tbuckley/cabot-search huggingface dataset:
2’, 5’-Oligoadenylate Synthetase 1 (OAS1) expression and function in prostate cancer
Authors: Roblena Walker, Ashley Evans, Tandeih Ghogomu, Jaideep Chaudhary
Journal: Cancer Research (2008)

4562  Our recent studies have suggested that androgens primarily regulate the immune inflammatory pathways in normal prostate epithelial cells. In general androgens up-regulate the anti-tumor acute inflammatory pathway but down-regulate the pro-tumor chronic inflammatory pathways in normal prostate epithelial cells. In prostate cancer, this regulatory role of androgens is switched in which there is a general loss or decrease in expression of acute inflammatory response genes (e.g. IFN) and a concomitant increase in chronic inflammatory response genes (e.g. IL6). One of the key androgen regulated acute inflammatory gene is 2’, 5’-oligoadenylate synthetase 1 (OAS1). OAS1 is also an IFN regulated gene that is expressed as part of the innate immune response to viruses. The induction of OAS1 leads to the polymerization of ATP to 2’-5’ -linked adenosine oligomers or 2-5A (pppA(2’p5’A)n) in the presence of dsRNA. 2-5A in turn activates RNASEL, which degrades viral dsRNA. The expression and function of OAS1 is therefore critical for functional RNaseL. RNASEL gene inactivation has also been linked to hereditary prostate cancer. Recently, RNASEL has been reported to have tumor suppressor activities in vitro. However, in sporadic prostate cancer no RNASEL mutations or a significant change in its expression is observed. These observations led us to hypothesize that upstream regulators of RNASEL, such as OAS1 may be disrupted leading to loss of RNASEL function and prostate cancer. In order to test this hypothesis, we performed OAS1 reverse transcription (RT) polymerase chain reactions (PCR) on prostate cancer cell lines PC3, DU145, and LNCaP. Our observations indicate that OAS1 is highly expressed in PC3, but not in DU145 or LNCaP cells. Interestingly, RNASEL is only expressed in DU145 but not in PC3 or LNCaP cells. These results suggest that the OAS1-RNASEL pathway is non-functional in prostate cancer cells. Attenuation of the pathway through genetic approach is currently being used to address the significance of OAS-RNaseL in prostate cancer cell survival and viral response and will be presented.
THU0650 The effect of anti-tnf therapy on work productivity and activity impairment in patients with rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis over one year – real life data from the czech biologics registry attra
Authors: J Zavada, L Szczukova, K Pavelka, P Horák, J Vencovsky
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Objectives</h3> To assess the effect of anti-TNF therapy on work productivity using the Work Productivity and Activity Impairment-Specific Health Problem (WPAI-SHP) questionnaire in patients with RA, PSA and AS in the real life setting. In the Czech Republic, anti-TNF-therapy is reimbursed for RA if DAS28&gt;5.1 despite therapy with csDMARDs, for PSA if disease is not “adequately controlled” with csDMARDs, and for AS if BASDAI&gt;4 and CRP/ESR elevated above normal. <h3>Methods</h3> WPAI-SHP scores were collected for all patients enrolled in ATTRA since 2012 at baseline and after 12 months of anti-TNF exposure. Bionäive patients with RA (n=352), AS (n=442) and PSA (n=133) starting anti-TNF therapy with available baseline data on demography, disease duration and physical function, and WPAI-SHP at baseline and at 12 months were included in this analysis. Patients older than 60 years, on maternity leave or students were excluded. Only patients working for pay at baseline were assessed for WPAI-SHP summary scores: absenteeism (mean % work time missed), presenteeism (mean % productivity loss at work), overall work impairment (mean % overall work productivity loss), and activity impairment (mean % productivity loss in regular activities). <h3>Results</h3> Baseline characteristic were significantly different between diagnoses (Table 1). Working status changed significantly only in patients with RA (employed 69→64%, p=0.013), but not in AS (77→78%) or PSA (77→73%). In patients employed for pay both at baseline and after 12 months, all WPAI-SHP scores improved significantly over one year of anti-TNF therapy (Table 2). <h3>Conclusions</h3> In the real life setting of the Czech Republic, anti-TNF therapy effectively reduced absenteeism, presenteeism, activity impairment and work impairment over one year in employed patients with RA, AS and PSA. <h3>Disclosure of Interest</h3> None declared
SAT0105 Survival in first line of biologic agents in an apulian cohort of rheumatoid arthritis patients with occult hepatitis b virus infection
Authors: G Carlino, M Fornaro, F D'Onofrio, N Maruotti, A Semeraro, C Zuccaro, L Santo, A Marsico, R Bucci, L Quarta, O Casilli, PCF Falappone, F Iannone
