tbuckley/cabot-search huggingface dataset:
The Network of Cancer Genes (NCG): a comprehensive catalogue of known and candidate cancer genes from cancer sequencing screens
Authors: Dimitra Repana, Joel Nulsen, Lisa Dressler, Michele Bortolomeazzi, Santhilata Kuppili Venkata, Aikaterini Tourna, Anna Yakovleva, Tommaso Palmieri, Francesca D. Ciccarelli
Journal: Genome biology (2019)

The Network of Cancer Genes (NCG) is a manually curated repository of 2372 genes whose somatic modifications have known or predicted cancer driver roles. These genes were collected from 275 publications, including two sources of known cancer genes and 273 cancer sequencing screens of more than 100 cancer types from 34,905 cancer donors and multiple primary sites. This represents a more than 1.5-fold content increase compared to the previous version. NCG also annotates properties of cancer genes, such as duplicability, evolutionary origin, RNA and protein expression, miRNA and protein interactions, and protein function and essentiality. NCG is accessible at http://ncg.kcl.ac.uk/ .
FRI0219 CD4+CD25+FOXP3+ REGULATORY T CELLS IN SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS: THE NEGATIVE ASSOCIATION WITH DISEASE ACTIVITY, ACUTE COURSE, TRANSITIONAL B CELLS AND IGG LEVELS
Authors: Elena Aleksandrova, Anna Mesnyankina, Alexander Novikov, Andrey Aleksankin, Sergey Solovyev, Galina Lukina
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> CD4+ CD25+ Foxp3+ regulatory T (Treg) cells play a key role in maintaining peripheral tolerance and preventing autoimmune disease. Quantitative and/or qualitative deficiencies of Treg have been associated with immune disturbances in systemic lupus erythematosus (SLE). <h3>Objectives</h3> The main goal of the study was to determine the relationship of CD4+CD25+FoxP3+Treg cells with clinical and immunological manifestations in SLE patients (pts). <h3>Methods</h3> Frequencies and absolute numbers of peripheral blood CD4+CD25+FoxP3+Treg cells were assessed in 21 healthy donors and 20 SLE pts (2012 SLICC classification criteria); (1M/19F); age 32±13 years; disease duration median (25–75 percentile) 5(1-10) years; SLEDAI2K≥10 - 15(10-22) (14 pts), &lt;10 – 7(6-8) (6 pts). All pts were treated with prednisone, hydroxychloroquine, azathioprine, mycophenolate mofetil, clophosphamide. CD4+CD25+FoxP3+ Treg cells and B-cell subsets were analyzed using multicolor flow cytometry. <h3>Results</h3> Compared with healthy donors, SLE pts demonstrated significant lower the absolute number of Tregs (0.05; 0.04-0.06 vs 0.03;0.02-0.05x10<sup>9</sup>/L, p&lt;0,036), with a high percentage of Treg (8.8;7.5-10.5 vs 12.0;8.8-17.0%, p&lt;0.02). The median percentage of Tregs was lower in pts with acute SLE compared to chronic SLE pts (9.0;8.3-9.9 vs 13.5;12.7-18.7%, p&lt;0,02). SLE pts with high activity had a lower frequencies of Tregs (10.2;8.5-15.0 vs 15.8;12.7-20.4%, r=-0,51, p&lt;0,05). Low count of Tregs correlated with elevated level of IgG (r=-0,52, p&lt;0,05). Absolute number of Tregscorrelated negatively with percentage and absolute count of transitional (CD19+IgD+CD10+CD38++CD27-) B cells (r=-0,66 and r=-0,63, p&lt;0,05). <h3>Conclusion</h3> Decreased amount of T regs in SLE is associated with high disease activity, acute course and expansion of autoreactive B cells. <h3>References</h3> [1] Zhang SX, Ma XW, Li YF, Lai NL, Huang ZH, Fan K, Wang CH, Li XF. The Proportion of Regulatory T Cells in Patients with Systemic Lupus Erythematosus: A Meta-Analysis. J Immunol Res. 2018 Sep 3;2018:7103219. doi: 10.1155/2018/7103219. [2] Żabińska M, Krajewska M, Kościelska-Kasprzak K, Jakuszko K, Bartoszek D, Myszka M, Klinger M. CD4(+)CD25(+)CD127(-) and CD4(+)CD25(+)Foxp3(+) Regulatory T Cell Subsets in Mediating Autoimmune Reactivity in Systemic Lupus Erythematosus Patients. Arch Immunol Ther Exp (Warsz). 2016 Oct;64(5):399-407. doi: 10.1007/s00005-016-0399-5. <h3>Disclosure of Interests</h3> None declared
