tbuckley/cabot-search huggingface dataset:
THU0247 LRRN4: A NOVEL PROGNOSTIC BIOMARKER OF RENAL OUTCOME IN LUPUS NEPHRITIS PATIENTS
Authors: Heng Cao, Jin Lin
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Lupus nephritis (LN) is the most common organ-threatening manifestation of systemic lupus erythematosus (SLE) and can result in kidney deterioration and end-stage renal disease (ESRD). Newly discovered biomarkers exhibit qualities of disease activity and damage, predict long term preservation of renal function. <h3>Objectives:</h3> Combine the transcriptomics profile of kidney with long-term renal outcome in LN patients, to explore the novel non-invasive predictive biomarker for renal outcome. <h3>Methods:</h3> The transcriptomics profile of kidney in 24 LN patients was obtained by using Affymetrix human HTA 2.0 gene expression chip. Random Forest method was used to screen the candidate mRNA biomarkers by correlate the gene expression profile with eGFR slope during the follow-up (Mean time 5.2±1.2 years). In addition, in an independent LN cohort enrolled 45 patients, qRT-PCR and immunochemistry staining was performed to validate the correlation of mRNA level and protein level of candidate gene with renal outcome. <h3>Results:</h3> (1) There were 3212 gene was regulated in LN kidney (Fold change&gt;1.5, FDA&lt;0.05, compared with healthy control. DCBLD2, NPNT, CPVL, RGS5, LRRN4 were found to have the leading correlation with eGFR slope of LN patients by using random forest method. (2) In the independent cohort, we validate that the mRNA and protein level of DCBLD2, NPNT, CPVL, RGS5, LRRN4 was significantly evaluated in tubulointerstitial component in LN kidney, compared with healthy controls (p&lt;0.05), and also significantly correlated with eGFR slope [LRRN4(r=-0.715, P&lt;0.0001, DCBLD2(r=-0.620, P&lt;0.0001, CPVL(r=-0.517, P=0.004, RGS5(r=-0.489, P=0.008, NPNT(r=-0.412, P=0.016]. In addition, the mRNA level of LRRN4 and DCBLD2 in kidney was correlated with SLEDAI score(r=0.611and r=0.512, respectively, P&lt;0.001 and serum C3 level (r=0.501, r=0.435, P&lt;0.05). LRRN4 mRNA level also significantly associated with tubulointerstitial fibrosis scoring(r=0.432, P&lt;0.05;(3 he protein of LRRN4 was expressed both in glomeruli and tubulointerstitial tissue. And IHC level of LRRN4 protien was significantly associated with eGFR slope(r=0.534, P&lt;0.05 in LN patients. <h3>Conclusion:</h3> LRRN4 in kidney may be used as a novel predictive biomarker of renal outcome in LN patients. <h3>References:</h3> [1] &nbsp;Dall'Era M, Cisternas MG, Smilek DE, et al. Predictors of long-term renal outcome in lupus nephritis trials: lessons learned from the Euro-Lupus Nephritis cohort. Arthritis Rheumatol. 2015 May; 67(5):1305-13. [2] Misra R, Gupta R. Biomarkers in lupus nephritis. Int J Rheum Dis. 2015 Feb; 18(2):219-32. <h3>Disclosure of Interests:</h3> None declared
Abstract 17906: Wearable Vibroacoustic Transthoracic Stimulation (VATS) Provides Cardioprotection by Syndecan-4 Mechanosensor Regulation of NFAT, JNK/ERK in Rats After Myocardial Infarction
Authors: Arkady Uryash, Jose A Adams
Journal: Circulation (2017)

Background: Myocardial infarction (MI) remains an important cause of morbidity and mortality. Ischemic injury during MI produces impairment of left ventricular (LV) function. The MI induces elevati...
