tbuckley/cabot-search huggingface dataset:
THU0240 SELECTIVE DEPLETION OF AUTOREACTIVE B CELLS USING A PEPTIDE VACCINATION APPROACH
Authors: R. Singh
Journal: Annals of the Rheumatic Diseases (2020)

Background: B cell depletion is currently approved or being tested in clinical trials for the treatment of many autoimmune diseases including rheumatoid arthritis, myositis, systemic sclerosis, and lupus. We previously demonstrated that the heavy chain variable regions (V H ) of anti-DNA antibodies contain epitopes that can bind MHC class I molecules. 1 Vaccination of autoimmune-prone NZB/NZWF1 mice with plasmid DNA vectors carrying minigenes that encode such epitopes induced CD8 + cytotoxic T lymphocytes (CTL) that killed anti-DNA antibody-producing B cells, reduced serum anti-DNA antibody levels, retarded the development of nephritis, and improved survival. 1 Treatment with peptides alone did not induce such CD8 + T-cells, as we and others have reported impaired CD8+ regulatory and CTL responses in mice and humans. 2,3 Here, we asked if we could overcome such impairment using synthetic oligodeoxynuleotides containing unmethylated cytidine-phosphate-guanosine dinucletides (CpG-ODN) that can enhance innate and adaptive immunity. Objectives: To determine if peptides representing MHC class I binding epitopes in the autoantibody V H regions conjugated to CpG-ODN will elicit CD8 + CTLs that will ablate autoantibody-producing B cells, reduce serum autoantibody levels, and retard the development of autoimmune disease. Methods: We first sceeened V H regions of anti-dsDNA and other autoantibodies for MHC class I-binding epitopes uisng various bioinformatic approaches, and then verified the binding using cellular binding approaches. We immunized lupus-prone (NZB/NZW F1) mice that develop lupus that mimics human lupus with CpG-ODN or a control ODN, and assessed CTL responses. We then treated these mice with CpG-ODN conjugated to MHC class I-binding VH epitopes. We monitored lupus mice for proteinuria, serum anti-dsDNA antibodies, and survival. Results: Immunization with CpG-ODN corrected the impairment in peptide-specific CTL responses in lupus-prone mice. The CpG-ODN conjugated with MHC class I-binding, anti-dsDNA antibody V H -derived epitopes induced potent peptide-specific CTL responses against autoreactive B cells that expressed the respectie epitopes, and against B cells from diseased lupus-prone mice. The animals treated with CpG-ODN-peotde conjugates had reduced serum anti-DNA antibody levels and proteinuria, significantly delayed development of nephritis, and improved survival as compared to animals injected with a control ODN. Conclusion: Seletive ablation of autoreactive B cells by CTLs induced by peptide vaccines conjugated to CpG-ODN represents a novel approach to treat autoantibody-mediated diseases. References: [1]Fan G and Singh RR. J Exp Med 2002;196:731-741. [2]Singh RR. Curr Opin Rheumatol 2000;12:399-406. [3]Singh RR. Mol Immunol 2004;40:1137-1145. Disclosure of Interests: : None declared
Endoplasmic Reticulum stress-dependent expression of ERO1L promotes aerobic glycolysis in Pancreatic Cancer
Authors: Junfeng Zhang, Jianyu Yang, Chaoyi Lin, Wei Liu, Yanmiao Huo, Minwei Yang, Shu-Heng Jiang, Yongwei Sun, Rong Hua
Journal: Theranostics (2020)

Rationale: Endoplasmic reticulum oxidoreductase 1 alpha (ERO1L) is an endoplasmic reticulum (ER) luminal glycoprotein that has a role in the formation of disulfide bonds of secreted proteins and membrane proteins. Emerging data identify ERO1L as a tumor promoter in a wide spectrum of human malignancies. However, its molecular basis of oncogenic activities remains largely unknown. Methods: Pan-cancer analysis was performed to determine the expression profile and prognostic value of ERO1L in human cancers. The mechanism by which ERO1L promotes tumor growth and glycolysis in pancreatic ductal adenocarcinoma (PDAC) was investigated by cell biological, molecular, and biochemical approaches. Results: ERO1L was highly expressed in PDAC and its precursor pancreatic intraepithelial neoplasia and acts as an independent prognostic factor for patient survival. Hypoxia and ER stress contributed to the overexpression pattern of ERO1L in PDAC. ERO1L knockdown or pharmacological inhibition with EN460 suppressed PDAC cell proliferation in vitro and slowed tumor growth in vivo. Ectopic expression of wild type ERO1L but not its inactive mutant form EROL-C394A promoted tumor growth. Bioinformatics analyses and functional analyses confirmed a regulatory role of ERO1L on the Warburg effect. Notably, inhibition of tumor glycolysis partially abrogated the growth-promoting activity of ERO1L. Mechanistically, ERO1L-mediated ROS generation was essential for its oncogenic activities. In clinical samples, ERO1L expression was correlated with the maximum standard uptake value (SUVmax) in PDAC patients who received 18F-FDG PET/CT imaging preoperatively. Analysis of TCGA cohort revealed a specific glycolysis gene expression signature that is highly correlated with unfolded protein response-related gene signature. Conclusion: Our findings uncover a key function for ERO1L in Warburg metabolism and indicate that targeting this pathway may offer alternative therapeutic strategies for PDAC.
