tbuckley/cabot-search huggingface dataset:
Experimental risk assessment for chikungunya virus transmission based on vector competence, distribution and temperature suitability in Europe, 2018
Authors: Anna Heitmann, Stephanie Jansen, Renke Lühken, Michelle Helms, Björn Pluskota, Norbert Becker, Carola Kuhn, Jonas Schmidt-Chanasit, Egbert Tannich
Journal: Eurosurveillance (2018)

BackgroundOver the last decade, the abundant distribution of the Asian tiger mosquito Aedes albopictus in southern Europe and the import of chikungunya virus (CHIKV) by infected travellers has resulted in at least five local outbreaks of chikungunya fever in France and Italy. Considering the ongoing spread of Ae. albopictus to central Europe, we performed an analysis of the Europe-wide spatial risk of CHIKV transmission under different temperature conditions. Methods:Ae. albopictus specimens from Germany and Italy were orally infected with CHIKV from an outbreak in France and kept for two weeks at 18 °C, 21 °C or 24 °C. A salivation assay was conducted to detect infectious CHIKV. Results: Analyses of mosquito saliva for infectious virus particles demonstrated transmission rates (TRs) of > 35%. Highest TRs of 50% for the mosquito population from Germany were detected at 18 °C, while the Italian population had highest TRs of 63% at 18 °C and 21 °C, respectively. Temperature data indicated a potential risk of CHIKV transmission for extended durations, i.e. sufficiently long time periods allowing extrinsic incubation of the virus. This was shown for areas already colonised by Ae. albopictus, as well as for large parts of central Europe that are not colonised. Conclusion: The current risk of CHIKV transmission in Europe is not primarily restricted by temperature, which allows extrinsic incubation of the virus, but rather by the vector distribution. Accordingly, all European countries with established populations of Ae. albopictus should implement respective entomological surveillance and monitoring systems, as basis for suitable control measures.
Abstract 16560: Impact of Assuming a Circular Orifice on Flow Error Through Elliptical Regurgitant Orifices: A Computational Fluid Dynamics (CFD) Analysis
Authors: Sumeet S Mitter, Gregory J Wagner, Alex J Barker, Michael Markl, James D Thomas
Journal: Circulation (2015)

Introduction: Hydrodynamic theory predicts fluid approaches a point orifice with accelerating velocity in hemispheric shells, forming the basis for the proximal isovelocity surface area (PISA) method to quantify valve regurgitation. Previous CFD and in vitro work has shown that with a finite, non-point orifice, there is a small, systematic underestimation of flow that is approximately the ratio of contour velocity (va) to maximal orifice velocity (vo), e.g., roughly an 8% error if a 40 cm/s contour is used with a 5 m/s jet. The PISA method is further questioned in the setting of noncircular orifices, with concerns of further underestimation. We sought to quantify this impact with CFD. Hypothesis: Application of standard PISA analysis to an elliptical orifice leads to further flow underestimation, but the magnitude is negligible. Methods: Mathematical modeling of flow through a finite elliptical orifice was computed using the open-source incompressible flow solver Nalu. Forty-five permutations of valve flow were characterized by varying valve orifice area (0.1, 0.3 and 0.5 cm^2), ellipse axis ratios (1:1, 2:1, 3:1, 5:1, and 10:1), and max velocity (400, 500 and 600 cm/s). Computed hemispherical flow contours scaled to true orifice flow (Qc/Qo) and scaled computed area to true orifice area (Ac/Ao) were plotted against distance from the orifice scaled to a circular orifice with equivalent orifice area. Results: Qc/Qo and Ac/Ao for each ellipse axis ratio when plotted against normalized orifice distance produced the same curves for each permutation of valve orifice area and max velocity. Plotting Qc/Qo (or Ac/Ao) against va/vo reveals marginal underestimation of flow with physiologic elliptical axis ratios of 2:1 and 3:1 against a circular orifice with axis ratios of 1:1 (Figure 1). Conclusions: The added error in using PISA to approximate flow through an elliptical mitral valve orifice area is minimal compared to traditional assumptions of a circular mitral valve orifice.
Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: analysis of individual patient data from randomised trials
Authors: Peter M Rothwell, Nancy R Cook, J Michael Gaziano, Jacqueline F Price, Jill F F Belch, Maria Carla Roncaglioni, Takeshi Morimoto, Ziyah Mehta
Journal: The Lancet (2018)

