tbuckley/cabot-search huggingface dataset:
Role of the sigma-1 receptor chaperone in rod and cone photoreceptor degenerations in a mouse model of retinitis pigmentosa
Authors: Huan Yang, Yingmei Fu, Xinying Liu, Pawan K. Shahi, Timur A. Mavlyutov, Jun Li, Annie Yao, Steven Z.-W. Guo, Bikash R. Pattnaik, Lian-Wang Guo
Journal: Molecular Neurodegeneration (2017)

Retinitis pigmentosa (RP) is the most common inherited retinal degenerative disease yet with no effective treatment available. The sigma-1 receptor (S1R), a ligand-regulated chaperone, emerges as a potential retina-protective therapeutic target. In particular, pharmacological activation of S1R was recently shown to rescue cones in the rd10 mouse, a rod Pde6b mutant that recapitulates the RP pathology of autonomous rod degeneration followed by secondary death of cones. The mechanisms underlying the S1R protection for cones are not understood in detail. By rearing rd10/S1R−/− and rd10/S1R+/+ mice in dim light to decelerate rapid rod/cone degeneration, we were able to compare their retinal biochemistry, histology and functions throughout postnatal 3–6 weeks (3 W–6 W). The receptor-interacting protein kinases (RIP1/RIP3) and their interaction (proximity ligation) dramatically up-regulated after 5 W in rd10/S1R−/− (versus rd10/S1R+/+) retinas, indicative of intensified necroptosis activation, which was accompanied by exacerbated loss of cones. Greater rod loss in rd10/S1R−/− versus rd10/S1R+/+ retinas was evidenced by more cleaved Caspase3 (4 W) and lower rod electro-retinographic a-waves (4 W–6 W), concomitant with reduced LC3-II and CHOP (4 W–6 W), markers of autophagy and endoplasmic reticulum stress response, respectively. However, the opposite occurred at 3 W. This study reveals previously uncharacterized S1R-associated mechanisms during rd10 photoreceptor degeneration, including S1R's influences on necroptosis and autophagy as well as its biphasic role in rod degeneration upstream of cone death.
Achievement of a negative minimal residual disease state after hypomethylating agent therapy in older patients with AML reduces the risk of relapse
Authors: P Boddu, J Jorgensen, H Kantarjian, G Borthakur, T Kadia, N Daver, Y Alvarado, N Pemmaraju, P Bose, K Naqvi, M Yilmaz, S Pierce, M Brandt, C D DiNardo, E J Jabbour, M Konopleva, G Garcia-Manero, J Cortes, F Ravandi
Journal: Leukemia (2017)
AB1031 Anti-drug antibodies: assay performance in patients treated with ANTI-TNF biodrugs
Authors: B Hock, JL O'donnell, J Liu, P Keating, M Spellerberg, L Stamp, M Barclay
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Minimum biodrug concentrations of ∼7mg/l are predictive of disease remission<sup>1</sup>. Very low/absent biodrug concentrations associate with loss of benefit which may be due to ADA<sup>2</sup> however the clinical utility of ADA is assay dependant. In rheumatoid arthritis the combination of low/absent drug concentration and the presence of ADA appears to have the greatest utility<sup>3</sup>. Canterbury Health Laboratories, New Zealand (CHL) has developed a competitive binding ELISA to detect neutralising antibodies whereas most commercial assays utilise a bridging methodology <h3>Objectives</h3> Compare performance of a competitive binding assay with two commercial bridging assays in the detection of ADA to anti-TNFα biodrugs in serum samples with low/absent biodrug concentration <h3>Methods</h3> Serum samples referred for anti TNF biodrug concentrations found to have very low/undetectable concentrations (&lt;1mg/l) were tested for ADA using the competitive-bind assay and two bridging assays (TANI Medikal and GRIFOLS) <h3>Results</h3> Over a 22 month period (Jan 2014 – Oct 2016), 67% (331/497) of referred samples had biodrug concentrations below 7mg/l and 15% (n=79) had low/undetectable biodrug concentrations (adalimumab n=36 or infliximab n=43). ADAs were detected in 53% (42/79) of this latter group. The competitive binding assay detected ADAs in all samples