tbuckley/cabot-search huggingface dataset:
Stress Myocardial Blood Flow Ratio by Dynamic CT Perfusion Identifies Hemodynamically Significant CAD
Authors: Junjie Yang, Guanhua Dou, Bai He, Qinhua Jin, Zhiye Chen, Jing Jing, Marcelo F. Di Carli, Yundai Chen, Ron Blankstein
Journal: JACC. Cardiovascular imaging (2019)
Development of 2 Bromodomain and Extraterminal Inhibitors With Distinct Pharmacokinetic and Pharmacodynamic Profiles for the Treatment of Advanced Malignancies
Authors: Gerald Falchook, Seth Rosen, Patricia LoRusso, Justin Watts, Shilpa Gupta, Catherine C. Coombs, Moshe Talpaz, Razelle Kurzrock, Monica Mita, Ryan Cassaday, Wael Harb, Julio Peguero, David C. Smith, Sarina A. Piha-Paul, Russ Szmulewitz, Marcus S. Noel, Swamy Yeleswaram, Phillip Liu, Julie Switzky, Gongfu Zhou, Fred Zheng, Amitkumar Mehta
Journal: Clinical Cancer Research (2019)

Bromodomain and extraterminal (BET) proteins are key epigenetic transcriptional regulators, inhibition of which may suppress oncogene expression. We report results from 2 independent first-in-human phase 1/2 dose-escalation and expansion, safety and tolerability studies of BET inhibitors INCB054329 (study INCB 54329-101; NCT02431260) and INCB057643 (study INCB 57643-101; NCT02711137).Patients (≥18 years) with advanced malignancies, ≥1 prior therapy, and adequate organ functions received oral INCB054329 (monotherapy) or INCB057643 (monotherapy or in combination with standard-of-care) in 21-day cycles (or 28-day cycles depending on standard-of-care combination). Primary endpoints were safety and tolerability.Sixty-nine and 134 patients received INCB054329 and INCB057643, respectively. Study INCB 54329-101 has been completed; INCB 57643-101 is currently active, but not recruiting (no patients were receiving treatment as of January 8, 2019). Terminal elimination half-life was shorter for INCB054329 versus INCB057643 (mean [SD], 2.24 [2.03] vs. 11.1 [8.27] hours). INCB054329 demonstrated higher interpatient variability in oral clearance versus INCB057643 (CV%, 142% vs. 45.5%). Most common (>20%) any-grade treatment-related adverse events were similar for both drugs (INCB054329; INCB057643): nausea (35%; 30%), thrombocytopenia (33%; 32%), fatigue (29%; 30%), decreased appetite (26%; 22%). Two confirmed complete responses and 4 confirmed partial responses with INCB057643 were reported as best responses.INCB057643 exhibited a more favorable PK profile versus INCB054329; exposure-dependent thrombocytopenia was observed with both drugs which limited the target inhibition that could be safely maintained. Further efforts are required to identify patient populations that can benefit most, and an optimal dosing scheme to maximize therapeutic index.
Fresh frozen plasma transfusion in patients with cirrhosis and coagulopathy: Effect on conventional coagulation tests and thrombomodulin-modified thrombin generation
Authors: Amanda Bruder Rassi, Elbio Antonio d'Amico, Armando Tripodi, Tânia Rubia Flores da Rocha, Beatriz Yuri Migita, Caroline Marcondes Ferreira, Flair José Carrilho, Alberto Queiroz Farias
Journal: Journal of Hepatology (2019)
Pursuing Global Equity in Access to Cancer Drugs
Authors: Joseph Friedman, Fangning Gu, Jeffrey D. Klausner
Journal: JAMA Oncology (2019)

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 Oncology 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 Oncology journal
Abstract 13219: Association Between Device Size and Presence of a High Risk Patent Foramen Ovale: Exploratory Analysis of the RESPECT Trial
Authors: Madeleine Barker, Atman Shah, John Carroll, Richard Smalling, Brian Whisenant, Helmi Lutsep, Eric Horlick
Journal: Circulation (2018)

