Cycle 1: 51.0% vs 30.6%, P<0.05; cycle 2: 60.0% vs 33.3%, P<0.05). In patients using opioids across the first two cycles (Table), opioids used most frequently were oxycodone (Cycle 1: 45.3%; Cycle 2: 44.6%) and tramadol (Cycle 1: 43.2%; Cycle 2: 42.5%). In patients on gilteritinib, those dependent on transfusions were generally more likely to use opioids, and for more days (time-averaged) during each cycle than patients independent of transfusions.
Conclusions: Patients with FLT3mut+ R/R AML receiving gilteritinib or SC demonstrated modest changes in responses to pain-related assessments at EOT compared with BL values. Opioids were used more frequently by patients receiving HIC regimens and transfusion-dependent patients receiving gilteritinib. These data suggest that treatments for FLT3mut+ R/R AML may impact opioid use; further study should be done to determine the relationships between these factors and their potential impact on overall quality of life.
Cella: DSI: Consultancy, Research Funding; Evidera: Consultancy; Ipsen: Consultancy, Research Funding; Mei Pharma: Consultancy; Oncoquest: Consultancy; ASAHI KASEI PHARMA CORP.: Consultancy; BMS: Consultancy, Research Funding; IDDI: Consultancy; Kiniksa: Consultancy; Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Apellis: Consultancy; Alexion: Research Funding; Clovis: Research Funding; Janssen: Research Funding; Pled Pharma: Research Funding; PROMIS Health Org: Membership on an entity's Board of Directors or advisory committees, Other; BlueNote: Consultancy; Astellas: Consultancy, Honoraria; FACIT.org: Membership on an entity's Board of Directors or advisory committees, Other: President; Abbvie: Consultancy, Research Funding. Ritchie:Abbvie: Honoraria; Sierra Oncology: Honoraria; Novartis: Honoraria; Pfizer: Honoraria, Research Funding; Jazz pharmaceuticals: Honoraria, Research Funding; Incyte: Speakers Bureau. Kanda:Pfizer: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Janssen: Honoraria; Shionogi: Research Funding; Chugai Pharma: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Celgene: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Eisai: Honoraria, Research Funding; Novartis: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceuticals: Honoraria; Alexion Pharmaceuticals: Honoraria; Shire: Honoraria; Daiichi Sankyo: Honoraria; Ono Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria, Research Funding; Mochida Pharmaceutical: Honoraria; Mundipharma: Honoraria; Sanofi: Honoraria, Research Funding; Meiji Seika Kaisha: Honoraria; Merck Sharp & Dohme: Honoraria. Ivanescu:Astellas: Other: IQVIA employee which is a contracted by Astellas. Pandya:Astellas Pharma, Inc.: Current Employment. Shah:Astellas: Current Employment.
| v2 |
2018-06-21T12:41:03.901Z | 2018-06-01T00:00:00.000Z | 46922161 | s2ag/train | Anticoagulation for people with cancer and central venous catheters.
BACKGROUND
Central venous catheter (CVC) placement increases the risk of thrombosis in people with cancer. Thrombosis often necessitates the removal of the CVC, resulting in treatment delays and thrombosis-related morbidity and mortality. This is an update of the Cochrane Review published in 2014.
OBJECTIVES
To evaluate the efficacy and safety of anticoagulation for thromboprophylaxis in people with cancer with a CVC.
SEARCH METHODS
We conducted a comprehensive literature search in May 2018 that included a major electronic search of Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), and Embase (Ovid); handsearching of conference proceedings; checking of references of included studies; searching for ongoing studies; and using the 'related citation' feature in PubMed. This update of the systematic review was based on the findings of a literature search conducted on 14 May 2018.
SELECTION CRITERIA
Randomized controlled trials (RCTs) assessing the benefits and harms of unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), vitamin K antagonists (VKA), or fondaparinux or comparing the effects of two of these anticoagulants in people with cancer and a CVC.
DATA COLLECTION AND ANALYSIS
Using a standardized form, we extracted data and assessed risk of bias. Outcomes included all-cause mortality, symptomatic catheter-related venous thromboembolism (VTE), pulmonary embolism (PE), major bleeding, minor bleeding, catheter-related infection, thrombocytopenia, and health-related quality of life (HRQoL). We assessed the certainty of evidence for each outcome using the GRADE approach (Balshem 2011).
MAIN RESULTS
Thirteen RCTs (23 papers) fulfilled the inclusion criteria. These trials enrolled 3420 participants. Seven RCTs compared LMWH to no LMWH (six in adults and one in children), six RCTs compared VKA to no VKA (five in adults and one in children), and three RCTs compared LMWH to VKA in adults.LMWH versus no LMWHSix RCTs (1537 participants) compared LMWH to no LMWH in adults. The meta-analyses showed that LMWH probably decreased the incidence of symptomatic catheter-related VTE up to three months of follow-up compared to no LMWH (risk ratio (RR) 0.43, 95% confidence interval (CI) 0.22 to 0.81; risk difference (RD) 38 fewer per 1000, 95% CI 13 fewer to 52 fewer; moderate-certainty evidence). However, the analysis did not confirm or exclude a beneficial or detrimental effect of LMWH on mortality at three months of follow-up (RR 0.82, 95% CI 0.53 to 1.26; RD 14 fewer per 1000, 95% CI 36 fewer to 20 more; low-certainty evidence), major bleeding (RR 1.49, 95% CI 0.06 to 36.28; RD 0 more per 1000, 95% CI 1 fewer to 35 more; very low-certainty evidence), minor bleeding (RR 1.35, 95% CI 0.62 to 2.92; RD 14 more per 1000, 95% CI 16 fewer to 79 more; low-certainty evidence), and thrombocytopenia (RR 1.03, 95% CI 0.80 to 1.33; RD 5 more per 1000, 95% CI 35 fewer to 58 more; low-certainty evidence).VKA versus no VKAFive RCTs (1599 participants) compared low-dose VKA to no VKA in adults. The meta-analyses did not confirm or exclude a beneficial or detrimental effect of low-dose VKA compared to no VKA on mortality (RR 0.99, 95% CI 0.64 to 1.55; RD 1 fewer per 1000, 95% CI 34 fewer to 52 more; low-certainty evidence), symptomatic catheter-related VTE (RR 0.61, 95% CI 0.23 to 1.64; RD 31 fewer per 1000, 95% CI 62 fewer to 51 more; low-certainty evidence), major bleeding (RR 7.14, 95% CI 0.88 to 57.78; RD 12 more per 1000, 95% CI 0 fewer to 110 more; low-certainty evidence), minor bleeding (RR 0.69, 95% CI 0.38 to 1.26; RD 15 fewer per 1000, 95% CI 30 fewer to 13 more; low-certainty evidence), premature catheter removal (RR 0.82, 95% CI 0.30 to 2.24; RD 29 fewer per 1000, 95% CI 114 fewer to 202 more; low-certainty evidence), and catheter-related infection (RR 1.17, 95% CI 0.74 to 1.85; RD 71 more per 1000, 95% CI 109 fewer to 356; low-certainty evidence).LMWH versus VKAThree RCTs (641 participants) compared LMWH to VKA in adults. The available evidence did not confirm or exclude a beneficial or detrimental effect of LMWH relative to VKA on mortality (RR 0.94, 95% CI 0.56 to 1.59; RD 6 fewer per 1000, 95% CI 41 fewer to 56 more; low-certainty evidence), symptomatic catheter-related VTE (RR 1.83, 95% CI 0.44 to 7.61; RD 15 more per 1000, 95% CI 10 fewer to 122 more; very low-certainty evidence), PE (RR 1.70, 95% CI 0.74 to 3.92; RD 35 more per 1000, 95% CI 13 fewer to 144 more; low-certainty evidence), major bleeding (RR 3.11, 95% CI 0.13 to 73.11; RD 2 more per 1000, 95% CI 1 fewer to 72 more; very low-certainty evidence), or minor bleeding (RR 0.95, 95% CI 0.20 to 4.61; RD 1 fewer per 1000, 95% CI 21 fewer to 95 more; very low-certainty evidence). The meta-analyses showed that LMWH probably increased the risk of thrombocytopenia compared to VKA at three months of follow-up (RR 1.69, 95% CI 1.20 to 2.39; RD 149 more per 1000, 95% CI 43 fewer to 300 more; moderate-certainty evidence).
AUTHORS' CONCLUSIONS
The evidence was not conclusive for the effect of LMWH on mortality, the effect of VKA on mortality and catheter-related VTE, and the effect of LMWH compared to VKA on mortality and catheter-related VTE. We found moderate-certainty evidence that LMWH reduces catheter-related VTE compared to no LMWH. People with cancer with CVCs considering anticoagulation should balance the possible benefit of reduced thromboembolic complications with the possible harms and burden of anticoagulants. | v2 |
2019-04-10T13:13:13.202Z | 2018-11-29T00:00:00.000Z | 104368821 | s2ag/train | Increased Mac 2-Binding Protein Glycan Isomer (M2BPGi) Would Predict Late Non-Relapse Mortality after Allogeneic Hematopoietic Cell Transplantation
[Background]
Macrophages are known to play a crucial role in chronic graft-versus-host disease (cGVHD). Recent studies revealed that increased expression and secretion of Galectine-3 (GAL3) were associated with macrophage activation and fibrosis, and Mac 2-Binding Protein (M2BP), which was known as GAL3 ligand, induced the secretion of IL-1, IL-6, and other cytokines by monocytes and macrophages. Meanwhile, Mac 2-Binding Protein Glycan Isomer (M2BPGi) has been developed as a reliable biomarker of liver fibrosis through glycoproteomic biomarker screening using lectin microarray technologies. We hypothesized that GAL3, M2BP, or M2BPGi could be associated with cGVHD and non-relapse mortality (NRM) in allogeneic hematopoietic cell transplant (HCT) recipients.
[Patients & Methods]
Patients gave written consent allowing blood sample collection. We retrospectively reviewed the medical records of consecutive adult patients who underwent their first allogenic HSCT at our center from January 2010 to December 2016. The plasma levels around day +180 were measured in 110 patients who survived for >180 days without disease relapse after allogeneic HCT, and the predictive potential of 3 markers for NRM was assessed using the discovery (n=55) and validation (n=55) cohorts. Samples were obtained at a median of 178 days (range, 133 to 274 days) after HCT. Among the 110 patients in total, the median age at HCT was 47 years (range 18 to 66 years). GVHD prophylaxis consisted of calcineurin inhibitors and short-term methotrexate. In vivo T-cell depletion with anti-thymocyte globulin or alemtuzumab was performed in HCT for aplastic anemia or HLA mismatched HCT.
[Results]
In the discovery cohort, receiver operating characteristics curve analysis showed that the best cutoff of GAL3, M2BP and M2BPGi at day +180 was 18, 70 and 1.5 with an area under the curve of 0.64, 0.75, and 0.91, respectively (Figure 1). Using this threshold, elevated M2BP and M2BPGi were significantly associated with higher NRM (M2BP; 15.0% vs. 0.0% at 5 years, P = 0.038, and M2BPGi; 15.0% vs. 0.0% at 5 years, P = 0.001). In the validation cohort, although M2BP was not significantly associated with NRM (29.8% vs. 13.4% at 5 years, P = 0.101), the adverse impact of M2BPGi on NRM was confirmed (34.0% vs. 8.4% at 5 years, P = 0.014) (Figure 2). The median sample collection timing was 179 days (range, 167 to 266 days) after HCT in the higher M2BPGi group compared with 178 days (range, 133 to 274 days) after HCT in the lower M2BPGi group (P = 0.620).
On the other hand, M2BPGi was not increased in healthy individuals (n = 20) nor in patients who received autologous HCT (n = 11). Samples were collected at similar times around day +180 after autologous HCT. These results suggested that increased M2BPGi might be involved in the network in allogenic immune responses.
In the entire cohort (n=110), M2BPGi was well related to liver involvement of cGVHD, while there was no association with other organ involvement. At day +180, increased M2BPGi was also correlated with higher cGVHD NIH global severity score (P = 0.004) as well as liver severity score (P < 0.001) (Figure 3), and lower platelet counts (P = 0.005). Multivariate analysis including cGVHD NIH global severity score, liver severity score and platelet counts at day +180 demonstrated that increased M2BPGi at day +180 was an independent risk factor for NRM (HR, 1.27; P < 0.001).
Next, we determined the impact of M2BPGi on other time points. In earlier time point at day +90, NRM did not differ significantly according to M2BPGi in the validation cohort (the discovery cohort; 20.9% vs. 2.9% at 5 years, P = 0.016, and the validation cohort; 22.7% vs. 8.5% at 5 years, P = 0.690). In contrast, high M2BPGi at day +365 remained the significant risk factor for NRM in both cohorts (the discovery cohort; 17.6% vs. 0.0% at 5 years, P = 0.007, and the validation cohort; 40.8% vs. 6.1% at 5 years, P = 0.008). Because an increase in M2BPGi early after HCT can be caused by various reasons other than cGVHD, such as acute liver GVHD, thrombotic microangiopathy and drug exposure, its implications might be different from that during later period.
[Conclusion]
In conclusion, M2BPGi was a powerful predictor for late NRM after HCT. Further studies are required to determine the mechanism of elevations in M2BPGi after HCT. Importantly, this study indicated that the novel glycan profiling technologies might help to identify the potential biomarkers for GVHD in near future.
Nakasone: Phizer: Honoraria; Novartis: Honoraria; Kyowa Hakko Kirin: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Kimura:Astellas: Honoraria; Pfizer: Honoraria; Sumitomo Dainippon Pharma: Honoraria; MSD: Other: Investigator in the institute; Nippon Kayaku: Honoraria; Celgene: Honoraria; Kyowa Hakko Kirin: Honoraria; Takeda: Honoraria. Kako:Takeda Pharmaceutical Company Limited.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; Celgene K.K.: Honoraria; Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria. Kanda:Dainippon-Sumitomo: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; MSD: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Taisho-Toyama: Research Funding; CSL Behring: Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Tanabe-Mitsubishi: Research Funding; Taiho: Research Funding; Sanofi: Research Funding; Otsuka: Research Funding; Nippon-Shinyaku: Research Funding; Asahi-Kasei: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria.
| v2 |
2021-05-19T06:17:03.184Z | 2021-05-18T00:00:00.000Z | 234769971 | s2ag/train | Interventions for preventing nausea and vomiting in women undergoing regional anaesthesia for caesarean section.
BACKGROUND
Nausea and vomiting are distressing symptoms which are experienced commonly during caesarean section under regional anaesthesia and in the postoperative period. OBJECTIVES: To assess the efficacy of pharmacological and non-pharmacological interventions versus placebo or no intervention given prophylactically to prevent nausea and vomiting in women undergoing regional anaesthesia for caesarean section.
SEARCH METHODS
For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) (16 April 2020), and reference lists of retrieved studies.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) of studies and conference abstracts, and excluded quasi-RCTs and cross-over studies.
DATA COLLECTION AND ANALYSIS
Review authors independently assessed the studies for inclusion, assessed risk of bias and carried out data extraction. Our primary outcomes are intraoperative and postoperative nausea and vomiting. Data entry was checked. Two review authors independently assessed the certainty of the evidence using the GRADE approach.
MAIN RESULTS
Eighty-four studies (involving 10,990 women) met our inclusion criteria. Sixty-nine studies, involving 8928 women, contributed data. Most studies involved women undergoing elective caesarean section. Many studies were small with unclear risk of bias and sometimes few events. The overall certainty of the evidence assessed using GRADE was moderate to very low. 5-HT3 antagonists: We found intraoperative nausea may be reduced by 5-HT3 antagonists (average risk ratio (aRR) 0.55, 95% confidence interval (CI) 0.42 to 0.71, 12 studies, 1419 women, low-certainty evidence). There may be a reduction in intraoperative vomiting but the evidence is very uncertain (aRR 0.46, 95% CI 0.29 to 0.73, 11 studies, 1414 women, very low-certainty evidence). There is probably a reduction in postoperative nausea (aRR 0.40, 95% CI 0.30 to 0.54, 10 studies, 1340 women, moderate-certainty evidence), and these drugs may show a reduction in postoperative vomiting (aRR 0.47, 95% CI 0.31 to 0.69, 10 studies, 1450 women, low-certainty evidence). Dopamine antagonists: We found dopamine antagonists may reduce intraoperative nausea but the evidence is very uncertain (aRR 0.38, 95% CI 0.27 to 0.52, 15 studies, 1180 women, very low-certainty evidence). Dopamine antagonists may reduce intraoperative vomiting (aRR 0.41, 95% CI 0.28 to 0.60, 12 studies, 942 women, low-certainty evidence) and postoperative nausea (aRR 0.61, 95% CI 0.48 to 0.79, 7 studies, 601 women, low-certainty evidence). We are uncertain if dopamine antagonists reduce postoperative vomiting (aRR 0.63, 95% CI 0.44 to 0.92, 9 studies, 860 women, very low-certainty evidence). Corticosteroids (steroids): We are uncertain if intraoperative nausea is reduced by corticosteroids (aRR 0.56, 95% CI 0.37 to 0.83, 6 studies, 609 women, very low-certainty evidence) similarly for intraoperative vomiting (aRR 0.52, 95% CI 0.31 to 0.87, 6 studies, 609 women, very low-certainty evidence). Corticosteroids probably reduce postoperative nausea (aRR 0.59, 95% CI 0.49 to 0.73, 6 studies, 733 women, moderate-certainty evidence), and may reduce postoperative vomiting (aRR 0.68, 95% CI 0.49 to 0.95, 7 studies, 793 women, low-certainty evidence). Antihistamines: Antihistamines may have little to no effect on intraoperative nausea (RR 0.99, 95% CI 0.47 to 2.11, 1 study, 149 women, very low-certainty evidence) or intraoperative vomiting (no events in the one study of 149 women). Antihistamines may reduce postoperative nausea (aRR 0.44, 95% CI 0.30 to 0.64, 4 studies, 514 women, low-certainty evidence), however, we are uncertain whether antihistamines reduce postoperative vomiting (average RR 0.48, 95% CI 0.29 to 0.81, 3 studies, 333 women, very low-certainty evidence). Anticholinergics: Anticholinergics may reduce intraoperative nausea (aRR 0.67, 95% CI 0.51 to 0.87, 4 studies, 453 women, low-certainty evidence) but may have little to no effect on intraoperative vomiting (aRR 0.79, 95% CI 0.40 to 1.54, 4 studies; 453 women, very low-certainty evidence). No studies looked at anticholinergics in postoperative nausea, but they may reduce postoperative vomiting (aRR 0.55, 95% CI 0.41 to 0.74, 1 study, 161 women, low-certainty evidence). Sedatives: We found that sedatives probably reduce intraoperative nausea (aRR 0.65, 95% CI 0.51 to 0.82, 8 studies, 593 women, moderate-certainty evidence) and intraoperative vomiting (aRR 0.35, 95% CI 0.24 to 0.52, 8 studies, 593 women, moderate-certainty evidence). However, we are uncertain whether sedatives reduce postoperative nausea (aRR 0.25, 95% CI 0.09 to 0.71, 2 studies, 145 women, very low-certainty evidence) and they may reduce postoperative vomiting (aRR 0.09, 95% CI 0.03 to 0.28, 2 studies, 145 women, low-certainty evidence). Opioid antagonists: There were no studies assessing intraoperative nausea or vomiting. Opioid antagonists may result in little or no difference to the number of women having postoperative nausea (aRR 0.75, 95% CI 0.39 to 1.45, 1 study, 120 women, low-certainty evidence) or postoperative vomiting (aRR 1.25, 95% CI 0.35 to 4.43, 1 study, 120 women, low-certainty evidence). Acupressure: It is uncertain whether acupressure/acupuncture reduces intraoperative nausea (aRR 0.55, 95% CI 0.41 to 0.74, 9 studies, 1221 women, very low-certainty evidence). Acupressure may reduce intraoperative vomiting (aRR 0.52, 95% CI 0.33 to 0.80, 9 studies, 1221 women, low-certainty evidence) but it is uncertain whether it reduces postoperative nausea (aRR 0.46, 95% CI 0.27 to 0.75, 7 studies, 1069 women, very low-certainty evidence) or postoperative vomiting (aRR 0.52, 95% CI 0.34 to 0.79, 7 studies, 1069 women, very low-certainty evidence). Ginger: It is uncertain whether ginger makes any difference to the number of women having intraoperative nausea (aRR 0.66, 95% CI 0.36 to 1.21, 2 studies, 331 women, very low-certainty evidence), intraoperative vomiting (aRR 0.62, 95% CI 0.38 to 1.00, 2 studies, 331 women, very low-certainty evidence), postoperative nausea (aRR 0.63, 95% CI 0.22 to 1.77, 1 study, 92 women, very low-certainty evidence) and postoperative vomiting (aRR 0.20, 95% CI 0.02 to 1.65, 1 study, 92 women, very low-certainty evidence). Few studies assessed our secondary outcomes including adverse effects or women's views.
AUTHORS' CONCLUSIONS
This review indicates that 5-HT3 antagonists, dopamine antagonists, corticosteroids, sedatives and acupressure probably or possibly have efficacy in reducing nausea and vomiting in women undergoing regional anaesthesia for caesarean section. However the certainty of evidence varied widely and was generally low. Future research is needed to assess side effects of treatment, women's views and to compare the efficacy of combinations of different medications. | v2 |
2019-08-20T06:13:07.311Z | 2003-07-01T00:00:00.000Z | 221777221 | s2ag/train | Late‐breaking ddw abstracts
Background. Ca 2 (cid:1) regulates a number of critical processes in the liver, including bile secretion, glucose release, cell proliferation, and apoptosis. Ca 2 (cid:1) signaling is controlled by the InsP 3 in hepatocytes, which express the type I and the type II isoforms of the InsP 3 R. However, the relative importance of each isoform for Ca 2 (cid:1) signalingisunknown. Aim: Todeterminetherelativeimportanceofeachisoformfor Ca (cid:1) signaling. Antisense constructs for the two InsP R isoforms were invivo 2 (cid:1) were measured in isolated hepatocytes by confocal time lapse imag- ing. Results. The adenoviral-antisense construct for the type II isoform of the type but not the type I InsP in a model cell vein, which lead to 90-100% transfection efficiency of hepatocytes within 48 hr. TypeIIInsP 3 Rantisensenearlyeliminatedexpressionofpericanalicular(typeII)but not type I InsP 3 R, as determined by confocal immunofluorescence. Similarly, de- creases in expression of the type I but not the type II InsP 3 R were observed after injection of type I antisense. Hepatocytes were stimulated with maximal (10- 100nM) concentrations of vasopressin (VP), and the resulting Ca 2 (cid:1) signals were monitored.VPinducedCa 2 (cid:1) signalsin90-93%ofcellslackingthetypeIinsP3R,but in only 65-70% of cells lacking the type II isoform. The average delay between perifusionwithVPandtheonsetofCa 2 (cid:1) signalingwastwiceaslongincellslacking the type II InsP 3 R. Conclusion. Ca 2 (cid:1) signaling in hepatocytes depends critically uponthetypeIIisoformoftheInsP 3 R.ThetypeIisoformmediatesCa 2 (cid:1) signalingto In primary biliary cirrhosis (PBC) biliary and liver cells exhibit both necrosis and apoptosis. Tumor necrosis factor- (cid:1) (TNF- (cid:1) ) can cause apoptosis by bind-ing to its specific receptors and may signal for apoptosis via caspase activation. Our aim was to assess: 1- the relationship between serum and tissue TNF- (cid:1) as caspase activator and liver damage in PBC patients, 2- the effect of ursodeoxy- cholic acid (UDCA) on inhibiting (TNF- (cid:1) ) signaling for apoptosis in these patients. Serum levels of TNF- (cid:1) , and caspase 3 activity were determined using ELISA in 150 PBC patients. 320 healthy volunteers were used as controls. The ANOVA or Mann-Whitney test as were used to compare continuous variables among and between groups. Correlations were done using simple linear re-gression. Levels of TNF- (cid:1) in patients with PBC were significantly higher than in healthy controls (p (cid:2) 0.001). TNF- (cid:1) correlated significantly with more ad-vanced histological activity index (HAI). Patients with cirrhosis and HAI (cid:3) 6 had significantly higher TNF- (cid:1) (720 (cid:4) 160 vs. 170 (cid:4) 15 pg/ml, p (cid:5) 0.001). signaling for apoptosis by reducing caspase activity in patients with PBC. Background: Histopathological assessment is considered essential for the differen-tiationofrecurrenthepatitisC(RHC)fromacutecellularrejection(ACR)postlivertransplantation,howeveritsreliabilityhasnotbeenstudiedsystematically.Differen-tiationmaybedifficultasinmanycasestheappearanceofACRmayalsoreflectacomponentofRHC. Aim: To determine the interobserver and intraobserver agree- ment of the histopathological diagnosis of RHC versus ACR, and to determine the reliability of specific histopathological features for the differentiation of RHC from ACR. Methods: Liverbiopsyspecimensfrom102consecutivepatients,transplanted for HCV related liver disease were studied. All biopsies were performed for evalua- tion of abnormal liver enzymes within the 1st year post transplant. The slides were blindly coded and assessed by five liver pathologists, practicing at three Transplant Centers. Each pathologist read the slides independently and was asked to render a diagnosis, and determine the severity of the disease. Four of the pathologists were askedtodeterminethepresenceandseverityof33histopathologicalfeatures.Thirty-fiveofthesampleswereblindlyresubmittedto4pathologiststodeterminetheintraobserveragreement. Results: Atotalof102specimenswereobtainedfrom102 consecutive HCV liver transplant patients, M:F, The mechanisms by which mutations in the FIC1 gene cause Byler disease (PFIC1) are unknown. Elevated ileal ASBT mRNA expression was detected in two patients with PFIC1 (FIC1 mRNA absent). Paradoxically, ileal lipid bind-ingprotein(ILBP)mRNAexpressionwasrepressed,suggestingacentraldefectinbileacidresponse.IlealFXRmRNAlevelswerereducedinthesametwopatients.InCaco-2cells,antisense-mediatedeliminationofendogenousFIC1wasassociatedwithup-regulationofASBTmRNAexpressionanddown-reg-ulationofFXR,ILBPandshortheterodimerpartnermRNA.InFIC1mRNAnegativeCaco-2cells,theactivityofthehumanASBTpromoterwasenhanced,whilethehumanFXRandbilesaltexcretorypump(BSEP)promotersactivitieswerereduced.FIC1thereforeappearstomediatetranscriptionalactivationofFXR.LossofFIC1leadstodiminishedFXRexpressionwithsubsequentpo-tentialforpathologicalterationsinintestinalandhepaticbileacidtransporterexpression.Cholestasiswoulddeveloppresumablyduetobothenhancedilealuptakeofbilesaltsviaup-regulationofASBTanddiminishedcanalicularsecretionofbilesaltssecondarytodown-regulationofBSEP.Disclosure:Nodisclosurerelevanttothisresearch;Contentofpresentationdoesnotincludediscussionofoff-label/investigativeuseorapplicationofmedicine(s),medicaldevices,orprocedure(s) The mechanisms underlying the immunological advantage of hepatic allo- grafts relative to other organs are incompletely understood. Bone marrow derived hepatic oval cells play a role in regeneration of an injured liver, but have not been shown to participate in regeneration of liver allografts. The aim of this study was to investigate: 1) whether recipient-derived stem cells repop- ulate the cellular components of transplanted liver allograft; 2) whether this repopulation process is promoted during liver regeneration after partial liver transplantation. Methods: MHC mismatched, spontaneously accepted, orthotopic whole liver transplants (OLT) and (50%) partial liver transplants (PLT) were performed using Lewis (RT1 1 , C3-negtive) donor into DA (RT1 a , C3-positive) recipient rats. Liver repopulation was quantified using immunohistochemistry (C3 antigen-positive cells) and histologic assessment (hematoxylin and eosin). Hepatocytes were isolated from liver allografts, and hepatocyte repopulation was assessed using flow cytometry (C3-positive cells). Results: 15 to 25% of liver allograft cells were recipient derived (C3-positive) by 30 days post-OLT. By 1 year post-transplant C3-positive cells completely replaced the hepatocyte fraction within the liver allograft as well as the endo-theliuminbothportalandcentralveins.InPLTmodels,recipient-derivedcellsrepopulated20to30%(onday7),40-50%(onday10),60-70%(onday20)andmorethan80%(3months)ofcellsinliverallograftspost-PLT.C3-positivecellspartially(onday20)orcompletely(3months)replacedbothepithelium findings new insight into the mechanisms of liver regeneration, as well as the immunobiology of liver transplantation. | v2 |
2019-04-04T13:14:44.488Z | 1971-01-01T00:00:00.000Z | 93177481 | s2ag/train | Acidity of hydrocarbons. XXXVII. Broensted correlation and hydrogen isotope exchange kinetics of fluorenes, benzfluorenes, and indene with methanolic sodium methoxide
