tbuckley/cabot-search huggingface dataset:
Pathogenic CARD11 mutations affect B cell development and differentiation through a noncanonical pathway
Authors: Zheng Wei, Yan Zhang, Jingjing Chen, Yu Hu, Pan Jia, Xuelei Wang, Qifang Zhao, Yicong Deng, Ni Li, Yi Zang, Jun Qin, Xiaoming Wang, Wei Lu
Journal: Science Immunology (2019)

Revealing an NF-κB–independent new aspect of CARD11 function by leveraging various pathogenic CARD11 mutants.
An Evaluation of US Food and Drug Administration’s Program to Register HIV Drugs for Use in Resource-Constrained Settings
Authors: Harinder Singh Chahal, Kalli Koukounas, Peter Capella, Ryan Presto, Jeffrey S. Murray, Martin Shimer, Karen Riley, Mary Lou Valdez
Journal: JAMA Network Open (2019)

<h3>Importance</h3> The US Food and Drug Administration (FDA) program to review antiretroviral drugs for use in low-resource settings via the US President’s Emergency Plan for AIDS Relief (PEPFAR) now supports treatment of more than 14 million patients with HIV. However, an in-depth evaluation of the program has not been undertaken. <h3>Objective</h3> To conduct a quantitative analysis of the FDA-reviewed antiretroviral drug applications in order to assess the contributions of PEPFAR and to identify areas for improvement. <h3>Design, Setting, and Participants</h3> A cross-sectional study was conducted of all PEPFAR applications submitted to the FDA from December 1, 2004, to May 31, 2018. The analyses were conducted between October 2018 and February 2019. <h3>Main Outcomes and Measures</h3> Numbers and types of applications reviewed, how long it took for applications to obtain approval or tentative approval (time to registration), how often the FDA issued a complete response letter (CRL) identifying deficiencies precluding application approval or tentative approval and their reasons, and the association between CRLs and time to registration. <h3>Results</h3> Overall, 260 PEPFAR applications for 327 antiretroviral therapies were reviewed by FDA, of which 216 applications (83%) for 272 drugs were authorized for use. Of the 216 authorized applications, 184 applications for 231 drugs remain in active status and, thus, are available for use. Twenty-six percent (56 of 216) of the applications were for pediatric-specific formulations or strengths; the remainder were for adults. For all 216 applications, the median (interquartile range) time to registration was 10.0 (7.0-17.5) months. Thirty-seven percent (95 of 260) of the applications received 1 or more CRLs, resulting in a total of 172 CRLs; most applications received 1 CRL, whereas some were issued up to 6 CRLs. Among all CRLs, 264 deficiency reasons were identified; the most common deficiencies were associated with manufacturing processes (155 [44%]), followed by product labeling (62 [23%]), and failing facility inspections (54 [20%]). Complete response letters were associated with an increased time to registration. Applications without CRLs had a median (interquartile range) time to registration of 9.0 (5.5-12.0) months, whereas those with at least 1 CRL took a median (interquartile range) of 22.0 (14.0-38.0) months (<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> The FDA’s PEPFAR program has made many antiretroviral drugs available for global use. However, FDA and the pharmaceutical companies could take steps to improve the quality of applications submitted to prevent avoidable deficiencies in manufacturing processes and labeling. Further efforts to develop better, easier to use pediatric-specific therapies are needed.
Benign biliary strictures: how we are evolving to the perfect endoscopic strategy
Authors: Arthur Kaffes
Journal: Endoscopy (2019)

