tbuckley/cabot-search huggingface dataset:
Major Adverse Cardiovascular Events Following Simultaneous Pancreas and Kidney Transplantation in the United Kingdom
Authors: Petros Yiannoullou, Angela Summers, Shu C. Goh, Catherine Fullwood, Hussein Khambalia, Zia Moinuddin, Iestyn M. Shapey, Josephine Naish, Christopher Miller, Titus Augustine, Martin K. Rutter, David van Dellen
Journal: Diabetes Care (2019)

OBJECTIVE People with type 1 diabetes and kidney failure have an increased risk for major adverse cardiovascular events (MACE). Simultaneous pancreas and kidney transplantation (SPKT) improves survival, but the long-term risk for MACE is uncertain. RESEARCH DESIGN AND METHODS We assessed the frequency and risk factors for MACE (defined as fatal cardiovascular disease and nonfatal myocardial infarction or stroke) and related nonfatal MACE to allograft failure in SPKT recipients with type 1 diabetes who underwent transplantation between 2001 and 2015 in the U.K. In a subgroup, we related a pretransplant cardiovascular risk score to MACE. RESULTS During 5 years of follow-up, 133 of 1,699 SPKT recipients (7.8%) experienced a MACE. In covariate-adjusted models, age (hazard ratio 1.04 per year [95% CI 1.01–1.07]), prior myocardial infarction (2.6 [1.3–5.0]), stroke (2.3 [1.2–4.7]), amputation (2.0 [1.02–3.7]), donor history of hypertension (1.8 [1.05–3.2]), and waiting time (1.02 per month [1.0–1.04]) were significant predictors. Nonfatal MACE predicted subsequent allograft failure (renal 1.6 [1.06–2.6]; pancreas 1.7 [1.09–2.6]). In the subgroup, the pretransplant cardiovascular risk score predicted MACE (1.04 per 1% increment [1.02–1.06]). CONCLUSIONS We report a high rate of MACE in SPKT recipients. There are a number of variables that predict MACE, while nonfatal MACE increase the risk of subsequent allograft failure. It may be beneficial that organs from hypertensive donors are matched to recipients with lower cardiovascular risk. Pretransplant cardiovascular risk scoring may help to identify patients who would benefit from risk factor optimization or alternative transplant therapies and warrants validation nationally.
SP0115 Value of inflammatory biomarkers in clinical decision making
Authors: M. Sefik Bukilica
Journal: Annals of the Rheumatic Diseases (2018)

<h3></h3> Inflammation is known to play a major role in rheumatologic disorders. Inflammatory biomarkers can help clinicians diagnose rheumatic diseases and assess disease activity more accurately. These markers have been incorporated into classification criteria of several diseases to enable early diagnosis and timely initiation of treatment. Quantification of inflammation has become essential to tailor the treatment strategy, especially in patients with rheumatoid arthritis, polymyalgia rheumatica and vasculitides. Inflammation can be measured from different perspectives – the measures that quantify biomarkers participating in inflammation, surrogate markers of inflammation, and the by-products of the inflammation process. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels are among the most commonly used acute phase reactants in the detection and follow-up of rheumatologic disorders. These markers are not specific to trigger factors of inflammation, limiting their capacity to discriminate the cause for stimuli as well as the organs involved. In the current presentation the advantages and limitations of new and established inflammatory biomarkers in clinical decision making will be discussed illustrated by case reports. <h3>Disclosure of Interest</h3> None declared
Do Guideline-Based Indications Result in an Outcome Penalty for Patients With Severe Aortic Regurgitation?
