tbuckley/cabot-search huggingface dataset:
OP0327 Cxcl4 drives fibrosis by promoting several key cellular and molecular processes
Authors: W. Marut, A. Affandi, T. Carvalheiro, A. Ottria, J. Haan, M. Brandt, R. Tieland, M. Brans, B. Malvar-Fernandez, C. Bekker, M. van der Linden, B. Giovannone, D.-J. Heijnen, A. Kowalska, R. Lafyatis, C. Cheng, S. de Jager, J. van Roon, T. Radstake
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Fibrosis, characterised by excessive accumulation of extracellular matrix (ECM) through myofibroblasts, is a leading cause of mortality worldwide<sup>1,2</sup>. Understanding the pathways involved in myofibroblasts activation is crucial to develop novel treatment strategies. Systemic sclerosis (SSc) is a prototypic fibrotic disease in which we previously identified CXCL4 to be strongly correlated with skin and lung fibrosis<sup>3</sup>. <h3>Objectives</h3> We aimed to elucidate the role of CXCL4 in fibrosis development using <i>in vitro</i> and <i>in vivo</i> assays. <h3>Methods</h3> Human primary dermal fibroblasts, endothelial cells, and pericytes, were (co-) cultured in the presence or absence of recombinant human CXCL4. CXCL4-/- mice were used in bleomycin-induced skin and lung fibrosis model, and pressure-overload cardiac fibrosis model. Gene expression was assessed by qPCR, protein expression was determined by western blot or immunofluorescence, and collagen content was measured by trichrome staining or hydroxyproline assay. <h3>Results</h3> We found that CXCL4 induced the expression of myofibroblast markers αSMA and SM22α, and collagen synthesis in human dermal fibroblasts, endothelial cells, and pericytes. CXCL4 also suppressed endothelial cell tubular formation in a co-culture with pericytes. In mice, CXCL4 expression was increased in a variety of mouse inflammatory and fibrotic models. Using CXCL4-/- mice, we confirmed the essential role of CXCL4 in promoting fibrotic events in the skin, lung, and heart using two independent fibrosis models. <h3>Conclusions</h3> CXCL4 drives myofibroblast transformation from different precursors and it is required for fibrosis development across organs. Our findings implicate a pivotal role of CXCL4 in fibrosis further substantiating the potential role for neutralising CXCL4 as a novel therapeutic strategy. <h3>References</h3> [1] Rockey, Bell, Hill, N. Engl. J. Med2015. [2] Hinz B, et al. Am. J. Pathol2007. [3] van Bon, Affandi, Broen, et al. N. Engl. J. Med2015. <h3>Disclosure of Interest</h3> None declared
FRI0657 Construct validity and responsiveness of three stiffness items in rheumatoid arthritis: an application of the omeract filter 2.1
Authors: E.T. Craig, C.O. Bingham, S.J. Bartlett, U. Haque, A. Leong, A.-M. Orbai
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background:</h3> Stiffness is frequent and important to people with rheumatoid arthritis (RA), but measuring it is an unmet need. Qualitative research with people with RA has shown that stiffness duration, severity and interference have face and content validity. These items are being evaluated to develop a patient reported outcome measure (PROM) for stiffness. <h3>Objectives:</h3> To evaluate individual stiffness item measurement properties using the OMERACT Filter 2.1. <h3>Methods:</h3> Consecutive patients in a longitudinal RA cohort were enrolled. Participants completed 3 items assessing stiffness severity, interference, and duration. PROMs collected included patient global assessment (PGA), pain VAS, self-reported flare (Y/N), PROMIS measures, and patient global impression of change (PGIC). Physician assessments included 28 tender/swollen joint counts, and global (EGA). Disease activity indices were CDAI and DAS28-CRP. Stiffness construct validity was assessed using Spearman correlation coefficients. To assess discrimination in groups expected to change vs stable groups, we calculated standardized response means (SRMs) using multiple anchors. <h3>Results:</h3> 196 patients with RA were included. Construct validity: all stiffness items correlated highly with pain; moderately with DAS-28 CRP and CDAI; and low with joint counts and EGA. Stiffness severity and interference correlated highly with