Are questionable research practices facilitating new discoveries in sport and exercise medicine? The proportion of supported hypotheses is implausibly high
Authors: Fionn Büttner, Elaine Toomey, Shane McClean, Mark Roe, Eamonn Delahunt
Journal: British Journal of Sports Medicine (2020)

Questionable research practices (QRPs) are intentional and unintentional practices that can occur when designing, conducting, analysing, and reporting research, producing biased study results. Sport and exercise medicine (SEM) research is vulnerable to the same QRPs that pervade the biomedical and psychological sciences, producing false-positive results and inflated effect sizes. Approximately 90% of biomedical research reports supported study hypotheses, provoking suspicion about the field-wide presence of systematic biases to facilitate study findings that confirm researchers' expectations. In this education review, we introduce three common QRPs (ie, HARKing, P-hacking and Cherry-picking), perform a cross-sectional study to assess the proportion of original SEM research that reports supported study hypotheses, and draw attention to existing solutions and resources to overcome QRPs that manifest in exploratory research. We hypothesised that ≥ 85% of original SEM research studies would report supported study hypotheses. Two independent assessors systematically identified, screened, included, and extracted study data from original research articles published between 1 January 2019 and 31 May 2019 in the British Journal of Sports Medicine, Sports Medicine, the American Journal of Sports Medicine, and the Journal of Orthopaedic & Sports Physical Therapy We extracted data relating to whether studies reported that the primary hypothesis was supported or rejected by the results. Study hypotheses, methodologies, and analysis plans were preregistered at the Open Science Framework. One hundred and twenty-nine original research studies reported at least one study hypothesis, of which 106 (82.2%) reported hypotheses that were supported by study results. Of 106 studies reporting that primary hypotheses were supported by study results, 75 (70.8%) studies reported that the primary hypothesis was fully supported by study results. The primary study hypothesis was partially supported by study results in 28 (26.4%) studies. We detail open science practices and resources that aim to safe-guard against QRPs that bely the credibility and replicability of original research findings.
Potential synergistic anti-tumor effects between sorafenib and the MEK inhibitor CI1040 in hepatocellular carcinoma (HCC)
Authors: Da-Liang Ou, Ying-Chun Shen, Sung-Liang Yu, Wei-Chung Lee, Ling-Chun Yeh, Chiun Hsu, Ann-Lii Cheng
Journal: Cancer Research (2008)

1435  Sorafenib, a RAF and VEGFR kinase inhibitor, has been proved to prolong overall survival and time-to-progression in patients with advanced HCC. This study sought to explore whether combination of sorafenib with CI1040, an MEK inhibitor, has synergistic anti-tumor effect in HCC. The in vitro grow-inhibitory effects of sorafenib and CI1040 were tested in HCC cell lines Huh-7 and Hep3B and the human umbilical vascular endothelial (HUVEC) cells. Apoptosis was measured by flow cytometry and TUNEL assay. The effects of sorafenib and CI1040 on ERK phosphorylation, caspase activation, and levels of apoptosis-regulatory proteins were measured by western blotting. The gene expression profiles of Huh-7 cells after sorafenib and CI1040 treatment were measured by DNA microarray. The in vivo anti-tumor activity of sorafenib and CI1040 were tested in a xenograft HCC model. At clinically achievable concentrations of sorafenib and CI1040, combination of these two agents inhibited the phosphorylation of ERK in a more complete and more sustained way in both HCC and HUVEC cells. Sorafenib and CI1040 inhibited cell growth and induced apoptosis of both HCC and HUVEC cells synergistically. The apoptosis-inducing effects of sorafenib and CI1040 appeared independent of caspase 3 and caspase 7 activity. Expression of the pro-apoptotic protein bim was increased in both HCC and HUVEC cells, while the expression of other apoptotic regulatory proteins, including bax, bad, bcl-2, and Mcl-1, showed no consistent changes among the cell lines tested. The gene expression profiles of Huh-7 cells after sorafenib and CI1040 treatment suggested that several signaling pathways, including the transforming growth factor-β and the insulin-like growth factor receptor pathways, may be involved in the apoptosis -inducing effects of sorafenib-CI1040 combination. Sorafenib-CI1040 combination also inhibited tumor growth synergistically in the xenograft HCC model. Our data suggest that sorafenib and CI1040 has synergistic anti-tumor effects in HCC by inhibiting 2 targets sequentially along the raf/MEK/ERK pathway and up-regulation of bim expression may partly account for this phenomenon. (Supported by grants 95R0066-BM01-02 from the Ministry of Education, Taiwan and 96-3112-B-002-036 from the National Science Council, Taiwan).
