tbuckley/cabot-search huggingface dataset:
AB0103 Anti-inflammatory and immunomodulatory effects by human umbilical cord mesenchymal stem cell derived microvesicles in rats with collagen induced
Authors: M Tian, K Xu, L Zhang, J Gao
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Immunologic deranging and persistent inflammation is closely associated with the arising and developing of rheumatoid arthritis (RA). Increasing investigators demonstrated microvesicles (MVs) derived from mesenchymal stem cell (MSC-MVs) might simulate immune regulation and tissue repair of the parental cells. However,the immunotherapeutic potential of MVs in RA remains unknown. <h3>Objectives</h3> We investigated the therapeutic effects of MSC-MVs in RA model collagen induced arthritis (CIA) rats. <h3>Methods</h3> We tested the therapeutic effects of MSC-MVs on CIA rats,levels of T helper 17(Th17), regulatory T cell,and cytokines related,as well as specific transcriptional regulation factor Foxp3 and ROR-γT analysis was performed. <h3>Results</h3> Here, we show that MSC-MVs administration effectively improve arthritic symptoms, inhibit synovial hyperplasia,thus delaying the progression to inflammatory bone destruction, as effective as their original cells, exerting arthralprotective effects. MSC-MVs treating inhibited the proliferation of T cell,accelerated the apoptosis. MSC-MVs treating reduce proinflammatory cell Th17,cytokines IL-17, while a incline in the level of an-inflammatory cell Treg,ncytokines TGF-β. In the spllen and ankle joint of CIA rats, MSC-MVs treating increased the expression level of Foxp3 and coinciding with the ROR-γT suppressed, which, the enhanced therapeutic effects correlated with the increase of dosage in a certain range. <h3>Conclusions</h3> MSC-MVs showing anti-inflammatory and immunomodulatory activities on CIA rats, suggesting a new and feasible strategy for protection against RA. <h3>References</h3> E.M. Gravallese, S.R. Goldring, Cellular mechanisms and the role of cytokines in bone erosions in rheumatoid arthritis, Arthritis Rheum. 43 (10) (2000) 2143–2151. S. Culshaw, I.B. McInnes, F.Y. Liew, What can the periodontal community learn from the pathophysiology of rheumatoid arthritis? J. Clin. Periodontol. 38(Suppl. 11) (2011) 106–113. Schett, G., D. Elewaut, I.B. McInnes, J.M. Dayer, and M.F. Neurath, How cytokine networks fuel inflammation: Toward a cytokine-based disease taxonomy. Nat Med, 2013. 19(7): p. 822–4. <h3>Disclosure of Interest</h3> None declared
Phase I dose-escalating study of PM02734 in a 24-hour infusion schedule every 21 days in advanced solid tumors
Authors: T. R. Evans, A. Oaknin, R. J. Jones, A. Vandermeeren, C. Coronado, A. Soto-Matos, J. R. Germa, D. Crawford, P. Frontelo, R. Salazar
Journal: Journal of Clinical Oncology (2009)

2511 Background: PM02734 is a chemically synthesized depsipeptide with a broad spectrum of activity against solid tumors in vitro (breast, colon, lung, neuroblastoma, prostate, sarcoma and thyroid) and in vivo (breast, prostate, melanoma); as well as an acceptable non-clinical toxicology profile. Methods: Patients (pts) with metastatic or advanced solid tumors were enrolled in a phase I, open-label, dose-escalating study to assess safety, tolerability, pharmacokinetics (PK), and to identify the dose limiting toxicity (DLT) and recommended dose (RD) of PM02734 infused over 24 hours every 21 days (d). The starting dose was 0.48 mg/m 2 . Cohorts of 1–6 pts were treated at different dose levels. Results: Thirty seven pts were treated in this study. The median age was 55 years (40–75), sex: males/females 20/19. The median PS was 1 (range 0–2). The most frequent cancer types were colon/ gastric/ sarcoma (n=8/5/5). Most patients were heavily pretreated, with a median of prior therapy lines of 4 (1–12). Patients were treated at 8 dose levels (0.48, 0.72, 1.0, 1.6, 2.4, 3.6, 5.4, and 6.8 mg/m 2 ), the MTD was 6.8 mg/m 2 and the RD was 5.4 mg/m 2 (10 mg flat dose).Common toxicities grade ≤ 2 included