tbuckley/cabot-search huggingface dataset:
Abstract 3379: Feasibility Of Adrenomedullin Infusion In Patients With Acute Myocardial Infarction -a Possible Cardioprotective Therapy Against Ischemic Injury-
Authors: Satoshi Yasuda, Shunichi Miyazaki, Noritoshi Nagaya, Yu Kataoka, Teruo Noguchi, Isao Morii, Atsushi Kawamura, Kenji Kangawa, Kunio Miyatake
Journal: Circulation (2007)

Background : Adrenomedullin (ADM) is a 52-amino-acid vasodilator peptide that was originally isolated from human pheochromocytoma. In the previous experimental study with rat ischemia/reperfusion model, ADM reduced infarct size and inhibited myocyte apoptosis. ADM also suppressed the production of oxygen-free-radicals. The present study was designed to evaluate the feasibility of intravenous administration of ADM in patients with acute myocardial infarction (AMI). Methods : We studied 10 patients with first AMI (M/F;9/1, mean age;65 years, peak CPK level; 4090 U/L[median]), who were hospitalized within 12 hours of symptom onset. ADM infusion preceded percutaneous coronary intervention (PCI) and was continued at concentration of 0.0125 − 0.025μg/kg/minute for 12 hours. We also studied 10 control AMI patients matched for age, sex and infarct size, who did not receive ADM. Results : During ADM infusion, hemodynamics kept stable except one patient with right ventricular infarction. Urinary levels of 8-iso-prostaglandine F2α, which was measured after the reperfusion therapy with ADM infusion as a marker of oxidative stress, was significantly lower in patients who received ADM than those who did not (76 ± 40 vs 174±21 pmol/mol of creatinine, P&lt;0.01). Infarct area (IA) evaluated by magnetic resonance imaging and brain natriuretic peptide (BNP) levels were also different between the two groups (Table ). Conclusions : Intravenous administration of ADM, which possesses a variety of cardiovascular protective actions, is feasible and can be adjunctive to PCI. Suppression of oxidative stress generation may be beneficial for attenuation of left ventricular dysfunction and remodeling following AMI.
Cell-derived microvesicles in infective endocarditis: Role in diagnosis and potential for risk stratification at hospital admission
Authors: Milton Henriques Guimarães Júnior, Teresa Cristina Abreu Ferrari, Andréa Teixeira-Carvalho, Marcela de Lima Moreira, Lorena Júnia de Souza Santos, Matheus Fernandes Costa-Silva, Rodrigo Matos Pinto Coelho, Pedro Henrique Oliveira Murta Pinto, Tijmen Hermen Ris, Jonathas Teixeira Salles, Lívia Silva Araújo Passos, Maria Carmo Pereira Nunes
Journal: Journal of Infection (2019)
OP0234 EFFICACY AND SAFETY OF BRODALUMAB, AN ANTI-INTERLEUKIN-17 RECEPTOR A MONOCLONAL ANTIBODY, IN PATIENTS WITH AXIAL SPONDYLOARTHRITIS: A 16 WEEK RESULTS OF A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY
Authors: James Cheng-Chung Wei, Tae-Hwan Kim, Mitsumasa Kishimoto, Takuya Morishige, Naoki Ogusu, Shigeto Kobayashi
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> It is known that clinical features and pathophysiological pathways of ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA) have similarities. Recent reports suggest that IL-17 signaling pathway may be involved in development of axial spondyloarthritis (axSpA). Here we reported the confirmatory phase 3 trial of brodalumab, a human anti-interleukin-17 receptor A monoclonal antibody, in patients with axSpA (4827-006 Study, NCT02985983). <h3>Objectives</h3> To evaluate the efficacy and safety of brodalumab in axSpA (including AS and nr-axSpA) patients at week 16. <h3>Methods</h3> In this phase 3, multicenter, randomized, double-blind, placebo-controlled study conducted in Japan, South Korea and Taiwan, eligible axSpA patients were randomized 1:1 to brodalumab subcutaneously (s.c.) 210 mg or placebo at baseline, weeks 1 and 2, every 2 weeks thereafter. At week 16, all subjects entered an open label extension phase and received brodalumab 210 mg s.c. Q2W. ASAS 40 (Assessment of SpondyloArthritis international Society) response rate at week 16 was the primary endpoint. Secondary outcomes and safety profiles were also assessed. <h3>Results</h3> A total of 159 patients were randomized, and 77/80 patients in brodalumab arm and 69/79 patients in placebo arm were completed the 16 weeks' double-blind phase study. The ASAS 40 response rate at week 16 was significantly higher