tbuckley/cabot-search huggingface dataset:
Rifaximin is associated with modest, transient decreases in multiple taxa in the gut microbiota of patients with diarrhoea-predominant irritable bowel syndrome
Authors: Anthony A. Fodor, Mark Pimentel, William D. Chey, Anthony Lembo, Pamela L. Golden, Robert J. Israel, Ian M. Carroll
Journal: Gut Microbes (2018)

Rifaximin, a non-systemic antibiotic, is efficacious for the treatment of diarrhoea-predominant irritable bowel syndrome (IBS-D). Given the emerging association between the gut microbiota and IBS, this study examined potential effects of rifaximin on the gastrointestinal microbial community in patients with IBS-D. TARGET 3 was a randomised, double-blind, placebo-controlled, phase 3 study. Patients with IBS-D initially received open-label rifaximin 550 mg 3 times daily (TID) for 2 weeks. Patients who responded to the initial treatment and then relapsed were randomised to receive 2 repeat courses of rifaximin 550 mg TID or placebo for 2 weeks, with each course separated by 10 weeks. Stool samples were collected at the beginning and end of open-label treatment, at the beginning and end of the first double-blind treatment, and at the end of the study. As a secondary analysis to the TARGET 3 trial, the composition and diversity of the gut microbiota were assessed, from a random subset of patients, using variable 4 hypervariable region 16S ribosomal RNA gene sequencing. Samples from 103 patients were included. After open-label rifaximin treatment for 2 weeks, 7 taxa (e.g. Peptostreptococcaceae, Verrucomicrobiaceae, Enterobacteriaceae) had significantly lower relative abundance at a 10% false discovery rate threshold. The effects of rifaximin were generally short-term, as there was little evidence of significantly different changes in taxa relative abundance at the end of the study (up to 46 weeks) versus baseline. The results suggest that rifaximin has a modest, largely transient effect across a broad range of stool microbes. Future research may determine whether the taxa affected by rifaximin are causally linked to IBS-D. ClinicalTrials.gov identifier number: NCT01543178.
Risk of stroke and transient ischaemic attack in patients with a diagnosis of resolved atrial fibrillation: retrospective cohort studies
Authors: Nicola J Adderley, Krishnarajah Nirantharakumar, Tom Marshall
Journal: BMJ (2018)

Abstract Objectives To determine rates of stroke or transient ischaemic attack (TIA) and all cause mortality in patients with a diagnosis of “resolved” atrial fibrillation compared to patients with unresolved atrial fibrillation and without atrial fibrillation. Design Two retrospective cohort studies. Setting General practices contributing to The Health Improvement Network, 1 January 2000 to 15 May 2016. Participants Adults aged 18 years or more with no previous stroke or TIA: 11 159 with resolved atrial fibrillation, 15 059 controls with atrial fibrillation, and 22 266 controls without atrial fibrillation. Main outcome measures Primary outcome was incidence of stroke or TIA. Secondary outcome was all cause mortality. Results Adjusted incidence rate ratios for stroke or TIA in patients with resolved atrial fibrillation were 0.76 (95% confidence interval 0.67 to 0.85, P&lt;0.001) versus controls with atrial fibrillation and 1.63 (1.46 to 1.83, P&lt;0.001) versus controls without atrial fibrillation. Adjusted incidence rate ratios for mortality in patients with resolved atrial fibrillation were 0.60 (0.56 to 0.65, P&lt;0.001) versus controls with atrial fibrillation and 1.13 (1.06 to 1.21, P&lt;0.001) versus controls without atrial fibrillation. When patients with resolved atrial fibrillation and documented recurrent atrial fibrillation were excluded the adjusted incidence rate ratio for stroke or TIA was 1.45 (1.26 to 1.67, P&lt;0.001) versus controls without atrial fibrillation. Conclusion Patients with resolved atrial fibrillation remain at higher risk of stroke or TIA than patients without atrial fibrillation. The risk is increased even in those in whom recurrent atrial fibrillation is not documented. Guidelines should be updated to advocate continued use of anticoagulants in patients with resolved atrial fibrillation.
TRAF4-mediated ubiquitination of NGF receptor TrkA regulates prostate cancer metastasis
Authors: Ramesh Singh, Dileep Karri, Hong Shen, Jiangyong Shao, Subhamoy Dasgupta, Shixia Huang, Dean P. Edwards, Michael M. Ittmann, Bert W. O’Malley, Ping Yi
Journal: Journal of Clinical Investigation (2018)

