tbuckley/cabot-search huggingface dataset:
The Inhibitor of Apoptosis Protein Livin Confers Resistance to Fas-Mediated Immune Cytotoxicity in Refractory Lymphoma
Authors: Eiji Sugihara, Norisato Hashimoto, Satoru Osuka, Takatsune Shimizu, Sayaka Ueno, Shogo Okazaki, Tomonori Yaguchi, Yutaka Kawakami, Kenjiro Kosaki, Taka-Aki Sato, Shinichiro Okamoto, Hideyuki Saya
Journal: Cancer Research (2020)

Death receptor Fas-mediated apoptosis not only eliminates nonspecific and autoreactive B cells but also plays a major role in antitumor immunity. However, the possible mechanisms underlying impairment of Fas-mediated induction of apoptosis during lymphomagenesis remain unknown. In this study, we employed our developed syngeneic lymphoma model to demonstrate that downregulation of Fas is required for both lymphoma development and lymphoma cell survival to evade immune cytotoxicity. CD40 signal activation significantly restored Fas expression and thereby induced apoptosis after Fas ligand treatment in both mouse and human lymphoma cells. Nevertheless, certain human lymphoma cell lines were found to be resistant to Fas-mediated apoptosis, with Livin (melanoma inhibitor of apoptosis protein; ML-IAP) identified as a driver of such resistance. High expression of Livin and low expression of Fas were associated with poor prognosis in patients with aggressive non-Hodgkin's lymphoma. Livin expression was tightly driven by bromodomain and extraterminal (BET) proteins BRD4 and BRD2, suggesting that Livin expression is epigenetically regulated in refractory lymphoma cells to protect them from Fas-mediated apoptosis. Accordingly, the combination of CD40-mediated Fas restoration with targeting of the BET proteins-Livin axis may serve as a promising immunotherapeutic strategy for refractory B-cell lymphoma. SIGNIFICANCE: These findings yield insights into identifying risk factors in refractory lymphoma and provide a promising therapy for tumors resistant to Fas-mediated antitumor immunity. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/20/4439/F1.large.jpg.
EIF4A3-induced circular RNA ASAP1 promotes tumorigenesis and temozolomide resistance of glioblastoma via NRAS/MEK1/ERK1–2 signaling
Authors: Yutian Wei, Chenfei Lu, Peng Zhou, Lin Zhao, Xiao Lyu, Jianxing Yin, ZhuMei Shi, Yongping You
Journal: Neuro-Oncology (2020)

Abstract Background Acquired chemoresistance is a major challenge in the clinical treatment of glioblastoma (GBM). Circular RNAs have been verified to play a role in tumor chemoresistance. However, the underlying mechanisms remain unclear. The aim of this study was to elucidate the potential role and molecular mechanism of circular (circ)RNA ADP-ribosylation factor GTPase activating proteins with Src homology 3 domain, ankyrin repeat and Pleckstrin homology domain 1 (circASAP1) in temozolomide (TMZ) resistance of GBM. Methods We analyzed circRNA alterations in recurrent GBM tissues relative to primary GBM through RNA sequencing. Real-time quantitative reverse transcription PCR verified the expression of circASAP1 in tissues and cells. Knockdown and overexpressed plasmids were used to evaluate the effect of circASAP1 on GBM cell proliferation and TMZ-induced apoptosis. Mechanistically, fluorescent in situ hybridization, dual-luciferase reporter, and RNA immunoprecipitation assays were performed to confirm the regulatory network of circASAP1/miR-502-5p/neuroblastoma Ras (NRAS). An intracranial tumor model was used to verify our findings in vivo. Results CircASAP1 expression was significantly upregulated in recurrent GBM tissues and TMZ-resistant cell lines. CircASAP1 overexpression enhanced GBM cell proliferation and TMZ resistance, which could be reduced by circASAP1 knockdown. Further experiments revealed that circASAP1 increased the expression of NRAS via sponging miR-502-5p. Moreover, circASAP1 depletion effectively restored the sensitivity of TMZ-resistant xenografts to TMZ treatment in vivo. Conclusions Our data demonstrate that circASAP1 exerts regulatory functions in GBM and that competing endogenous (ce)RNA-mediated microRNA sequestration might be a potential therapeutic strategy for GBM treatment.
Prospective Multicenter Study of Early Antiviral Therapy in Liver and Kidney Transplant Recipients of HCV‐Viremic Donors
Authors: Norah A. Terrault, James Burton, Mark Ghobrial, Elizabeth Verna, Johanna Bayer, Christina Klein, David Victor, Sumit Mohan, James Trotter, Jennifer Dodge, Claus U. Niemann, Raymond A. Rubin
Journal: Hepatology (2020)

