tbuckley/cabot-search huggingface dataset:
HIV-1 proviral landscapes distinguish posttreatment controllers from noncontrollers
Authors: Radwa Sharaf, Guinevere Q. Lee, Xiaoming Sun, Behzad Etemad, Layla M. Aboukhater, Zixin Hu, Zabrina L. Brumme, Evgenia Aga, Ronald J. Bosch, Ying Wen, Golnaz Namazi, Ce Gao, Edward P. Acosta, Rajesh T. Gandhi, Jeffrey M. Jacobson, Daniel Skiest, David M. Margolis, Ronald Mitsuyasu, Paul Volberding, Elizabeth Connick, Daniel R. Kuritzkes, Michael M. Lederman, Xu G. Yu, Mathias Lichterfeld, Jonathan Z. Li
Journal: Journal of Clinical Investigation (2018)

HIV posttreatment controllers (PTCs) represent a natural model of sustained HIV remission, but they are rare and little is known about their viral reservoir. We obtained 1,450 proviral sequences after near-full-length amplification for 10 PTCs and 16 posttreatment noncontrollers (NCs). Before treatment interruption, the median intact and total reservoir size in PTCs was 7-fold lower than in NCs, but the proportion of intact, defective, and total clonally expanded proviral genomes was not significantly different between the 2 groups. Quantification of total but not intact proviral genome copies predicted sustained HIV remission as 81% of NCs, but none of the PTCs had a total proviral genome greater than 4 copies per million peripheral blood mononuclear cells (PBMCs). The results highlight the restricted intact and defective HIV reservoir in PTCs and suggest that total proviral genome burden could act as the first biomarker for identifying PTCs. Total and defective but not intact proviral copy numbers correlated with levels of cell-associated HIV RNA, activated NK cell percentages, and both HIV-specific CD4+ and CD8+ responses. These results support the concept that defective HIV genomes can lead to viral antigen production and interact with both the innate and adaptive immune systems.
Vasodilator Therapy of Cardiac Failure
Authors: Jay N. Cohn, Joseph A. Franciosa
Journal: New England Journal of Medicine (1977)

Acute Myocardial InfarctionVasodilator therapy has been advocated for two purposes in patients with acute myocardial infarction: improvement in pump function; and reduction in myocardial ischemia.Pump FunctionLeft ventricular dysfunction in acute myocardial infarction is characterized by a high left ventricular diastolic pressure and a low stroke volume.32 Since the left ventricle usually is not much dilated despite the high filling pressure some of the rise in pressure has been attributed to a reduction in diastolic compliance.33 Clinical signs of left ventricular failure often coexist with the hemodynamic derangement, but sometimes the lungs are clear and the heart sounds . . .
Quantitative Spatial Profiling of PD-1/PD-L1 Interaction and HLA-DR/IDO-1 Predicts Improved Outcomes of Anti–PD-1 Therapies in Metastatic Melanoma
Authors: Douglas B. Johnson, Jennifer Bordeaux, Ju Young Kim, Christine Vaupel, David L. Rimm, Thai H. Ho, Richard W. Joseph, Adil I. Daud, Robert M. Conry, Elizabeth M. Gaughan, Leonel F. Hernandez-Aya, Anastasios Dimou, Pauline Funchain, James Smithy, John S. Witte, Svetlana B. McKee, Jennifer Ko, John M. Wrangle, Bashar Dabbas, Shabnam Tangri, Jelveh Lameh, Jeffrey Hall, Joseph Markowitz, Justin M. Balko, Naveen Dakappagari
Journal: Clinical Cancer Research (2018)