Utilization of COVID-19 Treatments and Clinical Outcomes among Patients with Cancer: A COVID-19 and Cancer Consortium (CCC19) Cohort Study
Authors: Donna R. Rivera, Solange Peters, Orestis A. Panagiotou, Dimpy P. Shah, Nicole M. Kuderer, Chih-Yuan Hsu, Samuel M. Rubinstein, Brendan J. Lee, Toni K. Choueiri, Gilberto de Lima Lopes, Petros Grivas, Corrie A. Painter, Brian I. Rini, Michael A. Thompson, Jonathan Arcobello, Ziad Bakouny, Deborah B. Doroshow, Pamela C. Egan, Dimitrios Farmakiotis, Leslie A. Fecher, Christopher R. Friese, Matthew D. Galsky, Sanjay Goel, Shilpa Gupta, Thorvardur R. Halfdanarson, Balazs Halmos, Jessica E. Hawley, Ali Raza Khaki, Christopher A. Lemmon, Sanjay Mishra, Adam J. Olszewski, Nathan A. Pennell, Matthew M. Puc, Sanjay G. Revankar, Lidia Schapira, Andrew Schmidt, Gary K. Schwartz, Sumit A. Shah, Julie T. Wu, Zhuoer Xie, Albert C. Yeh, Huili Zhu, Yu Shyr, Gary H. Lyman, Jeremy L. Warner
Journal: Cancer Discovery (2020)

Abstract Among 2,186 U.S. adults with invasive cancer and laboratory-confirmed SARS-CoV-2 infection, we examined the association of COVID-19 treatments with 30-day all-cause mortality and factors associated with treatment. Logistic regression with multiple adjustments (e.g., comorbidities, cancer status, baseline COVID-19 severity) was performed. Hydroxychloroquine with any other drug was associated with increased mortality versus treatment with any COVID-19 treatment other than hydroxychloroquine or untreated controls; this association was not present with hydroxychloroquine alone. Remdesivir had numerically reduced mortality versus untreated controls that did not reach statistical significance. Baseline COVID-19 severity was strongly associated with receipt of any treatment. Black patients were approximately half as likely to receive remdesivir as white patients. Although observational studies can be limited by potential unmeasured confounding, our findings add to the emerging understanding of patterns of care for patients with cancer and COVID-19 and support evaluation of emerging treatments through inclusive prospective controlled trials. Significance: Evaluating the potential role of COVID-19 treatments in patients with cancer in a large observational study, there was no statistically significant 30-day all-cause mortality benefit with hydroxychloroquine or high-dose corticosteroids alone or in combination; remdesivir showed potential benefit. Treatment receipt reflects clinical decision-making and suggests disparities in medication access. This article is highlighted in the In This Issue feature, p. 1426
Association of Hepatic Steatosis With Major Adverse Cardiovascular Events, Independent of Coronary Artery Disease
Authors: Nandini M. Meyersohn, Thomas Mayrhofer, Kathleen E. Corey, Daniel O. Bittner, Pedro V. Staziaki, Balint Szilveszter, Travis Hallett, Michael T. Lu, Stefan B. Puchner, Tracey G. Simon, Borek Foldyna, Deepak Voora, Geoffrey S. Ginsburg, Pamela S. Douglas, Udo Hoffmann, Maros Ferencik
Journal: Clinical Gastroenterology and Hepatology (2020)
Assessment of cognitive and neural recovery in survivors of pediatric brain tumors in a pilot clinical trial using metformin
Authors: Ramy Ayoub, Rebecca M. Ruddy, Elizabeth Cox, Adeoye Oyefiade, Daniel Derkach, Suzanne Laughlin, Benjamin Ades-aron, Zahra Shirzadi, Els Fieremans, Bradley J. MacIntosh, Cynthia B. de Medeiros, Jovanka Skocic, Eric Bouffet, Freda D. Miller, Cindi M. Morshead, Donald J. Mabbott
Journal: Nature Medicine (2020)
SAT0085 Meloxicam has a low risk of serious gastrointestinal complications: pooled analysis of 27,039 patients
Authors: G Singh, G Triadafilopoulos
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Gastrointestinal (GI) complications are the most common adverse events associated with nonsteroidal anti-inflammatory drugs (NSAIDs). Although serious gastrointestinal complications, such as perforated ulcers and catastrophic bleeding, are uncommon, these events area. <h3>Objectives</h3> We reviewed the incidence of serious upper GI (UGI) complications, including perforations, obstructions and hemodynamically-significant bleeds in a pooled data analysis of Meloxicam clinical trials that were at least 3 weeks in duration and included at least 20 patients per arm. <h3>Methods</h3> Thirty-five trials