Intrinsic disorder in the T cell receptor creates cooperativity and controls ZAP70 binding

payt.helady61 shared this article with you from Inoreader Intrinsic disorder in the T cell receptor creates cooperativity and controls ZAP70 binding Via Biophysical Journal Many immunoreceptors have cytoplasmic domains that are intrinsically disordered (i.e., have high configurational entropy), have multiple sites of post-translational modification (e.g., tyrosine phosphorylation), and participate in nonlinear signaling pathways (e.g., exhibiting switch-like behavior). Several hypotheses to explain the origin of these nonlinearities fall under the broad hypothesis that modification at one site changes the immunoreceptor's entropy, which in turn changes further modification dynamics. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Targeting telomeres: Molecular dynamics and free energy simulation of gold-carbene binding to DNA

payt.helady61 shared this article with you from Inoreader Targeting telomeres: Molecular dynamics and free energy simulation of gold-carbene binding to DNA Via Biophysical Journal DNA sequences in regulatory regions and in telomers at the ends of chromosomes frequently contain tandem repeats of guanine nucleotides that can form stacked structures stabilized by Hoogsten pairing and centrally bound monovalent cations. The replication and elongation of telomeres requires the disruption of these G-quadruplex structures. Hence, drug molecules such as gold(Au)-carbene that stabilize G-quadruplexes may also interfere with the elongation of telomeres and in turn could be used to control cell replication and growth. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Circadian rhythms of early afterdepolarizations and ventricular arrhythmias in a cardiomyocyte model

payt.helady61 shared this article with you from Inoreader Circadian rhythms of early afterdepolarizations and ventricular arrhythmias in a cardiomyocyte model Via Biophysical Journal Sudden cardiac arrest is a malfunction of the heart's electrical system, typically caused by ventricular arrhythmias, that can lead to sudden cardiac death (SCD) within minutes. Epidemiological studies have shown that SCD and ventricular arrhythmias are more likely to occur in the morning than in the evening, and laboratory studies indicate that these daily rhythms in adverse cardiovascular events are at least partially under the control of the endogenous circadian timekeeping system. However, the biophysical mechanisms linking molecular circadian clocks to cardiac arrhythmogenesis are not fully understood. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Development and Evaluation of a Risk-Adjusted Measure of Intraoperative Hypotension in Patients Having Nonemergent, Noncardiac Surgery

payt.helady61 shared this article with you from Inoreader Development and Evaluation of a Risk-Adjusted Measure of Intraoperative Hypotension in Patients Having Nonemergent, Noncardiac Surgery Via Anesthesia & Analgesia - Published Ahead-of-Print BACKGROUND: Intraoperative hypotension is common and associated with organ injury and death, although randomized data showing a causal relationship remain sparse. A risk-adjusted measure of intraoperative hypotension may therefore contribute to quality improvement efforts. METHODS: The measure we developed defines hypotension as a mean arterial pressure 30 cases during the 12-month measurement period. Kidney injury and in-hospital mortality were most common in patients whose anesthesia providers had worse scores. However, a sensitivity analysis in 1 hospital showed that score distributions differed markedly between anesthesiology fellows and attending anesthesiologists or certified registered nurse anesthetists; score distributions also varied as a function of the fraction of cases that were inpatients. CONCLUSIONS: Intraoperative hypotension was common and was associated with acute kidney injury and in-hospital mortality. There were substantial variations in clinician-level scores, and the measure score distribution suggests that there may be opportunity to reduce hypotension which may improve patient safety and outcomes. However, sensitivity analyses suggest that some portion of the variation results from limitations of risk adjustment. Future versions of the measure should risk adjust for important patient and procedural factors including comorbidities and surgical complexity, although this will require more consistent structured data capture in anesthesia information management systems. Including structured data on additional risk factors may improve hypotension risk prediction which is integral to the measure's validity. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Nonopioid GTS-21 Mitigates Burn Injury Pain in Rats by Decreasing Spinal Cord Inflammatory Responses