Authors: Christophe de Meester, Bernhard L Gerber, David Vancraeynest, Anne-Catherine Pouleur, Philippe Noirhomme, Agnès Pasquet, Laurent de Kerchove, Gébrine El Khoury, Jean-Louis Vanoverschelde
Journal: JACC. Cardiovascular imaging (2019)
THU0005 Whole genome linkage and exome sequencing analyses in takayasu arteritis families
Authors: E. Tahir Turanlı, I. Karacan, S.N. Esatlioglu, S. Sahin, O. Kasapcopur, A. Tolun, E. Seyahi
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Takayasu arteritis (TA) is an inflammatory large vessel vasculitis affecting mainly aorta and its branches. Inflammation in vessels causes thickening of walls, fibrosis, dilatation and nonspecific symptoms such as fever, hypertension and arthralgia. It is a rare disorder with unknown etiology and the worldwide incidence is 0.4 to 2.6 per million. <h3>Objectives</h3> We studied three consanguineous families with consisting of two affected daughters each and their healthy parents in order to identify the disease locus and the causative mutation <h3>Methods</h3> In two of the families, genome-wide single nucleotide polymorphism (SNP) genotyping was performed for available family members using Illumina OmniExpress-24 BeadChip targeting ~700,000 SNP markers. Using genotyping data, we performed multipoint parametric linkage analysis assuming recessive inheritance and complete penetrance. Also exome sequencing was performed for four of the patients to search for rare, homozygous deleterious variants. For TA1 and TA2 families whether the variants were located in a region IBD (identical by descent) in affected sisters or not was investigated. <h3>Results</h3> Whole genome linkage and exome analyses identified homozygous, rare (MAF &lt;0.01) candidate variants shared by the affected sister pairs in the first two families. Candidate variants for the first family were in <i>ANXA8L1, EHBP1L1, TULP2, MYH14</i> and<i> SHANK1</i> and for the second family in <i>AP4B1, RIMBP3, VCX3B</i> and<i> NXF2</i>. In the third family, no candidate homozygous variant was common for the affected sibs, who had different fathers. <i>In silico</i> functional predictions of the candidate variants shared by each sister-pair were determined. <h3>Conclusions</h3> This is the first whole genome linkage analysis and subsequent exome sequencing in TA patients with suggestive recessive inheritance. Possible candidate variants in two out of the three families were determined. However, we could not find any genetic change in terms of genetic mutations, exonic deletions or structural variations shared by these families. We had hoped that the study in these rare families with a pair of TA sibs would unravel a gene responsible for TA. We now question whether the inheritance is dominant with reduced penetrance which requires more familial cases to be studied. <h3>Acknowledgements</h3> This study was supported by TÜBıTAK (Grant No 114Z829). <h3>Disclosure of Interest</h3> None declared
PD-L1 Blockade with Atezolizumab in Higher-Risk Myelodysplastic Syndrome: An Initial Safety and Efficacy Analysis
Authors: Aaron T. Gerds, Bart L Scott, Peter L Greenberg, Samer K. Khaled, Tara L Lin, Daniel A Pollyea, Amit Verma, Monique Dail, Cherie Green, Connie Ma, Bruno C Medeiros, Patrick Phuong, Michael Wenger, Mark Yan, William B. Donnellan
Journal: Blood (2018)
Modulation of the tumor suppressor p53 pathway by arginine methyltransferases
Authors: Ariane Scoumanne, Xinbin Chen
Journal: Cancer Research (2008)

1564  The tumor suppressor p53 is the most commonly mutated gene in human cancer. As a transcription factor, p53 plays an essential role in the induction of cellular processes such as cell cycle arrest, apoptosis, and senescence in response to stress signals. Post-translational modifications and interaction with cofactors are the primary mediators of p53 stabilization and activation upon cellular stresses. Protein arginine methyltransferases (PRMTs) are known to methylate histones and many cellular proteins involved in diverse processes such as DNA repair, transcription, and RNA processing. Here, we showed that inhibition of protein methyltransferases, especially arginine methyltransferases, prevents the induction of p21 and MDM2 as well as the repression of ECT2 in response to DNA damage, in a p53-dependent manner. To identify which arginine methyltransferase is required for p53 transcriptional activity, we generated multiple cell lines in which PRMT1, CARM1, or PRMT5 are inducibly knocked down by the tetracycline-inducible shRNA expression system in MCF7 breast adenocarcinoma cells. We found that PRMT1 and/or CARM1 knockdown has a limited effect on cell proliferation. In addition, PRMT1 and CARM1 deficiency do not have an effect on p53 stabilization and transcriptional activity upon DNA damage or MDM2 inhibition. However, we found that PRMT5 is required for cell proliferation. In addition, we showed that deficiency in PRMT5 leads to cell cycle arrest in G1. Interestingly, we also found that PRMT5 knockdown attenuates p53 stabilization upon DNA damage, leading to a decreased induction of MDM2 and p21. Taken together, we uncovered that the arginine methyltransferase family member PRMT5 has a pro-survival function and also acts as a novel modulator of p53 transcriptional activity.
