tbuckley/cabot-search huggingface dataset:
Soluble Urokinase Plasminogen Activator Receptor and Decline in Kidney Function in Autosomal Dominant Polycystic Kidney Disease
Authors: Salim S. Hayek, Douglas P. Landsittel, Changli Wei, Martin Zeier, Alan S.L. Yu, Vicente E. Torres, Sharin Roth, Christina S. Pao, Jochen Reiser
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement Soluble urokinase plasminogen activator receptor (suPAR), a marker of inflammation, is also an independent marker for incidence and progression of renal diseases. Mechanistically, it has been shown to activate podocytes in glomerular diseases. In this study, the authors provide the first description linking suPAR levels with disease progression for a major genetic renal disease that mainly affects the extraglomerular compartment, autosomal dominant polycystic kidney disease (ADPKD). They found an association between suPAR levels and height-adjusted total kidney volume, independent of age, sex, race, hypertension, and eGFR. In addition, patients with suPAR levels &gt;2.82 ng/ml had a 3.38-fold increase in risk of incident ESRD. These findings suggest that suPAR levels may be useful for early identification of patients with ADPKD at high risk of disease progression. Background Levels of soluble urokinase plasminogen activator receptor (suPAR), an inflammation marker, are strongly predictive of incident kidney disease. Patients with autosomal dominant polycystic kidney disease (ADPKD) experience progressive decline in renal function, but rates of decline and outcomes vary greatly. Whether suPAR levels are predictive of declining kidney function in patients with ADPKD is unknown. Methods We assessed suPAR levels in 649 patients with ADPKD who underwent scheduled follow-up for at least 3 years, with repeated measurements of height-adjusted total kidney volume and creatinine-derived eGFR. We used linear mixed models for repeated measures and Cox proportional hazards to characterize associations between baseline suPAR levels and follow-up eGFR or incident ESRD. Results The median suPAR level was 2.47 ng/ml and median height-adjusted total kidney volume was 778, whereas mean eGFR was 84 ml/min per 1.73 m 2 . suPAR levels were associated with height-adjusted total kidney volume ( β =0.02; 95% confidence interval, 0.01 to 0.03), independent of age, sex, race, hypertension, and eGFR. Patients in the lowest suPAR tertile (&lt;2.18 ng/ml) had a 6.8% decline in eGFR at 3 years and 22% developed CKD stage 3, whereas those in the highest tertile (suPAR&gt;2.83 ng/ml) had a 19.4% decline in eGFR at 3 years and 68% developed CKD stage 3. suPAR levels &gt;2.82 ng/ml had a 3.38-fold increase in the risk of incident ESRD. Conclusions suPAR levels were associated with progressive decline in renal function and incident ESRD in patients with ADPKD, and may aid early identification of patients at high risk of disease progression.
Targetable genetic alterations of <i>TCF4</i> ( <i>E2-2</i> ) drive immunoglobulin expression in diffuse large B cell lymphoma
Authors: Neeraj Jain, Keenan Hartert, Saber Tadros, Warren Fiskus, Ondrej Havranek, Man Chun John Ma, Alyssa Bouska, Tayla Heavican, Dhiraj Kumar, Qing Deng, Dalia Moore, Christine Pak, Chih Long Liu, Andrew J. Gentles, Elena Hartmann, Robert Kridel, Karin Ekstrom Smedby, Gunnar Juliusson, Richard Rosenquist, Randy D. Gascoyne, Andreas Rosenwald, Filippo Giancotti, Sattva S. Neelapu, Jason Westin, Julie M. Vose, Matthew A. Lunning, Timothy Greiner, Scott Rodig, Javeed Iqbal, Ash A. Alizadeh, R. Eric Davis, Kapil Bhalla, Michael R. Green
Journal: Science Translational Medicine (2019)

The activated B cell (ABC-like) subtype of diffuse large B cell lymphoma (DLBCL) is characterized by chronic activation of signaling initiated by immunoglobulin μ (IgM). By analyzing the DNA copy number profiles of 1000 DLBCL tumors, we identified gains of 18q21.2 as the most frequent genetic alteration in ABC-like DLBCL. Using integrative analysis of matched gene expression profiling data, we found that the TCF4 (E2-2) transcription factor gene was the target of these alterations. Overexpression of TCF4 in ABC-like DLBCL cell lines led to its occupancy on immunoglobulin (IGHM) and MYC gene enhancers and increased expression of these genes at the transcript and protein levels. Inhibition of TCF4 activity with dominant-negative constructs was synthetically lethal to ABC-like DLBCL cell lines harboring TCF4 DNA copy gains, highlighting these gains as an attractive potential therapeutic target. Furthermore, the TCF4 gene was one of the top BRD4-regulated genes in DLBCL cell lines. BET proteolysis-targeting chimera (PROTAC) ARV771 extinguished TCF4, MYC, and IgM expression and killed ABC-like DLBCL cells in vitro. In DLBCL xenograft models, ARV771 treatment reduced tumor growth and prolonged survival. This work highlights a genetic mechanism for promoting immunoglobulin signaling in ABC-like DLBCL and provides a functional rationale for the use of BET inhibitors in this disease.