Organs from hepatitis C virus (HCV)-viremic donors have been used in HCV-uninfected recipients (D+/R-), but the optimal treatment approach has not been defined. We evaluated the kinetics of HCV infection following transplant in D+/R- kidney-transplant (KT) and liver-transplant (LT) recipients when a preemptive antiviral strategy was used.Six US transplant programs prospectively treated D+/R- primary LT and KT recipients with sofosbuvir-velpastasvir for 12 weeks starting once viremia was confirmed following transplant and the patients were judged to be clinically stable, including estimated glomerular filtration rate >30 mL/min. Primary endpoints were sustained virologic response at 12 weeks following transplant and safety (assessed by proportion of treatment-related adverse and serious adverse events). Of the 24 patients transplanted (13 liver, of whom 2 had prior-treated HCV infection; 11 kidney), 23 became viremic after transplant. The median (interquartile range) time from transplant to start of antiviral therapy was 7.0 (6.0, 12.0) versus 16.5 (9.8, 24.5) days, and the median (interquartile range) HCV-RNA level 3 days after transplant was 6.5 (3.9, 7.1) versus 3.6 (2.9, 4.0) log10 IU/mL in LT versus KT recipients, respectively. By week 4 of treatment, 10 of 13 (77%) LT, but only 2 of 10 (20%) KT, had undetectable HCV RNA (P = 0.01). At the end of treatment, all LT recipients were HCV RNA-undetectable, whereas 3 (30%) of the kidney recipients still had detectable, but not quantifiable, viremia. All achieved sustained virologic response at 12 weeks following transplant (lower 95% confidence interval bound: 85%). Serious adverse events considered possibly related to treatment were antibody-mediated rejection, biliary sclerosis, cardiomyopathy, and graft-versus-host disease, with the latter associated with multiorgan failure, premature treatment discontinuation, and death.Despite differing kinetics of early HCV infection in liver versus non-liver recipients, a preemptive antiviral strategy is effective. Vigilance for adverse immunologic events is warranted.
From doctors as patients: a manifesto for tackling persisting symptoms of covid-19
Authors: Nisreen A Alwan, Emily Attree, Jennifer Mary Blair, Debby Bogaert, Mary-Ann Bowen, John Boyle, Madeleine Bradman, Tracy Ann Briggs, Sarah Burns, Daniel Campion, Katherine Cushing, Brendan Delaney, Chris Dixon, Grace E Dolman, Caitriona Dynan, Ian M Frayling, Nell Freeman-Romilly, Iulia Hammond, Jenny Judge, Linn Järte, Amali Lokugamage, Nathalie MacDermott, Mairi MacKinnon, Visita Majithia, Tanya Northridge, Laura Powell, Clare Rayner, Ginevra Read, Ekta Sahu, Claudia Shand, Amy Small, Cara Strachan, Jake Suett, Becky Sykes, Sharon Taylor, Kevin Thomas, Margarita Thomson, Alexis Wiltshire, Victoria Woods
Journal: BMJ (2020)