PB1719 TRENDS IN EFFICACY PARAMETERS STUDIED IN CLINICAL TRIALS FOR ACUTE MYELOID LEUKAEMIA
Authors: D. Said, J.J. Borg, M. Attard Pizzuto, A. Serracino‐Inglott
Journal: HemaSphere (2019)

Background: Acute myeloid leukaemia (AML) accounts for one third of adult leukaemias in developing countries and is associated with poor prognosis in Europe. Biomarker‐based endpoints have been validated as surrogate measures to predict overall survival (OS) in AML, potentially leading to shorter clinical trial (CT) durations and faster patient access to innovative treatments. Aims: To analyse the evolvement of efficacy endpoints over time for CTs in AML conducted in the European Union (EU). Methods: Interventional Phase II to Phase IV AML CTs registered in the EU Clinical Trials Register over an 11‐year period (2007‐2017) were identified. Therapeutic CTs reporting efficacy data in the English language for investigational medicinal products (IMPs) of chemical, biological and biotechnological origin were included in the study. A protocol design or age filter was not applied to avoid limiting the scope of outcomes identified. Primary and secondary efficacy endpoints were extracted from the selected CTs and categorised according to type of measurement. Descriptive and inferential statistics were operated in a data mining process to detect trends in outcomes studied by pharmaceutical developers. Results: The final data set comprised 161 CTs representing 46,914 patients, with the majority of trials (67%, n=108) recruiting only patients from the adult (18‐64 years) and elderly (&gt;=65 years) populations. Twenty‐nine unique efficacy measures were identified and stratified into the endpoint clusters of survival (n=4), time‐to‐event (n=5), response rates and biomarkers (n=13) and other (n=7) parameters. Sixty‐eight per cent (n=110) of the trials reported 4‐10 outcomes, with a mean of 5 per CT. The principal outcomes examined included OS (CTs: 78%, n=126), complete response rate (CR) (CTs: 52%, n=84) and event‐free survival (EFS) (CTs: 44%, n=71). The endpoints EFS, OS and complete response rate with incomplete blood recovery (CRi) registered the highest frequency change of selection pre‐ and post‐2012 (EFS: 30%, p &lt; 0.001; OS: 27%, p &lt; 0.001; CRi: 18%, p = 0.01). Summary/Conclusion: The increase in uptake of EFS and CRi as efficacy parameters in AML CTs is in line with previous findings correlating these measures to OS. Significant heterogeneity in the selection of efficacy endpoints was observed. This warrants future work on the development of a core, standardised set of efficacy outcomes prioritised by relevant stakeholders for AML CTs.
AB0507 HEARING LOSS IN SYSTEMIC LUPUS ERYTHEMATOSUS
Authors: Eloise Akemi Tanaka, Harymy Barros, José Fernando Polanski, F. G dos Santos. Thiago Alberto, Thelma Laroca Skare. dos Santos, Thelma Laroca Skare
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Systemic lupus erythematosus(SLE) is a systemic disease that may affect the inner ear. <h3>Objectives:</h3> To study hearing function in SLE and its possible association with clinical and serological profile as well as with antimalarial use. <h3>Methods:</h3> Cross sectional study of 84 individuals(43 SLE patients and 41 controls) with audiometry and impedanciometry tests. Epidemiological, clinical, serological and treatment profile of SLE patients were extracted from the charts. <h3>Results:</h3> SLE patients had more sensorineural hearing loss than controls(23.2% vs 0; p=0.001). The hearing loss was seen at 250 Hz, 500 Hz, 1000 Hz and 4000 Hz. No bone conduction impairment was observed. Serological and clinical profile in patients with and without hearing loss was the same (all p=ns). Patients on antimalarial had the same