asthenia, nausea/emesis, lymphopenia, injection site reactions and asymptomatic elevated transaminases (TAs). DLT were grade 3 asymptomatic, reversible TA elevations at 6.8 mg/m 2 . Preliminary PK data is characterized by long half life (&gt;100 h), a wide distribution and high inter-patient variability. Clearance was not correlated with dose or body surface area (BSA), therefore, flat dose was implemented and the RD was explored with this schedule. Efficacy data showed one complete response (CR) of +28 months observed in a pt with metastatic large cell esophageal carcinoma, and five more showed stable disease (SD) for more than 3 months in different histologies. Conclusions: PM02734 shows to be safe, well tolerated and with evidence of activity (1 CR and 5 SD &gt; 3 months) in pts with advanced solid tumors. The DLT was grade 3 asymptomatic and reversible TA elevations, and the RD for further phase II studies is 10 mg. [Table: see text]
SAT0655 Early endothelial damage in patients with raynaud's phenomenon
Authors: R Gualtierotti, F Ingegnoli, T Schioppo, S Griffini, E Grovetti, MO Borghi, M Cugno, PL Meroni
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Raynaud9s phenomenon (RP) can be the first manifestation of systemic sclerosis (SSc) or other connective tissue diseases (CTDs), often preceding an overt disease by years. It is not known if markers of endothelial damage are detectable in those RP patients who subsequently develop a CTD. <h3>Objectives</h3> We studied RP patients at their first evaluation to correlate the levels of endothelial markers with the subsequent development of an overt disease 36 months later. <h3>Methods</h3> Eighty-two patients with RP at their first evaluation were recruited. We measured plasma levels of tissue-type plasminogen activator (t-PA) and von Willebrand factor (vWF), two markers of endothelial damage, and interleukin-6 (IL-6), a pro-inflammatory cytokine. Thirty healthy subjects served as healthy controls. <h3>Results</h3> At baseline, 67 patients showed capillaroscopic normal pattern and 15 patients, of which 11 were very early SSc, had scleroderma pattern. Plasma levels of t-PA, vWF and IL-6 were higher in patients with capillaroscopic normal pattern (p=0.0001) than in normal controls and even much higher in patients with scleroderma pattern (p=0.0001). In patients with capillaroscopic normal pattern and RP of recent onset (&lt;18 months), vWF plasma levels were higher when autoantibodies were present (p=0.020). After 36 months, among 48 RP patients with capillaroscopic normal pattern who remained in follow-up, 24 were diagnosed as primary and 24 as secondary RP. In secondary RP, basal levels of t-PA, IL-6 and particularly vWF were higher than in primary RP (p=0.005, p=0.004, p=0.0001 respectively) and normal controls (p=0.0001 for all). <h3>Conclusions</h3> Our findings indicate that markers of endothelial damage are elevated in RP patients who subsequently develop SSc or other CTDs, even in the absence of capillaroscopic abnormalities. <h3>Disclosure of Interest</h3> None declared
AB0073 Accumulation of advanced glycation end products (AGES) in osteoarthritic cartilage is related to an impairment of the adaptative mechanism of GLYOXALASE-1
Authors: S Trellu, A Courties, S Jaisson, B Friguet, X Houard, F-P Ehkirch, C Jacques, F Berenbaum, J Sellam
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Advanced glycation end-products (AGEs) that result from a non-enzymatic reaction between a sugar and a protein, are generated during tissular ageing. Accumulation of AGEs could also be part of the osteoarthritis (OA) process by modifying the biomechanic properties of cartilage and by inducing chondrocyte activation. Glyoxalase-1 (Glo-1) is the main enzyme involved in the removal of AGEs precursors, especially the AGE carboxymethyllysine (CML). <h3>Objectives</h3> We aimed to quantify CML in human osteoarthritic cartilage, to investigate Glo-1 expression in chondrocytes and to study chondrocytic Glo-1 regulation in an inflammatory context. <h3>Methods</h3> 1) <i>Ex vivo:</i> Osteoarthritic cartilages from patients undergoing knee replacement were collected, dissected and incubated for 24h with or without IL-1β (5ng/ml). We quantified CML in these cartilage explants using liquid chromatography and mass spectrometry, Glo-1 protein expression (Western Blot and immunohistochemistry) and Glo-1 enzymatic activity by measuring the kinetic of formation of the Glo-1 product (S-D lactoylglutathione) using spectrophotometry at 240nm during 10 minutes. 