Receptor tyrosine kinases (RTKs) are important drivers of cancers. In addition to genomic alterations, aberrant activation of WT RTKs plays an important role in driving cancer progression. However, the mechanisms underlying how RTKs drive prostate cancer remain incompletely characterized. Here we show that non-proteolytic ubiquitination of RTK regulates its kinase activity and contributes to RTK-mediated prostate cancer metastasis. TRAF4, an E3 ubiquitin ligase, is highly expressed in metastatic prostate cancer. We demonstrated here that it is a key player in regulating RTK-mediated prostate cancer metastasis. We further identified TrkA, a neurotrophin RTK, as a TRAF4-targeted ubiquitination substrate that promotes cancer cell invasion and found that inhibition of TrkA activity abolished TRAF4-dependent cell invasion. TRAF4 promoted K27- and K29-linked ubiquitination at the TrkA kinase domain and increased its kinase activity. Mutation of TRAF4-targeted ubiquitination sites abolished TrkA tyrosine autophosphorylation and its interaction with downstream proteins. TRAF4 knockdown also suppressed nerve growth factor (NGF) stimulated TrkA downstream p38 MAPK activation and invasion-associated gene expression. Furthermore, elevated TRAF4 levels significantly correlated with increased NGF-stimulated invasion-associated gene expression in prostate cancer patients, indicating that this signaling axis is significantly activated during oncogenesis. Our results revealed a posttranslational modification mechanism contributing to aberrant non-mutated RTK activation in cancer cells.
Biology Needs Evolutionary Software Tools: Let’s Build Them Right
Authors: Anton Nekrutenko, Galaxy Team, Jeremy Goecks, James Taylor, Daniel Blankenberg
Journal: Molecular Biology and Evolution (2018)

Research in population genetics and evolutionary biology has always provided a computational backbone for life sciences as a whole. Today evolutionary and population biology reasoning are essential for interpretation of large complex datasets that are characteristic of all domains of today’s life sciences ranging from cancer biology to microbial ecology. This situation makes algorithms and software tools developed by our community more important than ever before. This means that we, developers of software tool for molecular evolutionary analyses, now have a shared responsibility to make these tools accessible using modern technological developments as well as provide adequate documentation and training.
Pretreatment levels of absolute and relative eosinophil count to improve overall survival (OS) in patients with metastatic melanoma under treatment with ipilimumab, an anti CTLA-4 antibody.
Authors: Katja Schindler, Kaan Harmankaya, Michael Andrew Postow, Sophie Frantal, Danielle Bello, Charlotte Eielson Ariyan, Olivier Alain Michielin, Christoph Hoeller, Hubert Pehamberger, Jedd D. Wolchok
Journal: Journal of Clinical Oncology (2013)

9024 Background: Ipilimumab, a fully human monoclonal Ab directed against the CTLA-4 receptor on T-cells, has shown significant improvement in OS for patients with metastatic melanoma in randomized phase III trials. Eosinophilia in peripheral blood of those patients has been observed, but its clinical significance as a prognostic factor has not been assessed. Methods: We report on a retrospective multi-center analysis of 123 patients who received ipilimumab in three centers between 2010 and 2013. Patients treated had AJCC unresectable stage III or stage IV melanoma of any origin and received ipilimumab in first- and second-line setting at the approved standard dosage of 3mg/kg (4 times q21d). Four patients were excluded due to missing baseline values in eosinophil count (EC). Results: Median OS for patients in final analysis (n=119) was 9.57 months. Based on cut-offs assessed by ROC curves, OS was estimated by Kaplan-Meier curves. Baseline absolute eosinophil count (AEC) ≥ 0.1 (10 9 /l) was significantly associated with improved OS (p= 0.002) with 6-, 12- and 18-month survival rates of 79%, 60% and 48% compared to rates of 48%, 37% and 19% for pts with baseline AEC below 0.1. Baseline relative eosinophil counts (REC) of ≥ 1.75% showed an even stronger significance (p&lt;0.0001) with 6-, 12- and 18-months survival rates of 79% vs. 52%, 60% vs. 40% and 51% vs. 17.1% respectively. Conclusions: This retrospective analysis elucidates the possible association of baseline EC with OS of patients treated with Ipilimumab. Improvement of OS was highly significant in both analyses considering AEC (p= 0.002) and REC (p&lt;0.0001). Since easily detectable biomarkers could be of great potential value, further effort on understanding the potential role of eosinophil granulocytes as possible effector cells in the immune-mediated response to anti CTLA-4 abs should be undertaken.
The Autotaxin—Lysophosphatidic Acid Axis Promotes Lung Carcinogenesis
Authors: Christiana Magkrioti, Nikos Oikonomou, Eleanna Kaffe, Marios-Angelos Mouratis, Nikos Xylourgidis, Iliana Barbayianni, Petros Megadoukas, Vaggelis Harokopos, Christos Valavanis, Jerold Chun, Alexandra Kosma, Georgios T. Stathopoulos, Evangelos Bouros, Demosthenes Bouros, Konstantinos Syrigos, Vassilis Aidinis
Journal: Cancer Research (2018)