prevalence of hearing loss than those not using it but at 8.000 Hz, antimalarial non-users performed worse than users(p=0.03). <h3>Conclusion:</h3> There is a high prevalence of hearing loss in SLE that is not affected by disease characteristics neither by antimalarial use. <h3>References</h3> [1] - Di Stadio A, Ralli M. Systemic Lupus Erythematosus and hearing disorders: Literature review and meta-analysis of clinical and temporal bone findings. J Int Med Res. 2017; 45:1470-80. [2] - Ralli M, D'Aguanno V, Di Stadio A, De Virgilio A, Croce A, Longo L, et al. Audiovestibular symptoms in systemic autoimmune diseases. J Immunol Res. 2018; 2018: 5798103. eCollection 2018. [3] - Jourde-Chiche N, Mancini J, Dagher N, Taugourdeau S, Thomas G, Brunet C, et al. Antimalarial ototoxicity: an underdiagnosed complication? A study of spontaneous reports to the French Pharmacovigilance Network. Ann Rheum Dis. 2012; 71: 1586. <h3>Disclosure of Interests:</h3> None declared
A new <i>ex vivo</i> human oral mucosa model reveals that p38 <scp>MAPK</scp> inhibition is not effective in preventing autoantibody‐induced mucosal blistering in pemphigus
Authors: D.T. Egu, A.M. Sigmund, E. Schmidt, V. Spindler, E. Walter, J. Waschke
Journal: British Journal of Dermatology (2019)

Pemphigus vulgaris (PV) is an autoimmune disease characterized by blister formation in the epidermis and oral mucosa due to loss of keratinocyte cohesion. Autoantibodies present in patients with PV (PV‐IgG) are known to primarily target desmoglein (Dsg)1 and Dsg3 in desmosomes. The mucosal‐dominant subtype of PV (mdPV) is caused by PV‐IgG autoantibodies against the cadherin‐type adhesion molecule Dsg3. p38 mitogen‐activated protein kinase (p38MAPK) signalling has been characterized as an important pathway downstream of PV‐IgG binding and its inhibition is protective in ex vivo human skin. However, the role of p38MAPK signalling in mdPV is unknown as no experimental model has been available. To establish a human ex vivo oral mucosa culture, and evaluate the p38MAPK dependency of blister formation and of ultrastructural alterations of desmosomes induced by mdPV‐IgG. Human labial mucosa was injected with mdPV‐IgG as well as AK23, a pathogenic mouse monoclonal Dsg3 antibody, in the presence or absence of p38MAPK inhibitors. Viability was evaluated by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay and apoptosis by terminal deoxynucleotidyl transferase dUTP nick‐end labelling assay. Blister score was determined following haematoxylin and eosin staining and Dsg3 distribution by immunostaining. Samples were processed for transmission electron microscopy to analyse desmosome ultrastructure. Both AK23 and mdPV‐IgG induced blisters and caused reduction in desmosome size and number in labial mucosa. Inhibition of p38MAPK was not effective in preventing these alterations. In contrast with human epidermis, PV‐IgG and AK23 induce blisters and desmosome ultrastructural changes in labial mucosa via a mechanism not dependent on p38MAPK. What's already known about this topic? Pemphigus vulgaris IgG (PV‐IgG) induces blistering as well as a reduction in desmosome number and size mediated by p38 mitogen‐activated protein kinase (p38MAPK) signalling in ex vivo human skin. What does this study add? This study establishes a new human ex vivo mucosa model to test pathomechanisms mediated by PV‐IgG. The study demonstrates that both AK23 and mucosal‐dominant PV induce blisters and associated ultrastructural changes in labial mucosa via a mechanism not dependent on p38MAPK signalling. What is the translational message? This study highlights the respective tissue‐specific responses of oral mucosa and skin related to PV pathogenesis, similar to the patient situation.
