tbuckley/cabot-search huggingface dataset:
Stimulation of the cytosolic dsRNA sensor MDA-5 induces cell death in fibroblast-like synoviocytes
Authors: Olga N Karpus, Paul P Tak, Jörg Hamann
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background and objectives</h3> Rheumatoid arthritis is characterised by hyperplasia of the synovial tissue due to local proliferation of stromal and recruitment of inflammatory immune cells. Accumulation of synovial fibroblasts likely is due to an imbalance between cell proliferation, survival and death. Virus RNA receptors can initiate pro-apoptotic signalling in a variety of cell types. Based on our recent observation that fibroblast-like synoviocytes (FLS) are equipped with functional endosomal (TLR3) and cytosolic (MDA5 and RIGI) sensors for double-stranded (ds)RNA, the authors have studied the consequences of stimulation with dsRNA on the survival of FLS. <h3>Materials and methods</h3> FLS from arthritis patients were stimulated with extracellular poly(I:C) or poly(I:C)/3pRNA complexed with PEI for intracellular uptake. Activation of TLR3, MDA5 and RIG-I was confirmed by semi-quantitative PCR of response genes. Cell death of FLS after triggering of dsRNA sensors was detected by FACS analysis (annexin V/PI staining) and MTT assay. mRNA level of 46 genes involved in apoptosis was tested with a multiplex ligation-dependent probe amplification (MLPA) assay. Changes in protein expression were confirmed by Western blot analysis. <h3>Results</h3> At concentrations &gt;0.01 µg/ml, stimulation of MDA5 by intracellular delivery of poly(I:C) caused massive cell death in up to 75% of cultured FLS. In contrast, transfection of 3pRNA triggering RIG-I had a much smaller effect on cell viability, and extracellular administration of the TLR3 ligand poly(I:C) induced death only at the high concentration of 100 µg/ml. Type I IFNs did not kill FLS, indicating that cell death was not secondary to IFN receptor signaling. MLPA and biochemical analysis demonstrated a strong induction of the BH3-only pro-apoptotic proteins Puma and Noxa upon dsRNA triggering but was not restricted to MDA5 signaling, suggesting the existence of additional regulatory mechanisms. Treatment of cells with the pan-caspase inhibitor QVD reduced cell death by about 50%, indicating that MDA5-induced cell death in FLS may involve also caspase-independent mechanisms. <h3>Conclusions</h3> Triggering of the endosomal dsRNA sensor MDA5 induces expression of pro-apoptotic Puma and Noxa and causes death in cultured FLS. Ligation of MDA5 might be a therapeutic target to overcome apoptosis resistance of FLS in rheumatoid arthritis.
Abstract 2037: Anti-miRNA-21 confers radiosensitivity through inhibition of PI3K/AKT pathway and enhancing autophagy
Authors: Ho-Shin Gwak, Tae Hoon Kim, Seung Hoon Lee, Heon Yoo, Jong Bae Park
Journal: Cancer Research (2010)

Abstract Radiation is a core part of therapy for malignant glioma, which has been given after debulking surgery and prolonged patient's survival. However, the mass of glioma hardly shows response to radiation and frequently become radioresistant after the initial radiation. Among onco-microRNAs, microRNA-21 regulates expression of various molecules involved in anti-apoptosis, invasion, and metastasis in cancer. Yet, there has been known to the relationship between microRNA-21 and radioresistance of glioma. In this study, we investigate the effect of anti-mir-21 on radiosensitivity in glioblastoma and cervical cancer cell lines. Induction of mature microRNA-21 was confirmed by Nothern blotting after irradiation and the transfection of anti-mir-21 resulted in radiosenstivity on colony forming assay. The radiosensitive is thought to be the results of impairment of DNA repair in irradiated cancer cells, which is proved by γ-H2AX staining. In contrast to control group, a significant percentage of anti-mir-21 transfected cells retain DNA foci at 24 hours after irradiation. The suppression of radiation-activated PI3K/Akt pathway is proved on Western blot and thought to be one of the mechanisms for anti-mir-21 induced radiosensitization. Cell cycle analysis shows significant increase of G2/M phase arrest in anti-mir-21 treated cells compared to the control while subG1 population representing apoptotic cells reveals no significant difference between two groups. To investigate further the responsible cell death mechanism other than apoptosis, we measured the degree of autophagy in irradiated cells by both counting acid vesicular organelles using flow cytometry and Western blotting for LC-3 band. The autophagy is significantly increased in anti-mir-21 treated cells after radiation compared to mock treated cells. We suggest that microRNA-21 is a pivotal regulator of mechanisms to evade radiation-induced cell death in cancer cell. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2037.