Pathogenesis and progression of lung cancer are governed by complex interactions between the environment and host genetic susceptibility, which is further modulated by genetic and epigenetic changes. Autotaxin (ATX, ENPP2) is a secreted glycoprotein that catalyzes the extracellular production of lysophosphatidic acid (LPA), a growth-factor-like phospholipid that is further regulated by phospholipid phosphatases (PLPP). LPA's pleiotropic effects in almost all cell types are mediated through at least six G-protein coupled LPA receptors (LPAR) that exhibit overlapping specificities, widespread distribution, and differential expression profiles. Here we use both preclinical models of lung cancer and clinical samples (from patients and healthy controls) to investigate the expression levels, activity, and biological role of the above components of the ATX/LPA axis in lung cancer. ENPP2 was genetically altered in 8% of patients with lung cancer, whereas increased ATX staining and activity were detected in patient biopsies and sera, respectively. Moreover, PLPP3 expression was consistently downregulated in patients with lung cancer. Comparable observations were made in the two most widely used animal models of lung cancer, the carcinogen urethane-induced and the genetically engineered K-rasG12D -driven models, where genetic deletion of Enpp2 or Lpar1 resulted in disease attenuation, thus confirming a procarcinogenic role of LPA signaling in the lung. Expression profiling data analysis suggested that metabolic rewiring may be implicated in the procarcinogenic effects of the ATX/LPA axis in K-ras- G12D -driven lung cancer pathogenesis.Significance: These findings establish the role of ATX/LPA in lung carcinogenesis, thus expanding the mechanistic links between pulmonary fibrosis and cancer. Cancer Res; 78(13); 3634-44. ©2018 AACR.
ENDOSCOPIC FINDINGS AND OUTCOME IN CAUSTIC INGESTION OF ACID AND ALKALINE AGENTS IN ADULTS
Authors: M Hollenbach, J Tünnemann, MF Struck, J Feisthammel, T Schlosser, T Schaumburg, J Mössner, A Hoffmeister
Journal: Endoscopy (2018)

Caustic ingestion in adults is a rare but potentially life-threatening problem. It remains controversial whether endoscopic findings and survival differ between acid and alkali ingestion. Thus, we compared ingestion of these agents and evaluated prediction parameters for survival and complications.
P574Activation of the regulatory T-cell-indoleamine 2,3 dioxygenase Axis promotes vascular tolerance mechanisms and reduces atherosclerosis
Authors: M J Forteza, K A Polyzos, R Baumgartner, B Suur, M Mussbacher, D Johansson, A Hermansson, G K Hansson, DFJ Ketelhuth
Journal: Cardiovascular Research (2018)

vivo (Sugen Hypoxia rat model).Importantly, 6-MP improved impaired cardiac function compared to control group.Conclusions: Our data indicate that Nur77 is a novel critical modulator in PAH through increasing BMP signalling while decreasing proliferation and inflammation.Therefore, activation of Nur77 via 6-MP might be useful for the treatment of PAH.
Retreatment of patients who failed glecaprevir/pibrentasvir treatment for hepatitis C virus infection
Authors: David Wyles, Ola Weiland, Betty Yao, Frank Weilert, Jean-Francois Dufour, Stuart C. Gordon, Albrecht Stoehr, Ashley Brown, Stefan Mauss, Zhenzhen Zhang, Tami Pilot-Matias, Lino Rodrigues, Federico J Mensa, Fred Poordad
Journal: Journal of Hepatology (2019)
Changing Susceptibility to Non-Optimum Temperatures in Japan, 1972–2012: The Role of Climate, Demographic, and Socioeconomic Factors
Authors: Yeonseung Chung, Daewon Yang, Antonio Gasparrini, Ana M. Vicedo-Cabrera, Chris Fook Sheng Ng, Yoonhee Kim, Yasushi Honda, Masahiro Hashizume
Journal: Environmental Health Perspectives (2018)

