tbuckley/cabot-search huggingface dataset:
Abstract 15664: Prior Oral Anticoagulant Status and Outcomes in Patients With Atrial Fibrillation With an Acute Coronary Syndrome and/or Undergoing Percutaneous Coronary Intervention: Insights From the Augustus Trial
Authors: Robert C Welsh, Renato D Lopes, Daniel Wojdyla, Ronald Aronson, Christopher B Granger, Stephan Windecker, Amit Vora, Dragos Vinereanu, Sigrun Halvorsen, Alexander Parkhomenko, Roxana Mehran, John H Alexander, Shaun G Goodman
Journal: Circulation (2020)

Background: Managing antithrombotic therapy transitions at hospital admission and discharge in patients with atrial fibrillation (AF) and an acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) is challenging and is affected by prior treatment. We examined oral anticoagulant (OAC) use prior to enrollment and the relationship with outcomes in the AUGUSTUS trial. Methods: Patients in AUGUSTUS (N=4,614) were analyzed according to whether they were [n=2262] or were not [n=2352] on a prior OAC. Bleeding and clinical outcomes were compared by Kaplan-Meier (KM) estimates at 180 days. For each outcome, KM estimates and treatment interactions were determined by randomized arm and prior OAC status. Results: Those with prior OAC use had higher CHA 2 DS 2 -VASC and HAS-BLED scores and more comorbid medical conditions (hypertension, heart failure, diabetes, prior stroke), and were more likely to have been enrolled following elective PCI. Prior OAC use included vitamin K antagonists (VKAs) 47%, rivaroxaban 22%, apixaban 22%, dabigatran 12%, and edoxaban 1%. There was no difference in combined ISTH major/clinically relevant non-major (CRNM) bleeding with or without prior OAC use (13.5% vs. 13.5%; HR 1.00, 95% CI 0.85-1.18). Patients with prior OAC use had lower risk of death or ischemic events (5.4% vs. 7.6%; HR 0.72, 95% CI 0.57-0.91). No interactions were observed between randomized treatment (apixaban vs. VKA and aspirin vs. placebo) and prior OAC status for outcomes other than MI where apixaban (vs. VKA) was associated with a lower risk of MI in those with prior OAC use (Figure). Conclusion: In AUGUSTUS, OAC prior to enrollment was more common in patients with comorbidities and those enrolled following elective PCI. Prior OAC was associated with fewer ischemic events but not more bleeding. Our results support the use of apixaban plus a P2Y12 inhibitor without aspirin for patients with AF and ACS/PCI, irrespective of prior OAC use.
IMMU-18. FAVORABLE OUTCOME IN REPLICATION REPAIR DEFICIENT HYPERMUTANT BRAIN TUMORS TO IMMUNE CHECKPOINT INHIBITION: AN INTERNATIONAL RRD CONSORTIUM REGISTRY STUDY
Authors: Eric Bouffet, Sumedha Sudhaman, Jiil Chung, Jacalyn Kelly, Ailish Coblentz, Melissa Edwards, Tatiana Lipman, Cindy Zhang, Ayse Bahar Ercan, Lauren Sambira, Anne Bendel, Stefan Bielack, Elisabeth Koustenis, Deborah Blumenthal, Daniel Bowers, Alberto Broniscer, Annika Bronsema, Sara Carroll, Stefano Chiaravalli, Kristina Cole, Shlomi Constantini, Rebecca Loret De Mola, Gavin Dunn, Charlotta Fröjd, David Gass, Karen Gauvain, Ben George, Nobuko Hijiya, Lindsey Hoffman, Jeffrey Knipstein, Ted Laetsch, Valérie Larouche, Alvaro Lassaletta, Scott Lindhorst, Alexander Lossos, Sandra Luna-Fineman, Vanan Magimairajan, Gary Mason, Warren Mason, Maura Massimino, Oz Mordechai, Enrico Opocher, Michal Oren, Michael Osborn, Alyssa Reddy, Mark Remke, Sumita Roy, Magnus Sabel, David Samuel, Kami Schneider, Santanu Sen, Duncan Stearns, David Sumerauer, Gregory Thomas, Patrick Tomboc, An Van Damme, Margaret Wierman, Ira Winer, Lee Yi Yen, Michal Zapotocky, David Ziegler, Stefanie Zimmermann, Rina Dvir, Gidi Rechavi, Carol Durno, Melyssa Aronson, Michael Taylor, Peter Dirks, Trevor Pugh, Adam Shlien, Cynthia Hawkins, Daniel Morgenstern, Uri Tabori
Journal: Neuro-Oncology (2020)