Gastrointestinal manifestations of common variable immunodeficiency disease
Authors: Joshua Samuel, Nicholas Agresti, Juan Munoz
Journal: Endoscopy (2015)

A 30-year-old woman with history of common variable immunodeficiency disease (CVID), Von Willebrand disease, and factor VII hemophilia presented to the emergency department with complaints of diarrhea and weight loss for 2 weeks. On admission her vital signs were stable. She reported 6 – 8 watery bowel movements per day, which were not improved with Imodium, but had no hematochezia or melanotic stools. The findings from the physical examination were noncontributory. She had work-up for diarrhea, which was negative for infectious etiology. A positive fecal fat test suggested malabsorption.
Abstract 5213: KiSS1R signaling in breast cancer
Authors: Matthew M. Zajac, Andy Babwah, Moshmi Bhattacharya
Journal: Cancer Research (2010)

Abstract KiSS1R, a G-protein coupled receptor (GPCR), and its ligands, collectively known as the kisspeptins, were originally discovered to have anti-metastatic effects. In melanoma, the expression of KiSS1R and the kisspeptins correlates with positive prognosis. However, in breast tumors, higher mRNA expression of KiSS1R and kisspeptins has been shown to correlate with progressing tumour grade. In large, the mechanism(s) by which kisspeptin-signaling via KiSS1R regulates breast cancer cell migration and invasion, required for metastasis, is unknown, and is the focus of this study. Commonly targeted in breast cancer therapy, aberrant signaling of the epidermal growth factor receptor (EGFR) is able to lead to increased migration and invasion, culminating in a more aggressive metastatic phenotype. EGFR's ability to interact with other GPCRs, whether directly by transactivation or indirectly by down-stream crosstalk, is well known. We have found that Kp-10, the most potent kisspeptin, stimulates the migration and invasion of highly invasive human MDA-MB-231 cells stably expressing FLAG-KiSS1R. In addition, we have observed co-localization of FLAG-KiSS1R and EGFR-GFP in human embryonic kidney (HEK 293) cells in response to Kp-10 or EGF stimulation. Stimulation of MDA-MB-231 cells with Kp-10 resulted in the activation of EGFR. Taken together, our findings suggest a potential mechanism by which kisspeptins and KiSS1R may stimulate breast cancer cell migration and invasion. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5213.
Abstract P6-10-07: Risk-Benefit Framework To Evaluate Gene-Expression Profiling in Early Stage Breast Cancer: A Decision Model Developed in Collaboration with Stakeholders
Authors: JA Roth, DL Veenstra
Journal: Cancer Research (2010)

Abstract Objectives Recent comparative effectiveness research recommendations have emphasized that stakeholder involvement in research prioritization and design is critical for ultimate acceptance of results. With this recommendation in mind, an interactive risk-benefit model was developed to evaluate gene-expression profiling (GEP) to guide use of adjuvant chemotherapy in early stage breast cancer compared to clinical guidelines. Methods A stakeholder collaborative feedback process was utilized to develop a decision model to estimate the comparative benefits and harms of GEP relative to NCCN guidelines, including disease recurrences, adverse events, and quality-adjusted life years (QALYs). The model allows users to specify the GEP, node status, patient cohort age, adjuvant chemotherapy relative risk reduction, and patient chemotherapy preferences in each risk stratum. A Markov process was utilized to estimate long-term clinical outcomes. Based on stakeholder concerns about QALY-based outcomes, alternative outcomes such as disease recurrences and adjuvant chemotherapy serious adverse events were presented. The prognostic and predictive properties of the GEPs were derived from published retrospective analyses of RCTs. Adjuvant chemotherapy utility decrements were derived from trial-based adverse event rates. The base case patient was a pre-menopausal woman of age 44. Results Preliminary analyses indicate that a 2-risk strata GEP, 3-risk strata GEP, and clinical guidelines would identify 50%, 46% and 92% of women to receive adjuvant chemotherapy, respectively. Based on this level of uptake, relative to a scenario where no patients receive adjuvant chemotherapy, these prognostic approaches would prevent 29%, 36% and 34% of distant recurrences, respectively. This scenario results in 17.4 QALYs, 18.1 QALYs, and 17.7 QALYs, respectively. These findings indicate that depending on the specific GEP examined, testing may lead to a net harm or net benefit relative to clinical guidelines, due to variation in risk of disease recurrence, despite avoidance of chemotherapy and side effects in 42% and 46% of women, respectively. Conclusions GEP to inform adjuvant chemotherapy treatment decisions in early stage breast cancer could lead to an increase or decrease in QALYs relative to the use of clinical guidelines, depending on the specific GEP examined. Stakeholder feedback has indicated that acceptance of model results will likely depend on its degree of transparency, ease of use and interpretation, and ability to present relevant outcome measures. Ongoing efforts are focused on additional collaboration with stakeholders to align model structure and output with current needs. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-10-07.