Splatter: simulation of single-cell RNA sequencing data
Authors: Luke Zappia, Belinda Phipson, Alicia Oshlack
Journal: Genome biology (2017)

As single-cell RNA sequencing (scRNA-seq) technologies have rapidly developed, so have analysis methods. Many methods have been tested, developed, and validated using simulated datasets. Unfortunately, current simulations are often poorly documented, their similarity to real data is not demonstrated, or reproducible code is not available. Here, we present the Splatter Bioconductor package for simple, reproducible, and well-documented simulation of scRNA-seq data. Splatter provides an interface to multiple simulation methods including Splat, our own simulation, based on a gamma-Poisson distribution. Splat can simulate single populations of cells, populations with multiple cell types, or differentiation paths.
SAT0366 GENDER DIFFERENCES IN PSORIATIC ARTHRITIS – IMPACT ON TUMOR NECROSIS FACTOR INHIBITORS PERSISTENCE AND RESPONSE
Authors: Elsa Vieira-Sousa, Mónica Eusébio, Pedro Ávila-Ribeiro, Nikita Khmelinskii, Ana Rita Cruz-Machado, Teresa Martins-Rocha, Miguel Bernardes, Daniela Faria, Joana Silva, Helena Santos, Claudia Miguel, Pedro Carvalho, Tiago Costa, Lídia Teixeira, Tiago Meirinhos, Patrícia Nero, Joao Eurico Fonseca, Maria Jose Santos
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> The impact of gender on tumor necrosis factor inhibitors (TNFi) effectiveness has been poorly studied in Psoriatic Arthritis (PsA) patients. <h3>Objectives:</h3> To study gender differences in persistence and response of 1<sup>st</sup> TNFi in PsA patients. <h3>Methods:</h3> PsA patients prospectively followed at the Rheumatic Diseases Portuguese Registry (Reuma.pt), treated with a 1<sup>st</sup> TNFi, between 2001 and 2016. Drug retention assessed by Kaplan-Meier survival analysis and Cox models, adjusted for the year of starting a TNFi. Response rates measured by EULAR response, DAPSA remission, MDA and ASDAS response, applying LUNDEX method, were compared between genders. Baseline predictors of discontinuation and response were identified (Cox and logistic regression models). <h3>Results:</h3> 750 PsA patients, mean age 47.6 (± 11.6) years and 50.3% (n=377) females. PsA females showed significantly different baseline PsA disease characteristics in comparison with males and had more severe peripheral disease activity (Table 1). The overall TNFi survival rate for females was also significantly lower when compared with males (Figure 1). Additionally, females experienced lower rates of response at 3 and 6 months (Figure 2). Female gender was further identified as an independent predictor factor of worse persistence and showed a lower chance of good EULAR response. <h3>Conclusion:</h3> PsA females from Reuma.pt have distinct PsA features and worse persistence and response to a 1<sup>st</sup> TNFi in comparison with males. This might be related to gender dependent inflammatory pathways and was independent of baseline disease activity. <h3>Disclosure of Interests:</h3> Elsa Vieira-Sousa Grant/research support from: MSD, Novartis, Mónica Eusébio: None declared, Pedro Ávila-Ribeiro: None declared, Nikita Khmelinskii: None declared, Ana Rita Cruz-Machado: None declared, Teresa Martins-Rocha: None declared, Miguel Bernardes: None declared, Daniela Faria: None declared, Joana Silva: None declared, Helena Santos: None declared, Claudia Miguel: None declared, Pedro Carvalho: None declared, Tiago Costa: None declared, Lídia Teixeira: None declared, Tiago Meirinhos: None declared, Patrícia Nero: None declared, Joao Eurico Fonseca: None declared, Maria Jose Santos: None declared
Abstract 10281: Cangrelor’s Anti-Infarct Effect Requires Phosphorylation of Sphingosine in Platelets: The Missing Link