We write as a group of doctors affected by persisting symptoms of suspected or confirmed covid-19.We aim to share our insights from both personal experience of the illness and our perspective as physicians.Tackling this problem will involve collaboration between politicians, healthcare services, public health professionals, scientists, and society.We call for the following principles to be used so that the best possible outcomes can be achieved for all people affected by persisting symptoms of covid-19.
Ischemia and Infarction in Isolated Chronic Total Coronary Artery Occlusion Assessed by Cardiovascular Magnetic Resonance
Authors: Ahmed M.S.E.K. Abdelaty, Charley A. Budgeon, Simon Hetherington, Ciaran Grafton-Clarke, Andrew Ladwiniec, Anthony H. Gershlick, Gerry P. McCann, Jayanth R. Arnold
Journal: JACC. Cardiovascular imaging (2020)
Afterload induced changes on left ventricular contractility are preload independent and mediated by CaMK II- the Anrep effect revisited
Authors: J.C. Reil, G.H. Reil, M. Hohl, P. Steendijk, D. Lavall, C. Maack, J. Backs, H.R. Neuberger, M. Boehm
Journal: European Journal of Heart Failure (2015)
Partha Kar: NICE needs better support to do its job
Authors: Partha Kar
Journal: BMJ (2020)

The National Institute for Health and Care Excellence (NICE) is simultaneously vilified and admired.The way it assesses evidence, the way it's been set up and structured, and the very fact it exists have all been criticised and praised, with some asking (unfairly, I'd say) whether it's relevant in today's healthcare system.
Noncanonical IL6 Signaling-Mediated Activation of YAP Regulates Cell Migration and Invasion in Ovarian Clear Cell Cancer
Authors: Walid J. Azar, Elizabeth L. Christie, Chris Mitchell, David S. Liu, George Au-Yeung, David D.L. Bowtell
Journal: Cancer Research (2020)

Ovarian clear cell adenocarcinoma (OCCA) is characterized by a particularly poor response to conventional chemotherapy and a short overall survival time in women with established disease. The development of targeted treatments for OCCA relies on a better understanding of its molecular characteristics. IL6 is strongly expressed in OCCA and may therefore provide a novel therapeutic target. Here we use CRISPR/Cas9 and conditional short hairpin interfering RNA to perform loss-of-function studies in human OCCA cell lines to explore the requirement for IL6 in vitro and in vivo. While reduction of IL6 expression exerted limited effects in vitro, its attenuation significantly impaired tumor growth and neovascularization in vivo. In contrast to typical signaling via STAT3, IL6 in OCCA signaled via a noncanonical pathway involving gp130, Src, and the Hippo pathway protein YAP. A high-throughput combination drug screen identified agents that enhanced cell killing following reduction of IL6 signaling. Intersection of screen hits obtained from two cell lines and orthogonal approaches to attenuation of IL6 yielded AKT and EGFR inhibitors as enhancers of the inhibitory monoclonal IL6 receptor antibody tocilizumab. This study defines for the first time the requirements for, and mechanisms of, signaling by IL6 in human OCCA cell lines and identifies potential combinatory therapeutic approaches. Given the molecular diversity of OCCA, further in vitro and in vivo studies are warranted to determine whether such approaches will overcome the limited efficacy of tocilizumab observed in ovarian cancer to date. SIGNIFICANCE: This study defines the requirements for and mechanisms of noncanonical signaling by IL6 in human ovarian clear cell adenocarcinoma cell lines and identifies combinatory therapeutic approaches to be explored clinically.
FRI0037 Results of a pivotal (phase iii) placebo and active comparator controlled efficacy trial of rofecoxib 25 and 50 mg in adult patients with rheumatoid arthritis (ra)
Authors: KE Truitt, PP Guesens, LM DeTora, PL Zhao, B Kress
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To determine the efficacy and safety profile of rofecoxib 25 mg and 50 mg versus placebo and naproxen in patients with RA. <h3>Methods</h3> 1058 RA patients were randomised in a double-blind fashion to: placebo (n = 299), rofecoxib 25 mg (n = 315), 50 mg (n = 297), or naproxen 1000 mg (given as 500 mg bid; n = 147). Eligible patients were chronic NSAID users and demonstrated a clinical worsening or flare upon withdrawal of prestudy NSAID(s). Efficacy assessments included all components of the ACR core set. Four endpoints were prespecified as primary: the patient and investigator global assessments of disease activity and counts of tender and swollen joints. The proportion of patients meeting the ACR20 criteria, patient assessment of pain, and a modified HAQ score were key secondary measurements. Safety was assessed based on adverse experience reporting by investigators (particularly discontinuations due to adverse experiences [AEs]) and routine laboratory and vital sign measurements. <h3>Results</h3> After 12 weeks, patients receiving rofecoxib 25 mg, 50 mg, and naproxen showed similar improvements compared with placebo: a 3 to 4- joint reduction in the number of tender joints; a 1-joint reduction in the number of swollen joints; a 7 to 10 mm improvement on the patient global assessment (1 -100 mm VAS) and a 0.3 to 0.4-unit reduction on the investigator global assessment (0 to 4 Likert scale). All improvements were statistically significant (p &lt; 0.05) versus placebo, except naproxen on swollen joint count. For key secondary measurements, all three active treatments showed a &gt;10% difference (p &lt; 0.05) versus placebo for the proportion of patients meeting the ACR20 criteria. All active treatments showed a significant difference from placebo, consistent with improvement, for the modified HAQ and the patient assessment of pain. No statistically significant differences were noted between 25 mg and 50 mg rofecoxib or between naproxen and either rofecoxib group for any efficacy measurement. Fewer patients discontinued due to AEs in the rofecoxib 25 mg group (3.8%) compared with the other active treatment groups (~8%) and placebo (4.7%). <h3>Conclusion</h3> Overall, improvements with 25 mg rofecoxib were similar to those with 50 mg rofeocixb and naproxen but with improved tolerability, supporting the use of 25 mg rofecoxib for treating the signs and symptoms of RA in adults. This study was supported by a grant from Merck and Co., Inc.
Health System Reform in Mexico 2 - Priority setting for health interventions in Mexico's system of Social Protection in Health
Authors: Eduardo Gonzalez-Pier, Cristina Gutierrez-Delgado, Gretchen Stevens, Mariana Barraza-Llorens, Raul Porras-Condey, Natalie Carvalho, Kristen Loncich, Rodrigo H Dias, Sandeep Kulkarni, Anna Casey, Yuki Murakami, Majid Ezzati, Joshua A Salomon
Journal: The Lancet (2006)
Challenges Facing Family Practice and Primary Care—Reply
Authors: Kevin Grumbach, Thomas Bodenheimer
Journal: JAMA (2003)

