tbuckley/cabot-search huggingface dataset:
FRI0411 Dual pro-inflammatory and anti-fibrotic role of il-17a in systemic sclerosis skin
Authors: A.M. Dufour, M. Alvarez, S. Lemeille, M.-E. Truchetet, N.C. Brembilla, C. Chizzolini
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Increased levels of IL-17A have been reported in systemic sclerosis (SSc) which role in fibrogenesis is still debated.<sup>1</sup> Furthermore, epithelial cells are preferential targets of IL-17A and recent findings suggest that keratinocytes may participate in dysregulated extracellular matrix homeostasis.<sup>2</sup> <h3>Objectives</h3> Our aim was to investigate the interactions between epidermis and dermis in the presence of IL-17A, taking into perspective the fibrotic process. <h3>Methods</h3> Primary human keratinocytes were primed with IL-17A and/or TGF-β and conditioned-media were used to stimulate healthy donors (HD) and SSc fibroblasts. Alternatively, organotypic cultures of HD full human skin were challenged with these cytokines. Responses were assessed by quantifying inflammatory mediators and type I collagen (Col-I) levels. The factors produced by keratinocytes were identified by a proteomic approach and their contribution was evaluated by neutralisation assays. Changes in gene expression in full human skin after treatment with IL-17A and/or TGF-β were analysed by RNA sequencing (RNA-seq). <h3>Results</h3> Unstimulated HD- and SSc-derived keratinocyte-conditioned media (KCM) promoted collagen production by fibroblasts to a similar extent and in a dose-dependent manner. Cytokine array analysis and neutralising assays showed that TGF-β was, at least in part, responsible for the pro-fibrotic effect of KCM. Priming of keratinocytes with IL-17A directly decreased Col-I production and significantly reduced Col-I induced by TGF-β both in SSc and HD fibroblasts. In full human skin, IL-17A promoted pro-inflammatory responses by inducing 2- to 4-fold increase of IL-8, IL-6, MCP-1 and MMP-1 levels, while showing direct anti-fibrotic effects, as well as decreasing by 2-fold collagen production triggered by TGF-β (p=0.02). RNA-seq revealed that TGF-β induced the expression of many collagen genes, while this was not the case for IL-17A. However, IL-17A promoted a pro-inflammatory signature in the skin and strongly downregulated expression of serpin family members, known to be involved in fibrogenesis. <h3>Conclusions</h3> Keratinocytes profoundly influence dermal fibroblast responses, which are further modulated in the presence of IL-17A. These data support a role for keratinocytes in the pathogenesis of SSc. IL-17A acts as a potent anti-fibrotic factor in the model of keratinocyte – fibroblast interactions, as well as in the full human skin, promoting pro-inflammatory and anti-fibrotic responses. <h3>References</h3> [1] Truchetet ME, et al. Arthritis &amp; Rheumatol2013;65:1347–56. doi:10.1002/art.37860 [2] Takahashi T, et al, J Exp Med. 2017Feb 23. doi:10.1084/jem.20160247 <h3>Acknowledgements</h3> Work supported in part by grant 310030–1 59 999 from the Swiss National Science Foundation to CC. <h3>Disclosure of Interest</h3> None declared
ESC Working Group on Cellular Biology of the Heart: position paper for Cardiovascular Research: tissue engineering strategies combined with cell therapies for cardiac repair in ischaemic heart disease and heart failure
Authors: Rosalinda Madonna, Linda W Van Laake, Hans Erik Botker, Sean M Davidson, Raffaele De Caterina, Felix B Engel, Thomas Eschenhagen, Francesco Fernandez-Aviles, Derek J Hausenloy, Jean-Sebastien Hulot, Sandrine Lecour, Jonathan Leor, Philippe Menasché, Maurizio Pesce, Cinzia Perrino, Fabrice Prunier, Sophie Van Linthout, Kirsti Ytrehus, Wolfram-Hubertus Zimmermann, Peter Ferdinandy, Joost P G Sluijter
Journal: Cardiovascular Research (2019)

