tbuckley/cabot-search huggingface dataset:
Untangling the protease web in COPD: metalloproteinases in the silent zone
Authors: Simon R Johnson
Journal: Thorax (2016)

The idea that unregulated protease activity underlies the pathogenesis of COPD has been prominent since the recognition that genetic loss of α1 antitrypsin led to unregulated neutrophil elastase activity and premature emphysema.1 Increased proteolysis by other proteases, particularly the matrix metalloproteinases (MMPs), has since been implicated in COPD. The MMPs are a family of over 20 zinc-dependent endopeptidases, initially identified as extracellular matrix (ECM) degrading enzymes and classified according to their ECM substrates. In individual studies, genetic association, overexpression, and in fewer cases, activity of individual proteases have been associated with COPD in humans and smoke-induced emphysema in animals. While a number of MMPs and disintegrin and metalloproteinases have been studied in COPD at some level, most interest has focused on MMP-1, MMP-12 and MMP-9. MMP-1 is overexpressed by alveolar macrophages, type II pneumocytes and airway epithelial cells. The protein is induced by cigarette smoke and is capable of degrading collagens I and III, the most abundant lung proteins.2 ,3 MMP-9 expressed by neutrophils and macrophages is overexpressed in COPD although MMP-9 activity, rather than protease expression, is suppressed in stable patients compared with healthy smokers but activated during exacerbations.4 ,5 Although MMP-9 has elastase activity in vitro, its action in COPD may be due to generation of prolyl–glycine–proline (PGP), a collagen-derived neutrophil chemotactic matrikine rather than elastolysis.6 MMP-12 is an elastase associated with the development of COPD by genome-wide association study,7 whose presence and activity in sputum are associated airflow obstruction8 and in which single-nucleotide polymorphisms that reduce enzyme activity are associated with protection from emphysema in COPD.9 While the ‘classical’-matrix-degrading actions of these proteases can be easily related to the pathogenesis of COPD, unfortunately the reality is not that straightforward. …
Retinal lipid and glucose metabolism dictates angiogenesis through the lipid sensor Ffar1
Authors: Jean-Sébastien Joyal, Ye Sun, Marin L Gantner, Zhuo Shao, Lucy P Evans, Nicholas Saba, Thomas Fredrick, Samuel Burnim, Jin Sung Kim, Gauri Patel, Aimee M Juan, Christian G Hurst, Colman J Hatton, Zhenghao Cui, Kerry A Pierce, Patrick Bherer, Edith Aguilar, Michael B Powner, Kristis Vevis, Michel Boisvert, Zhongjie Fu, Emile Levy, Marcus Fruttiger, Alan Packard, Flavio A Rezende, Bruno Maranda, Przemyslaw Sapieha, Jing Chen, Martin Friedlander, Clary B Clish, Lois E H Smith
Journal: Nature Medicine (2016)
Apocynin augments IL-6, IL-8 and TNF expression in A549 cells
Authors: Joanna Stefanska, Milena Sokolowska, Rafal Pawliczak
Journal: European Respiratory Journal (2011)

Reactive oxygen species (ROS) play an important role in many pathways and processes. An enzyme responsible for ROS production - NADPH oxidase represents an attractive therapeutic target. Apocynin is a small molecule that reversibly blocks NADPH oxidase activation and therefore inhibits ROS formation.

Apocynin, in our previous studies, reduced some ROS concentrations in exhaled breath condensate of asthmatics, COPD patients, and healthy subjects. Therefore we decided to investigate apocynin influence on expression of IL-6, IL-8 and TNF in vitro .

A549 cells were incubated with apocynin in concentrations: 0.25, 0.5, 1, 2 and 3 mg/ml. After 1h, 2h and 4h of incubation with each concentration RNA was isolated and reverse transcription was made. mRNA expression was assessed using real-time PCR.

