tbuckley/cabot-search huggingface dataset:
Nucleic acid polymer REP 2139 and nucleos(T)ide analogues act synergistically against chronic hepadnaviral infection in vivo in Pekin ducks
Authors: Jonathan Quinet, Catherine Jamard, Madeleine Burtin, Matthieu Lemasson, Sylviane Guerret, Camille Sureau, Andrew Vaillant, Lucyna Cova
Journal: Hepatology (2017)

Nucleic acid polymer (NAP) REP 2139 treatment was shown to block the release of viral surface antigen in duck HBV (DHBV)‐infected ducks and in patients with chronic HBV or HBV/hepatitis D virus infection. In this preclinical study, a combination therapy consisting of REP 2139 with tenofovir disoproxil fumarate (TDF) and entecavir (ETV) was evaluated in vivo in the chronic DHBV infection model. DHBV‐infected duck groups were treated as follows: normal saline (control); REP 2139 TDF; REP 2139 + TDF; and REP 2139 + TDF + ETV. After 4 weeks of treatment, all animals were followed for 8 weeks. Serum DHBsAg and anti‐DHBsAg antibodies were monitored by enzyme‐linked immunosorbent assay and viremia by qPCR. Total viral DNA and covalently closed circular DNA (cccDNA) were quantified in autopsy liver samples by qPCR. Intrahepatic DHBsAg was assessed at the end of follow‐up by immunohistochemistry. On‐treatment reduction of serum DHBsAg and viremia was more rapid when REP 2139 was combined with TDF or TDF and ETV, and, in contrast to TDF monotherapy, no viral rebound was observed after treatment cessation. Importantly, combination therapy resulted in a significant decrease in intrahepatic viral DNA (&gt;3 log) and cccDNA (&gt;2 log), which were tightly correlated with the clearance of DHBsAg in the liver. Conclusion: Synergistic antiviral effects were observed when REP 2139 was combined with TDF or TDF + ETV leading to control of infection in blood and liver, associated with intrahepatic viral surface antigen elimination that persisted after treatment withdrawal. Our findings suggest the potential of developing such combination therapy for treatment of chronically infected patients in the absence of pegylated interferon. (H epatology 2018;67:2127‐2140).
Understanding How to Improve Quality and Value for Patients With Acute Myocardial Infarction
Authors: Jason H. Wasfy, Robert W. Yeh
Journal: JAMA Cardiology (2017)

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 Cardiology 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 Cardiology journal
The Locomotion Tug-of-War: Cholinergic and Dopaminergic Interactions Outside the Striatum
Authors: Konstantin Kaganovsky, Jun B. Ding
Journal: Neuron (2017)

In this issue of Neuron, Moehle et al. (2017) demonstrate that presynaptic muscarinic receptors counteract the effects of dopamine in an output nucleus of the basal ganglia. They provide intracellular, anatomical, and network-level mechanisms for this cholinergic-dopaminergic interplay.
Abstract 16192: Abnormal Sinus Node Response Identifies Diabetics at Increased Risk of Sudden Cardiac Arrest
Authors: Yang Yang, Aapo L Aro, Sandeep G Nair, Reshmy Jayaraman, Kyndaron Reinier, Carmen Teodorescu, Audrey Uy-Evanado, Hirad Yarmohammadi, Jonathan Jui, Sumeet S Chugh
Journal: Circulation (2016)

Introduction: Diabetes is an increasingly prevalent disease that is independently associated with increased risk of sudden cardiac arrest (SCA), with an urgent need to identify novel risk markers. ...
Fibrinolytic Pathways In Interleukin-17A-induced lung Injury
Authors: Sreerama Shetty, Venkadesa Perumal, Nivedita Tiwari, Amarnath Marudamuthu, Shwetha Kumari, Seong Park, Rashmi Shetty
Journal: Journal of Allergy and Clinical Immunology (2018)
Presence of Medical Students and Length of Stay in the Emergency Department: Presence of Medical Students and Length of Stay in the Emergency Department—Reply
Authors: Patricia McGettigan, Jean McKendree, Kimon L. H. Ioannides, Benjamin S. Abella, Kevin R. Scott
Journal: JAMA (2016)