Kinetic results are reported for tritium exchange of several hydrocarbons related to fluorene with methanolic sodium methoxide. The second-order rate constant for fluorene increases with NaOMe concentration and a comparison with Hresults is presented. Primary isotope effects are high and indicate the absence of significant amounts of internal return. k ~ , kl,, and kT are interrelated for 9-phenylfluorene and 9-methylfluorene. The secondary isotope effect for exchange of fluorene-9,9-d2 is 15z. Tritium exchange rates given as lO%s (M' sec-l) at 45", AH* (kcal/mol), and AS* (eu) are, respectively, 1,12-o-phenylene-7,12-dihydropleiadene, 5630, 17.13, -5.99; 9-phenyl-3,4-benzfluorene, 1030, , ; 9-phenylfluorene, 173, 21.30, 0.20; 3,4-benzfluorene, 90.3, 20.95, -2.20; indene, 50.0, 20.29, 5.43; 1,2-benzfluorene, 31.9, 18.49, 11.98; 4,5-methylenephenanthrene, 6.85, 23.66, 1.21; fluorene, 3.95, 23.26, -1.16; 2,3-benzfluorene, 2.15, These rates give a linear Bronsted plot with pK's derived from cesium cyclohexylamide with a slope, a , of 0.37. No curvature is detectable in this correlation. The significance of the value of CY is discussed. , . or the past several years we have undertaken a sysF tematic survey of rates of deuterium and tritium exchange of relatively acidic hydrocarbons with methanolic sodium methoxide for comparison with relative equilibrium pK values determined in cyclohexylamine. The hydrocarbons studied are those which lead to highly conjugated carbanions; that is, fluorenes, polyarylmethanes, etc. In this paper, we discuss the results with the more reactive group of hydrocarbons: fluorene and some 9-substituted fluorenes, indene, and several benzfluorenes. These compounds have in common a cyclopentadiene nucleus which confers relatively high acidity on the hydrocarbons such that hydrogen isotope exchange kinetics can be followed conveniently with methanolic sodium methoxide. In the paper we treat the kinetic form of the reaction with a detailed study of fluorene, consider primary and secondary isotope effects, examine the question of internal return by comparing primary deuterium and tritium isotope effects with two 9-substituted fluorenes, and discuss the reactivities of the entire range of these hydrocarbons in terms of a Brgnsted correlation with pK values. Results and Discussion Sodium Methoxide Kinetics with Fluorene. At the time this work was begun some years ago there were several reports of exchange reactivities of fluorene: Shatenshtein and Zvyagintseva4 reported rates in ND3, (1) Supported in part by Grant No. GM-12855 of the National Institutes of Health, U. S. Public Health Service, Grant No. 6125X of the National Science Foundation, and Grant No. 1761-C of the Petroleum Research Fund, American Chemical Society. Some preliminary results were reported previously in A. Streitwieser, Jr., A. P. Marchand, and A. H. Pudjaatmaka, J . Amer. Chem. Soc., 89, 693 (1969). at the 155th National Meeting of the American Chemical Society, San Francisco, Calif., 1968, Division of Petroleum Chemistry, Abstracts, p A7, and in A. Streitwieser, Jr., and J. H . Hammons, Progr. Phys. Org. Chem., 3, 41 (1965). (2) (a) A. I . D . Fellow, 1961-1965; (b) National Institutes of Health Predoctoral Fellow, 1968-1970; (c) National Science Foundation Postdoctoral Fellow, 1966-1967. (3) (a) A. Streitwieser, Jr., J. H . Hammons, E. Ciuffarin, and J. I . Brauman, J . Amer. Chem. SOC., 89, 59 (1967); (b) A. Streitwieser, Jr., E. Ciuffarin, and J. H. Hammons, ibid., 89, 63 (1967). ND2C2H4ND2, ND2C2H40D, and NaOEt-EtOD, other authors; gave additional data in ethanol, Dessy, et u I . , ~ reported some results in aqueous dimethylformamide, and Andreades7 contributed one run in methanolic sodium methoxide. None of these studies has the scope and detail of the present investigation. More recently, Cram and his research group have reported important kinetic and stereochemical studies of fluorene and derivatives8-l0 that complement the present work. In order to compare a range of hydrocarbons over a variety of conditions, it was important to determine the exact kinetic order of methanol as a function of concentration. In an early phase of this work we examined the rate of loss of deuterium from fluorene-9-d using ir spectroscopy. Much of this work was of unsatisfactory precision and is not discussed here." In subsequent work low voltage mass spectrometry was used for the deuterium analyses and extensive kinetic results were obtained for tritium exchange reactivities. These experiments were carried out by treating fluorene-9-t with methanolic sodium methoxide under controlled conditions ; aliquots were isolated periodically and analyzed for tritium by liquid scintillation counting. These tritium results are summarized in Table I . Note that many individual investigators contributed experimental results. This system was used as small undergraduate research programs and for training students in exchange kinetics. As a result the rate constants are of variable quality but have a precision gen(4) A. I . Shatenshtein and E. N. Zvyagintseva, Proc. Acad. Sci. USSR, Phys. Chem., 117, 781 (1957). ( 5 ) M. Avramoff and Y . Sprinzak, J . Amer. Chem. SOC., 82, 4953 (1960); N. N. Zatzepina, A. W. Kirova, and J. F. Tupizin, Org. React i c . ( U S S R ) , 5, 70 (1968). (6) R. E. Dessy, Y . Okuzumi, and A. Chen, J . Amer. Chem. SOC., 84, 2899 (1962). (7) S. Andreades, ibid., 86, 2003 (1964). (8) D. J. Cram and L. Gosser, ibid., 85, 3890 (1963); 86, 2950 (1964). (9) W. T. Ford, E. W. Graham, and D. J. Cram, ibid., 89, 689, 690, 4661 (1967). ( IO) D. J. Cram and W. D. Kollmeyer, ibid., 90, 1791 (1968). (1 1) A. H. Pudiaatmaka, Dissertation, University of California, Berkeley, 1966. . Journal of the American Chemical Society / 93:20 / October 6, 1971 | v2 |
2014-10-01T00:00:00.000Z | 1995-01-01T00:00:00.000Z | 17373121 | s2ag/train | Interaction of ct-Actinin with the Cadherin/Catenin Cell-Cell Adhesion Complex via oL-Catenin
Cadherins are CaZ+-dependent, cell surface glycoproteins involved in cell--cell adhesion. Extracellularly, transmembrane cadherins such as E-, P-, and N-cadherin self-associate, while intracellularly they interact indirectly with the actin-based cytoskeleton. Several intraceUular proteins termed catenins, including a-catenin, B-catenin, and plakoglobin, are tightly associated with these cadherins and serve to link them to the cytoskeleton. Here, we present evidence that in fibroblasts a-actinin, but not vinculin, colocalizes extensively with the N-cadherin/catenin complex. This is in contrast to epithelial cells where both cytoskeletal proteins colocalize extensively with E-cadherin and catenins. We further show that a-actinin, but not vinculin, co-immunoprecipitates specifically with aand ~3-catenin from Nand E-cadherin--expressing cells, but only if a-catenin is present. Moreover, we show that a-actinin coimmunoprecipitates with the N-cadherin/catenin complex in an actin-independent manner. We therefore propose that cadherin/catenin complexes are linked to the actin cytoskeleton via a direct association between a-actinin and a-catenin. T HE cadherins form a family of cell surface glycoproteins that function in promoting Ca-dependent cellcell adhesion and serve as the transmembrane components of cell--cell adherens junctions (Takeichi, 1988; Geiger, 1989; Geiger et al., 1990; Takeichi, 1991; Geiger and Ayalon, 1992; Grunwald, 1993). Adherens junctions are found between many cell types, including epithelial cells, cardiac myocytes, and fibroblasts (Volk and Geiger, 1984; Geiger et al., 1987, 1990; Geiger and Ayalon, 1992; Heaysman and Pegrum, 1973). Extracellularly the individual cadherins self-associate to promote specific cell-cell interactions (Nose et al., 1988, 1990; Friedlander et al., 1989), while intracellularly they interact with a group of proteins, collectively termed catenins (Ozawa and Kemler, 1992; Ozawa et al., 1989; Magee and Buxton, 1991). The catenins (e~, [~, and 7) are thought to link cadhefins to the actin-based cytoskeleton, although the mechanism is not understood. Both the cadherin cytoplasmic domain and the associated catenins have been shown to be required for full cadherin activity (Nagafuchi and Takeichi, 1988, 1989; Ozawa et al., 1989, 1990; Jaffe et al., 1990; Tsukita et al., 1992; Hirano et al., 1992). c~-Catenin is a 102-kD protein with homology to vinculin (Nagafuchi et al., 1991; Herrenknecht et al., 1991). [3-cateAddress all correspondense to Dr. Margaret J. Wheelock, Department of Biology, University of Toledo, Toledo, OH 43606. Tel.: (419) 537-4919. FAX: (419) 537-7737. K. J. Johnson and M. J. Wheelock contributed equally to this study. Scientific correspondence may be directed to any of the authors. nin is a 92-kD protein related to both the protein product of armadillo, a Drosophila segment polarity gene, and plakoglobin (Peifer and Wieschaus, 1990; McCrea et al., 1991), a vertebrate protein found at desmosomes and cellcell adherens junctions (Cowin et al., 1986). Plakoglobin also associates with cadherins and is thought to be the same as 7-catenin (Peifer et al., 1992; Knudsen and Wheelock, 1992). A variety of cell types express cadherins that have been shown to promote specific cell-ceU adhesion. E-cadherin is the major cadherin expressed by polarized epithelial cells, whereas both Eand P-cadherin are expressed by squamous epithelial cells (reviewed by Takeichi, 1988). N-cadherin is expressed by developing and mature cardiomyocytes (Volk and Geiger, 1984) and has been shown to play an important role in promoting both myocyte interaction and myofibrillogenesis (Peralta Soler and Knudsen, 1994). N-cadherin, along with other adhesion molecules, functions as a cell-cell adhesion molecule in nerve (Matsunaga et al., 1988) and in developing skeletal muscle (Knudsen et al., 1990). N-cadherin has been shown to be expressed by primary chicken fibroblasts and P-cadherin by a normal rat fibroblast cell line (Hirano et al., 1987; Geiger et al., 1990; Itoh et al., 1991). Cadherins localize to the cell--cell adherens junctions in epithelial cells and cardiomyocytes. At the electron microscopic level, these junctions are characterized by close plasma membrane apposition between interacting cells and by the presence of electron dense material at the intracellular face of the plasma membrane. The dense, submembranous material, sometimes referred to as the plas© The Rockefeller University Press, 0021-9525195/07167111 $2.00 The Journal of Cell Biology, Volume 130, Number 1, July 1995 67-77 67 on A uust 6, 2017 jcb.rress.org D ow nladed fom malemmal undercoat, contains a number of cytoplasmic proteins, many of which are well characterized (Tsukita et al., 1989, 1992; Tsukita et al., 1993). Examples include a-catenin, 13-catenin, plakoglobin, vinculin, a-actinin, radixin, the 220-kD protein (ZO-1), zyxin, spectrin, and actin. Exactly how these various proteins interact with one another is an area of on-going investigation. Some interactions among these cytoplasmic proteins have been described, whereas others are still a matter of speculation. For example, vinculin and zyxin have both been shown to bind to a-actinin (Belkin and Koteliansky, 1987: Wachsstock et al., 1987; Crawford et al., 1992; McGregor et al., 1994). Vinculin (Menkel et al., 1994) and a-actinin (Burridge and Feramisco, 1982; Blanchard et al., 1989) both interact with actin. Radixin caps the barbed end of actin filaments (Tsukita et al., 1989) and the 220-kD protein may interact with spectrin (Itoh et al., 1991). Due to homology between a-catenin and a domain in vinculin thought to be involved in vinculin self-association, a-catenin has been proposed to self-associate and thereby consolidate cadherins in the adherens junction (Nagafuchi et al., 1991; Herrenknecht et al., 1991). Alternatively, c~-catenin has been proposed to bind to vinculin and thereby link the cadherirdcatenin complex to the cytoskeleton. However, no evidence has been presented to date to support either of these possibilities. In this paper we show that a-actinin, but not vinculin, colocalizes extensively with the N-cadherin/catenin complex expressed by fibroblasts. This is in contrast to epithelial cells where both a-actinin and vinculin colocalize with the E-cadherin/catenin complex. We present evidence that a-actinin, but not vinculin, coimmunoprecipitates specifically with c~and 13-catenin from Nand E-cadherin--expressing cells, but only if a-catenin is present. In addition, we present evidence that a-actinin associates with the N-cadherin/catenin complex in a manner not dependent upon the presence of actin. We therefore propose that cadherin/ catenin complexes are linked to the actin cytoskeleton via a direct interaction between c~-catenin and ~-actinin. Materials and Methods | v2 |
2019-11-16T14:06:05.695Z | 2019-11-14T00:00:00.000Z | 208036601 | s2ag/train | A multicenter prospective study of first-line antibiotic therapy for early-stage gastric mucosa-associated lymphoid tissue lymphoma and diffuse large B-cell lymphoma with histological evidence of mucosa-associated lymphoid tissue
Several independent clinical studies have demonstrated that first-line Helicobacter pylori (HP) eradication (HPE) therapy can lead to successful durable complete remission (CR) in 56–100% of patients with HP-positive, early-stage gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). According to the 2008 World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues, diffuse large Bcell lymphoma (DLBCL) with accompanying MALT lymphoma should be classified as DLBCL, and not highgrade transformed MALT lymphoma, because gastric DLBCL are not necessarily transformed MALT lymphomas and cannot be distinguished from de novo DLBCL. Several prospective studies have demonstrated that first-line HPE results in CR in two-thirds of patients with HP-positive stage IE gastric DLBCL with histological evidence of MALT [DLBCL(MALT)], and other studies have also demonstrated that some patients with HP-positive gastric DLBCL(MALT) respond to HPE. These findings may also justify the expansion of the study population to include patients with stage IIE1 gastric DLBCL(MALT) in the present prospective trial of firstline HPE. A t(11;18)(q21;q21) translocation results in the production of the fusion protein BIRC3–MALT1, causing constitutive activation of nuclear factor kappa-lightchain-enhancer of activated B cells (NF-κB) and contributing to the HP-independent growth of gastric MALT lymphomas. This translocation, however, rarely occurs in gastric DLBCL(MALT). Immunohistochemical detection of the nuclear translocation of B-cell lymphoma/leukemia 10 (BCL10) or NF-κB is useful in predicting HP independence (the lack of complete lymphoma regression after HPE) in both early-stage MALT lymphoma and DLBCL(MALT) of the stomach, irrespective of the presence of the t(11;18)(q21;q21) translocation. In addition to HP-independent markers, we recently reported that the expression of cytotoxin-associated gene A (CagA) of the HP and CagA signaling molecules, phospho-Src homology-2 domain-containing phosphatase (p-SHP2) and phospho-extracellular signalregulated kinase (p-ERK), in tumor cells is closely associated with the HP dependence of gastric MALT lymphoma and gastric DLBCL(MALT). In April 2006, our institution and the National Health Research Institutes of Taiwan initiated a prospective phase II, multicenter trial evaluating the efficacy of firstline HPE treatment and the ability of nuclear BCL10 or NF-κB expression and the t(11;18)(q21;q21) translocation to predict HP independence in early-stage (i.e., stages IE and IIE1) HP-positive gastric MALT lymphoma and gastric DLBCL(MALT): the Taiwan Cooperative Oncology Group (TCOG) 3206 trial (ClinicalTrials.gov, NCT00327132). The enrolled patients were required to have histologically confirmed primary gastric lymphoma, including MALT lymphoma or DLBCL(MALT). Those who had undergone prior chemotherapy or radiotherapy for this tumor were excluded. MALT lymphoma and DLBCL(MALT) were diagnosed by histopathologists at individual hospitals, in accordance with specified criteria, with each diagnosis reviewed by members of the TCOG Pathology Committee. The diagnostic criteria for MALT lymphoma and DLBCL(MALT) are described in full in the Online Supplementary Methods). Detailed information on the staging work-up, diagnosis of HP infection, HPE regimens, and follow-up are provided in the Online Supplementary Methods and in Online Supplementary Figure S1. Full details on CR criteria [Groupe d’Etude des Lymphomes de l’Adult (GELA) histological scoring system] for tumors; molecular studies of the t(11;18)(q21;q21) translocation and immunohistochemical expression of BCL10, NF-κB, and CagA; primary and secondary endpoints; and statistical analyses are listed in the Online Supplementary Methods. All experimental protocols were approved by the Institutional Review Board of the Research Ethical Committee of National Taiwan University Hospital (n. 950606). Of the 47 patients enrolled in this prospective study, one was excluded because of stage III disease. The clinicopathological characteristics of the 46 eligible patients, including 36 diagnosed with MALT lymphoma and 10 with DLBCL(MALT), are listed in Table 1 and in the Online Supplementary Results. The depth of lymphoma involvement in the gastric wall was determined by endoscopic ultrasonography in 28 patients. HP infection was successfully treated in all 36 patients with MALT lymphoma who completed the study protocol (22 after firstline treatment, 10 after second-line treatment and four after third-line treatment) and in nine (90.0%) of the ten patients with DLBCL(MALT) after first-line treatment. Of the 46 patients, 34 (73.9%) achieved complete remission (CR) (HP-dependent tumors) after the completion of HPE, including 26 of 36 (72.2%) with MALT lymphoma and eight of the ten (80%) with DLBCL(MALT) (P=1.000) (Figure 1A-H). Of ten patients with DLBCL(MALT), three patients (diffuse blast components; 20–30%) achieved CR, while five (71.4%) of seven patients (diffuse blast components; 80–90%) achieved CR. GELA criteria-based analyses showed that 30 (88.2%) of the 34 patients who achieved CR did so within 12 months after the completion of HPE, whereas the other four (11.8%) achieved CR after 12 months. The median time to CR after the completion of antibiotic therapy in all 34 patients was 4 months (range, 1–16 months), identical to that in patients with MALT lymphoma (4 months; range, 1–16 months) and DLBCL(MALT) (4 months; range, 1–10 months) (P=0.530) (Figure 1I). After a median follow-up of 87 months [95% confidence interval (95% CI): 75.2–98.8 months), only two patients died of causes unrelated to lymphoma an 82year old woman with MALT lymphoma who died of cardiovascular disease and an 80-year old man with DLBCL(MALT) who died of pneumonia. No patient with MALT lymphoma who was unresponsive to HPE during treatment and follow-up showed high-grade transformation to DLBCL. The 8-year overall survival rate for all patients was 92.4% (95% CI: 81.2–100%): 90% in patients with DLBCL(MALT) and 93.8% in patients with MALT lymphoma (P=0.195) (Figure 1J). The median follow-up time after CR (calculated from the date of first CR to the date of tumor relapse or June 30, 2018) was 80 months (95% CI: 61.2–98.8 months) in all 34 HP-dependent patients, 82 months (95% CI: 56.8–107.3 months) in the MALT lymphoma group, and 59 months (95% CI: 23.0–95.0 months) in the DLBCL(MALT) group. Relapses were observed in two (7.7%) of 26 patients with MALT lymphoma, but in none of the eight patients | v2 |
2017-04-08T02:50:57.934Z | 2005-01-01T00:00:00.000Z | 14161771 | s2ag/train | termediate in gummy stem blight resistance between For long-term storage (
ing transportation and in storage because of the disease commonly known on fruit as black rot, caused by D Gummy stem blight, caused by Didymella bryoniae (Auersw.) bryoniae as well (Leupschen, 1961; Norton, 1978; Sowell Rehm, is a major disease of watermelon [Citrullus lanatus (Thunb.) Matsum. & Nakai]. Plant breeders need sources of resistance that and Pointer, 1962). can be incorporated into adapted breeding lines to help control the Gummy stem blight on watermelon plants is evident disease. We tested all the available accessions from the USDA-ARS as crown blight, stem cankers, and extensive defoliation, watermelon germplasm collection, including C. lanatus var. citroides with symptoms observed on the cotyledons, hypocotyls, (L.H. Bailey) Mansf., for resistance to gummy stem blight. The experileaves, and fruit (Maynard and Hopkins, 1999). Didyment was a randomized complete block with 1332 cultigens, two sites mella bryoniae is a fungus that is seed-borne (Lee et al., (field and greenhouse), two or four replications, and two to six plants 1984), air-borne (van Steekelenburg, 1983), or soil-borne per plot. The resistant check was PI 189225 and the susceptible check (Bruton, 1998; Keinath, 1996). Important factors favorwas ‘Charleston Gray’. PI 279461, PI 482379, PI 254744, PI 526233, ing either artificial or natural inoculations are the presPI 482276, PI 271771, PI 164248, PI 244019, PI 296332, and PI 490383 were selected as the most resistant cultigens to be used in future ence of wounds, particularly on old leaves (Blakeman, breeding efforts. The most susceptible cultigens were PI 183398, PI 1971; Pharis et al., 1982; Svedelius, 1990; van Steekelen169286, PI 223764, PI 226445, PI 525084, PI 534597, and PI 278041. burg, 1985a), and the presence of free water on the foliage (van Steekelenburg, 1981, 1984, 1985a). Adequate control of gummy stem blight through funW is a major vegetable crop in the USA, gicide applications (Keinath, 1995, 2000) and good culwith a total production in 2001 of about two miltural practices (Keinath, 1996; Rankin, 1954) is difficult, lion megagrams of marketable fruit (USDA-ARS, particularly during periods of frequent rainfall when 2001). Gummy stem blight caused by Didymella bryorelative humidity remains high for a long period. There niae (Auersw.) Rehm [ Mycosphaerella citrullina have been reports of acquired resistance of D. bryoniae (C.O. Sm.) Gross. and Mycosphaerella melonis (Pass) to fungicides (Kato et al., 1984; Keinath and Zitter, Chiu & Walker] and its anamorph Phoma cucurbita1998; Malathrakis and Vakalounakis, 1983; Miller et al., cearum (Fr.:Fr.) Sacc. [ Ascochyta cucumis Fautrey & 1997; van Steekelenburg, 1987). Genetic resistance to Roum] (Keinath et al., 1995) is one of the most destrucgummy stem blight has received attention (Norton et tive diseases of this crop. Resistance to gummy stem al., 1993, 1995, 1986) and would be preferable to other blight was ranked for several years by watermelon remethods if resistant germplasm can be identified and searchers in the USA as the third most important trait used to develop adapted cultivars. for germplasm evaluation [after bacterial fruit blotch, Methods of seedling evaluation for resistance to caused by Acidovorax avena subsp. citrulli (Schaad et gummy stem blight have been reported in watermelon al.) Willems et al. Pseudomonas pseudoalcaligenes (Boyhan et al., 1994; Dias et al., 1996), melon (Cucumis subsp. citrulli, and Fusarium wilt, caused by Fusarium melo L.) (Zhang et al., 1997), squash (Cucurbita pepo oxysporum Schlechtend.:Fr. f. sp. niveum (E.F. Sm.) L.) (Zhang et al., 1995), and cucumber (St. Amand and W.C. Snyder & H.N. Hans]. Wehner, 1995b; Wehner and Shetty, 2000; Wehner and Gummy stem blight was first described by Fautrey St. Amand, 1993). These studies shared a similar inocuand Roumeguere in France as the disease caused on lation technique, based on spraying the seedlings with cucumber (Cucumis sativus L.) by Ascochyta cucumis a water suspension of spores collected from in vitro in 1891 (Chiu and Walker, 1949; Sherf and MacNab, cultures of the pathogen. Spore concentration used to 1986). In 1917, gummy stem blight was reported for the evaluate cucurbits for resistance to gummy stem blight first time in the USA, affecting watermelon fruit from differed among experiments and species ranging beFlorida (Sherbakoff, 1917), where it is still an important tween 105 and 107 spores/mL (Boyhan et al., 1994; St. limiting factor for the watermelon industry (Keinath, Amand and Wehner, 1995a, 1995b; van Deer Meer et al., 1995; Schenck, 1962). One severe gummy stem blight 1978; van Steekelenburg, 1981; Wehner and St. Amand, epidemic on watermelon was reported in the southeastern 1993; Zhang et al., 1995, 1997). Inoculation of cotyledons USA, with over 15% of the watermelon crop in South was tested and shown to be unreliable for resistance to Carolina abandoned before harvest (Power, 1992). In gummy stem blight (Chiu and Walker, 1949; van Deer addition, severe economic losses have been reported durMeer et al., 1978; Wyszogrodzka et al., 1986). In previous studies, there were genetic differences Dep. of Horticultural Science, North Carolina State Univ., Campus for gummy stem blight resistance among commercial box 7609, Raleigh, NC 27695-7609. Received 23 July 2003. Crop Breedcultivars of watermelon. ‘Congo’ was the least susceping, Genetics & Cytology. *Corresponding author (todd_wehner@ ncsu.edu). tible, ‘Fairfax’ was intermediate, and Charleston Gray was the most susceptible (Schenck, 1962). PI 189225 was Published in Crop Sci. 45:582–588 (2005). the most resistant of 439 accessions evaluated from the © Crop Science Society of America 677 S. Segoe Rd., Madison, WI 53711 USA USDA-ARS watermelon germplasm collection (Sowell 582 Published online February 23, 2005 | v2 |
2018-04-03T00:00:38.419Z | 2015-03-05T00:00:00.000Z | 206933061 | s2ag/train | Hypomorphic mutation in TTC7A causes combined immunodeficiency with mild structural intestinal defects.
To the editor:
Biallelic TTC7A mutations have recently been shown to cause early-onset inflammatory bowel disease or multiple intestinal atresias accompanied by severe combined immunodeficiency (MIA-SCID), a disease usually fatal in infancy without curative treatment.1-4
We studied a patient (P1) born in the thirty-third gestational week (to healthy Turkish consanguineous parents) who suffered from combined immunodeficiency and chronic diarrhea. Two older siblings had previously died of severe diarrhea. Within the first 2 months, P1 suffered from constipation followed by watery diarrhea without identifiable cause. Radiographic colonography revealed normal rectum diameter but hypoplastic descending and sigmoid colon and dilated small intestine and ascending and transverse colon (Figure 1A). Duodenal (Figure 1B) and colonic biopsies (supplemental Figure 1A, available online on the Blood Web site) showed graft-versus-host disease (GVHD)–like lesions. P1 experienced several pneumonia episodes (including Klebsiella pneumoniae septicemia) and pyelonephritis. Thymic tissue was hypoplastic (Figure 1C). At 3.5 months, P1 exhibited B lymphopenia and hypogammaglobulinemia (supplemental Table 1) requiring immunoglobulin substitution and trimethoprim/sulfamethoxazole prophylaxis. P1 died at age 15 months of sepsis without an identified causative agent.
Figure 1
Identification and intestinal histopathology of TTC7A-mutated patients. (A) Radiograph colonography with barium enema in P1 showing decreased diameter of the descending and sigmoid colon, dilated small intestine segments, and dilation of ascending and ...
Given the consanguinity, we assumed an autosomal-recessive inheritance and performed homozygosity mapping (Figure 1D) and exome sequencing. Unexpectedly, we identified a perfectly segregating homozygous missense mutation in TTC7A ({"type":"entrez-nucleotide","attrs":{"text":"NM_020458","term_id":"572876398","term_text":"NM_020458"}}NM_020458:c.T1037C;p.L346P) (Figure 1E and supplemental Figure 1B). The substitution of the highly conserved TTC7ALeu346 residue (supplemental Figure 1D) to TTC7APro346 was predicted damaging to TTC7A function by SIFT and PolyPhen-2 prediction algorithms.
Concomitantly, we investigated another patient (P2) with classical MIA-SCID manifesting in lymphopenia with near-absent CD8+ T cells, hypogammaglobulinemia, undetectable thymic tissue (supplemental Figures 1F, 2, and 3B), and extended intestinal atresia (Figure 1G). Molecular analysis revealed a large genomic deletion comprising TTC7A exons 6 through 8, causing frameshift and premature transcriptional stop codon ({"type":"entrez-nucleotide","attrs":{"text":"NM_020458","term_id":"572876398","term_text":"NM_020458"}}NM_020458:c765_1065del;p.N256Qfs*7) (Figure 1H and supplemental Figure 2B-C).
The pronounced immunodeficiency despite mild structural intestinal defects in P1 prompted us to compare the lymphocyte compartments of P1 and P2. Both showed B-cell lymphopenia and hypogammaglobulinemia (supplemental Table 1) despite the presence of naive, marginal zone–like and class-switched memory B cells (supplemental Figure 3A). Increased proportion of transitional B cells in P1 indicated a partial developmental block (supplemental Figure 3A) reminiscent of the tonic BCR- or BAFF-signaling defects resulting in decreased B-cell survival and hypogammaglobulinemia.5,6 TTC7A is required for tethering of phosphatidylinositol 4-kinase, catalytic, alpha (PI4KCA) to the plasma membrane,2 which in turn phosphorylates phosphatidylinositol into phosphatidylinositol(4,5)P2, a second messenger in the phospholipase C gamma-2 (PLCγ2) and phosphatidylinositol 3′-kinase (PI3K) signaling cascades downstream of lymphocyte antigen receptors.7
P1 had unremarkable T-cell counts (supplemental Table 1), CD4+ and/or CD8+ T-cell distribution (supplemental Figure 3B), and T-cell repertoire (supplemental Figure 1E). Maternal cells were absent. A significant proportion of CD4+ T cells in P2 but not in P1 expressed CD25 activation marker, possibly as a compensatory mechanism that would otherwise lead to proliferative expansion8 (supplemental Figure 3B). Cell-surface expression of CD44, CD62L, and CD69 and neutrophil counts and oxidative burst were normal (not shown).
Higher TTC7A expression in thymic stroma compared with thymocytes had suggested aberrant thymic (micro)environment as a T-cell extrinsic cause for T-lymphopenia in TTC7A deficiency.1 We challenged this finding by monitoring T-cell proliferation of pulse-labeled patient peripheral blood mononuclear cells after anti-CD3 stimulation. Whereas P2’s T cells showed no proliferative response, proliferation of T cells from P1 was only partially impaired (Figure 1I). TTC7APro346 protein in HEK293 cells was stable and detectable at levels similar to those for TTC7Awildtype (supplemental Figure 3D), implying that TTC7ALeu346Pro represents a hypomorphic variant allowing for residual protein function. Furthermore, T cells from both patients were unable to upregulate CD25 expression after anti-CD3 stimulation, suggesting T-cell receptor (TCR)–signaling defects (Figure 1I). Accordingly, the majority of P1’s T cells had naive CD45RA+ phenotype (supplemental Figure 3C). One possible explanation might be the inability of mutant TTC7A to recruit PI4KCA to the plasma membrane, required for its interaction with CD4-p56lck and downstream signal transduction.9 Because lymphocyte-specific protein tyrosine kinase (LCK) interaction with CD4 and/or CD8 is essential for T-cell development and activation,10 TTC7A might be an integral component of the TCR signalosome. Notably, in contrast to previous observations of defective T-cell proliferation1,4 and our findings, a recent study identified patients with hyperproliferative TTC7A-mutant T cells,11 underlining the phenotypic variability of TTC7A-mutant immunodeficiency.