Time-response analysis revealed apocynin most effective influence after 2 and 4 hours of incubation. It caused increased expression of IL-6 (expression level (RQ) 0.64 – 2h and 0.62 – 4h vs. 0.007 – base), and IL-8 (RQ 25.18 – 2h and 25.12 – 4h vs. 1.74 – base) in A549. Moreover, apocynin caused TNF expression increase in A549 after one and four hours of incubation (RQ 0.037 – 1h and 0.036 – 4h vs. 0.017 – base).

Dose-response analysis showed apocynin to be most effective in concentration of 0.5 mg/ml. This dose caused increase of IL-6 expression (RQ 2 vs. 0.02 - control sample (CS)) and IL-8 expression (RQ 101 vs. 2 - CS, but also 1 mg/ml – RQ 30 vs. 2 - CS). TNF expression was increased in samples incubated with 0.25 mg/ml (RQ 0,037 vs. 0.02 - CS)

These findings may provide a novel therapeutic strategy and might be of importance in relation to inflammatory diseases.
Prediction of First Cardiovascular Disease Event in Type 1 Diabetes Mellitus
Authors: Dorte Vistisen, Gregers Stig Andersen, Christian Stevns Hansen, Adam Hulman, Jan Erik Henriksen, Henning Bech-Nielsen, Marit Eika Jørgensen
Journal: Circulation (2016)

Background— Patients with type 1 diabetes mellitus are at increased risk of developing cardiovascular disease (CVD), but they are currently undertreated. There are no risk scores used on a regular basis in clinical practice for assessing the risk of CVD in type 1 diabetes mellitus. Methods and Results— From 4306 clinically diagnosed adult patients with type 1 diabetes mellitus, we developed a prediction model for estimating the risk of first fatal or nonfatal CVD event (ischemic heart disease, ischemic stroke, heart failure, and peripheral artery disease). Detailed clinical data including lifestyle factors were linked to event data from validated national registers. The risk prediction model was developed by using a 2-stage approach. First, a nonparametric, data-driven approach was used to identify potentially informative risk factors and interactions (random forest and survival tree analysis). Second, based on results from the first step, Poisson regression analysis was used to derive the final model. The final CVD prediction model was externally validated in a different population of 2119 patients with type 1 diabetes mellitus. During a median follow-up of 6.8 years (interquartile range, 2.9–10.9) a total of 793 (18.4%) patients developed CVD. The final prediction model included age, sex, diabetes duration, systolic blood pressure, low-density lipoprotein cholesterol, hemoglobin A 1c , albuminuria, glomerular filtration rate, smoking, and exercise. Discrimination was excellent for a 5-year CVD event with a C-statistic of 0.826 (95% confidence interval, 0.807–0.845) in the derivation data and a C-statistic of 0.803 (95% confidence interval, 0.767–0.839) in the validation data. The Hosmer-Lemeshow test showed good calibration ( P &gt;0.05) in both cohorts. Conclusions— This high-performing CVD risk model allows for the implementation of decision rules in a clinical setting.
Public supports commercial access to patient records when public benefit is clear
Authors: Nigel Hawkes
Journal: BMJ (2016)

Most people are willing to have their health records used by commercial organisations, as long as there is a clear public benefit and it is not solely for private profit.

The conclusions emerged from one of the most detailed studies yet into what the public thinks about the use of its data by commercial organisations.1 The Wellcome Trust commissioned Ipsos MORI to carry out the research, which included workshops and a poll of 2000 people. The aim was to inform and influence a review being carried out for the health secretary for England, Jeremy Hunt, by Fiona Caldicott, the national data guardian.