with 27,309 patients on Meloxicam, comparator NSAID?s, or placebo were included in the analysis. Nearly 39% (8109) patients were over age 65, and 1002 patients (4%) had a previous history of perforation, ulcer or bleed. Cases of suspected GI events were ascertained based on pre-defined criteria. Case report forms and supporting details were blinded and submitted to an independent Endpoint Committee for adjudication. <h3>Results</h3> A total of 448 potential cases were identified and sent for adjudication. The Endpoint Committee determined that 54 of these cases met the predefined criteria for a clinically significant event. <h3>Conclusion</h3> The risk of clinically significant UGI events with meloxicam is dose-dependent and low at the recommended doses of 7.5 mg and 15 mg.
SAT0161 THE ANALGESIC EFFECT OF TOFACITINIB MAY HAVE CLINICAL SIGNIFICANCE IN PATIENTS WITH RHEUMATOID ARTHRITIS. DATA FROM THE MOSCOW UNIFIED REGISTER OF ARTHRITIS (MUAR)
Authors: E. Zhilyaev, G. Lukina, E. Koltsova, E. Shmidt, K. Lytkina
Journal: Annals of the Rheumatic Diseases (2020)

Background: Some theoretical data suggest that the JAK-kinase blocker tofacitinib (TOFA) may have a direct analgesic effect. Objectives: to evaluate the clinical significance of the analgesic effect in patients with rheumatoid arthritis (RA) in real clinical practice. Methods: Hypothesis being tested: the analgesic effect of TOFA may be manifested by a decrease in the ratio of subjective to objective indicators of arthritis activity. Data from RA patients receiving biologics (bDMARD) and/or TOFA and included in the MUAR register were analyzed. The tender joints count (TJC), the HAQ-DI functional ability index, and the RAPID3 disease activity index were considered as subjective estimates. The swollen joints count (SJC) and the level of CRP were treated as objective indicators. The estimation of quotients from the division of subjective indicators into objective ones in all combinations is made. Taking into account the observational nature of the study, we searched for confounders for each of these ratios. Comparison of the calculated indices during the treatment with various targeted DMARDs (tDMARDs) was made with an adjustment for the detected confounders. Results: the analysis included 944 treatment episodes in 832 patients, including 93 episodes of TOFA treatment. The average age was 55.3 ± 12.4 years, women - 698 (83.9%), seropositive for RF -672 (80.8%). The analysis of the adjusted values showed that the ratios of the TJC, HAQ-DI and RAPID3 to the SJC during the treatment with TOFA was significantly lower than with tDMARDs on average. There were no significant differences in the ratios of objective indicators to the CRP level (Table). Table. Ratios of objective and subjective indicators during the treatment with tofacitinib and with tDMARDs therapy in general Conclusion: the severity of subjective feelings and functional disorders in RA patients receiving TOFA may be less with the same level of objective signs of arthritis compared with bDMARDs. Disclosure of Interests: Evgeniy Zhilyaev Speakers bureau: Novartis, UCB, Pfizer, Biocad, Abbvie, MSD, Roche, Galina Lukina Speakers bureau: Novartis, Pfizer, UCB, Abbvie, Biocad, MSD, Roche, Ekaterina Koltsova: None declared, Evgeniya Shmidt Speakers bureau: MSD, Novartis, Pfizer, Karine Lytkina Speakers bureau: Novartis, Eli Lilly, Pfizer, UCB, Abbvie, Biocad, MSD, Jonson&amp;Jonson
AB1109 THE TIME-TO-EVENT ANALYSIS OF THE APPLICATION OF ULTRASOUND TO DISTINGUISHING PMR
Authors: T. Kawaguchi, M. Ogasawara, K. Yamaji, N. Tamura
Journal: Annals of the Rheumatic Diseases (2020)

Background: Japan is the world’s most aged country. The number of patients with polymyalgia rheumatic (PMR) is expected to increase more. Classification criteria including ultrasound findings were published in 2012(1), but the ability to differentiate PMR from other mimicking diseases was unknown. It is difficult to diagnose PMR accurately. We will clarify whether recently reported ultrasound findings (2, 3) which could be characteristic in PMR are helpful for distinguishing from other mimicking diseases and treatment outcome in suspected PMR patients. Neither diagnostic laboratory test nor specific antibody exist, and inflammatory markers such as C reactive