Anastomotic biliary strictures are the most common biliary complication of orthotopic liver transplantation. They occur frequently, with a reported incidence of 5 % – 30 % [1]. Endoscopic therapy is accepted as first-line treatment with the classic approach being multiple plastic stent (MPS) placement, balloon dilation, or a combination of these two techniques. The role of single plastic stents is now obsolete, as shown by van Boeckel et al., who published an excellent and comprehensive review that showed the limitation of single plastic stents for benign biliary strictures (BBS) [2]. The durability of single plastic stents is poor, and the adverse events are unacceptably high. Hence, single plastic stent intervention should only be used as an initial approach in very selected cases prior to engaging definite strategies.
Phase II trial of carboplatin, nab-paclitaxel and bevacizumab for advanced non-squamous non-small cell lung cancer (CARNAVAL study; TORG1424/OLCSG1402)
Authors: T. Kubo, N. Nogami, A. Bessho, A. Morita, S. Ikeo, T. Yokoyama, M. Ishihara, T. Honda, N. Fujimoto, S. Murakami, K. Kaira, T. Harada, K. Nakamura, S. Iwasawa, T. Shimokawa, K. Kiura, N. Yamashita, H. Okamoto
Journal: Annals of Oncology (2019)
Is coding a relevant metaphor for building AI?
Authors: Adam Santoro, Felix Hill, David Barrett, David Raposo, Matt Botvinick, Timothy Lillicrap
Journal: Behavioral and Brain Sciences (2019)

Abstract Brette contends that the neural coding metaphor is an invalid basis for theories of what the brain does. Here, we argue that it is an insufficient guide for building an artificial intelligence that learns to accomplish short- and long-term goals in a complex, changing environment.
A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics
Authors: Sabue Mulangu, Lori E. Dodd, Richard T. Davey, Olivier Tshiani Mbaya, Michael Proschan, Daniel Mukadi, Mariano Lusakibanza Manzo, Didier Nzolo, Antoine Tshomba Oloma, Augustin Ibanda, Rosine Ali, Sinaré Coulibaly, Adam C. Levine, Rebecca Grais, Janet Diaz, H. Clifford Lane, Jean-Jacques Muyembe-Tamfum, None the PALM Writing Group
Journal: New England Journal of Medicine (2019)

Although several experimental therapeutics for Ebola virus disease (EVD) have been developed, the safety and efficacy of the most promising therapies need to be assessed in the context of a randomized, controlled trial.
Airway Mucus Hyperconcentration in Non–Cystic Fibrosis Bronchiectasis
Authors: Kathryn A. Ramsey, Alice C. H. Chen, Giorgia Radicioni, Rohan Lourie, Megan Martin, Amy Broomfield, Yong H. Sheng, Sumaira Z. Hasnain, Graham Radford-Smith, Lisa A. Simms, Lucy Burr, David J. Thornton, Simon D. Bowler, Stephanie Livengood, Agathe Ceppe, Michael R. Knowles, Peadar G. Noone, Scott H. Donaldson, David B. Hill, Camille Ehre, Brian Button, Neil E. Alexis, Mehmet Kesimer, Richard C. Boucher, Michael A. McGuckin
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: Non-cystic fibrosis bronchiectasis is characterized by airway mucus accumulation and sputum production, but the role of mucus concentration in the pathogenesis of these abnormalities has not been characterized.Objectives: This study was designed to: 1) measure mucus concentration and biophysical properties of bronchiectasis mucus; 2) identify the secreted mucins contained in bronchiectasis mucus; 3) relate mucus properties to airway epithelial mucin RNA/protein expression; and 4) explore relationships between mucus hyperconcentration and disease severity.Methods: Sputum samples were collected from subjects with bronchiectasis, with and without chronic erythromycin administration, and healthy control subjects. Sputum percent solid concentrations, total and individual mucin concentrations, osmotic pressures, rheological properties, and inflammatory mediators were measured. Intracellular mucins were measured in endobronchial biopsies by immunohistochemistry and gene expression. MUC5B (mucin 5B) polymorphisms were identified by quantitative PCR. In a replication bronchiectasis cohort, spontaneously expectorated and hypertonic saline-induced sputa were collected, and mucus/mucin concentrations were measured.Measurements and Main Results: Bronchiectasis sputum exhibited increased percent solids, total and individual (MUC5B and MUC5AC) mucin concentrations, osmotic pressure, and elastic and viscous moduli compared with healthy sputum. Within subjects with bronchiectasis, sputum percent solids correlated inversely with FEV1 and positively with bronchiectasis extent, as measured by high-resolution computed tomography, and inflammatory mediators. No difference was detected in MUC5B rs35705950 SNP allele frequency between bronchiectasis and healthy individuals. Hypertonic saline inhalation acutely reduced non-cystic fibrosis bronchiectasis mucus concentration by 5%.Conclusions: Hyperconcentrated airway mucus is characteristic of subjects with bronchiectasis, likely contributes to disease pathophysiology, and may be a target for pharmacotherapy.
Association of Genetic Factors with Long-Term Outcome in Refractory r/r B-ALL Patients after CAR T-Cell Therapy
Authors: Jing PAN, Xu Xiuwen, Guo Huilin, Zhuojun Ling, Song Weiliang, Jinlong Xu, Jiajia Duan, Junhan Yang, Zelin Wang, Alex Hong Chang, Qinglong Zheng
Journal: Blood (2019)
It Will Be Good for Us
Authors: Jude T. Okonkwo
Journal: JAMA (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 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
Abstract 10672: Incidence of Major Adverse Cardiovascular Events Among Patients With Provoked and Non-Provoked Venous Thromboembolism: A Review of the RIETE Registry
Authors: Iva Golemi, Lauren Cote, Omer Iftikhar, Benjamin Brenner, Alfonso Tafur, Carmen Fernández-Capitan, José María Pedrajas, Remedios Otero, Roberto Quintavalla, Manuel Monreal
Journal: Circulation (2018)