The Caldicott review, which is expected to be published soon, will include …
Patterns of PD-L1 expression and CD8 T cell infiltration in gastric adenocarcinomas and associated immune stroma
Authors: Elizabeth D Thompson, Marianna Zahurak, Adrian Murphy, Toby Cornish, Nathan Cuka, Eihab Abdelfatah, Stephen Yang, Mark Duncan, Nita Ahuja, Janis M Taube, Robert A Anders, Ronan J Kelly
Journal: Gut (2016)

<h3>Objective</h3> Recent data supports a significant role for immune checkpoint inhibitors in the treatment of solid tumours. Here, we evaluate gastric and gastro-oesophageal junction (G/GEJ) adenocarcinomas for their expression of programmed death-ligand 1 (PD-L1), infiltration by CD8+ T cells and the relationship of both factors to patient survival. <h3>Design</h3> Thirty-four resections of primary invasive G/GEJ were stained by immunohistochemistry for PD-L1 and CD8 and by DNA in situ hybridisation for Epstein–Barr virus (EBV). CD8+ T cell densities both within tumours and at the tumour–stromal interface were analysed using whole slide digital imaging. Patient survival was evaluated according to PD-L1 status and CD8 density. <h3>Results</h3> 12% of resections showed tumour cell membranous PD-L1 expression and 44% showed expression within the immune stroma. Two cases (6%) were EBV positive, with one showing membranous PD-L1 positivity. Increasing CD8+ densities both within tumours and immune stroma was associated with increasing percentage of tumour (p=0.027) and stromal (p=0.005) PD-L1 expression. Both tumour and immune stromal PD-L1 expression and high intratumoral or stromal CD8+ T cell density (&gt;500/mm<sup>2</sup>) were associated with worse progression-free survival (PFS) and overall survival (OS). <h3>Conclusions</h3> PD-L1 is expressed on both tumour cells and in the immune stroma across all stages and histologies of G/GEJ. Surprisingly, we demonstrate that increasing CD8 infiltration is correlated with impaired PFS and OS. Patients with higher CD8+ T cell densities also have higher PD-L1 expression, indicating an adaptive immune resistance mechanism may be occurring. Further characterisation of the G/GEJ immune microenvironment may highlight targets for immune-based therapy.
Paediatrician shortage is putting child services at risk, warns college
Authors: Adrian O’Dowd
Journal: BMJ (2016)

A shortage of paediatricians could put the health of children at risk, a report from the Royal College of Paediatrics and Child Health has warned.

The college’s latest workforce survey report, published on 7 March, found that increasing numbers of trainee paediatricians were opting to take time out of clinical training to take part in research, while others were taking parental leave.1

These changing patterns of work meant that many more doctors would need to be recruited to the specialty to ensure …
Analysis of the genomic profile of biphenotypic tumors compared to cholangiocarcinoma and hepatocellular carcinoma.
Authors: Jesse W. Keller, Maria Majella Doyle, Andrea Wang-Gillam, Elizabeth Brunt, Neeta Vachhajarani, William Chapman, Benjamin R. Tan
Journal: Journal of Clinical Oncology (2014)

226 Background: Biphenotypic (combined HCC/Cholangiocarcinoma) tumors represent a minority of primary liver cancers. While databases such as the Catalog of Somatic Mutations in Cancer (COSMIC) have genetic information on a large number of cases of HCC and Cholangiocarcinoma, there is little known about rarer Biphenotypic tumors. In this analysis we examine the results of targeted next-generation sequencing to assess genomic differences between these tumors. We utilize the COSMIC database for comparison. Methods: The database of theIRB-approved Washington University Hepatobiliary Registry identified patients with HCC, cholangiocarcinoma and biphenotypic tumors with specimens evaluated utilizing next generation sequencing via a Comprehensive Cancer Gene Set. Further data on corresponding genes was collected from the COSMIC database (v66) for comparison. Results: In this descriptive analysis 15 patients with biphenotypic tumors, 7 patients with HCC and 6 patients with cholangiocarcinoma are presented. The percent of samples with corresponding genetic mutations are outlined (table). These are compared to existing COSMIC data. Conclusions: Biphenotypic tumors had high levels of mutations in EGFR, P53 and Flt3. Mutations in MET, BRAF, CSF1, and MAPK1 were largely isolated to biphenotypic tumors. Mutations in CTNBB1 were isolated to cases of HCC. Notably, mutations in EGFR, Flt3 and FGFR4 were found in all three tumors in higher numbers than seen via review of COSMIC data. Overall, Biphenotypic tumors are genetically complex tumors that share many features of HCC and cholangiocarcinoma. [Table: see text]
Elevated exhaled NO is a predictor of exercise-induced bronchoconstriction in adolescents
Authors: Henrik Johansson, Christer Janson, Katarina Norlander, Kjell Alving, Leif Nordang, Lennart Nordvall, Andrei Malinovschi, Margareta Emtner
Journal: European Respiratory Journal (2014)