Morbidity and mortality from ischaemic heart disease (IHD) and heart failure (HF) remain significant in Europe and are increasing worldwide. Patients with IHD or HF might benefit from novel therapeutic strategies, such as cell-based therapies. We recently discussed the therapeutic potential of cell-based therapies and provided recommendations on how to improve the therapeutic translation of these novel strategies for effective cardiac regeneration and repair. Despite major advances in optimizing these strategies with respect to cell source and delivery method, the clinical outcome of cell-based therapy remains unsatisfactory. Major obstacles are the low engraftment and survival rate of transplanted cells in the harmful microenvironment of the host tissue, and the paucity or even lack of endogenous cells with repair capacity. Therefore, new ways of delivering cells and their derivatives are required in order to empower cell-based cardiac repair and regeneration in patients with IHD or HF. Strategies using tissue engineering (TE) combine cells with matrix materials to enhance cell retention or cell delivery in the transplanted area, and have recently received much attention for this purpose. Here, we summarize knowledge on novel approaches emerging from the TE scenario. In particular, we will discuss how combinations of cell/bio-materials (e.g. hydrogels, cell sheets, prefabricated matrices, microspheres, and injectable matrices) combinations might enhance cell retention or cell delivery in the transplantation areas, thereby increase the success rate of cell therapies for IHD and HF. We will not focus on the use of classical engineering approaches, employing fully synthetic materials, because of their unsatisfactory material properties which render them not clinically applicable. The overall aim of this Position Paper from the ESC Working Group Cellular Biology of the Heart is to provide recommendations on how to proceed in research with these novel TE strategies combined with cell-based therapies to boost cardiac repair in the clinical settings of IHD and HF.
AB0686 Arterial aneurysms in behcet’sdisease: a retrospective descriptive analysis and long-term outcome
Authors: N.H.A. El Ghobashy, A. EL-Garf, K. EL-Garf
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Behcet's Disease (BD) was described in 1937 after Hulusi Bechet; as a triad of recurrent aphthous and genital ulcers together with iridocyclitis.<sup>1,2</sup> Arterial disease is seen in 3%–5% of the patients.<sup>3,4</sup> Thrombosis and/or aneurysmal formation are common sequelae mainly false aneurysms(.<sup>5</sup> In spite of the fact that BD is not uncommon in the clinical practice in Egypt; the paucity of data that looked specifically to the arterial aneurysms in the Egyptian patients with BD had prompted the present study. <h3>Objectives</h3> Arterial aneurysm in Behçet's disease is a rare manifestation of Behçet's disease. The presence of Arterial aneurysm in Behçet's disease change the course of disease and it is management remains a challenge for rheumatologists <h3>Methods</h3> A retrospective revision of files of 160 patients admitted and followed up in the rheumatology department, Cairo University Hospitals between 2004–2017 was done. We looked specifically for the prevalence of arterial aneurysms. Demographic characteristics of patients with aneurysms, clinical presentation, and associated clinical features. <h3>Results</h3> Twenty-seven (16.8%) patients had arterial aneurysms. All of them were males and the onset of development of the aneurysm is usually under the age of 40 years, 74% of the patients developed aneurysm3.2±3.0 years after their disease onset. Apart from the oro-genital ulcerations; deep venous thrombosis was the most common associated manifestation. Pulmonary artery was the most common artery involved in 12 (44.4%) of patients, followed by the abdominal aorta in 4 (14.8%). Surgical intervention was done for 11 (40.7%) patients; all of them received cyclophosphamide pulses before surgery except one. Four (14.8%) patients in this study died. <h3>Conclusions</h3> Arterial aneurysms are common in Egyptian patients with BD. The profile of Egyptian BD patient that is susceptible for development of arterial aneurysm is a male patient, under the age of 40 years, smoker with relatively short disease duration. <h3>References</h3> [1] Behcet H. Uber rezidivierende, aphthosedurchein virus verursachtegeschwure am mund, am auge und an der genitalen. DermatologischeWochenschrift1937;36: 1152–1157 [2] Mutlu S, Scully C. The person behind the eponym: HulusiBehcet (1889–1948). J Oral Pathol Med1994;23:289–290. [3] Sarica-Kucukoglu R, Akdag-Kose A, KayabalI M,Yazqanoqlu KD, Disci R, Erzengin D, et al. Vascular involvement in Behçet's disease: a retrospective analysis of 2319 cases. Int J Dermatol2006; 45:919–921. [4] Saadoun D, Asli B, Wechsler B, Houman H, Geri G, Desseaux K, et al. Long-term Outcome of Arterial Lesions in Behcet's Disease. A series of 101 patients. Medicine (Baltimore). 