testing positive for ADA by binding assay. In addition a further 8 samples were positive for ADA by the competitive assay: 53% (42/79) positive for ADA by the competitive assay and 33% positive by one or other of the commercial assays <h3>Conclusions</h3> The competitive binding ELISA was more sensitive in detecting biodrug ADAs in serum samples with very low/undetectable biodrug concentrations <h3>References</h3> Felice C, Marco M, Pugliese D,et al. Expert Opin Biol Ther 2015;15:1107–1117. Schaeverbeke T, Truchetet M, Kostine M, Barnetche T et al. Rheumatology 2016;55:210–220. Jani M,Chinoy, Warren R, et al. Arthritis and Rheumatology 2015;67:2011–2019. <h3>Disclosure of Interest</h3> None declared
Regulatory NK cells mediated between immunosuppressive monocytes and dysfunctional T cells in chronic HBV infection
Authors: Haijun Li, Naicui Zhai, Zhongfeng Wang, Hongxiao Song, Yang Yang, An Cui, Tianyang Li, Guangyi Wang, Junqi Niu, Ian Nicholas Crispe, Lishan Su, Zhengkun Tu
Journal: Gut (2017)

HBV infection represents a major health problem worldwide, but the immunological mechanisms by which HBV causes chronic persistent infection remain only partly understood. Recently, cell subsets with suppressive features have been recognised among monocytes and natural killer (NK) cells. Here we examine the effects of HBV on monocytes and NK cells.Monocytes and NK cells derived from chronic HBV-infected patients and healthy controls were purified and characterised for phenotype, gene expression and cytokines secretion by flow cytometry, quantitative real-time (qRT)-PCR, ELISA and western blotting. Culture and coculture of monocytes and NK cells were used to determine NK cell activation, using intracellular cytokines staining.In chronic HBV infection, monocytes express higher levels of PD-L1, HLA-E, interleukin (IL)-10 and TGF-β, and NK cells express higher levels of PD-1, CD94 and IL-10, compared with healthy individuals. HBV employs hepatitis B surface antigen (HBsAg) to induce suppressive monocytes with HLA-E, PD-L1, IL-10 and TGF-β expression via the MyD88/NFκB signalling pathway. HBV-treated monocytes induce NK cells to produce IL-10, via PD-L1 and HLA-E signals. Such NK cells inhibit autologous T cell activation.Our findings reveal an immunosuppressive cascade, in which HBV generates suppressive monocytes, which initiate regulatory NK cells differentiation resulting in T cell inhibition.
THU0638 Prevalence and direct healthcare costs of upper gastrointestinal (UGI) adverse events in asian rheumatic patients on long-term non-steroidal anti-inflammatory drugs (NSAIDS)
Authors: SL Pok, FH Shabaruddin, JY Teng, M Dahlui, CT Ng, S Sockalingam, MS Said, A Rosman, IS Lau, L Mohd Isa, H Hussain, S Mahadeva
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> NSAIDs are frequently used in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). NSAID-induced UGI adverse events are well described in the Western population but data is lacking in Asian patients. <h3>Objectives</h3> To describe the prevalence and direct healthcare costs of NSAID-induced UGI adverse events in a large cohort of RA and OA patients in Malaysia. <h3>Methods</h3> A retrospective cohort study of RA and/or OA patients who received long-term NSAIDs (minimum 4 weeks prescription of any NSAID) between 2010 and 2013 was conducted in 4 large tertiary care centres with rheumatology units in Malaysia. Electronic clinical records and pharmacy prescriptions were reviewed. Resource use data was collected in patients who developed UGI adverse events within the 24 months follow up period. Unit costs were estimated by combining top down (general overheads for hospital services) and bottom up (activity-based costing for clinic visits, hospitalisation, diagnostic investigations, medications) approaches. <h3>Results</h3> 634 patients were included in the final analysis with mean age 53.4±12.5 years, 90% female, diagnosis of RA in 60%, OA in 10% and both RA and OA in 30%. 