Transient Receptor Potential V Channels Are Essential for Glucose Sensing by Aldolase and AMPK
Authors: Mengqi Li, Chen-Song Zhang, Yue Zong, Jin-Wei Feng, Teng Ma, Meiqin Hu, Zhizhong Lin, Xiaotong Li, Changchuan Xie, Yaying Wu, Dong Jiang, Ying Li, Cixiong Zhang, Xiao Tian, Wen Wang, Yanyan Yang, Jie Chen, Jiwen Cui, Yu-Qing Wu, Xin Chen, Qing-Feng Liu, Jianfeng Wu, Shu-Yong Lin, Zhiyun Ye, Ying Liu, Hai-Long Piao, Li Yu, Zhuan Zhou, Xiao-Song Xie, D. Grahame Hardie, Sheng-Cai Lin
Journal: Cell Metabolism (2019)

Fructose-1,6-bisphosphate (FBP) aldolase links sensing of declining glucose availability to AMPK activation via the lysosomal pathway. However, how aldolase transmits lack of occupancy by FBP to AMPK activation remains unclear. Here, we show that FBP-unoccupied aldolase interacts with and inhibits endoplasmic reticulum (ER)-localized transient receptor potential channel subfamily V, inhibiting calcium release in low glucose. The decrease of calcium at contact sites between ER and lysosome renders the inhibited TRPV accessible to bind the lysosomal v-ATPase that then recruits AXIN:LKB1 to activate AMPK independently of AMP. Genetic depletion of TRPVs blocks glucose starvation-induced AMPK activation in cells and liver of mice, and in nematodes, indicative of physical requirement of TRPVs. Pharmacological inhibition of TRPVs activates AMPK and elevates NAD
PF327 RECOMBINANT FACTOR VIII FC FUSION PROTEIN IN SURGERIES IN HEMOPHILIA A
Authors: V. Patil, C. S, F. Jijina, S. Shetty, S. Mohanty, N. Wasekar
Journal: HemaSphere (2019)

Background: Surgical interventions in hemophilia patients is a challenging task in view of risk of perioperative bleeding associated with these cases. Many types of factor products are available to raise factor levels of these patients prior to surgery and in postoperative period. We studied efficacy of extended half life product - recombinant factor VIII Fc fusion protein (rFVIIIFc) in major surgeries in hemophilia A patients. Aims: To study perioperative hemostatic efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in surgeries in hemophilia A patients in real world. Methods: This retrospective study was carried out in KEM Hospital, Mumbai. Data of patients with hemophilia (PWH) who underwent major surgeries using rFVIIIFc was analyzed. These patients had received rFVIIIFc in peri-operative period according to the type of surgery, the clinical status and the factor recovery. Major surgery was defined as any elective or emergent surgical procedure that usually (but not always) involved general anesthesia and/or respiratory assistance and in which more extensive resection is performed, e.g. a body cavity is entered, organs are removed, or normal anatomy is altered. Efficacy outcomes for surgeries included rFVIIIFc dose per infusion and the number of infusions required to maintain hemostasis during the surgical period, estimated blood loss during surgery, the number of transfusions and the incidence of postoperative bleeding episodes. Results: A total of 23 patients of hemophilia A underwent major surgical procedures. Of these surgeries, 7 were arthroplasties, 7 were pseudotumor excisions, 2 were hernia repairs, 2 were neurosurgeries, 4 were orthopedic procedures and 1 was urological surgery. Mean rFVIIIFc requirement for all surgeries per patient per day was 43.8 U/kg/day. Mean rFVIIIFc requirement before procedure was 50.1 U/kg. Average 1.8 doses required on day 1 of surgeries with mean factor requirement of 70.7 U/kg on first day. Mean factor requirement in first three days of surgeries was 51.3 U/kg. Mean factor requirement post day 3 was 38.3 U/kg. Around 7 patients required PRC transfusion in peri-operative and immediate post-operative period. Of all 22 patients, 17 patients achieved excellent hemostasis and 6 patients achieved good hemostasis. 3 patients developed postoperative complications in the form of post-operative wound infection. Summary/Conclusion: Extended half life product (rFVIIIFc) achieved good hemostasis in hemophilia patients in peri-operative period. Requirement of blood products and bleeding in intra-operative and immediate post-operative period was less compared to that is required with conventional factor. More elaborative studies are needed to confirm our findings and also to assess if less frequent dosing schedule can be adopted using these extended half life products.