2) <i>In vitro:</i> Primary cultured murine chondrocytes (C57B6) were stimulated 72 h with increasing IL-1β doses (0 to 10ng/mL). Glo-1 expression was assessed by quantitative RT-PCR, Western blot and enzymatic activity. To analyze whether oxidative stress is involved in Glo-1 regulation induced by IL-1β, cells were treated with inhibitors of mitochondrial oxidative stress (MitoTEMPO) or of nitric oxide (NO) synthase (L-NAME). <h3>Results</h3> 1) <i>Ex vivo</i>, CML was found in all human OA cartilage samples and its level increased according to age (correlation coefficient CML/age: r=0.78, p&lt;0.01). In parallel to CML increase, Glo-1 protein was expressed in chondrocytes on all layers of cartilage. A positive correlation was found between Glo-1 enzymatic activity and the age of the patients (r=0.45, p&lt;0.05) but was lost in case of incubation with IL-1β (r=-0.09, p non significant). 2) <i>In vitro</i>, in murine chondrocytes cultures, we observed a dose-dependent decrease of IL1β-induced Glo-1 mRNA (0.67 fold, p&lt;0.05), protein quantity (0.56 fold, p&lt;0.05) and enzymatic activity (0.7 fold, p&lt;0.05) (n=5). The blockade of NO by L-NAME, and of mitochondrial oxidative stress by MitoTEMPO counteracted the downregulation of IL1β-induced Glo-1 expression and enzymatic activity (n=5). <h3>Conclusions</h3> We show here that the age-dependent accumulation of AGEs in OA cartilage could be due to an impairment of the adaptative mechanism of Glo-1, mediated by oxidative stress. Further studies aiming at targeting Glo-1 restauration as a therapeutical strategy for ageing-related OA are needed. <h3>Disclosure of Interest</h3> None declared
SP0152 Learning from clinical trials in systemic lupus erythematosus
Authors: DA Isenberg
Journal: Annals of the Rheumatic Diseases (2017)

An enormous sense of frustration has surrounded the results of clinical trials in patients with systemic lupus erythematosus (SLE). A steady stream of trials including those studying the effects of Epratuzumab, Abatacept, Rituximab, Tabalumab and Silfalimumab have failed to meet their endpoints. Even though Benlysta (which blocks the B-cell activating factor BAFF) did meet its endpoints, it only demonstrated a difference of around 10% between the Benlysta-treated and placebo-treated arms in trials involving over 800 patients. However, there are some bright spots on the horizon. Trials comparing the use of Mycophenolate with other classic immunosuppressive drugs clearly showed it to be as good as Cyclophosphamide in getting patients into renal remission and demonstrated its superiority in maintaining that remission compared to Azathioprine<sup>(1)</sup>. The use of Atacicept which blocks two B-cell activating factors has shown some extremely promising results<sup>(2)</sup> as have trials of both Rontalizumab and Anifrolumab<sup>(3)</sup> (which block interferon-alpha). Some key messages learnt from the running of the lupus trials include the importance of minimising the concomitant steroids and immunosuppression; ensuring the quality of those assessors participating in the clinical trials and the utility of employing an independent peer-review panel to monitor data as it is collected from the participating centres during the course of the trial. It is also evident that selecting patients who are more serologically active is likely to be of benefit both in clinical trials and in the clinic. However, we still need better biomarkers to help guide us; the identification of individuals