tbuckley/cabot-search huggingface dataset:
Methylation of RCAN1.4 mediated by DNMT1 and DNMT3b enhances hepatic stellate cell activation and liver fibrogenesis through Calcineurin/NFAT3 signaling
Authors: Xue-Yin Pan, Hong-Mei You, Ling Wang, Yi-Hui Bi, Yang Yang, Hong-Wu Meng, Xiao-Ming Meng, Tao-Tao Ma, Cheng Huang, Jun Li
Journal: Theranostics (2019)

Background: Liver fibrosis is characterized by extensive deposition of extracellular matrix (ECM) components in the liver. RCAN1 (regulator of calcineurin 1), an endogenous inhibitor of calcineurin (CaN), is required for ECM synthesis during hypertrophy of various organs. However, the functional role of RCAN1 in liver fibrogenesis has not yet been addressed. Methods: We induced experimental liver fibrosis in mice by intraperitoneal injection of 10 % CCl4 twice a week. To investigate the functional role of RCAN1.4 in the progression of liver fibrosis, we specifically over-expressed RCAN1.4 in mice liver using rAAV8-packaged RCAN1.4 over-expression plasmid. Following the establishment of the fibrotic mouse model, primary hepatic stellate cells were isolated. Subsequently, we evaluated the effect of RCAN1.4 on hepatic fibrogenesis, hepatic stellate cell activation, and cell survival. The biological role and signaling events for RCAN1 were analyzed by protein-protein interaction (PPI) network. Bisulfite sequencing PCR (BSP) was used to predict the methylated CpG islands in the RCAN1.4 gene promoter. We used the chromatin immunoprecipitation (ChIP assay) to investigate DNA methyltransferases which induced decreased expression of RCAN1.4 in liver fibrosis. Results: Two isoforms of RCAN1 protein were expressed in CCl4-induced liver fibrosis mouse model and HSC-T6 cells cultured with transforming growth factor-beta 1 (TGF-β1). RCAN1 isoform 4 (RCAN1.4) was selectively down-regulated in vivo and in vitro. The BSP analysis indicated the presence of two methylated sites in RCAN1.4 promoter and the downregulated RCAN1.4 expression levels could be restored by 5-aza-2'-deoxycytidine (5-azadC) and DNMTs-RNAi transfection in vitro. ChIP assay was used to demonstrate that the decreased RCAN1.4 expression was associated with DNMT1 and DNMT3b. Furthermore, we established a CCl4-induced liver fibrosis mouse model by injecting the recombinant adeno-associated virus-packaged RCAN1.4 (rAAV8-RCAN1.4) over-expression plasmid through the tail vein. Liver- specific-over-expression of RAN1.4 led to liver function recovery and alleviated ECM deposition. The key protein (a member of the NFAT family of proteins) identified on PPI network data was analyzed in vivo and in vitro. Our results demonstrated that RCAN1.4 over-expression alleviates, whereas its knockdown exacerbates, TGF-β1-induced liver fibrosis in vitro in a CaN/NFAT3 signaling-dependent manner. Conclusions: RCAN1.4 could alleviate liver fibrosis through inhibition of CaN/NFAT3 signaling, and the anti-fibrosis function of RCAN1.4 could be blocked by DNA methylation mediated by DNMT1 and DNMT3b. Thus, RCAN1.4 may serve as a potential therapeutic target in the treatment of liver fibrosis.
