tbuckley/cabot-search huggingface dataset:
Substructured Population Growth in the Ashkenazi Jews Inferred with Approximate Bayesian Computation
Authors: Ariella L Gladstein, Michael F Hammer
Journal: Molecular Biology and Evolution (2019)

The Ashkenazi Jews (AJ) are a population isolate sharing ancestry with both European and Middle Eastern populations that has likely resided in Central Europe since at least the tenth century. Between the 11th and 16th centuries, the AJ population expanded eastward leading to two culturally distinct communities in Western/Central and Eastern Europe. Our aim was to determine whether the western and eastern groups are genetically distinct, and if so, what demographic processes contributed to population differentiation. We used Approximate Bayesian Computation to choose among models of AJ history and to infer demographic parameter values, including divergence times, effective population sizes, and levels of gene flow. For the ABC analysis, we used allele frequency spectrum and identical by descent-based statistics to capture information on a wide timescale. We also mitigated the effects of ascertainment bias when performing ABC on SNP array data by jointly modeling and inferring SNP discovery. We found that the most likely model was population differentiation between Eastern and Western AJ ∼400 years ago. The differentiation between the Eastern and Western AJ could be attributed to more extreme population growth in the Eastern AJ (0.250 per generation) than the Western AJ (0.069 per generation).
Abstract 12914: The Effect of Isosorbidemononitrate on Myocardium in a Swine Model of Cardiac Arrest
Authors: Ziren Tang, Tao Wang, Chenchen Hang, Caijun Wu, Rui Shao, Yingying Fang, Shen Zhao, Wanchun Tang
Journal: Circulation (2015)

Introduction: To investigate the protective effect of isosorbidemononitrate (IM) on myocardial injury after the return of spontaneous circulation (ROSC) in a swine model of ventricular fibrillation cardiac arrest (VFCA). Methods: Ventricular fibrillation was induced and untreated for 8 minutes in twenty domestic pigs. Defibrillation was attempted after 2 minutes of CPR. The animals were randomized into two groups: IM group (n=10) and saline control group (SA group, n=10). IM (2μg/kg/min) or the same volume of saline was administered for 6 hrs post-resuscitation. Post resuscitation myocardial function was evaluated using pulse-induced contour cardiac output (PiCCO) at 1, 6 and 24 hrs after ROSC. Serum troponin I was tested using the enzyme-linked immunosorbent assay (ELISA) at the same time points during 24 hours post-resuscitation. Echocardiography and transmission electron microscopy were performed at 72 hrs after ROSC. The duration of survival was monitored in all animals. Results: Significantly greater ejection fraction (EF) and cardiac output (CO) in the IM group at 1, 6 and 24 hrs after ROSC (Fig.1). Troponin I in the IM group was significantly lower than that in the SA group at 6 and 24 hrs after ROSC. Better cardiac function (Table 1) and less ultrastructural deterioration were observed in the MI group at 72 hrs after resuscitation. However, there is no significant difference in the duration of survival between the two groups. Conclusions: In a swine model of cardiac arrest, isosorbidemononitrate attenuated post-resuscitation myocardial dysfunction.
Abstract 390: Actin Arcs are Essential Templates for Sarcomere Assembly in Cardiomyocytes
Authors: Dylan T Burnette, Aidan Fenix, Nilay Taneja, Annabelle Williams, David Bader, Jennifer Gutzman, Matthew Tyska
Journal: Circulation Research (2017)