expressing a high interferon alpha signature (and who thus might better benefit from an interferon alpha blocker) is one such example. It remains ironic that Rituximab, the most widely used monoclonal antibody in SLE, failed its endpoint in two clinical trials. However, detailed analyses of data from those trials have shown some encouraging trends including falls in dsDNA antibodies and improvement in some clinical parameters. <h3>References</h3> Dooley MA et al. N Engl J Med 2011; 365; 188. Isenberg et al. Ann Rheum Dis 2015; 74; 2006–18. Furie R et al. Arthritis Rheum 2015; 67 (suppl 10) (abstract). <h3>Disclosure of Interest</h3> None declared
SAT0543 Clinical predictors and radiographic evidences of occult crystal deposition disease with knee osteoarthritis
Authors: RHA Mohammed
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Osteoarthritis is a slowly progressive degenerative disorder that affects joint components from cartilage to meniscus, subchondral bones and might even lead to synovial inflammation. <h3>Objectives</h3> To investigate the clinical and radiographic findings associated with asymptomatic crystal deposition disease in patients with knee osteoarthritis. <h3>Methods</h3> A single-center cross sectional study, sixty adult patients with knee OA diagnosed according to the ACR criteria were enrolled. Participants were all subjected to history taking, general as well as musculoskeletal clinical examination, serum uric acid, and plain radiography. Examination of the knee joints for intraarticular/periarticular crystal deposits was done using a Logic p5 ultrasound machine (GE) with linear array probe (8–13 MHz) according to the standard EULAR guidelines. <h3>Results</h3> A total of sixty adult patients were enrolled, fifty three patients satisfied the inclusion criteria, 44 females (83%) &amp; 9 males (17%), mean values for; ages 53.5 years ± 8.3 SD, disease duration 42.5 months ± 49.5 SD. Crystal deposits were sono-graphically diagnosed in 73 knees with normal serum uric acid values (68.9%&gt; MSU in 31.1%, CPPD in 63.2%, a picture of mixed deposits in 5.7%). Plain radiography revealed chondrocalcinosis in 3 patients only. Regression analysis models and Forest Plot test revealed a 4.1 fold incidence of crystal deposition in patients with sonographic bursitis than those without (OR=4.13, CI=1.5–11.2, p=0.01) and a 3.2 fold incidence of crystal deposition in patients with sonographic effusion than those without (OR=3.16, CI=1.34–7.44, p=0.01). <h3>Conclusions</h3> The study concluded a number of clinical as well as radiographic associates that might be considered as predictors of silent CDD in patients with knee OA as diagnosed by ultrasonography, the most commonly reported clinical associates were bursitis and effusion. <h3>References</h3> Naredo E, Cabero F, Palop MJ, Collado P, Cruz A, Crespo M. Ultrasonographic findings in knee osteoarthritis: A comparative study with clinical and radiographic assessment. Osteoarthr Cartil. 2005; 13(7):568–74. Doherty M, Jones A, Cawston T. Osteoarthritis. In: Oxford Textbook of Rheumatology. Isenberg D. Lanyon P.Muir K. Doherty S. eds. 3rd ed. Oxford University Press. 2004; 1091- 1118. <h3>Disclosure of Interest</h3> None declared
Toll-like receptor 4 (TLR4) promotes survival of ovarian cancer cells through induction of cell proliferation and apoptosis resistance
Authors: Marta Szajnik, Miroslaw Szczepanski, Malgorzata Czystowska, Theresa Whiteside
Journal: Cancer Research (2008)