PF312 RESPONSES TO R-CHOP CHEMOTHERAPY INCORPORATING BIOSIMILAR RITUXIMAB (TRUXIMA®) FOR THE FIRST LINE TREATMENT OF DIFFUSE LARGE B-CELL LYMPHOMA – INITIAL EXPERIENCE AT UNIVERSITY COLLEGE LONDON HOSPITAL
Authors: S. Cheesman, R. Shah, J. Lambert, K. Cwynarski, W. Townsend, C. McNamara, A. Virchis, K. Ardeshna
Journal: HemaSphere (2019)

Background: In April 2017 the first biosimilar rituximab (Truxima®; NAPP) was approved in the UK for all indications of the reference biologic (MabThera®; Roche). The adoption of biosimilars is expected to deliver significant cost savings in the treatment of many conditions. The approval of Truxima® was based on comprehensive analytical and pre-clinical testing together with confirmatory clinical trials in advanced follicular lymphoma and rheumatoid arthritis with subsequent extrapolation to all licensed indications of MabThera®. There is an absence of clinical trial data supporting the use of biosimilar rituximab in other haematological malignancies, including diffuse large B-cell lymphoma (DLBCL) where the standard of care is R-CHOP chemo-immunotherapy. In the clinical trial leading to the approval of MabThera® for this indication the complete response rate at the end of treatment was 76% in patients who received R-CHOP compared to 62% in the group who received CHOP alone1. Aims: To assess the response to treatment for all patients treated for de novo stage II-IV DLBCL with R-CHOP chemo-immunotherapy including biosimilar rituximab (Truxima®). Methods: All patients starting treatment with R-CHOP for de novo stage II-IV DLBCL were identified from the electronic chemotherapy prescribing system and the following data collected: baseline demographics, performance status, staging, Revised International Prognostic Index (R-IPI), brand of rituximab received, number of R-CHOP cycles received, number of rituximab doses received, CNS prophylaxis received and response to therapy as assessed by end of treatment PET scan. Results: A total of 70 patients have completed treatment with R-CHOP chemo-immunotherapy incorporating biosimilar rituximab (Truxima®). Patients received a median of 6 cycles of CHOP (range: 1–6) and 6 doses of rituximab (range: 2–8). 58 patients completed treatment exclusively with Truxima®. 12 patients switched from MabThera® to Truxima® during their treatment after a median of 3 doses (range: 1–6). Response rates for the whole cohort of patients were as follows: Complete Response (CR): 51/70 (73%), Partial Response (PR): 11/70 (16%), Progressive Disease (PD): 6/70 (9%). Two patients died before response could be assessed. 4/70 (6%) patients switched from R-CHOP to R-GCVP chemo-immunotherapy after a median of 2 cycles (range: 1–5); all four patients achieved a CR.Summary/Conclusion: In our single-centre experience the use of biosimilar rituximab (Truxima®) does not appear to adversely impact the response rate to R-CHOP chemo-immunotherapy in patients with stage II-IV diffuse large B-cell lymphoma as assessed by post-treatment PET scan. Longer term follow-up in a larger patient group is required to confirm these results.
Endothelial function and dysfunction in the cardiovascular system: the long non-coding road
Authors: João P Monteiro, Matthew Bennett, Julie Rodor, Axelle Caudrillier, Igor Ulitsky, Andrew H Baker
Journal: Cardiovascular Research (2019)

Present throughout the vasculature, endothelial cells (ECs) are essential for blood vessel function and play a central role in the pathogenesis of diverse cardiovascular diseases. Understanding the intricate molecular determinants governing endothelial function and dysfunction is essential to develop novel clinical breakthroughs and improve knowledge. An increasing body of evidence demonstrates that long non-coding RNAs (lncRNAs) are active regulators of the endothelial transcriptome and function, providing emerging insights into core questions surrounding EC contributions to pathology, and perhaps the emergence of novel therapeutic opportunities. In this review, we discuss this class of non-coding transcripts and their role in endothelial biology during cardiovascular development, homeostasis, and disease, highlighting challenges during discovery and characterization and how these have been overcome to date. We further discuss the translational therapeutic implications and the challenges within the field, highlighting lncRNA that support endothelial phenotypes prevalent in cardiovascular disease.