Introduction: There is overlap between risk factors for coronary artery disease (CAD) and venous thromboembolism (VTE), yet there is paucity of data on incidence of Major Acute Coronary Events (MAC...
Microgravity and Cosmic Radiations During Space Exploration as a Window Into Neurodegeneration on Earth
Authors: Giulia Sprugnoli, Yvonne D. Cagle, Emiliano Santarnecchi
Journal: JAMA Neurology (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 Neurology 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 Neurology journal
Vitamin D3 supplementation to improve fatigue in patients with advanced cancer.
Authors: Dragan Trivanovic, Stjepko Plestina, Renata Dobrilla-Dintinjana, Lorena Honovic, Lems Jerin, Irena Hrstic
Journal: Journal of Clinical Oncology (2012)

9097 Background: Fatigue is one of the most common symptoms of patients diagnosed with cancer. Vitamin D deficiency has been associated with an increased risk of mortality in oncology patients. We conducted a prospective vitamin D (cholecalciferol) supplementation study to analyse the response to oral D3 supplementation on fatigue in this population of chemo-naïve patients. Methods: Eligibility critera included life expectancy ≥ 6 months, ECOG PS 0-3, low serum 25-hydroxyvitamin D3 at the time of diagnosis (using cutoff value of 32 ng/mL), and normal serum calcium level. Cancer related fatigue was measured with the Functional Assessment of Cancer Therapy Fatigue module (FACT-F). Patients were randomized to receive oral supplementation with 2,000 IU of Vitamin D3 daily for 3 months with standard cancer treatment or to continue standard treatment without vit D3 supplementation. Primary endpoint was changes in the FACT-F scale. Secondary endpoints was improvement of vitamin D serum levels and safety. Results: 69 vit D deficient patients enrolled in the this study between November 2009 and November 2011 returned a baseline FACT-F. The mean serum 25(OH)D levels were 18.7 ng/ml (SD = 7.4) at baseline. Patients in experimental arm showed marked improvement from baseline in fatigue (p&lt;0.05) and vitamin D serum levels after 3 months (p&lt;0.001). There were significant difference in fatigue score in patients with experimental arm and control arm after 3 months of treatment (p&lt; 0.001). Conclusions: Vitamin D supplementation resulted in a significant increase in Fatigue score and serum 25(OH)D levels in vitamin D deficient patients. Fatigue improve rapidly but remain worse in control arm. The safety profile of vitamin D in combination with chemotherapy or BSC was acceptable. [Table: see text]
Relation between Interleukin -4 (590C/T) gene polymorphism and hepatocellular carcinoma risk in HBV and HCV patients
Authors: S.F. Gohar, B. Montaser, N. Elabd, M. Elhamoly, A. Saleh, E. Salem, G. Abo-Zeid, M. Rizk
Journal: Annals of Oncology (2019)
A pain in the neck
Authors: Farzahna Mohamed, Frederick Raal
Journal: BMJ (2019)