1035    Introduction:   Toll-like receptor 4 (TLR4), a main receptor for bacterial lipopolysaccharide (LPS) is highly expressed on antigen presenting cells and play important role in innate immunity. Recently, TLR4 has been found to be expressed by various types of human tumor cells. However, the role and biological significance of TLR4 expressed by tumor cells are unknown. The goal of this study was to analyze TLR4 expression on ovarian cancer cells and the effects of LPS and Paclitaxel on tumor cell proliferation and sensitivity to apoptosis.      Materials and methods:   TLR4 and adaptor protein MyD88 expression in human OVCAR-3 and SKOV-3 cell lines was determined using reverse transcription RT-PCR analysis and immunohistochemistry assays. Activation of the NF-κB translocation was measured by confocal microscopy. Culture supernatants were tested for levels of cytokines/chemokines in a Luminex-based assay. Proliferation of cancer cells was measured in CFSE assays. Annexin V (Anx) binding to cancer cells was studied by multicolor flow cytometry after co-incubation with Paclitaxel (2μmol/L). Western Blot analysis was used to measure activation of PI3K/Akt survival pathway in tumor cells.      Results:  TLR4 mRNA was expressed in both human ovarian epithelial cancer cell lines, but the expression of the receptor on the cell surface was detected only in OVCAR-3 cells. The expression of adaptor protein MyD88 was confirmed by immunofluorescence analysis in both ovarian cancer cell lines. In TLR4 positive OVCAR-3 cells the receptor ligation by LPS  (10μg/ml) induced significant proliferation (proliferation index 18 vs.7, p   Conclusions:  Our study suggests that TLR4 is constitutivly expressed and functionally active on OVCAR-3 cells and may play an important role in promoting immune escape of ovarian cancer by promoting tumor cells proliferation inducing resistance to drug -induced apoptosis.
OP0256-HPR Physical activity and inactivity in patients with systemic lupus erythematosus
Authors: C Boström, F Russ, F Eriksson, S Pettersson, I Gunnarsson, E Svenungsson
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Previous studies indicate that patients with systemic lupus erythematosus (SLE) have a reduced physical activity compared to controls and public health recommendations. However, most studies have used questionnaires without expressing the energy requirements for the activities. <h3>Objectives</h3> We investigated if self-reported physical activity, expressed in Metabolic Equivalent of Task (METs)-minutes/week, in patients with SLE is reduced. The aim was also to investigate if they fulfil the public health recommendations for physical activity. <h3>Methods</h3> 103 patients (93 women/10 men, mean age 51.5 (SD 15.9) years) with SLE according to the 1982 revised ACR criteria for SLE were involved. Physical activity was assessed with the short version of the International Physical Activity Questionnaire (IPAQ), which measure physical activity the last seven days. The IPAQ scientific group classify physical activity into the following categories: "inactive", "minimally active"(equal to public health recommendations) and "health enhancing physical activity". Those individuals who do not meet the criteria for the two latter categories are considered inactive. <h3>Results</h3> The patients reported that they were physically active in median 1666 (interquartile range 693; 3759) METs-minutes/week (n=84). The patients answered that they were sitting in median 6 (interquartile range 4; 8) hours/day the last week (n=98). 59.6% of the patients achieved a minimum of at least 600 METs-minutes/week, i.e. they were active 5 or more days with any combination of walking, moderate-intensity or vigorous intensity activities ("minimally active"). 17.9% achieved a minimum of at least 1500 METs-minutes/week, i.e. they were active on vigorous-intensity on at least 3 days or; achieved a minimum of at least 3000 METs-minutes/week, i.e. they were active 7 or more days on any combination of walking, moderate-intensity or vigorous intensity activities (" health enhancing physical activity"). 22.6% of the patients were "inactive". <h3>Conclusions</h3> In the investigated patients with SLE, the majority were "minimally active" according to IPAQ-categories, which is sufficiently physically active according to the minimum level of public health recommendations. However, only 1/5 reached "health enhancing physical activity" category and 1/5 were considered physically "inactive". Health professionals could use the short version of IPAQ to find out which patients with SLE need support in physical activity programmes. <h3>References</h3> Eriksson K et al. Physical activity in patients with systemic lupus erythematosus and matched controls. Scand J Rheumatol 2012; 41: 290–297. Ahn GE et al. Self-reported and objectively measured physical activity in adults with systemic lupus erythematosus. Arthritis Care &amp; Research 2015; 67:701–707. <h3>Disclosure of Interest</h3> None declared