Authors: Michael V Cohen, Xi-Ming Yang, James White, Derek Yellon, Robert Bell, James M Downey
Journal: Circulation (2015)

Patients with myocardial infarction routinely receive a platelet P2Y12 receptor antagonist prior to percutaneous coronary intervention. In monkeys, rabbits, and rats P2Y12 antagonists act as potent postconditioning-mimetics. Unlike ischemic postconditioning, however, the P2Y12 antagonist cangrelor could not reduce infarct size in Krebs buffer-perfused hearts. We tested whether platelets were required for protection from cangrelor. Rats were treated with intraperitoneal placebo or anti-rat thrombocyte serum (ARTS), 0.5ml, which decreased platelet counts by at least 96%. After 24h the heart was exposed and left coronary artery occluded for 30min and reperfused for 2h. Risk zone and infarct size were measured. In placebo rats infarct size averaged 45.3±1.2% of risk zone, while an intravenous bolus of cangrelor, 60μg/kg, 10 min before reperfusion followed by infusion of 6μg/kg/min decreased infarction to 25.0±1.8% (p&lt;0.001). ARTS alone had no effect on infarct size (50.5±3.7%). However, ARTS blocked cangrelor’s protective effect (48.4±3.4% infarction). Hence cangrelor’s cardioprotective effect depends on platelets. But how can cangrelor cause platelets to trigger postconditioning’s protective signaling? Activated platelets release sphingosine -1 phosphate (S1P), a known trigger for conditioning. Some of the S1P from platelets comes from a sphingomyelinase that is recruited during activation and catabolizes membrane sphingomyelin to sphingosine (sph) which is quickly phosphorylated by sph kinases. We blocked sph kinase with intravenous N-N-dimethylsphingosine (DMS), 0.33 mg/kg, administered 15 min after coronary occlusion. DMS alone had no effect on infarction (43.8±2.3%). But it abrogated cangrelor’s protective effect (42.8±2.0%). In the presence of cangrelor platelets can’t aggregate and plug vascular defects caused by ischemic injury. We propose that in cangrelor-treated post-ischemic hearts platelets enter the interstitial space early in reperfusion and release S1P when they contact collagen which postconditions the heart and protects against reperfusion injury. Thus blocking aggregation allows platelets to produce a pharmacological trigger of postconditioning that reduces infarction.
Estimating Time to the Common Ancestor for a Beneficial Allele
Authors: Joel Smith, Graham Coop, Matthew Stephens, John Novembre
Journal: Molecular Biology and Evolution (2018)

The haplotypes of a beneficial allele carry information about its history that can shed light on its age and the putative cause for its increase in frequency. Specifically, the signature of an allele's age is contained in the pattern of variation that mutation and recombination impose on its haplotypic background. We provide a method to exploit this pattern and infer the time to the common ancestor of a positively selected allele following a rapid increase in frequency. We do so using a hidden Markov model which leverages the length distribution of the shared ancestral haplotype, the accumulation of derived mutations on the ancestral background, and the surrounding background haplotype diversity. Using simulations, we demonstrate how the inclusion of information from both mutation and recombination events increases accuracy relative to approaches that only consider a single type of event. We also show the behavior of the estimator in cases where data do not conform to model assumptions, and provide some diagnostics for assessing and improving inference. Using the method, we analyze population-specific patterns in the 1000 Genomes Project data to estimate the timing of adaptation for several variants which show evidence of recent selection and functional relevance to diet, skin pigmentation, and morphology in humans.