A 39 year old woman presented with a one week history of progressive swelling and pain on the right side of her neck that was aggravated by eating. She had no relevant dental history. She was apyrexial and physical examination revealed a swelling of the right submandibular region extending to the angle of the mandible posteriorly. The swelling was firm in consistency and tender on palpation. The woman’s blood test results are shown in table 1.

View this table:

Table 1 
Results of relevant blood investigations



Abdominal ultrasonography showed a normal liver and gall …
Benefits of Participating With a Partner in the National Diabetes Prevention Program
Authors: Natalie D. Ritchie, Katherine J.W. Baucom, Katherine A. Sauder
Journal: Diabetes Care (2019)

The evidence-based National Diabetes Prevention Program (NDPP) can reduce type 2 diabetes risks, although strategies to improve outcomes are needed. Attendance and weight loss are suboptimal, especially among racial/ethnic minorities, and men are underrepresented (1). Promoting participation with household members may be important given risk concordance (2,3) and benefits of partner/family support in diabetes management interventions (2). Less is known about the role of close others in diabetes prevention. Here, we examined whether engaging in the NDPP with a household member improves outcomes.

The NDPP was implemented in a safety net health care system following standard guidelines (4). During 2013–2017, 2,946 adults with diabetes risks (e.g., overweight/obesity, prediabetes) enrolled in classes, available in person at no cost, following outreach from NDPP coaches. Eligible patients were identified from medical records and provider and self-referrals. Individuals in the same class with a shared address were considered dyads. NDPP delivery was otherwise identical whether participants enrolled alone or with a household member. Outcomes included attending ≥1 session, percentage of sessions attended, duration, program completion (≥3 sessions attended in months 1–6 and duration ≥9 months), percent weight loss, and achieving ≥5% weight loss. t tests and χ2 analyses determined demographic differences …
Gain-of-Function Mutant p53 R273H Interacts with Replicating DNA and PARP1 in Breast Cancer
Authors: Gu Xiao, Devon Lundine, George K. Annor, Jorge Canar, Viola Ellison, Alla Polotskaia, Patrick L. Donabedian, Thomas Reiner, Galina F. Khramtsova, Olufunmilayo I. Olopade, Alexander Mazo, Jill Bargonetti
Journal: Cancer Research (2019)

Abstract Over 80% of triple-negative breast cancers (TNBC) express mutant p53 (mtp53) and some contain oncogenic gain-of-function (GOF) p53. We previously reported that GOF mtp53 R273H upregulates the chromatin association of mini chromosome maintenance (MCM) proteins MCM2-7 and PARP and named this the mtp53–PARP–MCM axis. In this study, we dissected the function and association between mtp53 and PARP using a number of different cell lines, patient-derived xenografts (PDX), tissue microarrays (TMA), and The Cancer Genome Atlas (TCGA) database. Endogenous mtp53 R273H and exogenously expressed R273H and R248W bound to nascent 5-ethynyl-2´-deoxyuridine-labeled replicating DNA. Increased mtp53 R273H enhanced the association of mtp53 and PARP on replicating DNA. Blocking poly-ADP-ribose gylcohydrolase also enhanced this association. Moreover, mtp53 R273H expression enhanced overall MCM2 levels, promoted cell proliferation, and improved the synergistic cytotoxicity of treatment with the alkylating agent temozolomide in combination with the PARP inhibitor (PARPi) talazoparib. Staining of p53 and PARP1 in breast cancer TMAs and comparison with the TCGA database indicated a higher double-positive signal in basal-like breast cancer than in luminal A or luminal B subtypes. Higher PARP1 protein levels and PAR proteins were detected in mtp53 R273H than in wild-type p53-expressing PDX samples. These results indicate that mtp53 R273H and PARP1 interact with replicating DNA and should be considered as dual biomarkers for identifying breast cancers that may respond to combination PARPi treatments. Significance: p53 gain-of-function mutant 273H and PARP1 interact with replication forks and could serve as potential biomarkers for breast cancer sensitivity to PARP inhibitors.
Low coverage whole genome sequencing enables accurate assessment of common variants and calculation of genome-wide polygenic scores
Authors: Julian R. Homburger, Cynthia L. Neben, Gilad Mishne, Alicia Y. Zhou, Sekar Kathiresan, Amit V. Khera
Journal: Genome Medicine (2019)