TTC7A deficiency was recently identified as the molecular cause for MIA with or without accompanying SCID.1,3 The hallmark feature of TTC7A deficiency was varying degree of intestinal aberrations. The mildest case presented with intestinal aberrations consisting of bloody diarrhea, apoptotic enterocolitis, and acute GVHD-like symptoms, but no atresias, and the extent of the observed lymphopenia remained unclear.2 P1 had B-lymphopenia, hypogammaglobulinemia, and functional T-cell defects, but intestinal structural aberrations were mild and GVHD-like signs were discrete. Collectively, the clinical spectrum of TTC7A deficiency is considerably more variable than previously appreciated, which should alert physicians to consider TTC7A mutational analysis in (S)CID patients. | v2 |
2018-11-22T14:45:35.479Z | 1986-05-01T00:00:00.000Z | 54189991 | s2ag/train | Indian Women's Development: Four Lenses
What consll1Uf88 -emanclpallon,. -development,and "llberallonfor IndM women? ~18 during the last five decadeI to change the roles, 81a1US, and posIIIon of dIff..nt groups of IndiM women haw resulted In many obvious, sometIme8 drMl8llc, changes In Indicators such as literacy and Ife ~. The88 changes have been partlc ularly IIpparent In I8rge cI1Ie8 In the 8lrata of educated, middle-class women. However, there appears to have been, In p.....IeI, M Incr.... of crIme8 ageln8t women such • 1nJrder8 which are some1Irne8 eu pheml81lc8lly termed dowry deaths. Even If some of this IIpp..nt Incre... In violence Ilg"nst women eM be attributed to a 80CIebli wIIUngll888 to publicly IlCknowledge such Inclc:lences, It 18 cIe.that .. 18 not well Md development 18 not unequlvocdy In1>rovlng the 1Iv.. of IndM women. What we have been IurnIng, as lIu8lrated by con fronting Incldel'lC88 such .. dowry deaths, 18 that development of women's Itatu. 18 not measurable by Isolated, quMUflabIe Indlcator8 of W8II-beIng such .Iteracy. We need to oblerve the changing contours of various p...1I'n8t8nl of women's condition, eetIIng theee obe8rvalloll8 within the context of that 88ClIon of IndiM 80CIety to which the pll'tlcular women belong. IndiM women, over 383 million of them In 1885, are, obviously, heterogeneou.. with dIff.-ent needs, constr"nlB, opportunl1lel, and MPlrallona. These vary with many faetora but molt In1>Ortan1Iy by whether they .... urban or Nr"; 80CIaI class (often closely M80cIated In India with CMt8, pll'tlcullU1y In Nfll .....): Md age and marItIIltatu. (faetora which Iffect a wornM'S relative poeltlon within her family). The growing literature on IndiM women h. highlighted this heterogeneity, subltantlatlng that dff..nt groups of IndM women have been affect ed quite dIff••nuy from men of their group, Md from .ach other, by the poll-Independence c:lecac:1e8 of plMned moc:lemlzallon.' But some over..-chlng con1tr81n18 OF*ata, to vll'Ylng c:legrees, on .. Indian women limply because they .... fM1IIe. In fact, some of theee forces Intluence women everywtwe and are of unlv«ul feninlst co~. Molt 8ffor1lI to In1Wve the lot of IndiM women (excluding measures Introduced In the spirit of "8OcI" welt..... and lid), have focu8ed on their economic poIItIon. ThIs Ie not surprising, given the ICII'CIIy of avlllable r-.ourwe In India and that women ~ have been dis enfranchI8ed from their control. But thII II a one-dlmen8loNli approach, ... attributable to the gIolM11 cIomInance of economlc8 In development planning. If the pl.ce of women In 1radltloNli culturea, Ik. IndIn, II to be undlr8tood, development of their ....... InJ8t be thought of In much more Integrated and 1nJ1t1-f1C8t8d ways. Four par8llel apecIB of .... Indian woman'. poIItIon InJIt be unc:leratooc:l and recognized • Interc:lepenc:lent They ••: 1) The womM'. economic/resource base; 2) The publlclpolltlcllarena IIIowed her by 8OCIety, 3) H« family I1rUCIUre and the Itrengthl It provlclel and the ImIIB It Imposes on her; and 4) "-hap. molt ~rtant, the psychologlcll/lc:leologlcal ...... about women In her 8OCIety, a 8en88 which shepes her own J*C8PtIon of her8eIf and the options she IIIows her8eIf to consider. Insight Into theee faceIB of a woman's place In her 80CIety eM be gleaned by drawing upon eev«11 dleclplnea Including economics, W'Ithropology, po/IlIcIII science, psychology, psychoM~, and sociology. Ttvough M eclectic cro88-dlsclpUnllY drawing 1og8ther of Ic:Iea a systemic view can be obtained. ThIs provlc:1e8 a fr8m8WOl'k which 18 useful for exll1llnlng and thinking about Indian women Md their c:IeveIopment The four "Ien8e8" U8ted above .... used In this PII*' to examine IndM women's c:IeveIoprnent, focusing on the lives of Nrll women from a vlDage her. c811ec1 SugllO, In Deccan MahlrMh1ra, IndiL The c:levelopment and Ch~ that have occurred In this village hive been cIocumented elsewhere, and the detIIl8 wIU not be repeated her. but a brief overview of the "nt characterl8tlcl might be useful. SugllO 18 IocaI8d In satara DI8trIct on the Deccan PIa1eIu of Maharah1r. State, IndlL ClIrnatlcdy, It 18 In the DJDIl zone, which reoeIve8 suftlclent r..nfd for one reUabIe wet-tl8&llOn crop. SugllO 18 In 1rMeltlon In 88V ... ways. lIB agriculture 18 8hIfIIng from subel8tence f.mlng to cuh cropping, Md there 18 a concomitant monetization of the village econ ~. Land-to-mM ratioa .... c:Iecrea8Ing (having dropped from 1.3 acreeJF*80n In 1842 to 0.84 acreaIF*80n In 1877), an outcoml of Increasee of the population In the polt-Independence c:lecac:1e8. Sugso 18 ov« 150 mIIe8 from Bombay (a bu""y ten-hour bu. ride), Md Ik. molt other v1Ullgea In the region, hu been ..ndng Its adult men to the city, pll'tlcullU1y to the t8lCtIIe muIs, for work. ThIs mlgrallon 18 ....ntlll. Currently mor. thW'I h8If of SugllO'. adult men live outside the vlUage and there 18 an Incr....ng c:lependency on cash Md In-kind remlt tInce8 from adult male mlgrMts. The migration of men to Bomb.y has resulted In 28 pwcent of the Sugao farms being cultivated predominMtIy by women In 1877. In ad dition, 72 pwcent of those working • agriculturll laborers w-. women. It might be expected that this fact would have had profound In1>UcaIIons for changes In the status, roles, and reaponelbilltle8 of SugllO women. But It apptWI that SugllO women'. work In subllatence production h. not In1>roved their status nor IncreI8ed their control In the v1Uage. Women's growing role In agriculture has not Increased their power In SugllO and In fact, In some In8tancee, women'. position has declined. ThIs II a pll'&cloldcal phenomenon. An 8Xlminallon ttvough the four Ien8eI eM provide some explanation. | v2 |
2019-04-07T13:05:24.639Z | 2008-12-05T00:00:00.000Z | 102168291 | s2ag/train | Surface Studies of Thiolate Adsorbates on Some Metals
7 Abstract The results and discussions in this thesis are based on my studies about selfassembled thiol layers on gold, platinum, silver and copper surfaces. These kinds of layers are two-dimensional, one molecule thick and covalently organized at the surface. They are an easy way to modify surface properties. Self-assembly is today an intensive research field because of the promise it holds for producing new technology at nanoscale, the scale of atoms and molecules. These kinds of films have applications for example, in the fields of physics, biology, engineering, chemistry and computer science. Compared to the extensive literature concerning self-assembled monolayers (SAMs) on gold, little is known about the structure and properties of thiolbased SAMs on other metals. In this thesis I have focused on thiol layers on gold, platinum, silver and copper substrates. These studies can be regarded as a basic study of SAMs. Nevertheless, an understanding of the physical and chemical nature of SAMs allows the correlation between atomic structure and macroscopic properties. The results can be used as a starting point for many practical applications. X-ray photoelectron spectroscopy (XPS) and synchrotron radiation excited high resolution photoelectron spectroscopy (HR-XPS) together with time-offlight secondary ion mass spectrometry (ToF-SIMS) were applied to investigate thin organic films formed by the spontaneous adsorption of molecules on metal surfaces. Photoelectron spectroscopy was the main method used in these studies. In photoelectron spectroscopy, the sample is irradiated with photons and emitted photoelectrons are energy-analyzed. The obtained spectra give information about the atomic composition of the surface and about the chemical state of the detected elements. It is widely used in the study of thin layers and is a very powerful tool for this purpose. Some XPS results were complemented with ToF-SIMS measurements. It provides information on the chemical composition and molecular structure of the samples. Thiol (1-Dodecanethiol, CH3(CH2)11SH) solution was used to create SAMs on metal substrates. Uniform layers were formed on most of the studied metal surfaces. On platinum, surface aligned molecules were also detected in investigations by XPS and ToF-SIMS. The influence of radiation on the layer structure was studied, leading to the conclusion that parts of the hydrocarbon chains break off due to radiation and the rest of the layer is deformed. The results obtained showed differences depending on the substrate material. The influence of oxygen on layer formation was also studied. Thiol molecules were found to replace some of the oxygen from the metal surfaces. List of Publications 8 List of publications The content of this thesis is based on the following published papers. The author was also responsible for performing all the XPS measurements and most of the sample preparations. The papers are referred to by their Roman numerals in the text. I T. Laiho, J.A. Leiro and J. Lukkari: XPS study of irradiation damage and different metal-sulfur bonds in dodecanethiol monolayers on gold and platinum surfaces. Applied Surface Science 2003, 212-213, 525-529. II T. Laiho, J.A. Leiro, S. Mattila, M. Heinonen and J. Lukkari: Photoelectron spectroscopy study of irradiation damage and metalsulfur bonds of thiol on silver and copper surfaces. Journal of Electron Spectroscopy and Related Phenomena 2005, 142, 105-112. III T. Laiho, J. Lukkari, M. Meretoja, K. Laajalehto, J. Kankare and J.A. Leiro: Chemisorption of alkyl thiols and S-alkyl thiosulfates on Pt(111) and polycrystalline platinum surfaces. Surface Science 2005, 584, 83–89. IV T. Laiho and J.A. Leiro: Influence of initial oxygen on the formation of thiol layers. Applied Surface Science 2006, 252, 6304–6312. V T. Laiho and J.A. Leiro: ToF-SIMS study of 1-dodecanethiol adsorption on Au, Ag, Cu and Pt surfaces. Surface and Interface Analysis 2008, 40, 51-59. List of Publications 9 A list of other published articles, concerning XPS studies of sulfur-containing species and of thin organic layers, where I am a co-author. These publications are related to this work, but were not included in the thesis. K. Laajalehto, I. Kartio, T. Kaurila, T. Laiho and E. Suoninen: Investigation of copper sulfide surfaces using synchrotron radiation excited photoemission spectroscopy, Mathieu, H.J., Reihl, B. and Briggs, D. (Ed.), Proc. of 6th European Conference on Applications of Surface and Interface Analysis (ECASIA 95), pp. 717-720, John Wiley & Sons, Chichester, England (1996). I. Kartio, G. Wittstock, K. Laajalehto, D. Hirsch, J. Simola, T. Laiho, R. Szargan and E. Suoninen: Detection of elemental sulfur on galena oxidized in acidic solution. International Journal of Mineral Processing 1997, 51, 293-301. K. Laajalehto, J. Leppinen, I. Kartio and T. Laiho: XPS and FTIR study of the influence of electrode potential on activation of pyrite by copper or lead. Colloids and Surfaces A 1999, 154, 193-199. K. Laajalehto, I. Kartio, M. Heinonen and T. Laiho: Temperature controlled photoelectron spectroscopic investigation of volatile species on PbS (100) surface. Japanese Journal of Applied Physics 1999, 38-1, 265-268. J. Lukkari, M. Salomaki, T. Aaritalo, K. Loikas, T. Laiho and J. Kankare: Preparation of multilayers containing conjugated thiophene-based polyelectrolytes. Layer-by-layer assembly and viscoelastic properties. Langmuir 2002, 18(22), 8496-8502. J.A. Leiro, M.H. Heinonen, T. Laiho and I.G. Batirev: Core-level XPS spectra of fullerene, highly oriented pyrolitic graphite, and glassy carbon. Journal of Electron Spectroscopy and Related Phenomena 2003, 128(23), 205-213. A. Viinikanoja, J. Lukkari, T. Aaritalo, T. Laiho and J. Kankare: Phosphonic acid derivatized polythiophene: a building block for metal phosphonate and polyelectrolyte multilayers. Langmuir 2003, 19(7), 2768-2775. List of Publications 10 J.P. Matinlinna, K. Laajalehto, T. Laiho, I. Kangasniemi, L.V.J. Lassila and P.K. Vallittu: Surface analysis of Co-Cr-Mo-alloy and Ti substrates silanized with trialkoxysilanes and silane mixtures. Surface and Interface Analysis 2004, 36(3), 246-253. M. Salomaki, T. Laiho and J. Kankare: Counteranion-controlled properties of polyelectrolyte multilayers. Macromolecules 2004, 37(25), 9585-9590. H. Paloniemi, T. Aaritalo, T. Laiho, H. Liuke, N. Kocharova, K. Haapakka, F. Terzi, R. Seeber, J. Lukkari: Water-soluble full-length single-wall carbon nanotube polyelectrolytes: preparation and characterization. Journal of Physical Chemistry B 2005, 109(18), 8634-8642. S. Mattila, J.A. Leiro, M. Heinonen and T. Laiho: Core level spectroscopy of MoS2. Surface Science 2006, 600(24), 5168-5175. | v2 |
2021-11-25T16:21:12.955Z | 2021-11-05T00:00:00.000Z | 244557881 | s2ag/train | Immune-Depleted Tumor Microenvironment Signature Is Associated with BTK Inhibitor Resistance in Mantle Cell Lymphoma
Background - The tumor microenvironment (TME) plays a vital role in the growth and survival of mantle cell lymphoma (MCL) cells. However, characterization of the TME transcriptomic profile in MCL, its prognostic impact and response to Bruton's tyrosine kinase inhibitors (BTKi) is unknown. Unlike other lymphomas, the TME in MCL patients has not been fully characterized at the transcriptomic and genomic levels. To further understand the relevance of tumor-immune landscape in tissue microenvironments in the context of BTKi, we performed multi-omic profiling of the TME in tissues from MCL patients.
Methods - Tissue biopsies were collected from MCL patients treated with BTKi. The study was conducted under an Institutional Review Board-approved protocol at The University of Texas MD Anderson Cancer Center. A total of 42 patients treated with BTKi were included. Among evaluable patients, DNA and RNA extraction was performed from fresh biopsies from lymph nodes and non-nodal tissues (including bone marrow). Whole exome (WES) and bulk RNA sequencing (RNA-seq) were performed to assess the somatic mutation profile, copy number abnormalities and gene expression profile to identify TME gene clusters. RNA sequencing data from an independent cohort of MCL patients from Scott et al (n = 122) was analyzed. Joint WES and RNA-seq, mutation calling, expression analysis, and cell type deconvolution from the transcriptome were performed using the BostonGene automated pipeline. Overall survival was calculated after starting BTKi therapy.
Results - We obtained 42 MCL tissue samples (28 lymph nodes, 13 various tissues and one bone marrow) from patients treated with BTKi. Samples were obtained at/after starting treatment with BTKi at clinical progression. Unsupervised clustering based on the activities of the proposed transcriptomic signatures identified four distinct MCL subtypes based on tumor-immune cell gene signatures. We identified the four distinct MCL microenvironment signatures - normal lymph node like (N; n = 27), immune cell-enriched or "Hot" (IE; n = 46), mesenchymal (M; n = 44) and immune depleted/deserted or 'cold' (D; n = 51). The tumor proliferation rate signature and PI3K pathways were significantly overexpressed in immune-depleted (D) TME group. Evaluable patients were further classified based on response to BTKi as sensitive (n = 17), primary resistant (n = 11) or acquired resistant (n = 11). The TME was further dichotomized into immune cell rich and immune desert categories based on commonly involved immune cells and pathways. BTKi resistant MCL primarily exhibited immune depleted TME subtype.
To explore the somatic mutation profile in relation to TME clusters, we performed a multiomic analysis combining WES data with RNA sequencing data and depicted according to the four TME clusters. Somatic mutations in TP53, NSD2, NOTCH1, KMT2D, SMARCA4, which were previously reported in ibrutinib-resistant MCL and/or in refractory high-risk MCL patients, were predominant in the immune-depleted TME cluster (D).
Conclusions - Overall, we defined BTKi sensitivity and resistance by immune-hot and immune-cold TME portraits, respectively. The immune-depleted TME subtype (D) was characterized by dominant proliferation gene signature, overexpressed PI3K pathway, BTKi resistance and poor outcomes in MCL patients.
Jain: Lilly: Consultancy; kite: Consultancy. Nomie: BostonGene, Corp: Current Employment, Current holder of stock options in a privately-held company. Segodin: boston gene: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Egorov: BostonGene: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Kotlov: BostonGene Corp: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Vega: CRISPR Therapeutics and Geron: Research Funding; i3Health, Elsevier, America Registry of Pathology, Congressionally Directed Medical Research Program, and the Society of Hematology Oncology: Research Funding. Svekolkin: BostonGene Corp.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Bagaev: BostonGene Corp.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: BostonGene. Frenkel: boston gene: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Attaulakhanov: boston gene: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties. Fowler: BostonGene, Corp: Current Employment, Current holder of stock options in a privately-held company; Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, TG Therapeutics and Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Flowers: Sanofi: Research Funding; Amgen: Research Funding; EMD: Research Funding; Iovance: Research Funding; Janssen: Research Funding; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Bayer: Consultancy, Research Funding; BeiGene: Consultancy; Pfizer: Research Funding; Celgene: Consultancy, Research Funding; Denovo: Consultancy; Novartis: Research Funding; Nektar: Research Funding; Epizyme, Inc.: Consultancy; Morphosys: Research Funding; Genmab: Consultancy; AbbVie: Consultancy, Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; Ziopharm: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; Biopharma: Consultancy; Pharmacyclics/Janssen: Consultancy; Kite: Research Funding; Guardant: Research Funding; SeaGen: Consultancy; Cellectis: Research Funding; Karyopharm: Consultancy; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Allogene: Research Funding; Adaptimmune: Research Funding; Spectrum: Consultancy; Acerta: Research Funding; 4D: Research Funding; Pharmacyclics: Research Funding. Wang: BGICS: Honoraria; Newbridge Pharmaceuticals: Honoraria; BioInvent: Research Funding; VelosBio: Consultancy, Research Funding; Juno: Consultancy, Research Funding; InnoCare: Consultancy, Research Funding; Hebei Cancer Prevention Federation: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Research Funding; Mumbai Hematology Group: Honoraria; Scripps: Honoraria; The First Afflicted Hospital of Zhejiang University: Honoraria; Loxo Oncology: Consultancy, Research Funding; Moffit Cancer Center: Honoraria; Lilly: Research Funding; Bayer Healthcare: Consultancy; OMI: Honoraria; Imedex: Honoraria; Epizyme: Consultancy, Honoraria; Celgene: Research Funding; Physicians Education Resources (PER): Honoraria; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria, Research Funding; Chinese Medical Association: Honoraria; Clinical Care Options: Honoraria; Dava Oncology: Honoraria; CStone: Consultancy; DTRM Biopharma (Cayman) Limited: Consultancy; Genentech: Consultancy; Oncternal: Consultancy, Research Funding; Molecular Templates: Research Funding; CAHON: Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Anticancer Association: Honoraria; Acerta Pharma: Consultancy, Honoraria, Research Funding.
| v2 |
2021-09-28T15:44:10.390Z | 2021-07-21T00:00:00.000Z | 240869611 | s2ag/train | Learning astronomy through Augmented Reality: EduINAF resources to enhance students’ motivation and understanding
<p>In this presentation, we will illustrate Augmented Reality (AR) resources developed by INAF (The Italian National Institute of Astrophysics) for communicating astronomy, distributed to schools and the general public by EduINAF, the online magazine devoted to education and outreach, (https://edu.inaf.it/). The impact of these initiatives and future perspectives will also be provided. AR and other innovative technologies have a very high potential in astronomy communication, outreach and education. By adding texts, images, overlays, sounds and other effects, AR enhances users’ experience, allowing personal and interactive choices and offering unique educational opportunities. Due to its benefits of providing an engaging and immersive learning space, the use of AR in education has been recognized as a powerful instrument for educators and students.  Among the first attempts and experiments with AR, in 2019 we created an augmented reality app - both in Italian and English - dedicated to the Museum of Specola inside the Astronomical Observatory of Palermo, in order to promote the cultural heritage of the institute. Using a simple tool like the app <em>Zappworks Studio Widgets</em> and a smartphone, the public could interact with the history and the instruments held in the museum, choosing between seven different levels of information. In 2020 - on the occasion of “Esperienza InSegna 2020”, a science fair for schools, which every year counts about 15.000 participants - INAF created an interactive game called “Terra Game” using Metaverse Studio. Discovering the “ingredients for life” and the composition, temperature and atmosphere of different planets, students were able to understand how special the Earth is in comparison to the other planets of the Solar System and to exoplanets orbiting around other stars. In 2021, to catch teenage students’ attention, we integrated new technologies in the learning path dedicated by EduINAF to Mars on the occasion of the landing on Mars of NASA’s rover Perseverance. We developed the augmented reality experience “MARS2020 Perseverance” with <em>Zap works Studio Design</em>, showing the objectives of the mission, other rovers landed on Mars and the sophisticated instruments onboard. Using this app people can discover the instruments used by the rover for acquiring information about Martian geology, atmosphere, environmental conditions and potential biosignatures. The app also gives the opportunity to visit NASA resources and take a selfie with the Perseverance and the drone Ingenuity and share the pictures with friends through social media. To mark the event of the <em>Supermoon</em> of 26th May 2021 EduINAF also published educational resources dedicated to the moon. Among these, the augmented reality experience “Maree Lunatiche”, developed with Zap works Studio Design. This app explains the phenomenon of tides. From the menu, there is also the opportunity to interact with a 3D model of the moon and to take a selfie with the full moon. The impact of these and other AR initiatives in EduINAF, as well as their future perspectives, will also be provided in this talk.</p>
<p><img src="data:image/jpeg;base64, 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| v2 |
2018-08-23T13:02:51.309Z | 2018-04-01T00:00:00.000Z | 52067601 | s2ag/train | Impact of Building Human Capital with Support of Information Technology on Efficiency of Hospital Activities
Thepurposeofthisarticleistopresenttheresultsofaresearchontheimpactoffocusingofmanagers onhumancapitalwithsupportofinformationandcommunicationtechnologyonaneffectivenessof Polishhospitalactivities.AsurveyquestionnaireaddressedtothemanagersofPolishhospitalswas usedinordertocollectresearchdata.Astatisticalmethod-structuralequationmodeling(SEM)was appliedtoanalyzethegathereddata.Aresearchmodelproposedinthestudywasproperlymatchedto thedataandpresentedapositiveandcausalrelationshipbetweenthelevelofinformationtechnology developmentandfocusingmanagersonthebuildingofhumancapitalonoperationalefficiencyof Polishhospitalsactivities. KEywoRdS Healthcare Management, Information Technology, Management of Human Capital, Operational Efficiency of Hospitals INTRodUCTIoN Knowledgeandskillsofemployeesareoftencalledhumancapital.Itisanessentialcomponentof broadlydefinedintellectualcapitalofanorganization,whichconsistsofathinkingpart-(thehuman capital)andanon-thinkingcapital(structuralcapital)(Roos,Roos,Dragonetti,&Edvinsson,1997). Thus,humancapitalmanagementshouldbeapriorityforanorganization,especiallyintheprovisionof medicalservices.Inthiscasetheknowledgeandskillsofmedicalpersonnelhaveagreatimportance. Nowadayseconomicactivity(withveryfewexceptions)isnotpossiblewithouttheparticipation ofinformationandcommunicationtechnology.Informationandcommunicationtechnologyshould improvetheefficiencyofanybusiness(Jelonek,Stepniak,Turek,&Ziora,2013).However,areflection ontheimpactofICT,forexample,ontheeffectivenessoftheeconomicactivitiesarestillimportant. Thequalityandeffectivenessofhealthcareplaysignificantroleforboththeoveralleconomy andforthehealth-careofaconsumer.Cost-effectivehealthcareiscrucialtothefinancialstability ofmanystakeholders,sothatthequalityandeffectivenessofprogramsareparticularlyimportant intimesofeconomicchallenges.Qualityandefficiencyoccupyasignificantpositioninthereform anddevelopmentofthehealthcaresystem. This paper presents the result of analysis concerning relationships between the level of developmentofICT,buildinghumancapitalandefficiencyofactivitiesinhospitalsofPoland. SEM modeling allows scientists to test substantive theories and also allows to draw causal conclusionsbasedonnon-experimentalresearch.Thisisoneofthemostimportantreasonsforusing SEMinmanyareasofscience.Thesecondreasonisthefactofexplicitlytakingintoaccountthe measurementerrorsthatarecommoninmostdisciplinesandthetypicaluseoflatentvariables.The numberofPolishhospitalsisover1000andtheresearchsamplewas156returnedquestionnaires. International Journal of Ambient Computing and Intelligence Volume 9 • Issue 2 • April-June 2018 2 FoCUSING oN BUILdING HUMAN CAPITAL Inthemajorityofmoderncommercialandnon-profitorganizations,includingpublicorganizations, managersshouldtakeintoaccounttheimportanceofknowledgemanagementaswellasmanagement of information processes (Nowicki & Sitarska, 2010). These and other intangible resources are significantelementsofmanagementoforganization.Themanagersshouldperceiveknowledgeas averyimportantresourceinanorganization.Knowledgemanagementisbecomingmoreandmore importantfieldofmanagers’responsibilitysuchascapitalmanagement,humanresources,economic performanceorphysicalresources.Thisalsoconcernsmedicalactivities(medicalservices).These servicesareveryimportanttopatients.Theyshouldbeperformedbyqualifiedstaffwhichusesthe newestscientificandmedicaltechnologiesaccomplishments. A.TofflerandH.Toffler(1995)statethatthefoundationofalleconomicsystemsisknowledge, andalleconomicactivitiesdependonitscollectedintellectualresources.Economistsandentrepreneurs usuallyomitthiselementintheiraccountsofcosts,asopposedtothecapital,labor,andland. I.NonakaandH.Takeuchi(1995,p.11)suggestthatknowledgemanifestsitselfintwoforms oftacitknowledgeandexplicitknowledge,i.e.available,mainlyinformalizedandcodifiedforms. Tacitknowledgeistheresultofexperiencegainedbypeople.Explicitandtacitknowledgeusedin humaneconomicactivityisoftencalledhumancapitalasperhapsthemostimportantelementof eachorganization’sintellectualcapital.AccordingtoN.Bontis(2001),humancapitalisthemost importanttypeofbusinessassets.Humancapitalisvariousknowledgethatpeoplepossess,create andenrich.Theyhavetheabilitytothinkcreatively,sotheymaybeasourceofnewideas,solutions andthedevelopmentofeconomicentity.Otherdefinitionsandcomprehensivecharacteristicsofthe conceptofhumancapitalarepresentedin(Goldin,2016). Acharacteristic featureof themodern economy is thegrowing importanceof the so-called intangibleassetsandespeciallythegrowingimportanceofhumancapital.Thisisparticularlyimportant inorganizationsthatprovideso-calledprofessionalservices,forexample,inmedicalentities. Efficient and professional management of medical entities and their human capital is very importantforthefollowingreasons: • Provisionofmedicalservicesrequiresextensiveknowledgeandrelevantskills, • Healthcareisfinancedfrompublicfundsinmostcountries, • Medicalservicesareveryimportantforpatients-healthisoneofthegreatestvalues, • Healthcareentitiesoperateonthepartlycontrolledmarket. Insummary,focusingonhumancapitalmanagementisveryimportant,especiallyintheentities providingmedicalservices. THE RoLE oF INFoRMATIoN ANd CoMMUNICATIoN TECHNoLoGy IN HEALTH CARE Theroleofinformationandcommunicationtechnologyisveryimportantinanykindofeconomic activitybutalsodifficulttoclassifyduetotheveryrapiddevelopmentofICT.Thesameistruefor theso-calledhospitalsinformationsystems. Theinformationsystemofmostmedicalentitiesreferstoseveralbasicareasoftheiractivity: • Patient’sstayandmedicaldatarelatedtothatstay • Provisionofmedicalservices • Administrationandotherauxiliaryactivities 13 more pages are available in the full version of this document, which may be purchased using the "Add to Cart" button on the product's webpage: www.igi-global.com/article/impact-of-building-human-capitalwith-support-of-information-technology-on-efficiency-ofhospital-activities/205572?camid=4v1 This title is available in InfoSci-Artificial Intelligence and Smart Computing eJournal Collection, InfoSci-Journals, InfoSci-Journal Disciplines Computer Science, Security, and Information Technology, InfoSci-Journal Disciplines Engineering, Natural, and Physical Science, InfoSci-Select. Recommend this product to your librarian: www.igi-global.com/e-resources/libraryrecommendation/?id=166 | v2 |
2020-07-23T09:04:28.166Z | 2020-07-20T00:00:00.000Z | 225529971 | s2ag/train | Japan's approval of detergents for SARS-CoV-2 and its potential as a hand sanitizer
During the SARS-CoV outbreak in 2003, Japan's National Institute for Infectious Diseases (NIID) showed, on their website, that SARS-CoV, an enveloped virus, could be deactivated by a 200-fold dilution of a neutral detergent 1. Based on these findings, our clinic began using a 200-fold diluted solution of kitchen detergent in early March to wipe down materials and soak instruments as well as the hands of patients and staff for the purpose of SARS-CoV-2 disinfection. Our tweet on April 10, 2020 regarding this gained 6 million views in Japan 2. There have been no experimental studies confirming the deactivation effect of detergents on SARS-CoV or SARS-CoV-2. On April 15, the Ministry of Economy, Trade and Industry (METI) of Japan announced that they would test the disinfecting effects of detergents on SARS-CoV-2. On April 21, our clinic was interviewed by METI. The final results were publicly announced on June 26, 2020 3. To date, no English reviews of this Japan’s public presentation 4 exist. Validation studies using SARS-CoV-2 (JPN/TY/WK-521) and VeroE6/TMPRSS2 cells were conducted at five institutes in Japan, including NIID and Kitasato University (KU) 4. At NIID, the surfactant was mixed with the virus for periods between 20 seconds and 5 minutes. After removing the surfactant with resin, they evaluated the antiviral value using the TCID50 method. An infectious titer reduction rate of over 99.99% was obtained confirming the disinfection efficiency. At KU, VeroE6/TMPRSS2 cells were incubated for an hour with the surfactant and virus. After observing its cytopathic effect (CPE) for three days, the RNA titer was measured using qRT-PCR in the culture supernatant. Only when no CPE was observed in all wells and no increase in RNA titer was observed, was it judged as having a disinfection effect. NIID finally judged and published the following 9 surfactants, that were determined as possessing a disinfection effect at either the NIID or KU or both, as effective disinfectants for SARS-CoV-2 under the following conditions: Sodium linear alkylbenzene sulfonate; 20 seconds with 0.1% at NIID, 5 minutes with 0.1% at KU. Alkyl glycoside; 20 seconds with 0.0.5% at NIID, 1 minute with 0.1% at KU. Alkylamine oxide; 20 seconds with 0.05% at NIID, 1 minute with 0.05% at KU. Benzalkonium chloride; 2 minutes with 0.05% at NIID, 1 minute with 0.05% at KU. Benzethonium chloride; 1 minute with 0.05% at NIID, 5 minutes with 0.05% at KU. Dialkyldimethyl ammonium chloride; 40 seconds with 0.01% at NIID, 5 minutes with 0.01% at KU. Polyoxyethylene alkyl ether; 5 min with 0.2% at NIID, (not effective in 5 min with 0.1% at KU). Pure-soap component: 1 minute with 0.24% potassium salts of fatty acids at NIID, (not effective at 5 minutes with 0.12% at NIID and at 5 min with 0.1% at KU). Pure-soap component: 1 minute with 0.22% sodium of fatty acids at NIID, (not effective at 5 minutes with 0.11% at NIID and at 10 minutes with 0.1% at KU). However, the use of detergent for hand sanitizers was discouraged by NIID 3. From early March 2020 to the present (July 15 2020), we applied a 200-fold dilution of kitchen detergent (Charmy V Quick; LION corp., Japan), which contains 30% surfactant (alkylamine oxide, sodium alpha-olefin sulfonate, polyoxyethylene fatty acid alkanolamide, and polyoxyethylene alkyl ether), to the hands of at least 500 patients, and five members of medical staff as a SARS-CoV-2 disinfectant. The hands of patients and medical staff were not rinsed for approximately 15 minutes and 1 hour after application, respectively. The only adverse effects observed were mild hand sores in all the staff. Ethanol as hand sanitizer also causes hand sores. Dishwashing with bare hands using undiluted neutral kitchen detergent has been widely practiced around the world. In some European countries, it is common not to rinse the detergent completely when washing dishes and bathing. Given these practices, toxicity is unlikely to be an issue if a thin layer of detergent is left on the hands for a couple of hours; however, further verification is necessary.Ethanol dries and loses its disinfection property rapidly, whereas detergents do not easily dry out on skin and cloth, enabling longer contact with the virus. Furthermore, detergents remain on the skin after it dries, and may melt and become effective when wet droplets adhere. This can be expected on the skin as well as in other materials including face masks and clothing. Detergents are inexpensive and are unlikely to be in short supply. Studies confirming the prolonged effectiveness of dried detergents on surfaces and the toxicity of the above methods are necessary. References 1. National Institute for Infectious Diseases, SARS ni kansuru shoudoku (3teiban) [Disinfection on SARS (3rd Ed.)]. http://idsc.nih.go.jp/disease/sars/sars03w/index.html. Published December 18, 2003. 2. @blanc0981. (2020, April 10). Toindeha Ikkagetsukan, 200bainiusumetanodaidokorosenzaide Sutaffu, kanatani tewonurashite, arainagasazuniitemorattemasuga, Hitorimotearenadono Shinkokunauttaehanai. Kaimenkasseizainosugoitenha kansoshitemonokori, sonoatonaniwosawattemo sonohifuni koteingusareta kaimenkasseizaide koronawokorosukanoseigatakai. [We have our staff and patients wet their hands with 200 times diluted kitchen detergent for a month without rinsing it off. Not a single person has complained of serious complaints such as rough hands. The great thing about surfactants is that they stay on after they dry, and whatever you touch afterwards is likely to kill the corona with the surfactant coated on that skin.] [Twitter post]. Retrieved from https://twitter.com/blanc0981/status/1248415995527483394?s=20 3. Surfactants and Hypochlorous Acid Solution for Removal of Coronavirus from Surfaces (Final Announcement). https://www.meti.go.jp/english/press/2020/0626_004.html Published June 26, 2020. Accessed July 15, 2020. 4. Shingatacoronauirusunitaisuru daigaeshoudokuhouhounoyuukouseihyouka (Saishuuhoukoku) [Evaluation of the Effectiveness of Alternative Disinfection Methods for New Coronavirus (Final Report)]. https://www.nite.go.jp/data/000111315.pdf Published June 29, 2020. Accessed July 15, 2020. | v2 |
2019-05-14T14:01:57.381Z | 2009-01-01T00:00:00.000Z | 153284741 | s2ag/train | Quantitative finance : its development, mathematical foundations, and current scope
Preface. PART I: PERSPECTIVE AND PREPARATION. 1. Introduction and Overview. 1.1 An Elemental View of Assets and Markets. 1.1.1 Assets as Bundles of Claims. 1.1.2 Financial Markets as Transportation Agents. 1.1.3 Why Is Transportation Desirable? 1.1.4 What Vehicles Are Available? 1.1.5 What Is There to Learn about Assets and Markets? 1.1.6 Why the Need for Quantitative Finance? 1.2 Where We Go from Here. 2. Tools from Calculus and Analysis. 2.1 Some Basics from Calculus. 2.2 Elements of Measure Theory. 2.2.1 Sets and Collections of Sets. 2.2.2 Set Functions and Measures. 2.3 Integration. 2.3.1 Riemann-Stieltjes. 2.3.2 Lebesgue/Lebesgue-Stieltjes. 2.3.3 Properties of the Integral. 2.4 Changes of Measure. 3. Probability. 3.1 Probability Spaces. 3.2 Random Variables and Their Distributions. 3.3 Independence of R.V.s. 3.4 Expectation. 3.4.1 Moments. 3.4.2 Conditional Expectations and Moments. 3.4.3 Generating Functions. 3.5 Changes of Probability Measure. 3.6 Convergence Concepts. 3.7 Laws of Large Numbers and Central Limit Theorems. 3.8 Important Models for Distributions. 3.8.1 Continuous Models. 3.8.2 Discrete Models. PART II: PORTFOLIOS AND PRICES. 4. Interest and Bond Prices. 4.1 Interest Rates and Compounding. 4.2 Bond Prices, Yields, and Spot Rates. 4.3 Forward Bond Prices and Rates. 4.4 Empirical Project #1. 5. Models of Portfolio Choice. 5.1 Models That Ignore Risk. 5.2 Mean-Variance Portfolio Theory. 5.2.1 Mean-Variance 'Efficient' Portfolios. 5.2.2 The Single-Index Model. 5.3 Empirical Project #2. 6. Prices in a Mean-VarianceWorld. 6.1 The Assumptions. 6.2 The Derivation. 6.3 Interpretation. 6.4 Empirical Evidence. 6.5 Some Reflections. 7. Rational Decisions under Risk. 7.1 The Setting and the Axioms. 7.2 The Expected-Utility Theorem. 7.3 Applying Expected-Utility Theory. 7.3.1 Implementing EU Theory in Financial Modeling. 7.3.2 Inferring Utilities and Beliefs. 7.3.3 Qualitative Properties of Utility Functions. 7.3.4 Measures of Risk Aversion. 7.3.5 Examples of Utility Functions. 7.3.6 Some Qualitative Implications of the EU Model. 7.3.7 Stochastic Dominance. 7.4 Is the Markowitz Investor Rational? 7.5 Empirical Project #3. 8. Observed Decisions under Risk. 8.1 Evidence about Choices under Risk. 8.1.1 Allais? Paradox. 8.1.2 Prospect Theory. 8.1.3 Preference Reversals. 8.1.4 Risk Aversion and Diminishing Marginal Utility. 8.2 Toward 'Behavioral' Finance. 9. Distributions of Returns. 9.1 Some Background. 9.2 The Normal/Lognormal Model. 9.3 The Stable Model. 9.4 Mixture Models. 9.5 Comparison and Evaluation. 10. Dynamics of Prices and Returns. 10.1 Evidence for First-Moment Independence. 10.2 Random Walks and Martingales. 10.3 Modeling Prices in Continuous Time. 10.3.1 Poisson and Compound-Poisson Processes. 10.3.2 Brownian Motions. 10.3.3 Martingales in Continuous Time. 10.4 Empirical Project #4. 11. Stochastic Calculus. 11.1 Stochastic Integrals. 11.1.1 Ito Integrals with Respect to a B.m. 11.1.2 From It^o Integrals to It^o Processes. 11.1.3 Quadratic-Variations of It^o Processes. 11.1.4 Integrals with Respect to It^o Processes. 11.2 Stochastic Differentials. 11.3 Ito's Formula for Differentials. 11.3.1 Functions of a B.m. Alone. 11.3.2 Functions of Time and a B.m. 11.3.3 Functions of Time and General It^o Processes. 12. Portfolio Decisions over Time. 12.1 The Consumption-Investment Problem. 12.2 Dynamic Portfolio Decisions. 12.2.1 Optimizing via Dynamic Programming. 12.2.2 A Formulation with Additively-Separable Utility. 13. Optimal Growth. 13.1 Optimal Growth in Discrete Time. 13.2 Optimal Growth in Continuous Time. 13.3 Some Qualifications. 13.4 Empirical Project #5. 14. Dynamic Models for Prices. 14.1 Dynamic Optimization (Again). 14.2 Static Implications: The CAPM. 14.3 Dynamic Implications: The Lucas Model. 14.4 Assessment. 14.4.1 The Puzzles. 14.4.2 The Patches. 14.4.3 Some Reflections. 15. Efficient Markets. 15.1 Event Studies. 15.1.1 Methods. 15.1.2 A Sample Study. 15.2 Dynamic Tests. 15.2.1 Early History. 15.2.2 Implications of the Dynamic Models. 15.2.3 Excess Volatility. PART III: PARADIGMS FOR PRICING. 16. Static Arbitrage Pricing. 16.1 Pricing Paradigms: Optimization vs. Arbitrage. 16.2 The APT. 16.3 Arbitraging Bonds. 16.4 Pricing a Simple Derivative Asset. 17. Dynamic Arbitrage Pricing. 17.1 Dynamic Replication. 17.2 Modeling Prices of the Assets. 17.3 The Fundamental P.D.E. 17.3.1 The Feynman-Kac Solution to the P.D.E. 17.3.2 Working out the Expectation. 17.4 Allowing Dividends and Time-Varying Rates. 18. Properties of Option Prices. 18.1 Bounds on Prices of European Options. 18.2 Properties of Black-Scholes Prices. 18.3 Delta Hedging. 18.4 Does Black-Scholes StillWork? 18.5 American-Style Options. 18.6 Empirical Project #6. 19. Martingale Pricing. 19.1 Some Preparation. 19.2 Fundamental Theorem of Asset Pricing. 19.3 Implications for Pricing Derivatives. 19.4 Applications. 19.5 Martingale vs. Equilibrium Pricing. 19.6 Numeraires, Short Rates, and E.M.M.s. 19.7 Replication & Uniqueness of the E.M.M. 20. Modeling Volatility. 20.1 Models with Price-Dependent Volatility. 20.1.1 The C.E.V. Model. 20.1.2 The Hobson-Rogers Model. 20.2 ARCH/GARCH Models. 20.3 Stochastic Volatility. 20.4 Is Replication Possible? 21. Discontinuous Price Processes. 21.1 Merton's Jump-Diffusion Model. 21.2 The Variance-Gamma Model. 21.3 Stock Prices as Branching Processes. 21.4 Is Replication Possible? 22. Options on Jump Processes. 22.1 Options under Jump-Diffusions. 22.2 A Primer on Characteristic Functions. 22.3 Using Fourier Methods to Price Options. 22.4 Applications to Jump Models. 23. Options on S.V. Processes. 23.1 Independent Price/Volatility Shocks. 23.2 Dependent Price/Volatility Shocks. 23.3 Adding Jumps to the S.V. Model. 23.4 Further Advances. 23.5 Empirical Project #7. Solutions to Exercises. References. Index. | v2 |
2020-11-05T09:07:49.351Z | 2020-11-05T00:00:00.000Z | 228914581 | s2ag/train | Impact of Genetic Abnormalities and Measurable Residual Disease Levels on Outcome in Patients with MDS/AML Pre-Emptively Treated with Azacitidine: Correlative Results of the Prospective RELAZA2 Trial
Background: Monitoring of measurable residual disease (MRD) in patients (pts) with advanced myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) who achieve complete remission (CR) can predict hematological relapse. Recently published data from the first cohort of the RELAZA2-trial have shown that pre-emptive therapy with azacitidine (AZA) can prevent or substantially delay an overt relapse in MRD-positive pts with MDS or AML (Platzbecker et al. Lancet Oncol. 2018).