45% and 8% of patients were on concomitant prednisone and aspirin respectively. 89% of patients had no previous upper GI disease. 59% and 41% of patients were grouped under non-selective and COX-2 inhibitor respectively. 84 (13.2%) patients developed UGI adverse events (Figure 1), consisting of 78 (12.3%) patients with dyspepsia, 5 (0.79%) with peptic ulcer disease (PUD) and 1 (0.16%) with upper GI bleeding (UGIB). The total direct cost was RM37,352 (USD 11,419) with a mean cost of RM447±535 (USD 137±163) per patient (Table 1). The largest cost components were pharmacotherapy (34%), oesophagoduodenoscopies (OGD) (23%) and outpatient visits (18%). The mean cost of dyspepsia was RM409±513 (USD 125±157) per patient. The mean cost of PUD and UGIB was approximately double (RM806±579) (USD 246±177) and quadruple (RM1,602) (USD 490) of dyspepsia respectively. <h3>Conclusions</h3> The low prevalence of UGI adverse events in Malaysian rheumatology patients suggests judicious use of NSAIDs in tertiary care setting resulting in a low cost implication for the management of these events. <h3>Disclosure of Interest</h3> None declared
AB0696 Retention rates of adalimumab, etanercept, and infliximab as first- or second-line biotherapies for spondyloarthritis patients in daily practice in auvergne (france)
Authors: M Soubrier, B Castagné, B Pereira, A Fan, T Frayssac, M Couderc, S Malochet-Guinamand, S Mathieu, Z Tatar, A Tournadre, J-J Dubost
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The use of tumour necrosis factor alpha (TNF-α) inhibitors – or anti-TNFs – has considerably improved the treatment of spondyloarthritis (SpA). The first three of these available anti-TNFs (infliximab, adalimumab, and etanercept) are the most widely used in the treatment of SpA. Their efficacy and safety have been demonstrated in extensive randomised controlled trials (RCTs).Nevertheless, the randomized studies were of short duration and included a selected population that differed from patients treated in daily practice <h3>Objectives</h3> To compare, in real-life settings, the retention rates of the initial anti-TNF treatment (etanercept [ETN], adalimumab [ADA],and infliximab [IFX]) used as first-line biotherapy for spondyloarthritis (SpA), and to evaluate treatment switches to another anti-TNF inhibitor in the event of treatment failure. <h3>Methods</h3> Monocentric retrospective cohort including all SpA patients starting an initial anti-TNF therapy between 2001 and 2015. <h3>Results</h3> Of the 249 SpA patients analysed (135 radiographic cases, 114 non-radiographic), 102 were given ETN, 62 ADA, and 85 IFX. In total, 103 discontinued treatment. The median retention duration was 69.7 months (17–$∞)$ (ETN: 55.4 [17.6–94.6], ADA 57.6 [13.9–∞], and IFX: not reached). Retention was longer for IFX compared with ETN (HR=0.62 [0.39–0.99]) but non-significant compared with ADA (HR: 0.91 [0.56–1.48]). The percentage of patients continuing treatment after 5 years was 47% for ETN, 46% for ADA, and 62% for IFX. In multivariate analysis, the predictive factors for retention were a low BASDAI score (HR: 1.02 [1.01–1.04]), high CRP levels (HR 0.98 [0.97–0.99]), the concomitant use of disease-modifying therapy (HR: 0.4 [0.21–0.75]), and radiographic SpA (HR: 1.5 [1.0–2.52]). In total, 61 patients switched to another anti-TNF therapy. No difference was observed among the three anti-TNF therapies with regard to the median retention duration, but the retention rate was higher in the event of treatment switches from one monoclonal antibody to another. <h3>Conclusions</h3> The retention rate in SpA patients proved high, and retention for IFX was superior to that of ETN. <h3>Disclosure of Interest</h3> None declared
FRI0696 Impact of adalimumab therapy on brachial endothelial function and large artery stiffness in patients with rheumatoid arthritis
Authors: AL Demoux, K Aissi, B Chaudier, S Carijn, P-Y Chouc, H De Baillou, P Rossi