Previous studies have shown that population susceptibility to non-optimum temperatures has changed over time, but little is known about the related time-varying factors that underlie the changes.Our objective was to investigate the changing population susceptibility to non-optimum temperatures in 47 prefectures of Japan over four decades from 1972 to 2012, addressing three aspects: minimum mortality temperature (MMT) and heat- and cold-related mortality risks. In addition, we aimed to examine how these aspects of susceptibility were associated with climate, demographic, and socioeconomic variables.We first used a two-stage time-series design with a time-varying distributed lag nonlinear model and multivariate meta-analysis to estimate the time-varying MMT, heat- and cold-related mortality risks. We then applied linear mixed effects models to investigate the association between each of the three time-varying aspects of susceptibility and various time-varying factors.MMT increased from 23.2 [95% confidence interval (CI): 23, 23.6] to 28.7 (27.0, 29.7) °C. Heat-related mortality risk [relative risk (RR) for the 99th percentile of temperature vs. the MMT] decreased from 1.18 (1.15, 1.21) to 1.01 (0.98, 1.04). Cold-related mortality risk (RR for the first percentile vs. the MMT) generally decreased from 1.48 (1.41, 1.54) to 1.35 (1.32, 1.40), with the exception of a few eastern prefectures that showed increased risk. The changing patterns in all three aspects differed by region, sex, and causes of death. Higher mean temperature was associated (p<0.01) with lower heat risk, whereas higher humidity was associated with higher cold risk. A higher percentage of elderly people was associated with a higher cold risk, whereas higher economic strength of the prefecture was related to lower cold risk.Population susceptibility to heat has decreased over the last four decades in Japan. Susceptibility to cold has decreased overall except for several eastern prefectures where it has either increased or remained unchanged. Certain climate, demographic, and socioeconomic factors explored in the current study might underlie this changing susceptibility. https://doi.org/10.1289/EHP2546.
Integrated Genomic and Immunophenotypic Classification of Pancreatic Cancer Reveals Three Distinct Subtypes with Prognostic/Predictive Significance
Authors: Martin Wartenberg, Silvia Cibin, Inti Zlobec, Erik Vassella, Serenella Eppenberger-Castori, Luigi Terracciano, Micha David Eichmann, Mathias Worni, Beat Gloor, Aurel Perren, Eva Karamitopoulou
Journal: Clinical Cancer Research (2018)

Purpose: Current clinical classification of pancreatic ductal adenocarcinoma (PDAC) is unable to predict prognosis or response to chemo- or immunotherapy and does not take into account the host reaction to PDAC cells. Our aim is to classify PDAC according to host- and tumor-related factors into clinically/biologically relevant subtypes by integrating molecular and microenvironmental findings.Experimental Design: A well-characterized PDAC cohort (n = 110) underwent next-generation sequencing with a hot spot cancer panel while next-generation tissue microarrays were immunostained for CD3, CD4, CD8, CD20, PD-L1, p63, hyaluronan-mediated motility receptor (RHAMM), and DNA mismatch repair proteins. Previous data on FOXP3 were integrated. Immune cell counts and protein expression were correlated with tumor-derived driver mutations, clinicopathologic features (TNM 8th edition, 2017), survival, and epithelial-mesenchymal transition (EMT)-like tumor budding.Results: Three PDAC subtypes were identified: the "immune escape" (54%), poor in T and B cells and enriched in FOXP3+ regulatory T cells (Treg), with high-grade budding, frequent CDKN2A, SMAD4, and PIK3CA mutations, and poor outcome; the "immune rich" (35%), rich in T and B cells and poorer in FOXP3+ Tregs, with infrequent budding, lower CDKN2A and PIK3CA mutation rate, and better outcome and a subpopulation with tertiary lymphoid tissue (TLT), mutations in DNA damage response genes (STK11 and ATM), and the best outcome; and the "immune exhausted" (11%), with immunogenic microenvironment and two subpopulations-one with PD-L1 expression and a high PIK3CA mutation rate and a microsatellite-unstable subpopulation with a high prevalence of JAK3 mutations. The combination of low budding, low stromal FOXP3 counts, presence of TLTs, and absence of CDKN2A mutations confers significant survival advantage in patients with PDAC.Conclusions: Immune host responses correlate with tumor characteristics, leading to morphologically recognizable PDAC subtypes with prognostic/predictive significance. Clin Cancer Res; 24(18); 4444-54. ©2018 AACRSee related commentary by Khalil and O'Reilly, p. 4355.
A work flow to build and validate patient specific left atrium electrophysiology models from catheter measurements
Authors: Cesare Corrado, Steven Williams, Rashed Karim, Gernot Plank, Mark O’Neill, Steven Niederer
Journal: Medical Image Analysis (2018)