PGA, pain interference and fatigue. Stiffness interference correlated highly with physical function. Discrimination: all stiffness items had moderate effect size for resolution of flare, and for 'much improved' by PGIC. Interference had moderate effect for improved CDAI category and for 'little improved' by PGIC. Stiffness duration had large effect for new RA flare, and 'much worse' by PGIC; severity and interference had moderate effect for RA flare; severity had moderate effect for worsened CDAI and for 'little worse' and 'much worse' by PGIC (Tbl). <h3>Conclusions:</h3> In this cohort of RA patients there is emerging evidence for good construct validity for stiffness duration, severity and interference; moderate discrimination for improvement in RA disease state, and moderate to high discrimination for worsening RA. Additional items are being tested to assemble an instrument for measuring stiffness in RA. <h3>Disclosure of Interest:</h3> None declared
Transcriptomic Profiling of the Tumor Microenvironment Reveals Distinct Subgroups of Clear Cell Renal Cell Cancer: Data from a Randomized Phase III Trial
Authors: A. Ari Hakimi, Martin H. Voss, Fengshen Kuo, Alejandro Sanchez, Ming Liu, Briana G. Nixon, Lynda Vuong, Irina Ostrovnaya, Ying-Bei Chen, Victor Reuter, Nadeem Riaz, Yuan Cheng, Parul Patel, Mahtab Marker, Albert Reising, Ming O. Li, Timothy A. Chan, Robert J. Motzer
Journal: Cancer Discovery (2019)

Abstract Metastasis remains the main reason for renal cell carcinoma (RCC)–associated mortality. Tyrosine kinase inhibitors (TKI) impart clinical benefit for most patients with RCC, but the determinants of response are poorly understood. We report an integrated genomic and transcriptomic analysis of patients with metastatic clear cell RCC (ccRCC) treated with TKI therapy and identify predictors of response. Patients in the COMPARZ phase III trial received first-line sunitinib or pazopanib with comparable efficacy. RNA-based analyses revealed four distinct molecular subgroups associated with response and survival. Characterization of these subgroups identified mutation profiles, angiogenesis, and macrophage infiltration programs to be powerful predictors of outcome with TKI therapy. Notably, predictors differed by the type of TKI received. Our study emphasizes the clinical significance of angiogenesis and immune tumor microenvironment and suggests that the critical effects its various aspects have on TKI efficacy vary by agent. This has broad implications for optimizing precision treatment of RCC. Significance: The determinants of response to TKI therapy in metastatic ccRCC remain unknown. Our study demonstrates that key angiogenic and immune profiles of the tumor microenvironment may affect TKI response. These findings have the potential to inform treatment personalization in patients with RCC. This article is highlighted in the In This Issue feature, p. 453
Abstract 11189: Single Phone Call Follow-up Was an Effective Strategy to Improve Heart Failure Patients’ Outcomes
Authors: Tsuey-yuan Huang, Li-Yueh Huang, Ming-Fen Tsai, Chun-Li Wang, Chun-Chi Chen, Terry A Lennie
Journal: Circulation (2014)

Introduction: Shorten hospital stays for health insurance reasons limits time for patient education. Although empirical studies demonstrated more intensive outpatient follow up can ameliorate psych...
SP0072 Does obesity influence ra outcomes ?
Authors: P.D. Kiely
Journal: Annals of the Rheumatic Diseases (2018)

<h3></h3> The prevalence of obesity at diagnosis of rheumatoid arthritis (RA) has doubled in N. European and N. American populations from ~14% ten years ago to ~30% now. Several prospective studies of patients with early RA, treated with csDMARD regimes, have found an association of baseline obesity with worse short and long term outcomes including DAS28 remission, low DAS, HAQ, pain assessed by VAS and SF36 physical and mental components. The most recently published cohorts report O.R. of obese RA patients at baseline achieving DAS28 remission of 0.71 (0.55–0.93) at 2 years (versus non obese) and 0.53 (0.39–0.71) at 3 years (versus normal BMI). A variety of composite responses (DAS28, CDAI, SDAI, EULAR) to TNF inhibitors, whether given in fixed dose s.c. or weight dosed i.v. formulations are significantly worse in obese RA patients from trial and registry data. In contrast the DAS28 response to Rituximab in RA patients is not affected by BMI, and ACR responses in Abatacept and Tocilizumab treated RA patients, whilst numerically less good in obese patients, are not disadvantaged by fixed s.c. dosing in comparison to i.v. dosing adjusted by weight. Obesity is an increasingly prevalent co-morbidity and is associated with worse outcomes, including DAS28 remission, HAQ and pain scores. <h3>Disclosure of Interest</h3> P. Kiely Speakers bureau: BMS, Pfizer, Roche