A one-dose-fits-all approach to use of aspirin has yielded only modest benefits in long-term prevention of cardiovascular events, possibly due to underdosing in patients of large body size and excess dosing in patients of small body size, which might also affect other outcomes.
A Rare Missense Variant in TCF7L2 Associates with Colorectal Cancer Risk by Interacting with a GWAS-Identified Regulatory Variant in the MYC Enhancer
Authors: Jiang Chang, Jianbo Tian, Yang Yang, Rong Zhong, Jiaoyuan Li, Kan Zhai, Juntao Ke, Jiao Lou, Wei Chen, Beibei Zhu, Na Shen, Yi Zhang, Yajie Gong, Ying Zhu, Danyi Zou, Xiating Peng, Kun Huang, Xiaoping Miao
Journal: Cancer Research (2018)

Abstract Genome-wide association studies (GWAS) of colorectal cancer have identified several common susceptible variants in gene regulatory regions. However, low-frequency or rare coding risk variants have not been systematically investigated in patients with colorectal cancer from Chinese populations. In this study, we performed an exome-wide association analysis with 1,062 patients with colorectal cancer and 2,184 controls from a Chinese population. Promising associations were further replicated in two replication sets: replication stage I with 2,478 cases and 3,880 controls, and replication stage II with 3,761 cases and 4,058 controls. We identified two variants significantly associated with colorectal cancer risk: a novel rare missense variant in TCF7L2 [rs138649767, OR = 2.08, 95% confidence interval (CI): 1.69–2.57, P = 5.66 × 10−12] and a previous European GWAS-identified 3′-UTR variant in ATF1 (rs11169571, OR = 1.18, 95% CI: 1.13–1.24, P = 1.65 × 10−12). We found a significant interaction between the TCF7L2 missense variant rs138649767 and a previous GWAS-identified regulatory variant rs6983267 in the MYC enhancer (Pinteraction = 0.0002). Functional analysis of this variant revealed that TCF7L2 with rs138649767-A allele harbored the ability to activate the MYC enhancer with rs6983267-G allele and enhance colorectal cancer cell proliferation. In addition, the ATF1 rs11169571 variant significantly correlated with ATF1 expression by affecting hsa-miR-1283 and hsa-miR-520d-5p binding. Further ChIP-seq and gene coexpression analyses showed that oncogenes NRAS and BRAF were activated by ATF1 in colorectal cancer. These results widen our understanding of the molecular basis of colorectal cancer risk and provide insight into pathways that might be targeted to prevent colorectal cancer. Significance: Exome-wide association analysis identifies a rare missense variant in TCF7L2 and a common regulatory variant in ATF1 as susceptibility factors of colorectal cancer. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/17/5164/F1.large.jpg. Cancer Res; 78(17); 5164–72. ©2018 AACR.
Abstract 16819: Type 1 Diabetes Mellitus-induced Cardiac Dysfunction is Further Impaired After Transplantation - Involvement of the Pi3k/akt Pathway
Authors: Sevil Korkmaz-Icöz, Shiliang Li, Sivakkanan Loganathan, Tamás Radovits, Mihály Ruppert, Paige Brlecic, Thomas Fleming, Brune Maik, Patrick Most, Matthias Karck, Gábor Szabó
Journal: Circulation (2016)

Introduction: Cardiac transplantation is the only sufficient therapy in end-stage heart failure, however it is severely limited by the marked shortage of appropriate donor organs. The discovery of ...
Extensive intraspecific gene order and gene structural variations between Mo17 and other maize genomes
Authors: Silong Sun, Yingsi Zhou, Jian Chen, Junpeng Shi, Haiming Zhao, Hainan Zhao, Weibin Song, Mei Zhang, Yang Cui, Xiaomei Dong, Han Liu, Xuxu Ma, Yinping Jiao, Bo Wang, Xuehong Wei, Joshua C. Stein, Jeff C. Glaubitz, Fei Lu, Guoliang Yu, Chengzhi Liang, Kevin Fengler, Bailin Li, Antoni Rafalski, Patrick S. Schnable, Doreen H. Ware, Edward S. Buckler, Jinsheng Lai
Journal: Nature Genetics (2018)