Aims: To evaluate outcome of the entire patient cohort of the RELAZA2-trial and determine whether MRD-guided pre-emptive AZA treatment could prevent relapse in molecularly defined cohorts.
Methods: Between 12/2011 and 07/2018 380 pts with advanced MDS or AML, who had achieved CR after conventional chemotherapy or allogeneic hematopoietic stem-cell transplantation (allo-HCT) were prospectively screened for MRD in monthly intervals either in bone marrow (BM) or peripheral blood (PB). A total of 94 pts (AML, n=83; MDS, n=11) became MRD positive during 24 months from baseline by either quantitative PCR (qPCR) or analysis of CD34+ donor-chimerism and entered the treatment phase. Preemptive MRD-triggered treatment consisted of AZA 75 mg/m2 per day subcutaneously on days 1-7 of a 29-day cycle for up to 24 cycles. After six cycles, MRD status was reassessed and pts with MRD negativity were eligible for treatment de-escalation. Primary endpoint was relapse-free survival (RFS) six months after start of pre-emptive treatment. For mutational analysis next generation sequencing (NGS) with a panel of 54 genes was performed (Illumina Trusight Myeloid).
Results: Median age was 60 yrs (range: 22-80 yrs); 52 (55%) of the pts were female. Prior therapy consisted of chemotherapy in 42 (45%) and allo-HCT in 52 (55%) of the pts. Cytogenetics could be analyzed in 93 (99%) of the 94 pts. Risk categorization according to ELN 2017 was favorable in 30 (37%), intermediate in 31 (38%) and adverse in 21 (26%) of the AML pts, respectively. Type of MDS was advanced in all 11 pts and all were previously transplanted. Fifty-two (61%) of 85 pts with available NPM1 status were positive. NGS on 64 (68%) pts with available DNA at the time of first diagnosis revealed additional mutations in DNMT3A (n=25), TET2 (n=15), FLT3-ITD (n=12), IDH1 (n=9), FLT3-TKD (n=8), ASXL1, NRAS, TP53 (n=7, each), IDH2 (n=6), PTPN11, WT1 (n=5, each), GATA2, U2AF1 (n=4, each), CBL (n=3), CEBPA, CSFR3, CUX1, EZH2, KIT, RAD21, RUNX1, SF3B, STAG2, ZRSR2 (n=2, each), and KRAS (n=1).
MRD data were correlated with outcome in 45 pts for NPM1, in 3 for RUNX1-RUNX1T1, whereas CD34-donor-chimerism was analyzed in 39 pts (missing, n=7). There was a significant faster and deeper decline of MRD in PB as compared to BM (P=0.03). The same held true with regard to the increase of donor-chimerism, which was achieved faster in PB as compared to BM (P=0.05). Secondary molecular abnormalities (MAs) had no impact on MRD response as measured by qPCR, which was also true if MAs were categorized functionally. Similarly, additional chromosomal abnormalities had no impact on MRD response in both MRD methods. However, in pts with measurement of donor-chimerism ASXL1 mutations were a negative factor for MRD response (P<0.001). At hematological relapse, only 1 (2%) of 45 pts with NPM1 measurement was not congruently MRD positive. Six months after start of MRD-guided therapy, 56 (60%) of 94 pts were still in CR while a total of 38 pts (40%) developed a hematological relapse after median of 3 AZA cycles. 38 (40%) pts responded with either a decline of MRD below a predefined threshold (increasing donor-chimerism to ≥80% or PCR MRD <1%), while a stabilization in the absence of relapse was achieved in 18 (19%) pts. Overall response rate was not statistically different between pts with (63%) or without (55%) antecedent allo-HCT (P=0.5). RFS rate at 6 months was 60% (56/94 pts). With a median follow-up of 9 months after start of MRD-guided pre-emptive treatment 12-months overall and progression-free survival rates were 94% and 44%, respectively.
Conclusions: AZA as a pre-emptive therapy was effective in delaying hematological relapse of advanced MDS or AML pts, regardless of the underlying genetic signature. Based on these encouraging results, intensifying treatment with AZA in combination with pembrolizumab is currently investigated as MRD-guided treatment in NPM1 positive AML (PEMAZA; ClinicalTrials.gov Identifier: NCT03769532).
Wolf: Celgene: Honoraria, Research Funding. Bug:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hexal: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Eurocept: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Jazz: Honoraria; Neovii: Other: Travel; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Sanofi: Other: Travel. Götze:Celgene: Research Funding. Stelljes:Amgen: Consultancy, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau. Subklewe:Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Seattle Genetics: Research Funding; Morphosys: Research Funding; Janssen: Consultancy; AMGEN: Consultancy, Honoraria, Research Funding; Roche AG: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Gilead Sciences: Consultancy, Honoraria, Research Funding. Haenel:Amgen, Novartis, Roche, Celgene, Takeda, Bayer: Honoraria. Rollig:Amgen, Astellas, BMS, Daiichi Sankyo, Janssen, Roche: Consultancy; Abbvie, Novartis, Pfizer: Consultancy, Research Funding. Müller-Tidow:Pfizer: Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding; BiolineRx: Research Funding; Janssen-Cilag GmbH: Speakers Bureau. Platzbecker:Novartis: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria. Thiede:AgenDix GmbH: Other: Co-owner and CEO.
Off-label: treatment with azacitidine to prevent or substantially delay an overt relapse in MRD-positive patients with MDS or AML
| v2 |
2021-09-28T15:43:11.137Z | 2021-07-21T00:00:00.000Z | 242312181 | s2ag/train | Do hypervelocity impacts on carbonaceous asteroids cause significant volatile loss?
<p>Carbonaceous asteroids, which are minor bodies but enriched in water and organics, have been extensively explored by HAYABUSA2 and OSIRIS-REx recently because they are thought to be the major carrier of volatiles to the inner planets in our solar system. The recent explorations revealed that two carbonaceous asteroids, Ryugu and Bennu, and their parent bodies suffered impact bombardments with a variety of impact energies. It has been hypothesized that Ryugu has lost a fraction of the volatiles due to some sorts of heating events [Kitazato et al., 2019]. In contrast, Bennu apparently did not suffer such a volatile loss [Hamilton et al., 2019]. Shock recovery experiments with metal containers performed in the 1980s suggested that chondritic meteorites could easily lose their volatiles during hypervelocity impacts [Tyburczy et al., 1986], leading to different impact histories being inferred to explain the difference in volatile contents. In this study, we revisited the total gas production during impact devolatilization of carbonaceous chondrite analog [Britt et al., 2019], hereafter referred to as CI simulant, with a two-stage light gas gun. We applied a new experimental technique for gas guns, which is referred to as the “two-valve method” [Kurosawa et al., 2019], to minimize the chemical contamination from the gun operation. The two-valve method allows us to investigate impact devolatilization in a fully open system where is the same geometry of natural impact phenomena. </p>
<p>  Hypervelocity impact experiments were performed with a two-stage light gas gun placed at Planetary Exploration Research Center of Chiba Institute of Technology, Japan. An Al<sub>2</sub>O<sub>3</sub> projectile with a diameter of 2 mm accelerated to two different impact velocities <em>v</em><sub>imp</sub> = 3.7 km/s and 5.8 km s<sup>-1</sup>. Hereafter, we refer the two velocities as “the low <em>v</em><sub>imp</sub>” and “the high <em>v</em><sub>imp</sub>”, respectively. Helium gas was used to accelerate the projectile instead of frequently-used hydrogen gas to exclude the possibility that a trace amount of the gas for projectile acceleration causes the chemical reduction. A quadrupole mass spectrometer (QMS) was used to measure the composition and amounts of impact-generated gases.</p>
<p>The experimental results are summarized as follows: (1) The total gas production was limited only to a few wt.% of the projectile mass even at the high <em>v</em><sub>imp</sub>, (2) the most abundant product was CO<sub>2</sub> in all the shots, (3) the chemical composition, including CO/CO<sub>2</sub> ratio and H<sub>2</sub>/CO ratio, did not depend on impact velocity, (4) the impact-generated vapor was depleted in sulfur with respect to the elemental composition of the CI simulant.</p>
<p>Here, we discuss about the controlling mechanism of impact devolatilization. Since the carbon source in the CI simulant is only crushed coal grains, which is mixed into the CI simulant as an analog for insoluble organic matters, the detected C-bearing gases, which are CO and CO<sub>2</sub>, must be produced due to oxidation of the organics in the CI simulant. Thus, the molar ratio of CO to CO<sub>2</sub> is simply determined by the oxygen fugacity, which strongly depends on temperature, in the region where the devolatilization occurs. We could estimate the temperature of the devolatilization region by comparing the oxygen fugacity for the elemental composition of the CI chondrites [Schaefer and Fegley, 2017], suggesting that the temperature is 1,200–1,650 K at both high and low <em>v</em><sub>imp</sub>. We also conducted shock physics modelling with the iSALE shock physics code [Amsden et al., 1980; Ivanov et al., 1997; Wünnemann et al., 2006; Collins et al., 2016]. We estimated post-shock residual temperature field after pressure release with the ANEOS serpentine by taking the endothermic decomposition of hydrous minerals and organics in the CI simulant into account. We found that the temperature in the iSALE was much lower than the temperature of the devolatilization region inferred from the CO/CO<sub>2 </sub>ratio. The large gap in the temperature between the experiment and the shock physics modelling indicates that a local energy concentration may be caused by velocity shear between the different grains with a large contrast in shock impedance. The above hypothesis about local heating is consistent with the low efficiency of impact devolatilization. Our experiment, shock physics modelling, and thermodynamic consideration suggest that hypervelocity impacts are not responsible for significant volatile loss from the parent body of Ryugu or from Ryugu itself [Kurosawa et al., Under review].</p>
<p> </p>
<p>Acknowledgements: This work was supported by ISAS/JAXA as a collaborative program with the Hypervelocity Impact Facility. We appreciate the developers of iSALE, including G. Collins, K. Wünnemann, B. Ivanov, J. Melosh, and D. Elbeshausen. We also thank Tom Davison for the development of the pySALEPlot.</p>
<p> </p>
<p>Key references:</p>
<p>Amsden, A., Ruppel, H. & C. Hirt. SALE: A simplified ALE computer program for fluid flow at all speeds. <em>Los Alamos National Laboratories Report</em>, LA-8095:101p (1980).</p>
<p>Collins, G. S., Elbeshausen, D., Davison, T. M., Wünnemann, K., Ivanov, B. A., and Melosh, H. J. iSALE-Dellen manual, <em>Figshare</em>, https://doi.org/10.6084/m9.figshare.3473690.v2 (2016).</p>
<p>Hamilton, V. E. et al. Evidence for widespread hydrated minerals on asteroid (101955) Bennu. <em>Nature Astronomy</em> <strong>3</strong>, 332–340 (2019).</p>
<p>Ivanov, B. A., Deniem, D. & Neukum G. Implementation of dynamic strength models into 2-D hydrocodes: Applications for atmospheric breakup and impact cratering. <em>Int. J. Impact Eng.</em> <strong>20</strong>, 411–430 (1997).</p>
<p>Kitazato, K. et al. The surface composition of asteroid 162173 Ryugu from Hayabusa2 near-infrared spectroscopy, <em>Science</em> <strong>364</strong>, 272–275 (2019).</p>
<p>Kurosawa, K., Moriwaki, R., Komatsu, G., Okamoto, T., Sakuma, H., Yabuta, H. & Matsui, T. Shock vaporization/devolatilization of evaporitic minerals, halite and gypsum, in an open system investigated by a two-stage light gas gun. <em>Geophysical Research Letters</em> <strong>46</strong>, 7258–7267 (2019).</p>
<p>Schaefer, L., & Fegley, B. Jr. Redox states of initial atmospheres outgassed on rocky planets and planetesimals. <em>The Astrophysical Journal</em> <strong>843</strong>, 120 (2017).</p>
<p>Tyburczy, J. A., Frisch, B., and Ahrens, T. J. Shock-induced volatile loss from a carbonaceous chondrite: implications for planetary accretion. <em>Earth and Planetary Science Letters</em> <strong>80</strong>, 201–207 (1986).</p> | v2 |
2018-04-03T02:58:22.646Z | 2001-05-11T00:00:00.000Z | 35835791 | s2ag/train | Global Warming: An Insignificant Trend?
An alarming view of global warming, reflecting the summaries of the United Nations' Intergovernmental Panel on Climate Change (IPCC), was presented by Donald Kennedy in “An unfortunate U-turn on carbon” (Editorial, 30 Mar., p. [2515][1]). However, the overwhelming balance of evidence shows no appreciable warming trend in the past 60 years; hence, it is unlikely to be significant in the future.
Support for this view comes primarily from weather satellites, which provide the only truly global data, independently confirmed by balloon sondes, and endorsed in a National Research Council report ([1][2]). Also, surface data from U.S. weather stations show the warmest years of the twentieth century as being around 1940 ([2][3]). The post-1940 global warming claimed by the IPCC comes mainly from distant surface stations and from tropical sea surface readings, with both data sets poorly controlled in both quality and location. Furthermore, there are no “fingerprints,” such as a characteristic geographic distribution, that might link such a claimed warming to increasing greenhouse-gas emissions.
Climate models all predict a faster warming for the atmosphere than for the Earth's surface. This throws further doubt on the reality of the reported surface warming and lowers our confidence in model-predicted future changes. Independent evidence against current climate models and the IPCC surface record comes from a variety of non-thermometer “proxy” data. While showing temperatures rising up to about 1940, they do not show a warming trend thereafter. The recent shrinking of glaciers and of Arctic sea ice, while real, is most likely a delayed consequence of the pre-1940 warming; so is the warming of the deep ocean.
Finally, sea-level rise has gone on since the peak of the last Ice Age, and will doubtless continue at the present rate (of ∼18 cm per century) for several more millennia as Antarctic ice continues to melt slowly—independent of any human actions. Quite apart from these scientific points, economists suggest that a moderate warming would produce net benefits, raising the gross national product and average income, especially for the agriculture and forestry sectors ([3][4]). On the other hand, enforcing the Kyoto Protocol—reducing energy use by more than 30% within a decade—would not only be very costly but also ineffective. Even if rigidly enforced, it would reduce calculated temperatures in 2050 by an insignificant 0.06°C ([4][5]). However, these shortcomings of the Kyoto Protocol in no way invalidate “no regrets” policies, like striving for increased conservation and higher energy efficiencies wherever they make economic sense.
1. [↵][6]1. National Research Council
, Reconciling Observations of Global Temperature Change (National Academy Press, Washington, DC, 2000).
2. [↵][7]1. S. F. Singer
, testimony to Senate Commerce Committee (July 18, 2000), [www.sepp.org/NewSEPP/senatetestimony.htm][8].
3. [↵][9]1. R. Mendelsohn, 2. J.E. Neumann
, Eds. The Impact of Climate Change on the United States Economy (Cambridge University Press, Cambridge, 1999).
4. [↵][10]1. M. Parry 2. et al.
, Nature 395, 741 (1998)S. F. Singer, Hot Talk, Cold Science: Global Warming's Unfinished Debate , (The Independent Institute, Oakland, CA, ed. 2, 1999), p. 68.
[OpenUrl][11][CrossRef][12][GeoRef][13][Web of Science][14]
# Response {#article-title-2}
Singer makes much of the alleged discrepancy between satellite and surface measurements, and references the National Research Council report ([1][2]). Here is what the Executive Summary of that report says: “In the opinion of the panel, the warming trend in global-mean surface temperature observations during the past 20 years is undoubtedly real and is substantially greater than the average rate of warming during the twentieth century. The disparity between surface and upper air trends in no way invalidates the conclusion that surface temperatures are rising.”
1. 1. National Research Council
, Reconciling Observations of Global Temperature Change (National Academy Press, Washington, DC, 2000).
# {#article-title-3}
With its ardent rhetoric about President Bush's caution against immediate action on climate change, Donald Kennedy's editorial undermines the proper role of Science. That role is to provide scientific analyses, not to argue for specific politically derived proposals. To join that fray is to endanger the credibility scientists still have with a public that is increasingly cynical about its sources of information.
It is the job of policymakers to consider all factors, including economics and international political issues, before setting policies and taking actions. Stephen Schneider of Stanford University, a leading expert in atmospheric research, has said, “Of course, whether to act is not a scientific judgment, but a value-laden political choice that cannot be resolved by scientific methods” ([1][2]). Bush has declined to classify carbon dioxide as a pollutant under the Clean Air Act. Since, like water, it is essential to all life, his decision seems a reasonable one and it does not prejudice future actions. He also had the courage to end years of dithering about the Kyoto Protocol after concluding that it was unworkable, inappropriate, and unjustified, a conclusion that echoes a view long held by economists. And this decision also does not prejudice future action.
I am a regular reader of climate-related articles in Science, and it seems they tell us that while progress is being made, much more research remains to be done in the daunting task of understanding the climate system. Science should take a leading role in communicating this progress. It should not pollute this role by jumping into the political arena.
1. 1. S. H. Schneider
, Science 243, 778 (1989).