Abstract Purpose: PD-1/L1 axis–directed therapies produce clinical responses in a subset of patients; therefore, biomarkers of response are needed. We hypothesized that quantifying key immunosuppression mechanisms within the tumor microenvironment by multiparameter algorithms would identify strong predictors of anti–PD-1 response. Experimental Design: Pretreatment tumor biopsies from 166 patients treated with anti–PD-1 across 10 academic cancer centers were fluorescently stained with multiple markers in discovery (n = 24) and validation (n = 142) cohorts. Biomarker-positive cells and their colocalization were spatially profiled in pathologist-selected tumor regions using novel Automated Quantitative Analysis algorithms. Selected biomarker signatures, PD-1/PD-L1 interaction score, and IDO-1/HLA-DR coexpression were evaluated for anti–PD-1 treatment outcomes. Results: In the discovery cohort, PD-1/PD-L1 interaction score and/or IDO-1/HLA-DR coexpression was strongly associated with anti–PD-1 response (P = 0.0005). In contrast, individual biomarkers (PD-1, PD-L1, IDO-1, HLA-DR) were not associated with response or survival. This finding was replicated in an independent validation cohort: patients with high PD-1/PD-L1 and/or IDO-1/HLA-DR were more likely to respond (P = 0.0096). These patients also experienced significantly improved progression-free survival (HR = 0.36; P = 0.0004) and overall survival (HR = 0.39; P = 0.0011). In the combined cohort, 80% of patients exhibiting higher levels of PD-1/PD-L1 interaction scores and IDO-1/HLA-DR responded to PD-1 blockers (P = 0.000004). In contrast, PD-L1 expression was not predictive of survival. Conclusions: Quantitative spatial profiling of key tumor-immune suppression pathways by novel digital pathology algorithms could help more reliably select melanoma patients for PD-1 monotherapy. Clin Cancer Res; 24(21); 5250–60. ©2018 AACR.
Exercise and Cognitive Decline in Dementia
Authors: Anita Slomski
Journal: JAMA (2018)

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 HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Single-cell transcriptome analysis of lineage diversity in high-grade glioma
Authors: Jinzhou Yuan, Hanna Mendes Levitin, Veronique Frattini, Erin C. Bush, Deborah M. Boyett, Jorge Samanamud, Michele Ceccarelli, Athanassios Dovas, George Zanazzi, Peter Canoll, Jeffrey N. Bruce, Anna Lasorella, Antonio Iavarone, Peter A. Sims
Journal: Genome Medicine (2018)

Despite extensive molecular characterization, we lack a comprehensive understanding of lineage identity, differentiation, and proliferation in high-grade gliomas (HGGs). We sampled the cellular milieu of HGGs by profiling dissociated human surgical specimens with a high-density microwell system for massively parallel single-cell RNA-Seq. We analyzed the resulting profiles to identify subpopulations of both HGG and microenvironmental cells and applied graph-based methods to infer structural features of the malignantly transformed populations. While HGG cells can resemble glia or even immature neurons and form branched lineage structures, mesenchymal transformation results in unstructured populations. Glioma cells in a subset of mesenchymal tumors lose their neural lineage identity, express inflammatory genes, and co-exist with marked myeloid infiltration, reminiscent of molecular interactions between glioma and immune cells established in animal models. Additionally, we discovered a tight coupling between lineage resemblance and proliferation among malignantly transformed cells. Glioma cells that resemble oligodendrocyte progenitors, which proliferate in the brain, are often found in the cell cycle. Conversely, glioma cells that resemble astrocytes, neuroblasts, and oligodendrocytes, which are non-proliferative in the brain, are generally non-cycling in tumors. These studies reveal a relationship between cellular identity and proliferation in HGG and distinct population structures that reflects the extent of neural and non-neural lineage resemblance among malignantly transformed cells.
Molecular Basis of Cardioprotection
Authors: GerdHeusch
Journal: Circulation Research (2015)

Reperfusion is mandatory to salvage ischemic myocardium from infarction, but reperfusion per se contributes to injury and ultimate infarct size. Therefore, cardioprotection beyond that by timely reperfusion is needed to reduce infarct size and improve the prognosis of patients with acute myocardial infarction. The conditioning phenomena provide such cardioprotection, insofar as brief episodes of coronary occlusion/reperfusion preceding (ischemic preconditioning) or following (ischemic postconditioning) sustained myocardial ischemia with reperfusion reduce infarct size. Even ischemia/reperfusion in organs remote from the heart provides cardioprotection (remote ischemic conditioning). The present review characterizes the signal transduction underlying the conditioning phenomena, including their physical and chemical triggers, intracellular signal transduction, and effector mechanisms, notably in the mitochondria. Cardioprotective signal transduction appears as a highly concerted spatiotemporal program. Alth...
Cell-specific histone modification maps in the human frontal lobe link schizophrenia risk to the neuronal epigenome
Authors: Kiran Girdhar, Gabriel E. Hoffman, Yan Jiang, Leanne Brown, Marija Kundakovic, Mads E. Hauberg, Nancy J. Francoeur, Ying-chih Wang, Hardik Shah, David H. Kavanagh, Elizabeth Zharovsky, Rivka Jacobov, Jennifer R. Wiseman, Royce Park, Jessica S. Johnson, Bibi S. Kassim, Laura Sloofman, Eugenio Mattei, Zhiping Weng, Solveig K. Sieberts, Mette A. Peters, Brent T. Harris, Barbara K. Lipska, Pamela Sklar, Panos Roussos, Schahram Akbarian
Journal: Nature Neuroscience (2018)
First-in-human study of LY3039478, an oral Notch signaling inhibitor in advanced or metastatic cancer
Authors: C. Massard, A. Azaro, J.-C. Soria, U. Lassen, C. Le Tourneau, D. Sarker, C. Smith, U. Ohnmacht, G. Oakley, B.K.R. Patel, E.S.M. Yuen, K.A. Benhadji, J. Rodon
Journal: Annals of Oncology (2018)