Meta-omics analysis of elite athletes identifies a performance-enhancing microbe that functions via lactate metabolism
Authors: Jonathan Scheiman, Jacob M. Luber, Theodore A. Chavkin, Tara MacDonald, Angela Tung, Loc-Duyen Pham, Marsha C. Wibowo, Renee C. Wurth, Sukanya Punthambaker, Braden T. Tierney, Zhen Yang, Mohammad W. Hattab, Julian Avila-Pacheco, Clary B. Clish, Sarah Lessard, George M. Church, Aleksandar D. Kostic
Journal: Nature Medicine (2019)
COPD: Analysing factors associated with a successful treatment
Authors: A. Duarte-de-Araújo, P. Teixeira, V. Hespanhol, J. Correia-de-Sousa
Journal: Pulmonology (2019)

To evaluate if non-adherence to inhaled medications, inhalers mishandling or the prescribers' non-adherence to GOLD strategy are associated with mMRC grade, CAT score, COPD acute exacerbations or FEV1%. A cross-sectional study on COPD was conducted in the ambulatory pulmonary clinic of Hospital de Guimarães. Patients ≥40 years diagnosed according to GOLD criteria were recruited consecutively. A survey of demographic and clinical data was used. Adherence was assessed by using the Measure of Treatment Adherence (MTA) questionnaire. Inhalation technique was evaluated by using checklists of correct steps and critical errors, and inhalers' misuse was defined when one or more critical errors were made, whatever the number or types of inhalers in use. To evaluate the prescriber non-adherence to GOLD strategy, the patients' current medication was compared with therapeutic standards proposed by the GOLD 2017 strategy for the same ABCD groups. A statistical analysis was performed with IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp. We studied 303 participants, 79.5% males, mean age = 67.5 years. A total of 285 completed the MTA questionnaire. Non-adherence was referred by 47 (16.5%) patients, and a significant negative association was found between adherence and CAT score and FEV1%. 285 patients performed 499 inhalations manoeuvres with 10 different IDs. Inhaler misuse was observed in 113 (39.6%) patients, and was not associated with CAT score, mMRC grade, ECOPD or FEV1%. We found deviations from the GOLD strategy in 133 (44.3%) patients, which were negatively related to CAT score, mMRC grade and ECOPD. In the present study we failed to prove a positive association between non-adherence to medication, inhalers mishandling or prescribers' non-adherence to GOLD strategy with symptoms, exacerbations and airflow limitation. Conversely, more symptomatic and more obstructed patients were more adherent to medication, previous ECOPD seems to improve prescribers' adherence to treatment guidelines, and symptoms, ECOPD and FEV1% were not significantly associated with inhaler technique.