PRE-IMPLANT COAGULOPATHY AND IN-HOSPITAL MORTALITY AMONG ADVANCED HEART FAILURE PATIENTS RECEIVING LEFT VENTRICULAR ASSIST DEVICE: A UNITED STATES NATIONAL STUDY
Authors: Marjan Mujib, Nabila K. Mazumder, Wilbert S. Aronow, Dhaval Kolte, Sahil Khera, Tanush Gupta, Neha M. Paul, Sachin Sule, Gregg Lanier, Ali Ahmed, Robert G. Lerner, Diwakar Jain, Gregg Fonarow, Sumanth Prabhu, Howard Cooper, Alan Gass, William Frishman, Julio Panza
Journal: Journal of the American College of Cardiology (2016)
497 FACTORS ASSOCIATED WITH REGRESSION OF CIRRHOSIS IN PATIENTS WITH CHORNIC HEPATITIS B (CHB) INFECTION TREATED WITH TENOFOVIR DISOPROXIL FUMARATE (TDF)
Authors: N. Afdhal, M. Buti, S. Fung, E. Gane, J. Flaherty, E. Martins, N. Bekele, J. Bornstein, P. Marcellin
Journal: Journal of Hepatology (2012)
FRI0447 Cardiovascular risk factors in ankylosing spondylitis
Authors: F. Vreju, B. Chisalau, P. Ciurea, A. Rosu, I. Cojocaru-Gofita, A. Barbulescu, C. Hoanca, M. Florea, A. Musetescu
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Dyslipidemia (DL) is one the main reason of atherosclerosis and thus, one of the main cardiovascular risk factors in patients with inflammatory arthritis, but data about the connection between DL and ankylosing spondylitis (AS) are limited. <h3>Objectives</h3> To evaluate the DL in patients with ankylosing spondylitis and to show the relationship between DL and inflammation in those patients. <h3>Methods</h3> 50 patients with AS without cardiovascular diseases were included in the study (mean age ± standard deviation 46,68±12,84 years). 45 healthy age-matched controls without inflammatory diseases were examined as well (mean age 45,08±13,37). AS activity was expressed using BASDAI index, the number of dactylitis found (0-3 points), the value of ESR and C reactive protein (CRP). Total cholesterol (TC), triglycerides (TG), arterial pressure, BMI and individual cardiac history were noted. <h3>Results</h3> Increase of TC was found in patients with AS in comparison with controls (199,84± 63,11 vs. 178,17± 35,41 mg/dl, p=0,04). We found an increased value of TG in patients with AS comparative with controls (155,08 vs 113,15mg/dl; p&lt; 0,05). We found no significant correlations between cholesterol/TG and markers of systemic inflammation, but with the disease duration (r=0,43), which may sugest that not the disease activity at a specific moment has an influence, but the longer exposure to inflammation. There was a correlation between TC and blood pressure (r=0,51; p&lt;0,05) and between TC and BMI (r=0,54; p&lt;0,05). In the same way, we found a correlation between TG and blood pressure (r=0,46; p&lt;0,01). <h3>Conclusions</h3> DL is more frequent in SA than in the control group, with a total cholesterol and triglycerides values increased but it is not highly related to disease activity at a specific moment. <h3>Disclosure of Interest</h3> None Declared
Testosterone Undecanoate Treatment Reduces Joint Morbidities Induced by Anastrozole Therapy in Postmenopausal Women with Breast Cancer: Results of a Double-Blind, Randomized Phase II Trial.