2012;91:24–31. [5] Hamuryudan V, Er T, Seyahi E, Akman C, Tuzun H, Fresko I, et al. Pulmonary artery aneurysms in Behcet syndrome. Am J Med2004,117: 867–870. <h3>Disclosure of Interest</h3> None declared
Lentiglobin Gene Therapy for Patients with Transfusion-Dependent β-Thalassemia (TDT): Results from the Phase 3 Northstar-2 and Northstar-3 Studies
Authors: Franco Locatelli, Mark C. Walters, Janet L. Kwiatkowski, John Porter, Martin G. Sauer, Isabelle Thuret, Suradej Hongeng, Andreas E. Kulozik, Ashutosh Lal, Adrian J. Thrasher, Evangelia Yannaki, Heidi Elliot, Ge Tao, Mohammed Asmal, Alexis A. Thompson
Journal: Blood (2018)
AB0623 Pregnancy outcome in systemic lupus erythematosus: a retorspective study
Authors: R. Dumitriu, C. Vasiliu
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Pregnancy represents a challenge for patients with systemic lupus erythematosus. One of the major risk is the occurence of a flare during pregnancy. The influences are mutual, and the risk of complications depend mostly on the disease activity in the last 6–12 months before pregnancy. Therefore, these patients need a multidisciplinary approach, the obstetrician should collaborate with the rheumatologist and nephorologist. <h3>Objectives</h3> To determinate the associations between disease activity and pregnancy outcomes, and the risk factors that predict pregnancy complications and flare. <h3>Methods</h3> We present a retrospective study conducted between january 2010 and december 2015. We enrolled 35 pregnant patients, diagnosed with SLE with ages between 21 and 46 years old. All patients were followed up since the beginning of the pregnancy until delivery. We tested the correlations between different biomarkers and clinical manifestations of disease activity and pregnancy outcomes. <h3>Results</h3> Maternal complications occured in 71,24% of the cases. The most common complications were: miscarriages, hematologic abnormalities (anemias, thrombocytopenia), premature birth and preeclampsia. The prematurity rate was 11% and most common delivery mode was the caesarian section. Also, the planning of the pregnancy was a predictor of a good fetal outcome (p=0,01). The presence of the lupus anticoagulant was associated with prematurity (p=0,046) at univaryate analysis. Antiphospholipidic syndrome was associated in 12% of the cases. Univaryate analysis did not show a correlation between the presence of the syndrome and any pregnancy outcome. <h3>Conclusions</h3> Pregnancy should be planned when the disease is in remission. Lupus nephritis, is an important risk factor for preeclampsia. Also, the presence of lupus anticoagulant is a risk factor for preeclampsia, and hematologic determinations during pregnancy. The risk factors for pregnancy complications were; secondary antiphospholipid syndrome, presence of lupus nephropaty, thrombocytopenia. our study showes that the exacerbations depend on the disease activity in the moment of conception. <h3>Disclosure of Interest</h3> None declared
Diagnostic Performance of Dobutamine Stress Echocardiography in End-Stage Liver Disease
Authors: Anisiia T. Doytchinova, Thomas D. Feigenbaum, Roja C. Pondicherry-Harish, Peter Sepanski, Deborah Green-Hess, Harvey Feigenbaum, Stephen G. Sawada
Journal: JACC. Cardiovascular imaging (2019)
Loss of HDAC3 results in nonreceptive endometrium and female infertility
Authors: Tae Hoon Kim, Jung-Yoon Yoo, Kyung-Chul Choi, Jung-Ho Shin, Richard E. Leach, Asgerally T. Fazleabas, Steven L. Young, Bruce A. Lessey, Ho-Geun Yoon, Jae-Wook Jeong
Journal: Science Translational Medicine (2019)

Histone deacetylase 3 plays a critical role for early pregnancy through transcriptional regulation of COL1A1 and COL1A2 genes.