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Anti-TNF alpha treatment may improve endothelial function and mechanical properties of large artery stiffness in patients with inflammatory rheumatic diseases, however studies remain controversial. <h3>Objectives</h3> To study the effect of TNF alpha blockage with adalimumab for 24 weeks on brachial endothelial function and sub-clinical markers of atherosclerosis in patients with inflammatory rheumatic diseases. <h3>Methods</h3> A total of 26 patients (14 males, 12 females; mean age, 47±11 years) with inflammatory rheumatic diseases (16, rheumatoid arthritis; 9, ankylosing spondylitis, 1, psoriasic rheumatism), resistant to disease-modifying antirheumatic drugs, were studied before the first infusion of adalimumab and again after 24 weeks of treatment. Endothelial function was assessed by measuring flow mediated dilatation using an ultrasound Doppler technique on the brachial artery. Other markers of sub clinical atherosclerosis were assessed by arterial stiffness via aortic pulse wave velocity, augmentation index and central blood pressure, and carotid intima-media thickness. Data for body mass index, disease activity using DAS-PCR and BASDAI, C-reactive protein, fasting glycaemia, and lipid profile were collected before treatment and after 24 weeks. <h3>Results</h3> 24 weeks of adalimumab therapy resulted in a reduction of disease activity score and serum levels of C-reactive protein. No significant differences were found in body mass index, total cholesterol, triglycerides and fasting glycaemia. Brachial blood pressure and heart rate remained similar, as well as carotid intima-media thickness. After 24 weeks of treatment with adalimumab, flow mediated dilatation improved significantly; central systolic and diastolic blood pressure decreased significantly; however central pulse pressure, augmentation index and aortic pulse wave velocity remained unchanged. <h3>Conclusions</h3> In patients with inflammatory rheumatic diseases, treatment with adalimumab for 24 weeks resulted in a significant improvement of endothelial function and central arterial pressure. <h3>Disclosure of Interest</h3> A. L. Demoux Grant/research support from: Abbvie, K. aissi: None declared, B. chaudier: None declared, S. carijn: None declared, P.-Y. chouc: None declared, H. de baillou: None declared, P. rossi: None declared
T Cells Deficient in Diacylglycerol Kinase ζ Are Resistant to PD-1 Inhibition and Help Create Persistent Host Immunity to Leukemia
Authors: Weiqing Jing, Jill A. Gershan, Sandra Holzhauer, James Weber, Katie Palen, Laura McOlash, Kirthi Pulakanti, Erin Wesley, Sridhar Rao, Bryon D. Johnson, Matthew J. Riese
Journal: Cancer Research (2017)

Abstract Efforts to improve the efficacy of adoptive T-cell therapies and immune checkpoint therapies in myelogenous leukemia are desired. In this study, we evaluated the antileukemia activity of adoptively transferred polyclonal cancer antigen-reactive T cells deficient in the regulator diacylglycerol kinase zeta (DGKζ) with or without PD-1/PD-L1 blockade. In the C1498 mouse model of myeloid leukemia, we showed that leukemia was eradicated more effectively in DGKζ-deficient (DGKζ−/−) mice than wild-type mice. T cells transferred from DGKζ-deficient mice to wild-type tumor-bearing recipients conferred this benefit. Leukemia clearance was similar to mice treated with anti-PD-L1. Strikingly, we found that the activity of adoptively transferred DGKζ−/− T cells relied partly on induction of sustainable host T-cell immunity. Transferring DGKζ-deficient T cells increased the levels of IFNγ and other cytokines in recipient mice, especially with coadministration of anti-PD-L1. Overall, our results offered evidence that targeting DGKζ may leverage the efficacy of adoptive T-cell and immune checkpoint therapies in leukemia treatment. Furthermore, they suggest that DGKζ targeting might decrease risks of antigen escape or resistance to immune checkpoint blockade. Cancer Res; 77(20); 5676–86. ©2017 AACR.