Exhaled nitric oxide (FeNO) is a marker of airway inflammation in asthma and high FeNO levels can predict later onset of asthma in healthy children. Elevated FeNO relates to bronchial responsiveness to mannitol in population-based studies of young adults, but the relation to exercise-induced bronchoconstriction (EIB) has been limitedly studied in such a setting.

FeNO measurement and standardized exercise challenge test were performed in 128 adolescents, 13-16 years, representing a subsample from a population-based study analyzing prevalence of exercise-induced dyspnea. Subjects with current asthma were excluded.

Subjects with EIB (FEV1-fall ≥10%) (n=39) had higher FeNO than subjects without EIB (n=89); 17.0 ppb (CI 13.4, 21.4) vs. 13.0 (CI 11.5, 14.6), p=0.03. Subjects with EIB were characterized by being more likely to report exercise-induced dyspnea, to have a FeNO>20 ppb, a lower pre-exercise FEV1 and having a trend towards comprising a higher proportion of females and subjects with ever asthma (Table 1). High FeNO (>20 ppb) (OR 3.6 (1.3, 10.1)), exercise-induced dyspnea (OR 3.6 (1.2, 10.8)) and female gender (OR 3.1 (1.1, 9.1)) were independent predictors of EIB in a multiple logistic regression model, adjusted for variables in Table 1.

In conclusion, elevated FeNO, exercise-induced dyspnea and female gender were independently related to EIB in adolescents.

View this table:

Table 1
Abstract 3561: Relation of Serum Heat Shock Protein 60 Level to Severity and Prognosis in Chronic Heart Failure
Authors: Takeshi Niizeki, Masaki Oguma, Yasuchika Takeishi, Isao Kubota
Journal: Circulation (2009)

Background: Heat shock proteins 60 (Hsp 60) are induced by a variety of stressors including anoxia, oxidative stress, and inflammatory and have a protective role against stress-induced cardiomyocyt...
State and Territorial Ebola Screening, Monitoring, and Movement Policy Statements — United States, August 31, 2015
Authors: Gregory Sunshine, Dawn Pepin, Marty Cetron, Matthew Penn
Journal: MMWR Morbidity and Mortality Weekly Report (2015)

Abbreviation: CI = confidence interval.* Used cigarettes or cigars on one or more days, but did not use marijuana during the 30 days preceding the surveys.† Used marijuana one or more times, but did not use cigarettes or cigars during the 30 days preceding the surveys.§ Used cigarettes or cigars on one or more days, or used marijuana one or more times during the 30 days preceding the surveys.¶ Students with missing data for cigarette use, cigar use, marijuana use, or sex and students who did not self-identify as non-Hispanic black, non-Hispanic white, or Hispanic were excluded from the analysis.** Significant linear trend during 1997-2013 (p<0.01).† † Significant quadratic trend during 1997-2013 (p<0.01).
Abstract 2731: Establishment and characterization of immortalized nasopharyngeal epithelial cells with stable infection of Epstein-Barr virus
Authors: Lin Jia, Chi Man Tsang, Yim Ling Yip, Wai Tak Law, Jun Zhang, George SW Tsao
Journal: Cancer Research (2015)