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The occurrence of hepatitis B virus (HBV) infection may be a concern during the treatment of patients with Rheumatoid Arthritis (RA). We wondered whether a state of HBV occult infection (anti-HBcAg-pos, HBsAg-neg, HBV-DNA-neg) might influence the effectiveness of biological drugs in RA patients in real-world settings. <h3>Objectives</h3> We performed a retrospective analysis to evaluate the survival on first line biologic drug of RA Apulian patients with HBV occult infection. <h3>Methods</h3> We analyzed longitudinal data of 384 consecutive RA patients starting a first biological drug in a time frame from 1st January 2008 to 31st December 2014. Demographic and disease related characteristics were collected at baseline and at last observation visit. Baseline serological markers of HBV infection and causes of discontinuation of treatment were also recorded. Primary endpoint was the influence of anti-HBcAg-pos on drug survival, estimated by Kaplan-Meier life table analysis. Estimates hazard ratios (HRs) of drug discontinuation or achievement of Clinical Disease Activity Index (CDAI) based remission at last visit, adjusted for disease characteristics, biological drug class and anti-HBcAg-pos were computed by Cox-regression models. <h3>Results</h3> No baseline demographic and disease characteristics difference between anti-HBcAg-pos and anti-HBcAg-neg RA patients were detected, except for DAS28 that was significantly higher in anti-HBcAg-pos group. Drug survival rate was significantly lower in anti-HBcAg-pos (57.6%, median survival time (95% CI) 54 months (38–69)) than in anti-HBcAg-neg patients (67.8%, median survival time (95% CI) 77 months (59–94)). Median survival time for ineffectiveness was 15 months (12–17) for anti-HBcAg-pos and 24 months (18–30) for anti-HBcAg-neg patients (p=0.04). Cox regression models showed a significant association between anti-HBcAg-neg (HR 0.60, 0.39–0.92) or RF/ACPA-neg (HR 1.69, 1.16–2.46) and drug discontinuation, while co-therapy with MTX (HR 2.14, 1.01–4.58) or with steroids (HR 0.38, 0.16–0.91), and RF/ACPA neg (HR 0.45, 0.21–0.95) were independently associated with the achievement of CDAI based remission. <h3>Conclusions</h3> HBV occult infection seems to influence negatively the effectiveness of biological therapies in RA patients. However, being a real-life setting, unknown confounding factors might generate an apparent association or mask a true correlation between the HBcAb status and clinical outcomes. <h3>Disclosure of Interest</h3> None declared
SAT0724-HPR Gothenburg nurse led tight control study – gotnet. patients' experiences of nurse-led care and tight control. a qualitative study of patients with rheumatoid arthritis
Authors: U Bergsten, A-S Sjö
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Rheumatoid arthritis (RA) is a chronic inflammatory illness, using both pharmacological and non-pharmacological therapies. Some patients experience good treatment, knowledge about their illness and situation. For other patients, it might look different depending on how much they know about their illness. Earlier research has primary focused on patients in remission. In order to strengthen and support patients with RA that are not feeling well, to give them more knowledge about their situation, one strategy could be that they have access to a nurse-led rheumatology clinic with person-centered care (PCC). <h3>Objectives</h3> The aim of this study was to describe patients9 experiences of nurse-led care tight control. <h3>Methods</h3> Qualitative design was used in order to receive deeper understanding of the phenomenon. Interviews were conducted with 12 informants (with strategic sample) that participated in the intervention group of a randomized controlled trial exploring the effect of patient centered care, the Got-Net study. The interviews were analyzed using phenomenography approach. <h3>Results</h3> The informants9 experiences of nurse-led care tight control emerged in three categories. The three categories describe the process, the relationship between the concepts. The first step describes the <i>Meeting of competence</i>, the next step that the informant experienced was <i>Relationship building</i> and the last step to have <i>Made a personal journey</i>. <h3>Conclusions</h3> Patients with RA who got the opportunity of nurse-led care and tight control became strengthen, got extended knowledge about their illness. Patients have been treated on their own level, knowledge and needs, by using a person-centered approach. <h3>Disclosure of Interest</h3> None declared
FRI0603 Clinical implications of ultrasonography in monitoring disease activity of relapsing polychondritis: the assessment of auricular chondritis in 3 cases
Authors: H Nishikawa, Y Taniguchi, Y Terada