CRISPR-Pass: Gene Rescue of Nonsense Mutations Using Adenine Base Editors
Authors: Choongil Lee, Dong Hyun Jo, Gue-Ho Hwang, Jihyeon Yu, Jin Hyoung Kim, Se-eun Park, Jin-Soo Kim, Jeong Hun Kim, Sangsu Bae
Journal: Molecular Therapy (2019)

A nonsense mutation is a substitutive mutation in a DNA sequence that causes a premature termination during translation and produces stalled proteins, resulting in dysfunction of a gene. Although it usually induces severe genetic disorders, there are no definite methods for inducing read through of premature termination codons (PTCs). Here, we present a targeted tool for bypassing PTCs, named CRISPR-pass, that uses CRISPR-mediated adenine base editors. CRISPR-pass, which should be applicable to 95.5% of clinically significant nonsense mutations in the ClinVar database, rescues protein synthesis in patient-derived fibroblasts, suggesting potential clinical utility. A nonsense mutation is a substitutive mutation in a DNA sequence that causes a premature termination during translation and produces stalled proteins, resulting in dysfunction of a gene. Although it usually induces severe genetic disorders, there are no definite methods for inducing read through of premature termination codons (PTCs). Here, we present a targeted tool for bypassing PTCs, named CRISPR-pass, that uses CRISPR-mediated adenine base editors. CRISPR-pass, which should be applicable to 95.5% of clinically significant nonsense mutations in the ClinVar database, rescues protein synthesis in patient-derived fibroblasts, suggesting potential clinical utility.
SAT0383 COMPARISON OF THE EFFICACY AND SAFETY OF TOFACITINIB AND APREMILAST IN PATIENTS WITH ACTIVE PSORIATIC ARTHRITIS: A BAYESIAN NETWORK META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS
Authors: Young Ho Lee, Gwan Gyu Song
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> The therapeutic options for psoriatic arthritis (PsA) include conventional disease-modifying antirheumatic drugs and biologics. However, an unmet need exists for PsA therapies owing to drug intolerance, non-responsiveness, and therapeutic resistance. Therefore, there is a need for additional treatment options with novel mechanisms of action. Tofacitinib is an orally administered JAK inhibitor and apremilast is a novel oral phosphodiesterase 4 inhibitor that regulates inflammatory mediators. <h3>Objectives:</h3> The aim of this study is to assess the relative efficacy and safety of tofacitinib and apremilast at different doses in patients with active PsA. <h3>Methods:</h3> We conducted a Bayesian network meta-analysis to combine evidence from randomized controlled trials (RCTs) for examination of the efficacy and safety of tofacitinib 10 mg, tofacitinib 5 mg, apremilast 30 mg, and apremilast 20 mg in PsA. <h3>Results:</h3> Eight RCTs including 3,086 patients met the inclusion criteria. There were 10 pairwise comparisons including 6 direct comparisons of 5 interventions. All the interventions achieved a significant American College of Rheumatology 20 (ACR20) response compared with placebo. Tofacitinib 10 mg and apremilast 30 mg were among the most effective treatments for active PsA, followed by tofacitinib 5 mg, and apremilast 20 mg. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that tofacitinib 10 mg had the highest probability of being the best treatment in terms of the ACR20 response rate (SUCRA = 0.785), followed by apremilast 30 mg (SUCRA = 0.670), tofacitinib 5 mg (SUCRA = 0.596), apremilast 20 mg (SUCRA = 0.448), and placebo (SUCRA = 0.001). No significant differences were observed in the incidence of serious adverse events after treatment with tofacitinib 10 mg, apremilast 30 mg, tofacitinib 5 mg, apremilast 20 mg, or placebo. <h3>Conclusion:</h3> In active PsA patients, tofacitinib 10 mg and apremilast 30 mg were the most