BackgroundDeregulated Notch signaling due to mutation or overexpression of ligands and/or receptors is implicated in various human malignancies. γ-Secretase inhibitors inhibit Notch signaling by preventing cleavage of transmembrane domain of Notch protein. LY3039478 is a novel, potent Notch inhibitor decreases Notch signaling and its downstream biologic effects. In this first-in-human study, we report the safety, pharmacokinetic (PK) profile, pharmacodynamic effects, and antitumor activity of LY3039478 in patients with advanced or metastatic cancer.MethodsThis phase I, open-label, multicenter, nonrandomized, and dose-escalation phase study determined and confirmed the recommended phase II dose of LY3039478 (oral dose: 2.5–100 mg, thrice weekly (TIW) on a 28-day cycle). The primary objectives are to determine (part A) and confirm (part B) a recommended phase II dose that may be safely administered to patients with advanced or metastatic cancer, and secondary objectives include evaluation of safety, tolerability, PK parameters, and preliminary antitumor activity of LY3039478.ResultsA total of 110 patients were treated with LY3039478 monotherapy between 31 October 2012 and 15 July 2016. Dose-limiting toxicities were thrombocytopenia, colitis, and nausea. Most adverse events were gastrointestinal. The recommended phase II dose was 50 mg TIW, because of its better tolerability compared with 75 mg. The PKs of LY3039478 appeared dose proportional. Pharmacodynamic data indicate an ∼80% inhibition of plasma Aβ, and >50% inhibition of Notch-regulated genes hairy and enhancer of split-1, cyclin D1, and Notch-regulated ankyrin repeat at 45–100-mg dose. Clinical activity (tumor necrosis, metabolic response, or tumor shrinkage) was observed in patients with breast cancer, leiomyosarcoma, and adenoid cystic carcinoma.ConclusionPotent inhibition of Notch signaling by LY3039478 was well tolerated at doses associated with target engagement, and demonstrated evidence of clinical activity in heavily pretreated patients. Further investigation with LY3039478 as monotherapy and in combination with targeted agent or chemotherapy is ongoing.Clinicaltrials.gov IDNCT01695005.
The role of mitochondria in aging
Authors: Ji Yong Jang, Arnon Blum, Jie Liu, Toren Finkel
Journal: Journal of Clinical Investigation (2018)

The biological basis of human aging remains one of the greatest unanswered scientific questions. Increasing evidence, however, points to a role for alterations in mitochondrial function as a potential central regulator of the aging process. Here, we focus primarily on three aspects of mitochondrial biology that link this ancient organelle to how and why we age. In particular, we discuss the role of mitochondria in regulating the innate immune system, the mechanisms linking mitochondrial quality control to age-dependent pathology, and the possibility that mitochondrial-to-nuclear signaling might regulate the rate of aging.
Induction Chemotherapy Followed by Cetuximab Radiotherapy Is Not Superior to Concurrent Chemoradiotherapy for Head and Neck Carcinomas: Results of the GORTEC 2007-02 Phase III Randomized Trial
Authors: Lionnel Geoffrois, Laurent Martin, Dominique De Raucourt, Xu Shan Sun, Yungan Tao, Philippe Maingon, Joëlle Buffet, Yoann Pointreau, Christian Sire, Claude Tuchais, Emmanuel Babin, Alexandre Coutte, Frédéric Rolland, Marie-Christine Kaminsky, Marc Alfonsi, Michel Lapeyre, Marie Saliou, Cédric Lafond, Eric Jadaud, Bernard Gery, Ayman Zawadi, Jean-Marc Tourani, Cédric Khoury, Anne Rose Henry, Ali Hasbini, François Guichard, Christian Borel, Nicolas Meert, Pierre Guillet, Marie-Hélène Calais, Pascal Garaud, Jean Bourhis
Journal: Journal of Clinical Oncology (2018)