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Relapsing polychondritis (RP) is a rare systemic inflammatory disorder and might often be refractory. Therefore, the discover of imaging modality would be required on diagnosis and treatment of RP. <h3>Objectives</h3> To assess the clinical implications of ultrasonography (US) in monitoring disease activity of relapsing polychondritis (RP). <h3>Methods</h3> Three cases of a 78-year-old man with RP, a 74-year-old woman with RP associated with optic perineuritis and a 42-year-old woman with RP associated with uveitis were assessed by US before and after treatments. <h3>Results</h3> Ultrasonography (US) of the auricle before treatment showed low-echoic swollen auricular cartilage with increased power Doppler signals (PDS) in all cases. US findings corresponded to the above-mentioned biopsy findings. After treatment with prednisolone combined with methotrexate, the auricular swelling completely resolved in all cases. Then, US findings also showed dramatic reductions in swelling of cartilage with the decrease in PDS. <h3>Conclusions</h3> US imaging can be used to differentiate between inflammation, vascular lesions, and tumors in the ear pinna. RP could be differentiated from the damage of repeated trauma (i.e. rugby) with producing subperichondrial serous effusion. As in the present cases, US imaging of the external ear and auricular cartilage in RP also facilitates evaluation of auricular lesions and monitoring of disease activity, especially when we consider the treatment response and the timing of drug tapering. <h3>Disclosure of Interest</h3> None declared
AB0446 Additive inhibition of interferons, b and t cell activation and tfh-related cytokine cxcl13 by leflunomide and hydroxychloroquine supports rationale for combination therapy in pss patients
Authors: EH van der Heijden, SA Hartgring, AA Kruize, TR Radstake, JA van Roon
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> T and B cell-driven immunity is critically involved in immunopathology of pSS. Recently we demonstrated synergistic T and B-cell activation upon T cell triggering and TLR7/9-driven B cell activation in pSS patients, accompanied by synergistic induction of immunoglobulins and IFN-γ- and IL-17-producing T cells<sup>1</sup>. In addition, TLR7/9-expressing activated pDCs associated with increased type I IFNs and IFN-inducible genes are increased pSS patients. Several studies have shown that the DMARDs leflunomide and hydroxycholoroquine inhibit immune activation in pSS but only show moderate efficacy. However, LEF and HCQ target different pathways with overlapping, but also potentially additive mechanisms, where LEF primarily targets T and B cells and HCQ TLR7/9-driven B cell and pDC activation. <h3>Objectives</h3> To assess the additive effects of LEF and HCQ on CD4 T- and B-cell activation and production of interferons IFN-α and IFN-γ, Tfh-related cytokine CXCL13, as well as IgG and IgM <i>in vitro</i> employing SEB/TLR9-triggered PBMC. <h3>Methods</h3> PBMCs of healthy individuals (n=9) and of pSS patients (n=8) were cultured with antigen (SEB), TLR9 and their combination, in presence or absence of LEF, HCQ and their combination in clinical relevant concentrations. Proliferation of T and B cells and release of IFN-α, IFN-γ, CXCL13, IgG and IgM were measured. <h3>Results</h3> In line with robust T and B cell activation, IFN-γ, IFNα, CXCL13, IgG and IgM production was achieved by a combination of SEB and TLR9 (all at least p&lt;0.001). LEF dose dependently inhibited B and T cell proliferation, Interferon, CXCL13 and immunoglobulin production. HCQ dose dependently inhibited B cell proliferation, IFN-α, CXCL13, and immunoglobulin production. T cell proliferation and IFN-γ production were inhibited by HCQ only at higher concentrations. At several suboptimal concentrations LEF and HCQ additively inhibited T cell proliferation both in healthy individuals and in pSS patients. (Figure 1). Significant additive effects were seen for all outcome measures except IFN-α. Since IFNa was already robustly inhibited by HCQ alone (eg.for pSS 90% at 3.3 μM, p&lt;0.001), only trends towards additive effects were observed. <h3>Conclusions</h3> LEF and HCQ robustly inhibited proliferation of T and B cells, cytokine production and immunoglobulin production with clear additive efficacy in both healthy individuals as in pSS patients. These data support the potential surplus value of combination therapy with LEF and HCQ for patients with pSS. <h3>References</h3> Bikker et al. Interleukin-7 and Toll-Like Receptor 7 induce synergistic B cell and T cell activation. PLoS ONE 9(4): e94756. <h3>Disclosure of Interest</h3> None declared
The CCTG PA.7 trial: A randomized phase II study of gemcitabine and nab-paclitaxel vs. gemcitabine, nab-paclitaxel, durvalumab, and tremelimumab as 1st line therapy in metastatic pancreatic ductal adenocarcinoma (PDAC).