payt.helady61 shared this article with you from Inoreader Nonopioid GTS-21 Mitigates Burn Injury Pain in Rats by Decreasing Spinal Cord Inflammatory Responses Via Anesthesia & Analgesia - Published Ahead-of-Print BACKGROUND: Burn injury (BI) pain consists of inflammatory and neuropathic components and activates microglia. Nicotinic alpha 7 acetylcholine receptors (α7AChRs) expressed in microglia exhibit immunomodulatory activity during agonist stimulation. Efficacy of selective α7AChR agonist GTS-21 to mitigate BI pain and spinal pain-mediators was tested. METHODS: Anesthetized rats after hind-paw BI received intraperitoneal GTS-21 or saline daily. Allodynia and hyperalgesia were tested on BI and contralateral paw for 21 days. Another group after BI receiving GTS-21 or saline had lumbar spinal cord segments harvested (day 7 or 14) to quantify spinal inflammatory-pain transducers or microglia activation using fluorescent marker, ionized calcium-binding adaptor protein (Iba1). RESULTS: BI significantly decreased allodynia withdrawal threshold from baseline of ~9–10 to ~0.5–1 g, and hyperalgesia latency from ~16–17 to ~5–6 seconds by day 1. Both doses of GTS-21 (4 or 8 mg/kg) mitigated burn-induced allodynia from ~0.5–1 to ~2–3 g threshold (P = .089 and P = .010), and hyperalgesia from ~5–6 to 8–9 seconds (P View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Derivation and validation of a novel method to subgroup patients with functional dyspepsia: beyond upper gastrointestinal symptoms

payt.helady61 shared this article with you from Inoreader Derivation and validation of a novel method to subgroup patients with functional dyspepsia: beyond upper gastrointestinal symptoms Via Alimentary Pharmacology & Therapeutics Summary Background Conventionally, patients with functional dyspepsia are subgrouped based on upper gastrointestinal symptoms, according to the Rome criteria. However, psychological co‐morbidity and extraintestinal symptoms are also relevant to functional gastrointestinal disorders. Aim To investigate whether it is possible to subgroup people with functional dyspepsia using factors beyond upper gastrointestinal symptoms. Methods We collected demographic, symptom and psychological health data from adult subjects meeting the Rome III criteria for functional dyspepsia in two secondary care cross‐sectional surveys in Canada and the UK. We performed latent class analysis, a method of model‐based clustering, to identify specific subgroups (clusters). For each cluster, we drew a radar plot, and compared these by visual inspection, describing cluster characteristics. Results In total, 400 individuals met Rome III criteria for functional dyspepsia in the Canadian cohort, and 262 the UK cohort. A four‐cluster model was the optimum solution and the characteristics of the clusters were almost identical between the two cohorts. The clusters were defined by a pattern of gastrointestinal symptoms and were further differentiated by the extent of extraintestinal and psychological co‐morbidity. Cluster 1 (mean age 46.7 years, 66.7% female) consisted of epigastric pain and nausea with high psychological burden, cluster 2 (mean age 41.5 years, 77.7% female) high overall gastrointestinal symptom severity with high psychological burden, cluster 3 (45.8 years, 67.2% female) oesophageal symptoms and early satiety with low psychological burden, and cluster 4 (mean age 40.4 years, 71.5% female) postprandial fullness with low psychological burden. We validated the model derived using the Canadian study population externally by applying it to the UK dataset. We demonstrated reproducibility; it would perform similarly when applied to a different dataset. Conclusions Latent class analysis identified four distinct functional dyspepsia subgroups characterised by varying degrees of gastrointestinal symptoms, extraintestinal symptoms and psychological co‐morbidity. Further research is needed to assess whether they might be used to direct treatment. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Phenome‐wide association study in adult coeliac disease: role of HLA subtype