Gene-by-Sex Interactions in Mitochondrial Functions and Cardio-Metabolic Traits
Authors: Frode Norheim, Yehudit Hasin-Brumshtein, Laurent Vergnes, Karthickeyan Chella Krishnan, Calvin Pan, Marcus M. Seldin, Simon T. Hui, Margarete Mehrabian, Zhiqiang Zhou, Sonul Gupta, Brian W. Parks, Axel Walch, Karen Reue, Susanna M. Hofmann, Arthur P. Arnold, Aldons J. Lusis
Journal: Cell Metabolism (2019)
Nanomedicine, Biofabrication, Tissue Engineering and Much More – <i>Advanced Healthcare Materials</i> Welcomes 2019
Authors: Emily Hu, Irem Bayindir‐Buchhalter, Uta Goebel
Journal: Advanced Healthcare Materials (2019)

has been a very successful year for Advanced Healthcare Materials.While completing its 7 th year of publication, we have published more articles than ever before, have received record submissions, and achieved an Impact Factor increase to 5.609.The most important highlights of 2018 were our three Special issues at the frontiers of biomaterials research:Just recently we
<i>Rhodiola</i> species: A comprehensive review of traditional use, phytochemistry, pharmacology, toxicity, and clinical study
Authors: Hongxun Tao, Xu Wu, Jiliang Cao, Yu Peng, Anqi Wang, Jin Pei, Jianbo Xiao, Shengpeng Wang, Yitao Wang
Journal: Medicinal Research Reviews (2019)

Rhodiola species, belonging to the family Crassulaceae, have long been used as an adaptogen, tonic, antidepressant, and antistress medicine or functional food in Asia and Europe. Due to the valuable application, the growing demand of Rhodiola species has led to a rapid decrease in resource content. This review aims to summarize the integrated research progress of seven mainstream Rhodiola species. We first outline both traditional and current use of Rhodiola for the treatment of various diseases. A detailed summary and comparison of chemical, pharmacological, toxicological, and clinical studies of various Rhodiola species highlight recent scientific advances and gaps, which gives insights into the understanding of Rhodiola application and would be helpful to improve the situation of biological resources and diversities of Rhodiola plants.
p53-Suppressed Oncogene TET1 Prevents Cellular Aging in Lung Cancer
Authors: Piotr T. Filipczak, Shuguang Leng, Carmen S. Tellez, Kieu C. Do, Marcie J. Grimes, Cynthia L. Thomas, Stephanie R. Walton-Filipczak, Maria A. Picchi, Steven A. Belinsky
Journal: Cancer Research (2019)

The role of transcriptional regulator ten-eleven translocation methylcytosine dioxygenease 1 (TET1) has not been well characterized in lung cancer. Here we show that TET1 is overexpressed in adenocarcinoma and squamous cell carcinomas. TET1 knockdown reduced cell growth in vitro and in vivo and induced transcriptome reprogramming independent of its demethylating activity to affect key cancer signaling pathways. Wild-type p53 bound the TET1 promoter to suppress transcription, while p53 transversion mutations were most strongly associated with high TET1 expression. Knockdown of TET1 in p53-mutant cell lines induced senescence through a program involving generalized genomic instability manifested by DNA single- and double-strand breaks and induction of p21 that was synergistic with cisplatin and doxorubicin. These data identify TET1 as an oncogene in lung cancer whose gain of function via loss of p53 may be exploited through targeted therapy-induced senescence. SIGNIFICANCE: These studies identify TET1 as an oncogene in lung cancer whose gain of function following loss of p53 may be exploited by targeted therapy-induced senescence.See related commentary by Kondo, p. 1751.