[OpenUrl][15]
[1]: /lookup/doi/10.1126/science.1060922
[2]: #ref-1
[3]: #ref-2
[4]: #ref-3
[5]: #ref-4
[6]: #xref-ref-1-1 "View reference 1 in text"
[7]: #xref-ref-2-1 "View reference 2 in text"
[8]: http://www.sepp.org/NewSEPP/senatetestimony.htm
[9]: #xref-ref-3-1 "View reference 3 in text"
[10]: #xref-ref-4-1 "View reference 4 in text"
[11]: {openurl}?query=rft.jtitle%253DNature%26rft.stitle%253DNature%26rft.volume%253D395%26rft.issue%253D6704%26rft.spage%253D741%26rft.atitle%253DAdapting%2Bto%2Bthe%2Binevitable%26rft_id%253Dinfo%253Adoi%252F10.1038%252F27316%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx
[12]: /lookup/external-ref?access_num=10.1038/27316&link_type=DOI
[13]: /lookup/external-ref?access_num=1998073316&link_type=GEOREF
[14]: /lookup/external-ref?access_num=000076607400024&link_type=ISI
[15]: {openurl}?query=rft.jtitle%253DScience%26rft.volume%253D243%26rft.spage%253D778%26rft.atitle%253DSCIENCE%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx | v2 |
2022-06-06T02:09:43.201Z | 1996-01-01T00:00:00.000Z | 249371531 | s2ag/train | Comparison of a b-Glucosidase and a b-Mannosidase from the Hyperthermophilic Archaeon Pyrococcus furiosus
Two distinct exo-acting, b-specific glycosyl hydrolases were purified to homogeneity from crude cell extracts of the hyperthermophilic archaeon Pyrococcus furiosus: a b-glucosidase, corresponding to the one previously purified by Kengen et al. (Kengen, S. W. M., Luesink, E. J., Stams, A. J. M., and Zehnder, A. J. B. (1993) Eur. J. Biochem. 213, 305–312), and a b-mannosidase. The b-mannosidase and b-glucosidase genes were isolated from a genomic library by expression screening. The nucleotide sequences predicted polypeptides with 510 and 472 amino acids corresponding to calculated molecular masses of 59.0 and 54.6 kDa for the b-mannosidase and the b-glucosidase, respectively. The b-glucosidase gene was identical to that reported by Voorhorst et al. (Voorhorst, W. G. B., Eggen, R. I. L., Luesink, E. J., and deVos, W. M. (1995) J. Bacteriol. 177, 7105–7111; GenBank accession no. U37557). The deduced amino acid sequences showed homology both with each other (46.5% identical) and with several other glycosyl hydrolases, including the b-glycosidases from Sulfolobus solfataricus, Thermotoga maritima, and Caldocellum saccharolyticum. Based on these sequence similarities, the b-mannosidase and the b-glucosidase can both be classified as family 1 glycosyl hydrolases. In addition, the b-mannosidase and b-glucosidase from P. furiosus both contained the conserved active site residues found in all family 1 enzymes. The b-mannosidase showed optimal activity at pH 7.4 and 105 °C. Although the enzyme had a half-life of greater than 60 h at 90 °C, it is much less thermostable than the b-glucosidase, which had a reported half-life of 85 h at 100 °C. Km and Vmax values for the b-mannosidase were determined to be 0.79 mM and 31.1 mmol para-nitrophenol released/min/mg with p-nitrophenyl-b-D-mannopyranoside as substrate. The catalytic efficiency of the b-mannosidase was significantly lower than that reported for the P. furiosus b-glucosidase (5.3 versus 4, 500 s mM with p-nitrophenyl-b-Dglucopyranoside as substrate). The kinetic differences between the two enzymes suggest that, unlike the b-glucosidase, the primary role of the b-mannosidase may not be disaccharide hydrolysis. Other possible roles for this enzyme are discussed. The hyperthermophilic archaeon Pyrococcus furiosus is an obligately anaerobic heterotroph, which grows optimally at 98–100 °C (1). It employs a fermentative type of metabolism (2), using polysaccharides, such as starch, glycogen, and pullulan (3), or disaccharides, such as maltose (3) and cellobiose (4), as carbon and energy sources. In order to utilize the different carbohydrates, P. furiosus synthesizes several intracellular and extracellular glycosyl hydrolases. Specifically, a-amylase (5), amylopullulanase (6), a-glucosidase (7), and b-glucosidase (4) activities have been purified and characterized. The a-amylase, amylopullulanase, and a-glucosidase are believed to work cooperatively to degrade a-linked polysaccharides, such as starch, glycogen, or pullulan (8). The endo-acting, a-specific amylase and amylopullulanase degrade a-linked polysaccharides to diand trisaccharides (5, 6). a-Glucosidase presumably hydrolyzes these shorter oligosaccharides to glucose for use in a novel Embden-Meyerhof pathway (8, 9). Although P. furiosus cannot grow on cellulose or carboxymethylcellulose (4), it is not clear whether P. furiosus can utilize other b-linked complex carbohydrates as growth substrates. To date, no endo-acting, b-specific glycosyl hydrolases, such as cellulases, xylanases, or mannanases, have been identified in P. furiosus. However, when P. furiosus is grown on 5 mM cellobiose, a cell density of 7 3 10 cells/ml has been reported (4). Apparently, cellobiose is transported across the cell membrane and hydrolyzed to glucose by the intracellular b-glucosidase (9). Thus, the aand b-glucosidases may play similar roles in the degradation of polysaccharides for the nutritional requirements of P. furiosus. In addition to the physiological role of these glycosyl hydrolases within P. furiosus, it is also interesting to examine their relationship to similar enzymes from the other domains of life. This can be done on the basis of substrate specificity. However, many glycosyl hydrolases have a broad range of specificities (10). Henrissat (10) proposed an alternate and complementary classification scheme for glycosyl hydrolases based on amino acid sequence similarities. For example, glycosyl hydrolase family 1 is composed of exo-acting, b-specific enzymes with similar amino acid sequences. Based on substrate specificity, enzymes in this family have been characterized as b-glucosidases (EC 3.2.1.21), b-galactosidases (EC 3.2.1.23), phospho-bgluco/galactosidases (EC 3.2.1.86/85), lactase-phlorizin hydrolases (EC 3.2.1.108/62), and thioglucosidases (EC 3.2.3.1). Family 1 glycosyl hydrolases provide a favorable framework for comparative studies of mesophilic and thermophilic enzymes for a number of reasons. First, the enzymes in this family function over a wide range of temperatures from mesophilic (11–22, 24–26) to moderately thermophilic (27–31) to hyperthermophilic (4, 32, 33). Second, enzymes in this family have been isolated from all three domains (bacteria, eucarya, and archaea), allowing the analysis of possible evolutionary relationships. Finally, crystal structures have been determined for * This work was supported by grants from the National Science Foundation and the Department of Energy and a Department of Education GAANN fellowship (to M. W. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. The nucleotide sequence(s) reported in this paper has been submitted to the GenBank/EBI Data Bank with accession number(s) U60214. ¶ To whom correspondence should be addressed: Dept. of Chemical Engineering, North Carolina State University, Raleigh, NC 276957905. Tel.: 919-515-6396; Fax: 919-515-3465; E-mail: kelly@che. ncsu.edu. THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 271, No. 39, Issue of September 27, pp. 23749–23755, 1996 © 1996 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in U.S.A. | v2 |
2019-03-28T13:40:49.814Z | 1970-01-01T00:00:00.000Z | 86681931 | s2ag/train | Paper-chromatographic Identification of Flavonoids from a Scarlet-flowering Dahlia and Crystallization of Pelargonidin and Butein
Nine major flavonoids were detected in scarlet petals of a dahlia cultivar, Alice ". Among these flavonoids, the two pigments were crystallized from ethanolic extracts, and identified as pelargonin and Butein. During the survey of genuine anthocyanins in a variety of dahlia cultivarsl,2>, an appreciable amount of yellow pigments was obtained simultaneously from an ethanolic extract of scarlet petals, which was composed mainly of chalcones, especially butein (aglycone of coreopsin) and some others. This preliminary finding has tempted us to carry out a comprehensive study of flavonoids in scarlet petals. While the chalcones were isolated from the yellow flowers of dahlia3,4,5,s,7', the same group of pigments in scarlet dahlia has not been described in the literatureg'. In this work, scarlet petals of Dahlia variabilis DESF, cv. "Alice" were used as material for the examination of major flavonoids, and also for the crystallization of pelargonin and butein. Material and Methods Material. A cultivar of scarlet pcmpom dahlia, "Alice ", was used as material, which was cultivated in Matsukata farm in Tokyo. The flower color is described as rosy cerise with white base in England9', while as scarlet in Japan. Extraction and identification. Fresh petals were immersed in 80°o ethanol, and pressed. The resulting yellowish orange extract was filtered by suction, and spotted directly on Toyo-Roshi paper No. 51 together with the authentic samples side by side, and co-chromatographed using the solvents : butanol/acetic acid/water (4: 1 : 5, v/v), acetic acid/hydrochloric acid/water (15 : 3 : 82, v/v), and 30% acetic acid. Individual spots of flavonoids on the chromatograms were cut out, and eluted with appropreate solvents, and used for chromatographic and spectroscopic identifications. Quantitative analysis o f major pigments. The pigment solutions quantitatively prepared from the petal extracts were spotted on a sheet of filter paper with a micro-pipette, and chromatographed two-dimentionally using the solvents, butanol/ acetic acid/water (4:1: 5, v/v) and 30% acetic acid, one after another. The flavor noid spots separeted were cut out, eluted with ethanol, and their contents were measured by colorimetric means at definite wave lengths: 382 m~u for butein, 374 m~C for 2', 4', 4-trihydroxychalcone, and 500 mp for pelargonin (in 5°o HC1), respectively. * Chemical Laboratory , Meiji-Gakuin University, Tokyo 230 SAITO, N., et al. Vol. 83 Isolation and crystallization of major flavonoids. Fresh petals (2 kg) were immersed in 80% ethanol, heated at 60-70° for one hour, and left overnight. The orange red extract (1.51) was filtered, and concentrated to 1/10 volume . The concentrate was shaken with an equal volume of ethyl acetate, whereupon the organic layer containing yellow flavonoids was separated from the aqueous layer. The organic layer was evaporated to dryness in vacuo, and the residue was dissolved in hot acetone (60 ml) containing a small amount of water. After standing overnight , pale yellow needle-shaped crystals of butein were obtained (ca. 6 g) (Fig. 1). This was recrystallized twice from aqueous acetone. Yield: ca. 3 g. Anal. Cal. for C15H12O5 . H20: H2O 5.84%; C 66.18%; H 4.41%. Found : H2O 5.46, 5.52%; C 66.11, 65.92%; H 4.68, 4.62%. M. p. 210°. UV absorption peaks : 263 and 382 mp in ethanol. The IR data were identical with those of the synthetic specimen of butein (measured by the KBr-method). The anthocyanin-containing, aqueous layer obtained above was added with a small amount of conc. HC1 up to the final concentration of ca. 0.5% acid. The red, acidic solution was concentrated to 1/5 volume and stood for 24 hours in a refrigerator, whereby pelargonin chloride was gradually separated as crystals (1.65 g). Recrystallization was made four times from hot aqueous ethanol containing 0.5% HCI. Yield ca. 1 g (Fig. 3). Anal. Cal. for C27H31015C1 . 3 H20: H2O 9.09%; C 51.41%; H 4.91%. Found : H2O 8.72, 8.73%; C 51.26, 51.13%; H 5.05, 5.02%. M. p. 178-182°. UV-maxima: 273 and 500-505 mp in 5% HCI. Results and Discussion The flavonoids in 80% ethanolic extract of scarlet petals of dahlia were separated on the two-dimensional paper chromatogram as shown in Fig. 3, on which about eighteen spots of flavonoids were recognized. Among them, nine major flavonoids were separated and identified in the usual way (Table 1). The anthocyanins are pelargonin (0.48%), pelargonidin-3-glucoside, cyanin, chrysanthemin, and probably pelargonidin-3-diglucoside. The chalcones are butein (0.82%), coreopsin, 2', 4', 4-trihydroxychalcone (0.310), 2', 4', 4-trihydroxychalcone-4'-glucoside, and aurone (sulphretin-6-glucoside). Besides, many other unknown spots of minor flavonoid components were observed. Two major flavonoids, butein and pelargonin, were separated and crystallized as needles (Fig. 1 and 2) in the manner described below. It is noteworthy that a large amount of sugar-free pigments, butein and 2', 4', 4Fig. 1. butein (x ca. 680) Fig. 2. pelargonin chloride (x ca. 680) July, 1970 On Major Flavonoids Deteched in a Scarlet-flowering Dahlia 231 Fig. 3. Diagram of typical paper chromatogram of cured petal extract. Designation of the spots : 1, pelargonidin-3-diglucoside (?) ; 2, cyanidin-3glucoside ; 3, pelargonin ; 4, cyanin ; 5, 2', 4', 4-trihydroxychalcone ; 6, 2', 41,4 trihydroxychalcone-4'-glucoside ; 7, butein ; S, butein-4'-glucoside ; 9, sulphuretin6-glucoside. Table 1. Some from chemical properties of the Dahlia variabilis, cultivar flavonoids "Alice " . isolated 232 SAITO, N., et al. Vol. 83 trihydroxychalcone, was found in an aqueous extract of fresh petals. However, they did not always appear upon quick extraction with aqueous alcohol in the cold.. Therefore, it seems that the aglycones found in the petals are present mostly in the form of glycoside in situ. On the other hand, seasonal change of the. flavonoids in flowers was also examinedd paper-chromatographically during the period from early summer to late autumn. In this case, sugar-free flavonoids were sometimes detected in alcoholic extracts. Possibly, they are only artifacts produced enzymatically during extraction process. In all, the major flavonoids of scarlet-red dahlia "Alice" are pelargonin, butein4'-glucoside, and 2', 4', 4-trihydroxychalcone-4'-glucoside. The sugar-free pigments, butein and 2', 4', 4-trihyroxychalcone, may also be found in the petals probably as the products of enzymic fission. The identification of minor flavonoid components is still under way. | v2 |
2020-12-09T03:07:20.868Z | 2013-01-01T00:00:00.000Z | 227699681 | s2ag/train | Speed control of separately excited DC motor using chopper
This paper describes speed control of separately excited DC motor using Chopper as power converter and PI as speed and current controller. The separately excited DC motor can be controlled from below and up to rated speed . Optimization filter of speed is obtained using Modulus Hugging Approach . After obtaining the complete model of DC drive system, the model is simulated by MATLAB. The simulation is done and analyzed under varying speed and varying load torque conditions like rated speed and load torque, half the rated load torque and half speed . : صلختسملا شطيسٍ عٍ ) ٓسذق شيغٍ ( عطقٍ ًاذختساب تيقتسٍ ٓساثا ور شَتسٍ سايت كشحٍ تعشس ًيع ةشطيسىا تقيشط ثحبىا رضىي ٍِ ٓساشلاا عطقَىا ذذق ةشئاد ٌيتست .ٔبىيطَىا ٔعشسىا تياغى كشحَىا عشس ًيع ٓشطيسىا ِنَي ٔقيشطىا ٓزهب ييٍانت يبساْت ٍْ ًىا ٓشيغتٍ ٔيتىىف زيهدتى شطيسَىا ٔعشسيى هولاا ِيشطيسٍ زيفْتو ٌيَصت ٌت . ٔبىيطَىا ٔعشسىا ًىا هىصىيى كشحَى ا حت ٓساثا ورشَتسٍ سايت كشحَى جرىــَّ زخا ٌت .ٔيىاع ٔيساشقتسابو ٓذيخ تبادتسا ثار ُاسود تعشس ًيع هىصحيى لىرو سايتيى يّاثىاو فـْت ٌت . بلاتاَىا ًاذختساب ةاماحٍ جرىَْب ٔـيـيثَتو ٔيقتسٍ وثٍ وَحىا ًزع و ٔعشسىا ِيب ثاقلاعىا و حئاتْىا وييحتو ةاماحَىا زـي ٔعشسىا ِيسحت فيٍ دىخىب وَحىا فصّ عٍ ٓسشقَىا ٔعشسىا فصّ ِيب ٔقلاعىاو وـٍانىا وَحىا ًزع عٍ ٔبىيطَىا ٔعشسىا تقلاع . يشخا ةشٍ ٍٔذعبو ةشٍ 1Introduction: DC motor is considered a(Single Input and Single Output) system having torque/speed characteristics compatible with most mechanical loads. This makes a D.C motor controllable over a wide range of speeds by proper adjustment of the terminal voltage [1,2]. Now days Induction motors, Brushless D.C motors and Synchronous motors have gained widespread use in electric traction system. Hence dc motors are always a good option for advanced control algorithm because the theory of dc motor speed control is known more than other types. Speed control techniques in separately excited dc motor By varying the armature voltage for below rated speed. By varying field flux should to achieve speed above the rated speed. The PI based speed control has many advantages like fast control, low cost and simplified structure [3]. 1-1DC Chopper A chopper is a static power electronic device that converts fixed dc input voltage to a variable dc output voltage. A Chopper may be considered as dc equivalent of an ac transformer since they behave in an identical manner. Chopper involves one stage conversion, these are more efficient Chopper systems offer smooth control, high efficiency . A chopper is a high speed on or off semiconductor switch. It connects source to load and disconnect the load from source at a fast speed [4] 1-2Basic idea : The basic principle behind DC motor speed control is that the output speed of DC motor can be varied by controlling armature voltage for speed below and up to rated speed keeping field voltage constant. The output speed is compared with the reference speed and error signal is fed to speed controller [5] . Controller output will vary whenever there is a difference in the reference speed and the speed feedback. The output of the speed controller is the control voltage that controls the Journal of KerbalaUniversity , Vol. 11 No.1 Scientific . 2013 27 operation duty cycle of (here the converter used is a Chopper) . The converter output give Va required to make the motor return to the desired speed. The reference speed is provided through a potential divider because the voltage from potential divider is linearly related to the speed of the DC motor[8]. The output speed of motor is measured by Tacho-generator and since Tacho voltage will not be perfectly dc and will have some ripple. So, we require a filter with a gain to bring Tacho output back to controller level [6]. Fig(1):Closed loop system model for speed control of dc motor [7,8]. 1-3Current controller design : Fig(2): Block Model for Current Controller Design . Transfer function of the above model: [ ( )( ) ( )( ) ] ( ) [( ) ( )] [ ] Journal of KerbalaUniversity , Vol. 11 No.1 Scientific . 2013 28 1-4Speed controller design[9] : Fig(3): Block model for Speed Controller design[7]. By converting the block model in transfer function, we will get: [ ( ) ( )( ) ] [( )( )] [ ( ) ] Ideally, ω(s) =1/S (S2+αs+β) . The damping constant is zero in above transfer function because of absence of S term, which results in oscillatory and unstable system. To optimize this we must get transfer function whose gain is close to unity [10 ,5] . 1-5Complete layout for DC motor speed control : Fig(4): Complete layout for DC motor speed control 2Problem statement : A separately excited DC motor with name plate ratings of 300KW, 40 0V(DC), 50 rad/sec is used in all simulations. Following parameter values are associated with Moment of Inertia, J = 80 Kg-m. Back EMF Constant = 8 Volt-sec/rad. Rated Current = 670 A. Maximum Current Limit = 1000 A. Journal of KerbalaUniversity , Vol. 11 No.1 Scientific . 2013 29 Resistance of Armature, Ra = 0.025 ohm. Armature Inductance, La = 0.812 mH. Speed Feedback Filter Time Constant , T1 = 20 ms. Current Filter Time Constant , T2 = 3ms. 2-1Current controller parameter : Current PI type controller is given by [( ) ] Here, and ( ) For analog circuit maximum controller output is ± 10 Volts . Therefore, Kt = 400/10 = 40. Also, K2 = 10/1000 = 1/100. Now, putting value of Ra, Ta, K2, Kt and T2 we get: Kc = 0.333 2-2Speed controller parameter : Speed PI type controller is given by [( ) ] Here, ( ) ( ) Also ( ) | v2 |
2020-01-02T21:10:56.221Z | 2019-12-16T00:00:00.000Z | 214219821 | s2ag/train | Examining the relationship between the price, the characteristics and the visitor evaluation of attributes of Italian farmhouses with an educational farm
The purpose of this paper is to examine the relationship between the price charged for a guest room in a farmhouse with an educational farm, the farmhouse characteristics and the visitor evaluation of the principal external and internal farmhouse attributes.,A large sample of 10,880 visitor reviews, extrapolated from the websites of 399 Italian farmhouses with an educational farm (FEF), was analyzed. Principal component analysis (PCA) was performed to identify the main latent dimensions of the farmhouses (visitor satisfaction with farmhouse attributes, farmhouse dimensions, visitor frequency, farmhouse services, types of accommodation and altitude) that affect the price charged for a guest room. Subsequently, multivariate regression was applied to measure the impact of these new latent factors on the price.,Overall, the results indicate that the price of a farmhouse with an educational farm – in the context of this niche of the Italian agritourism sector – reflects the visitor evaluation of the farmhouse attributes (especially activities and facilities available in the surrounding countryside), the farmhouse dimensions, the types of accommodation, the number of services on offer and the presence of connectivity (WI-FI). In addition, the results reveal that the price represents an important driver that guides guests in their choice of a farmhouse and that it affects visitor satisfaction with farmhouse attributes.,Because of the sample chosen, the data gathered are limited to one type of organization – Italian FEF. Furthermore, it may be important to investigate in more depth some issues that remain partly unanswered that concern this niche of the Italian agritourism sector.,Thanks to the identification of latent dimensions by PCA and the examination of their impact on the farmhouse price, farmhouse operators can understand a priori the main determinants on which to focus to improve the quality of activities and facilities available in the farmhouse location to better satisfy visitor expectations.,This study provides new and practical insights into the farmhouse experience in Italian municipalities, an area where very limited research has been conducted. Indeed, this is one of the few studies to focus on online reviews to evaluate more than two farmhouse attributes and their impact on pricing.,本文旨在探讨教育农场的农舍房间价格、农舍特性与游客对农舍内外主要属性的评价之间的关系。,本研究从意大利农舍的网站上, 对399教育农场里, 选出10880条访客评论, 对其进行了样本分析。采用主成分分析法确定影响客房价格的农舍主要潜在维度（游客对农舍属性的满意度、农舍规模、游客频率、农舍服务、住宿类型和海拔高度）。之后, 运用多元回归方法来衡量这些新的潜在因素对价格的影响。,总的来说, 结果表明, 在意大利农业旅游大环境下的这一小众市场, 即有教育农场的农舍, 其价格反映了游客对农舍属性（特别是周边乡村可用的活动和设施）、农舍规模、住宿类型的评价, 提供的服务以及网络（WI-FI）的评价。此外, 研究结果还显示, 价格是引导客人选择农舍的一个重要因素, 它影响了游客对农舍的满意度。,由于所选的样本限制, 所收集的数据仅限于一种类型——有教育意义的意大利农舍。此外, 更深入地调查一些与意大利农业旅游业这一小众市场有关的问题是十分必要的, 因为这些问题仍有一部分没有得到解决。,通过主成分分析识别潜在维度并检查其对农舍价格的影响, 农舍经营者可以预先了解需要关注的主要决定因素, 以提高农舍所在地的活动和设施的质量, 从而更好地满足游客的需求期望。,这项研究为意大利市政当局的农舍经验提供了新的和实际的见解, 这一领域的现有研究非常有限。实际上, 这是为数不多的侧重于在线评论的研究, 以评估两个以上的农舍属性对定价的影响。,关键词 有教育农场的农舍；农舍属性；在线评论；价格；访客评价。,El objetivo de este articulo es examinar la relacion entre el precio cobrado por una habitacion de invitados en una granja con una granja educativa, las caracteristicas de la granja y la evaluacion de los visitantes de los principales atributos externos e internos de la granja.,Se analizo una gran muestra de 10.880 comentarios de visitantes, extrapolados de los sitios web de 399 granjas Italianas con una granja educativa. El analisis del componente principal se realizo para identificar las principales dimensiones latentes de las casas de campo (satisfaccion del visitante con los atributos de la casa de campo, dimensiones de la casa de campo, frecuencia de visitantes, servicios de casa de campo, tipos de alojamiento y altitud) que afectan el precio cobrado por una habitacion de invitados. Posteriormente, se aplico la regresion multivariada para medir el impacto de estos nuevos factores latentes en el precio.,En general, los resultados indican que el precio de una granja con una granja educativa, en el contexto de este nicho del sector del agroturismo Italiano, refleja la evaluacion de los visitantes de los atributos de la granja (especialmente las actividades e instalaciones disponibles en el campo circundante), la granja dimensiones, los tipos de alojamiento, la cantidad de servicios ofrecidos y la presencia de conectividad (WI-FI). Ademas, los resultados revelan que el precio representa un factor importante que guia a los huespedes en su eleccion de una granja y que afecta la satisfaccion del visitante con los atributos de la granja.,Debido a la muestra elegida, los datos recopilados se limitan a un tipo de organizacion: granjas Italianas con granjas educativas. Ademas, puede ser importante investigar con mayor profundidad algunos temas que quedan en parte sin respuesta y que conciernen a este nicho del sector del agroturismo Italiano.,Gracias a la identificacion de las dimensiones latentes mediante el analisis de componentes principales y el examen de su impacto en el precio de la granja, los operadores de la granja pueden entender a priori los principales determinantes en los que enfocarse para mejorar la calidad de las actividades e instalaciones disponibles en la ubicacion de la granja. para satisfacer mejor las expectativas de los visitantes.,Este estudio proporciona informacion nueva y practica sobre la experiencia de la granja en los municipios Italianos, un area donde se han realizado investigaciones muy limitadas. De hecho, este es uno de los pocos estudios que se centra en las revisiones en linea para evaluar mas de dos atributos de la granja y su impacto en los precios.,Cortijo con granjas educativas, atributos de la granja, revisiones en linea, precio, juicios de visitantes | v2 |
2018-10-27T16:49:23.475Z | 1997-08-21T00:00:00.000Z | 53551201 | s2ag/train | Urea production by the marine bacteria Delaya venusta and Pseudomonas stutzeri grown in a minimal medium
The present experiment showed that the marine bacteria Delaya venusta and Pseudomonas stutzen produced urea when grown in a minimal medium without an external supply of organic nitrogen. The urea production rate depended on the bacterial state of growth, and the highest urea accumulation rates in the medium were found in the growth deceleration phase and in the beginning of the stationary phase. Urea did not accumulate in D. venusta cells, whereas the intracellular accumulation of urea in P. stutzeri cells exceeded urea accumulation in the medium during exponential growth. Further, D. venusta could, in contrast to P. stutzen, hydrolyse urea. We suggest that intracellular purines and pyrimidines (in particular RNA) were potential sources for the observed urea production. K E Y WORDS: Marine bacteria. Urea . Production . Turnover. Growth phases Urea is an important organic nitrogen compound in the marine environment (e.g. Remsen 1971, McCarthy et al. 1977, Sorensson & Sahlsten 1987, Price & Harrison 1988, Lomstein et al. 1989, Cochlan & Harrison 1991, Therkildsen & Lomstein 1994). Urea production has been related to the presence and input of readily degradable organic material (Satoh 1980, Lomstein et al. 1989, Therkildsen & Lomstein 1994) and the highest concentrations of urea have been found in the sediment surface, which is characterized by a low C/N ratio. A low C/N ratio has been used as an indicator of high quality organic matter (Blackburn 1986, Lomstein et al. 1989, Therkildsen & Lomstein 1994). Bacteria can play a significant role in the overall production of urea in marine sediments (Pedersen et al. 1993a, Therkildsen & Lomstein 1994). Purines and pyrimidines are potential precursors for bacterial urea production (e.g. Vogels & Van der Drift 1976, Busse et al. 1984, Gott'Addressee for correspondence. E-mail: [email protected] schalk 1986, Kaspari & Busse 1986). A substrate addition experiment with anoxic, defaunated marine sediment showed a considerable urea production, when the sediment was supplemented with adenosine 5'monophosphate (AMP), cytidine 5'-monophosphate (CMP), and 16s ribosomal RNA (Therkildsen et al. 1996). However, bacterial urea production from purines and pyrimidines is even more favourable under oxic conditions (Vogels & Van der Drift 1976). Bovine serum albumin did not stimulate sediment urea production, which indicated that urea was not an important intermediate in protein degradation (Therkildsen et al. 1996). Culture experiments with Thiosphaera pantotropha showed that the bacteria produced urea during exponential growth when cultured under oxic and anoxic conditions in a minimal medium (Pedersen et al. 1993b). The present experiment was designed to investigate urea production by the marine bacteria Delaya venusta and Pseudomonas stutzeri grown without any supplements of organic nitrogen under oxic conditions. Urea production was followed during the different growth phases of the cultures. D. venusta is an aerobic bacterium belonging to the family Halomonadaceae. The uptake, transport and turnover of urea by D. venusta has been studied by Jahns (1992). P. stutzeri is a facultative, aerobic, nonfluorescent, denitrifying pseudomonad commonly encountered in diverse habitats, including marine environments, soil, and sewage (Ward & Cockcroft 1993). Methods. Delaya venusta was grown at 30°C, at pH 7.3, in a minimal medium and under oxic conditions. Pseudomonas stutzen was grown at 18"C, at pH 7.0, in a similar minimal medium and under oxic conditions. The minimal medium contained the following in g I-': Na,HPO,, 2.44; KHpP04, 1.52; (NH4)2S04, 0.5; MgSO, . 7H20, 0.2; CaC12 2H20, 0.05; NaCl, 29.22; 0 Inter-Research 1997 214 Mar Ecol Prog Ser 13: 213-217, 1997 and 5 m1 of the trace element solution described in Finster et al. (1992). Glucose was added to a final concentration of 10 mM. Samples were withdrawn from the cultures at regular time intervals to follow the change in the urea concentration in the medium, the total concentration of urea (medium+bacteria) and bacterial density. The concentration of urea in the medium was measured on 0.2 pm Nucleopore filtered samples by the diacetylmonoxime method (Mulvenna & Savidge 1992). The total concentration of urea (medium+bacteria) was measured by addition of the acid reagent from the diacetylrnonoxime method directly to unfiltered samples. The diacetylmonoxime-sample mixture was thoroughly mixed and reacted for 10 min before centrifugation at 11 000 X gfor 10 min. The remaining reagents in the Mulvenna & Savidge (1992) urea method were added to the supernatant, and the concentration of urea was measured. Bacterial density was measured as optical density on a Milton Roy, Spectronic 601 spectrophotometer at 600 nm. Additional samples were withdrawn from the cultures in the beginning and at the end of the experiment to measure the NH4+ concentration. NH,' was measured by the salicylatehypochlorite method (Bower & Holm-Hansen 1980). Urea turnover was measured twice in Delaya venusta and Pseudomonas stutzeri cultures by the 14C-urea isotope dilution technique (Lund & Blackburn 1989). Eight subsamples (2 m1 culture) were collected and transferred to 10 m1 sterile glass containers (Exetainer, Labco) in each turnover measurement. Half of the samples were used to follow the change in the concentration of urea during incubation and the remaining samples were injected with 14C-urea. The '4C-incubation was modified slightly from Lund & Blackburn (1989): (1) the incubation was performed as a 4 point time course (-0, 1.0, 1.5,3.5 h); (2) the activity of the injected 10pl of tracer was 9.6 nCi p1-' (56 mCi mmol-'; Amersham Radiochemical Center); (3) the incubation was terminated by addition of 2 m1 2.5% NaOH; (4) the scintillation fluid was pH-adjusted OPTIFLUORTM from Packard (1:lO v/v 0.1 M NaOH:OPTIFLUORTM). Urea turnover rates were calculated by the nonsteady-state model I, described in Lund & Blackburn (1989). The purity of the Delaya venusta cultures were confirmed microscopically before and after the experiment and during the experiment by the characteristic pea (Pisum sp.) odour of the cultures. Purity of the Pseudomonas stutzen' cultures were confirmed microscopically and by the rnicromethod API 20 NE for identification of nonenteric Gram-negative rods (bioMerieux) before and after the experiment. D. venusta and P. stutzeri cultures were purchased from DSM-Deutsche Sammlung von Mikroorganismen und Zeukulturen, Germany. 0.0 0 10 20 30 40 50 Time (h) | v2 |
2022-06-10T01:24:03.516Z | 2003-01-01T00:00:00.000Z | 249523291 | s2ag/train | Complete amino acid sequence ofmurine 182-microglobulin : Structural evidence for strain-related polymorphism . ( histocompatibility antigens / radiosequence analysis )
Primary structural analyses of 32-microglobulin isolated from the tumor cell lines EL4.BU (derived from a C57BL/6 mouse).and C14 (derived from a BALB/c mouse) have revealed the presence of an amino acid difference at position 85 of this molecule. fl2-Microglobulin isolated fron histocompatibility antigens of EL4.BU has alanine at this position, whereas that from C14 has aspartic acid. Determination of the sequence of these molecules has employed radiochemical methodology that was developed in studies of murine histocompatibility antigens. The sequence obtained in this study is: Ile Gln Lys Thr Pro Gln fle Gln Val Tyr Ser Arg His Pro Pro Glu Asn Gly Lys Pro Asn Ile Leu Asn Cys Tyr Val Thr Gln Phe His Pro Pro His Ile Glu Hle Gln Met Leu Lys Asn Gly Lys Lys Ile Pro Lys Val Glu Met Ser Asp Met Ser Phe Ser Lys Asp Trp Ser Phe Tyr Ile Leu Ala His Thr Glu Phe Thr Pro Thr Glu Thr Asp Thr -Tyr Ala Cys Arg Val Lys His Ala/Asp Ser Met Ala Glu Pro Lys Thr Val Tyr Trp Asp Arg Asp Met. Comparison of the sequence of murine f32-microglobulin to the sequences reported for the homologues from man, rabbit, and guinea pig indicate identities of 68%, 66%, and 61%, respectively. 132-Microglobulin (/32-M) (molecular weight 11,800) was discovered in human urine (1), and has been found to be noncovalently associated with several membrane antigens (2), including the major histocompatibility antigens of man (HLA), mouse (H-2), and other species (3-5). Despite its known attachment to various cell surface proteins, the function of 832-M remains unclear, although there is some evidence that the molecule may stabilize the tertiary structure of associated proteins (6). The complete amino acid sequence has been determined for the human molecule (7), as well as for the rabbit (8) and guinea pig (9) homologues. A partial sequence of the first 40 residues of mouse ,B2M has been reported (10). In the course of establishing the primary structure of the H2d and H-2b alloantigens of the mouse by radiosequence techniques (11-14), significant amounts of radiolabeled /32-M have been copurified. The present work describes the determination of the primary structure of murine f32-M entirely by radiosequence methodology and documents the discovery of a polymorphism in the structures of the f32-M isolated from tumor cell lines derived from two different mouse strains. MATERIALS AND METHODS Preparation of Radiolabeled Murine P2-M. Radiolabeled amino acids were incorporated into murine tumor cell lines EL4.BU (H-2b), a lymphoblastoid cell line derived from C57BL/6 mice, and C14 (H-2d), an Abelson virus-induced cell line derived from BALB/c mice (12). The H-2Kb, H 2Kd, and H-2Dd alloantigens were isolated by specific immunoprecipitation as described (11-13). The associated 832-M was separated by chromatography on a column (190 x 2 cm) of Sephadex G75 in 1 M formic acid (11-13). Cleavage with CNBr. Radiolabeled 32-M was dissolved in 4 m of 70% (vol/vol) formic acid and allowed to react with 1.1 g of CNBr (Eastman Kodak) in the presence of 40 mg of sperm whale myoglobin (Sigma) as described (11, 12). Resulting peptides are indicated by C. Citraconylation. Radiolabeled f32-M was dissolved in 2 ml of 2 M guanidine hydrochloride (Gdn HCl)/50 mM sodium borate, pH 8.3, together with 2 mg of horse heart cytochrome c (Sigma). A total of 50 ,ul of citraconic anhydride (Eastman.Kodak) was added in 10 aliquots, while the pH was maintained between 8 and 9 with 2 M NaOH. Thirty minutes after the last addition, the citraconylated material was desalted on a column of Sephadex G-10 (30 X 2 cm) equilibrated with 20 mM NH4HCO3, pH 8.0, and lyophilized. Citraconyl groups were removed by incubating peptides in 50% (vol/vol) acetic acid for 4 hr at room temperature, followed by dilution to 10% acetic acid and lyophilization. Reduction and Alkylation. Lyophilized C1 peptides containing 2-4 mg of carrier protein (horse heart cytochrome c) were dissolved in 2 ml of 6 M Gdn-HCV0.8 M Tris-HCl, pH 8.2/10 mM EDTA and flushed with N2 for 5 min. After the addition of 0.4 ml of 0.1 M dithiothreitol, the mixture was stirred for 1 hr at room temperature. After the addition of 17.4 mg of iodoacetic acid (Sigma), the reaction mixture was stirred in the dark for 20 min prior to gel filtration on a column (0.9 X 200 cm) of Sephadex G-50 superfine equilibrated in 2 M formic acid. Lyophilized TlTl peptides were dissolved in 3 ml of 6 M Gdn-HCV0.2 M N-methylmorpholine, pH 8.6, and flushed with N2. Thirty microliters of 0.1 M dithiothreitol was added and the reaction mixture was incubated at 50°C for 30 min under N2. A total of 0.15 ml of 1 M N-(iodoethyl)trifluoroacetamide (Aminoethyl-8, Pierce) in methanol was added in two aliquots over a period of 2 hr. Aminoethylated peptides were desalted on a column (1.5 X 25 cm) of Sephadex G-25 in 2 M formic acid and lyophilized. Enzymatic Digestion of Peptides. Peptides C1A and T1 were further digested by using 1% trypsin [treated with L-(tosylamido-2-phenyl)ethyl chloromethyl ketone; Worthington] for 2 hr at 37°C, whereas C1B peptides were-digested with1% Staphylococcus aureusV8 protease (V8) (Miles) for 24 hr at 37°C in 25 mM NH4HCO3, pH 8.1. The citraconylated ,32-M and the aminoethylated TiTi peptides were digested by using 2% trypsin for 4 hr at 37°C in 25 mM NH4HCO3, pH 8.1. Desalting of Peptides. All material pooled from columns equilibrated in 6 M Gdn-HCl was desalted on a Sephadex G-10 Abbreviations: 82-M, (32-microglobulin; HPLC, high-pressure liquid chromatograph; Gdn-HCl, guanidine hydrochloride; V8, Staphylococcus aureus V8 protease. 554 The publication costs ofthis article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact. Proc. Natd Acad. Sci. USA 78 (1981) 555 | v2 |
2018-04-03T00:51:42.066Z | 2012-03-01T00:00:00.000Z | 12312591 | s2ag/train | 5-Oxoprolinuria as a cause of high anion gap metabolic acidosis.
We report a case of high anion gap metabolic acidosis (HAGMA) caused by 5-oxoprolinuria resulting from chronic intermittent paracetamol therapy, malnutrition and concomitant moderate renal/hepatic dysfunction.
A 36-year-old Caucasian woman was brought to our intensive care unit after intubation at another hospital. She initially presented with drowsiness and tachypnoea. The initial working diagnosis was bibasilar bronchopneumonia, and she received a dose of ceftriaxone. Arterial blood gas (prior to intubation) showed pH 6.99, partial pressure of CO2 14 mmHg, partial pressure of O2 80 mmHg and 92% saturation on oxygen 2 l min−1 via nasal cannulae. She had past medical history of migraine, seizures, depression, chronic obstructive pulmonary disease, malnutrition, anaemia and deranged hepatic transaminases for 4 years following a prior suicide attempt with paracetamol. She had a history of marijuana, methamphetamine, dextromethorphan cold tablet and ethanol abuse, in addition to 40 pack-year history of smoking. Her prescription medications included divalproex sodium, levetiracetam, olanzapine, promethazine, mirtazapine, fenofibrate, lactulose, omeprazole and paracetamol as needed. On examination, she was malnourished (body mass index 17.9 kg m−2), pale, tachypnoeic (40 breaths min−1) and tachycardic (hear rate 102 min−1) with a blood pressure of 105/60 mmHg and weak peripheral pulses.