EnglishMr Ioannides and colleagues1 examined 15 years of emergency department (ED) data and determined that length of stay was 5 minutes longer when medical students were present vs when they were absent. We agree that this is unlikely to be clinically significant. The authors provided substantial ED data, acknowledged the absence of visit-level data, but omitted what the students actually did during their clerships. They stated “… students were assigned approximately nine 8- to-12-hour shifts over 3 weeks, during which they were expected to evaluate and follow-up several patients presenting to the ED.” EnglishThe setting of Drs McGettigan and McKendree’s study evaluating the association between the presence of students and outcomes was a rehabilitation unit,1 which is a very different setting from the EDs of our study. The ED comprises inherently dissimilar patient encounters requiring rapid evaluation, decision making, and intervention for undifferentiated acute complaints.
Abstract 17902: Cost effectiveness of Coronary CTA or Vasodilator Stress Cardiac MRI for Determination of Invasive Angiography Following Equivocal Nuclear SPECT
Authors: Marcus Y Chen, W. P Bandettini, Sujata Shanbhag, Li-Yueh Hsu, Andrew E Arai
Journal: Circulation (2012)

Objective:  To assess the cost effectiveness of coronary CTA or vasodilator stress cardiac MRI (CMR) for determining the need of invasive angiography in patients with suspected coronary artery disease (CAD) and an equivocal SPECT.   Background:  More than 10 million cardiac nuclear SPECT studies are performed in the United States per year and up to 10% are considered equivocal. The rate of obstructive CAD through invasive angiography with prior equivocal non-invasive testing is only 27%. The real-world cost effectiveness of CTA or CMR functioning as a gatekeeper to invasive angiography is not known in patients with a prior equivocal SPECT.   Methods:  We prospectively enrolled 107 subjects with suspected CAD and an equivocal SPECT exam within 90 days. Vasodilator stress CMR was performed on a 1.5 Tesla scanner and was classified as ischemic or normal. CTA was performed on a 320 row system and was classified as obstructive CAD (≥50% or unevaluable) or non-obstructive. Studies were read blinded. Subjects were followed for one year to assess for downstream cardiovascular testing or major adverse cardiovascular events. Costs for CTA and CMR were estimated based on 2012 Medicare reimbursement rates plus downstream testing including catheterization. The reference comparator cost was determined assuming invasive angiography in all subjects with an equivocal SPECT and avoiding “layered” non-invasive imaging.   Results:  Subjects averaged 56.1±11.9 years and 53% were men. Follow-up duration averaged 397±113 days and was obtained in all subjects. Of the 107 subjects, there were 18 obstructive and one unevaluable CTA. There were 15 ischemic and 3 non-diagnostic CMRs. There were 4 false negative CMRs and each had obstructive CTA confirmed by invasive angiography. No cardiovascular events occurred during the follow-up period in subjects with non-obstructive CTA. By utilizing a non-invasive test as a gatekeeper to invasive angiography, CTA had an overall cost savings of 51% and CMR had a 21% savings compared with an invasive strategy.   Conclusion:  Layered non-invasive testing with CTA or CMR is more cost effective than an invasive strategy in patients with equivocal SPECT scans. Cardiac CTA has additional cost savings primarily due to lower expenses and higher sensitivity than CMR.
CD44 is required for the pathogenesis of experimental crescentic glomerulonephritis and collapsing focal segmental glomerulosclerosis
Authors: Jennifer Eymael, Shagun Sharma, Markus A. Loeven, Jack F. Wetzels, Fieke Mooren, Sandrine Florquin, Jeroen K. Deegens, Brigith K. Willemsen, Vikram Sharma, Toin H. van Kuppevelt, Marinka A. Bakker, Tammo Ostendorf, Marcus J. Moeller, Henry B. Dijkman, Bart Smeets, Johan van der Vlag
Journal: Kidney International (2017)
Darzi to lead new independent review of the NHS and social care
Authors: Gareth Iacobucci
Journal: BMJ (2017)

The UK surgeon and former health minister Ara Darzi is to lead a new independent review into the future of the NHS and social care.

The review will examine solutions for protecting and strengthening services in the face of current pressures as the NHS approaches its 70th year. It follows a decade which has seen an unprecedented slowdown in NHS funding and big cuts to social care budgets, which have combined to cause treatment rationing, longer waiting times, and deteriorating financial performance.