Exhausted Central Memory and Memory Stem T Cells Specific for Leukemia Infiltrate the Bone Marrow of AML Patients Relapsing after Allogeneic HSCT
Authors: Francesco Manfredi, Maddalena Noviello, Eliana Ruggiero, Tommaso Perini, Giacomo Oliveira, Filippo Cortesi, Pantaleo De Simone, Cristina Toffalori, Valentina Gambacorta, Raffaella Greco, Jacopo Peccatori, Monica Casucci, Giulia Casorati, Paolo Dellabona, Nicoletta Cieri, Attilio Bondanza, Luca Vago, Fabio Ciceri, Chiara Bonini
Journal: Blood (2018)
Outcome of Immune Tolerance Induction Using an Extended Half-Life Clotting Factor Concentrate — Recombinant Factor VIII Fc (Eloctate™) — a Report from India
Authors: Aby Abraham, Shashikant Apte, Chandrakala Shamukhaiah, Fouzia N., Kannan Subramaniam, Akshata Rahate, Abraham Sunder Singh, Aditi Joshi, Kavitha M Lakshmi, Rajesh Phatale, Shrimati Shetty, Sukesh Chandran Nair, Biju George, Vikram Mathews, Alok Srivastava
Journal: Blood (2018)
SAT0068 Bilirubin promotes down-regulation of runx2 and up-regulation of rankl gene expression in bone explants and in osteoblastic and osteocytic cell lines
Authors: S. Ruiz-Gaspà, A. Parés, A. Combalia, P. Peris, A. Monegal, N. Guañabens
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> <i>In vitro</i> studies have shown that the retained substances of cholestasis have deleterious effects in human osteoblasts and osteocytic cells. Bilirubin (BIL) and lithocholic acid (LCA) induce alterations in the proliferation, differentiation and apoptosis of osteoblastic and osteocytic cells. However, their effects in human bone tissue and in bone cell lines have not been deeply analysed. <h3>Objectives</h3> To investigate the effects of BIL, LCA and ursodeoxycholic acid (UDCA) in gene expression of human trabecular bone explants as well as in osteoblastic (SAOS2) and osteocytic cells (MLO-Y4/MLO-A5). <h3>Methods</h3> Bone tissue harvested from trabecular bone fragments, SAOS2 and MLO-Y4/MLO-A5 cells were cultured and treated with BIL (50 µM), LCA (10 µM) and UDCA (10/100 µM) for 24 hour. Gene expression of osteocalcin (<i>BGLAP</i>), Cbfa1 (<i>RUNX2</i>)/Osterix (<i>OSX</i>) and RANKL (<i>TNFRSF11</i>)/osteoprotegerin (<i>TNFRSF11B</i>) were quantified by real time PCR. <h3>Results</h3> BIL diminishes <i>RUNX2</i> gene expression in bone tissue (−37%), SAOS2 (−75%), MLO-Y4 (−56%) and MLO-A5 (−77%), and increases <i>RANKL</i> expression in 60%, 27%, 72% and 60%, respectively (p≤0.02). In bone tissue and in osteoblastic and osteocytic cells, LCA increases gene expression of <i>BGLAP</i> (NS) and <i>RANKL</i> (p≤0.03). UDCA 100 µM increases <i>RUNX2</i> and <i>OSX</i> expression in bone tissue (78% and 82%), MLO-Y4 (72% and 80%) and SAOS2 (75% and 70%) (p≤0.03). In addition, UDCA 100 µM significantly increases expression of <i>BGLAP</i>, <i>OPG</i> and <i>RANKL</i> in bone tissue and in osteocytic lines. UDCA 10/100 µM counteracts the decrease in <i>RUNX2</i> induced by BIL in bone tissue, SAOS2, MLO-A5 and MLO-Y4 cells. <h3>Conclusions</h3> The retained substances of cholestasis, particularly bilirubin, cause noxious effects on transcription factors of osteoblast differentiation and on osteoclastic activators in bone tissue and in osteoblastic and osteocytic cells. Ursodeoxycholic acid reverses the harmful effects of bilirubin. These results provide new insights into the low bone formation and at some stages, high resorption, associated with chronic cholestasis. <h3>Disclosure of Interest</h3> None declared
SP0097 Check-point inhibitors: what are they used for, about side-effects and prediction of efficacy
Authors: E. Kapiteijn