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 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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
Sympathetic nervous tone limits the development of myeloid-derived suppressor cells
Authors: James T. Nevin, Marmar Moussa, William L. Corwin, Ion I. Mandoiu, Pramod K. Srivastava
Journal: Science Immunology (2020)

Sympathetic nerves that innervate lymphoid organs regulate immune development and function by releasing norepinephrine that is sensed by immune cells via their expression of adrenergic receptors. Here, we demonstrate that ablation of sympathetic nervous system (SNS) signaling suppresses tumor immunity, and we dissect the mechanism of such immune suppression. We report that disruption of the SNS in mice removes a critical α-adrenergic signal required for maturation of myeloid cells in normal and tumor-bearing mice. In tumor-bearing mice, disruption of the α-adrenergic signal leads to the accumulation of immature myeloid-derived suppressor cells (MDSCs) that suppress tumor immunity and promote tumor growth. Furthermore, we show that these SNS-responsive MDSCs drive expansion of regulatory T cells via secretion of the alarmin heterodimer S100A8/A9, thereby compounding their immunosuppressive activity. Our results describe a regulatory framework in which sympathetic tone controls the development of innate and adaptive immune cells and influences their activity in health and disease.
Identifying Recommendations for Stopping or Scaling Back Unnecessary Routine Services in Primary Care
Authors: Eve A. Kerr, Mandi L. Klamerus, Adam A. Markovitz, Jeremy B. Sussman, Steven J. Bernstein, Tanner J. Caverly, Roger Chou, Lillian Min, Sameer D. Saini, Shannon E. Lohman, Sarah E. Skurla, David E. Goodrich, Whit Froehlich, Timothy P. Hofer
Journal: JAMA Internal Medicine (2020)