Abstract Maize is an important crop with a high level of genome diversity and heterosis. The genome sequence of a typical female line, B73, was previously released. Here, we report a de novo genome assembly of a corresponding male representative line, Mo17. More than 96.4% of the 2,183 Mb assembled genome can be accounted for by 362 scaffolds in ten pseudochromosomes with 38,620 annotated protein-coding genes. Comparative analysis revealed large gene-order and gene structural variations: approximately 10% of the annotated genes were mutually nonsyntenic, and more than 20% of the predicted genes had either large-effect mutations or large structural variations, which might cause considerable protein divergence between the two inbred lines. Our study provides a high-quality reference-genome sequence of an important maize germplasm, and the intraspecific gene order and gene structural variations identified should have implications for heterosis and genome evolution.
Verifiability is a core principle of science
Authors: Sanjay Srivastava
Journal: Behavioral and Brain Sciences (2018)

Abstract Scientific knowledge is supposed to be verifiable. Replications promote verifiability in several ways. Most straightforwardly, replications can verify empirical claims. Replication research also promotes dissemination of information needed for other aspects of verification; creates meta-scientific knowledge about what results to treat as credible even in the absence of replications; and reinforces a broader norm of scientists checking each other's work.
Efficacy and Pharmacokinetics of Glecaprevir and Pibrentasvir With Concurrent Use of Acid-Reducing Agents in Patients With Chronic HCV Infection
Authors: Steven Flamm, K. Rajender Reddy, Neddie Zadeikis, Tarek Hassanein, Bruce R. Bacon, Andreas Maieron, Stefan Zeuzem, Marc Bourliere, Jose L. Calleja, Matthew P. Kosloski, Rajneet K. Oberoi, Chih-Wei Lin, Yao Yu, Sandra Lovell, Dimitri Semizarov, Federico J. Mensa
Journal: Clinical Gastroenterology and Hepatology (2018)

Proton pump inhibitors (PPIs) are commonly prescribed to treat acid-related disorders. Some direct-acting antiviral regimens for chronic hepatitis C virus (HCV) infection have reduced efficacy in patients taking concomitant acid-reducing agents, including PPIs, due to interactions between drugs. We analyzed data from 9 multicenter, phase 2 and 3 trials to determine the efficacy and pharmacokinetics of an HCV therapeutic regimen comprising glecaprevir and pibrentasvir (glecaprevir/pibrentasvir) in patients taking concomitant acid-reducing agents.We analyzed data from 2369 patients infected with HCV genotypes 1-6 and compensated liver disease treated with an all-oral regimen of glecaprevir/pibrentasvir for 8-16 weeks. We compared efficacy and pharmacokinetics among patients receiving at least 1 dose of an acid-reducing agent (a PPI, an H2 blocker, or antacid). High-dose PPI was defined as daily dose greater than 20 mg omeprazole dose equivalent. The objectives were to evaluate rate of sustained virologic response 12 weeks post-treatment (SVR12) and to assess steady-state glecaprevir and pibrentasvir exposures in patients on acid-reducing agents.Of the 401 patients (17%) who reported use of acid-reducing agents, 263 took PPIs (11%; 109 patients took a high-dose PPI and 154 patients took a low-dose PPI). Rates of SVR12 were 97.0% among patients who used acid-reducing agents and 97.5% among those not using acid-reducing agents (P = .6). An SVR12 was achieved in 96.3% taking a high-dose PPI and 97.4% taking a low-dose PPI, with no virologic failures in those receiving a high-dose PPI (P = .7). Glecaprevir, but not pibrentasvir, bioavailability was affected; its exposure decreased by 41% in patients taking a high-dose PPI.In an analysis of data from 9 clinical trials, we observed a high rate of SVR12 (approximately 97%) among patients treated with glecaprevir/pibrentasvir for HCV infection-even among patients taking concomitant ARA or high-dose PPI. This was despite decreased glecaprevir exposures in patients when on high-dose PPIs. ClinicalTrials.gov numbers, NCT02243280 (SURVEYOR-I), NCT02243293 (SURVEYOR-II), NCT02604017 (ENDURANCE-1), NCT02640482 (ENDURANCE-2), NCT02640157 (ENDURANCE-3), NCT02636595 (ENDURANCE-4), NCT02642432 (EXPEDITION-1), NCT02651194 (EXPEDITION-4), NCT02446717 (MAGELLAN-I).
Follow-up Recommendations for Completely Resected Gastroenteropancreatic Neuroendocrine Tumors
Authors: Simron Singh, Lesley Moody, David L. Chan, David C. Metz, Jonathan Strosberg, Timothy Asmis, Dale L. Bailey, Emily Bergsland, Kari Brendtro, Richard Carroll, Sean Cleary, Michelle Kim, Grace Kong, Calvin Law, Ben Lawrence, Alexander McEwan, Caitlin McGregor, Michael Michael, Janice Pasieka, Nick Pavlakis, Rodney Pommier, Michael Soulen, David Wyld, Eva Segelov
Journal: JAMA Oncology (2018)