Morphometric Similarity Networks Detect Microscale Cortical Organization and Predict Inter-Individual Cognitive Variation
Authors: Jakob Seidlitz, František Váša, Maxwell Shinn, Rafael Romero-Garcia, Kirstie J. Whitaker, Petra E. Vértes, Konrad Wagstyl, Paul Kirkpatrick Reardon, Liv Clasen, Siyuan Liu, Adam Messinger, David A. Leopold, Peter Fonagy, Raymond J. Dolan, Peter B. Jones, Ian M. Goodyer, Armin Raznahan, Edward T. Bullmore
Journal: Neuron (2017)
Abstract 11845: Obstructive Sleep Apnea is Not Predictive of Worse Outcomes Following Percutaneous Coronary Intervention in Acute Coronary Syndromes (ACS)
Authors: Safwan Gaznabi, Ashraf Abugroun, Lloyd Klein
Journal: Circulation (2018)

Introduction: Obstructive sleep apnea (OSA) is associated with adverse clinical outcomes in ACS (STEMI, NSTEMI, & unstable angina). Hypothesis: This study was undertaken to evaluate whether OSA is ...
Conformational Plasticity in the HIV-1 Fusion Peptide Facilitates Recognition by Broadly Neutralizing Antibodies
Authors: Meng Yuan, Christopher A. Cottrell, Gabriel Ozorowski, Marit J. van Gils, Sonu Kumar, Nicholas C. Wu, Anita Sarkar, Jonathan L. Torres, Natalia de Val, Jeffrey Copps, John P. Moore, Rogier W. Sanders, Andrew B. Ward, Ian A. Wilson
Journal: Cell Host & Microbe (2019)

The fusion peptide (FP) of HIV-1 envelope glycoprotein (Env) is essential for mediating viral entry. Detection of broadly neutralizing antibodies (bnAbs) that interact with the FP has revealed it as a site of vulnerability. We delineate X-ray and cryo-electron microscopy (cryo-EM) structures of bnAb ACS202, from an HIV-infected elite neutralizer, with an FP and with a soluble Env trimer (AMC011 SOSIP.v4.2) derived from the same patient. We show that ACS202 CDRH3 forms a "β strand" interaction with the exposed hydrophobic FP and recognizes a continuous region of gp120, including a conserved N-linked glycan at N88. A cryo-EM structure of another previously identified bnAb VRC34.01 with AMC011 SOSIP.v4.2 shows that it also penetrates through glycans to target the FP. We further demonstrate that the FP can twist and present different conformations for recognition by bnAbs, which enables approach to Env from diverse angles. The variable recognition of FP by bnAbs thus provides insights for vaccine design.
Adaptive Mutations in RNA Polymerase and the Transcriptional Terminator Rho Have Similar Effects on Escherichia coli Gene Expression
Authors: Andrea González-González, Shaun M. Hug, Alejandra Rodríguez-Verdugo, Jagdish Suresh Patel, Brandon S. Gaut
Journal: Molecular Biology and Evolution (2017)

Modifications to transcriptional regulators play a major role in adaptation. Here, we compared the effects of multiple beneficial mutations within and between Escherichia coli rpoB, the gene encoding the RNA polymerase β subunit, and rho, which encodes a transcriptional terminator. These two genes have harbored adaptive mutations in numerous E. coli evolution experiments but particularly in our previous large-scale thermal stress experiment, where the two genes characterized alternative adaptive pathways. To compare the effects of beneficial mutations, we engineered four advantageous mutations into each of the two genes and measured their effects on fitness, growth, gene expression and transcriptional termination at 42.2 °C. Among the eight mutations, two rho mutations had no detectable effect on relative fitness, suggesting they were beneficial only in the context of epistatic interactions. The remaining six mutations had an average relative fitness benefit of ∼20%. The rpoB mutations affected the expression of ∼1,700 genes; rho mutations affected the expression of fewer genes but most (83%) were a subset of those altered by rpoB mutants. Across the eight mutants, relative fitness correlated with the degree to which a mutation restored gene expression back to the unstressed, 37.0 °C state. The beneficial mutations in the two genes did not have identical effects on fitness, growth or gene expression, but they caused parallel phenotypic effects on gene expression and genome-wide transcriptional termination.