The government has faced growing calls1 to launch a cross party review into the future of the …
Intensified Therapy with Inhaled Corticosteroids and Long-Acting β<sub>2</sub>-Agonists at the Onset of Upper Respiratory Tract Infection to Prevent Chronic Obstructive Pulmonary Disease Exacerbations. A Multicenter, Randomized, Double-Blind, Placebo-controlled Trial
Authors: Daiana Stolz, Hans H. Hirsch, Daniel Schilter, Renaud Louis, Janko Rakic, Lucas Boeck, Eleni Papakonstantinou, Christian Schindler, Leticia Grize, Michael Tamm
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

The efficacy of intensified combination therapy with inhaled corticosteroids (ICS) and long-acting β2-agonists (LABA) at the onset of upper respiratory tract infection (URTI) symptoms in chronic obstructive pulmonary disease (COPD) is unknown.To evaluate whether intensified combination therapy with ICS/LABA, at the onset of URTI symptoms, decreases the incidence of COPD exacerbation occurring within 21 days of the URTI.A total of 450 patients with stable, moderate to very severe COPD, were included in this investigator-initiated and -driven, double-blind, randomized, placebo-controlled study. At inclusion, patients were assigned to open-labeled low-maintenance dose ICS/LABA. Each patient was randomized either to intensified-dose ICS/LABA or placebo and instructed to start using this medication only in case of a URTI, at the onset of symptoms, twice daily, for 10 days.The incidence of any exacerbation following a URTI was not significantly decreased in the ICS/LABA group, as compared with placebo (14.6% vs. 16.2%; hazard ratio, 0.77; 95% confidence interval, 0.46-1.33; P = 0.321) but the risk of severe exacerbation was decreased by 72% (hazard ratio, 0.28; 95% confidence interval, 0.11-0.74%; P = 0.010). In the stratified analysis, effect size was modified by disease severity, fractional exhaled nitric oxide, and the body mass index-airflow obstruction-dyspnea, and exercise score. Compared with the stable period, evidence of at least one virus was significantly more common at URTI, 10 days after URTI, and at exacerbation.Intensified combination therapy with ICS/LABA for 10 days at URTI onset did not decrease the incidence of any COPD exacerbation but prevented severe exacerbation. Patients with more severe disease had a significant risk reduction for any exacerbation. Clinical trial registered with www.isrctn.com (ISRCTN45572998).
Subgroup efficacy evaluation of the AE37 HER2 vaccine in breast cancer patients in the adjuvant setting.
Authors: Kaitlin M. Peace, Elizabeth Ann Mittendorf, Sonia A. Perez, Panagiotis Tzonis, Nikolaos Fragkiskos Pistamaltzian, Eleftheria A Anastasopoulou, Timothy J. Vreeland, Diane F Hale, Guy T Clifton, Jennifer Keating Litton, Eric von Hofe, Alexandros Ardavanis, Michael Papamichail, George Earl Peoples
Journal: Journal of Clinical Oncology (2017)

3088 Background: AE37 is a Ii-Key hybrid of the HER2 peptide AE36 (HER2 776-790 ), which stimulates peptide-specific T cells. We have completed the active phase of a prospective, randomized, multi-center, phase II trial of the AE37 vaccine in the adjuvant setting. The primary analysis, performed after a median follow up (f/u) of 25 months (mo), did not show a significant difference in disease free survival (DFS) between vaccinated and control patients (pts). However, demonstrating the efficacy of cancer vaccines may require more time than other therapies, especially in malignancies with relatively late recurrences like breast cancer. Here, we present updated efficacy data after extended f/u in subgroups of pts stratified by clinicopathologic characteristics. Methods: Clinically disease-free, node positive or high-risk node negative pts with any level of HER2 expression were randomized to receive AE37 + GM-CSF (VG) or GM-CSF alone (CG) following standard of care therapy. Pts received 6 monthly intradermal inoculations during the primary vaccine series (PVS) followed by 4 boosters administered every 6 mo. Kaplan Meier and log rank analyses were performed from the time of the first inoculation in pts who completed at least the PVS, according to stage, node status, tumor size, HER2 expression and ER/PR status. Results: There were no clinicopathologic differences between groups in the 298 enrolled pts (VG = 153, CG = 145). The vaccine is safe and well tolerated. After a median f/u of 55 mo, there was a trend toward improved DFS in the VG among stage IIB/III pts (VG, n = 73, DFS 82% vs CG, n = 61, 67%, HR = 0.48, p = 0.06) and those with low HER2 expression (HER2 LE, VG, n = 68, 89% vs CG, n = 66, 51%, HR = 0.47, p = 0.1). Improved DFS in the VG was documented in patients with both stage IIB/III disease and HER2 LE (VG, n = 39, 90% vs CG, n = 38, 32%, HR 0.3, p = 0.02) and triple negative (TNBC) pts (VG, n = 21, 89% vs CG, n = 21, 0%, HR 0.26, p = 0.05). Conclusions: The AE37 vaccine is safe and well tolerated and has statistically significant efficacy in stage IIB/III pts with HER2 LE and in TNBC pts. This justifies further evaluation in a phase III study enrolling stage IIb/III pts not eligible for trastuzumab treatment and the very high risk TNBC group. Clinical trial information: NCT00524277.
An open-label, phase Ib study of NEO-PV-01 + adjuvant with nivolumab in patients with melanoma, non-small cell lung carcinoma, or transitional cell carcinoma of the bladder.
Authors: Aung Naing, Siwen Hu-Lieskovan, Ramaswamy Govindan, Kim Allyson Margolin, Melissa Ann Moles, Richard Gaynor, Matthew Jordan Goldstein, Patrick Alexander Ott
Journal: Journal of Clinical Oncology (2017)