Further laboratory studies showed an anion gap of 20, with bicarbonate 5 mequiv l−1 and creatinine 1.5 mg dl−1 (132.6 µmol l−1). The Δanion gap/Δbicarbonate ratio = 0.42 suggested a mixed anion and non-anion gap acidosis. The latter was presumed to be from renal dysfunction. Other pertinent laboratory values were as follows: haemoglobin 11.9 g dl−1 (119 g l−1), white blood cell count 40 000 mm−3 (40 × 109 l−1) and platelets 854 000 mm−3 (854 × 109 l−1). Total bilirubin was normal, aspartate aminotransferase 322 U l−1 (normal 5–40 U l−1), alanine aminotransferase 101 U l−1 (normal 7–56 U l−1), alkaline phosphatase 296 U l−1 (normal 38–126 U l−1), international normalized ratio 2.5, ammonia 78 µg dl−1 (45.7 µmol l−1; normal 17–60 µg dl−1), lipase 411 U l−1 (normal 7–60 U l−1), amylase 68 U l−1, activated partial thromboplastin time 50 s and valproate concentration 24 mg l−1 (subtherapeutic). Urinalysis and drug of abuse screen were unremarkable.
The following causes of metabolic acidosis were negative: lactic acid 1.0 mmol l−1, ethanol <0.01 mg dl−1, methanol <5 mg dl−1, isopropranolol <5 mg dl−1, ethylene glycol <10 mg dl−1, propylene glycol <0.04 mg dl−1, salicylate 4.3 mg dl−1, paracetamol <1.2 µg ml−1 and β-hydroxybutyrate 0.2 mmol l−1; and d-lactic acid, acetaldehyde, paraldehyde and acetone were not detected.
The patient's acidosis did not resolve over the next 2 days, so she was started on sodium bicarbonate infusion and later switched to continuous veno-venous haemodialysis, which proved very effective in correcting her metabolic derangement.
To explore other aetiologies of HAGMA, urine organic acid screen was sent on the initial urine sample, which revealed a markedly elevated excretion of 5-oxoproline. A diagnosis of HAGMA secondary to 5-oxoprolinuria was made. The patient regained her normal neurological state with no acid–base disturbance, and repeat urine organic acid screen on discharge 7 days later was negative, indicating a transient 5-oxoprolinuria. The transient 5-oxoprolinuria and the absence of haemolytic anaemia makes the concomitant existence of a genetic deficiency of glutathione synthetase in this patient unlikely.
Excess 5-oxoproline (also known as pyroglutamic acid) production is a rare cause of HAGMA. It is an intermediary in the γ-glutamyl cycle, which facilitates the transport of the tripeptide glutathione (glutamyl-cystinyl-glycine) and its constituent amino acids across cellular membranes and regenerates glutathione intracellularly. Reduced glutathione is required for detoxification and minimization of free-radical-induced oxidative stress. As shown in Figure 1, excess 5-oxoproline is generated via the γ-glutamyl cyclotransferase enzyme when glutathione synthetase is deficient [1]. Glutathione depletion exerts a negative feedback on γ-glutamyl cysteine synthetase. This negative feedback is decreased in situations of glutathione depletion, thus increasing production of γ-glutamyl cysteine, which acts as a substrate for γ-glutamyl cyclotransferase enzyme to generate 5-oxoproline. Glutathione depletion is seen in liver disease, paracetamol use, alcohol abuse, fad diets (e.g. low-protein diet), glycine deficiency, malnutrition and severe sepsis [1–4]. 5-Oxoproline is cleared renally and thus accumulates in renal dysfunction. It is oxidized by the enzyme 5-oxoprolinase to l-glutamate; however, certain drugs (flucloxacillin, netilmicin and vigabatrin) can inhibit 5-oxoprolinase, hence preventing its degradation [2, 5]. 5-Oxoproline concentrations are also increased in patients with burns and those on total parenteral nutrition [1].
Figure 1
γ-Glutamyl cycle showing generation of 5-oxoproline (pyroglutamic acid). AKI, acute kidney injury
Our patient was a malnourished woman with history of chronic paracetamol therapy, which in combination probably led to glutathione depletion. Importantly, supratherapeutic/toxic paracetamol concentrations do not appear to be required to cause 5-oxoprolinuria, as was seen in our patient and as reported by others [2, 6, 7]. The management of metabolic acidosis from 5-oxoprolinuria involves discontinuing the offending agents (antibiotics or antiepileptics) and providing supportive care. Some authors suggest using N-acetylcysteine to regenerate glutathione or using intravenous bicarbonate if pH is <7.0 [5, 8, 9].
Physicians should consider screening urine for organic acids when other common causes of HAGMA have been excluded, especially in patients who have been taking paracetamol. | v2 |
2019-03-18T14:04:29.702Z | 2018-11-29T00:00:00.000Z | 81055001 | s2ag/train | Ibrutinib and Obinutuzumab in CLL: Improved MRD Response Rates with Substantially Enhanced MRD Depletion for Patients with >1 Year Prior Ibrutinib Exposure
Background: Ibrutinib inhibits CLL cell proliferation and results in prolonged remission, but MRD responses are rare. Obinutuzumab is a second generation anti-CD20 monoclonal antibody that is effective in CLL and can result in MRD responses. In the IcICLLe study (ISRCTN12695354), 40 participants with CLL requiring treatment (20 treatment-naïve, 20 with relapsed/refractory [R/R] disease) received ibrutinib until complete remission with <0.01% Minimal Residual Disease (MRD) in the bone marrow or disease progression. The IcICLLe Extension Study expanded IcICLLe to examine the efficacy and safety of the combination of obinutuzumab and ibrutinib in 40 patients with R/R CLL, of which 10/40 had received prior ibrutinib on the IcICLLe trial. Initial results after 1 month of combination treatment indicated that adding obinutuzumab to ibrutinib improved CLL depletion, and 18 month follow-up data is now available.
Aim: to determine the MRD response rates for patients with R/R CLL treated with ibrutinib and obinutuzumab in ibrutinib-naïve trial participants compared to those treated with >1 year prior ibrutinib.
Patients: The IcICLLe Extension Study recruited 40 participants with relapsed/refractory CLL requiring treatment. They received continuous ibrutinib (420mg OD) with 6 cycles of obinutuzumab given over 6 months (M). Ten participants had >1 year of prior ibrutinib monotherapy in IcICLLe and 30 were ibrutinib-naïve with obinutuzumab started 24 hours after first ibrutinib dose. Patient characteristics and Adverse Events (AEs, collected from registration until 30 days after treatment cessation and reported at 1, 3, and 6M, and 6-monthly thereafter using the Common Terminology Criteria for Adverse Events v4.0) are shown in Table 1. MRD assessment was performed according to ERIC guidelines with a maximum detection limit of 0.001%/10-5.
Results: In the 20 R/R patients treated with ibrutinib monotherapy there were no IWCLL CR/CRi responses and no patients achieved <0.01% CLL in the PB or BM at the 6 month response assessment. PB MRD levels either remained stable or improved at subsequent timepoints, with 1/20 achieving <0.01% PB MRD at 18M. The addition of obinutuzumab did not have a discernible impact on safety but was associated with a higher response rates and greater depth of MRD depletion than observed in patients treated with ibrutinib monotherapy, particularly in patients who had received ibrutinib for >1 year prior to combination with obinutuzumab (see Table 1).
Patients receiving obinutuzumab after >1 year prior ibrutinib monotherapy achieved a higher response rate compared to ibrutinib-naive patients (IWCLL CR/CRi 50% vs. 30%), with a higher proportion of patients achieving <0.01% BM MRD (50% vs. 6%) and a greater depth of disease depletion (3.1 vs. 1.5 log reduction).
PB MRD levels continued to improve in ibrutinib-naïve patients after cessation of obinutuzumab with 30% (9/30 with 4/30 inevaluable) achieving PB MRD <0.01% rate at 12 months post-obinutuzumab, compared to 60% (6/10 with 2/10 inevaluable) of patients at the same timepoint (12 months post-obinutuzumab) who had received ibrutinib for >1 year prior to starting obinutuzumab. The difference in extent of disease depletion observed with obinutuzumab may be related to the pre-obinutuzumab disease bulk because the majority of patients (7/10) with >1 year prior ibrutinib treatment had already resolved any lymphadenopathy prior to receiving obinutuzumab.
Conclusions: The results suggest that the addition of obinutuzumab to ibrutinib may result in a substantial improvement in the depletion of CLL cells from the PB and BM for ibrutinib-naïve patients. However, a greater impact in MRD response rate and depth of depletion was seen when obinutuzumab was introduced after >1 year of ibrutinib treatment and tumour bulk was low. For patients with persistent disease during/ following pathway inhibition treatments, the addition of anti-CD20 antibody therapy may be effective at improving MRD response rates.
Rawstron: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; BD Bio-sciences: Research Funding; Beckman Coulter: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Munir:MorphoSys: Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria; Novartis: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Brock:GlaxoSmithKline: Equity Ownership; AstraZeneca: Equity Ownership; Merck Sharp Dohme: Other: Reimbursement of conference fees; Roche: Other: Reimbursement of expenses; Lilly: Honoraria. Pettitt:AstraZeneca: Research Funding; Celgene: Research Funding; Chugai: Research Funding; Roche: Research Funding; GSK/Novartis: Research Funding; Gilead: Research Funding; Napp: Research Funding. Fox:Celgene: Consultancy, Other: Travel support, Speakers Bureau; Janssen: Consultancy, Other: Personal fees and non-financial support, Speakers Bureau; Gilead: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Sunesis: Consultancy. Devereux:Janssen: Other: Personal fees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Fegan:Janssen: Honoraria; Gilead Sciences, Inc.: Honoraria; Abbvie: Honoraria; Roche: Honoraria; Napp: Honoraria. Bloor:Janssen: Research Funding; AbbVie: Research Funding. Hillmen:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; Acerta: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Novartis: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
| v2 |
2021-11-25T16:19:14.421Z | 2021-11-05T00:00:00.000Z | 244568621 | s2ag/train | Characterization of Indolent Chronic Myelomonocytic Leukemia Phenotypes and Identification of Dynamic Disease Features of Progression and Need for Treatment
Background
CMML is a markedly heterogenous clinical entity exhibiting features innate to both, myeloproliferative neoplasms (MPN) and myelodysplasia (MDS). Generally associated with poor outcomes, median overall survival (mOS) is 3 years (yrs). Multiple prognostic models consider cardinal clinical, cytogenetic and molecular features critical in estimating individual risk and outlining treatment. Identification and longitudinal assessment of features of interest become important to predict which patients tend to have a more indolent course compared to those who will progress.
Methods
Clinical and molecular data was collected retrospectively from a proprietary database of 729 patients with CMML treated at Moffitt Cancer Center (MCC). Pts were stratified into 2 cohorts: those remaining in observation for >3 yrs (indolent CMML) and those who required treatment <3 yrs after presentation (NI-CMML). Treatment-naïve pts lost to f/u within 3 yrs were excluded. For those pts with indolent disease who required treatment eventually, we aimed to identify changes in clinical and molecular features from baseline immediately anteceding the need for treatment to establish whether they predicted evolution of disease. Marrow features were examined at baseline and at specific time intervals prior to the initiation of therapy.
Results
Between August 1995 and October 2020, 729 pts with a diagnosis of CMML were identified at MCC. Out of these, 68.3% (498) were male and 88.5% (645) were Caucasian. Median age at diagnosis was 71 (17-95). A total of 123 pts (17%) did not require treatment within 3 yrs of diagnosis. mOS was 70 mo among those who did not require early treatment compared to 25 mo for those who did (p<.001).
Clinically, higher platelet count at baseline was associated with longer time to treatment (p=0.022). Elevated WBC (proliferative CMML), lymphocytes, monocytes, ANC, marrow blasts and cellularity, as well as low baseline Hb were associated with earlier initiation of treatment (p<.005). Pts not needing immediate treatment had lower risk disease by IPSS, R-IPSS and all CMML risk models (Table 1).
JAK2, SF3B1 and IDH2 mutations were associated with more indolent course obviating the need for intervention within 3 yrs (p<.005). NRAS portended a more aggressive course (p=0.004). Pts harboring ASXL1 showed a trend towards early progression (p=0.067) (Table 2).
Of the 123 pts with indolent disease, 37.4% (46) required intervention at some point. Need for treatment was secondary to worsening clinical symptoms and/or cytopenias in most cases. From a molecular perspective, 7 of the 46 pts had NGS assessment prior to and after starting treatment for comparison of clonal evolution.
Interestingly, pts with indolent CMML who progressed differed from baseline compared to those with static disease: they tended to harbor CBL (p=0.005), U2AF1 (p=0.022) and ETV6 mutations (p=0.05).
Histopathologically, the presence of ALIP (abnormally localized immature precursors), when reported, was an important feature in a significant number of cases needing treatment (77.8%, n=7), that was not present early in the course of the disease. Presence of ALIP prompted initiation of treatment and mirrored clinical decline. Also, changes in the M:E ratio from baseline always heralded abnormality, but whether that ratio was abnormally high or low was irrelevant and merely a reflection of the underlying pathophysiology (proliferative vs dysplastic). Change was synonymous with abnormality and was more prominent 1 month prior to treatment.
From a molecular standpoint, clonal evolution mirrored the need to start treatment usually in the form of new mutations: 5 (71.4%) of cases developed new or additional TET2 mutations, 2 (28.6%) gained EZH2 mutations, 1 ABL1 and yet another developed multiple mutations in TET2, SRSF2, STAG2 and CBL.
Conclusion
A small subset of CMML patients (17%) have a more indolent disease course associated with better outcomes. Clinical and molecular features at diagnosis can be assessed to identify them. Dynamic changes in M:E ratio from baseline (regardless of direction) and presence of ALIP heralded and/or mirrored clinical decline and need to start or switch treatment. Similarly, gain of mutations mirroring clonal evolution heralded need to start treatment.
Figure 1 Figure 1.
Sallman: Kite: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Incyte: Speakers Bureau; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kuykendall: PharmaEssentia: Honoraria; Abbvie: Honoraria; Novartis: Honoraria, Speakers Bureau; Prelude: Research Funding; BluePrint Medicines: Honoraria, Speakers Bureau; Incyte: Consultancy; CTI Biopharma: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sweet: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Lancet: ElevateBio Management: Consultancy; Celgene/BMS: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Astellas: Consultancy; Millenium Pharma/Takeda: Consultancy; BerGenBio: Consultancy; AbbVie: Consultancy; Jazz: Consultancy. Padron: Stemline: Honoraria; BMS: Research Funding; Taiho: Honoraria; Kura: Research Funding; Incyte: Research Funding; Blueprint: Honoraria. Komrokji: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy; Jazz: Consultancy, Speakers Bureau; Geron: Consultancy; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees.
| v2 |
2020-03-19T10:25:36.483Z | 2020-03-09T00:00:00.000Z | 216442671 | s2ag/train | Intestinal Organoid Dissociation and Nuclei Isolation for Single Cell ATAC-Seq v1
This protocol provides a procedure for human intestinal organoid dissociation into a single cell suspension and nuclei isolation prior to Single Cell ATAC-Sequencing. DOI dx.doi.org/10.17504/protocols.io.bdeui3ew PROTOCOL CITATION Heather Eckart, Ran RZ Zhou 2020. Intestinal Organoid Dissociation and Nuclei Isolation for Single Cell ATAC-Seq. protocols.io https://dx.doi.org/10.17504/protocols.io.bdeui3ew LICENSE This is an open access protocol distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited CREATED Mar 09, 2020 LAST MODIFIED Mar 13, 2020 PROTOCOL INTEGER ID 33972 GUIDELINES Nuclei isolation for Chromium Next GEM Single Cell ATAC Sequencing was performed following the protocol provided by 10X Genomics. For further guidelines and tips reference the original protocol below. (https://assets.ctfassets.net/an68im79xiti/5g035d2ngCW1aB9DFqPphO/71445a59fb282ea273a866c26cb5d3 19/CG000169_DemonstratedProtocol_NucleiIsolation_ATAC_Sequencing_RevD.pdf) Chromium Next GEM Single Cell ATAC Sequencing was performed following the protocol provided in the user guide from 10X Genomics. (https://assets.ctfassets.net/an68im79xiti/7L2MU4QSWfrEgd2h13Efac/d5326fcdc6363aa04e4fdf11b2a1f2f8/ CG000209_Chromium_NextGEM_SingleCell_ATAC_ReagentKits_v1.1_UserGuide_RevD.pdf) The primary human tissue that generates the organoids, are obtained from endoscopic biopsies after patient's consent and approval from Institutional Review Board at the University of Chicago (IRB Number: 15573A). 1 03/13/2020 Cita tion : Heather Eckart, Ran RZ Zhou (03/13/2020). Intestinal Organoid Dissociation and Nuclei Isolation for Single Cell ATAC-Seq. https://dx.doi.org/10.17504/protocols.io.bdeui3ew This is an open access protocol distributed under the terms of the Crea tive Com m ons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited BEFORE STARTING MATERIALS TEXT MATERIALS Magnesium chloride solution for molecular biology (1.00 M) Sigma – Aldr ich Catalog #M1028 TrypLETM Express Enzyme Thermo Fisher Scientif ic Catalog #12604013 Wheat Germ Agglutinin, Alexa FluorTM 594 Conjugate Thermo Fisher Catalog #W11262 Trizma Hydrochloride Solution pH 7.4 Sigma Aldr ich Catalog #T2194 Sodium Chloride Solution 5 M Sigma Aldr ich Catalog #59222C Magnesium Chloride Solution 1 M Sigma Aldr ich Catalog #M1028 Nonidet P40 Substitute Sigma Aldr ich Catalog # 74385 MACS BSA Stock Solution Miltenyi Biotec Catalog # 130-091-376 Flowmi Cell Strainer 40 μm BelArt Catalog #H13680-0040 Nuclei Buffer 20X 10x Genomics Catalog #2000153/2000207 DAPI Sigma Aldr ich Catalog #D9542 Note: 10x Genomics Nuclei Buffer 20X (2000153/2000207) is included in the 10x Genomics Single Cell ATAC Library Kits Diluted Nuclei Buffer 1mL Nuclei Buffer (20X) 50 ul (final concentration 1X) Nuclease free water 950 ul 2 03/13/2020 Cita tion : Heather Eckart, Ran RZ Zhou (03/13/2020). Intestinal Organoid Dissociation and Nuclei Isolation for Single Cell ATAC-Seq. https://dx.doi.org/10.17504/protocols.io.bdeui3ew This is an open access protocol distributed under the terms of the Crea tive Com m ons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited BEFORE STARTING Prepare diluted nuclei buffer, wash buffer, lysis buffer, and PBS with 0.04% BSA Organoid Dissociation 1 Incubate organoid in TrypLE for up to 20 minutes at 37°C 1.1 Every 5 minutes, pipette the cell suspension up and down 5-10x and check the digestion progress with a hemocytometer until enough single cells are present Nuclei Isolation 2 For freshly dissociated cells, perform 1-2 washes with PBS + 0.04% BSA (20ul BSA/1mL 1X PBS). Consult 10X Genomics protocol for using frozen cells 3 Determine the cell count after washing using a hemocytometer. 4 Add cell suspension of 100,000-1,000,000 cells to a 2-ml tube. For our experiment we started with 200,000 cells per sample. 5 Centrifuge at 300 rcf for 5 min at 4°C 300 x g, 4°C, 00:05:00 6 Remove ALL the supernatant without disrupting the cell pellet 7 Add 100 μl chilled Lysis Buffer. Pipette to mix 10x 100 μl Lysis Buffer 8 Incubate for 4 min on ice On ice 4 min Time may vary depending on cell type; 4 minutes is specific for organoid samples 3 03/13/2020 Cita tion : Heather Eckart, Ran RZ Zhou (03/13/2020). Intestinal Organoid Dissociation and Nuclei Isolation for Single Cell ATAC-Seq. https://dx.doi.org/10.17504/protocols.io.bdeui3ew This is an open access protocol distributed under the terms of the Crea tive Com m ons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited 9 Add 1 ml chilled Wash Buffer to the lysed cells. Pipette to mix 5x 1 mL Wash Buffer 10 Centrifuge at 500 rcf for 5 min at 4°C 500 x g, 4°C, 00:05:00 11 Remove the supernatant without disrupting the nuclei pellet 12 Based on your targeted nuclei recovery, cell concentration in step 4 and assuming ~50% nuclei loss during cell lysis, resuspend in chilled Diluted Nuclei Buffer (1x). Maintain on ice. (See Nuclei Stock Concentration Table and Example Calculation below) For our experiment, we targeted 5,000 nucle i . 13 Check nuclei integrity by staining with WGA and DAPI. Also determine the nuclei concentration using a hemocytometer 14 OPTIONAL: If cell debris and large clumps are observed, pass through a cell strainer. For low volume, use a 40 μm Flowmi Cell Strainer to minimize volume loss 4 03/13/2020 Cita tion : Heather Eckart, Ran RZ Zhou (03/13/2020). Intestinal Organoid Dissociation and Nuclei Isolation for Single Cell ATAC-Seq. https://dx.doi.org/10.17504/protocols.io.bdeui3ew This is an open access protocol distributed under the terms of the Crea tive Com m ons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited 15 Proceed immediately to Chromium Next GEM Single Cell ATAC Sequencing protocol (found in the Chromium Single Cell ATAC Solution User Guide) 5 03/13/2020 Cita tion : Heather Eckart, Ran RZ Zhou (03/13/2020). Intestinal Organoid Dissociation and Nuclei Isolation for Single Cell ATAC-Seq. https://dx.doi.org/10.17504/protocols.io.bdeui3ew This is an open access protocol distributed under the terms of the Crea tive Com m ons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited | v2 |
2020-10-28T19:12:48.724Z | 2020-08-04T00:00:00.000Z | 226377141 | s2ag/train | Late Amazonian lateral lava flows coeval with caldera eruptions at Arsia Mons
<p><strong>Introduction: </strong>The Tharsis dome is the main volcanic province on Mars. Being the locus of volcanism since at least the lower Hesperian, the age of emplacement and succession of its lava flows gives insights onto the thermal evolution of the planet since that time. Late Amazonian volcanic activity has taken the form of a large number of long and narrow lava flows, the vast majority of which unmapped to date. Mapping them is critical to characterize the recent dynamics of the Tharsis volcanism and relationships with tectonic activity. We focus on a group of fresh-looking lava flows located SE of Arsia Mons (Fig. 1). We map individual flows and determine their crater retention age, correlate with stratigraphy.</p>
<p><img src="data:image/jpeg;base64, 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| v2 |
2018-04-03T01:57:15.785Z | 2003-02-21T00:00:00.000Z | 5188811 | s2ag/train | A Part of the Human Genome Sequence
The sequencing and subsequent publication of the human genome ([1][1], [2][2]) captured the public imagination and marked the beginning of a new era in biological research. An unfortunate side effect of human genome sequencing has been the inappropriate elevation of the genome to almost mythical status as the seat of our humanness. The published genome is a collection of human DNA sequences, nothing more and nothing less. By acknowledging that my own DNA sample was part of the Celera Genomics sequencing effort, I hoped to dispel the notion that there is any such thing as a single human genome and to show that genome sequencing is neither harmful nor magical.
Therefore, I disagree with Donald Kennedy's view that acknowledging my contribution to the published genome was “tacky” (“Not wicked, perhaps, but tacky,” Editorial, 23 Aug. p. [1237][3]). I also strongly disagree with his assertion that the Institutional Review Board (IRB) process was “compromised.” Celera's IRB process was intended to safeguard the privacy of donors who wished to remain anonymous, which I support entirely. My personal disclosure did not violate of any of these protections ([3][4]).
Recent polls consistently show that a majority of people are concerned about having their genetic code used as a weapon against them in seeking employment or for health care coverage, and they are very concerned about genetic and medical information privacy. Only through legislation and education can we help to alleviate the public fears about misuse of genetic information. I believe that by acknowledging my contribution to the sequenced genome, I have taken a positive step in alleviating some of these fears.
When a decision was made at Celera to go beyond sequencing one individual, Celera consulted with its IRB committee, made up of leaders in science and ethics. Committee discussions focused on issues such as the following: Should Celera sequence genomes from individuals of diverse ethnic origin and, if it did, could this information be protected from racist groups that want to promote their own agenda? How could the company protect the privacy of the individual donors who volunteered from Celera or from any parties that might want Celera to reveal data about individuals, thereby putting them at potential risk for employment or for health insurance coverage? A Certificate of Confidentiality from the Department of Health and Human Services was issued to the Principal Investigator as added protection for the individual donors against third parties trying to force Celera to disclose their identities. By establishing and adhering to an IRB process and obtaining a certificate, Celera did all it could to ensure the donors' privacy.
An important principle about the Celera IRB process, which is explicitly stated in the company's informed consent document, is that individuals who wish to identify themselves as DNA donors are at liberty to do so. Some have chosen to make their participation public. One DNA donor wrote an article describing the donor process and what it meant for him to be a donor. Others have chosen not to identify themselves, which is their right.
On the basis of my beliefs, I candidly answered several reporters who asked me during the past 18 months whether I was a DNA donor. I do not know the identities of the other 20 people in the donor pool, except those who have publicly or privately disclosed to me that they were donors (and I will continue to respect their confidentiality). The sequence published by Celera is exactly as described: “The decision about whose DNA to sequence was based on a complex mix of factors, including the goal of achieving diversity as well as technical issues such as the quality of DNA libraries and availability of immortal cell lines” ([1][1], p. 1307). As we stated, the published genome is a composite of DNA from five donors. Thus, the published genome sequence is neither my genome, nor my genetic profile.
If it is the opinion of some editors that it was “tacky” to reveal that I was part of the sequencing pool, so be it. Opinions are like genomes: Everyone has one. I want to show the world that we do not need to fear our genetic information but, rather, that it can be a powerful new tool to help us prevent or better treat disease and lead healthier lives.
1. [↵][5]1. J. C. Venter 2. et al.
, Science 291, 1304 (2001).
[OpenUrl][6][Abstract/FREE Full Text][7]
2. [↵][8]1. International Human Genome Sequencing Consortium
, Nature 409, 860 (2001).
[OpenUrl][9][CrossRef][10][PubMed][11]
3. [↵][12]I left Celera Genomics in January 2002 and am no longer affiliated with the company. The views expressed here are my own.