Noninvasive Mechanical Joint Loading as an Alternative Model for Osteoarthritic Pain
Authors: Freija ter Heegde, Ana P. Luiz, Sonia Santana‐Varela, Iain P. Chessell, Fraser Welsh, John N. Wood, Chantal Chenu
Journal: Arthritis & Rheumatology (2019)

Mechanisms responsible for osteoarthritic (OA) pain remain poorly understood, and current analgesic therapies are often insufficient. This study was undertaken to characterize and pharmacologically test the pain phenotype of a noninvasive mechanical joint loading model of OA, thus providing an alternative murine model for OA pain.The right knees of 12-week-old male C57BL/6 mice were loaded at 9N or 11N (40 cycles, 3 times per week for 2 weeks). Behavioral measurements of limb disuse and mechanical and thermal hypersensitivity were acquired before mechanical joint loading and monitored for 6 weeks postloading. The severity of articular cartilage lesions was determined postmortem with the Osteoarthritis Research Society International scoring system. To assess efficacy of various treatments for pain, 9N-loaded mice were treated for 4 weeks with diclofenac (10 mg/kg), gabapentin (100 mg/kg), or anti-nerve growth factor (anti-NGF) (3 mg/kg).Mechanical hypersensitivity and weight bearing worsened significantly in 9N-loaded mice (n = 8) and 11N-loaded mice (n = 8) 2 weeks postloading, compared to baseline values and nonloaded controls. Maximum OA scores of ipsilateral knees confirmed increased cartilage lesions in 9N-loaded mice (mean ± SEM 2.8 ± 0.2; P < 0.001) and 11N-loaded mice (5.3 ± 0.3; P < 0.001), compared to nonloaded controls (1.0 ± 0.0). Gabapentin and diclofenac restored pain behaviors to baseline values after 2 weeks of daily treatment, and gabapentin was more effective than diclofenac. A single injection of anti-NGF alleviated nociception 2 days after treatment and remained effective for 2 weeks, with a second dose inducing stronger and more prolonged analgesia.Our findings show that mechanical joint loading induces OA lesions in mice and a robust pain phenotype that can be reversed using analgesics known to alleviate OA pain in patients. This establishes the use of mechanical joint loading as an alternative model for the study of OA pain.
Genetics Coming of Age in Type 1 Diabetes
Authors: Karen Cerolsaletti, Wei Hao, Carla J. Greenbaum
Journal: Diabetes Care (2019)

Decades of studies demonstrate that ∼50% of risk for type 1 diabetes (T1D) is heritable (1). The first loci linked to T1D were the HLA genes that have the largest effect size of any T1D susceptibility locus, followed by linkage of the insulin VNTR to T1D (2,3). Linkage studies have given way to genome-wide association studies (GWAS) that have identified >50 loci that contribute risk for developing T1D (4). Most of these loci impart modest relative risk for T1D (odds ratio ≤2.0) and together with HLA account for ∼80% of the heritability of T1D (5). The question remains: have GWAS delivered in terms of our ability to understand the causes of T1D and thus identify therapeutic targets or predict disease course?

