tbuckley/cabot-search huggingface dataset:
02.37 Il-37 is associated with increased atherogenesis rather than disease activity in patients with rheumatoid arthritis
Authors: Barbora Šumová, Tereza Lennerová, Romana Jandová, Hana Hulejová, Karel Pavelka, Jiří Vencovský, Ladislav Šenolt
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Interleukin-37 (IL-37) is one of few anti-inflammatory cytokines produced mainly by monocytes and dendritic cells. Recent data suggest its role in several autoimmune diseases. The aim of this study was to analyse the expression of IL-37 in synovial tissue, synovial fluid and serum of patient with established rheumatoid arthritis (RA) and osteoarthritis (OA) and to analyse its potential role in RA. <h3>Materials and methods</h3> Serum and synovial fluid levels of IL-37 were determined in 52 patients with established RA and 49 control subjects with osteoarthritis (OA) by ELISA. Disease activity was assessed based on the Disease Activity Score of 28 joints (DAS28-ESR). For <i>in vitro</i> studies, synovial tissue fibroblasts (SFs) were obtained from patients with RA and OA (n=6–9). Serum C-reactive protein (CRP) and lipid profile were determined. Immunofluorescence and immunohistological staining was used to detect IL-37 protein expression in synovial tissue (n=4–6) and SFs. <h3>Results</h3> The expression of IL-37 was upregulated in synovial tissue of patients with RA compared to OA, and co-localised with B-cell, T-cells, SFs and macrophages. In addition, stimulation with LPS increased the expression of IL-37 in RA synovial fibroblasts. However, the serum levels of IL-37 were significantly higher compared to synovial fluid levels of RA and OA patients (77.50±56.73 vs. 51.50±43.17, p&lt;0.001; 57.00±73.25 vs. 27.00±38.38, p&lt;0.001, respectively). Further, the synovial fluid levels, but not serum levels of IL-37 were significantly higher in RA patients compared to OA patients (77.5±56.73 vs. 57.0±73.25, p&lt;0.01) and there was a significant correlation between serum and synovial fluid IL-37 levels in RA patients (r=0.55, p&lt;0.001). Although, neither serum nor synovial fluid IL-37 levels were associated with disease activity, synovial fluid IL-37 levels positively correlated with serum levels of CRP (r=0.31, p&lt;0.05). Interestingly, serum levels of IL-37 negatively correlated with high density lipoprotein levels (r=−0.328, p&lt;0.05) and positively with atherogenic index (r=0.34, p&lt;0.05), suggesting that IL-37 can contribute to the cardiovascular manifestations in RA. <h3>Conclusions</h3> Our data suggest possible role of IL-37 in accelerated atherosclerosis and increased cardiovascular burden in patients with RA. <h3>Acknowledgement</h3> Supported by the project (Ministry of Health, Czech Republic) for conceptual development of research organisation 00023728 (Institute of Rheumatology).
Abstract 226: Mutual Interactive Factors β-Catenin and Oct4 Regulate Mesp1 Transcription
Authors: Yongqing Li, Robert Schwartz, Yu Liu
Journal: Circulation Research (2012)

The b-HLH family protein Mesp1 sits on the top of the regulatory hierarchy of factors that govern cardiac specification. Ectopic expression of Mesp1 drives precocious appearance of cardiac progenitors, while ablation of Mesp1 and its close genetic relative Mesp2 completely blocked the emergence of heart in mouse embryos. Despite its central importance in cardiac specification, the regulation of Mesp1 is largely unknown. In this study, we show several lines of evidences supporting that beta-catenin and Oct4 cooperate in regulating Mesp1 induction. (1) A conserved TCF/Lef-Oct4 composite binding site is identified near the transcription start site of Mesp1. (2) beta-catenin and Oct4 each activates a Mesp1-Luciferase reporter, with beta-catenin being more potent; while together, beta-catenin and Oct4 synergize in activating the Mesp1-Luciferase reporter. Point mutations within the TCF/Lef-Oct4 binding site impair reporter activation by beta-catenin. (3) beta-catenin and Oct4 individually binds to an oligo covering the putative TCF/Lef-Oct4 binging site on Mesp1 promoter, and together they form a ternary complex, as detected by electrophoresis mobility shift assays. (4) Mesp1 induction is absent in cells with null alleles of beta-catenin, or conditional null alleles of Oct4. (5) While a 6K promoter of Mesp1 effectively drives expression of a lacZ reporter at E7.5, mutants affecting the TCF/Lef-Oct4 binding site fail to do so, in transient transgenic assays. Together, our results show that the cooperation between beta-catenin and Oct4, for Mesp1 transcription and cardiac specification substantiate a novel regulatory mechanism governing cell fate determination and cardiac development, which also explain the mechanism of well-established roles of each factor in mesoderm formation and heart development. Such knowledge may be used to establish new technology to generate cardiac cells for therapeutic purposes.