SAT0141 FREQUENCY AND REASONS FOR SWITCHING BACK TO BIOLOGIC ORIGINATOR FOLLOWING INITIAL SWITCH TO BIOLOGIC BIOSIMILAR
Authors: Rebecca Davies, Lianne Kearsley-Fleet, Mark Lunt, Kath Watson, Kimme Hyrich
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Since February 2015, a number of biosimilar drugs have been introduced for treatment of rheumatoid arthritis (RA) in the UK. Biosimilars are required to have no clinically meaningful differences in efficacy or safety from the originator product. There are clear cost-saving implications when switching patients to a biosimilar; however, the longer term implications of switching have yet to be studied. <h3>Objectives:</h3> To describe the frequency of switching back to biologic-originator (BIO-O) in patients who initially switch from BIO-O to biologic biosimilar (BIO-B), focussing on etanercept (ETA) and infliximab (INF). <h3>Methods:</h3> The study population comprised RA subjects recruited to BSRBR-RA to 30/11/2018 who had switched from BIO-O to BIO-B (INF and ETA) and had completed at least one further study follow-up following switch. Baseline characteristics at point of switch and the proportion of patients who were recorded as switching back to BIO-O or discontinuing BIO completely following switch with reasons are described. <h3>Results:</h3> Nine hundred and sixty six patients were included (760 switching from ETA-O; 206 switching from INF-O). After a median follow-up of 22.5 months post-switch, the majority of patients remained on BIO-B (ETA-B = 619 (81%), INF-B =166 (81%)). Seven percent of patients switched back to originator, with a majority following reports of ineffectiveness or feeling generally unwell (Table). Eleven percent stopped BIO completely, with a majority stopping for serious adverse events such as malignancy or infection. Similar results were seen for both ETA and INF. Six ETA and 3 INF reported injection or infusion related reactions following switch (0.9% overall) leading to switch back (4 ETA) or biologic discontinuation (2 ETA/3 INF). <h3>Conclusion:</h3> Data from this study show that the majority of patients who switched from BIO-O to BIO-B remain on the biosimilar over the short term. A small proportion of patients have switched back to the originator drug with the majority doing so for reports of ineffectiveness rather than safety concerns. Hypersensitivity reactions, such as infusion reactions were rare reasons to stop either drug completely or switch back to originator. <h3>Disclosure of Interests:</h3> Rebecca Davies: None declared, Lianne Kearsley-Fleet: None declared, Mark Lunt: None declared, Kath Watson: None declared, Kimme Hyrich Grant/research support from: Grants to institution: BMS, Pfizer, UCB
Abstract 12655: Reduced Mammillary Body Volumes Associated With Memory Deficits in Single Ventricle Heart Disease
Authors: Cristina Cabrera-Mino, Mary A Woo, Bhaswati Roy, Sadhana Singh, Nancy J Halnon, Alan B Lewis, Rajesh Kumar, Nancy A Pike
Journal: Circulation (2018)

Introduction: Adolescents with single ventricle heart disease (SVHD) following staged surgical palliation show brain-related functional deficits, particularly in memory. The mammillary bodies are k...