Introduction: Prespecified subgroup analyses of the long-term outcomes of the RESPECT trial demonstrated that the rate of recurrent stroke may have been further reduced in subjects ages 18-60 who u...
Obtaining prescription drugs in America: it’s no bargain
Authors: Arthur L. Caplan
Journal: Journal of Clinical Investigation (2019)

Just about everything related to health care in America costs too much.The validity of that claim rests on what other economically advanced nations pay for the same health services and treatments.The prices of a hospital bed per night, physician salaries, medical devices, surgeries, lab tests, ambulances, and nursing home stays all are more per capita in the United States than they are in Europe, Japan, Australia, New Zealand, or Canada.Despite the across-the-board price disparities, nothing commands the outrage or the political rhetoric in the US more than the price of prescription drugs.
Red Blood Cells Microparticles Are Associated with Hemolysis Markers and Leg Ulceration in Patients with Sickle Cell Disease
Authors: Oladele Olatunya, Carolina Lanaro, Ana Leda Figueiredo Longhini, Carla Fernanda Franco-Penteado, Sara Teresinha Olalla Saad, Kleber Yotsumoto Fertrin, Adekunle Adekile, Fernando Ferreira Costa
Journal: Blood (2017)
Do Genetic Contributors to Warfarin Responsiveness or Common Thrombophilias Influence the Risk of Major Bleeding in Patients on Extended Duration Vitamin K Antagonist (VKA) for Venous Thromboembolic Disease?
Authors: Philip S Wells, Michael J. Kovacs, David Anderson, Susan R. Kahn, Clive Kearon, Sam Schulman, David M. Keeling, Scott Kaatz, Susan Solymoss, Daniel J Corsi, Marc Rodger
Journal: Blood (2016)
Cardiac Sodium-Calcium Exchanger Is Regulated by Allosteric Calcium and Exchanger Inhibitory Peptide at Distinct Sites
Authors: ChristophMaack, AnandGanesan, AgnieszkaSidor, BrianO’Rourke
Journal: Circulation Research (2005)

The sarcolemmal Na+-Ca2+ exchanger (NCX) is the main Ca2+ extrusion mechanism in cardiac myocytes and is thus essential for the regulation of Ca2+ homeostasis and contractile function. A cytosolic region (f-loop) of the protein mediates regulation of NCX function by intracellular factors including inhibition by exchanger inhibitory peptide (XIP), a 20 amino acid peptide matching the sequence of an autoinhibitory region involved in allosteric regulation of NCX by intracellular Na+, Ca2+, and phosphatidylinositol-4,5-biphosphate (PIP2). Previous evidence indicates that the XIP interaction domain can be eliminated by large deletions of the f-loop that also remove activation of NCX by intracellular Ca2+. By whole-cell voltage clamping experiments, we demonstrate that deletion of residues 562–679, but not 440– 456, 498–510, or 680–685 of the f-loop selectively eliminates XIP-mediated inhibition of NCX expressed either heterologously (HEK293 and A549 cells) or in guinea pig cardiac myocytes. In contrast, by plo...
PTPN2 regulates the generation of exhausted CD8+ T cell subpopulations and restrains tumor immunity
Authors: Martin W. LaFleur, Thao H. Nguyen, Matthew A. Coxe, Brian C. Miller, Kathleen B. Yates, Jacob E. Gillis, Debattama R. Sen, Emily F. Gaudiano, Rose Al Abosy, Gordon J. Freeman, W. Nicholas Haining, Arlene H. Sharpe
Journal: Nature Immunology (2019)
Concomitant <i>PIK3CD</i> and <i>TNFRSF9</i> deficiencies cause chronic active Epstein-Barr virus infection of T cells
Authors: Rémy Rodriguez, Benjamin Fournier, Debora Jorge Cordeiro, Sarah Winter, Kazushi Izawa, Emmanuel Martin, David Boutboul, Christelle Lenoir, Sylvie Fraitag, Sven Kracker, Tania H. Watts, Capucine Picard, Julie Bruneau, Isabelle Callebaut, Alain Fischer, Bénédicte Neven, Sylvain Latour
Journal: The Journal of Experimental Medicine (2019)