efficacious interventions and were not associated with a significant risk of serious adverse events. <h3>References</h3> [1] Mease P, Hall S, FitzGerald O, et al. (2017) Tofacitinib or Adalimumab versus Placebo for Psoriatic Arthritis. N Engl J Med 377:1537-1550 [2] Gladman D, Rigby W, Azevedo VF, et al. (2017) Tofacitinib for Psoriatic Arthritis in Patients with an Inadequate Response to TNF Inhibitors. N Engl J Med 377:1525-1536 [3] Schafer P (2012) Apremilast mechanism of action and application to psoriasis and psoriatic arthritis. Biochemical pharmacology 83:1583-1590 <h3>Disclosure of Interests:</h3> None declared
THU0429 DISEASE BURDEN OF PERSONS WITH OSTEOARTHRITIS: RESULTS OF A CROSS-SECTIONAL ANALYSIS FROM A SURVEY LINKED TO CLAIMS DATA IN THE PROCLAIR PROJECT
Authors: Johanna Callhoff, Katinka Albrecht, Imke Redeker, Toni Lange, Jens Goronzy, Klaus-Peter Günther, Angela Zink, Jochen Schmitt, Anne Postler
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Osteoarthritis (OA) is a major reason for chronic pain, stiffness and functional limitation. While disease burden is frequently examined prior to surgery in knee and hip OA, burden in patients with unknown indication of joint surgery and the impact of polyarticular involvement are less often studied. <h3>Objectives</h3> The aim was to analyze factors associated with the burden of OA, taking the pattern of joint involvement into account. <h3>Methods</h3> From a random sample of 8,995 persons with OA (ICD-10 codes M15 [polyarticular], M16 [hip] or M17 [knee]) from a large German statutory health insurance, 3,564 persons completed a questionnaire including the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Persons with knee, hip, concomitant knee and hip or polyarticular manifestation were compared concerning pain, stiffness, function, and impact on work/personal life, excluding asympomatic OA. Data were linked to dispensation records. The association of age, gender, BMI, symptom duration and WHO-5 with the WOMAC was assessed in multiple linear regression models. <h3>Results</h3> Persons with symptomatic knee (1,130), hip (538), knee and hip (131) and polyarthritic (653) OA were included. Concomitant knee and hip OA was accompanied with the highest WOMAC values (mean 51), frequent impairment on work (66%) and personal life (87%) and the highest use of analgesics (60% NSAIDs, 25% opioids and 40% others). In the regression analyses, BMI per 5 units and WHO-5 per 10% worsening were associated with an increase in WOMAC values of 3-4 points, irrespective of the joint manifestations. <h3>Conclusion</h3> Disease burden is high in persons with concomitant knee and hip OA, going along with frequent prescription of analgesics. The pattern of joint affection, BMI and depressive symptoms need to be considered when using the WOMAC as an outcome instrument. <h3>Acknowledgement</h3> This study was funded by the German Federal Ministry of Education and Research (01EC1405). <h3>Disclosure of Interests</h3> Johanna Callhoff: None declared, Katinka Albrecht: None declared, Imke Redeker: None declared, Toni Lange: None declared, Jens Goronzy: None declared, Klaus-Peter Günther: None declared, Angela Zink Speakers bureau: Speakers fees from AbbVie, Janssen, Pfizer, Roche, Sanofi, Jochen Schmitt: None declared, Anne Postler: None declared
Abstract 16962: Myocardial Creatine is Reduced in Obese Adults Despite Preserved Ejection Fraction and Global Longitudinal Shortening: A Cardiac Chemical Exchange Saturation Transfer MRI Study
Authors: Wissam AlGhuraibawi, Rebecca Kidney, Steve Leung, Tori Stromp, Moriel Vandsburger
Journal: Circulation (2017)

Introduction: Heart failure with preserved ejection fraction (HFpEF) is common in obese adults, yet little is known about corresponding changes in metabolic function. Compromised creatine (Cr) kina...