Abstract Pediatric brain tumors with replication repair deficiency (RRD) are hypermutant and may respond to immune checkpoint inhibition (ICI). We performed a consortium registry study of ICI in recurrent RRD cancers. Clinical and companion biomarkers were collected longitudinally on all patients. Biomarkers included tumor mutational burden (TMB), neoantigens and genetic signatures obtained from whole genome and exome sequencing. Immune inference was obtained by RNAseq and T cell rearrangement was collected in the tumor and in blood throughout treatment. Of the 46 tumors on the study, 32 were brain tumors with glioblastoma in 96%. Rapid, objective responses (&amp;gt;50%) were observed in 50% of glioblastomas. Three year overall survival for the whole cohort was 48+/-8% which compares favorably with historical controls. Brain tumors fared worse with OS of 39+/-10% and late recurrences observed even after 2 years of therapy (p=0.02). Tumor size and acute “flare” constitute poor outcome throughout all cancers. While all tumors are hypermutant, TMB and predicted neoantigens correlated with response to ICI (p=0.02). Specific signatures extracted from SNVs and total mutations predicted response to ICI and favorable outcome (p=0.005). RNA inference and TCR reveal that the FLARE phenotype is mostly acute nonspecific immune response and not true progression. Finally, glioblastomas (n=8) which failed single agent ICI had favorable responses to combinational immunotherapies with prolonged survival of 65%+/-8% at one year after failure vs 0 for other patients (p=0.01). RRD glioblastomas exhibit favorable outcome and responses to ICI. Combinational therapies based on tumor and immune signatures of these cancers are necessary.
Novel Transcriptomic Interactions Between Immune Content and Genomic Classifier Predict Lethal Outcomes in High-grade Prostate Cancer
Authors: Kosj Yamoah, Shivanshu Awasthi, Brandon A. Mahal, Shuang G. Zhao, G. Daniel Grass, Anders Berglund, Julieta Abraham-Miranda, Travis Gerke, Robert J. Rounbehler, Elai Davicioni, Yang Liu, Jong Park, John L. Cleveland, Julio M. Pow-Sang, Daniel Fernandez, Javier Torres-Roca, R. Jeffrey Karnes, Edward Schaeffer, Stephen J. Freedland, Daniel E. Spratt, Robert B. Den, Timothy R. Rebbeck, Felix Feng
Journal: European Urology (2020)
Lightening the viral load to lessen covid-19 severity
Authors: Stephen Burgess, David Smith, Julia C Kenyon, Dipender Gill
Journal: BMJ (2020)

Although the number of positive tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) across many European countries has risen sharply in recent weeks, increases in the number of hospital admissions and deaths from covid-19 have not been as steep.The case fatality rate (the proportion of deaths per positive test) in the UK was lower in May and June than in March and April 1 and seemed to steadily decline throughout July and August. 2 Reductions were also observed in the early stages of the outbreak across many countries. 3 Case fatality rates have varied in different countries, with relatively lower estimates observed in several African countries. 4 Why have case fatality rates decreased, and how does this relate to measures used to control the epidemic?Provenance and peer review: Not commissioned, externally peer reviewed.
EPCO-14. DECIPHERING DIFFERENTIATION HIERARCHIES, HERITABILITY AND PLASTICITY IN HUMAN GLIOMAS VIA SINGLE-CELL MULTI-OMICS
Authors: Federico Gaiti, Ronan Chaligne, Dana Silverbush, Joshua Schiffman, Hannah Weisman, lloyd Kluegel, Simon Gritsch, Sunil Deochand, Alyssa Richman, Johanna Klughammer, Tommaso Biancalani, Christoph Muus, Caroline Sheridan, Alicia Alonso, Franco Izzo, Orit Rozenblatt-Rosen, Aviv Regev, Mario Suva, Dan Landau
Journal: Neuro-Oncology (2020)

