tbuckley/cabot-search huggingface dataset:
Many Options, Few Solutions: Over 60 My Snakes Converged on a Few Optimal Venom Formulations
Authors: Agneesh Barua, Alexander S Mikheyev
Journal: Molecular Biology and Evolution (2019)

Abstract Gene expression changes contribute to complex trait variations in both individuals and populations. However, the evolution of gene expression underlying complex traits over macroevolutionary timescales remains poorly understood. Snake venoms are proteinaceous cocktails where the expression of each toxin can be quantified and mapped to a distinct genomic locus and traced for millions of years. Using a phylogenetic generalized linear mixed model, we analyzed expression data of toxin genes from 52 snake species spanning the 3 venomous snake families and estimated phylogenetic covariance, which acts as a measure of evolutionary constraint. We find that evolution of toxin combinations is not constrained. However, although all combinations are in principle possible, the actual dimensionality of phylomorphic space is low, with envenomation strategies focused around only four major toxin families: metalloproteases, three-finger toxins, serine proteases, and phospholipases A2. Although most extant snakes prioritize either a single or a combination of major toxin families, they are repeatedly recruited and lost. We find that over macroevolutionary timescales, the venom phenotypes were not shaped by phylogenetic constraints, which include important microevolutionary constraints such as epistasis and pleiotropy, but more likely by ecological filtering that permits a small number of optimal solutions. As a result, phenotypic optima were repeatedly attained by distantly related species. These results indicate that venoms evolve by selection on biochemistry of prey envenomation, which permit diversity through parallelism, and impose strong limits, since only a few of the theoretically possible strategies seem to work well and are observed in extant snakes.
Final analysis from RESONATE: Six-year follow-up in patients (pts) with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) on ibrutinib.
Authors: Paul M. Barr, Talha Munir, Jennifer R. Brown, Susan Mary O'Brien, Jacqueline Claudia Barrientos, Nishitha M. Reddy, Steven Coutre, Constantine Si Lun Tam, Stephen P. Mulligan, Ulrich Jäger, Thomas J. Kipps, Carol Moreno, Marco Montillo, Jan Andreas Burger, John C. Byrd, Peter Hillmen, Sandra Dai, Anita Szoke, James P. Dean, Jennifer Ann Woyach
Journal: Journal of Clinical Oncology (2019)

7510 Background: Ibrutinib (ibr), a first-in-class, once-daily Bruton’s tyrosine kinase inhibitor, has redefined treatment paradigms for CLL/SLL. We report final analysis with up to 6 years of follow-up on ibr from the phase 3 RESONATE study of single-agent ibr vs ofatumumab (ofa) in pts with relapsed/refractory (R/R) CLL/SLL. Methods: Pts were randomized to receive oral ibr 420 mg daily until PD or intravenous ofa for up to 24 weeks. Long-term efficacy endpoints were investigator-assessed. Results: Among 391 pts randomized to receive ibr (n=195) or ofa (n=196), 86% and 79%, respectively, were in the genomic high-risk population (del(17p), del(11q), TP53 mutation, and/or unmutated IGHV). At final analysis, median follow-up was 64 mo (range, 0.3-72) on ibr. Of pts randomized to ofa, 68% crossed over to receive ibr. Significant sustained PFS benefit was observed with ibr vs ofa, with median PFS 44.1 vs 8.1 mo (HR 0.15; 95% CI 0.11-0.20; P˂0.0001) and was consistent across baseline subgroups. Median PFS in genomic high-risk population was 44.1 vs 8.0 mo on ibr vs ofa (HR 0.11; 95% CI 0.08-0.15). ORR with ibr was 88% (CR/CRi in 11%). Initial ibr treatment conferred better OS than ofa when censored for crossover (HR 0.64; 95% CI 0.42-0.98). Median duration of ibr was 41 mo (range 0.2-71); 41% of pts received ibr &gt;4 yrs. AE profile with ibr remained consistent with prior reports. Cumulatively during long-term ibr therapy, all-grade (grade ≥3) hypertension and atrial fibrillation occurred in 21% (9%) and 12% (6%) of pts, respectively; major hemorrhage occurred in 10%. Most common reasons for ibr discontinuation (DC) prior to study closure were PD (37%) and AEs (16%); DC due to AEs occurred in 6%, 3%, 4%, 4%, 6% and 4% of pts during yrs 0-1, 1-2, 2-3, 3-4, 4-5 and 5-6, respectively. Conclusions: With up to 6 years of follow-up, extended ibr treatment showed sustained efficacy in pts with R/R CLL, including in pts with high-risk genomic features. Safety remained acceptable with low rates of DC due to AEs, and with no new safety signals over long-term therapy. These results establish long-term benefit and tolerability for continuous ibr treatment in pts with R/R CLL. Clinical trial information: NCT01578707.