Journal: Annals of the Rheumatic Diseases (2018)

<h3></h3> The development of immune checkpoint inhibitors targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) have significantly improved the treatment of a variety of metastasized cancers, such as melanoma, lung cancer, renal and bladder cancer. Immune checkpoint inhibitors enhance antitumor immunity by blocking negative regulators of T-cell function that exist both on immune cells and on tumour cells. Although these agents can lead to remarkable responses, their use can also be associated with unique immune-related adverse effects (irAEs). Consensus guidelines regarding the treatment of the most common irAEs including rash, colitis, hepatitis, endocrinopathies, and pneumonitis have been established. The mainstay of irAE treatment consists of immunosuppression with corticosteroids or other immunosuppressant agents such as infliximab; most irAEs will resolve with appropriate management. Nevertheless, a substantial proportion of patients treated with checkpoint inhibitors do not respond. Several markers have shown promising predictive value, including baseline and post-treatment changes in leucocyte counts, lactate dehydrogenase and C-reactive protein. To date, research on routinely available blood, biopsies and clinical markers has focused primarily on checkpoint inhibitors use in melanoma and lung cancer, but preliminary evidence is emerging for other cancer types. <h3>Disclosure of Interest</h3> None declared
Long‐Read RNA Sequencing Identifies Alternative Splice Variants in Hepatocellular Carcinoma and Tumor‐Specific Isoforms
Authors: Hui Chen, Feng Gao, Mian He, Xiao Fan Ding, Aikha M. Wong, Siu Ching Sze, Allen C. Yu, Tingting Sun, Anthony W‐H. Chan, Xin Wang, Nathalie Wong
Journal: Hepatology (2019)

Alternative splicing (AS) allows generation of cell type–specific mRNA transcripts and contributes to hallmarks of cancer. Genome‐wide analysis for AS in human hepatocellular carcinoma (HCC), however, is limited. We sought to obtain a comprehensive AS landscape in HCC and define tumor‐associated variants. Single‐molecule real‐time long‐read RNA sequencing was performed on patient‐derived HCC cells, and presence of splice junctions was defined by SpliceMap‐LSC‐IDP algorithm. We obtained an all‐inclusive map of annotated AS variants and further discovered 362 alternative spliced variants that are not previously reported in any database (neither RefSeq nor GENCODE). They were mostly derived from intron retention and early termination codon with an in‐frame open reading frame in 81.5%. We corroborated many of these predicted unannotated and annotated variants to be tumor specific in an independent cohort of primary HCC tumors and matching nontumoral liver. Using the combined Sanger sequencing and TaqMan junction assays, unique and common expressions of spliced variants including enzyme regulators (ARHGEF2, SERPINH1), chromatin modifiers (DEK, CDK9, RBBP7), RNA‐binding proteins (SRSF3, RBM27, MATR3, YBX1), and receptors (ADRM1, CD44v8‐10, vitamin D receptor, ROR1) were determined in HCC tumors. We further focused functional investigations on ARHGEF2 variants (v1 and v3) that arise from the common amplified site chr.1q22 of HCC. Their biological significance underscores two major cancer hallmarks, namely cancer stemness and epithelial‐to‐mesenchymal transition–mediated cell invasion and migration, although v3 is consistently more potent than v1. Conclusion: Alternative isoforms and tumor‐specific isoforms that arise from aberrant splicing are common during the liver tumorigenesis. Our results highlight insights gained from the analysis of AS in HCC.