Assessment of Updated Society of Thoracic Surgeons Score in Historical PARTNER II Patients
Authors: Mark Hensey, Janarthanan Sathananthan, Dale J. Murdoch, Abdullah Alkhodair, Jian Ye, Anson Cheung, Philipp Blanke, Jonathon Leipsic, David A. Wood, John G. Webb
Journal: Journal of the American College of Cardiology (2019)
AB1251 ASSOCIATION BETWEEN VITAMIN D DEFICIENCY AND A HIGHER RATE OF DISEASE ACTIVITY IN PATIENTS WITH SPONDYLOARTHRITIS
Authors: David Castro-Corredor, Marco Aurelio Ramírez Huaranga, Javier José Mateos Rodríguez, Mª Dolores Mínguez Sánchez, Marcos Paulino Huertas, José Luis Cuadra Díaz
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Spondyloarthritis is a group of chronic inflammatory diseases with involvement of the axial skeleton (mainly), and also of peripheral joints. Patients with spondyloarthritis have a significant prevalence of vitamin D levels below normal and that would correlate with the degree of activity of the disease. <h3>Objectives:</h3> To determine the association between vitamin D deficiency and the degree of activity of the disease (inflammatory activity) in a cohort of patients with spondyloarthritis. <h3>Methods:</h3> Observational, extensive and transversal study. We propose a retrospective review of the database of patients with spondyloarthritis who were treated in the outpatient clinics of the Rheumatology Service of the General University Hospital of Ciudad Real during September 2016 to September 2018. Patients with the data will be selected. necessary for the analysis of the variables under study. The variables evaluated will be described using measures of frequency and measures of central tendency/dispersion as appropriate. To assess the association between vitamin D deficit and activity index, the odds ratio (OR) will be calculated. All analyzes were performed with a confidence level of 95% using SPSS 21.0. <h3>Results:</h3> The first advances of the results of the study are presented. 101 patients were analyzed, of which 58 were men and 43 women, with an average age of 46.33 years (+/- 13.05 DE). 15 (14.85%) were non-radiographic axial spondyloarthritis, 48 (47.52%) ankylosing spondylitis, 24 (23.76%) psoriatic arthropathy, 3 (2.97%) spondyloarthropathy associated with inflammatory bowel disease, and 11 (10, 89%) were other types of spondyloarthritis. The average of the activity was a BASDAI of 4.355 (+/- 2.376 SD), 64 patients were in activity (BASDAI&gt; or = 4) and 31 patients (30.69%) with an elevation of acute phase reactants. Vitamin D levels were 24.52 (+/- 9.21 SD). 77 patients (76.24%) presented figures of vitamin D deficiency or insufficiency. When performing the association analysis, the vitamin D deficit/insufficiency presented an OR 12.46 (95% CI: 4.07-38.08)., p = &lt;0.0001) with the degree of activity measured with BASDAI. Regarding the comparative analysis of means between vitamin D deficiency/insufficiency and BASDAI it is +2,253 (95% CI: 1,241 to 3,266, p &lt;0.0001). <h3>Conclusion:</h3> In our study, patients with spondyloarthritis who have a vitamin D deficit correlate with presenting disease activity (BASDAI&gt; or = 4). Therefore, inflammation along with increased bone turnover and low levels of vitamin D could be related to the pathophysiology of osteoporosis related to spondyloarthritis, and may adversely affect the patient's functional status and quality of life. <h3> Disclosure of Interests:</h3> None declared
Chromosome contacts in activated T cells identify autoimmune disease candidate genes
Authors: Oliver S. Burren, Arcadio Rubio García, Biola-Maria Javierre, Daniel B. Rainbow, Jonathan Cairns, Nicholas J. Cooper, John J. Lambourne, Ellen Schofield, Xaquin Castro Dopico, Ricardo C. Ferreira, Richard Coulson, Frances Burden, Sophia P. Rowlston, Kate Downes, Steven W. Wingett, Mattia Frontini, Willem H. Ouwehand, Peter Fraser, Mikhail Spivakov, John A. Todd, Linda S. Wicker, Antony J. Cutler, Chris Wallace
Journal: Genome biology (2017)

Autoimmune disease-associated variants are preferentially found in regulatory regions in immune cells, particularly CD4+ T cells. Linking such regulatory regions to gene promoters in disease-relevant cell contexts facilitates identification of candidate disease genes. Within 4 h, activation of CD4+ T cells invokes changes in histone modifications and enhancer RNA transcription that correspond to altered expression of the interacting genes identified by promoter capture Hi-C. By integrating promoter capture Hi-C data with genetic associations for five autoimmune diseases, we prioritised 245 candidate genes with a median distance from peak signal to prioritised gene of 153 kb. Just under half (108/245) prioritised genes related to activation-sensitive interactions. This included IL2RA, where allele-specific expression analyses were consistent with its interaction-mediated regulation, illustrating the utility of the approach. Our systematic experimental framework offers an alternative approach to candidate causal gene identification for variants with cell state-specific functional effects, with achievable sample sizes.