The sarcomere is the basic contractile unit within cardiomyocytes. The proper assembly of sarcomeres during development and their maintenance during homeostasis are critical for the contraction of the heart. How molecular components of sarcomeres assemble remains a major unanswered question. Here we use newly plated h uman i nduced pluripotent stem cell-derived c ardio m yocytes (hiCM) combined with high-resolution microscopy to elucidate the steps of de novo sarcomere assembly. We found that sarcomere formation was preceded by bundles of actin filaments resembling the so-called “actin arcs” prevalent in migrating non-muscle cells. Live-cell imaging revealed that sarcomeres appeared along the length of actin arcs; suggesting they are acting as a template for sarcomere assembly. Actin arc formation in non-muscle cells is dependent on the actin filament nucleator, formin, and the molecular motor, n on-muscle m yosin II (NMII). Inhibiting formin with the small molecule SMIFH2 in hiCM stopped the formation of actin arcs and subsequent sarcomere assembly, but had no effect on pre-assembled sarcomeres. We found that two isoforms of NMII, NMIIA and NMIIB, localized to the actin arcs in hiCM. Knockdown of NMIIB, but not NMIIA, in hiCM resulted in a loss of sarcomere assembly, but, much like formin inhibition, did not affect pre-assembled sarcomeres. To test if loss of NMIIB resulted in less sarcomere assembly in vivo , we knocked down NMIIB in zebrafish embryos, and found a significant loss of sarcomeres within both the atrium and ventricle. Finally, we use super-resolution microscopy to show that NMII and the muscle isoform, β m yosin II (βMII), are found in the same filaments in hiCM and in vivo in neonatal mice and in human patients with hypertrophic cardiomyopathy, suggesting individual molecular components within actin arcs (e.g., NMII) could be acting as seeds for their muscle counterparts (e.g., βMII). Taken together, our data supports a model in which contractile systems in cardiomyocytes evolved from non-muscle contractile systems. Furthermore, cardiomyocytes still use some non-muscle contractile components for sarcomere assembly during development, and potentially during aberrant sarcomere formation during hypertrophic cardiomyopathy.
SAT0074 DAS-28 DISEASE ACTIVITY DEFINES THE TNFR1/2 CO-EXPRESSION PROFILE IN RHEUMATOID ARTHRITIS PATIENTS
Authors: Alina Alshevskaya, Julia Lopatnikova, Julia Zhukova, Oksana Chumasova, Nadezhda Shkaruba, Alexey Sizikov, Sergey Sennikov
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> TNF-alpha act as main proinflamantory cytokine in rheumatoid arthritis (RA) immune processes. However, TNF-alpha activity and functions may be regulate not only by soluble receptors (which act as decoys) but also by number, density, and co-expression of its membrane-bound receptors type 1 and 2 (TNFR1 and TNFR2). <h3>Objectives:</h3> To analyze the TNFR1\2 co-expression profile in RA patient with different disease activity in comparison to healthy donors (HD). <h3>Methods:</h3> PBMC were analyzed from 46 HD and 64 patients with RA using flow cytometry. Patients were divided according to the DAS-28 index into groups with high (n=22, 34.4%), moderate (n=30, 46.9%) and low (n=12, 18.8%) disease activity. Co-expression of TNFR1/2 was evaluated as percentage of cell with different receptors. Number of receptors of each type per cell was counted using QuantiBrite PE beads (BD, USA). The following populations were analyzed: total monocyte pool; common pool of B lymphocytes; common pool of T lymphocytes; cytotoxic T cells (CD8+), T helper cells (CD4+), activated (CD25+) cells among CD8+ and CD4+, T memory (CD45R0+) and naïve T cells (CD45RA+) among cytotoxic and T helper cells; T regulatory cells (CD4+CD25highCD127low); B1 cells (CD45+CD19+CD5+). <h3>Results:</h3> We found that analyzed cell populations differ significantly in the co-expression of type 1 and 2 receptors for TNFα both between each other and compared to healthy donors. The most pronounced differences between groups of patients in the expression profile were shown for B cells, T reg and memory cells (figure). The total proportion of cells with at least one type of receptors was significantly decreased as compared with HD (in the case of B cells, T-helper memory cells) or increased (in the case of naive cytotoxic T cells, naïve T helper cells, monocytes, T regs). This indicator may reflect the overall sensitivity of the cells of the subpopulation to the effects of cytokine. This mechanism may reflect the ability of the cells to react on certain TNF-alpha concentration or anti-cytokine therapy. <h3>Conclusion:</h3> The profile of TNFR1\2 co-expression is changed in RA compared to heath. RA disease activity is associated with the changes in the amount and co-expression of type 1 and type 2 receptors for TNF-alpha on the surface of immunocompetent cells. <h3>Disclosure of Interests:</h3> None declared
SAT0236 RELATIONSHIP BETWEEN RITUXIMAB CONCENTRATION AND AUTOANTIBODY LEVELS IN ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODY ASSOCIATED VASCULITIS
Authors: Amina Bensalem, David Ternant, Nicolas Azzopardi, Gilles Paintaud, Valérie Gouilleux-Gruart, Divi Cornec, Ulrich Specks, Denis Mulleman
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Rituximab is approved in patients with anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV). Antibodies to proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA) decrease with therapy (1) and may therefore be used as biomarkers. <h3>Objectives:</h3> To investigate the relationship between rituximab concentration and ANCA levels in AAV patients. <h3>Methods:</h3> 92 AAV patients from the RAVE trial (rituximab for ANCA- associated vasculitis) were assessed. Both MPO-ANCA, and PR3-ANCA antibody levels were used as biomarkers. ANCA levels were measured at baseline, at months 1, 2, 4, 6, 9, 18, and every 6 months until the second rituximab cycle if any, using ELISA supplied by Euroimmun. A semi-mechanistic model including a deep compartment which was sensitive to rituximab and a feedback mechanism, and a blood compartment were tested to describe the concentration-ANCA autoantibodies relationship. A population modeling approach using sequential methods was used for model building. Influence of sex, body surface area (BSA), BVAS/WG score, newly diagnosed status, major renal involvement at baseline, and relapse were investigated as covariates on pharmacodynamics parameters. <h3>Results:</h3> A two compartment model including feedback mechanism from the circulating ANCA well described the concentration autoantibody relationship. The mean (interindividual standard deviation) estimated rituximab IC50, assessing potency, in patients with MPO-ANCA and PR3-ANCA were 21.9 mg/l (28%) and 11.2 mg/l (48.6%), respectively. Moreover, among patients with PR3-ANCA, rituximab IC50 was higher in patients with major renal involvement at baseline (p=2.47 x 10<sup>-2</sup>) and newly diagnosed status (p=6.42 x 10<sup>-5</sup>) than in others. <h3>Conclusion:</h3> A two compartments model including feedback mechanism from the circulating ANCA well described concentration-ANCA levels relationship. The potency of rituximab was higher in patients with PR3-ANCA than in patients with MPO-ANCA. <h3>Reference</h3> [1] Fussner LA, et al. Factors Determining the Clinical Utility of Serial Measurements of Antineutrophil Cytoplasmic Antibodies Targeting Proteinase 3. Arthritis Rheumatol. 2016;68:1700-10. <h3>Disclosure of Interests:</h3> Amina Bensalem: None declared, David Ternant Speakers bureau: Sanofi, Amgen, Nicolas Azzopardi: None declared, Gilles Paintaud Grant/research support from: Novartis, Roche Pharma, Sanofi-Genzyme, Chugai, Pfizer and Shire, Valérie Gouilleux-Gruart: None declared, Divi Cornec: None declared, Ulrich Specks: None declared, Denis Mulleman Speakers bureau: Pfizer, Novartis, Grifols
GI infections are associated with an increased risk of Parkinson’s disease
Authors: Michael Nerius, Gabriele Doblhammer, Gültekin Tamgüney
Journal: Gut (2019)