Abstract Nasopharyngeal carcinoma (NPC), with a remarkably distinctive ethnic and geographic distribution, has the highest incidence among Southern Chinese. Unlike other types of head and neck cancers, a unique feature of NPC is its close association with Epstein-Barr virus (EBV). EBV infection represents an early event during the pathogenesis of NPC. Latent EBV infection is found in every cancer cell of virtually all cases of undifferentiated NPC in endemic regions. Genetic alterations in the premalignant epithelium may support the EBV latency. Although EBV-encoded proteins in its latent infection, including LMP1, LMP2A, etc., have been identified with crucial functions to initiate or promote oncogenesis, to date the exact role of EBV infection in the malignant transformation of nasopharyngeal epithelial (NPE) cells remains unclear. We have previously generated a panel of immortalized NPE cells by ectopic overexpression of hTert (catalytic unit of human telomerase). However, reliable in vitro models of stable EBV infection are also necessary for further elucidating the regulatory network supporting the persistent latency of EBV in NPE cells, and also the potential roles of EBV in the pathogenesis of NPC. In the present study, we established NP361hTert-EBV cells with stable EBV infection via co-culture with Akata B cells harboring EBV, followed by the effective enrichment of EBV-infected cells by FACS sorting. The loss of EBV episome in NPE cells was fast initially upon infection, and relatively stable maintenance of EBV could be achieved after enrichment of EBV-positive cells for three times. Results of western blotting analysis showed that the protein expression level of cyclin D1 was increased in NP361hTert-EBV cells, as compared to the non-infected NP361hTert cells. Meanwhile, we also observed increased expression of phosphorylated protein kinase Akt (Ser473) in NP361hTert-EBV cells, suggesting that the Akt signaling was activated, and such activation might contribute to the persistence of EBV in NP361hTert cells. The stable EBV-infected NPE cells will serve as a powerful in vitro model for further study in elucidating the functional role of EBV in the carcinogenesis of NPC. This work was partly supported by General Research Fund (HKU 779713M, HKU780911M), and the AoE NPC grant (AoE/M-06/08) from Hong Kong Research Grant Council; and Small Project Funding (201309176242) from The University of Hong Kong. Citation Format: Lin Jia, Chi Man Tsang, Yim Ling Yip, Wai Tak Law, Jun Zhang, George SW Tsao. Establishment and characterization of immortalized nasopharyngeal epithelial cells with stable infection of Epstein-Barr virus. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2731. doi:10.1158/1538-7445.AM2015-2731
Prioritizing Environmental Chemicals for Obesity and Diabetes Outcomes Research: A Screening Approach Using ToxCast™ High-Throughput Data
Authors: Scott Auerbach, Dayne Filer, David Reif, Vickie Walker, Alison C. Holloway, Jennifer Schlezinger, Supriya Srinivasan, Daniel Svoboda, Richard Judson, John R. Bucher, Kristina A. Thayer
Journal: Environmental Health Perspectives (2016)