AB0773 Effectiveness of golimumab in tnf-inhibitor inadequate responder patients with spondyloarthritis and psoriatic arthritis
Authors: L Santo, F D'Onofrio, MG Anelli, N Maruotti, R Bucci, A Semeraro, C Zuccaro, G Carlino, A Marsico, L Quarta, O Casilli, PCF Falappone, F Iannone
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> In real-life world settings, failure of a first TNF-inhibitor (TNFi) put rheumatologists against a crossroad to choose a further TNFi or a biologic drug with a different mechanism of action. <h3>Objectives</h3> Aim of this study was to assess effectiveness of golimumab (GOL) as second line drug after failure of a first TNFi as treatment of patients affected with rheumatoid arthritis (RA), psoriatic arthritis (PsA), or axial-spondyloarthritis (Ax-SpA). <h3>Methods</h3> GOAREL is a prospective cohort of patients starting GOL in community-based care rheumatology centers in Apulia (south Italy) since 2013. Of 494, we selected 368 patients (RA n.73, PsA n.168, and n. Ax-SpA 127) commencing GOL as first ever biological (n.206, 56%) or second treatment (n.161, 44%) after inadequate response to a first TNFi (adalimumab (ADA, n.51), etanercept (ETA, n.81), or infliximab (IFX, n.29). Three patients failing certolizumab were excluded. Primary endpoint was to compare the drug retention rate of biological naïve and TNFi inadequate responders (TNFi-IR) patients on treatment with GOL. In addition, drug retention of second line GOL patients according to the firs TNFi was assessed. Drug survival was estimated by Kaplan-Meier life table analysis. Estimates hazard ratios (HRs) of 2- years drug discontinuation adjusted for demographics, type of disease, disease characteristics, body mass index, co-therapy with glucocorticoids or methotrexate, and prior TNFi were computed by backward selection Cox-regression model. <h3>Results</h3> 2-year drug survival on GOL of naïve and TNF-IR patients was not significantly different (Figure 1). Mean survival time was 20.0 months (95% CI 18.9–21.0) for naïve and 20.4 months (95% CI 19.3–21.6) for TNFi-IR patients. Likewise, drug retention rates on GOL of TNFi-IR patients subdivided by previous TNFi was not significantly different and similar to naïve patients (Figure 1). Mean survival time was 19.0 months (95% CI 16.7–21.4) for prior-ADA, 20.5 months (95% CI 18.9–22.1) for prior-ETA, and 22.0 months (95% CI 19.6–24.3) for prior-IFX. Multiple Cox-regression model showed gender female as the only independent factor positively associated to the risk of GOL discontinuation (HR 2.5, 95% CI 1.5–4.2, p 0.0001). <h3>Conclusions</h3> In real-life setting effectiveness of GOL seems to be similar in naïve or TNFi-IR patients with RA, PsA, and Ax-Spa. Furthermore, clinical outcomes were not influenced by the previous TNFi. <h3>Disclosure of Interest</h3> None declared
Closing the gap between evidence and practice in chronic kidney disease
Authors: Meg J. Jardine, Bertram Kasiske, Dwomoa Adu, Mona Alrukhaimi, Gloria E. Ashuntantang, Shakti Basnet, Worawon Chailimpamontree, Jonathan C. Craig, Donal J. O'Donoghue, Vlado Perkovic, Neil R. Powe, Charlotte J. Roberts, Yusuke Suzuki, Tetsuhiro Tanaka, Katrin Uhlig
Journal: Kidney International Supplements (2017)
Development of chronic kidney disease in patients with non-alcoholic fatty liver disease: A cohort study
Authors: Dong Hyun Sinn, Danbee Kang, Hye Ryoun Jang, Seonhye Gu, Soo Jin Cho, Seung Woon Paik, Seungho Ryu, Yoosoo Chang, Mariana Lazo, Eliseo Guallar, Juhee Cho, Geum-Youn Gwak
Journal: Journal of Hepatology (2017)