OP0097 CHRONIC PAIN AND SICK LEAVE IN A 21-YEAR FOLLOW UP
Authors: Beata Drab, Katarina Aili, Emma Haglund, Stefan Bergman
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Chronic musculoskeletal pain (CMP) is a common cause of disability and impaired quality of life. In Sweden, chronic pain and mental illness are major causes of sick leave. But sick leave itself is also proposed as a risk factor for prolonged sick leave and disability pension. <h3>Objectives</h3> To study CMP and sick leave as potential risk factors for long term sick leave or disability pension in a 21 year follow up of a general population cohort. <h3>Methods</h3> In a cohort study, with a baseline survey in 1995, 1466 individuals aged 20-67 years were followed for 3 years and 691 for 21 years, or up to the age of 67. CMP (&gt;3 months duration) was reported on a pain mannequin. Sick leave and disability pension were self-reported. Mental health was measured by the mental health (MH) score of the SF-36 health status, and categorized into tertiaries (best, medium and worst). CMP, sick leave, and mental health at baseline, were studied as potential predictors for long term sick leave (disability pension or sick leave &gt;3 months) at a 3 and 21 year follow up. Other potential predictors (socioeconomic group, education, and immigrant status) were introduced in multiple regression analyzes but did not add to the results and were removed from the final models, which were controlled for age and sex. <h3>Results</h3> CMP and mental health predicted long term sick leave at the 3 year follow up (OR 2.11, p=0.010 and OR 3.52, p&lt;0.001). Mental health (OR 1.92, p=0.046), but not CMP (OR 0.77, p=0.409), was also a predictor at the 21 year follow up. Sick leave &gt;3 months, irrespectively if due to pain or not, predicted long term sick leave both at the 3 and the 21 year follow up (Table). Sick leave for ≤3 months also predicted long term sick leave at both follow ups when due to pain (OR 2.70, p=0.008 and OR 2.78, p=0.012), but not when due to other causes (OR 1.52, p=0.212 and OR 1.17, p=0.606). <h3>Conclusion</h3> Sick leave and especially sick leave due to pain predicted long term sick leave up to 21 years later, independently of pain status or mental health at baseline. It is thus important to early identify individuals at risk and minimize sick leave by providing proper rehabilitation. <h3>Disclosure of Interests</h3> None declared
CCR5AS lncRNA variation differentially regulates CCR5, influencing HIV disease outcome
Authors: Smita Kulkarni, Alexandra Lied, Viraj Kulkarni, Marijana Rucevic, Maureen P. Martin, Victoria Walker-Sperling, Stephen K. Anderson, Rodger Ewy, Sukhvinder Singh, Hoang Nguyen, Paul J. McLaren, Mathias Viard, Vivek Naranbhai, Chengcheng Zou, Zhansong Lin, Hiroyuki Gatanaga, Shinichi Oka, Masafumi Takiguchi, Chloe L. Thio, Joseph Margolick, Gregory D. Kirk, James J. Goedert, W. Keith Hoots, Steven G. Deeks, David W. Haas, Nelson Michael, Bruce Walker, Sylvie Le Gall, Fatema Z. Chowdhury, Xu G. Yu, Mary Carrington
Journal: Nature Immunology (2019)
FRI0471 BONE QUALITY ASSESSMENT IN PATIENTS WITH TYPE 2 DIABETES MELLITUS
Authors: Nassima Hanouchine, Salah Ouhadj, Chafia Dahou-Makhloufi