[1]: #ref-1
[2]: #ref-2
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[4]: #ref-3
[5]: #xref-ref-1-1 "View reference 1 in text"
[6]: {openurl}?query=rft.jtitle%253DScience%26rft.stitle%253DScience%26rft.issn%253D0036-8075%26rft.aulast%253DVenter%26rft.auinit1%253DJ.%2BC.%26rft.volume%253D291%26rft.issue%253D5507%26rft.spage%253D1304%26rft.epage%253D1351%26rft.atitle%253DThe%2BSequence%2Bof%2Bthe%2BHuman%2BGenome%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.1058040%26rft_id%253Dinfo%253Apmid%252F11181995%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx
[7]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEzOiIyOTEvNTUwNy8xMzA0IjtzOjQ6ImF0b20iO3M6MjM6Ii9zY2kvMjk5LzU2MTAvMTE4My5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=
[8]: #xref-ref-2-1 "View reference 2 in text"
[9]: {openurl}?query=rft.jtitle%253DNature%253B%2BPhysical%2BScience%2B%2528London%2529%26rft.stitle%253DNature%253B%2BPhysical%2BScience%2B%2528London%2529%26rft.aulast%253DLander%26rft.auinit1%253DE.%2BS.%26rft.volume%253D409%26rft.issue%253D6822%26rft.spage%253D860%26rft.epage%253D921%26rft.atitle%253DInitial%2Bsequencing%2Band%2Banalysis%2Bof%2Bthe%2Bhuman%2Bgenome.%26rft_id%253Dinfo%253Adoi%252F10.1038%252F35057062%26rft_id%253Dinfo%253Apmid%252F11237011%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx
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[12]: #xref-ref-3-1 "View reference 3 in text" | v2 |
2019-04-29T13:13:31.827Z | 2015-07-20T00:00:00.000Z | 137853311 | s2ag/train | Novel Environment-friendly Green Pigments for Over-glazed Decoration of Arita Ware
Environmental-friendly inorganic green pigments based on (Y0.9R0.1)2BaCuO5 (R = Sm3+, Gd3+, Yb3+, and Lu3+) solid solutions were synthesized and the dopant element was optimized to give the most greenish color. Among the samples, it was found that Lu-doped sample showed brilliant green hue. In response to the results, (Y1−xLux)2BaCuO5 (0 ≤ x ≤ 0.3) pigments were further synthesized and their color properties were characterized in an attempt to find a new environmentally friendly pigment that has more sufficient green chromaticity. Among the samples, the most vivid green hue was obtained for (Y0.9Lu0.1)2BaCuO5 with a greenness value (−a*) of 48.6 in the CIE L*a*b* system, which was significantly larger than those of commercially available Cr2O3 (−a* = 18.2) and CoO∙ZnO (−a* = 25.3) pigments. The Y2BaCuO5 and (Y0.9Lu0.1)2BaCuO5 pigments were used in paints for porcelain. The green colors of the overglazed decoration panels were brilliant. Therefore, these pigments could be the potential candidates for novel green pigments of over-glazed decoration of Arita ware. Key-words: Y2BaCuO5, Environment-friendly, Green pigment, Solid solution, Arita ware Original Research Paper J. Jpn. Soc. Colour Mater., 88〔7〕,203–207(2015) 203 © 2015 Journal of the Japan Society of Colour Material -1the XRD peak angles, which were refined using α-Al2O3 as a standard. Particle size and morphology were examined by field-emission scanning electron microscopy (FE-SEM; JEOL, JSM-6700FSS). The optical reflectance was measured using a UV-vis spectrometer (Shimadzu, UV-2600) with barium sulfate as a reference. The bandgap energies of the samples were determined from the absorption edge of the absorbance spectra represented by the Kubelka-Munk function, f (R) = (1−R)2/2R, where R is reflectance7). The color properties of the green pellets of the samples were estimated in terms of the CIE L*a*b*CH° system with a colorimeter (Konica-Minolta, CR-400). The parameter L* represents the brightness or darkness of a color relative to a neutral grey scale, while the parameters a* (the redgreen axis) and b* (the yellow-blue axis) qualitatively express the color. Since the a* value in the negative direction corresponds to the green component, it is desirable for a* to be small (for −a* to be large) as possible on the development of green pigments. The parameter C (chroma) represents saturation of the color and H° represents the hue angle. The chroma is defined as C = {(a*)2 + (b*)2}1/2. The hue angle, H°, is expressed in degrees and ranges from 0 to 360° and is calculated using the formula H° = tan−1(b*/a*). For pure green, H° = 180°. 2.3 Evaluation of overglazing pigment for Arita ware The Y2BaCuO5 or (Y0.9Lu0.1)2BaCuO5 pigment was added to a commercially available lead-free frit. Pigment concentrations of 5 and 7 wt% were used for painting. The mixture was mechanically mixed using a mortar grinder for 10 min to prepare overglazed enamels. The overglazed decoration pigment was painted on porcelain panels coated with limestone glazes and the panels were heated in an electric furnace at 1073 K for 30 min at a heating rate of 100 K h−1. The final glazes were evaluated in terms of their color hue by the CIE L*a*b*CH° system with a colorimeter (Nippon Denshoku, SQ-2000). The acid resistance of the Y2BaCuO5 pigment was evaluated using a small dish (diameter: 8 cm; capacity: 30 cm3). A 4-cm-square was painted or drawn inside the dish using the overglazed enamel and the dish was heated at 1073 K for 30 min. 4% acetic acid solution was then poured into the dish. After leaving it at 296 K for 24 h, the Cu and Y concentrations in the 4% acetic acid solution were measured by inductively-coupled plasma spectroscopy (ICP; Shimadzu, ICPS-8100). 3.Results and Discussion 3.1 Y2BaCuO5 and (Y0.9R0.1)2BaCuO5 (R = Sm3+, Gd3+, Yb3+, and Lu3+) Fig. 1 shows XRD patterns of the Y2BaCuO5 and (Y0.9R0.1)2BaCuO5 (R = Sm3+, Gd3+, Yb3+, and Lu3+) samples. A single-phase orthorhombic structure was observed for all samples, and no diffraction peaks of impurities were evident in the patterns. The XRD peaks shifted to lower angle direction when Sm3+ or Gd3+ was doped into the Y3+ site, because the ionic radii of Sm3+ (0.0958 nm)8) and Gd3+ (0.0938 nm)8) are larger than that of Y3+ (0.0900 nm)8). On the other hand, the peaks shifted to higher angle direction in the cases of Yb3+ and Lu3+ doping, due to smaller ionic radii of Yb3+ (0.0868 nm)8) and Lu3+ (0.0861 nm)8). The orthorhombic lattice volumes of the Y2BaCuO5 and (Y0.9R0.1)2BaCuO5 (R = Sm3+, Gd3+, Yb3+, and Lu3+) samples calculated from the diffraction angles in the XRD patterns are summarized in Table 1. The lattice volume of the orthorhombic phase depends on the ionic radius of the doped rare earth ion, indicating the formation of solid solutions. Fig. 2 depicts UV-vis diffuse reflectance spectra for the Y2BaCuO5 and (Y0.9R0.1)2BaCuO5 (R = Sm3+, Gd3+, Yb3+, and Lu3+) samples. All samples exhibited strong optical absorption at wavelengths shorter than 400 nm and longer than 600 nm, while strong reflection was recognized between 400 to 600 nm including the green region (500 ‒ 560 nm). As a result, the samples are green. The optical absorption shorter than 400 nm is attributed to the charge transfer transition from O2− to Cu2+, while that longer than 600 nm corresponds to the d-d transitions of Cu2+ 9-12). Fig. 1 XRD patterns of Y2BaCuO5 and (Y0.9R0.1)2BaCuO5 (R = Sm3+, Gd3+, Yb3+, and Lu3+). Table 1 Lattice volumes of Y2BaCuO5 and (Y0.9R0.1)2BaCuO5 (R = Sm3+, Gd3+, Yb3+, and Lu3+). Sample Lattice volume / nm3 Y2BaCuO5 0.4912 (Y0.9Sm0.1)2BaCuO5 0.4939 (Y0.9Gd0.1)2BaCuO5 0.4924 (Y0.9Yb0.1)2BaCuO5 0.4905 (Y0.9Lu0.1)2BaCuO5 0.4896 Original Research Paper 204 J. Jpn. Soc. Colour Mater., 88〔7〕(2015) | v2 |
2021-08-03T00:04:04.783Z | 2021-04-09T00:00:00.000Z | 236744551 | s2ag/train | Safety and Efficacy of Upadacitinib in Combination With Topical Corticosteroids in Adolescents and Adults With Moderate-to-Severe Atopic Dermatitis: Results From a Pivotal Phase 3, Randomised, Double-Blind, Placebo-Controlled Study (AD Up)
Background: Systemic therapies are typically combined with topical corticosteroids (TCS) in the management of moderate-to-severe atopic dermatitis (AD). Upadacitinib (UPA) is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2 being developed for AD. AD Up was designed to assess the efficacy and safety of UPA+TCS versus placebo (PBO)+TCS in adolescents and adults with moderate-to-severe AD.Methods: AD Up (ClinicalTrials.gov, NCT03568318) is an ongoing pivotal, phase 3, randomised, double-blinded, placebo-controlled, multicentre study that enrolled patients from 171 clinical centres across the Asia-Pacific region, Europe, Middle East, North America, and Oceania. Adolescents (aged 12–17 years) and adults (aged 18–75 years) with chronic AD (≥10% of body surface area affected, Eczema Area and Severity Index [EASI] ≥16, validated Investigator’s Global Assessment for AD [vIGA-AD™] ≥3, and Worst Pruritus Numerical Rating Scale [NRS] score ≥4) were eligible to participate. Patients were randomised (1:1:1) to receive UPA 15 mg, UPA 30 mg, or PBO once daily, all in combination with TCS (medium-potency TCS [or lowpotency TCS or topical calcineurin inhibitor for sensitive skin areas] until skin was clear or almost clear or for up to 3 consecutive weeks, followed by low-potency TCS for 7 days;if lesions returned or persisted, step-down approach was repeated), stratified by baseline disease severity, geographic region, and age using interactive response technology. Study investigators, study site personnel, and patients remained blinded throughout the study. Efficacy was analysed in the intention-to-treat population, defined as all patients who were randomised in the main study. The coprimary endpoints were proportion of patients achieving ≥75% reduction from baseline in EASI (EASI 75) at week 16 and proportion of patients achieving vIGA-AD of clear or almost clear with ≥2 grades of improvement (vIGA-AD 0/1) at week 16. Selected key secondary endpoints included proportions of patients achieving EASI 90 at weeks 4 and 16, EASI 75 at weeks 2 and 4, and percent Worst Pruritus NRS improvement ≥4 at weeks 1, 4, and 16. Safety was assessed via adverse event (AE) monitoring. Missing responses were handled based on nonresponder imputation incorporating multiple imputation to handle missing data due to coronavirus disease 2019 (COVID-19;NRI-C). Safety was analysed in all patients in the main study who received ≥1 dose of study drug.Findings: Between Aug 30, 2018, and Dec 20, 2019, 901 patients were randomised. At week 16, significantly greater proportions of patients treated with UPA 15 mg+TCS or UPA 30 mg+TCS than PBO+TCS achieved the coprimary endpoints—EASI 75 (64·6% [194 of 300 patients] and 77·1% [229 of 297] vs 26·4% [80 of 304];adjusted difference vs PBO+TCS: 38·1% [95% CI 30·8–45·4] and 50·6% [43·8–57·4];p<0·001 for both doses) and vIGA-AD 0/1 (39·6% [119 of 300] and 58·6% [174 of 297] vs 10·9% [33 of 304];adjusted difference vs PBO+TCS: 28·5% [22·1–34·9];47·6% [41·1–54·0];p<0·001 for both doses). The superiority of both UPA doses vs PBO was also demonstrated for all key secondary endpoints (p<0·001). During the double-blind period, UPA 15 and 30 mg were well tolerated in combination with TCS, and no new important safety signals beyond the events in the current label. Higher rates of acne were reported in this AD study. Incidences of AEs leading to discontinuation of study drug and serious AEs were similar among treatment groups. No deaths or opportunistic infections (excluding herpes zoster), active tuberculosis, lymphoma, adjudicated gastrointestinal perforations, adjudicated major adverse cardiovascular events, or adjudicated venous thromboembolic events were reported. Efficacy and safety results for adolescents were consistent with those for the overall population.Interpretation: In this phase 3 study, UPA+TCS was well tolerated and superior to PBO+TCS across coprimary and all k y secondary endpoints. UPA as combination therapy demonstrated a positive benefit-risk profile in adults and adolescents with moderate-to-severe AD.Trial Registration: ClinicalTrials.gov number: NCT03568318Funding: AbbVie Inc. Declaration of Interest: KR has served as advisor and/or paid speaker for and/or participated in clinical trials sponsored by AbbVie, Affibody, Almirall, Amgen, Avillion, Biogen, Bausch Health (Valeant), Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Centocor, Covagen, Dermira, Forward Pharma, Fresenius, Galapagos, GlaxoSmithKline, Janssen, Kyowa Kirin, LEO Pharma, Lilly, Medac, Merck, Novartis, Miltenyi Biotec, Ocean Pharma, Pfizer, Regeneron, Samsung Bioepis, Sanofi, Sun Pharma, Takeda, UCB, and XenoPort. HDT, JZ, XHuang, XHu, BH, BL, ADC are full-time employees of AbbVie Inc., and may hold AbbVie stock or stock options. MdB-W has been a consultant, advisory board member, and/or speaker for AbbVie, Almirall, Galderma, Janssen, LEO Pharma, Lilly, Pfizer, Regeneron, Sanofi Genzyme, and UCB. TB is an advisor, speaker, and researcher for AbbVie, Allmiral, AnaptysBio, Arena, Asana Biosciences, Astellas, Bayer, BioVersys, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Dermavant/Roivant, Dermtreat, Domain Therapeutics, DS Biopharma, RAPT Therapeutics (FLX Bio), Galapagos/MorphoSys, Galderma, Glenmark, GlaxoSmithKline, Incyte, Kymab, LEO Pharma, Lilly, L´Oréal, Menlo Therapeutics, Novartis, Pfizer, Pierre Fabre, Sanofi/Regeneron, and UCB. WS is a consultant for AbbVie, Pfizer, Regeneron, and Sanofi. He is a speaker for Regeneron and Sanofi, and has received research grants from AbbVie, AB Biosciences, Genentech, Glenmark, LEO Pharma, Regeneron, Sanofi, and Vanda. KK has received consulting fees, honoraria, or grant support or lecturing fees from AbbVie, Japan Tobacco, LEO Pharma, 24 Maruho, Mitsubishi Tanabe Pharma, Ono Pharmaceutical, Procter & Gamble, Sanofi, Taiho Pharmaceutical, and Torii Pharmaceutical. TW has received lecture or consultancy fees from AbbVie, Almirall, Astellas, Galderma, Janssen/Johnson & Johnson, LEO Pharma, Lilly, Novartis, Pfizer, and Regeneron/Sanofi. JIS is an advisor, speaker, or consultant for AbbVie, Asana Biosciences, Dermavant, Galderma, GlaxoSmithKline, Glenmark, Kiniksa, LEO Pharma, Lilly, Menlo Therapeutics, Novartis, Pfizer, Realm Pharma, and Regeneron-Sanofi. He is also a researcher for GlaxoSmithKline.Ethical Approval: Independent ethics committees or institutional review boards at each study site approved the study protocol, informed consent form(s), and recruitment materials prior to patient enrolment. The study was conducted in accord with the International Conference for Harmonisation guidelines, applicable regulations, and the Declaration of Helsinki. Adult patients and parents/legal guardians of adolescent patients provided written informed consent prior to any screening or study-related procedures. An adolescent substudy was added after the protocol was initiated to allow enrolment of additional adolescents to fulfil a regulatory commitment. | v2 |
2019-03-16T13:07:41.945Z | 2016-09-20T00:00:00.000Z | 116720051 | s2ag/train | Introduction to Special Issue on Pharmacy and Pharmaceutical Sciences: Celebrating the 10th Anniversary of School of Pharmacy, Walailak University
I feel honored to write the editorial article for this special issue of the Walailak Journal of Science and Technology focusing on pharmacy and pharmaceutical sciences, celebrating the 10th anniversary of the School of Pharmacy, Walailak University. Pharmaceutical development in drugs, cosmetics, and health products involves various processes, including raw material preparation, formulation development, the invention of drug delivery systems, and the study of product stability. Both knowledge and clinical skill in patient care are necessary to achieve efficiency and effectiveness of rational drug use, in order to apply effective treatment, prevention and health promotion. This special issue covers several topics, including chemical synthesis, natural product isolation, characterization, activity assay, and the development of drug carriers and drug delivery. Additionally, it includes research and expository papers devoted to important pharmaceutical results and topics of current interest. The first article from Weerasak Khampheeraphapkhul, Wiyadee Matcharoen, Apinya Kerdtalay, Ammar Darama, and Tanavij Pannoi, studies the prevalence and patient factors associated with high-risk medications (HRM). Elderly in-patients who received non-steroidal anti-inflammatory drugs (NSAIDs) and tricyclic antidepressants (TCAs) at a district hospital in the south of Thailand were screened, and logistic regression was used to analyze the association between patient factors and HRM. The second article involves the synthesis of novel series of pyrimidine derivatives, by Anshu Chaudhary, Anoop Singh, and Prabhakar Kumar Verma. The structures of such compounds were elucidated by IR, 1H-NMR, elemental analysis and mass spectroscopic techniques. Interestingly, several compounds exhibited significant anti-inflammatory activity in a carrageenan-induced rat paw edema model. The third article studies the dipeptidyl peptidase-IV (DPP-IV) inhibitory activity, antioxidant property, and phytochemical compositions of 14 medicinal herb extracts used in the Krom Luang Chomphon Thai folk recipe. The findings support the potential use of this recipe as an alternative treatment for diabetes. This research was performed by Mingkwan Rachpirom, Chitchamai Ovatlarnporn, Suriyan Tengyai, and Panupong Puttarak. The fourth article investigates the anti-obesity effect of the hexane fraction of ivy gourd root extract in high-fat diet induced obese mice. The extract caused a decrease in serum triglycerides, hepatic triglycerides, and total cholesterol levels. This study was performed by Ruthaiwan Bunkrongcheap, Masashi Inafuku, Hirosuke Oku, Nongporn Towatana, Chatchai Wattanapiromsakul, and Decha Sermwittayawong. The fifth article, from Kingkan Bunluepuech, Supinya Tewtrakul, and Chatchai Wattanapiromsakul, presents the anti-HIV-1 protease activity of 24 Thai plants. The authors could separate and elucidate 5 pure compounds from an ethanol extract of Cassia garrettiana which showed potent anti-HIV-1 protease activity. The sixth article describes the purification of pyridoxamine and pyridoxamine 5´-phosphate in a culture medium of gram negative bacterium Rhizobium sp. 6-1C1 by using a strong acid cation exchange chromatography and reverse phase HPLC. The work was done by Anutida Sangsai, Panawan Moosophon, and Yanee Trongpanich. The seventh article, deals with the characterization of drug-chitosan spray dried particles (SDPs) by using diclofenac sodium or theophylline as model drugs. Scanning electron microscopy was used to describe the morphology of drug-chitosan mixtures. The effect of temperature on drug states in the microspheres was examined by simultaneous measurement of powder X-ray diffraction and differential scanning calorimetry. A dissolution test was also performed, in order to study its drug release behavior. This work was done by Kampanart Huanbutta, Katsuhide Terada, Pornsak Sriamornsak, and Jurairat Nunthanid. The eighth article is from Kampanart Huanbutta, Tanikarn Sangnim, and Wancheng Sittikijyothin. They modified tamarind seed gum by carboxymethylation, and found that water solubility and flowability of those gum in the formulation of diclofenac sodium tablets were increased. These findings might be able to be developed for pharmaceutical dry binding in tablet formulation. The ninth article, describes the production of a CoQ 10 -enriched shell of ultra-small nanostructured lipid carriers using a hot high pressure homogenization technique, by Nuttakorn Baisaeng, Daniel Peters, Michel Prost, Philippe Durand, Rainer Helmut Muller, and Cornelia Keck. They compared the effect of particle size on antioxidant capacity using the DPPH method and the biological Kit Radicaux Libres (KRL) test. Formulations showed a good physicochemical stability at 4 and 20 °C for 3 months. The last article from Suchada Piriyaprasarth, Maneerat Juttulapa, and Pornsak Sriamornsak, investigated the physical properties of pectin-zein polyelectrolyte complexes at pH 4, where pectin and zein carried opposite charges. This provides a better understanding of the complexes for drug delivery carriers. Finally, I would like to take this opportunity to thank deeply the effort of Professor Dr. Pornsak Sriamornsak and Dr. Apichart Atipairin, in their role as guest editors, as well as all reviewers and authors. I sincerely hope that the knowledge presented will lead to the development of advancements in pharmacy and provide lasting benefits to society. Jiraporn CHINGUNPITAK School of Pharmacy, Walailak University, Thaiburi, Thasala, Nakhon Si Thammarat 80161, Thailand E-mail: [email protected] Jiraporn Chingunpitak is the dean of the School of Pharmacy, Walailak University. She received a B.Sc in pharmacy from Mahidol University in 1998, and a Ph.D. in pharmaceutics from the same in 2006. She was a production pharmacist and a general pharmacist in both public and private hospitals in Thailand. She has collaborated with Chiba University, Japan, and published various scientific research papers in peer reviewed international journals. Her article “Nanosuspension Technology for Drug Delivery” in 2007 remains the highest cited paper ever for Walailak Journal of Science and Technology. Her current researches focus on diverse areas, such as nanotechnology, herbal development, and cosmetics. Normal 0 false false false EN-US X-NONE TH /* Style Definitions */
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2022-09-27T03:42:01.090Z | 2018-03-30T00:00:00.000Z | 252539571 | s2ag/train | Environmental Crisis as The Ultimate Life Issue
The environmental-ecological problem that humanity faces today is believed to be as ‘the ultimate life issue.’Such is the rationale for the study. This research investigates the said issue thru descriptive-historical research. Lonergan’smethod is used as a framework of the study. Lonergan distinguishes four realms of meaning as: (1) common sense, (2) theory, (3) interiority, and (4) transcendence.
The investigation covers the gamut of the ecological problem, the causes and origins, the present environmental situation, its encompassing effects, and the different paradigmatic responses to it.
The environmental crisis can be traced from how the people’s mindset and cultural attitudes operate in relationto how nature can be used in the pursuit of science, modernization, growth, and progress. The sad state of theenvironmental degradation includes the prevalence of continued deforestation, uncontrolled flooding, topsoil erosion,heavily silted inland waterways, destruction of coral reefs, and various forms of pollution. Amidst the crisis, hope can be seenfrom the moral values and beliefs of Filipinos. Social principles can be transformed into practice through authentic humanfunctioning associated with knowledge and choice.
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2019-01-24T21:29:57.100Z | 2001-01-01T00:00:00.000Z | 92082181 | s2ag/train | Tissue inhibitors of metalloproteinases (TIMPS) in mammary gland morphogenesis, differentiation, and apoptosis
During the maturation of the mammary gland. mammary epithelial cells (mecs) exhibit many characteristics most offen reserved for embryonic cells. Although not pluripotent, mecs have the capacity to repeatedly undergo branching morphogenesis, d ifferentiation andfor apoptosis during the Ife of the female. These characteristics are not cell autonomous. but instead ofien involve reciprocal information exchanged between mecs and the extracellular matrix (ECM) on which they reside. We hypothesized that factors that can maintain ECM integrity, such as the four mernber family of tissue inhibiton of meialloproteinases (TIMPs), will influence mec morphogenesis, differentiation andlor apoptosis. Our initial efforts focused on the generaüon and characterization of transgenic mice with mammary gland downregulation of TIMP-I. Transgenics displayed augmentation of boa mammary ductal elongationlbranching concomitant with amplified epithelial proiiferation and excessive laminin degradation. Conversely, through biochemical manipulation. upregulation of mammary gland TIMP-1 inhibited ductal elongaüon and mec proliferaüon. These results indicate that TIMP-1 modulated mec proliferation and ECM integrity. which ultimately affected branching morphogenesis. Detemining the extent of in vivo mec differentiation in response to hormones is generally perfonned via manipulations of the endocrine system. However, we undertook a unique approach entailing examination of the mec response to physiological levels of hormones. We showed that morphological differentiation, mec proliferation and apoptosis were positively correlated with circulating progesterone levels, but not 17-pestradiol. Furthemore. TIMP-3, -4, matrix metalloproteinase (MMPs) -9, -1 3 mRNAs and ECM remodeling in the mammary gland exhibited regulation that was estrous stage-dependent. Therefore, the mammary gland response to systemic hormones is precisely controlled at the level of differentiation, cellular turnover, TIMPtMMP gene expression and ECM remodeling. Extensive mec apoptosis occurs during postlactational involution. TIMP-3 deficient mice were induced to undergo mammary gland involution to assess the function of this gene during physiological apoptosis. TIMP-3 deficient females exhibited rapid mammary gland involution, extensive unscheduled epithelial apoptosis, eariy loss of p-casein expression, and inappropriate MMP-2 activation and fibronectin fragmentation. Importantly. restoraüon of lactation, affer 2 days of involution, was inefficient in TlMP-3 deficient mice. These findings indicate that TIMP-3 is necessary for determining the kinetics of a process that is inherent to al1 marnmalian species. CO-AUTHORSHIP This thesis encompasses results h m previously published, submitted and in preparation for submission manuscripts. Co-authors include: Jimmie Fata, Rama Khokha, Kevin Leco, Roger Moorehead, Varun Chaudhary, David Martin and Elsie Yu. Al1 of the experimental work in this thesis was performed by Jimmie Fata except: Kevin Leco assisted with in situ hybridizations, perfonned an RNAse protection assay, and generated the TIMP-3 deficient mice. Roger Moorehead assisted in transgenic genotyping and tissue collection. Varun Chaudhary assisted in tissue collection and morphometry. David Martin assisted with zymography. Elsie Yu performed immunoblothg for fibronecün. Jimmie Fata and Rama Khokha wrote chapters 2 and 3 of this thesis. Jimmie Fata wrote chapters 1, 4 and 5. Appendix 1 represents a collaborative effort, with Dr. J. Penninger. Copyright permission for chapter 1, 2 and Appendix 1 has been granted (Appendix II). PUBLICATIONS: ~a ta ' JE, ~ o n g ' W, Li J, Sasaki T, IlieSasaki J, Moorehead RA, Elliott R, Scully S, Voura EB, Lacey DL, Boyle WJ, Khokha R, Penninger JM. The osteodast differentiation factor Osteoprotegenn-Ligand is essential for mammary gland developrnent '~ontributed equally. Ce11 103:4160,2000. Fata JE, Ho A. Lem KJ, Moorehead RA, Khokha R Cellular turnover and extracellular matnx remodelipg in female reproductive tissues: Functions of metalloproteinases and their inhibiton. Al authors contributed equally. Cellular and Molecular Life Sciences. 57:77-95,2000. Granovsky M, Fata JE, Pawling J, Muller WJ, Khokha R, Dennis JW. Suppression of tumor growth and metastasis in Mgat5defÏcient mice. Nature Medicine 6:306-312, 2000. Sasaki T, Ide-Sasaki J, Horie Y, Bachmaier K, Fata JE. Li M, Suzuki A. Bouchard D, Ho A, Redston M. Gallinger S. Khokha R, Mak TW, Hawkins PT, Stephens L, Scherer SW, Tsao M, Penninger JM Colorectal carcinomas in mice lacking the catalyüc subunit of PI(3)Kgamma. Nature 406:897-902 2000. Moorehead R, Fata JEy Johnson M, Khokha R. Inhibition of mammary epithelial apoptosis through sustained phosphorylation of AWPKB in MMTV-IGF-II transgenic mice. Ce1 Death and Dflerentiation (in press). Khokha R, Martin DC, Kruger A, Sanchez-Sweatman O, Ho A, Fata JE. Tumor suppressive capabilities of TIMP-1 in transgenic models. In: Tissue inhibitors of Metallopmfeinases in Development and Disease. Eds. Hawkes SP, Edwards DR, Khokha R. Hannrood Academic Publisher, Lusanne pp. 179-186,2000. Fata JE, Leco KJ, Moorehead RA, Martin DC, Khokha R. Timp-1 is important for epithelial proMeration and branching morphogenesis during mouse mammary development. Developmental Biology 21 1 :238-254,1999. Kruger A, Sanchez-Sweatman OH, Martin DC, Fata JE, Ho A, On MI, Ruther U, Khokha R. Host Timp-1 overexpression confers resistance to experirnental brain metastasis of a fi brosarcoma cell line. Oncogene 1 6:ZM 9-2423, 1 998. Kruger A, Fata JE, Khokha R. Altered tumor growth and metastasis of a T-cell lymphoma in Timp-1 transgenic mice. Blood 90:1993-2000,1997. Khokha R, Martin DC, Fata JE. Utilization of transgenic mice in the study of matrix degrading proteinases and their inhibitors. Cancer and Metastasis Reviews 14:97-111, 1995. PAPERS SUBMITTED OR IN PREPARATION: Fata JEy Chaudry V, Khokha R. lnherent Variations within the Mammary Glands of Adult Nulliparous Female Mice. Resubmission to Biology of Reproduction. Fata JE, Leco KJ, Yu H-Y, and Khokha R. Tissue Inhibitor of Metalloproteinase-3 (TIMP-3) Deficiency Augments Physiological Apoptosis During Mammary Gland Involution In preparaüon. Fata JE, Lem KJ, Gowing K, Moorehead RA, and Khokha R. Unscheduled Uterine Epithelial Apoptosis in Timp-3 Knockout Mice. In preparation. Moorehead R, Fata JE, Khokha, R. PTEN Expression in Mammary Epithelium is Regulated by IGF-II. In preparation Fata JE and Bissell MJ. Regulation of mammary gland branching morphogenesis by extracellular rnatrix and agents that rernodel it. lnvited review for Journal of Mammary Gland Bioiogy and Neoplasia. In preparation. | v2 |
2018-12-07T18:34:02.925Z | 2009-01-01T00:00:00.000Z | 127572441 | s2ag/train | Natural microorganisms’ effect on the growth of Lasthenia californica in post‐fire soil
The
effect
of
microorganisms
in
post-‐fire
soil
on
the growth
of
lasthenia
californica
was
studied
by comparing
growth
in
natural
soil
versus
autoclaved
soil. It
was
hypothesized
that
the
seeds
from
the
natural
soil would
have
more
growth
because
the
microorganisms have
a
symbio@c
rela@onship
with
the
plants.
Seeds were
grown
in
similar
condi@ons
in
both
autoclaved
and natural
soil.
ACer
44
days,
the
plants
were
uprooted and
split
into
shoots
and
roots.
Shoots
and
roots
were then
biomassed.
The
natural
soil
had
a
total
shoot biomass
of
3.031g
and
a
total
root
biomass
of
89.554g, while
the
autoclaved
soil
had
a
total
shoot
biomass
of 1.731g
and
a
total
root
biomass
of
21.4492g.
The
results were
consistent
with
the
hypothesis
showing
that microorganisms
do
have
an
effect
on
the
growth
of lasthenia
californica.
This
is
valuable
informa@on
for
any post-‐fire
recovery.
If
the
fire
was
hot
enough
to
kill
the microorganisms,
it
might
be
more
conducive
to lasthenia
californica
growth
to
add
microorganisms
back to
the
soil. Bryce
Lindley,
Taylor
Miller,
Tyler
Gibson,
Pepperdine
University,
Malibu,
California
90263 Introduc/on: A
plant’s
ability
to
produce
large
amounts
of
biomass
and store
carbon
is
dependent
on
their
interac@ons
with these
microorganisms
such
as
mycorrhizal
fungi.
These microorganisms
significantly
improve
photosynthe@c carbon
assimila@on
by
plants
and
approximately
85 percent
of
all
plant
species
are
dependent
on
such interac@ons
to
thrive.
Mycorhizal
fungi
that
grow
on
or within
roots
are
protected
from
compe@@on
with
other microorganisms
and
gains
access
to
excess
carbohydrates given
off
by
the
plant.
In
exchange,
the
mycorrhizal
fungi are
able
to
obtain
necessary,
but
scarce,
nutrients
such
as phosphate
and
nitrogen.
Most
of
these
nutrients
are transferred
to
the
growing
plant,
and
therefore,
the symbio@c
rela@onship
is
established.
To
quan@ta@vely test
the
effect
of
natural
microorganisms
on
growth
of
a California
sunflower,
Lasthenia
californica,
the
growth can
be
compared
to
Lasthenia
californica
growth
in autoclaved
soil.
By
autoclaving
the
soil
all
of
the microorganisms
within
the
soil
will
be
killed,
and therefore,
the
symbio@c
rela@onship
will
not
be
present. Method: Soil
was
collected
from
a
post-‐fire
site
of
the
Santa
Monica
Mountains
near
Pepperdine
campus. ACer
mixing
the
soil,
half
was
autoclaved
to
kill
any
microorganisms
in
the
soil.
Using
sterile equipment,
fiCeen
plas@c
plan@ng
pots
were
filled
with
400mL
of
autoclaved
soil
and
fiCeen
with 400mL
of
the
natural
soil.
Lasthenia
californica
seeds
were
planted
into
five
holes
four
cen@meters in
depth
of
each
container.
The
seeds
were
then
allowed
to
germinate
and
grow
in
a
controlled growth
chamber
for
six
and
a
half
weeks
receiving
equal
amounts
of
water
every
2-‐3
days.
A
1mL soil
sample
in
10mL
of
H2O
dilu@on
was
applied
to
an
agar
petri
dish.
The
dishes
were
allowed
to cul@vate
and
bacteria
colonies
were
counted
aCer
48
hours.
The
number
of
sprouts
was
counted, and
the
biomass
was
taken
of
the
shoots
and
roots
of
each
container. Conclusion: Lasthenia
californica
grows
be\er
in
natural
versus autoclaved
soil
due
to
the
presence
of
microorganisms. Both
shoot
and
root
biomasses
were
significantly different
between
the
two
soil
types.
Also,
comparisons of
pots
with
the
same
number
of
sprouts
showed
the natural
soil
to
have
a
higher
biomass.
This
means
that microorganisms
do
have
a
significant
effect
on
some aspects
of
the
growth
of
this
plant.
Results
indicated
that soil
with
more
bacteria
tended
to
yield
be\er
biomass results.
Both
bacteria
isola@on
and
root
biomass
data was
sta@s@cally
significant,
so
it
can
be
assumed
that
that autoclaving
the
soil
had
a
nega@ve
effect
on
bacterial growth
and
root
growth.
However,
shoot
growth
cannot be
considered
significant.
This
indicates
that
although the
plants
may
appear
the
same,
plants
with
bacterial
aid may
have
be\er
root
coverage
giving
them
be\er survivability
and
a
significant
advantage
over
plants which
do
not
have
these
bacteria.
Our
results
indicated that
bacteria
likely
play
a
very
important
role
in
plant development,
but
iden@fica@on
of
types
of
bacteria
is needed
to
determine
which
type
of
bacteria
is
doing what.
In
order
to
promote
growth
of
lasthenia
californica aCer
a
fire
was
hot
enough
to
kill
off
microorganisms,
it seems
that
it
would
be
best
to
reintroduce microorganisms
to
the
soil.
An
appropriate
way
to con@nue
this
research
would
be
to
actually
introduce microorganisms
to
post-‐fire
soil
in
the
field
and
track
the growth
of
the
plants
to
test
the
hypothesis
the
results
of this
experimenta@on
has
prompted. -‐0.05 0 0.05 0.1 0.15 0.2 0.25 1 2 3 4 5 Bi om as s
i n Gr am s Sample
Number Shoot
Biomass
of
Lasthenia
californica
Autoclaved
Shoots Nonautoclaved
Shoots 0 2 4 6 8 10 12 1 2 3 4 5 Bi om as s
i n Gr am s Sample
Number Root
Biomass
of
Lasthenia
californica
Autoclaved
Roots Nonautoclaved
Roots | v2 |
2021-11-26T16:40:00.767Z | 2021-11-05T00:00:00.000Z | 244646021 | s2ag/train | On-Target Activity of Imetelstat Correlates with Clinical Benefits, Including Overall Survival (OS), in Heavily Transfused Non-Del(5q) Lower Risk MDS (LR-MDS) Relapsed/Refractory (R/R) to Erythropoiesis Stimulating Agents (ESAs)
Introduction: Imetelstat is a first-in-class telomerase inhibitor that targets cells with high telomerase activity and human telomerase reverse transcriptase (hTERT) expression, characteristics observed in MDS patients (pts) across all disease stages. IMerge (MDS3001, NCT02598661) is a Phase 2/3 global study of imetelstat for red blood cell (RBC) transfusion dependent (TD) pts with non-del 5q LR-MDS ESA-R/R, who have limited treatment options. The results from the Phase 2 part indicated that imetelstat achieved durable transfusion independence (TI) with a manageable safety profile. Among 38 pts with median follow-up of 24 months, ≥8-week (w), ≥24-w, ≥1-year (y) TI rates were 42%, 32% and 29%, respectively (Steensma JCO 2020, Platzbecker ASH 2020).
Aims: To assess the correlation between imetelstat's on-target activity with clinical benefits and safety data as of 10-May 2021 in the Phase 2 part of IMerge.
Methods: Peripheral blood samples pre and after 1 and 2 cycles of imetelstat administration were collected to analyze hTERT level by Taqman RT-PCR assay. ≥50% hTERT reduction by imetelstat was considered optimal pharmacodynamic (PD) effect. Correlation analyses between the optimal PD and efficacy, including TI rates ≥8-w, ≥24-w, and ≥1-y, duration of the longest TI, and OS, as well as hematological and liver function lab parameters were performed.
Results: hTERT analyses on 35/38 pts with matched pre- and post-1 to 2 cycles of treatment samples available demonstrated on-target activity/optimal PD effect of imetelstat in 54.3% (19/35) of pts. Pts who achieved optimal PD had significantly higher rates of TI compared to pts who did not achieve optimal PD: 63.2% (12/19) vs 25% (4/16) had ≥8-w TI (p=0.0411); 57.9% (11/19) vs 12.5% (2/16) had ≥24-w TI (p=0.0125); and 52.6% (10/19) vs 6.3% (1/16) had ≥1-y TI (p=0.0125) (Fig A). Pts who achieved optimal PD effect had a greater reduction in transfusions (both absolute change in transfusion units and % of change in transfusion burden) in the best 8-week interval compared to pts who did not. In addition, pts who achieved optimal PD had a significantly longer median TI duration (68.4 w, 95% CI 4.9, 92.4) compared to those who did not (5.5 w, 95% CI 2.3, 6.6) with a hazard ratio of 0.364 (95% CI 0.167, 0.794, log-rank p value=0.0087, Fig B). Furthermore, median OS was 57.0 months (95% CI 34.6, -) in pts who achieved optimal PD vs 40.7 months (95% CI 26.9, -) in pts who did not, and the 4-year OS rate was 58.4% vs 31.0%, respectively, although not statistically significant. Pts who achieved optimal PD also had lower rates of Grade 3+neutropenia (52.6%), thrombocytopenia (57.9%), or liver function elevations (5.3%) compared to pts who did not achieve optimal PD (68.8%, 68.8% and 18.8%, respectively), although the differences were not statistically significant.