Inherited susceptibility to common, complex diseases may be caused by rare, pathogenic variants ("monogenic") or by the cumulative effect of numerous common variants ("polygenic"). Comprehensive genome interpretation should enable assessment for both monogenic and polygenic components of inherited risk. The traditional approach requires two distinct genetic testing technologies-high coverage sequencing of known genes to detect monogenic variants and a genome-wide genotyping array followed by imputation to calculate genome-wide polygenic scores (GPSs). We assessed the feasibility and accuracy of using low coverage whole genome sequencing (lcWGS) as an alternative to genotyping arrays to calculate GPSs.First, we performed downsampling and imputation of WGS data from ten individuals to assess concordance with known genotypes. Second, we assessed the correlation between GPSs for 3 common diseases-coronary artery disease (CAD), breast cancer (BC), and atrial fibrillation (AF)-calculated using lcWGS and genotyping array in 184 samples. Third, we assessed concordance of lcWGS-based genotype calls and GPS calculation in 120 individuals with known genotypes, selected to reflect diverse ancestral backgrounds. Fourth, we assessed the relationship between GPSs calculated using lcWGS and disease phenotypes in a cohort of 11,502 individuals of European ancestry.We found imputation accuracy r2 values of greater than 0.90 for all ten samples-including those of African and Ashkenazi Jewish ancestry-with lcWGS data at 0.5×. GPSs calculated using lcWGS and genotyping array followed by imputation in 184 individuals were highly correlated for each of the 3 common diseases (r2 = 0.93-0.97) with similar score distributions. Using lcWGS data from 120 individuals of diverse ancestral backgrounds, we found similar results with respect to imputation accuracy and GPS correlations. Finally, we calculated GPSs for CAD, BC, and AF using lcWGS in 11,502 individuals of European ancestry, confirming odds ratios per standard deviation increment ranging 1.28 to 1.59, consistent with previous studies.lcWGS is an alternative technology to genotyping arrays for common genetic variant assessment and GPS calculation. lcWGS provides comparable imputation accuracy while also overcoming the ascertainment bias inherent to variant selection in genotyping array design.
Gene Duplication Accelerates the Pace of Protein Gain and Loss from Plant Organelles
Authors: Rona Costello, David M Emms, Steven Kelly
Journal: Molecular Biology and Evolution (2019)

Organelle biogenesis and function is dependent on the concerted action of both organellar-encoded (if present) and nuclear-encoded proteins. Differences between homologous organelles across the Plant Kingdom arise, in part, as a result of differences in the cohort of nuclear-encoded proteins that are targeted to them. However, neither the rate at which differences in protein targeting accumulate nor the evolutionary consequences of these changes are known. Using phylogenomic approaches coupled to ancestral state estimation, we show that the plant organellar proteome has diversified in proportion with molecular sequence evolution such that the proteomes of plant chloroplasts and mitochondria lose or gain on average 3.6 proteins per million years. We further demonstrate that changes in organellar protein targeting are associated with an increase in the rate of molecular sequence evolution and that such changes predominantly occur in genes with regulatory rather than metabolic functions. Finally, we show that gain and loss of protein target signals occurs at a higher rate following gene duplication, revealing that gene and genome duplication are a key facilitator of plant organelle evolution.