GWAS have revealed several important aspects of T1D disease etiology. First, the majority of genes associated with T1D function in the immune system, underscoring the immune basis of disease initiation and progression (6). Second, GWAS have identified pathways that are important in disease pathogenesis, such as variants in the interleukin-2 (IL-2) signaling pathway ( IL2 , IL2RA , and PTPN2 loci) that are associated with disease (4,7,8). Third, T1D GWAS studies have identified a shared genetic architecture with other autoimmune diseases (e.g., PTPN22 , CTLA4 , SH2B3 , TYK2 , and CLEC16A loci), indicating common pathogenic mechanisms and the possibility of repurposing therapies for T1D that are in use for other autoimmune diseases. Additionally, genotype-phenotype studies have provided important windows into disease pathogenesis by revealing alterations in B-cell and T-cell development, tolerance checkpoints, regulatory T-cell fitness, …
Abstract 16894: The Effect of Cangrelor on Cardiovascular and Bleeding Events in Patients With Peripheral Artery Disease - Insights From CHAMPION PHOENIX
Authors: Antonio Gutierrez, Robert A Harrington, Gregg W Stone, Ph. G Steg, Michael C Gibson, Christian W Hamm, Matthew J Price, Jayne Prats, Efthymios N Deliargyris, Kenneth Mahaffey, Harvey D White, Deepak L Bhatt
Journal: Circulation (2015)

Background: Patients with peripheral artery disease (PAD) are high risk for adverse cardiovascular and bleeding events. In CHAMPION-PHOENIX, cangrelor, an intravenous P2Y12 inhibitor, reduced rates of ischemic events in patients undergoing PCI. Hypothesis: We hypothesize that cangrelor will safely reduce ischemic events in patients with PAD undergoing PCI. Methods: A total of 11,145 patients were randomly assigned in a double-dummy, double-blind manner to either cangrelor followed by clopidogrel 600 mg or to clopidogrel loading at PCI. The primary endpoint was a composite of death, MI, ischemia-driven revascularization (IDR), or stent thrombosis (ST) at 48 hours. Results: 837 (8%) patients with PAD and 9,994 (90%) patients with no prior history of PAD underwent PCI. Among the PAD cohort the primary endpoint occurred in 20 (4.5%) cangrelor vs. 44 (11.4%) clopidogrel patients (OR [95% CI] = 0.36 [0.21, 0.63]), and 235 (4.7%) cangrelor vs. 276 (5.5%) clopidogrel patients (OR [95%CI] = 0.86 [0.72, 1.03]) without PAD (p for interaction = 0.003). Among the PAD cohort the rate of GUSTO severe/life-threatening bleeding was 0.4% cangrelor vs. 0% clopidogrel (p = 0.19), and 0.1% cangrelor vs. 0.1% clopidogrel patients (OR [95%CI] = 1.78 [0.52, 6.07], p = 0.35) without PAD (p for interaction = 0.34). The rate of blood transfusion in the PAD cohort was 0.9% cangrelor vs. 0% clopidogrel (p = 0.06), and 0.4% cangrelor vs. 0.3% clopidogrel patients (OR [95%CI] = 1.42 [0.73, 2.76], p = 0.30) without PAD (p for interaction = 0.13). Conclusion: In CHAMPION-PHOENIX, cangrelor significantly reduced ischemic events with no significant increase in severe bleeding or transfusions in patients with PAD.
Abstract 16446: Modified Application of SAME-TTR Scoring System in Asian Patients With Atrial Fibrillation for the Selection of Oral Anticoagulants
Authors: Ki Hong Lee, Hyung Wook Park, Nam Sik Yoon, Jeong Gwan Cho, Ji Eun Kim, Youngkeun Ahn, Myung Ho Jeong, Jong Chun Park
Journal: Circulation (2016)

Introduction: Oral anticoagulants (OACs) are highly recommended to prevent thromboembolism (TE) in patients with atrial fibrillation (AF). SAMe-TT2R2 score has been utilized for the assessment of q...