Purpose Both concurrent chemoradiotherapy (CT-RT) and cetuximab radiotherapy (cetux-RT) have been established as the standard of care for the treatment of locally advanced squamous cell carcinoma of the head and neck. It was not known whether the addition of induction chemotherapy before cetux-RT could improve outcomes compared with standard of care CT-RT. Patients and Methods The current trial was restricted to patients with nonmetastatic N2b, N2c, or N3 squamous cell carcinoma of the head and neck and fit for taxotere, cisplatin, fluorouracil (TPF). Patients were randomly assigned to receive three cycles of TPF followed by cetux-RT versus concurrent carboplatin fluorouracil and RT as recommended in National Comprehensive Cancer Network guidelines. The trial was powered to detect a hazard ratio (HR) of 0.66 in favor of TPF plus cetux-RT for progression-free survival at 2 years. The inclusion of 180 patients per arm was needed to achieve 80% power at a two-sided significance level of .05. Results Between 2009 and 2013, 370 patients were included. All patients and tumors characteristics were well balanced between arms. There were more cases of grade 3 and 4 neutropenia in the induction arm, and the induction TPF was associated with 6.6% treatment-related deaths. With a median follow-up of 2.8 years, 2-year progression-free survival was not different between both arms (CT-RT, 0.38 v TPF + cetux-RT, 0.36; HR, 0.93 [95% CI, 0.73 to 1.20]; P = .58). HR was 0.98 (95% CI, 0.74 to 1.3; P = .90) for locoregional control and 1.12 (95% CI, 0.86 to 1.46; P = .39) for overall survival. These effects were observed regardless of p16 status. The rate of distant metastases was lower in the TPF arm (HR, 0.54 [95% CI, 0.30 to 0.99]; P = .05). Conclusion Induction TPF followed by cetux-RT did not improve outcomes compared with CT-RT in a population of patients with advanced cervical lymphadenopathy.
Chemoprevention for gastric carcinoma in rat duodenogastric reflux model by a selective cyclooxygenase-2 inhibitor, meloxicam
Authors: Takashi Fujimura, Masaru Oba, Katsunobu Oyama, Tomoharu Miyashita, Shinichi Kinami, Itasu Ninomiya, Sachio Fushida, Genichi Nishimura, Tetsuo Ohta, Koichi Miwa
Journal: Cancer Research (2006)

2355   Background & Aims: Reflux of duodenal contents to stomach is related with development of gastric carcinoma. Cyclooxygenase-2 (COX-2) expression, which involves tumor proliferation, suppressed apoptosis, and tumor invasion, is reported in human gastric carcinoma. The aims of this study are to investigate the relationship between COX-2 and gastric cancer, and to disclose the chemopreventive effect of a selective COX-2 inhibitor. Methods: Meloxicam (MLX, Boehringer Ingelheim) was used as a COX-2 inhibitor. The F344 male rats surgically induced duodenogastic reflux were allocated to two groups, given commercial chow (control) and experimental chow containing MLX (2.0 mg/Kg body weight/day). The animals were sacrificed postoperatively at every ten weeks between 20 and 60 weeks. Pathological findings, COX-2 expression, prostaglandin (PG) E2 production, and proliferative activity (BrdU labeling index) were assessed. Results: In the control group, gastritis cystica profunda (GCP) developed at the 20th week and its incidence reached to 100% at the 60th week, and incidences of adenomatous lesion (ADM) and carcinoma were 52% and 29% at the 60th week, respectively. In the MLX group, neither ADM nor carcinoma was observed though this study. The incidences of GCP, ADM, and carcinoma in the MLX group were significantly lower than the control group (p
Sixty seconds on . . . kidney stones
Authors: Zosia Kmietowicz
Journal: BMJ (2018)

You can say that again. The discomfort caused by kidney stones passing through the ureter has been compared to birth contractions with pain radiating across the lower abdomen and groin. The stones—which can vary in size, shape, and make-up—can also cause pain in the testicles and scrotum as well as nausea, frequent urination, and pain on urination.