AB0917 PATTERN OF SERUM CHOLECALCIFEROL (VITAMIN D3) LEVEL AMONG THE FEMALE IN RELATION TO CLOTHING’S
Authors: Mohammad Abdur Razzaque, Mirza Nurul Karim, Rajat Sanker Roy Biswas, Nazrul Islam, Satyajit Mallick
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Both clinical and subclinical low level vitamin D is common<sup>1</sup>. Various kinds of health hazard including musculoskletal symptoms are frequently seen among the Vitamin D deficients. It is also not uncommon even in a sunny country. Lack of sun exposure, particularly female using veil may be an important cause. <h3>Objectives</h3> To assess the relationship between using veil and serum vitamin D<sub>3</sub> (cholecalciferol) level <h3>Methods</h3> This prospective cross-sectional descriptive study was conducted during July 2017 to June 2018. Patients with common complaints related to lack of Vitamin D (muscle cramp, myalgia, fatigue, bone pain, generalized weakness, difficulty in getting up, climbing stairs and pain in weight bearing joints) were enrolled. Patient having other disease were excluded from study. Serum cholecalciferol was measured for each patient. Race, occupation, educational status, skin complexion, body mass index, sunlight exposure, covering of body with clothing's and use of sunscreen were taken under consideration in final analysis. Correlation of serum cholecalciferol level with different types of veils (Burkha, halve sleeve, full sleeve, quarter sleeve and Hijab) of individual's was analyzed. <h3>Results</h3> A total 79 female patients were enrolled after screening 108. All of them were of multi-ethnic Asian origin. Age distribution of them is 17 to 39 years 34.2%, 40 to 50 years 38%, 51 to 70 years 26.6% and above 70 years 1.3%. Maximum (93.7%) of them were house wife, 91.1% had no adequate sun exposure and 81% had no skin exposure to sunlight. Among clothing 79.7% used Burkha, 5.1% halve sleeve, 2.5% full sleeve and 12.7% quarter sleeve. Among Burkha 28.6% (18), 55.6% (35) &amp; 15.9% (10) and among quarter sleeve 50% (5), 40% (4) &amp; 10% (1) had deficient, insufficient &amp; sufficient vitamin D level respectively while 2 (100%) female with full sleeve and 4 (100%) female with halve sleeve had deficient and insufficient vitamin D level respectively. The cholecalciferol level among the users of veil is shown in Table-1. There was no significant difference between different types of clothing's (Table: 2). <h3>Conclusion</h3> Main source of Vitamin D is sunlight. Proper exposure to sunlight is essential for adequate vitamin D level even in a sunny country. Regarding in vitamin D absorption from sunlight, there may be no difference between Burkha and other covered dressings. Further study needed to have a conclusion. <h3>Reference</h3> [1] Jones AN, Hansen KE. Recognizing the musculoskeletal manifestations of vitamin D deficiency.J Musculoskelet Med. 2009; 26(10): 389 – 96. <h3>Disclosure of Interests</h3> None declared
AB1356-HPR PHYSICAL ACTIVITY BEFORE, DURING AND AFTER PREGNANCY IN WOMEN WITH SPONDYLOARTHRITIS – DATA FROM REVNATUS
Authors: Bente Jakobsen, Hege Svean Koksvik
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> There are no known studies on physical activity (PA) in pregnancy for women with spondyloarthritis (SpA). PA is an essential and well-documented part of treatment for SpA [1]. The Norwegian Mother and Child Cohort Study (MoBa) found that established regular exercise routines pre-pregnancy was the strongest correlate of regular exercise during pregnancy [2]. A Swedish study of patients with SpA has shown that only 7 out of 10 patients with SpA meet the World Health Organization (WHO) recommendations of PA [3]. In MoBa 46.4% were regular exercisers (≥ 3 times a week) before pregnancy, while 25% were non-exercisers (≤ 3 times a month). At pregnancy week 17, 28% were regular exercisers, and 41% were non-exercisers.By pregnancy week 30, only 20% were still regular exercisers and 53% were non-exercisers [2]. <h3>Objectives</h3> To describe the level of PA before, during and after pregnancy for Norwegian women with SpA. <h3>Methods</h3> Women with SpA (ICD-10 M45, M46.1, M46.8 and M46.9) enrolled in the Norwegian nationwide quality register RevNatus that have self-report their level of PA, are included. Data from seven time points are presented. <h3>Results</h3> BASDAI - Bath Ankylosing Spondylitis Disease Activity Index, BMI body mass index, VAS visual analogue scale <h3>Conclusion</h3> During pregnancy, the percentage of women with SpA in the non-exercising group are increasing. The percentage of regular exercisers is lower 12 months after delivery than pre-pregnancy. Throughout the seven time points, 68 91% of the women with SpA do not fulfil the WHO recommendations for PA. PA should be an integral part of standard care throughout the course of disease for people with SpA and healthcare providers should take responsibility for promoting it and make necessary referrals to ensure that people with SPA receive appropriate PA-interventions [1]. <h3>References</h3> [1] Rausch Osthoff, A.K., et al., 2018 EULAR recommendations for physical activity in people with inflammatory arthritis and osteoarthritis. Ann Rheum Dis, 2018. 