in brodalumab group (35/80, 43.8%, p=0.018) compared to placebo group (19/79, 24.1%). Other disease activity parameters demonstrated trend to improvement in therapeutic arm (Table). Brodalumab 210 mg had good safety profile. Most commonly reported adverse event was nasopharyngitis observed in both brodalumab (11.1%) and placebo (10.3%) arms. AE rates including SAE rates were comparable between groups. No suicidal ideation or behavior were observed. <h3>Conclusion</h3> Brodalumab s.c. 210 mg Q2W treatment was effective and tolerable in axSpA patients in this 16 week phase 3 clinical trial. Based on the ongoing trial results, brodalumab could be considered as a future therapeutic option for patients with axSpA. <h3>Disclosure of Interests</h3> James Cheng-Chung Wei Grant/research support from: Abbvie, BMS, Celgene, Janssen, Novartis, Pfizer, and UCB pharma, Consultant for: TSH Taiwan, Speakers bureau: Janssen, Novartis, Pfizer and TSH, Tae-hwan Kim: None declared, Mitsumasa Kishimoto Consultant for: Kyowa Hakko Kirin Co., Ltd., Takuya Morishige Employee of: Kyowa Hakko Kirin Co., Ltd., Naoki Ogusu Employee of: Kyowa Hakko Kirin Co., Ltd., Shigeto Kobayashi Grant/research support from: Chugai pharmaceutical Co., Ltd., Consultant for: Kyowa Hakko Kirin Co., Ltd., Eli Lilly, Novartis.
Mesangial Deposition Can Strongly Involve Innate-Like IgA Molecules Lacking Affinity Maturation
Authors: Batoul Wehbi, Christelle Oblet, François Boyer, Arnaud Huard, Anne Druilhe, François Paraf, Etienne Cogné, Jeanne Moreau, Yolla El Makhour, Bassam Badran, Marjolein Van Egmond, Michel Cogné, Jean-Claude Aldigier
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement IgA nephropathy (IgAN) is characterized by IgA glomerular mesangial deposition, but its pathogenesis remains unclear. Using humanized transgenic mouse models, the authors explored whether a hypogalactosylated hinge region (found in most mesangial IgA1 in human IgAN) is required for IgA deposition, demonstrating that hinge hypoglycosylation was not mandatory for deposition. To investigate whether low-affinity IgA produced by innate-like B cells might also yield mesangial deposits, they compared mice able to produce high-affinity mature IgA antibodies with mice lacking affinity maturation. They found that the low-affinity IgA can deposit in the mesangium and activate complement, that it is especially prone to induce glomerular cell thickening, and that it can initiate nephrotoxicity. These findings offer a new perspective regarding glomerular IgA deposits involving innate-like antibody responses. Background IgA nephropathy (IgAN) often follows infections and features IgA mesangial deposition. Polymeric IgA deposits in the mesangium seem to have varied pathogenic potential, but understanding their pathogenicity remains a challenge. Most mesangial IgA1 in human IgAN has a hypogalactosylated hinge region, but it is unclear whether this is required for IgA deposition. Another important question is the role of adaptive IgA responses and high-affinity mature IgA antibodies and whether low-affinity IgA produced by innate-like B cells might also yield mesangial deposits. Methods To explore the effects of specific qualitative variations in IgA and whether altered affinity maturation can influence IgA mesangial deposition and activate complement, we used several transgenic human IgA1-producing models with IgA deposition, including one lacking the DNA-editing enzyme activation-induced cytidine deaminase (AID), which is required in affinity maturation. Also, to explore the potential role of the IgA receptor CD89 in glomerular inflammation, we used a model that expresses CD89 in a pattern observed in humans. Results We found that human IgA induced glomerular damage independent of CD89. When comparing mice able to produce high-affinity IgA antibodies with mice lacking AID-enabled Ig affinity maturation, we found that IgA deposition and complement activation significantly increased and led to IgAN pathogenesis, although without significant proteinuria or hematuria. We also observed that hinge hypoglycosylation was not mandatory for IgA deposition. Conclusions In a mouse model of IgAN, compared with high-affinity IgA, low-affinity innate-like IgA, formed in the absence of normal antigen-driven maturation, was more readily involved in IgA glomerular deposition with pathogenic effects.