Authors: S. Birrell, W. Tilley
Journal: Cancer Research (2009)

Abstract Background: Approximately 50% of women taking 3rd generation aromatase inhibitors (AI) for adjuvant breast cancer therapy develop arthralgia, tenosynovitis or arthritis. In many women, the morbidity is significant and affects therapy compliance. The pathology of AI-induced joint morbidity is poorly understood, but clinical features in severe cases mimic rheumatoid arthritis. Afflicted women are treated with anti-inflammatory medication, but this does not address the etiology, which appears to involve steroid hormone imbalance. Testosterone can be metabolised to estrogen or the more potent androgen, 5alpha-dihydrotestosterone (DHT). Androgen levels decrease with age and this may be exacerbated by chemotherapy and, paradoxically, aromatase inhibition. We hypothesise that AI-associated joint morbidities are the result of testosterone deficiency and that testosterone treatment during AI therapy will be beneficial. Testosterone replacement had been contraindicated in women with breast cancer until the advent of powerful 3rd generation aromatase inhibitors that are highly efficacious in blocking conversion of testosterone to estrogen, thus allowing the examination of combinations of drugs such as anastrozole and testosterone.Materials and Methods: 90 women taking Arimidex® 1mg daily and registering a visual analogue scale (VAS) pain or stiffness score of ≥ 40mm on a 100mm scale, were randomized into 3 equal arms: placebo, 40 mg or 80 mg testosterone undecanoate daily, with follow-up at 1 and 3 months. The primary efficacy endpoint was reduction in pain at 3 months and the primary safety endpoints were signs of androgen excess with secondary safety endpoints being serum hormone levels, serum lipids and bone absorption markers.Results: The VAS scores at 3 months fell for all groups, with a marked placebo effect of 35% compared with 43% and 70% for the 40 and 80mg treatment arms (p=0.06 and p=0.04, respectively). No significant androgenic side-effects (hirsutism, alopecia and acne) were observed and serum lipids remained unaltered. Serum total testosterone and free-testosterone levels stabilized at 3 months in a dose-dependent fashion into a physiological range. There was no elevation in serum estradiol in either treatment arm and the serum sex hormone binding globulin level fell significantly in the 80mg treatment group (p=0.03). There was no significant change in bone absorption markers in any of the patient groups.Discussion: This study has demonstrated for the first time that testosterone replacement may be a viable option in the management of AI-induced arthralgia, tenosynovitis and arthritis with good tolerability and safety, without adversely reducing aromatase inhibitor efficacy (as indicated by serum estradiol levels).This study was supported AstraZeneca (UK). Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 804.
FRI0547 Predictive Factors of TMJ Involvement in 230 Consecutive JIA Patients Regularly Screened from 2000 to 2014 in A Single Pediatric Rheumatology Centre
Authors: M. Gattinara, E. Del Giudice, S. Lodi-Rizzini, I. Pontikaki, M. Romano, P.L. Meroni, V. Gerloni
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Juvenile Idiopathic Arthritis (JIA) has been shown to involve frequently the temporo-mandibular joint (TMJ). An important prognostic aspect is to diagnose and treat it promptly. <h3>Objectives</h3> To evaluate in a consecutive JIA patients (pts) cohort, regularly screened from year 2000 to 2014, the predictive factors of the TMJ involvement. <h3>Methods</h3> 230 consecutive pts (152 females, 78 males) affected by JIA according to ILAR classification, 164 oligoarthritis, 4 polyarthritis rheumatoid factor (RF) +, 34 polyarthritis RF-, 22 systemic onset JIA (soJIA), 4 enthesitis-related arthritis (ERA) HLA B27+, and 2 psoriatic arthritis were included in a retrospective evaluation. Mean disease onset age was 6.5 yrs (range 1-16), mean disease duration 12.7 yrs (range 0.2-46.2). We analyzed the correlation between TMJ involvement with the following items: ILAR categories, age at onset, gender, pattern of articular involvement (large joints, small ones, hips, cervical spine). <h3>Results</h3> 88/230 patients (38.3%), 36.8% of females and 41% of males