Infection of T cells by Epstein-Barr virus (EBV) causes chronic active EBV infection (CAEBV) characterized by T cell lymphoproliferative disorders (T-LPD) of unclear etiology. Here, we identified two homozygous biallelic loss-of-function mutations in PIK3CD and TNFRSF9 in a patient who developed a fatal CAEBV. The mutation in TNFRSF9 gene coding CD137/4-1BB, a costimulatory molecule expressed by antigen-specific activated T cells, resulted in a complete loss of CD137 expression and impaired T cell expansion toward CD137 ligand–expressing cells. Isolated as observed in one sibling, CD137 deficiency resulted in persistent EBV-infected T cells but without clinical manifestations. The mutation in PIK3CD gene that encodes the catalytic subunit p110δ of the PI3K significantly reduced its kinase activity. Deficient T cells for PIK3CD exhibited reduced AKT signaling, while calcium flux, RAS-MAPK activation, and proliferation were increased, suggestive of an imbalance between the PLCγ1 and PI3K pathways. These skewed signals in T cells may sustain accumulation of EBV-infected T cells, a process controlled by the CD137–CD137L pathway, highlighting its critical role in immunity to EBV.
Helen Salisbury: A hostile environment in the NHS
Authors: Helen Salisbury
Journal: BMJ (2019)

A temporary resident recently attended practice after coughing up blood.The likely cause was pneumonia, but tuberculosis and malignancy were on the list of differential diagnoses.My colleague duly sent the patient for chest radiography, but the request was refused as the patient-a visitor to this country-did not have an NHS number.We were told that radiography would be possible if the patient attended the emergency department.This is surely dangerous.From a public health perspective, highly infectious diseases-in this case possible open tuberculosis-must be diagnosed and treated as swiftly as possible.Primary care is available to everyone in the UK, so I don't understand why chest radiography requested by a GP is not counted as part of that primary care.
Adherence to recommendations of Barrett’s esophagus surveillance guidelines: a systematic review and meta-analysis
Authors: Carlijn A. M. Roumans, Ruben D. van der Bogt, Ewout W. Steyerberg, Dimitris Rizopoulos, Iris Lansdorp-Vogelaar, Prateek Sharma, Manon C. W. Spaander, Marco J. Bruno
Journal: Endoscopy (2019)

Abstract Background Guidelines aim to reduce treatment variation and improve quality of care. In the literature there is large variation in the reported rates of adherence to recommendations of surveillance for Barrett’s esophagus (BE). The aim of this systematic review was to identify explanatory parameters determining these differences in adherence rates. Methods Embase, Medline Epub, and Web of Science were searched. Studies reporting adherence in at least one of five domains were selected: general domain, surveillance interval, biopsy protocol, landmark identification, and histopathological information. Adherence was expressed as the proportion of endoscopies or endoscopists being in accordance with guideline recommendations. Variation in adherence was evaluated by 1) meta-regression of adherence rates in random effects meta-analysis to define subgroups, and 2) compiling an overview of the most reported explanatory parameters for (non)adherence. Results 56 studies, including 14 002 BE patients and 4932 endoscopists, were included. Subgroup analysis showed that variation in rates of adherences to surveillance interval recommendations (I 2 = 98 % – 99 %) was explained by difference in country (43 %), by practice type (90 %), and by year of publication (11 %). Variation in adherence to the Seattle protocol was explained by difference in country (14 %). Factors most frequently reported to be associated with better adherence were shorter BE length, salaried employment, surveillance in university hospitals, and dedicated programs. Conclusions This study provides insight into the variability of rates of adherence to BE surveillance recommendations between studies. Better adherence in university hospitals and dedicated programs indicate that persistent alertness of guidelines is important.
High-throughput sequencing contributes to the diagnosis of tubulopathies and familial hypercalcemia hypocalciuria in adults
Authors: Marguerite Hureaux, Emma Ashton, Karin Dahan, Pascal Houillier, Anne Blanchard, Catherine Cormier, Eugenie Koumakis, Daniela Iancu, Hendrica Belge, Pascale Hilbert, Annelies Rotthier, Jurgen Del Favero, Franz Schaefer, Robert Kleta, Detlef Bockenhauer, Xavier Jeunemaitre, Olivier Devuyst, Stephen B. Walsh, Rosa Vargas-Poussou
Journal: Kidney International (2019)
B-cell–specific IRF4 deletion accelerates chronic lymphocytic leukemia development by enhanced tumor immune evasion
Authors: Daniela Asslaber, Yuan Qi, Nicole Maeding, Markus Steiner, Ursula Denk, Jan Philip Höpner, Tanja Nicole Hartmann, Nadja Zaborsky, Richard Greil, Alexander Egle
Journal: Blood (2019)