They can’t have pethidine or an epidural, but the National Institute for Health and Care Excellence …
Soft Tissue Infections Among Injection Drug Users—San Francisco, California, 1996-2000
Journal: JAMA (2001)

FOCUSES ON INjection drug use and highlights ways that state and local health departments monitor injection drug userelated health issues and develop interventions to prevent substance abuse and infections among injection drug users (IDUs).Substance abuse and addiction are major underlying causes of preventable morbidity and mortality in the United States. 1 The risks increase when illicit substances are injected, which contributes to multiple health and social problems for IDUs, including transmission of bloodborne infections (e.g., human immunodeficiency virus [HIV] and hepatitis B and C infections) through sharing unsterile drug injection equipment and practicing unsafe sex. 2 In the United States, approximately one third of acquired immunodeficiency syndrome cases 3 and one half of new hepatitis C cases 4 are associated with injection drug use.Fatal drug overdoses also contribute to death among IDUs. 5 Although the number of persons who inject illicit drugs (primarily heroin, cocaine, and amphetamine) is not available, approximately one million persons in the United States are active IDUs. 6
Etripamil Nasal Spray for Rapid Conversion of Supraventricular Tachycardia to Sinus Rhythm
Authors: Bruce S. Stambler, Paul Dorian, Philip T. Sager, Douglas Wight, Philippe Douville, Diane Potvin, Pirouz Shamszad, Ronald J. Haberman, Richard S. Kuk, Dhanunjaya R. Lakkireddy, Jose M. Teixeira, Kenneth C. Bilchick, Roger S. Damle, Robert C. Bernstein, Wilson W. Lam, Gearoid O’Neill, Peter A. Noseworthy, Kalpathi L. Venkatachalam, Benoit Coutu, Blandine Mondésert, Francis Plat
Journal: Journal of the American College of Cardiology (2018)

There is no nonparenteral medication for the rapid termination of paroxysmal supraventricular tachycardia.The purpose of this study was to assess the efficacy and safety of etripamil nasal spray, a short-acting calcium-channel blocker, for the rapid termination of paroxysmal supraventricular tachycardia (SVT).This phase 2 study was performed during electrophysiological testing in patients with previously documented SVT who were induced into SVT prior to undergoing a catheter ablation. Patients in sustained SVT for 5 min received either placebo or 1 of 4 doses of active compound. The primary endpoint was the SVT conversion rate within 15 min of study drug administration. Secondary endpoints included time to conversion and adverse events.One hundred four patients were dosed. Conversion rates from SVT to sinus rhythm were between 65% and 95% in the etripamil nasal spray groups and 35% in the placebo group; the differences were statistically significant (Pearson chi-square test) in the 3 highest active compound dose groups versus placebo. In patients who converted, the median time to conversion with etripamil was <3 min. Adverse events were mostly related to the intranasal route of administration or local irritation. Reductions in blood pressure occurred predominantly in the highest etripamil dose.Etripamil nasal spray rapidly terminated induced SVT with a high conversion rate. The safety and efficacy results of this study provide guidance for etripamil dose selection for future studies involving self-administration of this new intranasal calcium-channel blocker in a real-world setting for the termination of SVT. (Efficacy and Safety of Intranasal MSP-2017 [Etripamil] for the Conversion of PSVT to Sinus Rhythm [NODE-1]; NCT02296190).
Convergent Mutations and New Kinase Fusions Lead to Oncogenic STAT3 Activation in Anaplastic Large Cell Lymphoma
Authors: Ramona Crescenzo, Francesco Abate, Elena Lasorsa, Fabrizio Tabbo', Marcello Gaudiano, Nicoletta Chiesa, Filomena Di Giacomo, Elisa Spaccarotella, Luigi Barbarossa, Maria Todaro, Michela Boi, Thomas Tousseyn, Andreas Rosenwald, Lukas Kenner, Davide Rossi, Laurence Mevellec, Jorge Vialard, Francesco Bertoni, Raul Rabadan, Giorgio Inghirami
Journal: Blood (2014)