Polymorphism-Aware Species Trees with Advanced Mutation Models, Bootstrap, and Rate Heterogeneity
Authors: Dominik Schrempf, Bui Quang Minh, Arndt von Haeseler, Carolin Kosiol
Journal: Molecular Biology and Evolution (2019)

Molecular phylogenetics has neglected polymorphisms within present and ancestral populations for a long time. Recently, multispecies coalescent based methods have increased in popularity, however, their application is limited to a small number of species and individuals. We introduced a polymorphism-aware phylogenetic model (PoMo), which overcomes this limitation and scales well with the increasing amount of sequence data whereas accounting for present and ancestral polymorphisms. PoMo circumvents handling of gene trees and directly infers species trees from allele frequency data. Here, we extend the PoMo implementation in IQ-TREE and integrate search for the statistically best-fit mutation model, the ability to infer mutation rate variation across sites, and assessment of branch support values. We exemplify an analysis of a hundred species with ten haploid individuals each, showing that PoMo can perform inference on large data sets. While PoMo is more accurate than standard substitution models applied to concatenated alignments, it is almost as fast. We also provide bmm-simulate, a software package that allows simulation of sequences evolving under PoMo. The new options consolidate the value of PoMo for phylogenetic analyses with population data.
Increased extracellular maspin levels after mechanical compression in vitro or allergen challenge in vivo
Authors: Sae-Hoon Kim, Jennifer A. Mitchel, Maureen McGill, Tiziana P. Cremona, Ji Won Baek, David I. Kasahara, Vikas Anathy, Elliot Israel, Jin-Ah Park
Journal: Journal of Allergy and Clinical Immunology (2019)
PB1781 THE OUTCOME OF PREGNANCY‐ASSOCIATED HEMATOLOGICAL CANCERS IN TAIWAN
Authors: S.‐S. Li, Y.‐T. Hsu, C.‐C. Yen, P.‐Y. Wu, Y.‐W. Chen, C.‐Y. Li, T.‐Y. Chen
Journal: HemaSphere (2019)

Background: Pregnancy‐associated cancers, usually defined as cancers diagnosed during pregnancy or one year after delivery, is a diagnostic and therapeutic challenge to doctors. Hematological malignancies are among the most common types of cancer in women of child‐bearing age. However, the impact of pregnancy on the maternal and neonatal outcome is largely unknown. Aims: To investigate the impact of pregnancy on the outcome of patients with pregnancy‐associated hematological malignancies. Methods: We identified patients with pregnancy‐associated cancers by intersecting the Taiwan Cancer Registry with the Birth Certificate Application. Patients were grouped into pregnant (diagnosed during pregnancy) and lactating (diagnosed within one year after delivery) group. Female patients of child‐bearing age (16‐49 years) who were not pregnant at the diagnosis of cancer were used as a control. Results: From the year 2001 to 2015, cancer was diagnosed during pregnancy and one year after delivery in 512 and 2151 patients, respectively. Lymphoma and leukemia are the 5th and 6th most common subtype of pregnancy‐associated cancer. Survival is not significantly different between pregnant, lactating, and non‐pregnant leukemia patients (p = 0.49). A higher proportion of aggressive B‐cell lymphomas is observed in lymphomas diagnosed during pregnancy (73.6%), as compared with the lactating (38.6%) and non‐pregnant (39.5%) group (p &lt; 0.01). The proportion of advanced stage lymphoma in the pregnant or lactating group was not different from that in the non‐pregnant group (Odds ratio [OR] 0.87 &amp; 0.98, p = 0.85 &amp; 0.97, respectively). Compared with the non‐pregnant group, the survival in pregnancy group was not significantly different (Hazard ratio [HR] 1.41, p = 0.40), while the survival in the lactating group is markedly better (HR 0.19, p &lt; 0.01). After controlled with age, stage, year of diagnosis, and histology, lactating status remained an independent prognostic marker (HR 0.12, p = 0.03). Summary/Conclusion: Lymphoma diagnosed within one year after delivery carries a good prognosis. Further study is needed to investigate the effect of lactation‐associated hormones in lymphoma. image