Chronic Rejection of Cardiac Allografts Is Associated With Increased Lymphatic Flow and Cellular Trafficking
Authors: Lindsey A. Edwards, Anna K. Nowocin, Nazila V. Jafari, Lucy L. Meader, Kathryn Brown, Aurélien Sarde, Carolyn Lam, Alex Murray, Wilson Wong
Journal: Circulation (2017)

Background: Cardiac transplantation is an excellent treatment for end-stage heart disease. However, rejection of the donor graft, in particular, by chronic rejection leading to cardiac allograft vasculopathy, remains a major cause of graft loss. The lymphatic system plays a crucial role in the alloimmune response, facilitating trafficking of antigen-presenting cells to draining lymph nodes. The encounter of antigen-presenting cells with T lymphocytes in secondary lymphoid organs is essential for the initiation of alloimmunity. Donor lymphatic vessels are not anastomosed to that of the recipient during transplantation. The pathophysiology of lymphatic disruption is unknown, and whether this disruption enhances or hinders the alloimmune responses is unclear. Although histological analysis of lymphatic vessels in donor grafts can yield information on the structure of the lymphatics, the function following cardiac transplantation is poorly understood. Methods: Using single-photon emission computed tomography/computed tomography lymphoscintigraphy, we quantified the lymphatic flow index following heterotrophic cardiac transplantation in a murine model of chronic rejection. Results: Ten weeks following transplantation of a minor antigen (HY) sex-mismatched heart graft, the lymphatic flow index was significantly increased in comparison with sex-matched controls. Furthermore, the enhanced lymphatic flow index correlated with an increase in donor cells in the mediastinal draining lymph nodes; increased lymphatic vessel area; and graft infiltration of CD4 + , CD8 + T cells, and CD68 + macrophages. Conclusions: Chronic rejection results in increased lymphatic flow from the donor graft to draining lymph nodes, which may be a factor in promoting cellular trafficking, alloimmunity, and cardiac allograft vasculopathy.
chitobionic共役polysorbitol遺伝子輸送体による高親和性腎臓標的化はラットにおける片側尿管閉塞を軽減する【Powered by NICT】
Authors: Islam Mohammad Ariful, Kim Sanghwa, Firdous Jannatul, Lee Ah-Young, Hong Seong-Ho, Seo Min Kyeong, Park Tae-Eun, Yun Cheol-Heui, Choi Yun-Jaie, Chae Chanhee, Cho Chong-Su, Cho Myung-Haing
Journal: Biomaterials (2016)
光応答性とロッド形ナノキャリア:AuNRsキャップとCe6をドープしたメソ多孔性シリカナノロッドに基づく光トリガ光熱および光線力学療法の単一波長【Powered by NICT】
Authors: Sun Qi, You Qing, Pang Xiaojuan, Tan Xiaoxiao, Wang Jinping, Liu Li, Guo Fang, Tan Fengping, Li Nan
Journal: Biomaterials (2017)
CDHR3 gene variation and childhood bronchiolitis
Authors: Anders Husby, Anu Pasanen, Johannes Waage, Astrid Sevelsted, Hennie Hodemaekers, Riny Janssen, Minna K. Karjalainen, Jakob Stokholm, Bo L. Chawes, Matti Korppi, Göran Wennergren, Andrea Heinzmann, Louis Bont, Hans Bisgaard, Klaus Bønnelykke
Journal: Journal of Allergy and Clinical Immunology (2017)
Assessing the impact of healthcare research: A systematic review of methodological frameworks
Authors: Samantha Cruz Rivera, Derek G. Kyte, Olalekan Lee Aiyegbusi, Thomas J. Keeley, Melanie J. Calvert
Journal: PLoS Medicine (2017)

Increasingly, researchers need to demonstrate the impact of their research to their sponsors, funders, and fellow academics. However, the most appropriate way of measuring the impact of healthcare research is subject to debate. We aimed to identify the existing methodological frameworks used to measure healthcare research impact and to summarise the common themes and metrics in an impact matrix.Two independent investigators systematically searched the Medical Literature Analysis and Retrieval System Online (MEDLINE), the Excerpta Medica Database (EMBASE), the Cumulative Index to Nursing and Allied Health Literature (CINAHL+), the Health Management Information Consortium, and the Journal of Research Evaluation from inception until May 2017 for publications that presented a methodological framework for research impact. We then summarised the common concepts and themes across methodological frameworks and identified the metrics used to evaluate differing forms of impact. Twenty-four unique methodological frameworks were identified, addressing 5 broad categories of impact: (1) 'primary research-related impact', (2) 'influence on policy making', (3) 'health and health systems impact', (4) 'health-related and societal impact', and (5) 'broader economic impact'. These categories were subdivided into 16 common impact subgroups. Authors of the included publications proposed 80 different metrics aimed at measuring impact in these areas. The main limitation of the study was the potential exclusion of relevant articles, as a consequence of the poor indexing of the databases searched.The measurement of research impact is an essential exercise to help direct the allocation of limited research resources, to maximise research benefit, and to help minimise research waste. This review provides a collective summary of existing methodological frameworks for research impact, which funders may use to inform the measurement of research impact and researchers may use to inform study design decisions aimed at maximising the short-, medium-, and long-term impact of their research.