protein and erythrocyte sedimentation rate are not specific. Objectives: Patients who were clinically suspected of PMR and underwent ultrasound examination from 2008 to 2018. And Patients who visited the hospital with PMR and were diagnosed with PMR from 2008 to 2018. Methods: Patients who visited the hospital and were diagnosed with PMR were extracted from the medical record database of the hospital. Patients who had been administrated GC at the first visit and whose records were not confirmed were excluded. Patients who were clinically diagnosed with PMR without ultrasound(Cli-PMR), patients who were diagnosed with PMR with ultrasound reports(US-Cli-PMR), patients who were diagnosed by the ultrasound expert only based on ultrasound images(US-PMR). Patient were followed up for one year. Clinical diagnoses were confirmed at the 6 months and 12 months since the first GC administration. Three groups were compared with each other in the rate of diagnosis change and the time intervals between the initiation of GC treatment and the occurrence of events: recurrence, methotrexate introduction and the normalization of C reactive protein. the Kaplan–Meier method was used to evaluate the outcomes. Statistical analyses were conducted with R software, version 3.5.2 (R Foundation for Statistical Computing) and EZR(4). Results: 545 PMR patients were extracted. 403 of 545 was excluded because of preexisting GC therapy and record availability. At the 6 months follow-up, 92.8% of the non-US PMR group and 97% of US-PMR group remain PMR and at the 12 months follow-up 88.8% and 95% respectively. There was no significant difference in the three time-to-event outcomes. Conclusion: Ultrasound did not contribute the improvement of the PMR outcomes. However, this finding was affected by confounding factors for example assignment to ultrasound and atypical cases and rheumatologists’ uncertainness. Despite confounding factors, US-PMR group was not inferior. These findings showed that ultrasound may be useful for the complicated cases. References: [1]ARTHRITIS &amp; RHEUMATISMVol. 64, No. 4, April 2012, pp 943–954 [2]Clin Med Insights Arthritis Musculoskelet Disord 2017;10: 1179544117745851. [3]Biomed Res Int 2017;2017: 4272560. [4]Bone Marrow Transplantation 2013: 48, 452–458 Disclosure of Interests: None declared
Assessment of outcomes of calciphylaxis lesions treated with intralesional sodium thiosulfate
Authors: Colleen K Gabel, Emily D Nguyen, Allison S Dobry, Olesya Baker, Anna Cristina Garza-Mayers, Lauren N Ko, Radhika Shah, Jessica St John, Lauren Strazzula, Sagar U Nigwekar, Daniela Kroshinsky
Journal: Journal of the American Academy of Dermatology (2020)
Need for sustainable biobanking networks for COVID-19 and other diseases of epidemic potential
Authors: Rosanna W Peeling, Debrah Boeras, Annelies Wilder-Smith, Amadou Sall, John Nkengasong
Journal: The Lancet Infectious Diseases (2020)

Outbreaks of infectious diseases are occurring with increasing frequency and unpredictability. The rapid development and deployment of diagnostics that can accurately and quickly identify pathogens as part of epidemic preparedness is needed now for the COVID-19 pandemic. WHO has developed a global research and innovation forum to facilitate, accelerate, and deepen research collaboration among countries and funders. Great progress has been made in the past decade, but access to specimens remains a major barrier for the development and evaluation of needed quality diagnostics. We present a sustainable model for a global network of country-owned biobanks with standardised methods for collection, characterisation, and archiving of specimens and pathogens to facilitate and accelerate diagnostics development and evaluation for COVID-19 and other diseases of epidemic potential. The biobanking network should be run on the guiding principles of transparency, equitable access, ethics, and respect for national laws that support country ownership and sustainability. Adapting the Nagoya Protocol on Access to Genetic Resources and the Fair and Equitable Sharing of Benefits, sharing of specimens from national biobanks can be rewarded through mechanisms such as equitable access to diagnostics at negotiated prices. Such networks should be prepared for any pathogen of epidemic potential.