Biophysical models of the atrium provide a physically constrained framework for describing the current state of an atrium and allow predictions of how that atrium will respond to therapy. We propose a work flow to simulate patient specific electrophysiological heterogeneity from clinical data and validate the resulting biophysical models. In 7 patients, we recorded the atrial anatomy with an electroanatomical mapping system (St Jude Velocity); we then applied an S1-S2 electrical stimulation protocol from the coronary sinus (CS) and the high right atrium (HRA) whilst recording the activation patterns using a PentaRay catheter with 10 bipolar electrodes at 12 ± 2 sites across the atrium. Using only the activation times measured with a PentaRay catheter and caused by a stimulus applied in the CS with a remote catheter we fitted the four parameters for a modified Mitchell-Schaeffer model and the tissue conductivity to the recorded local conduction velocity restitution curve and estimated local effective refractory period. Model parameters were then interpolated across each atrium. The fitted model recapitulated the S1-S2 activation times for CS pacing giving a correlation ranging between 0.81 and 0.98. The model was validated by comparing simulated activations times with the independently recorded HRA pacing S1-S2 activation times, giving a correlation ranging between 0.65 and 0.96. The resulting work flow provides the first validated cohort of models that capture clinically measured patient specific electrophysiological heterogeneity.
Association Between Functional Health Literacy and Postoperative Recovery, Health Care Contacts, and Health-Related Quality of Life Among Patients Undergoing Day Surgery
Authors: Maria Hälleberg Nyman, Ulrica Nilsson, Karuna Dahlberg, Maria Jaensson
Journal: JAMA Surgery (2018)

<h3>Importance</h3> Day surgery puts demands on the patients to manage their own recovery at home according to given instructions. Low health literacy levels are shown to be associated with poorer health outcomes. <h3>Objective</h3> To describe functional health literacy levels among patients in Sweden undergoing day surgery and to describe the association between functional health literacy (FHL) and health care contacts, quality of recovery (SwQoR), and health-related quality of life. <h3>Design, Setting, and Participants</h3> This observational study was part of a secondary analysis of a randomized clinical trial of patients undergoing day surgery and was performed in multiple centers from October 2015 to July 2016 and included 704 patients. <h3>Main Outcomes and Measures</h3> The primary end point was SwQoR in the FHL groups 14 days after surgery. Secondary end points were health care contacts, EuroQol-visual analog scales, and the Short Form (36) Health Survey in the FHL groups. <h3>Results</h3> Of 704 patients (418 [59.4%] women; mean [SD] age with inadequate or problematic FHL levels, 47 [16] years and 49 [15.1], respectively), 427 (60.7%) reported sufficient FHL, 223 (31.7%) problematic FHL, and 54 (7.7%) inadequate FHL. The global score of SwQoR indicated poor recovery in both inadequate (37.4) and problematic (22.9) FHL. There was a statistically significant difference in the global score of SwQoR (SD) between inadequate (37.4 [34.7]) and sufficient FHL (17.7 [21.0]) (<i>P</i> &lt; .001). The patients with inadequate or problematic FHL had a lower health-related quality of life than the patients with sufficient FHL in terms of EuroQol-visual analog scale scores (mean [SD], 73 [19.1], 73 [19.1], and 78 [17.4], respectively;<i>P</i> = .008), physical function (mean [SD], 72 [22.7], 75 [23.8], and 81 [21.9], respectively;<i>P</i> &lt; .001), bodily pain (mean [SD], 51 [28.7], 53 [27.4], and 61 [27.0], respectively;<i>P</i> = .001), vitality (mean [SD], 50 [26.7], 56 [23.5], and 62 [25.4], respectively;<i>P</i> &lt; .001), social functioning (mean [SD], 73 [28.2], 81 [21.8], and 84 [23.3], respectively;<i>P</i> = .004), mental health (mean [SD], 65 [25.4], 73 [21.2], and 77 [21.2], respectively;<i>P</i> &lt; .001), and physical component summary (mean [SD], 41 [11.2], 42 [11.3], and 45 [10.1], respectively;<i>P</i> = .004). There were no differences between the FHL groups regarding health care contacts. <h3>Conclusions and Relevance</h3> Inadequate FHL in patients undergoing day surgery was associated with poorer postoperative recovery and a lower health-related quality of life. Health literacy is a relevant factor to consider for optimizing the postoperative recovery in patients undergoing day surgery. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT02492191