SAT0166 Which biologic agent is most suitable for an extended-interval treatment for rheumatoid arthritis ? results from a multicenter study
Authors: K. Katayama, H. Matsuno, T. Matsubara
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background:</h3> Biological disease-modifying antirheumatic drugs (bDMARDs) have made apparent development of treating rheumatoid arthritis (RA). However, prescription of them appeared to be relatively difficult due to high cost. The newest EULAR recommendation advocates tapering of bDMARDs when RA activity is controlled. <h3>Objectives:</h3> A multicenter clinical study on a longer interval treatment with three bDMARDs, Golimumab (GOL), which is one of TNF inhibitors, and two of non-TNF inhibitor, Tocilizumab (TCZ) and Abatacept (ABT) was investigated. <h3>Methods:</h3> Patients, who were maintained at low disease activity by DAS28 score for more than 3 months treated with GLM, TCZ, ABT, were enrolled. These selected patients were treated with these drugs with 1.5 fold longer interval of standard schedule for 60 weeks, and the rate of patients, who preserved low disease activity were determined. The patients who were not tolerated these drugs because of the side effects or adverse events, were withdrawn from this study. <h3>Results:</h3> One hundred thirty-one patients treated with GLM, 149 with ABT (S.C. 61, I.V. 88) and 299 with TCZ (S.C. 87, I.V. 212) were enrolled. Among these, 57 patients treated with GLM (43%), 40 with ABT(26%, S.C 18, I.V 22), 93 with TCZ (31%, S.C 21, I.V 72) were successfully maintained at low disease activity with this 1.5 folds longer interval treatment, respectively. The age of patients in ABT group was 73.5±10.6, and significantly higher than those in TCZ (58.8±13.9) and GOL (58.1±14.7) groups. At 60 weeks, DAS28 in ABT group was 3.1±0.5, and significantly higher than those in TCZ (2.6±0.7) and GLM (2.6±0.7) groups. On the other hand, CDAI in GOL was 6.6±3.4, and was significantly higher than those in TCZ (4.4±2.6) or ABT (4.6±2.3) groups. Accordingly, successive rate at 60th week in ABT group was 52% and significantly lower than those in TCZ (69%) or in GOL (73%) groups as shown in figure. Finally, no significant difference in successive rate was observed between s.c. and i.v. <h3>Conclusions:</h3> This study clarified that TCZ and GLM had higher successive rate than ABT for maintaining low disease activity for 60 weeks by longer interval treatment. This effectiveness might relate to the high therapeutic efficacy of TCZ and low antigenicity of GOL. <h3>Disclosure of Interest:</h3> None declared
AB0522 Tacrolimus in refractory lupus nephritis: a prospective multicentric study carried out in clinical practice setting
Authors: M. Larosa, M. Zen, L. Iaccarino, A. Tincani, L. Andreoli, F. Conti, F.R. Spinelli, G. De Marchi, S. De Vita, A. Doria
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> The efficacy of tacrolimus (TAC) in lupus nephritis (LN) has been recently demonstrated in several randomised controlled trials in asian cohorts.<sup>1</sup> Nevertheless, data on real-life experience and long-term safety of TAC are still lacking. <h3>Objectives</h3> To assess efficacy and safety of TAC in SLE patients with refractory LN in a multi-centric prospective cohort. <h3>Methods</h3> Adult SLE patients with refractory LN from 4 Italian centres were prospectively followed for at least 12 months. Clinical and serological variables and previous/concomitant medications were collected at baseline,3,6,12 months after starting TAC. Renal response was assessed by using EULAR/ERA-EDTA definitions.<sup>2</sup> Adverse events (AEs) included non-infectious and infectious AEs; they were defined severe (SAE) when hospitalisation and/or death and/or life-threatening manifestations occurred. Data were analysed using SPSS (v.24.0). <h3>Results</h3> Thirteen SLE patients (8 females,5 males, mean age 33.7±10.2, mean disease duration 11.9±5.9) were enrolled (table 1). Concomitant medications included: prednisone(100%), mycophenolate mofetil(92.3%), hydroxychloroquine(53.8%), azathioprine(7.7%), belimumab(7.7%) and cyclosporine(7.7%). The average number of previous immunosuppressants taken by each patient was 3.15±1.90. Six-months renal response was achieved by 5/13 patients (38.5%): complete renal response (CRR) in 3 (60.0%) and partial renal response (PRR) in 2 patients (40.0%). Twelve-months renal response occurred in 4/13 patients (30.8%): CRR in 2/13 (50.0%) and PRR in 2/13 (50.0%). One patient achieved CRR at 6 and 12 months; one patient achieved PRR at 6 months and CRR at 12 months. Six patients (46.1%) discontinued TAC after an average follow up period of 10.2±7.8 months. Causes of discontinuation were: 3 non-infectious non-SAEs, 1 flare, 1 non-infectious SAE, and 1 non-response. Concerning AEs, no severe infections or deaths occurred. <h3>Conclusions</h3> Our preliminary data from clinical practice setting suggest that TAC could be a therapeutic rescue strategy for refractory LN. Further studies are needed to prove TAC efficacy in the long term. <h3>References</h3> [1] Mok CC, Ying KY, Yim CW, et al. Tacrolimus versus mycophenolate mofetil for induction therapy of lupus nephritis: a randomised controlled trial and long-term follow-up. Ann Rheum Dis2016;75:30e6. [2] Bertsias GK, Tektonidou M, Amoura Z, et al. Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis2012;0:1–12. <h3>Disclosure of Interest</h3> None declared