Conclusion: Optimal PD effect of imetelstat treatment was demonstrated by ≥50% hTERT reduction. A significant correlation was observed between optimal PD effect of imetelstat and durable TI and improved 4-year OS rate, effectively linking imetelstat activity to clinical efficacy. Additionally, pts who achieved an optimal PD effect by imetelstat treatment did not have higher rates of cytopenias or liver enzyme elevations compared to pts without optimal PD effect. Enrollment is ongoing for the Phase 3 part of IMerge, a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs. placebo.
Figure 1 Figure 1.
Santini: Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fenaux: JAZZ: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria. Raza: Celgene Inc: Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Genoptix: Speakers Bureau; Kura Oncology: Research Funding; Janssen R&D: Research Funding; Syros Pharmaceuticals: Research Funding; Onconova Therapeutics: Research Funding, Speakers Bureau. Germing: Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria. Font: CELGENE-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses; GILEAD: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau; Abbvie: Other: Travel, accomodations, expenses. Diez-Campelo: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Sherman: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Berry: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Feller: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Dougherty: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Sun: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Wan: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Rizo: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Huang: Geron Corp: Current Employment, Current equity holder in publicly-traded company. Platzbecker: Takeda: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Geron: Honoraria; Celgene/BMS: Honoraria.
Imetelstat, a first-in-class telomerase inhibitor, is under clinical development but not approved for treatment of MDS
| v2 |
2017-10-26T19:13:05.005Z | 2011-04-15T00:00:00.000Z | 167009721 | s2ag/train | What is essential for a shopping centre to be a success
Title of treatise : What is needed for a successful shopping centre? Name of Author : Me B Krugell Name of study leader : Mr J H Cruywagen Institution : Faculty of Engineering, Built Environment and Information Technology Date : October 2010 Shopping centres is part of our normal routine in the recent days. The question to be answered is what is needed for a shopping centre to be feasible. Five aspects are investigated that possibly can have an effect on the success of a shopping centre. The feasibility study of a shopping centre, the design of the shopping centre and how it should be designed, the tenants of a shopping centre, management of a shopping centre and the market and marketing research of a shopping centre were investigate Table of Contents CHAPTER 1: INTRODUCTION 1.1
BACKGROUND 1 1.2
STATEMENT
OF
THE
PROBLEM 1 1.3
STATEMENT
OF
SUBPROBLEMS 2 1.3.1
WHAT
MUST
BE
TAKEN
INTO
ACCOUNT
WITH
A
FEASIBILITY
STUDY?
2 1.3.2
WHAT
IS
THE
EFFECT
OF
THE
DESGN
OF
A
SHOPPING
CENTRE?
2 1.3.3
WHAT
ROLE
DO
TENANTS
OF
A
SHOPPING
CENTRE
PLAY?
2 1.3.4
WHAT
ARE
THE
BENEFITS
OF
THE
CENTRE
MANAGEMENT
FOR
A
SHOPPING
CENTRE?
3 1.3.5
WHAT
DOES
MARKET
RESEARHC
CONSIST
OF?
3 1.4
STATEMENT
OF
THE
HYPOTHESES 3 1.4.1
WHAT
MUST
BE
TAKEN
INTO
ACCOUNT
WITH
A
FEASIBILITY
STUDY?
3 1.4.2
WHAT
IS
THE
EFFECT
OF
THE
DESGN
OF
A
SHOPPING
CENTRE?
4 1.4.3
WHAT
ROLE
DO
TENANTS
OF
A
SHOPPING
CENTRE
PLAY?
4 1.4.4
WHAT
ARE
THE
BENEFITS
OF
THE
CENTRE
MANAGEMENT
FOR
A
SHOPPING
CENTRE?
4 1.4.5
WHAT
DOES
MARKET
RESEARHC
CONSIST
OF?
4 1.5
DELIMITATIONS 5 1.6
DEFINITION
OF
TERMS 5 1.7
IMPORTANCE
OF
STUDY 6 1.8
RESEARCH
METHODOLOGY 6 CHAPTER 2: WHAT MUST BE TAKEN INTO ACCOUNT WITH A FEASIBILITY STUDY? 2.1
WHAT
IS
A
FEASIBILITY
STUDY? 7 2.2
WHAT
DOES
THE
FEASIBILITY
STUDY
CONSIST
OF?
7 2.3
GUIDELINES
WHEN
PREPARING
A
FEASIBILITY
STUDY
8 2.4
OBJECTIVE
OF
THE
DEVELOPER 9 2.5
SOCIO-‐ECONOMIC
FEASIBILITY 10 2.6
PHYSICAL
AND
LEGAL
FEASIBILITY 13 2.6.1
SITE
CHARACTERISTIC 14 2.6.2
LOCATION 16 2.6.3
ENVIRONMENTAL
FACTORS 18 2.7
MARKETING
FEASIBILITY 19 2.7.1
DEMAND
ANALYSIS 19 2.7.2
SYPPLY
ANALYSIS 20 2.8
FINANCIAL
FEASIBILITY 21 2.8.1
CASH
FLOW
ANALYSIS 22 2.8.2
MEASURES
OF
RETURN 24 2.9
SUMMARY 26 2.10
CONCLUSION 26 2.11
TEST
OF
HYPOTHESIS 27 CHAPTER 3: WHAT IS THE EFFECT OF THE DESIGN OF A SHOPPING CENTRE? 3.1
INTRODUCTION 28 3.2
SHAPE
OF
THE
SHOPPING
CENTRE 29 3.3
LAYOUT
OF
THE
SHOPPING
CENTRE 30 3.4
PARKING 32 3.5
SERVICES
TO
THE
SHOPS 34 3.6
STRUCTURAL
DESIGN
OF
THE
SHOPPING
CENTRE
35 3.7
SHOP
DESIGN 36 3.8
SUMMARY 36 3.9
CONCLUSION 36 3.10
TESTING
OF
THE
HYPOTHESIS 37 CHAPTER 4: WHAT ROLE DO TENANTS OF A SHOPPING CENTRE PLAY? 4.1
INTRODUCTION 38 4.2
ANCHOR
TENANTS 38 4.3
TENANT
MIX 39 4.4
TENANT
PLANNING
DESIGN,
ETC. 42 4.5
TENANT
MIX
AND
THE
EFFECT
ON
RENTAL
LEVELS
44 4.6
SUMMARY 45 4.7
CONCLUSION 45 4.8
TESTING
OF
HYPOTHESIS 45 CHAPTER 5: WHAT ARE THE BENEFITS OF CENTRE MANAGEMENT FOR A SHOPPING CENTRE? 5.1.
INTRODUCTION 47 5.2.
BUILDING
MAINTENANCE 48 5.3.
PARKING
MANAGEMENT 49 5.4.
SECURITY
MANAGEMENT 51 5.5.
TENANT
MANAGEMENT 52 5.6.
SUMMARY 53 5.7.
CONCLUSION 53 5.8.
TESTING
OF
THE
HYPOTHESIS 53 CHAPTER 6: WHAT DOES MARKETING RESEARCH CONSIST OF? 6.1.
WHAT
IS
MARKETING
AND
MARKET
RESEARCH
55 6.2.
WHAT
ROLE
DOES
RESEARCH
PLAY
IN
CENTRE
MARKETING
55 6.3.
HOW
IS
DATA
COLLECTED
FOR
RESEARCH? 61 6.4.
SUMMARY 62 6.5.
CONCLUSION 62 6.6.
TESTING
OF
HYPOTHESIS 63 CHAPTER 7: SUMMARY, CONCLUSION AND RECOMMENDATION 7.1
BACKGROUND 64 7.2
SUMMARY 64 7.3
CONCLUSION 66 7.4
RECOMMENDATIONS 67 BIBLIOGRAPHY 69 | v2 |
2022-09-04T06:05:49.102Z | 2021-01-01T00:00:00.000Z | 252048871 | s2ag/train | CHEMORESISTANCE IN OVARIAN CANCER CELL LINES
EPV002/#308 Figure 1 PCA of a. PEO1 vs PEO4, b. A2780 vs C200, c. MR182 vs R182; PLS-DA of d. PEO1 vs PEO4, e. A2780 vs C200, f. MR182 vs R182 Abstract EPV002/#308 Figure 2 Heat map of a. PEO1 vs PEO4, b. A2780 vs C200, c. MR182 vs R182; Volcano plot with FDR £ 5% and absoulute fold-change 1.5 of d. PEO1 vs PEO4, e. A2780 vs C200, f. MR182 vs R182 AbstractsEPV002/#308 Figure 2 Heat map of a. PEO1 vs PEO4, b. A2780 vs C200, c. MR182 vs R182; Volcano plot with FDR £ 5% and absoulute fold-change 1.5 of d. PEO1 vs PEO4, e. A2780 vs C200, f. MR182 vs R182 Abstracts A30 Int J Gynecol Cancer 2021;31(Suppl 4):A1–A153 on N ovem er 3, 2022 by gest. P rocted by coright. http/ijgc.bm jcom / nt J G ynecol C acer: frst pulished as 10.11jgc-2021-IG C S 69 on 1 N ovem er 221. D ow nladed fom thought to be an integral part of chemoresistance, but the relation of these adaptations to chemoresistance is poorly understood. Our aim was to identify the metabolic adaptations that are specifically associated with platinum-resistant (PR) cell lines and its platinum-sensitive (PS) derivatives across multiple OC cell lines. Methods Targeted metabolic analysis evaluating 242 metabolites of the PS A2780, PEO1, and mR182 cell lines was performed along with their respective PR derivatives, C200, PEO4, R182. The group comparison was performed using unpaired t-tests followed by FDR correction. The differentially expressed metabolites were identified using two criteria: FDR £ 5% and absolute fold-change 1.5. The pathway analysis was performed using Metaboanalyst with the metabolites that have unadjusted p-value £5%. Results Many significantly impacted pathways were conserved among the PR cell lines. Compared to the PS counterparts, the PR PEO4, C200, and R182 lines had metabolite concentrations with FC 1.5 in 29, 44, and 28 measured metabolites, respectively. The top pathways impacted were ‘nicotinate and nicotinamide metabolism’, ‘purine metabolism’, and ‘phenylalanine, tyrosine, tryptophan biosynthesis’. A global analysis of PS vs PR was performed. The top five significantly impacted pathways were: Arginine biosynthesis, Pyrimidine and Purine metabolism, Phenylalanine, tyrosine and tryptophan biosynthesis’ and ‘Starch and sucrose metabolism’. Conclusions We identified multiple shared metabolomic pathways among established PR OC cell lines that highlight conserved motifs of PR. These may represent targetable pathways to predict or reverse chemoresistance. EPV003/#326 AN INTEGRATED GENOMIC, PROTEOMIC AND IMMUNOPEPTIDOMIC APPROACH TO DISCOVER NOVEL TUMOUR NEOANTIGENS IN AN IMMUNOLOGICALLY COLD OVARIAN CANCER FOR PERSONALISED T-CELL RECEPTOR THERAPY GY Ho*, P Faridi, J Wu, H Barker, T Nguyen-Dumont, J Chang, A Fell, P Eggenhuizen, J Steen, T Manolitsas, S Frentzas, J Bedo, C Vandenberg, T Papenfuss, C Scott, J Ooi, E Segelov. Monash University, School of Clinical Sciences, Clayton, Australia; Monash Health, Oncology Department, Clayton, Australia; Monash University, Monash Biomedicine Discovery Institute, Clayton, Australia; Walter and Eliza Hall Institute of Medical Research, Cancer Biology and Stem Cells Division, Parkville, Australia; University of Melbourne, Department of Medical Biology, Parkville, Australia; University of Melbourne, 6. Departcomputing and Information Systems, Parkville, Australia; University of Melbourne, Department of Computing and Information Systems, Parkville, Australia 10.1136/ijgc-2021-IGCS.70 Objectives Ovarian carcinosarcoma (OCS) are rare aggressive cancers with poor prognosis and limited effective treatments. The tumour mutation burden in OCS is often low. Therefore, these tumours are immunologically ‘cold’ and relatively irresponsive to single agent immunotherapy. We explored tumour neoantigen discovery in an OCS using various genomic and proteomic platforms for personalised T-cell receptor (TCR) therapy. Methods Whole genome sequencing (WGS) was performed on SFRC01177 OCS tumour specimen taken at surgery. Fresh tumour specimens obtained at surgery and biopsy at recurrence were engrafted subcutaneously in NOD-scidIL2Rgammanull (NSG) to generate a paired patient derived xenograft (PDX) model. Whole exome sequencing and RNA sequencing (WES/RNAseq) together with nano-ultra-performance liquid chromatography coupled to high-resolution mass spectrometry were performed on the snap frozen tumours from the baseline and recurrent PDX for tumour neoantigen (TNA) discovery. Results A total of 6,500 mutant TNA were predicted in silico from the baseline WGS data which were narrowed down to 65 and 33 respectively based on the baseline and recurrent PDX tumours WES/RNAseq data. The immunopeptidomic analysis revealed over 100 major histocompatibility complex bound antigens including mutant, spliced and cancer testis antigens. The PDX was re-established in NSG MHC mouse model and was shown to retain the platinum refractory in vivo response as well as to tolerate 1 million HLA-matched donor CD8+ T-cell injections. Conclusions We have discovered multiple tumour specific neoantigens using the comprehensive TNA discovery platforms, which will direct our TCR engineering. In parallel, we have also established an OCS PDX model suitable for cell-based therapy testing. EPV004/#360 INHIBITION OF CANCER CELL-DEPENDENT GLYCOLYSIS THROUGH AVB-500, A SELECTIVE INHIBITOR OF GAS6-AXL, IN COMBINATION WITH PACLITAXEL IN HIGH-GRADE ENDOMETRIAL CANCER S Bruce*, E Lomonosova, H Noia, E Stock, K Cho, D Khabele, L Kuroki, A Hagemann, C Mccourt, P Thaker, D Mutch, M Powell, L Shriver, G Patti, K Fuh. Washington University, Gynecologic Oncology, St. Louis, USA; Washington University, Chemistry, St. Louis, USA 10.1136/ijgc-2021-IGCS.71 Abstract EPV002/#308 Figure 3 a) Volcano plot of sensitive cohort vs resistant cohort; b) Heat map of sensitive cohort vs resistant cohort Abstract EPV002/#308 Figure 4 Top impacted pathways of combined PR cohort compared to PS cohort AbstractsEPV002/#308 Figure 4 Top impacted pathways of combined PR cohort compared to PS cohort Abstracts Int J Gynecol Cancer 2021;31(Suppl 4):A1–A153 A31 on N ovem er 3, 2022 by gest. P rocted by coright. http/ijgc.bm jcom / nt J G ynecol C acer: frst pulished as 10.11jgc-2021-IG C S 69 on 1 N ovem er 221. D ow nladed fom | v2 |
2019-11-22T00:53:03.277Z | 2019-11-13T00:00:00.000Z | 209273791 | s2ag/train | Phase 2 Study of the Response and Safety of P-Bcma-101 CAR-T Cells in Patients with Relapsed/Refractory (r/r) Multiple Myeloma (MM) (PRIME)
P-BCMA-101 is a novel chimeric antigen receptor (CAR)-T cell product targeting B Cell Maturation Antigen (BCMA). P-BCMA-101 is produced using the piggyBac® (PB) DNA Modification System instead of the viral vector that is used with most CAR-T cells, requiring only plasmid DNA and mRNA. This makes it less costly and produces cells with a high percentage of the favorable T stem cell memory phenotype (TSCM). The higher cargo capacity of PB permits the incorporation of multiple genes in addition to CAR(s), including a safety switch allowing for rapid CAR-T cell elimination with a small molecule drug infusion in patients if desired, and a selection gene allowing for enrichment of CAR+ cells. Rather than using a traditional antibody-based binder, P-BCMA-101 has a Centyrin™ fused to a CD3ζ/4-1BB signaling domain. Centyrins are fully human proteins with high specificity and a large range of binding affinities, but are smaller, more stable and potentially less immunogenic than traditional scFv. Cumulatively, these features are predicted to result in a greater therapeutic index. A Phase 1, 3+3 dose escalation from 0.75 to 15 x 106 P-BCMA-101 CAR-T cells/kg (RP2D 6-15 x 106 cells/kg) was conducted in patients with r/r MM (Blood 2018 132:1012) demonstrating excellent efficacy and safety of P-BCMA-101, including notably low rates and grades of CRS and neurotoxicity (maximum Grade 2 without necessitating ICU admission, safety switch activation or other aggressive measures). These results supported FDA RMAT designation and initiation of a pivotal Phase 2 study.
A Phase 2 pivotal portion of this study has recently been designed and initiated (PRIME; NCT03288493) in r/r MM patients who have received at least 3 prior lines of therapy. Their therapy must have contained a proteasome inhibitor, an IMiD, and CD38 targeted therapy with at least 2 of the prior lines in the form of triplet combinations. They must also have undergone ≥2 cycles of each line unless PD was the best response, refractory to the most recent line of therapy, and undergone autologous stem cell transplant or not be a candidate. Patients are required to be >=18 years old, have measurable disease by International Myeloma Working Group criteria (IMWG; Kumar 2016), adequate vital organ function and lack significant autoimmune, CNS and infectious diseases. No pre-specified level of BCMA expression is required, as this has not been demonstrated to correlate with clinical outcomes for P-BCMA-101 and other BCMA-targeted CAR-T products. Interestingly, unlike most CAR-T products patients may receive P-BCMA-101 after prior CAR-T cells or BCMA targeted agents, and may be multiply infused with P-BCMA-101. Patients are apheresed to harvest T cells, P-BCMA-101 is then manufactured and administered to patients as a single intravenous (IV) dose (6-15 x 106 P-BCMA-101 CAR-T cells/kg) after a standard 3-day cyclophosphamide (300 mg/m2/day) / fludarabine (30 mg/m2/day) conditioning regimen. One hundred patients are planned to be treated with P-BCMA-101. Uniquely, given the safety profile demonstrated during Phase 1, no hospital admission is required and patients may be administered P-BCMA-101 in an outpatient setting. The primary endpoints are safety and response rate by IMWG criteria. With a 100-subject sample, the Phase 2 part of the trial will have 90% power to detect a 15-percentage point improvement over a 30% response rate (based on that of the recently approved anti-CD38 antibody daratumumab), using an exact test for a binomial proportion with a 1-sided 0.05 significance level. Multiple biomarkers are being assessed including BCMA and cytokine levels, CAR-T cell kinetics, immunogenicity, T cell receptor diversity, CAR-T cell and patient gene expression (e.g. Nanostring) and others. Overall, the PRIME study is the first pivotal study of the unique P-BCMA-101 CAR-T product, and utilizes a number of novel design features. Studies are being initiated in combination with approved therapeutics and earlier lines of therapy with the intent of conducting Phase 3 trials.
Funding by Poseida Therapeutics and the California Institute for Regenerative Medicine (CIRM).
Costello: Takeda: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Gregory:Poseida: Research Funding; Celgene: Speakers Bureau; Takeda: Speakers Bureau; Amgen: Speakers Bureau. Ali:Celgene: Research Funding; Poseida: Research Funding. Berdeja:Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy; AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding; Poseida: Research Funding. Patel:Oncopeptides, Nektar, Precision Biosciences, BMS: Consultancy; Takeda, Celgene, Janssen: Consultancy, Research Funding; Poseida Therapeutics, Cellectis, Abbvie: Research Funding. Shah:University of California, San Francisco: Employment; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Indapta Therapeutics: Equity Ownership; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ostertag:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Martin:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Ghoddusi:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Shedlock:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Spear:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Orlowski:Poseida Therapeutics, Inc.: Research Funding. Cohen:Poseida Therapeutics, Inc.: Research Funding.
| v2 |
2020-08-22T13:01:31.479Z | 2020-08-20T00:00:00.000Z | 221220821 | s2ag/train | Antibiotic therapy for pelvic inflammatory disease.
BACKGROUND
Pelvic inflammatory disease (PID) affects 4% to 12% of women of reproductive age. The main intervention for acute PID is broad-spectrum antibiotics administered intravenously, intramuscularly or orally. We assessed the optimal treatment regimen for PID. OBJECTIVES: To assess the effectiveness and safety of antibiotic regimens to treat PID.
SEARCH METHODS
In January 2020, we searched the Cochrane Sexually Transmitted Infections Review Group's Specialized Register, which included randomized controlled trials (RCTs) from 1944 to 2020, located through hand and electronic searching; CENTRAL; MEDLINE; Embase; four other databases; and abstracts in selected publications.
SELECTION CRITERIA
We included RCTs comparing antibiotics with placebo or other antibiotics for the treatment of PID in women of reproductive age, either as inpatient or outpatient treatment. We limited our review to a comparison of drugs in current use that are recommended by the 2015 US Centers for Disease Control and Prevention guidelines for treatment of PID.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane. Two authors independently extracted data, assessed risk of bias and conducted GRADE assessments of the quality of evidence.
MAIN RESULTS
We included 39 RCTs (6894 women) in this review, adding two new RCTs at this update. The quality of the evidence ranged from very low to high, the main limitations being serious risk of bias (due to poor reporting of study methods and lack of blinding), serious inconsistency, and serious imprecision. None of the studies reported quinolones and cephalosporins, or the outcomes laparoscopic evidence of resolution of PID based on physician opinion or fertility outcomes. Length of stay results were insufficiently reported for analysis. Regimens containing azithromycin versus regimens containing doxycycline We are uncertain whether there was a clinically relevant difference between azithromycin and doxycycline in rates of cure for mild-moderate PID (RR 1.18, 95% CI 0.89 to 1.55; 2 RCTs, 243 women; I2 = 72%; very low-quality evidence). The analyses may result in little or no difference between azithromycin and doxycycline in rates of severe PID (RR 1.00, 95% CI 0.96 to 1.05; 1 RCT, 309 women; low-quality evidence), or adverse effects leading to discontinuation of treatment (RR 0.71, 95% CI 0.38 to 1.34; 3 RCTs, 552 women; I2 = 0%; low-quality evidence). In a sensitivity analysis limited to a single study at low risk of bias, azithromycin probably improves the rates of cure in mild-moderate PID (RR 1.35, 95% CI 1.10 to 1.67; 133 women; moderate-quality evidence), compared to doxycycline. Regimens containing quinolone versus regimens containing cephalosporin The analysis shows there may be little or no clinically relevant difference between quinolones and cephalosporins in rates of cure for mild-moderate PID (RR 1.05, 95% CI 0.98 to 1.14; 4 RCTs, 772 women; I2 = 15%; low-quality evidence), or severe PID (RR 1.06, 95% CI 0.91 to 1.23; 2 RCTs, 313 women; I2 = 7%; low-quality evidence). We are uncertain whether there was a difference between quinolones and cephalosporins in adverse effects leading to discontinuation of treatment (RR 2.24, 95% CI 0.52 to 9.72; 6 RCTs, 1085 women; I2 = 0%; very low-quality evidence). Regimens with nitroimidazole versus regimens without nitroimidazole There was probably little or no difference between regimens with or without nitroimidazoles (metronidazole) in rates of cure for mild-moderate PID (RR 1.02, 95% CI 0.95 to 1.09; 6 RCTs, 2660 women; I2 = 50%; moderate-quality evidence), or severe PID (RR 0.96, 95% CI 0.92 to 1.01; 11 RCTs, 1383 women; I2 = 0%; moderate-quality evidence). The evidence suggests that there was little to no difference in in adverse effects leading to discontinuation of treatment (RR 1.05, 95% CI 0.69 to 1.61; 17 studies, 4021 women; I2 = 0%; low-quality evidence). . In a sensitivity analysis limited to studies at low risk of bias, there was little or no difference for rates of cure in mild-moderate PID (RR 1.05, 95% CI 1.00 to 1.12; 3 RCTs, 1434 women; I2 = 0%; high-quality evidence). Regimens containing clindamycin plus aminoglycoside versus quinolone We are uncertain whether quinolone have little to no effect in rates of cure for mild-moderate PID compared to clindamycin plus aminoglycoside (RR 0.88, 95% CI 0.69 to 1.13; 1 RCT, 25 women; very low-quality evidence). The analysis may result in little or no difference between quinolone vs. clindamycin plus aminoglycoside in severe PID (RR 1.02, 95% CI 0.87 to 1.19; 2 studies, 151 women; I2 = 0%; low-quality evidence). We are uncertain whether quinolone reduces adverse effects leading to discontinuation of treatment (RR 0.21, 95% CI 0.02 to 1.72; 3 RCTs, 163 women; I2 = 0%; very low-quality evidence). Regimens containing clindamycin plus aminoglycoside versus regimens containing cephalosporin We are uncertain whether clindamycin plus aminoglycoside improves the rates of cure for mild-moderate PID compared to cephalosporin (RR 1.02, 95% CI 0.95 to 1.09; 2 RCTs, 150 women; I2 = 0%; low-quality evidence). There was probably little or no difference in rates of cure in severe PID with clindamycin plus aminoglycoside compared to cephalosporin (RR 1.00, 95% CI 0.95 to 1.06; 10 RCTs, 959 women; I2= 21%; moderate-quality evidence). We are uncertain whether clindamycin plus aminoglycoside reduces adverse effects leading to discontinuation of treatment compared to cephalosporin (RR 0.78, 95% CI 0.18 to 3.42; 10 RCTs, 1172 women; I2 = 0%; very low-quality evidence).
AUTHORS' CONCLUSIONS
We are uncertain whether one treatment was safer or more effective than any other for the cure of mild-moderate or severe PID Based on a single study at a low risk of bias, a macrolide (azithromycin) probably improves the rates of cure of mild-moderate PID, compared to tetracycline (doxycycline). | v2 |
2019-03-18T14:04:23.630Z | 2018-11-29T00:00:00.000Z | 196531511 | s2ag/train | Outcomes of Patients with Large B-Cell Lymphomas and Progressive Disease Following CD19-Specific CAR T-Cell Therapy
BACKGROUND: CD19-specific chimeric antigen receptor (CAR) T-cell therapy has proven to be highly effective in patients with relapsed or refractory large B-cell lymphomas, yielding early complete response (CR) rates of ~40%, which are typically sustained. Unfortunately, most patients will not experience prolonged disease control. Despite this fact, little data exist defining the outcomes and impact of subsequent therapies for such individuals. Limited data also exist on the ability for such patients to pursue further clinical trials or allogeneic hematopoietic stem-cell transplant (HSCT). This project details the specific interventions and outcomes of this population to better inform the management of patients who suffer progressive disease (PD) after CD19-specific CAR T-cell therapy.
METHODS: Adults with diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (tFL), primary mediastinal B-cell lymphoma (PMBCL), and high-grade B-cell lymphomas (HGBCL) who received CD19-specific CAR T-cells at the University of Washington/Seattle Cancer Care Alliance were included in this analysis. Patients who received CAR T-cell therapy in conjunction with additional protocol-specified therapy were excluded. Those who exhibited PD or persistent lymphoma after CAR T-cell therapy were the focus of this study. We defined initial PD as patients who had evidence of disease progression on the initial response assessment. Delayed PD was defined as achieving a CR, partial response (PR), or stable disease (SD) on the initial response assessment, but eventually progressed or received subsequent anti-lymphoma therapy. Baseline characteristics and all data were retrieved from the electronic medical record up until date of death or date of last contact in our system, including subsequent interventions and outcomes. Primary endpoint of this analysis was overall survival (OS).
RESULTS: Between October 2013 and May 2018, we identified 51 patients with PD following CD19-specific CAR T-cell therapy. Baseline characteristics are listed in the Table 1. Histologies included DLBCL (29), HGBCL (11), tFL (8) and PMBCL (3). Median age was 60 years (range 26-75), 65% were male, median prior regimens was 3 (range 1-8). Median time from CAR T infusion to PD was 42 days (range 11-609), with 27 (53%) patients exhibiting initial PD. Median follow up after time of progression was 4.2 months. Initial PD was associated with a higher risk of death (HR 2.376, 95% CI 1.19-4.75, p=0.0143, Figure 1). The median OS for those with initial PD and delayed PD was 5.1 months (95% CI 2.0-9.3) and 13.6 months (4.1-not reached) respectively. 39 (76%) patients received ≥ 1 subsequent therapies after PD. Initial therapies included: 2nd CAR T infusion (14), targeted therapy (10), chemotherapy +/- rituximab (7), other immunotherapy (3), radiotherapy (3), intrathecal chemotherapy (1) and allogeneic HSCT (1). 12 (24%) patients received no further therapy despite PD. Those who received ≥ 1 subsequent therapies after PD had a lower risk of death (HR 0.344, 95% CI 0.149-0.793, P=0.0122) compared to those who did not. There was no difference in survival if 2nd CAR T infusion was the next line therapy compared to others (p=0.449), targeted therapy compared to others (p=0.417), or chemotherapy compared to others (p=0.565). 5 (10%) patients enrolled onto a clinical trial as next line therapy. 4 (8%) patients eventually received an allogeneic HSCT after PD, 2 of whom are still alive. We identified 8 patients who were alive for ≥ 12 months after progression without evidence of lymphoma. Last line of therapy for these patients included allogeneic HSCT (2), subsequent CD19-specific CAR-T cell infusion (2), ibrutinib (2), lenalidomide/rituximab (1), and radiotherapy (1).
CONCLUSIONS: Patients with PD post anti-CD19 CAR T-cell therapy, particularly those exhibiting initial PD, have poor long-term outcomes. Patients receiving at least one anti-lymphoma therapy after PD had improved overall survival, although no single approach appeared to confer a survival benefit. Few enrolled onto a clinical trial or received an allogeneic HSCT. These data reinforce the need to both further improve the durable CR rate after CAR T-cell therapy and to develop effective strategies for those not achieving a CR.
Figure 1 Figure 1.
Gopal: Spectrum: Research Funding; Pfizer: Research Funding; BMS: Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Research Funding; Takeda: Research Funding; Brim: Consultancy; Janssen: Consultancy, Research Funding; Asana: Consultancy; Gilead: Consultancy, Research Funding; Aptevo: Consultancy; Incyte: Consultancy; Teva: Research Funding. Maloney:Juno Therapeutics: Research Funding; Roche/Genentech: Honoraria; Janssen Scientific Affairs: Honoraria; Seattle Genetics: Honoraria; GlaxoSmithKline: Research Funding. Turtle:Caribou Biosciences: Consultancy; Adaptive Biotechnologies: Consultancy; Nektar Therapeutics: Consultancy, Research Funding; Bluebird Bio: Consultancy; Precision Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics / Celgene: Consultancy, Patents & Royalties, Research Funding; Eureka Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Aptevo: Consultancy; Gilead: Consultancy. Smith:Genentech: Research Funding; Acerta Pharma BV: Research Funding; Incyte Corporation: Research Funding; Merck Sharp and Dohme Corp.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding. Shadman:TG Therapeutics: Research Funding; Mustang Biopharma: Research Funding; Acerta Pharma: Research Funding; AstraZeneca: Consultancy; Verastem: Consultancy; Gilead Sciences: Research Funding; AbbVie: Consultancy; Qilu Puget Sound Biotherapeutics: Consultancy; Beigene: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy; Celgene: Research Funding. Cassaday:Seattle Genetics: Other: Spouse Employment, Research Funding; Incyte: Research Funding; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy, Research Funding; Kite Pharma: Research Funding; Merck: Research Funding; Amgen: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy. Till:Mustang Bio: Patents & Royalties, Research Funding. Shustov:Seattle Genetics: Research Funding. Acharya:Juno Therapeutics: Research Funding; Teva: Honoraria. Lynch:Takeda Pharmaceuticals: Research Funding; T.G. Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A.: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Incyte Corporation: Research Funding.
| v2 |
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