SP0187 PATHOPHYSIOLOGY AND THERAPEUTIC CONSEQUENCES AUTO-INFLAMMATORY BONE DISORDERS
Authors: Christian Hedrich
Journal: Annals of the Rheumatic Diseases (2019)

<h3></h3> Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disorder, covering a clinical spectrum with asymptomatic inflammation of single bones at the one end, and chronic recurrent multifocal osteomyelitis (CRMO) at the other end. Bone inflammation, however, can also be a symptom of other autoimmune/inflammatory conditions. Rare monogenic autoinflammatory diseases with bone involvement have informed research and provide models for the more common and pathophysiologically complex disorder CNO/CRMO. Despite recent efforts, the exact molecular pathophysiology of CNO remains incompletely understood. Profound dysregulation of cytokine responses was demonstrated in CNO/CRMO. Failure to produce antiinflammatory cytokines interleukin (IL)-10 and IL-19 contributes to activation of inflammasomes and subsequent IL-1β release. In IL-10-deficient and in CNO-prone chronic multifocal osteomyelitis mice, IL-1β was linked to bone inflammation. Recently, increased inflammasome component expression and inflammasome assembly have been linked with CNO/CRMO in humans. Furthermore, alterations to the gut microbiome were suggested in contributing to IL-1β release from innate immune cells in mice, offering an interesting target in the search for molecular mechanisms in CNO. This presentation will review molecular alterations in autoinflammatory bone disease, focussing on CNO and discuss therapeutic consequences. <h3>References:</h3> [1] Brandt D, Sohr E, et al. CD14+ monocytes contribute to inflammation in chronic nonbacterial osteomyelitis (CNO) through increased NLRP3 inflammasome expression. Clin Immunol. 2018 Nov;196:77-84. [2] Hofmann SR, Schnabel A, et al. Chronic Nonbacterial Osteomyelitis: Pathophysiological Concepts and Current Treatment Strategies. J Rheumatol. 2016 Nov;43(11):1956-1964. [3] Hofmann SR, Kubasch AS, et al. Altered expression of IL-10 family cytokines in monocytes from CRMO patients result in enhanced IL-1β expression and release. Clin Immunol. 2015 Dec;161(2):300-7. [4] Zhao Y, Wu EY, et al. Consensus Treatment Plans for Chronic Nonbacterial Osteomyelitis Refractory to Nonsteroidal Antiinflammatory Drugs and/or With Active Spinal Lesions. Arthritis Care Res (Hoboken). 2018 Aug;70(8):1228-1237. [5] Ferguson PJ, Laxer RM. New discoveries in CRMO: IL-1β, the neutrophil, and the microbiome implicated in disease pathogenesis in Pstpip2-deficient mice. Semin Immunopathol. 2015 Jul;37(4):407-12. [6] Cox AJ, Darbro BW, et al. Recessive coding and regulatory mutations in FBLIM1 underlie the pathogenesis of chronic recurrent multifocal osteomyelitis (CRMO). PLoS One. 2017 Mar 16;12(3):e0169687. <h3>Disclosure of Interests:</h3> Christian Hedrich Grant/research support from: Novartis Pharmaceuticas for Research study on effector T cells in psoriasis, Speakers bureau: In 2016: Roche Pharmaceuticals, RheumatoLogisch, Dresden, Germany; Novartis, Advisory board &gt; Travel costs.