AB0340 PATIENTS WITH RHEUMATOID ARTHRITIS COMPLICATED WITH DEPRESSION HAVE A HIGHER FREQUENCY OF EXPERIENCING PHYSICAL DEPRESSIVE SYMPTOMS
Authors: Yusuke Miwa, Kenji Sanada, Yuko Mitamura
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Approximately 15% of patients with rheumatoid arthritis (RA) experience depression with an odds ratio of 1.42 (95% CI 1.3–1.5) compared to healthy people. Depression is related to disease activity and activities of daily living (ADL) of patients with RA. Previous studies have reported depressed mood, sleep disorder, and other such symptom separately with no reports addressing the factors constituting depression together. <h3>Objectives</h3> To examine the factors constituting depression in RA patients. <h3>Methods</h3> The subjects were 124 registered RA patients. The following patient characteristics were investigated: age, gender, body mass index, smoking history, and presence or absence of hypertension and diabetes. Baseline steroid dosage, methotrexate dosage, and serum matrix metalloproteinase–3 levels and creatinine level were examined. For evaluation, we used the simplified disease activity index (SDAI) for RA disease activity, the health assessment questionnaire disability index (HAQ-DI) score for ADL, and the Hamilton depression rating scale (HAM-D) score for depression status. Different items on the HAM-D scale were analyzed, and the correlation between HAM-D and each item was examined. <h3>Results</h3> Although 42 patients (33.9%) answered that they experienced "depressed moods", more than 50% of the patients answered that they had "anxiety somatic (79 patients, 63.7%)" and "somatic symptoms general (69 patients, 55.6%)". Patients, who responded that they had "work and activities (57 patients, 46.0%)", "hypochondriasis (53 patients, 42.7%)," and "genital symptom (49 patients, 36.5%)," exceeded the number of patients claiming to experience depression. "Depressed mood" correlated with SDAI (r=0.31, p&lt;0.01) and HAQ-DI (r=0.26, p&lt;0.01). "Somatic Symptoms General" correlated with SDAI (r=0.30, p&lt;0.01) and HAQ-DI (r=0.29, p&lt;0.01) as well. "Anxiety somatic" correlated with age (r=0.24, p&lt;0.01) only and no other factor. <h3>Conclusion</h3> Patients with rheumatoid arthritis patients experiencing a depressed state of mind have a high chance of exhibiting physical symptoms as compared to patients with "depressed mood" alone. These factors are not necessarily associated with RA disease activity or HAQ-DI. <h3>Acknowledgement</h3> Cooperation on data collection: All Showa University in Rheumatoid Arthritis (ASHURA) group <h3>Disclosure of Interests</h3> YUSUKE MIWA Grant/research support from: Mitsubishi Tanabe Pharma Corporation and AbbVie CK. Astellas Pharma Inc., Mitsubishi Tanabe Pharma Corporation, AbbVie CK, Pfizer Japan Inc., Chugai Pharmaceutical Co., Ltd., Eizai Co., Ltd, Asahi Kasei Pharm Co., Ltd, YL Biologics Ltd., Japan Blood Products Organization, Ono Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., and Teijin Pharma Ltd. This work was supported by JPJS KAKENHI Grant Number JP17K09324., Kenji Sanada: None declared, Yuko Mitamura: None declared
AB0962 UPDATE FOR THE CLINICAL PRACTICE: INTEGRATED, EVIDENCE-BASED APPROACH FOR THE MANAGEMENT OF JUVENILE SPONDYLOARTHRITIS
Authors: Mervat Eissa, Yasser El Miedany, Waleed Hassan, Dalia Mekkawy, Mohammed A. Mortada, Samah Ismail Nasef, Maha El Gaafary, Hala Lotfy, Yomna Farag, Ghada El Deriny, Mohammed Hassan Abu-Zaid, Yossra Atef, Nadia El Aroussy