Abstract 14194: Health-related Quality of Life After Out-of-hospital Cardiac Arrest : Analysis of the Parisian Registry
Authors: Guillaume Geri, Florence Dumas, Franck Bonnetain, Wulfran Bougouin, Benoit Champigneulle, Michel Arnaout, Jean Daniel Chiche, Frédéric Pène, Jean-Paul Mira, Jean-Philippe Empana, Alain Cariou
Journal: Circulation (2015)

Introduction: Data on health-related quality of life (HRQOL) of resuscitated out-of-hospital cardiac arrest (OHCA) patients remain scarce. Our aims were to compare long-term HRQOL of OHCA with that of the general population, and to assess factors associated with better HRQOL. Methods: We used a large cohort of OHCA patients admitted in a tertiary medical intensive care unit. The main outcome was HRQOL (SF-36 questionnaire). Each OHCA case was matched with 4 controls of same age and sex issued from general French population. The associations between pre and intra hospital variables and early interventions with the SF-36 dimensions were investigated using MANCOVA. Results: During the study period (2000-2013), 1829 OHCA patients were admitted and 602 have been discharged alive. SF-36 interview took place 50 [22-93] months after OHCA. Between discharge and the interview, 137 patients died, 210 were lost of follow-up and then 255 (median age 55 [45,64] y., mostly male (73.7%)) were interviewed. Initial rhythm was shockable in 210 (82.4%) cases. Global physical and mental components did not differ between OHCA survivors and general population (47.0 vs. 47.1, p=0.88 and 46.4 vs. 46.9, p=0.45). However, physical functioning and vitality were significantly altered in OHCA survivors (Figure. SF-36 dimensions of 255 OHCA patients (grey rectangles) and of matched controls (black circles)). Younger age and male gender were independently associated with almost all SF-36 dimensions. Initial VF/VT was associated with a gain in most of the SF-36 dimensions. Successful PCI was associated with a gain in physical functioning (+7.0, p=0.06) and in general health (+7.3, p=0.02) and in vitality (+4.4, p=0.08). Conclusions: HRQOL of OHCA survivors appears similar to general population, but some physical components of SF36 scale were significantly altered. Younger age, male gender, initial shockable rhythm and coronary reperfusion were independently associated with a better HRQOL.
02.11 Il-38 is not involved in the modulation of imq-induced skin inflammation
Authors: Jennifer Palomo, Sabina Troccaz, Emiliana Rodriguez, Dominique Talabot-Ayer, Cem Gabay, Gaby Palmer
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Psoriasis is a common chronic skin disorder caused by a dysregulated crosstalk between immune and resident cells (eg, keratinocytes). The identification of the pathogenic role of several cytokines in psoriasis led to the development of successful therapies. Recently, IL-36 cytokines, which belong to the IL-1 family, were shown to be involved in the pathogenesis of psoriasis. Mice deficient in IL-36 receptor (IL-36R) were protected from imiquimod (IMQ)-induced skin inflammation, whereas IL-36R antagonist (IL-36Ra) KO mice exhibited a more severe phenotype. The objective of our study was to examine the expression and function of IL-38, a newly discovered IL-1 family member with supposed IL-36 inhibitory properties, in the IMQ model of psoriasis. <h3>Materials and methods</h3> IL-38 mRNA expression was determined in skin samples, at steady state or after IMQ application. IL-38 KO or IL-36Ra KO mice and their respective WT littermates were challenged with the topical application of IMQ on the left ear during 7 days. The severity of skin inflammation was assessed by daily measurement of ear thickness using a calliper, by semi-quantitative histologic scoring, and by measuring mRNA levels of inflammatory markers. <h3>Results</h3> At the peak of IMQ-induced skin inflammation, IL-38 mRNA levels were lower than in normal skin, whereas IL-36Ra mRNA levels were increased in IMQ treated skin. The severity of skin inflammation, as assessed by ear thickness, histological changes (leukocyte infiltration and epidermis hyperplasia) and pro-inflammatory mediator transcript levels, was not significantly different in IL-38 KO and WT mice. After cessation of topical IMQ application, the resolution of skin inflammation was also not altered by IL-38 deficiency. As opposed to these findings, IL-36Ra deficient mice displayed more severe pathological changes as compared to WT mice. <h3>Conclusions</h3> We showed that endogenous IL-38 is not involved in the development and the resolution of IMQ-induced skin inflammation. Our findings suggest that IL-38 does not exert IL-36 inhibitory activities in the skin.