Lin28a Regulates Pathological Cardiac Hypertrophic Growth Through Pck2-Mediated Enhancement of Anabolic Synthesis
Authors: Hong Ma, Shuo Yu, Xiaojing Liu, Yingao Zhang, Thomas Fakadej, Ziqing Liu, Chaoying Yin, Weining Shen, Jason W. Locasale, Joan M. Taylor, Li Qian, Jiandong Liu
Journal: Circulation (2019)

Hypertrophic response to pathological stimuli is a complex biological process that involves transcriptional and epigenetic regulation of the cardiac transcriptome. Although previous studies have implicated transcriptional factors and signaling molecules in pathological hypertrophy, the role of RNA-binding protein in this process has received little attention.Here we used transverse aortic constriction and in vitro cardiac hypertrophy models to characterize the role of an evolutionary conserved RNA-binding protein Lin28a in pathological cardiac hypertrophy. Next-generation sequencing, RNA immunoprecipitation, and gene expression analyses were applied to identify the downstream targets of Lin28a. Epistatic analysis, metabolic assays, and flux analysis were further used to characterize the effects of Lin28a and its downstream mediator in cardiomyocyte hypertrophic growth and metabolic remodeling.Cardiac-specific deletion of Lin28a attenuated pressure overload-induced hypertrophic growth, cardiac dysfunction, and alterations in cardiac transcriptome. Mechanistically, Lin28a directly bound to mitochondrial phosphoenolpyruvate carboxykinase 2 ( Pck2) mRNA and increased its transcript level. Increasing Pck2 was sufficient to promote hypertrophic growth similar to that caused by increasing Lin28a, whereas knocking down Pck2 attenuated norepinephrine-induced cardiac hypertrophy. Epistatic analysis demonstrated that Pck2 mediated, at least in part, the role of Lin28a in cardiac hypertrophic growth. Furthermore, metabolomic analyses highlighted the role for Lin28a and Pck2 in promoting cardiac biosynthesis required for cell growth.Our study demonstrates that Lin28a promotes pathological cardiac hypertrophy and glycolytic reprograming, at least in part, by binding to and stabilizing Pck2 mRNA.
SAT0094 Physical function and health related quality of life in early rheumatoid arthritis patients who achieved only low disease activitycompared with remission
Authors: H.M. Lam, M.C. Wan, L.S. Tam
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Current treatment target for rheumatoid arthritis (RA) aims at reaching sustained remission or Low Disease Activity (LDA). It is unclear whether achieving clinical remission is necessary or achieving stable LDA is already sufficient to maintain physical function and Health Related Quality of Life (HRQoL) in patients with early RA. <h3>Objectives</h3> To compare physical function and health related quality of life in early RA patients who achieved sustained remission and those who achieved only sustained LDA. <h3>Methods</h3> Early RA patients with symptom onset &lt;2 years were recruited. Disease activity over time was determined by the cumulative average of Disease Activity Score 28 (caDAS28) and Simple Disease Activity Index (caSDAI) measured at month 3, 6, 9 and 12. Physical function was measured by the Health Assessment Questionnaire Disability Index (HAQ-DI). HRQoL was assessed by the Physical Component Scale (PCS) and Mental Component Scale (MCS) of the 36-Item Short Form Survey (SF-36) and the Euro Quality of Life Five Dimensions Questionnaire (EQ-5D). <h3>Results</h3> A total of 308 (53±13 years old, 80 [26.0%] male) patients completed one year follow up (table 1). 132 (42.9%) and 87 (28.2%) patients achieved caDAS28 remission and caDAS28 LDA while 48 (15.6%) and 156 (50.6%) patients achieved caSDAI remission and caSDAI LDA. Patients who achieved caDAS28 remission have better SF-36 PCS, HAQ-DI and EQ5D at year 1 than patients who achieved only caDAS28 LDA or remained active after adjusting for other potential confounders at baseline with multivariable regression analysis (Image 1). However, SF-36 PCS, HAQ-DI were not different between caSDAI remission and caSDAI LDA after adjustment for confounders. <h3>Conclusions</h3> Patients who achieved sustained caDAS28 LDA had significantly worse physical function and HRQoL than patients who achieved caDAS28 remission. <h3>Disclosure of Interest</h3> None declared