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Type 2 diabetes mellitus (T2DM) is a risk factor for osteoporotic fractures although bone mineral density is normal or even increased, Thus, diabetes may be associated with a reduction of bone strength that is not reflected in the measurement of bone mineral density (BMD) <h3>Objectives</h3> The aim of this study was to compare BMD with a non invasive assessment of trabecular microarchitecture, (Trabecular bone score) TBS, in patients with T2DM <h3>Methods</h3> In a prospective cross-sectional study, trabecular microarchitecture was examined in patients with T2DM and non diabetic control subjects. The exclusion criteria were diseases (hyperthyroidism, Cushing's syndrome, primary hyperparathyroidism, renal failure, malabsorption), rheumatic diseases and/or medications that might affect bone and mineral metabolism,post menopausal women. Lumbar spine BMD was measured by dual-emission x-ray absorptiometry (DXA), and TBS was calculated by examining pixel variations within the DXA images using TBS iNsight <h3>Results</h3> 205 patients (108 male, 97 female), aged 25 to 60 years with T2DM and 205 non diabetic control subjects ((105 male, 100 female) Mean TBS was lower in T2DM (1.256±0.103 vs. 1.291±0.101, p=0.001). Mean BMD was higher in T2DM Z score (0.516±1.346 vs. -0.8151±1.153, p= 0.016). <h3>Conclusion</h3> In T2DM,TBS is lower than control subjects. Abnormal trabecular microarchitecture may help explain the paradox of increased fractures at a higher BMD in T2DM <h3>References</h3> [1] Dhaliwal R, Cibula D, Ghosh C, Weinstock RS, Moses AM. Bone qualityassessment in type 2 diabetesmellitus. OsteoporosInt.2014;25:1969-73. -Leslie WD, Aubry-Rozier B, Lamy O, Hans D. TBS (Trabecular Bone Score) and Diabetes-Related Fracture Risk. J Clin EndocrinolMetab.2013;98:6029. -Kim JH, Choi HJ, Ku EJ, Kim KM, Kim SW, Cho NH, et al. Trabecular Bone Score as an Indicator for Skeletal Deterioration in Diabetes. J Clin EndocrinolMetab.2015;100:475-82. <h3>Disclosure of Interests</h3> None declared
OP0099 EFFECTIVENESS OF REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION IN PATIENTS WITH FAILED BACK SURGERY SYNDROME
Authors: Canan Bursali, Feyza Unlu Ozkan, Meryem Yilmaz Kaysin, Nimet Dortcan, Aktas Ilknur, Duygu Geler Kulcu
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Failed back surgery syndrome (FBSS) is the term of persistent back and/or leg pain after lumbar surgery (1). Repetitive transcranial magnetic stimulation (r-TMS) is a technique that allows non-invasive and relatively painless stimulation of cerebral cortex. It can reduce the experience of chronic pain by using magnetic field to produce small electrical currents in the cortex (2). <h3>Objectives</h3> The aim of this study is to determine the effectiveness of r-TMS treatment on patients with FBSS. <h3>Methods</h3> In this double-blinded, randomized, placebo-controlled trial, 20 patients (aged 34-65 years) clinically diagnosed as FBSS, who had a history of surgery for lumbar disk herniation with persistent back and leg pain. Only patients with no root compression in postoperative magnetic resonance imaging of lumbar spine were included. Patients were randomly assigned to r-TMS (n:10) and sham (n:10) groups. Patients in r-TMS group received 5 Hz of r-TMS, as a 20-min (1000 pulses) daily session, 5 days per weeks, for a total of 10 sessions. R-TMS applied with MagVenture device (MagPro X100, Denmark, 2009) and figure eight coil (MMC 140 parabolic, MagVenture). Control group received sham r-TMS with the same protocol. Patients were assessed before and after the 1st and 5th sessions, at the end of the treatment and at 2 weeks, 1 month and 3 months after treatment. Visual Analogue Scale (VAS), DN-4, Oswestry Disability Index (ODI), Beck Depression Inventory (BDI), Pittsburgh Sleep Quality Index (PSQI) were used for evaluation. <h3>Results</h3> There were no statistically significant differences between the groups for age, sex, number of surgery, pain duration, working status and drug usage. Significant improvements were achieved in DN4, ODI, BDI and PSQI scores in r-TMS group in comparison to sham group. Both groups displayed improvements in VAS scores while improvement in the sham group was limited to first month. Achieved improvements