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Juvenile onset spondyloarthritis (SpA) is a heterogeneous group of human leukocyte antigen (HLA) -B27 associated inflammatory syndromes that affect children and adolescents under the age of 16 years No specific recommendations for the treatment of juvenile spondyloarthritis have been established. Important differences exist between spondyloarthritis in children and adults, supporting the need for pediatric-specific recommendations. <h3>Objectives</h3> To set recommendations for the management of children and adolescents with spondyloarthritis. <h3>Methods</h3> Searching Medline for Juvenile spondyloarthritis management was done. A systematic literature search was conducted to collect the existing recommendations, guidelines involved line of treatment for Juvenile SpA &amp; adult SpA. These included 2011 ACR recommendations for the treatment of JIA and the 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. <h3>Results</h3> NSAIDs have been shown to improve symptoms, reduce inflammatory lesions and may slow spinal radiographs progression with continuous use. Glucocorticoid injections directed to the local site of musculoskeletal inflammation may be considered. Sulfasalazine may be considered in patients with peripheral arthritis. Initiation of a (tumor necrosis factor inhibitor (TNFi) was recommended for patients with active sacroiliac arthritis who have received an adequate trial of NSAIDs. Also, it should be initiated to those who fail to respond to synthetic disease modifying anti-rheumatic drugs (sDMARD). If TNFi therapy fails, switching to another TNFi should be done. If a patient is in sustained remission, tapering of a biological DMARD can be considered. <h3>Conclusion</h3> These guidelines provide up-to-date guidance on the management of patients with juvenile SpA, based on combining evidence and expert opinion. <h3>Disclosure of Interests</h3> None declared
Abstract 15006: Comparative Clinical Outcomes among Octogenarians and Nonagenarians after Transcatheter Aortic Valve Implantation: Insights from the FRANCE 2 Registry
Authors: Masanori Yamamoto, Gauthier Mouillet, Eric Bergoen, Pascal Lim, Jean-Luc Monin, Jean-Luc Dubois-Rande, Emmanuel Teiger
Journal: Circulation (2012)

Background: Transcatheter aortic valve implantation (TAVI) has been developing as an alternative treatment in elderly patients with high surgical risk. Although advanced age is associated with incr...
Melissa: Bayesian clustering and imputation of single-cell methylomes
Authors: Chantriolnt-Andreas Kapourani, Guido Sanguinetti
Journal: Genome biology (2019)

Measurements of single-cell methylation are revolutionizing our understanding of epigenetic control of gene expression, yet the intrinsic data sparsity limits the scope for quantitative analysis of such data. Here, we introduce Melissa (MEthyLation Inference for Single cell Analysis), a Bayesian hierarchical method to cluster cells based on local methylation patterns, discovering patterns of epigenetic variability between cells. The clustering also acts as an effective regularization for data imputation on unassayed CpG sites, enabling transfer of information between individual cells. We show both on simulated and real data sets that Melissa provides accurate and biologically meaningful clusterings and state-of-the-art imputation performance.
PB2156 RISK FACTORS ASSOCIATED WITH EARLY MORTALITY IN PATIENTS WITH MULTIPLE MYELOMA
Authors: A. Novikova, I. Nakastoev, Y. Balzhanova, V. Ryzhko, A. Grachev, A. Danilina, M. Kanaeva, G. Klyasova, E. Gribanova
Journal: HemaSphere (2019)

Background: Early mortality (EM) in multiple myeloma (MM) ranges from 4% to 25% mostly depending on the patients included and on treatment options. EM tends to be lower in clinical trials including younger, transplant‐eligible patients or in bortezomib‐ and lenalidomide‐based regimens in comparison with elderly patients and conventional chemotherapy treatment. Aims: To estimate risk factors associated with EM in patients with newly diagnosed MM. Methods Patients with newly diagnosed MM were included into the study (from Jan 2013 to Feb 2019). EM was defined if it occurred within 1 year of entry into the study. Adverse cytogenetic abnormalities were