TPS3116 Background: Cancer cells contain unique DNA mutations that result in altered amino acid sequences known as neoantigens. Growing evidence supports a central role for neoantigens as targets for tumor directed immune responses. Tumor mutational burden as well as neoantigen load have been associated with anti-tumor activity of checkpoint inhibitors. Vaccines targeting neoantigens offer a highly specific way to induce de novo T cell reactivity and to expand existing T cell responses against neoantigens. Here, we describe NEO-PV-01, a personalized, neoantigen vaccine designed specifically for the molecular profile of each individual’s tumor. Methods: NT-001 is a single-arm, phase IB study designed to evaluate the safety of administering NEO-PV-01 + adjuvant (Poly-ICLC) with nivolumab in patients with advanced melanoma, smoking-associated non-small cell lung carcinoma, or transitional cell carcinoma of the bladder who have received no more than one prior systemic treatment. Patients undergo a baseline tumor biopsy and HLA typing. DNA and RNA sequencing is performed on the tumors as well as peripheral blood to serve as normal DNA controls. On Day 1, patients begin treatment with nivolumab at a dose of 240 mg IV while their customized vaccine is being generated. Each vaccine is custom designed for the individual patient and contains up to 20 peptides 14-35 amino acids in length. The peptides are pooled into four groups and mixed with Poly-ICLC at the time of administration. Beginning at Week 12, patients receive five priming immunizations over a three-week period followed by booster vaccinations at Weeks 19 and 23. The primary endpoint is safety. Secondary endpoints are ORR, CBR, PFS, and assessment of response conversion between Week 12 and Week 24. Exploratory endpoints include extensive immune monitoring. Clinical trial information: NCT02897765.
Abstract 460: β <sub>1</sub> -Adrenergic Receptor O-glycosylation Regulates Receptor N-terminal Cleavage and Signaling Responses in Cardiomyocytes
Authors: Misun Park, Yang K Xiang, Gopireddy R Reddy, Gerd Wallukat, Susan F Steinberg
Journal: Circulation Research (2016)