There is no consensus on optimal follow-up for completely resected gastroenteropancreatic neuroendocrine tumors. Published guidelines for follow-up are complex and emphasize closer surveillance in the first 3 years after resection. Neuroendocrine tumors have a different pattern and timescale of recurrence, and thus require more practical and tailored follow-up. The Commonwealth Neuroendocrine Tumour Collaboration convened an international multidisciplinary expert panel, in collaboration with the North American Neuroendocrine Tumor Society, to create patient-centered follow-up recommendations for completely resected gastroenteropancreatic neuroendocrine tumors. This panel used the RAND/UCLA (University of California, Los Angeles) Appropriateness Method to generate recommendations. A large international survey was conducted outlining current the surveillance practice of neuroendocrine tumor practitioners and shortcomings of the current guidelines. A systematic review of available data to date was supplemented by recurrence data from 2 large patient series. The resultant guidelines suggest follow-up for at least 10 years for fully resected small-bowel and pancreatic neuroendocrine tumors and also identify clinical situations in which no follow-up is required. These recommendations stratify follow-up strategies based on evidence-based prognostic factors that allow for a more individualized patient-centered approach to this complex and heterogeneous malignant neoplasm.
Gut commensal <i>Parabacteroides goldsteinii</i> plays a predominant role in the anti-obesity effects of polysaccharides isolated from <i>Hirsutella sinensis</i>
Authors: Tsung-Ru Wu, Chuan-Sheng Lin, Chih-Jung Chang, Tzu-Lung Lin, Jan Martel, Yun-Fei Ko, David M Ojcius, Chia-Chen Lu, John D Young, Hsin-Chih Lai
Journal: Gut (2018)

Objective The medicinal fungus Ophiocordyceps sinensis and its anamorph Hirsutella sinensis have a long history of use in traditional Chinese medicine for their immunomodulatory properties. Alterations of the gut microbiota have been described in obesity and type 2 diabetes. We examined the possibility that H. sinensis mycelium (HSM) and isolated fractions containing polysaccharides may prevent diet-induced obesity and type 2 diabetes by modulating the composition of the gut microbiota. Design High-fat diet (HFD)-fed mice were treated with HSM or fractions containing polysaccharides of different molecular weights. The effects of HSM and polysaccharides on the gut microbiota were assessed by horizontal faecal microbiota transplantation (FMT), antibiotic treatment and 16S rDNA-based microbiota analysis. Results Fraction H1 containing high-molecular weight polysaccharides (&gt;300 kDa) considerably reduced body weight gain (∼50% reduction) and metabolic disorders in HFD-fed mice. These effects were associated with increased expression of thermogenesis protein markers in adipose tissues, enhanced gut integrity, reduced intestinal and systemic inflammation and improved insulin sensitivity and lipid metabolism. Gut microbiota analysis revealed that H1 polysaccharides selectively promoted the growth of Parabacteroides goldsteinii , a commensal bacterium whose level was reduced in HFD-fed mice. FMT combined with antibiotic treatment showed that neomycin-sensitive gut bacteria negatively correlated with obesity traits and were required for H1’s anti-obesogenic effects. Notably, oral treatment of HFD-fed mice with live P. goldsteinii reduced obesity and was associated with increased adipose tissue thermogenesis, enhanced intestinal integrity and reduced levels of inflammation and insulin resistance. Conclusions HSM polysaccharides and the gut bacterium P. goldsteinii represent novel prebiotics and probiotics that may be used to treat obesity and type 2 diabetes.
Future directions for therapeutic strategies in post-ischaemic vascularization: a position paper from European Society of Cardiology Working Group on Atherosclerosis and Vascular Biology
Authors: Andrea Caporali, Magnus Bäck, Mat J Daemen, Imo E Hoefer, Elizabeth A Jones, Esther Lutgens, Christian M Matter, Marie-Luce Bochaton-Piallat, Arndt F Siekmann, Judith C Sluimer, Sabine Steffens, José Tuñón, Cecile Vindis, Jolanda J Wentzel, Seppo Ylä-Herttuala, Paul C Evans
Journal: Cardiovascular Research (2018)