PB1979 ONLINE CME AS A TOOL TO INCREASE CLINICIANS’ KNOWLEDGE OF CLINICAL TRIAL DATA FOR GENE THERAPY IN HEMOPHILIA
Authors: S. Hurst, C. Warren, H. Kadkhoda
Journal: HemaSphere (2019)

Background: Gene therapy has the potential to fundamentally alter care for patients living with hemophilia. To educate and prepare clinicians for this potential paradigm shift, the National Hemophilia Foundation (NHF), European Haemophilia Consortium (EHC), the World Federation of Hemophilia (WFH), and Medscape Education established a multinational collaboration to develop an online continuing medical education (CME) curriculum. Aims: The current study assessed the ability of online CME to improve clinicians’ knowledge regarding the latest data from ongoing trials for gene therapy in hemophilia. Methods: A 15‐minute, CME‐certified, Expert Video Commentary activity was developed and launched online on 09/25/2018. Educational effectiveness was assessed with a repeated‐pairs pre‐/post‐assessment study design, with each individual serving as his/her own control. Responses to 3 multiple‐choice, knowledge questions and 1 self‐efficacy confidence question were analyzed. A chi‐squared test assessed changes pre‐ to post‐assessment. P values &lt;0.05 are statistically significant. Effect sizes were evaluated using Cramer's V (&lt;0.05 modest; 0.06‐0.15 noticeable effect; 0.16‐0.26 considerable effect; &gt;0.26 extensive effect). Results: To date, 2,747 clinicians, including 2,229 physicians, have participated in this educational activity. This analysis comprises data from the subset of hematologists/oncologists (n = 84; hem/oncs) and pediatric hematologists (n = 223) who answered all pre‐/post‐assessment questions during initial analysis period of 09/25/18 thru 11/09/18; data collection is ongoing. Both hem/oncs and pediatric hematologists exhibited significant improvements overall and in specific areas of assessment (Figure). A notable proportion of providers – 17% of hem/oncs and 35% of pediatric hematologists – expressed increased confidence with regard to their understanding of the latest safety and efficacy data for gene therapy. In addition to the positive impact of education, these findings also uncovered educational gaps, such as the need for additional education regarding vector‐related molecular biology, design, and dosing considerations. These topics may be the focus of future CME programs. Summary/Conclusion: Hematologists/oncologists and pediatric hematologists who participated in this online, Expert Video Commentary activity demonostrated significantly improved knowledge of efficacy and safety data from clinical trials in hemophilia. image
SAT0385 ASSOCIATION OF SUBCLINICAL MYOCARDIAL DEFORMATION AND DISEASE ACTIVITY IN PSORIATIC ARTHRITIS
Authors: Ivan Pletikosić, Daniela Marasović Krstulović, Zora Sušilović Grabovac, Darko Duplančić, Dijana Perković
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Subclinical impaired myocardial deformation is common in patients with PsA, even with no clinical evidence for CV disease (1). Recent evidence supports the link between the extent of inflammation and CV risk in patients with PsA (2). Elevated levels of inflammatory biomarkers and high activity of joint inflammation were associated with a higher burden of atherosclerosis (2). It is suggested that patients with active disease may have an impaired myocardial deformation (3). But it is unclear if the patients with higher activity of PsA have higher grade of myocardial impairment than the patients without activity of inflammatory rheumatic disease. Speckle-tracking echocardiography (STE), an angle-independent technique, was proposed as a reliable and sensitive method for assessment of subclinical myocardial dysfunction (4). <h3>Objectives:</h3> The aim of the study was to assess if there is an association of disease activity of PsA assessed by DAPSA with grade od myocardial impairment measured by Speckle-tracking echocardiography (STE). <h3>Methods:</h3> 48 PsA patients (28 females, 20 males) who fulfilled Caspar criteria, with no clinically evident CV disease or concomitant diseases, were included in the study. Patients who had classic CV risk factors or had experienced CV or cerebrovascular events were excluded. Upon clinical and laboratory evaluation, all subjects underwent conventional echocardiography and 2-dimensional speckle tracking echocardiography (STE). <h3>Results:</h3> The results of STE analysis showed that patients with higher DAPSA result have average global longitudinal strain AM ± SD -19.44 ± 2.98%. Significant correlation was determined between PsA patients with higher DAPSA result and lower values of the variable GLS (R=0,368; p=0.0036). <h3>Conclusion:</h3> Subclinical impaired myocardial deformation measured by STE was more common in PsA patients with higher disease activity, even in absence of traditional CV risk factors. Global longitudinal strain was associated with the status of PsA disease activity. <h3>References</h3> [1] Yilmazer B, Sahin T, Cefle A. Impaired myocardial deformation in psoriatic arthritis patients assessment by speckle tracking echocardiography. Acta Reumatol Port. 2016 Apr-Jun;41(2):131-7. [2] Eder L, Thavaneswaran A, Chandran V, Cook R, Gladman DD. Increased burden of inflammation over time is associated with the extent of atherosclerotic plaques in patients with psoriatic arthritis. Ann Rheum Dis. 2015 Oct;74(10):1830-5. [3] Shang Q, Tam LS, Sanderson JE, Lee AP, Li EK, Yu CM. Impaired left ventricular apical rotation is associated with disease activity of psoriatic arthritis. J Rheumatol. 2014 Apr;41(4):706-13. [4] Blessberger H, Binder T. NON-invasive imaging: Two dimensional speckle tracking echocardiography: basic principles. Heart. 2010 May;96(9):716-22. <h3>Disclosure of Interests:</h3> None declared
Abstract 12431: White Matter Brain Injury Increased in Heart Failure Subjects With Obstructive Sleep Apnea
Authors: Mary A Woo, Bhaswati Roy, Gregg C Fonarow, Rajesh Kumar
Journal: Circulation (2018)

Heart failure (HF) patients have a high incidence of obstructive sleep apnea (OSA), which has been linked to grey matter damage in brain areas that control breathing, including cerebellar climbing,...