β1-adrenergic receptors (β1ARs) mediate catecholamine actions in cardiomyocytes by coupling to both Gs/cAMP-dependent and Gs-independent/growth-regulatory pathways. Recent efforts to structurally characterize β1ARs have focused on the ligand binding sites in transmembrane helices and effector docking sites in the intracellular loops and C-terminus. The notion that the β1AR extracellular N-terminus (which is a substrate for both N- and O-linked glycosylation and a target for proteolytic cleavage) functions as a structural determinant of β1AR activation has never been considered. This study takes advantage of site-directed mutagenesis and expression studies in Chinese Hamster ovary cells that harbor a reversible glycosylation defect to map β1ARs O-glycosylation sites to Ser37/Ser41 and show that O-glycosylation at these sites prevents β1AR N-terminal cleavage. We then used an adenoviral overexpression approach to show that both full-length fully-glycosylated β1ARs (β1AR-FL) and N-terminally truncated glycosylation-defective β1ARs (β1AR-Δ52) increase cAMP accumulation and activate the ERK-MAPK signaling cascade in cardiomyocytes. However, isoproterenol-dependent cAMP accumulation is markedly enhanced, and ERK activation is markedly attenuated, in cardiomyocytes that express β1AR-Δ52, compared with β1AR-FL cultures. The conclusion that β1ARs are stabilized in a conformation that is biased toward the cAMP pathway as a result of N-terminal truncation gains further support from additional studies showing that agonistic β1AR autoantibodies induce a more rapid and robust increase in membrane PKA activity in cells that express glycosylation-defective β1ARs, compared to cells that express full-length glycosylated β1ARs. These results identify a novel role for O-glycosylation as a structural determinant of β1AR responsiveness in the heart.
Optical Analysis of Glioma: Fourier-Transform Infrared Spectroscopy Reveals the <i>IDH1</i> Mutation Status
Authors: Ortrud Uckermann, Tareq A. Juratli, Roberta Galli, Marina Conde, Ralf Wiedemuth, Dietmar Krex, Kathrin Geiger, Achim Temme, Gabriele Schackert, Edmund Koch, Gerald Steiner, Matthias Kirsch
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Somatic mutations in the human cytosolic isocitrate dehydrogenase 1 (IDH1) gene cause profound changes in cell metabolism and are a common feature of gliomas with unprecedented predictive and prognostic impact. Fourier-transform infrared (FT-IR) spectroscopy addresses the molecular composition of cells and tissue and was investigated to deduct the IDH1 mutation status. Experimental Design: We tested the technique on human cell lines that were transduced with wild-type IDH1 or mutated IDH1 and on 34 human glioma samples. IR spectra were acquired at 256 positions from cell pellets or tissue cryosections. Moreover, IR spectra were obtained from fresh, unprocessed biopsies of 64 patients with glioma. Results: IDH1 mutation was linked to changes in spectral bands assigned to molecular groups of lipids and proteins in cell lines and human glioma. The spectra of cryosections of brain tumor samples showed high interpatient variability, for example, bands related to calcifications at 1113 cm−1. However, supervised classification recognized relevant spectral regions at 1103, 1362, 1441, 1485, and 1553 cm−1 and assigned 88% of the tumor samples to the correct group. Similar spectral positions allowed the classification of spectra of fresh biopsies with an accuracy of 86%. Conclusions: Here, we show that vibrational spectroscopy reveals the IDH1 genotype of glioma. Because it can provide information in seconds, an implementation into the intraoperative workflow might allow simple and rapid online diagnosis of the IDH1 genotype. The intraoperative confirmation of IDH1 mutation status might guide the decision to pursue definitive neurosurgical resection and guide future in situ therapies of infiltrative gliomas. Clin Cancer Res; 24(11); 2530–8. ©2017 AACR. See related commentary by Hollon and Orringer, p. 2467
Abstract 52: The Gut Microbiome Alters Susceptibility to Coronary Inflammation in Kawasaki Disease
Authors: Rae S Yeung, Daniel Chan, Trang T Duong
Journal: Circulation (2015)

The gut microbiome has been shown to have immunomodulatory capabilities, and changes in the composition of the microbiome have altered the pathogenesis of inflammatory diseases. In this study, we sought to investigate the effects of the microbiome on the pathogenesis of Kawasaki Disease (KD) using the Lactobacillus cell wall extract (LCWE)-induced coronary arteritis model. Using qPCR on mouse fecal samples, we quantified bacterial communities through the 16S rRNA gene. Animals originating from the same supplier where housed in two independent facilities. There were marked elevations in Bacteroides, Bifidobacteria, Lactobacillus and segmented filamentous bacteria (SFB) and decrease in Clostridia in Facility A compared to Facility B. The transition to the newer Facility B resulted in a reduction in disease induction by LCWE to 26% (25/95), compared to 50% (35/70) at Facility A. Addition of antibiotics to the drinking water to deplete the microbiome reduced disease incidence to 40% (2/5) of mice housed at Facility A compared to 100% (5/5) of untreated mice, suggesting that components of the microbiome are necessary to exacerbate inflammation. To address whether the gut microbiome was sufficient to support disease susceptibility, the cecal contents of the susceptible mice at A were gavaged into the less susceptible mice at B. Recipients of the cecal contents from Facility A had an increased disease incidence of 91% (10/11) compared to 60% (6/10) in control mice which received cecal contents from mice housed in Facility B. We also report elevated levels of IL-17 in the serum of SFB-colonized mice. SFB, known to exacerbate several models of autoimmunity, was completely absent in mice housed at Facility B. Interestingly Th17 and its associated cytokine IL-17 have been associated with acute KD, but its role in pathogenesis remains unclear. Th17 cells have been implicated in autoimmunity, and are also important players in gut homeostasis. Our data provide evidence for the role of the gut microbiome in modulating the immunopathogenesis of KD, pointing to the important interactions of commensal and pathogenic factors as determinants of disease.