Authors: Daniel John Renouf, Petr Kavan, Neesha C. Dhani, Derek J. Jonker, Alice Chia-chi Wei, Tina Hsu, Patricia A. Tang, Barbara Graham, Dongsheng Tu, Christopher J. O'Callaghan
Journal: Journal of Clinical Oncology (2017)

TPS4149 Background: Gemcitabine (GEM) and Nab-Paclitaxel (Nab-P) has become a standard 1 st line therapy for advanced PDAC based on the MPACT Trial.Durvalumab (D) is a human monoclonal antibody (mAb) that inhibits binding of programmed cell death ligand 1 (PD-L1) to its receptor (PD-1). Tremelimumab (T) is a mAb directed against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Monotherapy with immune checkpoint inhibitors has thus far demonstrated limited activity in PDAC. This may be partly related to the activity of cancer associated fibroblasts (CAF) in promoting an immunosuppressive tumoural microenvironment in PDAC. GEM and Nab-P treatment may deplete stroma and CAFs, release neo-antigens and increase the immunogenicity of PDAC. This study is designed to evaluate whether the addition of PD-L1 and CTLA-4 inhibition to GEM/Nab-P increases treatment efficacy. Methods: This randomized phase II study (ClinicalTrials.gov NCT02879318) will assess the efficacy and safety of GEM/Nab-P vs. GEM/Nab-P/D/T in patients (pts) with metastatic PDAC (n = 190). Good performance status pts (ECOG &lt; 2) with untreated metastatic PDAC will be eligible. Prior adjuvant therapy is allowed provided recurrence is &gt; 6 months post-completion. There is a safety lead in of 10 pts receiving GEM/Nab-P/D/T. Assuming no safety concerns the study will go on to randomize pts in a 2:1 ratio to receive GEM (1000mg/m 2 D1, 8, 15)/Nab-P (125mg/m 2 D1, 8, 15) with/without D (1500 mg) D1 q 28 days and T (75 mg) D1 for first 4 cycles. Treatment will continue until disease progression, death, intolerable toxicity, or patient/investigator decision to stop. Primary endpoint is overall survival; secondary endpoints include progression free survival, safety, overall response rate and quality of life. Analysis will be according to randomized group stratified by ECOG PS and receipt of prior adjuvant chemotherapy. Blood, plasma, and archival tissue will be collected and assessed for potential prognostic and predictive biomarkers. As of February 1 2017, 11 pts have been enrolled and the initial safety analysis is ongoing. Clinical trial information: NCT02879318.
THU0347 Impact of obesity on the response to tumour necrosis factor inhibitors in axial spondyloarthritis
Authors: R Micheroli, M Hebeisen, A Scherrer, L Wildi, P Exer, G Tamborrini, J Bernhard, B Möller, P Zufferey, MJ Nissen, A Ciurea
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Few studies have investigated the impact of obesity on response to tumour necrosis factor inhibitors (TNFi) in patients with axial spondyloarthritis (axSpA). <h3>Objectives</h3> To investigate the impact of different Body Mass Index (BMI) categories on TNFi response in a large cohort of patients with axSpA. <h3>Methods</h3> Patients within the Swiss Clinical Quality Management cohort were included if they fulfilled the ASAS criteria for axSpA, started a first TNFi after recruitement and had available BMI data as well as a baseline and follow-up visit at 1 year (±6mo) (N=632). Patients were categorized according to BMI: normal (BMI 18.5 to &lt;25), overweight (BMI 25 to 30) and obese (BMI &gt;30). We evaluated the proportion of patients achieving the 40% improvement ASAS criteria (ASAS40) as well as Ankylosing Spondylitis Disease Activity Score (ASDAS) improvement and status scores at 1 year. Patients having discontinued the TNFi were considered non-responders. We controlled for age, sex, HLA-B27, axSpA-type, BASDAI, BASMI, elevated CRP, current smoking and physical exercise in multiple adjusted logistic regression analyses. <h3>Results</h3> In comparison to normal weight and overweight patients, obese individuals were significantly older, had a longer symptom duration and higher BASFI and BASMI levels, while ASDAS levels were comparable between the 3 groups (Table 1). Data to calculate the ASAS40 response was available in 496 patients (78%). It was reached by 44%, 35% and 28% of patients with normal weight, overweight and obesity, respectively, (p=0.02; Table 2). A significantly lower odds ratio (OR) for achieving ASAS40 response was found in adjusted analyses in obese patients vs patients with normal BMI (OR 0.30, 95% confidence interval (CI) 0.11–0.73, p=0.01). Comparable results were found for the other outcomes assessed. The respective adjusted ASAS40 OR in overweight vs. normal weight patients was 0.69, 95% CI 0.38–1.24, p=0.22. <h3>Conclusions</h3> Obesity is associated with significantly lower response rates to TNFi in patients with axSpA. <h3>Disclosure of Interest</h3> None declared