Abstract Human diffuse gliomas are incurable malignancies, where cellular state diversity fuels tumor progression and resistance to therapy. Single-cell RNA-sequencing (scRNAseq) studies recently charted the cellular states of the two major categories of human gliomas, IDH-mutant gliomas (IDH-MUT) and IDH-wildtype glioblastoma (GBM), showing that malignant cells partly recapitulate neurodevelopmental trajectories. This raises the central questions of how cell states are encoded epigenetically and whether unidirectional hierarchies or more plastic state transitions govern glioma cellular architectures. To address these questions, we generated multi-omics single-cell profiling, integrating DNA methylation (DNAme), transcriptome and genotyping of 1,728 cells from 11 GBM and IDH-MUT primary patient samples. Direct comparison of the methylomes of distinct glioma cell states revealed Polycomb repressive complex 2 (PRC2) targets DNAme as a key switch in the differentiation of malignant GBM cells. In contrast, dissecting aberrant circuits of hyper-methylation and gene expression in IDH-MUT gliomas, we observed a decoupling of the promoter methylation-expression relationship, with disruption of CTCF insulation and enhancer vulnerability which increases with cellular differentiation. To define cell state transition dynamics directly in patient samples, we generated high-resolution lineage histories of glioma cells using heritable DNAme changes, and projected the scRNAseq-derived cell states onto the lineage trees. This analysis demonstrated that cell states are heritable across malignant gliomas and, while in IDH-MUT differentiation far outpaces de-differentiation, GBM harbors a higher degree of cell state plasticity allowing reversion of GBM cells from a differentiated to a stem-like state. Overall, our work provides detailed insights into gliomagenesis, dissecting the epigenetic encoding, regulatory programs, and dynamics of the cellular states that drive human gliomas. Importantly, it also carries significant translational implication, as the high degree of de-differentiation in GBM challenges the paradigm of therapeutically targeting glioma stem-like cells to deprive tumors of their ability to regenerate.
Abstract 15722: Humoral Factors - Released by Remote Ischemic Conditioning in Pigs - Exert Their Cardioprotection in Isolated Rat Hearts by Activation of the Intrinsic Cardiac Nervous System
Authors: Helmut Raphael Lieder, Amelie Irmert, Andreas Skyschally, Gerd Heusch, Petra Kleinbongard
Journal: Circulation (2019)

Introduction: Short cycles of ischemia/reperfusion (I/R) in a tissue/organ remote from the heart reduce myocardial I/R injury. Such remote ischemic conditioning (RIC) is operative in all species te...
Challenges and Controversy in Determining UV Exposure as a Risk Factor for Cutaneous Melanoma in Skin of Color
Authors: Nkanyezi N. Ferguson
Journal: JAMA Dermatology (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
Do No Harm: The Know-Do Gap and Quality of Care for Childhood Diarrhoea and Pneumonia in India
Authors: Manoj Mohanan, Marcos Vera-Hernández, Veena Das, Soledad Giardili, Jeremy Goldhaber-Fiebert, Jeremy D. Goldhaber-Fiebert, Tracy L. Rabin, Sunil S. Raj, Jeremy I. Schwartz, Aparna Seth
Journal: JAMA Pediatrics (2015)
RARE-47. DIFFUSE LEPTOMENINGEAL DISSEMINATED GLIONEURONAL TUMOR: CASE-SERIES
Authors: Felipe Hada Sanders, Hamilton Matushita, Alessandra Azambuja, Fernando Frasseto, Sergio Rosemberg, Vicente Odone, Manoel Jacobsen Teixeira
Journal: Neuro-Oncology (2020)

Abstract Diffuse leptomeningeal disseminated glioneuronal tumor (DL-GNT) is a rare brain tumor that presents as a plaque-like subarachnoid tumor, commonly involving the basal cisterns and interhemispheric fissure of children but lacking intraparenchymal tumor. Here we report two cases focusing on clinicopathologic features. In all patients, radiography revealed characteristic leptomeningeal thickening and enhancement with minor superficial parenchymal lesions. The broadcast of the knowledge about this type of disease is important to increase awareness on this subject.
Covid-19: Moving London into tier 3 would be “big mistake,” warns leading epidemiologist
Authors: Rebecca Coombes
Journal: BMJ (2020)