Daratumumab Combined with Pomalidomide and Dexamethasone (DPd) for Patients with Relapsed/Refractory Multiple Myeloma in a Single Institution
Authors: Al-Ola Abdallah, Joseph P. McGuirk, Leyla Shune, Neil Dunavin, Zahra Mahmoudjafari, Erica Hochard, Siddhartha Ganguly
Journal: Blood (2017)
THU0115 IS INCIDENT RHEUMATOID ARTHRITIS INTERSTITIAL LUNG DISEASE ASSOCIATED WITH METHOTREXATE TREATMENT? RESULTS FROM A MULTIVARIATE ANALYSIS IN THE ERAS AND ERAN INCEPTION COHORTS:
Authors: KIELY Patrick, Amanda Busby, Elena Nikiphorou, Keith Sullivan, Adam Young
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Rheumatoid arthritis interstitial lung disease (RA-ILD) is a rare but significant manifestation of RA, with high mortality. Methotrexate (MTX) is known to cause hypersensitivity pneumonitis, but its effect on the onset of RA-ILD is less clear. <h3>Objectives</h3> To assess predictive factors for rheumatoid arthritis interstitial lung disease (RA-ILD) in two early RA inception cohorts with a focus on MTX exposure. <h3>Methods</h3> Patients with new diagnosis of RA recruited to the early RA study (ERAS) and the early RA network (ERAN). Standardised data including demographics, drug therapies and clinical outcomes including the presence of RA-ILD were collected at baseline, within 3- 6 months, at 12 months and annually for up to 25 years thereafter. Primary outcome was the association of MTX exposure with incident RA-ILD. Secondary outcomes were the association of demographic, comorbid and RA specific factors on incident RA-ILD using univariate and multivariate analyses and the association of MTX exposure on time to RA-ILD diagnosis using time to event Cox proportional hazards analysis. <h3>Results</h3> Of 92 eligible ILD cases, 39 occurred in 1578 (2.5%) MTX exposed and 53 in 1114 (4.8%) non-MTX exposed cases. The primary analysis of incident RA-ILD cases only developing after any csDMARD treatment (n=67) showed MTX exposure not to be associated with incident RA-ILD (O.R. 0.85 CI 0.49, 1.49 p=0.578) and a non-significant trend for delayed ILD diagnosis (O.R. 0.54 CI 0.28, 1.06 p=0.072) (see Figure). In an extended analysis including all RA-ILD cases (n=92, including those present pre csDMARD exposure), MTX exposure was associated with a significantly reduced risk of incident RA-ILD (O.R. 0.48, CI 0.3, 0.79 p=0.004) and longer time to ILD diagnosis (O.R. 0.41, CI 0.23, 0.75 p=0.004). Other independent baseline associations with incident RA-ILD were higher age of RA onset, ever smoking, male gender, rheumatoid nodules and longer time from first RA symptom to first out-patient visit (see Table). <h3>Conclusion</h3> In ERAS/ERAN, incident RA-ILD is significantly associated with older age of RA onset, ever smoking, nodules, RF positivity, male gender, ESR, and a longer time from first RA symptoms to first secondary care visit. There is no association between MTX treatment and incident RA-ILD. MTX may have a protective role in delaying the onset of RA-ILD. <h3>Acknowledgement</h3> All recruiting ERAS and ERAN&nbsp;centers <h3>Disclosure of Interests</h3> Patrick KIELY Paid instructor for: Amgen, Gilead, BMS, Speakers bureau: Abbvie, BMS, UCB, Lilly, Pfizer, Amanda Busby: None declared, Elena Nikiphorou: None declared, Keith Sullivan: None declared, Adam Young: None declared