FRI0694 Prevalence of rheumatic disease in an adult population from colombia. a copcord methodology study
Authors: AM Santos, JC Rueda, J-I Angarita, R Giraldo, E Forero, I Pelaez-Ballestas, JG Muñoz Ballesteros, E-L Saldarriaga, J Ramirez, C Toro, J Londono
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Rheumatic diseases are the leading cause of permanent disability. In our country are the fourth cause of consultation in health institutions. The COPCORD model constitutes an effective tool in the determination of the prevalence of diseases. Globally, this model has been carried out in Asia, Europe and in some countries of Latin America. In Colombia the epidemiology of rheumatic diseases is not known globally; this would be the first national study that uses the data collection questionnaire using the COPCORD instrument <h3>Objectives</h3> To estimate the prevalence of rheumatic disease and related factors in a Colombian population over 18 years of age in six Colombian cities <h3>Methods</h3> A Cross-sectional analytical study was designed in people older than 18 years. A probabilistic stratified sampling method using three stages. The first stage of sampling was the selection of cartographic sectors in each city. The second stage of sampling was the blocks of each sector. The third stage of sampling was the homes of each block. All household members were surveyed. The sample size was calculated to be 6,528 people (2336 from Bogotá, 1220 from Medellín and Cali each, 746 from Barranquilla, 503 from Bucaramanga and Cúcuta each). The COPCORD questionnaire adapted for Colombia, was applied in the first stage by standardized interviewers. Positive cases were reviewed at home by a first year rheumatology fellow. To assess whether it is a rheumatic disease; the positive cases for a probable rheumatic disease were reviewed by a second year rheumatology fellow and reviewed again with laboratory and image studies by a certified rheumatologist to establish the definitive diagnosis <h3>Results</h3> 3,146 men and 3,547 women were included. Pain in the last 7 days not associated with trauma was reported in 3,213 (48%) participants. The most frequent sites were knees (right 31%, left 29%), hands (right 25%, left 24%), lumbar spine (18%) and shoulders (right 16%, left 14%). Table 1 depicts the prevalence of rheumatic diseases in Colombia <h3>Conclusions</h3> Our study shows a similar prevalence to those worldwide in scleroderma, dermatomyositis, systemic lupus erythematosus, and spondyloarthritis. A lower prevalence was observed in Sjögren Syndrome, fibromyalgia, gout and osteoarthritis. A slightly higher prevalence of rheumatoid arthritis was observed in our population. The high prevalence of rheumatoid arthritis and soft tissue rheumatism should increase awareness in our governmental health entities given their long term disability risk <h3>Disclosure of Interest</h3> None declared
AB0014 Differential effects of a single dose of cyclophosphamide on circulating cell subpopulations in patients with vasculitides and autoimmune systemic diseases
Authors: G Gabcova, Z Mikulkova, M Skacelova, A Petrackova, A Smrzova, M Schubertova, F Mrazek, P Horak, E Kriegova
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> High-dose cyclophosphamide (CFA) is used for treatment of patients with severe manifestations of systemic autoimmune diseases. The knowledge about the effect of CFA on circulating cell populations in these diseases is still limited. <h3>Objectives</h3> To identify the effect of a single dose of CFA on circulating cell populations in patients with vasculitides and autoimmune systemic diseases. <h3>Methods</h3> We immunophenotyped T lymphocytes (CD3, CD4, CD8, CD25, CD127, HLA-DR), B lymphocytes (CD19, CD20, CD27), NK cells (CD3, CD16, CD56, CD69), neutrophils (CD15, CD11b, CD16, CD54, CD62L, CD64), and monocytes (CD11b, CD14, CD16, CD64, HLA-DR) using 6-color cytometer BD FACSCanto II (Becton Dickinson) in peripheral blood of patients with vasculitides (n=6) and systemic disorders of connective tissue (n=6). From each