Incidence and Mortality of Acute‐on‐Chronic Liver Failure Using Two Definitions in Patients with Compensated Cirrhosis
Authors: Nadim Mahmud, David E. Kaplan, Tamar H. Taddei, David S. Goldberg
Journal: Hepatology (2019)

The term acute‐on‐chronic liver failure (ACLF) is intended to identify patients with chronic liver disease who develop rapid deterioration of liver function and high short‐term mortality after an acute insult. The two prominent definitions (European Association for the Study of the Liver [EASL] and Asian Pacific Association for the Study of the Liver [APASL]) differ, and existing literature applies to narrow patient groups. We sought to compare ACLF incidence and mortality among a diverse cohort of patients with compensated cirrhosis, using both definitions. This was a retrospective cohort study of patients with incident compensated cirrhosis in the Veterans Health Administration from 2008 to 2016. First ACLF events were identified for each definition. Incidence rates were computed as events per 1,000 person‐years, and mortality was calculated at 28 and 90 days. Among 80,383 patients with cirrhosis with 3.35 years median follow‐up, 783 developed EASL and APASL ACLF, 4,296 developed EASL ACLF alone, and 574 developed APASL ACLF alone. The incidence rate of APASL ACLF was 5.7 per 1,000 person‐years (95% confidence interval [CI]: 5.4‐6.0), and the incidence rate of EASL ACLF was 20.1 (95% CI: 19.5‐20.6). The 28‐day and 90‐day mortalities for APASL ACLF were 41.9% and 56.1%, respectively, and were 37.6% and 50.4% for EASL ACLF. The median bilirubin level at diagnosis of EASL‐alone ACLF was 2.0 mg/dL (interquartile range: 1.1‐4.0). Patients with hepatitis C or nonalcoholic fatty liver disease had among the lowest ACLF incidence rates but had the highest short‐term mortality. Conclusion: There is significant discordance in ACLF events by EASL and APASL criteria. The majority of patients with EASL‐alone ACLF have preserved liver function, suggesting the need for more liver‐specific ACLF criteria.
Exposure to Perfluoroalkyl Substances during Fetal Life and Pubertal Development in Boys and Girls from the Danish National Birth Cohort
Authors: Andreas Ernst, Nis Brix, Lea Lykke Braskhøj Lauridsen, Jørn Olsen, Erik Thorup Parner, Zeyan Liew, Lars Henning Olsen, Cecilia Høst Ramlau-Hansen
Journal: Environmental Health Perspectives (2019)

Background: It remains unsettled whether prenatal exposure to perfluoroalkyl substances (PFASs) affects human reproductive health through potential endocrine disruption. Objectives: We aimed to explore the associations between prenatal exposure to several PFASs and various aspects of pubertal development in boys and girls. Methods: We studied two samples (n=722 and 445) from the Puberty Cohort, nested within the Danish National Birth Cohort (DNBC), measuring PFAS in maternal plasma from early gestation. Data on pubertal development were collected biannually from the age of 11 y until full maturation, using web-based questionnaires. Outcomes were age at menarche, voice break, first ejaculation, and Tanner stages 2 to 5 for pubic hair, breast, genital development, and a combined puberty indicator. A regression model for censored data was used to estimate mean difference (months) in age at achieving the pubertal outcomes across tertiles of PFAS concentrations and with a doubling of PFAS concentrations (continuous). For perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), a meta-analysis was used to provide a weighted average of the point estimates from samples 1 and 2. Results: Overall, prenatal exposure to PFOS, perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonate (PFHpS), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PDFA) (girls) and PFHxS and PFHpS (boys) was associated with lower mean age at puberty marker onset. PFDA and PFNA exposure was associated with higher mean age at onset of puberty in boys. Nonmonotonic associations in girls (PFOS, PFHpS, PFDA) and boys (PFDA, PFNA) were observed, showing larger mean age differences for the combined puberty indicator in the middle tertile [girls: PFOS: −3.73 mo, 95% confidence interval (CI): −6.59, −0.87; PFHpS: −4.92 mo, 95% CI: −11.68, 1.85; PFDA: −3.60 mo, 95% CI: −9.03, 1.83; and boys: PFNA: 4.45 mo, 95% CI: −1.30, 10.21; PFDA: 4.59 mo, 95% CI: −0.93, 10.11] than in the highest tertile with the lowest as reference. Conclusions: Our population-based cohort study suggests sex-specific associations of altered pubertal development with prenatal exposure to PFASs. These findings are novel, and replication is needed. https://doi.org/10.1289/EHP3567