PTU-059 Burden of liver disease in the west midlands: increased premature mortality
Authors: N Bhala, S Haroon, S Burwood, C Pennell, H Carter, A Daley, E Day, A El Sharkaway, J Ferguson, D Freshwater, V Gordon, A Holt, A Mittal, J Mukarati, I Perry, A Phillips, N Quann, M Tahir, R Thomson, E Unitt, C Bray, N Dennis, G Wrench
Journal: Gut (2017)

Introduction  Liver disease is a leading cause of premature death in the UK. We sought to assess the public health burden of common liver diseases in the West Midlands by measuring premature mortality.  Method  Routine data from Public Health England (PHE) Alcohol and Liver Disease West Midlands Profiles, principally from 2012–16 were assessed. Sources include the Office of National Statistics mortality and population estimates. Specific diseases assessed include: alcoholic liver disease (ALD); non-alcoholic fatty liver disease (NAFLD); chronic viral hepatitis B and C; and hepatocellular cancer (HCC).  Results  Premature mortality due to liver disease under 75 years was higher in West Midlands compared to rest of England (19.2 versus 17.8 deaths per 100,000). This was especially marked in Sandwell, Wolverhampton, Birmingham, Stoke-on-Trent and Dudley. Average annual liver disease deaths also vary by gender, age, and deprivation.  Despite a higher proportion of teetotallers (22%–25%), premature mortality of ALD under 75 years was higher than the national average (10.2 versus 8.6 deaths per 100,000). Premature mortality under 75 years from chronic viral hepatitis related end-stage liver disease/HCC were similar to the national average, and those for mortality under 75 years from NAFLD were lower than the national average.  Conclusion  Premature liver mortality under 75 years is significantly higher in the West Midlands compared to the rest of England. A collaborative liver health network in the West Midlands is required to help tackle the burden of preventable liver mortality.  References  . Annual Report of the Chief Medical Officer Report on Liver Disease2012  . Lancet Liver Commission Lancet2014  Disclosure of Interest  None Declared
Randomized phase II trial (RENO): Efficacy results of oral vinorelbine or etoposide combined with cisplatin in chemo-radiotherapy treatment of locally advanced NSCLC (LA-NSCLC)—SLCG 10/02.
Authors: Mariano Provencio, Ramon de las Penas, Amelia Insa, Natividad Martinez-Banaclocha, Raquel Marse Fabregat, Pilar Mut Sanchis, Teresa Moran, Angeles Sala, Bartomeu Massuti, Ana Laura Ortega, Jose Miguel Jurado, Jose Gómez-Codina, Pilar Diz, Angel Artal-Cortes, Vanesa Gutierrez Calderon, Maria Francisca Vazquez, Nuria Vinolas, Miguel Angel Muñoz Quintana, Ramon Garcia-Gomez, Dolores Isla
Journal: Journal of Clinical Oncology (2016)

8538 Background: This study aims to compare efficacy and safety of two widely used combinations of cisplatin (P) in this setting: as etoposide (E) and vinorelbine. This last, in its oral formulation (oV) which has achieved comparable results as the IV formulation and patients (pts) prefer it. Methods: Pts between 18-75years, with histologically proven untreated and unresectable LA-NSCLC, adequate respiratory function, V20 ≤ 35% and ECOG-PS 0-1, were randomized 1:1 to oV-P arm:2 induction cycles (cy) of oV-P followed by 2 cy more with RT; or to E-P arm: 2 cy of E-P concomitants to RT. Both arms with a total radiation dose of 66Gy administered 2 Gys daily. Primary endpoint was progression free survival (PFS) by RECIST 1.1. Secondary endpoints: overall response rate (ORR), overall survival (OS) and safety. With α-error of 0.05 (one-tailed test) and 0.1 β-error, median PFS unacceptable for the oV-P arm of 10 months (m) (p0) and a very acceptable of 15 m (p1), 122 eligible pts were required. Results: 140 pts from 23 institutions of SLCG were randomized between 08/2011-12/2014. 134 pts were treated (66 in oV-P and 68 in E-P arms). Results based on this 134 pts are presented. Median age 62 years [39-76]; PS 0/1, 45%/55%; current smoker 51%; squamous cell 51%; stage IIIB 54%. 