A leading epidemiologist has urged the government not to put the UK capital into strict tier 3 measures next week, saying the move would be a "big mistake."Tim Spector, professor of genetic epidemiology at King's College London and creator of the Covid Symptom Study app, 1 was responding to concerns that rising covid-19 cases in London in recent weeks would see it lose its tier 2 status.
Incidence and Characteristics of Nonfatal Opioid Overdose Among Youths Aged 11 to 24 Years by Sex
Authors: Sarah M. Bagley, Mam Jarra Gai, Joel J. Earlywine, Samantha F. Schoenberger, Scott E. Hadland, Joshua A. Barocas
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Opioid-related overdose has substantially increased among adolescents and young adults in recent years. How overdose differs by age and sex among youths and the factors associated with overdose by sex remain poorly described. <h3>Objective</h3> To compare the sociodemographic and clinical characteristics of female and male youths who have experienced a nonfatal opioid overdose (NFOD) and compare the incidence of NFOD by sex. <h3>Design, Setting, and Participants</h3> This retrospective cohort study used data on US individuals aged 11 to 24 years with a diagnosis of NFOD from the IBM MarketScan Commercial Database from January 1, 2006, through December 31, 2017. <h3>Exposure</h3> Sex. <h3>Main Outcomes and Measures</h3> The primary outcome was NFOD stratified by sex; covariates included sociodemographic and clinical characteristics. <h3>Results</h3> Among 20 312 youths aged 11 to 24 years who had a history of NFOD and met study eligibility criteria, the median age was 20 years (interquartile range, 18-22 years; mean [SD] age, 20.0 [2.9] years) and 56.7% were male. Compared with male youths, female youths had a higher baseline prevalence of mood or anxiety disorder (65.5% vs 51.9%,<i>P</i> &lt; .001), trauma and stress-related disorders (16.4% vs 10.1%,<i>P</i> &lt; .001), and history of suicide attempt or self-harm (14.6% vs 9.9%,<i>P</i> &lt; .001). Male youths had a higher prevalence of opioid use disorder (44.7% vs 29.2%,<i>P</i> &lt; .001), cannabis use disorder (18.3% vs 11.3%,<i>P</i> &lt; .001), and alcohol use disorder (20.3% vs 14.4%,<i>P</i> &lt; .001). The incidence rate ratio of NFODs in females vs males was greater than 1 for ages 11 to 16 years and was less than or equal to 1 after age 17 years. <h3>Conclusions and Relevance</h3> This cohort study found differences between female and male youths in sociodemographic and clinical characteristics and incidence of NFOD. Although female and male youths who experience overdose appear to have different risk factors, many of these risk factors may be amenable to early detection through screening and intervention.
Activation of N-methyl-D-aspartate receptor regulates insulin sensitivity and lipid metabolism
Authors: Xiao-Ting Huang, Jun-Xiao Yang, Zun Wang, Chen-Yu Zhang, Zi-Qiang Luo, Wei Liu, Si-Yuan Tang
Journal: Theranostics (2020)

Although significant progress has been made in understanding the mechanisms of steatosis and insulin resistance, the physiological functions of regulators in these processes remain largely elusive. Evidence has suggested that the glutamate/N-methyl-D-aspartic acid receptor (NMDAR) axis contributes to acute lung injury, pulmonary arterial hypertension, and diabetes, but the specific metabolic contribution of the glutamate/NMDAR axis is not clear. Here we provide data at the animal, cellular, and molecular levels to support the role of the glutamate/NMDAR axis as a therapeutic target for metabolic syndrome in obesity.
The mental health impact of the COVID-19 pandemic on people with and without depressive, anxiety, or obsessive-compulsive disorders: a longitudinal study of three Dutch case-control cohorts
Authors: Kuan-Yu Pan, Almar A L Kok, Merijn Eikelenboom, Melany Horsfall, Frederike Jörg, Rob A Luteijn, Didi Rhebergen, Patricia van Oppen, Erik J Giltay, Brenda W J H Penninx
Journal: The Lancet Psychiatry (2020)
Evaluation and management of extrahepatic manifestations of nonalcoholic fatty liver disease
Authors: Karn Wijarnpreecha, Elizabeth S. Aby, Aijaz Ahmed, Donghee Kim
Journal: Clinical and Molecular Hepatology (2020)

Nonalcoholic fatty liver disease (NAFLD) is a multisystemic disease and a rapidly growing cause of chronic liver disease in children and adults worldwide. Diagnosis and management of extrahepatic manifestations of NAFLD, including cardiovascular disease (CVD), type 2 diabetes mellitus, metabolic syndrome, chronic kidney disease, obstructive sleep apnea, polycystic ovarian syndrome, hypothyroidism, psoriasis, and extrahepatic malignancy are crucial for the treatment of patients with NAFLD. The leading cause of death in NAFLD is primarily from CVD, followed by liver-related mortality, extrahepatic cancer, liver cancer, and diabetes-related mortality. Therefore, clinicians need to identify high-risk patients earlier in the disease course and be aware of the extrahepatic manifestations of NAFLD to improve liver disease outcomes. In this review, we focus on the monitoring and management of the extrahepatic manifestations of NAFLD.
EXTH-44. DEVELOPMENT OF RETROVIRAL REPLICATING VECTORS ENCODING SEQUENCE-OPTIMIZED NITROREDUCTASE FOR PRODRUG ACTIVATOR GENE THERAPY IN HUMAN GLIOMA MODELS
Authors: Sara Collins, Akihito Inagaki, Chien-Kuo Tai, Christopher R Logg, Peter Searle, Mark Tangney, Noriyuki Kasahara
Journal: Neuro-Oncology (2020)