Background:Diabetes and obesity are major threats to public health in the United States and abroad. Understanding the role that chemicals in our environment play in the development of these conditions is an emerging issue in environmental health, although identifying and prioritizing chemicals for testing beyond those already implicated in the literature is challenging. This review is intended to help researchers generate hypotheses about chemicals that may contribute to diabetes and to obesity-related health outcomes by summarizing relevant findings from the U.S. Environmental Protection Agency (EPA) ToxCast™ high-throughput screening (HTS) program.Objectives:Our aim was to develop new hypotheses around environmental chemicals of potential interest for diabetes- or obesity-related outcomes using high-throughput screening data.Methods:We identified ToxCast™ assay targets relevant to several biological processes related to diabetes and obesity (insulin sensitivity in peripheral tissue, pancreatic islet and β cell function, adipocyte differentiation, and feeding behavior) and presented chemical screening data against those assay targets to identify chemicals of potential interest.Discussion:The results of this screening-level analysis suggest that the spectrum of environmental chemicals to consider in research related to diabetes and obesity is much broader than indicated by research papers and reviews published in the peer-reviewed literature. Testing hypotheses based on ToxCast™ data will also help assess the predictive utility of this HTS platform.Conclusions:More research is required to put these screening-level analyses into context, but the information presented in this review should facilitate the development of new hypotheses.Citation:Auerbach S, Filer D, Reif D, Walker V, Holloway AC, Schlezinger J, Srinivasan S, Svoboda D, Judson R, Bucher JR, Thayer KA. 2016. Prioritizing environmental chemicals for obesity and diabetes outcomes research: a screening approach using ToxCast™ high-throughput data. Environ Health Perspect 124:1141–1154; http://dx.doi.org/10.1289/ehp.1510456
HLA-Incompatible Kidney Transplantation — Worth the Risk?
Authors: Lionel P.E. Rostaing, Paolo Malvezzi
Journal: New England Journal of Medicine (2016)

Chronic kidney diseases are a major worldwide societal burden. In the United States, where the prevalence of chronic kidney disease is approximately 14%,1 close to 1 million persons have end-stage renal disease (ESRD). Of those affected, 700,000 (70.8%) are treated with dialysis, and the remaining 300,000 (29.2%) with kidney transplantation (i.e., 56 cases per 1 million population).2 Currently, just over 100,000 U.S. patients with ESRD are on the waiting list for a kidney transplant, but every year, only 15 to 16% will receive a kidney transplant, and of those kidneys, 32 to 34% are from live donors.3Annual U.S. expenditures . . .
Abstract 18936: Can Biomarkers Improve Risk Stratification of Atrial Fibrillation Patients? Analysis of 3578 Aspirin-treated Patients in ACTIVE and AVERROES
Authors: Thomas Vanassche, Stuart J Connolly, John W Eikelboom, Jeff S Healey, Mandy N Lauw, Simona Masiero, Jia Wang, Salim Yusuf
Journal: Circulation (2014)

Oral anticoagulants (OAC) reduce thromboembolism (TE) in atrial fibrillation (AF) but increase the risk of bleeding. Current approaches to risk stratification emphasize high sensitivity for stroke (>90%) but results in poor specificity (<20%), potentially exposing some patients unnecessarily to an increased risk of bleeding. NT-proBNP, D-dimer, and troponin predict stroke in anticoagulated AF patients, but it is unknown whether they can improve the specificity of selecting patients for OAC therapy. We analyzed rates of non-hemorrhagic stroke or systemic embolism according to baseline NT-proBNP, D-dimer, and troponin in 3578 aspirin-treated patients with CHA2DS2-VASc ≥1. Using the 1st quartile as a cut-off, we calculated hazard ratios (HR) of high vs low biomarker levels, adjusting for CHA2DS2-VASc factors. We used a Cox model to assess TE risk prediction with CHA2DS2-VASc compared with CHA2DS2-VASc plus biomarkers. Based on efficacy and safety data from AVERROES, we estimated the net clinical impact (addi...
Transfer of Blood Lymphocytes and Macrophages Between Histocompatible Progressor and Regressor Chickens Infected With Rous Sarcoma Virus&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: C E Whitfill, W J Akbar, N R Gyles, J A Thoma
Journal: JNCI Journal of the National Cancer Institute (1986)

The development of histocompatible White Leghorn (progressor) and Arkansas Regression (regressor) chicken lines was described. When challenged with Rous sarcoma virus, progressor chickens developed fatal tumors while the regressor chickens eliminated the sarcoma. When sensitized histocompatible peritoneal macrophages and blood lymphocytes were transferred from regressor donors to progressor recipients, they both eradicated growing tumors. Histoincompatible cells were ineffective in inducing tumor remission. Within the two age groups tested, the sensitized blood lymphocytes and macrophages were only effective when transferred between age-matched donor and recipient chickens.