Chronic lymphocytic leukemia (CLL) is a heterogenous disease that is highly dependent on a cross talk of CLL cells with the microenvironment, in particular with T cells. T cells derived from CLL patients or murine CLL models are skewed to an antigen-experienced T-cell subset, indicating a certain degree of antitumor recognition, but they are also exhausted, preventing an effective antitumor immune response. Here we describe a novel mechanism of CLL tumor immune evasion that is independent of T-cell exhaustion, using B-cell-specific deletion of the transcription factor IRF4 (interferon regulatory factor 4) in Tcl-1 transgenic mice developing a murine CLL highly similar to the human disease. We show enhanced CLL disease progression in IRF4-deficient Tcl-1 tg mice, associated with a severe downregulation of genes involved in T-cell activation, including genes involved in antigen processing/presentation and T-cell costimulation, which massively reduced T-cell subset skewing and exhaustion. We found a strong analogy in the human disease, with inferior prognosis of CLL patients with low IRF4 expression in independent CLL patient cohorts, failed T-cell skewing to antigen-experienced subsets, decreased costimulation capacity, and downregulation of genes involved in T-cell activation. These results have therapeutic relevance because our findings on molecular mechanisms of immune privilege may be responsible for the failure of immune-therapeutic strategies in CLL and may lead to improved targeting in the future.
Differential Effects of Aging in the Macular Retinal Layers, Neuroretinal Rim, and Peripapillary Retinal Nerve Fiber Layer
Authors: Balwantray C. Chauhan, Jayme R. Vianna, Glen P. Sharpe, Shaban Demirel, Christopher A. Girkin, Christian Y. Mardin, Alexander F. Scheuerle, Claude F. Burgoyne
Journal: Ophthalmology (2019)
Functional ageing in fibrotic interstitial lung disease: the impact of frailty on adverse health outcomes
Authors: Sabina A. Guler, Joanne M. Kwan, Janice M. Leung, Nasreen Khalil, Pearce G. Wilcox, Christopher J. Ryerson
Journal: European Respiratory Journal (2019)

Background Accelerated biological and functional ageing is common in fibrotic interstitial lung disease (ILD); however, their impact on adverse health outcomes has not been evaluated in this population. Methods Patients were prospectively recruited from a specialised ILD clinic. Functional ageing was determined by frailty index and biological age by measurement of absolute telomere length (aTL) from patients' peripheral blood leukocytes. Adverse health outcomes included health-related quality of life (St George's Respiratory Questionnaire), number and length of respiratory and non-respiratory hospitalisations, medication tolerability and time to death or lung transplantation. Multivariable models were used to determine the risks and rates of adverse health outcomes associated with the frailty index and aTL. Results 540 patients with fibrotic ILD, including 100 with idiopathic pulmonary fibrosis (IPF), provided 749 frailty index assessments, with 189 patients providing blood samples. The frailty index was strongly associated with quality of life, rate of hospitalisation, time to hospital discharge and mortality, including adjustment for age, sex, disease severity and IPF diagnosis. Mortality prognostication was improved by the addition of the frailty index to commonly used clinical parameters and previously validated composite indices. Conversely, aTL was not associated with most adverse health outcomes. The effect of chronological age on outcomes was mediated primarily by the frailty index, and to a lesser extent by aTL. Conclusions Functional ageing is associated with adverse health outcomes in patients with fibrotic ILD, indicating the need for consideration of the individual functional age into clinical decision-making.
Abstract #3129: Vascular endothelial growth factor receptor 1 expressing tumor side-population cells are involved in the formation of \#8220;tumor initiating niche\#8221; in vivo
Authors: Bikul Das, Rika Tsuchida, Shamim Lotfi, Micky Tsui, Sylvain Baruchel, David Malkin, Herman Yeger
Journal: Cancer Research (2009)