payt.helady61 shared this article with you from Inoreader Phenome‐wide association study in adult coeliac disease: role of HLA subtype Via Alimentary Pharmacology & Therapeutics Summary Background Coeliac disease arises in genetically susceptible individuals, in particular in carriers of HLA‐DQ2/DQ8 risk alleles and is associated with various comorbidities. Coeliac disease may confer an increased mortality, but the data are conflicting. Aims We aimed to characterize mortality and morbidity in patients with coeliac disease with a special focus on the role of the number of HLA risk alleles. Methods We studied coeliac disease‐associated morbidity and mortality in ~500 000 participants of the UK Biobank including 2482 individuals with the diagnosis of coeliac disease. We used an unbiased, multivariable Phenome‐Wide Association Study (PheWAS) method to uncover the coeliac disease‐associated disorders. The tag SNP approach was used to divide the coeliac disease subjects into HLA‐DQ2/DQ8‐based risk categories. Results We found 225 ICD‐10 codes significantly associated with coeliac disease. During the median follow‐up of 10.7 years, coeliac disease individuals (n = 2482) had higher overall mortality (HR 1.6 [95% CI, 1.4‐1.8]) than controls and both an increased occurrence of and an increased mortality from cancer, respiratory and cardiovascular diseases (HR 1.4‐1.6). Coeliac disease individuals with 2 HLA‐DQ2/8 risk alleles had a similar overall mortality as coeliac disease participants with 0‐1 HLA‐DQ2/8 alleles, but were more likely to die from lymphoproliferative diseases (HR 7.6 [95% CI, 1.01‐57.25]). Conclusions Our data suggest that the increased mortality from lymphoproliferative diseases is restricted to those coeliac patients with 2 HLADQ2/8 alleles and that a combination of coeliac disease and HLADQ2/8 alleles is needed to increase the susceptibility. Once confirmed, closer monitoring may be warranted in this high‐risk subpopulation. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Immune‐mediated diseases and risk of Crohn’s disease or ulcerative colitis: a prospective cohort study

payt.helady61 shared this article with you from Inoreader Immune‐mediated diseases and risk of Crohn's disease or ulcerative colitis: a prospective cohort study Via Alimentary Pharmacology & Therapeutics Summary Background Although immune‐mediated diseases (IMDs) including inflammatory bowel diseases (IBDs) are known to cluster, to what extent this is due to common environmental influences is unknown. Aim To examine the incidence of IBD in individuals with another IMD. Methods We used data from the prospective Nurses' Health Study II cohort (1995‐2017) to examine the effect of diagnoses of several common IMDs on subsequent risk of Crohn's disease (CD) or ulcerative colitis (UC) using Cox proportional hazards models, adjusting for detailed diet and lifestyle confounders. Results We documented 132 cases of CD and 186 cases of UC over 2 016 163 person‐years of follow‐up (median age at IBD diagnosis 50 years). Compared to participants with no history of IMD, the HRs of CD for those with 1 and ≥ 2 IMDs were 2.57 (95% CI 1.77‐3.74) and 2.74 (95% CI 1.36 to 5.49), respectively (P trend < 0.0001). This association was only modestly attenuated by adjustment for environmental risk factors (HR 2.35 and 2.46, respectively). The risk of UC was not increased, with multivariable‐adjusted HRs of 1.22 (95% CI 0.85‐1.76) and 1.33 (95% CI 0.67‐2.65) for those with 1 and ≥ 2 IMDs, respectively, compared to those with none (P trend 0.16) (P heterogeneity comparing CD and UC 0.037). Asthma, atopic dermatitis, psoriasis and rosacea were individually associated with higher risk of CD (HR ranging from 2.15 to 3.39) but not UC. Conclusions Individuals with one or more IMDs are at an increased risk for CD but not UC. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Infliximab-based Self-healing Hydrogel Composite Scaffold Enhances Stem Cell Survival, Engraftment, and Function in Rheumatoid Arthritis Treatment

payt.helady61 shared this article with you from Inoreader Infliximab-based Self-healing Hydrogel Composite Scaffold Enhances Stem Cell Survival, Engraftment, and Function in Rheumatoid Arthritis Treatment Via Acta Biomaterialia Publication date: Available online 5 December 2020 Source: Acta Biomaterialia Author(s): Yue Zhao, Chaohua Gao, Hou Liu, Hangrui Liu, Yubin Feng, Zuhao Li, He Liu, Jincheng Wang, Bai Yang, Quan Lin View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Prior Treatment for Non–small Cell Lung Cancer Is Associated With Improved Survival in Patients who Undergo Definitive Stereotactic Body Radiation Therapy for a Subsequent Lung Malignancy: A Retrospective Multivariate and Matched Pair Analysis