77(9): p. 1251-1260. [2] Owe, K.M., W. Nystad, and K. Bo, Correlates of regular exercise during pregnancy: the Norwegian Mother and Child Cohort Study. Scand J Med Sci Sports, 2009. 19(5): p. 637-45. [3] Haglund, E., et al., Differences in physical activity patterns in patients with spondylarthritis. Arthritis Care Res (Hoboken), 2012. 64(12): p. 1886-94. <h3>Disclosure of Interests</h3> None declared
SP0104 THE JANUS-FACED GLADIATOR: NEUTROPHILS IN STERILE INFLAMMATION AND AUTOIMMUNITY
Authors: Markus Hoffmann
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Neutrophils, and particularly neutrophil extracellular traps (NETs), have been connected with inflammatory and autoimmune diseases, such as RA, SLE, gout and many others. However, the outcome of a deficiency of NET-formation can be observed in chronic granulomatous disease and Papillon-Lefèvre syndrome and is characterized by non-resolving inflammation and frequent autoimmunity. <h3>Objectives:</h3> I will give an overview over pro- and anti-inflammatory effects of neutrophils and NETs, respectively, focusing on our results in gout and SLE. <h3>Methods:</h3> We investigated the impact of NET-deficiency and/or neutrophil-depletion on animal models of SLE (pristane-induced lupus) and gout (MSU crystal-induced arthritis). Mechanistic studies were performed with isolated neutrophils from mice and humans. <h3>Results:</h3> In experimental lupus and gouty arthritis neutrophil depletion or neutropenia worsens disease. Also mice strains with normal neutrophil numbers but defects in NET formation (NOX2 or PAD4-defieicnet mice) have exacerbated and unresolving inflammation. Release of inflammatory mediators by stimulated neutrophils was highest at intermediate cell densities (20–40 × 10<sup>6</sup> cells/cm<sup>3</sup>). Above such densities, mediator release by normal neutrophils was outweighed by proteolytic degradation via proteases expressed on aggregated NETs. Additionally, binding to aggregated NETs conferred protection of the serine protease neutrophil elastase (NE) against inactivation by α1-antitrypsin (A1AT). <h3>Conclusion:</h3> Although neutrophils are often regarded as archetypical pro-inflammatory cells, evidence is increasing that they can also exert anti- inflammatory and immunoregulatory function. Formation and aggregation of NETs and degradation of inflammatory mediators by serine proteases are important neutrophil tools to resolve gouty arthritis and other forms of localized inflammatory conditions. On the downside, NETs come at the price of collateral tissue damage and may cause occlusion of ductal structures. <h3>References:</h3> [1] Schauer, et al. Nature Med 2014, 20(5):511-7. [2] Kienhöfer et al. JCI Insight, 2(10). [3] Hahn et al. FASEB J 2019, 33(1):1401-1414. <h3>Disclosure of Interests:</h3> None declared
PS1287 INVASIVE ASPERGILLOSIS IN PATIENTS WITH B-CELL LYMPHOMA
Authors: J. Chudinovskikh, T. Semiglazova, M. Popova, O. Shadrivova, E. Frolova, T. Bogomolova, S. Ignatyeva, S. Alekseev, I. Zuzgin, L. Filatova, J. Oleinik, N. Klimko
Journal: HemaSphere (2019)

Background: Invasive yeast infection is rare invasive fungal disease but associated with high mortality rate in hematological patients. Data on Invasive yeast infection in hematopoietic stem cell transplantation (HSCT) recipients are limited. Aims: The aim of our study was to estimate epidemiology of invasive yeast infections in large HSCT recipients’ cohort for the 10-year period transplant activity in CIC725. Methods: Between 2008 and 2017 2430 stem cell transplantation have been performed in CIC 725: 1647 allogeneic HSCT and 783 autologous HSCT. A retrospective study included 30 cases of invasive yeast infections in patients with hematological malignances and non-malignant hematological diseases after HSCT. EORTC/MSG 2008 criteria were used for the diagnosis of proven yeast infections as well as to evaluate response to therapy. Results: Incidence of invasive yeast infections for the 10-year period of high transplant activity was 1,2%: 1,4% in allo-HSCT recipients (n = 23), 0,9% – auto-HSCT (n = 7) predominantly in patients with acute leukemia – 67% (n = 20). The median age was 10 y.o. (range, 1 month-59 years). In study population allo-HSCT from unrelated donor was performed in 50% (n = 15), haplo-HSCT in 27% (n = 8) and auto-HSCT in 23% (n = 7). In study cohort 30% of patients had no complete remission at the moment of HSCT. As a primary antifungal prophylaxis was used: fluconazole – 37% (n = 11), echinocandins – 13% (n = 4), without prophylaxis – 23% (n = 7); as a secondary prophylaxis – voriconazole in 27% (n = 8). The median day of onset of invasive yeast infections after allo-HSCT was 109 days (3–1337), auto-HSCT – 20 days (8–33). The etiology of invasive yeast infections was: Candida spp. – 87% (n = 26), Malassezia furfur – 7% (n = 2), Trichosporon asahii – 3% (n = 1), Cryptococcus spp. – 3% (n = 1). Febrile fever was the main clinical symptom and septic syndrome developed in 60% of cases. OS at 30 days from diagnosis of invasive yeast infection was 63%. The central venous catheter removal was the only factor significantly improved OS at 30 days after invasive yeast infection diagnosis (91% vs 17%, p = 0,001). Summary/Conclusion: Incidence of invasive yeast infections for the 10 years of observation was 1,2%: 1,4% in allo-HSCT recipients, 0,9% – auto-HSCT. The main etiology was Candida spp. (87%). Overall survival at 30 days from the diagnosis of invasive yeast infections was 60%. Removing of central venous catheter improved overall survival in hematological patients after HSCT with invasive yeast infections.
PS1198 MOLECULAR DIAGNOSIS OF RARE CONGENITAL ANEMIAS USING TARGETED NEXT-GENERATION SEQUENCING IN INDIAN PATIENTS
Authors: R. Dongerdiye, P. Kedar, P. Warang, R. Devendra, M. Madkaikar
Journal: HemaSphere (2019)

Background: Hereditary spherocytosis (HS) is one of the most frequent hereditary hemolytic disorders in Caucasian populations. With the emergence of the eosin-5’-maleimide (EMA) binding test, osmotic gradient ektacytometry, and targeted next-generation sequencing (tNGS), the role of single and combined diagnostic analyses remains unclear. Aims: To improve accuracy, robustness, and cost-effectiveness of the laboratory diagnosis of HS by the EMA binding test and osmotic gradient ektacytometry, individually and in combination, using the occurrence of diagnostic cytoskeleton protein gene mutations determined by tNGS as confirmation of HS. Methods: We included samples from all individuals referred to our laboratory with suspected HS between May 1st, 2017 and July 1st, 2018. In addition to a modified EMA-binding test using commercial Rainbow Beads as reference, we performed osmotic gradient ektacytometry using the Osmoscan module of the Laser-assisted Optical Rotational Deformability Cell Analyser (LoRRca MaxSis, RR Mechatronics, The Netherlands), as well as a comprehensive tNGS membranopathy panel (including α-spectrin, β-spectrin, ankyrin, band 3, protein 4.1, and protein 4.2). HS was defined as the occurrence of diagnostic cytoskeleton protein gene mutations. Results: A total of 99 individuals were included in the study. Of these, 41 individuals had no proven mutations in red blood cell cytoskeleton protein genes, 34 had one or more diagnostic mutations, and 24 had one or more variants of uncertain significance (VUS). We identified a total 78 different diagnostic mutations and VUS, including 42 novel mutations. The table depicts the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of the EMA binding test as well as the two ektacytometry-derived parameters Omin (osmotic resistance) and the maximal elongantion index (EImax). Rated individually, the ektacytometry-derived parameter EImax (<0.579) gave the highest accuracy (91%), when comparing results from individuals with diagnostic mutations and individuals with no mutations. When combining Omin >166 mOsm/kg and EImax <0.6, the highest sensitivity (100%) and accuracy (94.7 %) was reached. Twenty-seven of 34 individuals with diagnostic mutations had EMA ≥40, which was the optimal threshold in receiver operating characteristic (ROC) analysis. Five of 7 individuals with diagnostic mutations and EMA values <40 had mutations only in the SPTA1 gene.Summary/Conclusion: Individually, osmotic gradient ektacytometry was superior to the EMA binding test in the laboratory diagnosis of HS. In individuals with EMA ≥40 combined with Omin and EImax values of ≥166 mOsm/kg and <0.6, respectively, tNGS provided no additional value in the laboratory diagnosis of HS. In cases of discrepancy between results from the EMA binding test and selected Omin and EImax values, DNA testing may help explain this divergence.