showed a clinical TMJ involvement. Mean age at onset (or diagnosis) of TMJ involvement was 8.3 yrs. 62/88 pts (70.5%) had a bilateral clinical signs of condylar alteration. The involvement of TMJ was observed in 38.3% of the whole population (54.5% of oligoarthritis, 27.3% polyarthritis RF negative, 2.3% polyarthritis RF positive, 9.1% soJIA, 4.5% ERA and 2.3% juvenile psoriatic arthritis) 3 cases (2 females and 1 male) presented with an involvement of TMJ at the diagnosis of JIA. The rate of TMJ involvement was higher in the pts with an early onset of the disease (52.3% in the 0-6 yrs group, vs 36.4% in 7-12 yrs group and 11.3% in 13-16 yrs group). In 56/88 pts (63.3%) TMJ disease was associated with an involvement of large joints, in 4/88 (4.54%) with small joints, in 24/88 (27.7%) with hips and in 18/88 (20.45%) with cervical spine. <h3>Conclusions</h3> An early onset of JIA, the oligoarticular ILAR category and a pattern of large joints involvement seem correlated with a higher rate of TMJ disease. Predictive factors of TMJ involvement should be confirmed in a larger JIA population and may be useful for clinicians to adopt appropriate prevention strategies of TMJ disease. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.5816
SAT0552 Management of Rheumatoid Arthritis in Remission in Current Practice : the 3P Study
Authors: R.-M. Flipo, A. Cantagrel, C. Contre, B. Combe
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The goal of current rheumatoid arthritis management is to achieve remission or low disease activity<sup>1.</sup> However few studies have been performed on the management of patients in sustained remission, especially in daily practice. <h3>Objectives</h3> The primary objective of the 3P survey was to assess the attitude of French rheumatologists to the prescription of synthetic and biologic DMARDs (and in particular treatment discontinuation procedures) in patients with RA in remission. <h3>Results</h3> 326 rheumatologists replied. 67% had a private or mixed practice whereas 33% were exclusively hospital practitioners. 61.9% of rheumatologists were not aware of published controlled trials that assessed the reduction and/or discontinuation of biologics in patients with remission. In practice, most rheumatologists waited until the patient has achieved remission for at least 6 months before reducing therapies (18.3%: 3 months / 46.9 %: 6 months / 25.7 %: 1 year). 60.8% of rheumatologists required prior discontinuation of glucocorticoids before reducing the disease-modifying therapy (25.9% accepted a dose &lt;5 mg prednisone/day). In patients with sustained remission and treated with a combination of a synthetic DMARD and a biologic agent, 55.8% planned to stop the biologic first whereas 44.2% stopped the synthetic DMARD. Methotrexate dose, was reduced by 2.5 mg every two weeks in approximately half of the cases. Table 1 shows the rates of the different procedures used for stopping the 3 main TNF-alpha inhibitors. 63.7% of rheumatologists reported that the possibility of adjusting the dosage of biologic in patients in remission is an important criterion for the choice of initial biological therapy. <h3>Conclusions</h3> In the 3P study, most of rheumatologists start to reduce therapies after 6 months of sustained remission, in increasing the interval between injections or reducing the dose of treatment. Possibility of adjusting the dosage is taken in consideration in the choice of initial biologic. <h3>References</h3> J. Smolen et al. ARD 2010 <h3>Disclosure of Interest</h3> R.-M. FLIPO Grant/research support from: Pfizer, Roceh, Chugai, Consultant for: Abbott, Astra-Zenica, BMS, Ipsen, menarini, MSD, Pfizer, Roche, Chugai, UCB, Jannssen-Cilag, Paid instructor for: Abbott, Astra-zenica, BMS, Expansciences, Ipsen, Menarini, MSD, Nordic-Pharma, Pfizer, Roceh, Chugai, Genzyme, UCB, A. CANTAGREL Grant/research support from: Chugai, Pfizer, UCB, Consultant for: BMS, Chugai, Roche, MSD, Novartis, Pfizer, UCB, Paid instructor for: Abbott, BMS, Chugai, MSD, Nordic-Pharma, Novartis, Pfizer, Roche, Sanofi-Aventis, UCB, C. CONTRE Employee of: Pfizer France, B. COMBE Grant/research support from: Pfizer, Roche, Chugai, Consultant for: BMS, Celgene, Merck, Novartis, Pfizer, Roche, Chugai, UCB, Speakers bureau: Merck, Pfizer, UCB