ANCA renal risk score predicts outcome in the Manchester cohort
Authors: Anna S. Li, Christopher Saleh, Helen Denley, Mumtaz Patel, Silke R. Brix
Journal: Kidney International (2019)

Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides are multisystem autoimmune disorders that cause irreversible damage to affected organs. In past decades, patient and renal survival have improved. Disease control is achieved in most patients, and the most common cause of first-year mortality is infection. 1 Flossmann O. Berden A. de Groot K. et al. Long-term patient survival in ANCA-associated vasculitis. Ann Rheum Dis. 2011; 70: 488-494 Crossref PubMed Scopus (573) Google Scholar Therefore, the right balance is needed to gain rapid control of vasculitis without exposing patients to undue risk of aggressive immunosuppression. Recently we developed and validated a new clinico-pathologic score to improve outcome prediction. One of our aims was to identify a sub cohort of patients unlikely to regain kidney function that potentially could be spared full induction treatment for renal survival purposes. 2 Brix S.R. Noriega M. Tennstedt P. et al. Development and validation of a renal risk score in ANCA-associated glomerulonephritis. Kidney Int. 2018; 94: 1177-1188 Abstract Full Text Full Text PDF Scopus (108) Google Scholar To further validate the ANCA renal risk score, we retrospectively investigated another independent patient cohort of 105 patients with ANCA-associated glomerulonephritis from Manchester, UK. Development and validation of a renal risk score in ANCA-associated glomerulonephritisKidney InternationalVol. 94Issue 6PreviewPredicting renal outcome in antineutrophil cytoplasmic antibody (ANCA)–associated glomerulonephritis (GN) remains a major challenge. We aimed to identify reliable predictors of end-stage renal disease (ESRD) and to develop and validate a clinicopathologic score to predict renal outcome in ANCA-associated GN. In a prospective training cohort of 115 patients, the percentage of normal glomeruli (without scarring, crescents, or necrosis within the tuft) was the strongest independent predictor of death-censored ESRD. Full-Text PDF Open ArchiveThe authors replyKidney InternationalVol. 99Issue 2PreviewWe would like to thank Tan et al.1 for validating and confirming our antineutrophil cytoplasm antibody (ANCA) renal risk score.2 In a retrospective, single-center London cohort of 178 patients, the score determined renal survival dependent on patients’ risk groups at the 36-month follow-up (P < 0.001; 95%, 90%, and 45%, respectively). Full-Text PDF
Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution.
Authors: Abdel Nasser Hosein, Huocong Huang, Zhaoning Wang, Kamalpreet Parmar, Wenting Du, Jonathan Huang, Anirban Maitra, Eric Olson, Udit Verma, Rolf A. Brekken
Journal: Journal of Clinical Oncology (2019)

e15739 Background: Pancreatic ductal adenocarcinoma (PDA) is a major cause of cancer-related death with limited therapeutic options available. This highlights the need for improved understanding of the biology of PDA progression. The progression of PDA is a highly complex and dynamic process featuring changes in cancer cells and stromal cells; however, a comprehensive characterization of PDA cancer cell and stromal cell heterogeneity during disease progression is lacking. In this study, we aimed to profile cell populations and understand their phenotypic changes during PDA progression. Methods: We employed single-cell RNA sequencing technology to agnostically profile cell heterogeneity during different stages of PDA progression in genetically engineered mouse models. Results: Our data indicate that an epithelial-to-mesenchymal transition of cancer cells accompanies tumor progression. We also found distinct populations of macrophages with increasing inflammatory features during PDA progression. In addition, we noted the existence of three distinct molecular subtypes of fibroblasts in the normal mouse pancreas, which ultimately gave rise to two distinct populations of fibroblasts in advanced PDA, supporting recent reports on intratumoral fibroblast heterogeneity. Our data also suggest that cancer cells and fibroblasts are dynamically regulated by epigenetic mechanisms. Conclusions: This study systematically outlines the landscape of cellular heterogeneity during the progression of PDA. It strongly improves our understanding of the PDA biology and has the potential to aid in the development of therapeutic strategies against specific cell populations of the disease.
Time to Change the Limited-Stage Paradigm for Small Cell Lung Cancer?—In Reply
Authors: Ahmed Salem, Corinne Faivre-Finn
Journal: JAMA Oncology (2019)

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