payt.helady61 shared this article with you from Inoreader Prior Treatment for Non–small Cell Lung Cancer Is Associated With Improved Survival in Patients who Undergo Definitive Stereotactic Body Radiation Therapy for a Subsequent Lung Malignancy: A Retrospective Multivariate and Matched Pair Analysis Via American Journal of Clinical Oncology - Published Ahead-of-Print Background: Despite occurring commonly, the prognoses of second early-stage non–small cell lung cancers (NSCLC) are not well known. Methods: The authors retrospectively reviewed the charts of inoperable patients who underwent thoracic stereotactic body radiation therapy (SBRT) from February 2007 to April 2019. Those with previous small cell lung cancers or SBRT treatments for tumors other than NSCLC were excluded. Multivariate Cox regression and a matched pair cohort analyses evaluated the prognoses of patients undergoing definitive SBRT for a new second primary. Results: Of 438 patients who underwent definitive SBRT for NSCLC, 84 had previously treated NSCLC. Univariate log-rank tests identified gender, Karnofksy performance status (KPS), prior lung cancer, anticoagulation use, and history of heart disease to correlate with overall survival (OS) (P View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Impact of p53, HIF1a, Ki-67, CA-9, and GLUT1 Expression on Treatment Outcomes in Locally Advanced Cervical Cancer Patients Treated With Definitive Chemoradiation Therapy

payt.helady61 shared this article with you from Inoreader Impact of p53, HIF1a, Ki-67, CA-9, and GLUT1 Expression on Treatment Outcomes in Locally Advanced Cervical Cancer Patients Treated With Definitive Chemoradiation Therapy Via American Journal of Clinical Oncology - Published Ahead-of-Print Purpose/Objective: The objective of this study was to assess the association between pretreatment p53, hypoxia inducible factor 1a (HIF1a), Ki-67, carbonic anhydrase-9 (CA-9), and glucose transporter 1 (GLUT1) expression in locally advanced cervical cancer patients treated definitively with concurrent chemoradiation therapy (CRT) and treatment outcomes including overall survival (OS), progression-free survival (PFS), local-regional control (LC), and distant metastases–free survival (DMFS). Patients and Methods: Twenty-eight patients treated definitively and consecutively for cervical cancer with CRT had p53, HIF1a, Ki-67, CA-9, and GLUT1 protein expression assessed and scored semiquantitatively by 3 pathologists, blinded to the treatment outcomes. Outcomes were stratified by p53 (H-score: View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Nanoliposomal Irinotecan and Metronomic Temozolomide for Patients With Recurrent Glioblastoma: BrUOG329, A Phase I Brown University Oncology Research Group Trial

payt.helady61 shared this article with you from Inoreader Nanoliposomal Irinotecan and Metronomic Temozolomide for Patients With Recurrent Glioblastoma: BrUOG329, A Phase I Brown University Oncology Research Group Trial Via American Journal of Clinical Oncology - Published Ahead-of-Print Background: Liposomal formulations may improve the solubility and bioavailability of drugs potentially increasing their ability to cross the blood-brain barrier. We performed a phase I study to determine the maximum tolerated dose and preliminary efficacy of pegylated nanoliposomal irinotecan (nal-IRI)+metronomic temozolomide (TMZ) in patients with recurrent glioblastoma. Patients and Methods: Patients with glioblastoma who progressed after at least 1 line of therapy were eligible. All patients received TMZ 50 mg/m2/d until disease progression. Three dose levels of nal-IRI were planned, 50, 70, and 80 mg/m2, intravenously every 2 weeks. Patients were accrued in a 3+3 design. The study included a preliminary assessment after the first 13 evaluable patients. The trial would be terminated early if 0 or 1 responses were observed in these patients. Results: Twelve patients were treated over 2 dose levels (nal-IRI 50 and 70 mg/m2). At dose level 2, nal-IRI 70 mg/m2, 2 of 3 patients developed dose-limiting toxicities including 1 patient who developed grade 4 neutropenia and grade 3 diarrhea and anorexia and 1 patient with grade 3 diarrhea, hypokalemia fatigue, and anorexia. Accrual to dose level 1 was expanded to 9 patients. The Drug Safety Monitoring Board (DSMB) reviewed the data of the initial 12 patients—there were 0/12 responses (0%) and the median progression-free survival was 2 months and accrual was halted. Conclusions: The maximum tolerated dose of nal-IRI was 50 mg/m2 every 2 weeks with TMZ 50 mg/m2/d. The dose-limiting toxicities were diarrhea and neutropenia. No activity was seen at interim analysis and the study was terminated. Supported by Ipsen. The authors declare no conflicts of interest. Reprints: Howard Safran, MD, Department of Medicine, The Rhode Island Hospital, 593 Eddy Street, Providence, RI 02906. E-mail: hsafran@lifespan.org. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.