in r-TMS group in terms of VAS, DN4, ODI, BDI and PSQI scores were sustained at third month. <h3>Conclusion</h3> Repetitive transcranial magnetic stimulation might be an effective treatment alternative in patients with FBSS, further studies with larger groups are needed. <h3>References</h3> [1] Al Kaisy, A., Pang, D., Desai, M. J., Pries, P., North, R., Taylor, R. S.,. .. &amp; Rigoard, P. (2015). Failed back surgery syndrome: who has failed?. Neurochirurgie, 61, S6-S14. [2] Johnson, S., Summers, J., &amp; Pridmore, S. (2006). Changes to somatosensory detection and pain thresholds following high frequency repetitive TMS of the motor cortex in individuals suffering from chronic pain. Pain, 123(1-2), 187-192. <h3>Disclosure of Interests</h3> None declared
FRI0323 EVALUATION OF LIPID PROFILE AND ATHEROSCLEROSIS IN TREATMENT-NAϊVE PATIENTS DIAGNOSED WITH UNDIFFERENTIATED CONNECTIVE TISSUE DISEASE (UCTD)
Authors: Giorgos Papamichail, Athanasios Georgiadis, Theodora Markatseli, Charalampos Milionis, Alexandros Drosos, Paraskevi Voulgari
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Patients with UCTD cannot be definitely diagnosed with a <b>well-characterized systemic rheumatic disease. These patients</b> often exhibit one of several disease patterns, manifesting multiple nonspecific clinical or serologic abnormalities, sometimes of more than one defined rheumatic disorder. <h3>Objectives</h3> The aim of this study is to investigate lipid profile and atherosclerosis in UCTD patients. <h3>Methods</h3> This is a prospective, observational study which included 30 treatment-naϊve UCTD patients. Thirty patients and 30 healthy matched-controls were compared for total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c) and triglycerides (TGs). Furthermore, in order to describe endothelial dysfunction and presence of atherosclerosis, we assessed intima-media thickness (IMT) of common carotid artery with the contribution of an experienced sonographer. We also measured Apolipoprotein A1 (ApoA1), Apolipoprotein B (ApoB), Apolipoprotein E (ApoE), Lipoprotein A (LpA), erythrocyte sedimentation rate (ESR), high-sensitivity C-reactive protein (HSCRP) and fibrinogen in the group of patients only. <h3>Results</h3> Thirty UCTD patients were studied. There were 11(36.7%) men, 19(63.3%) women and 7(23.3%) smokers. The mean (SD) age was 54.4(13.1) years and disease duration was 17.3(10.4) years. All reported Raynaud's phenomenon, 22(73.3%) had esophagus disorders, 21(70%) had pulmonary fibrosis and 3(10%) pulmonary hypertension. Arthritis was present in a great majority of these patients (93%). The immunological evaluation of the patients showed that 4(13.3%) had positive anticardiolipin antibodies and 11(36.7%) had scl-70 (+). The comparison of IMT between patients and matched-controls revealed an increased IMT in UCTD patients [0.82 (0.32) vs 0.6 (0.13) mm; p&lt;0.001]. There was also a significant difference in mean (SD) TC [204.4(43.03) in patients vs 238(41.4) in controls; p value&lt;0.004] with respective reduced levels of mean(SD) HDL in patients [50.6(9.5) vs 61.3(13.3); p value&lt;0.002]. No statistically significant difference was found for LDL-c and TGs. These patients had mean (SD) ApoA1 146.9(27.6), ApoB 94.9(25.6), ApoE 42.1(10.7), LpA 12.8 (15.9), HSCRP 7.5(13.5), ESR 28.9 (22.6) and fibrinogen 422.9(101.3). <h3>Conclusion</h3> IMT measurement confirmed that UCTD patients are prone to endothelial dysfunction and consequently to atherosclerosis. Treatment-naive patients had reduced TC levels in combination with low levels of HDL-c reflecting high disease activity. Control of the disease and initiation of specific therapy may induce an improved lipid profile. <h3>Disclosure of Interests</h3> None declared