FRI0415 Human skeletal muscle xenografts to model sporadic inclusion body myositis
Authors: K. Britson, K. Russell, K. Wagner, L.W. Ostrow, T.E. Lloyd
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Sporadic inclusion body myositis (IBM) is the most common acquired muscle disease in adults over the age of 50, yet the underlying cause of the disease is unknown, and there are no disease-modifying therapies<sup>1</sup>. The robust endomysial inflammation in addition to an increased association of IBM with specific HLA haplotypes and other autoimmune diseases suggests that IBM is primarily an autoimmune disease<sup>3</sup>. However, an association with ageing, a lack of response to immunotherapy, and presence of pathological features such as ubiquitinated protein aggregates seen in neurodegenerative diseases suggest the immune response may be secondary to myodegeneration. Thus, the relationship between inflammation, inclusions, and myodegeneration in IBM is poorly understood. <h3>Objectives</h3> Fundamental obstacles to therapeutic development for IBM include the limited understanding of disease pathogenesis as well as a lack of animal models. It is our objective to address these deficiencies by developing a novel mouse xenograft model of IBM. <h3>Methods</h3> In this xenograft model, human muscle biopsy specimens are transplanted into immunodeficient mice. The human myofibers cut during the biopsy procedure degenerate, but new muscle fibres regenerate from the patient's satellite cells. This newly regenerated muscle is revascularized and innervated by the mouse host<sup>2</sup>. Xenografts are collected at various post-operative timepoints ranging from three to eleven months and cryosectioned to carry out histochemical and immunohistochemical analysis. <h3>Results</h3> Our preliminary data show that IBM xenografts develop pathologic features of the human disease. At 4 months, collections of xenografts from a patient with healthy muscle, a dermatomyositis patient, and an IBM patient display successful regeneration. Regeneration appears less robust in IBM xenografts and is inversely associated with number of human CD3 +cells and sarcoplasmic MHC-I upregulation. A proportion of the CD8 +T cells within the IBM xenografts are proliferative at 4 months, and this is significantly reduced at 6 months (Fisher exact test, p&lt;0.0001). In addition, at 8.5 months, the IBM xenograft shows rare fibres containing p62 positive punta. <h3>Conclusions</h3> This xenograft model will allow us to investigate the interactions between human muscle and immune system in a mouse host. We are using this model for mechanistic studies and preclinical therapeutic testing in IBM. <h3>References</h3> [1] Dalakas MC. The New England journal of medicine2015;373:393–394. doi:10.1056/NEJMc1506827 [2] Zhang Y, et al. Human molecular genetics2014;23:3180–3188. doi:10.1093/hmg/ddu028 [3] Benveniste O, et al. Acta Neuropathol2015;129:611–624. doi:10.1007/s00401-015-1384-5 [4] Schmidt J, Dalakas MC. Expert review of clinical immunology2013;9:1125–1133. doi:10.1586/1744666X.2013.842467 <h3>Disclosure of Interest</h3> None declared
FRI0354 Urine metabolomic fingerprint as diagnostic biomarker for lupus nephritis
Authors: D.A. Herrera Van Oostdam, C. Abud Mendoza, R. Flores Ramírez, M. Rodríguez Aguilar, M. Pierdant Pérez, M.U. Martínez Martínez
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Lupus nephritis (LN) represents the main prognostic factor for worsening in systemic lupus erythematosus (LES).<sup>1</sup> The relevant classes of LN –due to the need of treatment- are the proliferative (III, IV, III/IV+V) and membranous (V). <h3>Objectives</h3> The aim of the study was to find a urinary metabolomic fingerprint to diagnose proliferative and/or membranous LN. <h3>Methods</h3> Cross-sectional study. Inclusion criteria: lupus patients with and without clinical significant lupus nephritis (classes III, IV, V and mixed classes). Urine samples were screened for metabolites using gas chromatography mass spectrometry (coupled with electronic nose). Statistical analysis: principal component analysis (PCA), and for the selection of the metabolites we used Random Forest. <h3>Results</h3> We included 29 lupus patients, 11 with LN. The median SLEDAI score in LN patients was of 13 vs. 3 in those without NL (p&lt;0.0001). Class IV nephritis was present in 45%, mixed class in 36%, and class V in 18%. The median proteinuria of patients with NL was 1 g/L, (IQR 2.7). The variance explained using the first two principal components was 80%. With random forest we selected, 2 nonanone, as the metabolite with the best diagnostic accuracy, (sensitivity of 0.87 and specificity of 0.93) of proliferative LN. Obtaining the ratio of 2-bromopropane/2-nonanone, the diagnostic accuracy improved, with a positive likelihood ratio (LR) of 14 and a negative LR of 0.1(AUC 90%). Metabolic pathways involved in LN were: methane, glycolysis, pyruvate and glycerophospholipid pathways. <h3>Conclusions</h3> We identified a urinary metabolomic fingerprint that involved several metabolic pathways; 2-nonanone and the ratio of 2- bromopropane/2- nonanone had the best diagnostic accuracy in our study. <h3>Reference</h3> [1] Mok CC, et al. Arthritis Rheum2013;5:2154–2160. <h3>Disclosure of Interest</h3> None declared