244 and 131 cy were given in the oV-P and E-P arms, respectively. All irradiated pts in oV-P arm received at least 60Gy, 7 pts in the E-P arm received less than 60Gy (4 due to toxicity). 1 pt (1.5%) in oV-P arm and 12 pts (17.6%) in E-P arm presented esophagitis G3/4 (p = 0.002). 121 confirmed eligibility for efficacy analysis. ORR were 39 (64%) and 40 pts (67%) in the oV-P and E-P arms, respectively (p = 0.889). After 16 m [1-43] of follow-up, 66% pts progressed and 43% pts died. Median PFS is 11.4 m (IC95%; 6-17) in oV-P arm and 11.8 m (IC95%; 7-16) in E-P arm (p = 0.374). Conclusions: Both regimens achieve similar efficacy however oV-P has less toxicity, especially esophagitis G3/4. Further follow-up is needed for the survival analysis. Clinical trial information: EudraCT number 2010-022927-31.
Reply to Verbanck and Vanderhelst: The Respective Roles of Lung Clearance Index and Magnetic Resonance Imaging in the Clinical Management of Patients with Cystic Fibrosis
Authors: Nikhil Kanhere, Marcus J. Couch, Jonathan H. Rayment, Felix Ratjen, Giles Santyr
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
SAT0014 The mutated RNA splicing protein HNRNP-A3 is a novel autoantigen in systemic rheumatic diseases a link to warburg effect in RA
Authors: B Marklein, M Hansson, G Steiner, G Burmester, K Skriner
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The present study was undertaken to investigate novel anti-hnRNPs autoantibodies in rheumatic diseases. <h3>Objectives</h3> Novel mutated hnRNP A3 was cloned out of RA synovial tissue linking it directly to Warburg effect and lactate production in RA. Increased lactate production in RA synovia and tumors is klinked to alternative splicing process from PKM1 to PKM2 hnRNPs dependent. <h3>Methods</h3> After immunobloting and 2D-gel-eletrophoresis of a semipurified hnRNP fraction two protein spots were sequenced and identified to be highly similar to hnRNPA3. The hnRNP A3 variants were cloned from RA synovial tissue, which identified the isoforms found on protein level. 3700 RA sera were screened for the presence of mutated anti-hnRNP A3 autoantibodies using recombinant proteins and peptides thereof. Binding of RNA to hnRNP A3 (MA3) and mutated citrullinated A3 peptides (MCA3) the epitope recognition was investigated. Expression of hnRNP A3 in synovial tissue was analysed by <h3>Results</h3> Autoantibodies to MA3 protein were detected in 13% of RA (n=215) patients, in 9% SLE (n=154), in 27% of MCTD patients (n=44/10) and in less than 5% of 129 patients with other rheumatic disorders but not at all in healthy controls on immunoblot. When using renaturated MA3 on ELISA 22% of RA patients were detected and 87% of these patients had erosive arthritis. Same modification as in cancer cells were identified in synovial tissue and verified by MS and DNA sequencing. Using 2–3 citrullinated MCA3 peptides up to 81% of patients (n=150) with established and 67% (n=2926) of patients with an early RA with a specificity of 97% were detected. In early RA 27% and 25% in established RA of CCP2 negative and 93% of CCP2 positive patients were identified. By combining with the already established CCP2 and the new MCA3, 72% of early patients are positive. MCA3 autoantibodies predominantly occur (p&lt;0.001) in an erosive, severe course of disease and approximately 60% of these patients receive a TNF alpha blocker within a year. MRL Lpr/lpr sera were hnRNP-A3 reactive and the antibody generation is Toll 7 and 9 dependent. Anti-hnRNP-A3-antibodies are directed to conformational RNA binding epitopes. Expression of hnRNP-A3 revealed the antigen to be overexpressed in RA synovial tissue. <h3>Conclusions</h3> Mutated hnRNP-A3 is as a novel Toll7/9 dependent autoantigen in systemic rheumatic diseases. These mutated proteins are major components of RNA and DNA containing alternative splicing complexes leading to the Warburg effect and and autoantibodies predominantly occurre in an erosive, and severe courses of RA. <h3>Disclosure of Interest</h3> None declared