Abstract Early-phase clinical trials of Toca 511, a retroviral replicating vector (RRV) expressing an optimized form of yeast cytosine deaminase for prodrug activator gene therapy, showed highly promising evidence of therapeutic benefit and increased survival in recurrent high-grade glioma, but an international Phase 3 trial failed to meet primary and secondary endpoints. Nonetheless, promising results observed within predetermined subgroups, combined with the highly favorable safety profile of this approach, make it worthwhile to consider alternative prodrug-activating enzymes in order to increase therapeutic efficacy. In this study, we employed RRV to deliver modified versions of another prodrug activator gene, E.coli nitroreductase (NTR), which activates the prodrug CB1954 to generate a potent bifunctional alkylating agent. We constructed RRV encoding two different isoforms of wild-type E.coli NTR genes (NfsA, NfsB) as well as variants of both isoforms extensively modified to optimize human codon usage and vector stability. Further efforts to improve the potency of these prodrug activator enzymes included the construction of additional new vectors incorporating point mutations at the active site which have previously been demonstrated to improve prodrug conversion efficiency. NTR transgene insertion did not affect RRV replication, which resulted in increasing NTR expression over time in human glioma cells in culture. Sequence optimization resulted in enhanced genomic stability of the vectors upon serial passage and also in significantly reduced cell viability in vitro on treatment of fully transduced U87 and U87-EGFRviii glioma cells with CB1954 prodrug. In orthotopic U87-EGFRviii intracerebral tumor models, stereotactic intratumoral injection of sequence-optimized RRV-NTR and repeated cycles of prodrug treatment resulted in rapid and significant reduction of tumor burden as monitored by bioluminescence imaging, leading to prolonged survival benefit. These data indicate that improved therapeutic efficacy can be achieved with optimized NTR prodrug activator gene therapy delivered by RRV in experimental glioma models.
TAMI-09. ENERGY METABOLISM AND THERAPEUTIC T CELL EFFICACY IN THE GLIOBLASTOMA MICROENVIRONMENT
Authors: Meghan Logun, Maxwell Colonna, Arthur Edison, Lohitash Karumbaiah
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM), like most cancers, undergo metabolic alterations to primarily utilize aerobic glycolysis in the hypoxic tumor microenvironment (TME). Similarly, activated T cells switch to glycolysis upon antigen recognition to cope with proliferation needs but are not equally equipped to survive in the hypoxic TME. Metabolic reprogramming within GBM TME contributes to therapeutic resistance and tumor progression, but the effects of metabolic alterations on therapeutic T cell survival and efficacy have not been fully elucidated. We hypothesized that hypoxia in GBM/T-cell co-cultures will significantly impair T cell proliferation and function. We conducted in vitro co-culture assays and nuclear magnetic resonance (NMR)–based assessments in hypoxic (1%O2) or normoxic conditions to detect metabolic changes in real-time. Imaging cytometry for cell cycle assessment demonstrated that GSCs were unaffected by hypoxia, but roughly 90% of healthy T cells arrested in G0/G1 along with significant reduction in glycan precursor UDP-GlcNAc presence. Media samples over 96h in normal and hypoxic oxygen conditions from cells in solitary or co-cultures were analyzed using a Bruker Avance III HD spectrometer at 600 MHz for comparison over time using PCA analysis of metabolic intermediate differences. After 16h, there was observable differences in produced metabolites between the T cells cultured alone or co-culture with GSCs, compared to the GSCs alone or media alone controls. Quantifiable changes in glucose, lactate, fumarate, acetate and pyruvate, among others, indicated a large shift in T cell metabolism dependent on oxygen conditions and co-culture interactions, while GSCs are less metabolically responsive to culture conditions. Ongoing experiments will examine precise changes in UDP-GlcNAc and glycosylation precursors in T cells and CAR-T cells via targeted NMR analysis, which we expect will help us understand energy dependent mechanisms of T cell exhaustion and lead to development of novel strategies to sustain T cell function in the hostile TME.