patient, we obtained paired samples before and one month after a single CFA dose. Statistical tests were performed using GraphPad Prism (GraphPad Software, Inc). <i>P</i>-value &lt;0.05 was considered as significant. <h3>Results</h3> Single dose of CFA resulted in increase of percentage of CD8+ T lymphocytes (<i>P</i>=0.002), leading to marked decrease of CD4+/CD8+ ratio (<i>P</i>=0.009). Except three patients, overall percentage of neutrophils decreased after the treatment (<i>P</i>=0.01). Although CFA pulse did not influence the percentage of NK cells, the percentage of NK cells carrying stimulatory receptor CD69 increased after CFA (<i>P</i>=0.037). Similarly, CFA enhanced the percentage of co-stimulatory molecule CD27 on B lymphocytes (<i>P</i>=0.048). Among subsets of monocytes, CFA treatment increased percentage of CD14-CD16+ monocytes (<i>P</i>=0.006) and increased expression (MFI) of Fc fragment CD64 (<i>P</i>=0.02). Moreover, increase of HLA-DR was observed on CD14-CD16+ monocytes (<i>P</i>=0.037). The investigations whether the changes in immune cell subpopulations in treated patients have prognostic potential are ongoing. <h3>Conclusions</h3> Single dose of CFA resulted in increase of CD8+ T lymphocytes, activation of NK, B lymphocytes and monocytes as well as in some patients decrease in neutrophil counts. Further investigation of selected markers may lead to identification of new prognostic markers and predict the effectiveness of the treatment. <h3>Acknowledgements</h3> Grant support: MZ CR VES15–28659A, IGA_LF_2017_009 <h3>Disclosure of Interest</h3> None declared
AB0001 First description and functional proteomic analysis of a protective for rheumatoid arthritis gene polymorphism
Authors: A Sarantopoulos, I Theodorou, A Notopoulos, I Koulas, P Boura
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Rheumatoid Arthritis (RA) is the most common systemic autoimmune disease, with a respective expanded genetic research<sup>1</sup>. Immunogenetic studies have documented the positive correlation of various gene loci with incidence and/or disease profile. However, the description of gene loci negatively related to the incidence of RA is rarely documented. Apart from an early study involving HLA class II, there has been no reference to any genetic locus associated with a protective role against RA incidence. <h3>Objectives</h3> To identify the sequence of the functional areas of the TRAF1 (TNF receptor associated factor 1 - a protein involved in the intracellular signaling pathway of TNF) gene. <h3>Methods</h3> 172 patients and 95 controls were genetically assessed for the sequence of the seven exons of the gene TRAF1. <h3>Results</h3> On the position 9:120905076 of exon 7, the registered polymorphism G/A (rs143265058) was described in the controls group. The same polymorphism was not confirmed in any of the patients. Further functional proteomic study of the polymorphism with computing programs (software), revealed that the presence of this polymorphism leads to a differentiation of the quaternary structure of TRAF1 protein, possibly affecting the cohesion of intracellular TNF signaling pathway<sup>2</sup>. <h3>Conclusions</h3> The present reference is one of the extremely rare genetic studies describing a protective gene locus against rheumatoid arthritis, and a pioneer of its kind in the use of Applied Informatics in the depiction of the quaternary structure of the encoded protein. At the same time, it is one of the few immunogenetic studies describing the functional proteomics of the encoded protein, plotting on a molecular level specific interaction modifications affecting the intracellular signaling pathway of TNF. <h3>References</h3> Kim K, Bang SY, Lee HS, Bae SC. Update on the genetic architecture of rheumatoid arthritis. Nat Rev Rheumatol. 2017 Jan; 13 (1): 13–24. A. Sarantopoulos. TRAF-1 immunogenic study in Rheumatoid Arthritis. PhD Thesis, Aristotle University of Thessaloniki, 2016. (Http://thesis.ekt.gr/thesisBookReader/id/38410#page/1/mode/2up). <h3>Disclosure of Interest</h3> None declared