Modulation of vessel growth holds great promise for treatment of cardiovascular disease. Strategies to promote vascularization can potentially restore function in ischaemic tissues. On the other hand, plaque neovascularization has been shown to associate with vulnerable plaque phenotypes and adverse events. The current lack of clinical success in regulating vascularization illustrates the complexity of the vascularization process, which involves a delicate balance between pro- and anti-angiogenic regulators and effectors. This is compounded by limitations in the models used to study vascularization that do not reflect the eventual clinical target population. Nevertheless, there is a large body of evidence that validate the importance of angiogenesis as a therapeutic concept. The overall aim of this Position Paper of the ESC Working Group of Atherosclerosis and Vascular biology is to provide guidance for the next steps to be taken from pre-clinical studies on vascularization towards clinical application. To this end, the current state of knowledge in terms of therapeutic strategies for targeting vascularization in post-ischaemic disease is reviewed and discussed. A consensus statement is provided on how to optimize vascularization studies for the identification of suitable targets, the use of animal models of disease, and the analysis of novel delivery methods.
Strong Programmed Death Ligand 1 Expression Predicts Poor Response and De Novo Resistance to EGFR Tyrosine Kinase Inhibitors Among NSCLC Patients With EGFR Mutation
Authors: Shan Su, Zhong-Yi Dong, Zhi Xie, Li-Xu Yan, Yu-Fa Li, Jian Su, Si-Yang Liu, Kai Yin, Rui-Lian Chen, Shu-Mei Huang, Zhi-Hong Chen, Jin-Ji Yang, Hai-Yan Tu, Qing Zhou, Wen-Zhao Zhong, Xu-Chao Zhang, Yi-Long Wu
Journal: Journal of Thoracic Oncology (2018)
An assessment of disease features and immune response in breast cancer patients that did not recur after receiving HER2 peptide, AE37 vaccine in a randomized phase II trial.
Authors: Diane F Hale, Sonia A. Perez, Timothy J Vreeland, Alfred F Trappey, Raetasha Sheavette Dabney, John S. Berry, Alexandros Ardavanis, Alan K. Sears, Michael Papamichail, Guy T. Clifton, Efi Pappou, Ritesh Patil, Eleftheria Anastasopoulou, Sathibalan Ponniah, Nathan M. Shumway, George Earl Peoples, Elizabeth Ann Mittendorf
Journal: Journal of Clinical Oncology (2012)

625 Background: In a phase I trial of AE37, the Ii-Key hybrid of HER2 derived peptide AE36 (776-790), administered with immunoadjuvant GMCSF demonstrated the vaccine to be safe and capable of stimulating CD4 + helper T cells with HER2 specific anti-tumor activity. Here we present analysis of immune markers and patient feature that may impact recurrence from an ongoing prospective, randomized, single-blinded Phase IIb trial of AE37+GMCSF v GMCSF alone in adjuvant high risk breast cancer (BC) patients. Methods: After completion of standard therapy; disease-free, node positive or high risk node negative BC patients (pts) were randomized to receive either AE37+GMCSF or GMCSF in 6 monthly intradermal inoculations. Immunologic responses were measured using [ 3 H]-thymidine incorporation assay (in vitro), delayed-type hypersensitivity (DTH) reactions (in vivo) and T regulatory cells (Tregs). Among those vaccinated recurrent pts (VR) are compared to non recurrent (VNR) pts. Results: We have vaccinated 109 pts with 8.3% recurrence rate at 2 year median follow up. VR v VNR were younger (44 v 50 yo p=0.11), had higher grade (67% v 44% p=0.32), more ER/PR- (44% v 38% p=0.75), larger tumors (89% v 50% p=0.06), and node positive (89% v 70% p=0.37). No difference for HER2 status (IHC 3+, 44% v 49% p=0.64). Both VR and VNR responded to vaccine though the mean DTH and proliferative stimulation index was approximately 10% less in VR pts (18 v 20 p=0.73; 1.96 v 2.2 p=0.77 respectively). The most predictive measure was change in Tregs with VR pts less likely to decrease their Tregs levels (50% v 76% p=0.17) after vacination and more likely experience increased Tregs (17% v 8% p=0.48). A decrease in Tregs had an inverse trend towards recurrence (p=0.17). Conclusions: Preliminarily, it appears most pts immunologically respond to vaccine though slightly less for VR in most assays. The changes of Tregs appear to correlate best with disease recurrence. Whether this reflects an association with disease status or a failure of the vaccine is yet to be seen. These levels may become important in predicting risk for clinical recurrence in future vaccine trials.