Rapid Evolution of Genes Involved in Learning and Energy Metabolism for Domestication of the Laboratory Rat
Authors: Lin Zeng, Chen Ming, Yan Li, Ling-Yan Su, Yan-Hua Su, Newton O Otecko, He-Qun Liu, Ming-Shan Wang, Yong-Gang Yao, Hai-Peng Li, Dong-Dong Wu, Ya-Ping Zhang
Journal: Molecular Biology and Evolution (2017)

The laboratory rat, widely used in biomedical research, is domesticated from wild brown rat. The origin and genetic mechanism underlying domestication of the laboratory rat remain largely elusive. In the present study, large scale genomes supported a single origin for the laboratory rat, possibly from a sister group to wild rats from Europe/Africa/Middle East. Genomic and transcriptomic analyses uncovered many artificially selected genes (e.g., FOXP2, B3GAT1, and CLOCK) involved in the nervous system. These genes associate with learning ability and regulation of circadian rhythm, which likely enabled the successful domestication of the laboratory rat. Particularly, many genes, including mitochondrial genes responsible for energy metabolism, displayed a substantially increased expression in the brain of laboratory rats compared with wild rats. Our findings demystify the origin and evolution of this model animal, and provide insight into the process of its domestication.
AB0675 Anti-mda5 positive dermatomyositis: an emerging entity
Authors: V Ortiz-Santamaria, A Ponce, N Busquets, N Del Castillo, X Surís
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Hypo or amyopathic dermatomyositis (DM) represent about 20% of the classic DM. Melanoma differentiation-associated gene 5 antibody or anti-MDA5 antibody, formerly known as anti-CADM140 antibody, has been reported in the last decade. This antibody is detected in more than 50% of patients with hypo or amyopathic DM and it has specific features such as the presence of ulcerative vascular lesions and rapid progression of the interstitial lung disease. <h3>Objectives</h3> To report anti-MDA5 positive DM cases diagnosed at a university county hospital, between 2012 and 2016. <h3>Methods</h3> Design: Retrospective descriptive study. Location: University county hospital. Reference area: ?350.000 inhabitants. Clinical manifestations, analytical results, diagnostic approach, treatment administered and follow-up have been exposed. <h3>Results</h3> We report four anti-MDA5 positive DM with a mean age at diagnosis of 54 years (35–77). Caucasian origin in 2 men and Maghreb origin in 2 women. They had no relevant medical history neither neoproliferative process was detected. ANA were negative and CK values were normal in all the cases. Nailfold capillaroscopy was characteristic of DM pattern. Case B did not present cutaneous manifestations and he was diagnosed as anti-MDA5 DM after his death. <h3>Discussion</h3> B and C cases showed abnormal heart rhythm that could be related to myocardial involvement, as suggested in a recent publication of anti-MDA5 DM (1). In case C, sinus tachycardia was resolved with the clinical response to treatment. In the literature reviewed, anti-MDA5 positive DM has been reported as a dermato-pulmonary syndrome, but probably the clinical profile of these patients remains to be defined. In our cases, one of them did not present skin lesions and another case did not develop pulmonary involvement 18 months after the diagnosis. <h3>Conclusions</h3> Keep in mind anti-MDA5 antibody in patients with cutaneous manifestations of DM with vasculopathy lesions, minimal or absent muscular disease, heart rhythm abnormalities not explained by other causes and/or rapidly progressive pulmonary involvement. Anti-MDA5 positive DM may have a poor response to treatment and fatal outcome. It remains to be seen if early diagnosis could improve the life expectancy of these patients. <h3>References</h3> J Eur Acad Dermatol Venereol 2014; 28: 1097–102. <h3>Disclosure of Interest</h3> None declared