Recently, we isolated a small fraction of migratory and hypoxia resistant side-population cells [SPm(hox)] from several solid tumors and demonstrated their in vivo localization in the hypoxic niche (1). These SPm (hox) cells are highly tumorigenic and express embryonic stem cell signature genes Oct 4 and Nanog, whereas non-migratory SP cells and non-SP cells are poorly tumorigenic and do not express Oct4/Nanog (1). The SPm (hox) fraction expressed a higher level of VEGFR1 (VEGF receptor, Flt1) compared to the non-SP fraction (2). Treatment with neutralizing anti-VEGF antibody rapidly converted SP to non-SP cells in vitro (3). Therefore, we hypothesized that VEGFR1 expressing SPm(hox) cells may initiate the formation of a \#8220;tumor initiation niche\#8221; in vivo. The \#8220;niche\#8221; may secrete a high level of VEGF to maintain the \#8220;stemness\#8221; state of the SPm(hox) cells. To investigate this possibility, SPm(hox) cells were isolated from SK-N-BE2 (neuroblastoma) and RH-4 (rhabdomyosarcoma) cell lines as described (1), mixed with matrigel and injected subcutaneously into Balb/c nude mice (50000 cells/plug; 8 mice). Ten days after the injection, matrigel plugs were studied for the microenvironmental changes including stromal cell infiltration, vessel cooption, angiogenesis, secretion of growth factors, and hypoxia/oxidative stress microenvironment as described (4). The SPm (hox) plug showed rapid proliferation of tumor cells, vessel cooption and marked infiltration of stromal cells within ten days of injection as compared to non-migratory SP cells (P  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3129.
Diagnostic Accuracy of a Fast Computational Approach to Derive Fractional Flow Reserve From Coronary CT Angiography
Authors: Zehang Li, Jiayin Zhang, Lei Xu, Wenjie Yang, Guanyu Li, Daixin Ding, Yunxiao Chang, Mengmeng Yu, Pieter Kitslaar, Su Zhang, Johan H.C. Reiber, Armin Arbab-Zadeh, Fuhua Yan, Shengxian Tu
Journal: JACC. Cardiovascular imaging (2019)
Vascularised human skin equivalents as a novel in vitro model of skin fibrosis and platform for testing of antifibrotic drugs
Authors: Alexandru-Emil Matei, Chih-Wei Chen, Lisa Kiesewetter, Andrea-Hermina Györfi, Yi-Nan Li, Thuong Trinh-Minh, Xiaohan Xu, Cuong Tran Manh, Toin van Kuppevelt, Jan Hansmann, Astrid Jüngel, Georg Schett, Florian Groeber-Becker, Jörg H W Distler
Journal: Annals of the Rheumatic Diseases (2019)

Objectives Fibrosis is a complex pathophysiological process involving interplay between multiple cell types. Experimental modelling of fibrosis is essential for the understanding of its pathogenesis and for testing of putative antifibrotic drugs. However, most current models employ either phylogenetically distant species or rely on human cells cultured in an artificial environment. Here we evaluated the potential of vascularised in vitro human skin equivalents as a novel model of skin fibrosis and a platform for the evaluation of antifibrotic drugs. Methods Skin equivalents were assembled on a three-dimensional extracellular matrix by sequential seeding of endothelial cells, fibroblasts and keratinocytes. Fibrotic transformation on exposure to transforming growth factor-β (TGFβ) and response to treatment with nintedanib as an established antifibrotic agent were evaluated by quantitative polymerase chain reaction (qPCR), capillary Western immunoassay, immunostaining and histology. Results Skin equivalents perfused at a physiological pressure formed a mature, polarised epidermis, a stratified dermis and a functional vessel system. Exposure of these models to TGFβ recapitulated key features of SSc skin with activation of TGFβ pathways, fibroblast to myofibroblast transition, increased release of collagen and excessive deposition of extracellular matrix. Treatment with the antifibrotic agent nintedanib ameliorated this fibrotic transformation. Conclusion Our data provide evidence that vascularised skin equivalents can replicate key features of fibrotic skin and may serve as a platform for evaluation of antifibrotic drugs in a pathophysiologically relevant human setting.