Much of health care involves established, routine use of medical services for chronic conditions or prevention. Stopping these services when the evidence changes or if the benefits no longer outweigh the risks is essential. Yet, most guidelines focus on escalating care and provide few explicit recommendations to stop or scale back (ie, deintensify) treatment and testing.To develop a systematic, transparent, and reproducible approach for identifying, specifying, and validating deintensification recommendations associated with routine adult primary care.A focused review of existing guidelines and recommendations was completed to identify and prioritize potential deintensification indications. Then, 2 modified virtual Delphi expert panels examined the synthesized evidence, suggested ways that the candidate recommendations could be improved, and assessed the validity of the recommendations using the RAND/UCLA Appropriateness Method. Twenty-five physicians from Veterans Affairs and US academic institutions with knowledge in relevant clinical areas (eg, geriatrics, primary care, women's health, cardiology, and endocrinology) served as panel members.Validity of the recommendations, defined as high-quality evidence that deintensification is likely to improve patient outcomes, evidence that intense testing and/or treatment could cause harm in some patients, absence of evidence on the benefit of continued or repeated intense treatment or testing, and evidence that deintensification is consistent with high-quality care.A total of 409 individual recommendations were identified representing 178 unique opportunities to stop or scale back routine services (eg, stopping population-based screening for vitamin D deficiency and decreasing concurrent use of opioids and benzodiazepines). Thirty-seven recommendations were prioritized and forwarded to the expert panels. Panelists reviewed the evidence and suggested modifications, resulting in 44 recommendations being rated. Overall, 37 recommendations (84%) were considered to be valid, as assessed by the RAND/UCLA Appropriateness Method.In this study, a total of 178 unique opportunities to deintensify routine primary care services were identified, and 37 of these were validated as high-priority deintensification recommendations. To date, this is the first study to develop a model for identifying, specifying, and validating deintensification recommendations that can be implemented and tracked in clinical practice.
A Novel Hybrid Silk Fibroin/Polyurethane Arteriovenous Graft for Hemodialysis: Proof‐of‐Concept Animal Study in an Ovine Model
Authors: Stefania Adele Riboldi, Matteo Tozzi, Mara Bagardi, Giuliano Ravasio, Giorgio Cigalino, Luca Crippa, Solange Piccolo, Amal Nahal, Mattia Spandri, Valentina Catto, Matteo Tironi, Francesco Giovanni Greco, Andrea Remuzzi, Fabio Acocella
Journal: Advanced Healthcare Materials (2020)

Abstract To solve the problem of vascular access failure, a novel semi‐degradable hybrid vascular graft, manufactured by electrospinning using silk fibroin and polyurethane (Silkothane), has been previously developed and characterized in vitro. This proof‐of‐concept animal study aims at evaluating the performances of Silkothane grafts in a sheep model of arteriovenous shunt, in terms of patency and short‐term remodeling. Nine Silkothane grafts are implanted between the common carotid artery and the external jugular vein of nine sheep, examined by palpation three times per week, by echo‐color Doppler every two weeks, and euthanized at 30, 60, and 90 days ( N = 3 per group). At sacrifice, grafts are harvested and submitted for histopathology and/or scanning electron microcopy (SEM). No cases of graft‐related complications are recorded. Eight of nine sheep (89%) show 100% primary unassisted patency at the respective time of sacrifice (flow rate 1.76 ± 0.61 L min −1 , one case of surgery‐related thrombosis excluded). Histopathology and SEM analysis evidence signs of inflammation and pseudointima inside the graft lumen, especially at the venous anastomosis; however, endoluminal stenosis never impairs the functionality of the shunt and coverage by endothelial cells is observed. In this model, Silkothane grafts grant safety and 100% patency up to 90 days.
Abstract 17090: Perinatal Coxsackievirus B4 Infection Leads To Preferential Damage Of The Left Ventricle
Authors: Vipul Sharma, Sara N Rohrbough, Lisa S Goessling, Anoop K Brar, Pirooz Eghtesady
Journal: Circulation (2019)

Introduction: Coxsackieviruses, particularly serotype B (CVB) account for up to half of all clinical cases of pediatric myocarditis and have been associated with congenital heart defects (CHD). We ...