specified as gain(1q), t(4;14), t(14;16), t(14;20) or del(17p). Results: A total of 174 patients with newly diagnosed MM (82 male, 92 female; median age 61 years) were involved in the study. Follow‐up period was 1‐71.4 months (median 8 months). The majority of patients developed an advanced stage of disease (Duriе‐Salmon stage 3–141 (81.1%), ISS stage 3–99 (56.9%)). All patients received chemotherapy regimens containing proteasome inhibitors as first‐line therapy and immunomodulatory drugs, intensive and conventional chemotherapy regimens as second‐ or next‐line therapy. During follow‐up period fatal outcome was observed in 45 (25.9%) of 174 patients, of them 16 (9.2%) patients with EM. Median early mortality was 4.7 months. The age of patients with EM and patients survived &gt; 1 year was comparable (median age 64.5 vs. 61, respectively). A larger proportion of patients with EM had Durie‐Salmon stage 3 (93.8% vs 79.7%), ISS stage 3 (75.0% vs 55.1%). Fish in situ hybridization analysis was conducted in 126 (72.4%) patients, adverse cytogenetic abnormalities were present in 4/8 (50.0%) patients with EM and 33/118 (27.9%) patients survived &gt;1 year. Risk factors assotiated with EM were ECOG performance status ≥ 3 score (87.5% vs 40.5%, p = 0.0003), C‐reactive protein level &gt; 10 mg/L (62.5% vs 26.6%, p = 0.007), high lactic acid dehydrogenase activity (81.3% vs 46.2%, p = 0.008), platelet count &lt; 150 × 10 9 /L (43.8% vs 18.9%, p = 0.047) (tab.). For the 16 patients with EM, 11 (68.8%) of deaths were related to MM progression, 4 (25.0%) were due to infections and 1 (6.2%) ‐ heart failure. Summary/Conclusion: EM in patients with newly diagnosed MM was 9.2%. Risk factors associated with EM were poor performance status, elevated serum LDH activity, low platelet count, high serum C‐reactive protein. image
AB0152 IL-23 INDUCES OSTEOCLASTS TO EXPRESS PRO-OSTEOGENIC FACTORS RATHER THAN ANTI-OSTEOGENIC FACTORS
Authors: Dan-Dan Pang, LI Cai, Sheng-Ming Dai
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> The formation of new bone or syndesmophytes is the dominant factor of the damage caused by AS, but the mechanisms responsible for syndesmophyte formation in AS have not been elucidated. <h3>Objectives:</h3> To explore whether IL-23 indirectly facilitates new bone formation through osteoclasts in ankylosing spondylitis, here we analyzed whether IL-23 enhances the expression levels of osteogenic factors by osteoclasts. <h3>Methods:</h3> Mouse bone marrow mononuclear cells were cultured in the presence of M-CSF (50ng/ml) and receptor activator of NF-λB ligand (RANKL, 30ng/ml) to induce osteoclast formation<i> in vitro</i>. The mRNA and protein expression levels of the osteogenesis-modulating factors, such as ephrin B2, sphingosine kinase 1 (SPHKl), bone morphogenetic protein 2 (BMP2), BMP6, Wnt10b, semaphorin 4D and HtrA1, were analyzed by quantitative real-time RT-PCR and Western blotting. <h3>Results:</h3> Mature osteoclasts were successfully induced from primary bone marrow mononuclear cells in the presence of both M-CSF and RANKL. Mature osteoclasts were identified by elevated expression levels of tartrate-resistant acid phosphatase (TRAP) and NFATc1, as well as positive TRAP staining with more than 3 nuclei. IL-23 increased the mRNA expression levels of pro-osteogenic ephrin B2, SPHKl and BMP2 in osteoclasts to 2.1, 2.46 and 1.46 folds, respectively. The elevated protein levels of ephrin B2 and SPHK1 in IL-23-stimulated osteoclasts were also confirmed by Western blotting. IL-23 failed to enhance the expression levels of pro-osteogenic BMP6 and Wnt10b and showed no effects on the expression levels of anti-osteogenic semaphorin 4D and HtrA1 in osteoclasts. <h3>Conclusion:</h3> IL-23 induces osteoclasts to express pro-osteogenic factors rather than anti-osteogenic factors, suggesting IL-23 may indirectly promote the differentiation of osteoblasts through osteoclasts in ankylosing spondylitis. <h3>Disclosure of Interests:</h3> None declared