Abstract 15842: Atrial Fibrillation Diagnosis Based on a Smartphone Derived Ppg Waveform: A Diagnostic Accuracy Study versus Single-Lead
Authors: Thijs Vandenberk, Caroline Pelckmans, Christophe Mortelmans, Ruth Van Haelst, Valerie Storms, Inge M Thijs, Bert Vaes, Pieter M Vandervoort
Journal: Circulation (2018)

Introduction: Atrial Fibrillation (AF) is the most common cardiac arrhythmia in clinical practice. Difficulties in the detection of AF arise as the clinical presentation is often non-specific or as...
Factorial phase II randomized trial of continuous (C) or intermittent (I) docetaxel (D) with or without estramustine (E) as first-line treatment for castration-resistant prostate cancer (CRPC): Preliminary results of HOPLITE trial.
Authors: Orazio Caffo, Giovanni Lo Re, Teodoro Sava, Sebastiano Buti, Cosimo Sacco, Umberto Basso, Fable Zustovich, Thomas Martini, Alessandra Perin, Antonello Veccia, Lucianna Russo, Gaetano Facchini, Carmen Barile, Angela Gernone, Giovanni L. Pappagallo, Enzo Galligioni
Journal: Journal of Clinical Oncology (2012)

e15160 Background: Pts who receive first line for CRPC are usually treated with 8-10 consecutive courses of D. The pts quality of life (QL) may be worsened and an I administration could limit this effect. E is an old drug showing a synergistic action with D. This study is aimed to compare QL of C and I D and whether E added to D improved its activity, in a 2 × 2 factorial design. Methods: CRPC pts were randomized to: C D 70 mg/m2 IV q 3 wks for 8 courses alone (arm A) or with E 280 mg/TID PO for 5 days starting 1 day prior to D (arm B), or the same treatments given with a 3-month rest period after the first 4 courses (arm C and D, respectively). The primary end points were QL (EORTC QLQ C30 and BPI) of A+B vs C+D and 1-y PFS (according to PCWG2) of A+C vs B+D. Results: 148 CRPC pts were enrolled from 11/06 to 10/10 with 128 pts evaluable at this time. The median age was 69 (range 42-81) and the median baseline PSA was 55.6 (range 0.33-4212). The major hematological toxicities were: anemia G3 (3 pts), neutropenia G3 (4 pts) – G4 (5 pts), febrile neutropenia (5 pts). Comparing C and I, QL outcomes were not statistically different in terms of general QL items. Comparing D and DE, 1-y PFS was superimposable (10% and 13.5%, respectively). The 2-y overall survival was not different between I and C arms 42.5% and 53.7% respectively) and between D and DE arms (42.8% and 53.5% respectively). Conclusions: These preliminary results suggest that I treatment did not produce a QL advantage compared to C treatment, while the addition of E to D did not improve 1-y PFS of CRPC pts.
Mutation of a histidine-rich calcium-binding-protein gene in wheat confers resistance to Fusarium head blight
Authors: Guoqiang Li, Jiyang Zhou, Haiyan Jia, Zhongxia Gao, Min Fan, Yanjun Luo, Panting Zhao, Shulin Xue, Na Li, Yang Yuan, Shengwei Ma, Zhongxin Kong, Li Jia, Xia An, Ge Jiang, Wenxing Liu, Wenjin Cao, Rongrong Zhang, Jicai Fan, Xiaowu Xu, Yanfang Liu, Qianqian Kong, Shouhang Zheng, Yao Wang, Bin Qin, Shouyang Cao, Yunxiao Ding, Jinxing Shi, Haisheng Yan, Xin Wang, Congfu Ran, Zhengqiang Ma
Journal: Nature Genetics (2019)