We have read with interest the recent publication of Perez-Pardo and colleagues1 reporting the role of the TLR4 in the gut–brain axis in Parkinson’s disease (PD). These findings prompted us to investigate the role of common GI infections (GIIs) in the pathogenesis of PD. In this prospective cohort study, we assessed the risk of PD in patients who previously suffered from GIIs compared with the control group not exposed to GIIs (table 1). At study entry (1 January 2005), the analysis sample from health claims data of the largest German health insurer consisted of2 28 485 individuals aged 50 years and older, which were followed for a mean time of 8.6 years (median=11.0 years; IQR=7.6 years). PD and GIIs were defined by ICD-10 codes as described in the supplementary material. Overall, 6195 individuals (2.7%) developed PD and 50 492 individuals (22.1%) were affected by any GII during the observation period between 2005 and 2015. The most frequent GIIs were those that caused infectious gastroenteritis and colitis of unspecified origin (IGCUs; 39 093 individuals, 17.1%), followed by viral intestinal infections (VIIs; 9328 individuals, 4.1%) and bacterial …
Abstract 20580: A Multiplexed Nucleotide-Labeled Antibody-Based Proteomic Assay Reveals Novel Candidate Biomarkers of Myocardial Injury
Authors: Debby Ngo, Michelle J Keyes, Laurie A Farrell, Mark D Benson, Michael A Fifer, Robert E Gerszten
Journal: Circulation (2017)

Background: Current proteomic technologies have been slow to identify and validate new cardiac biomarkers. A multiplexed proximity extension assay (PEA) that uses nucleotide-labeled antibodies coup...
Abstract 16333: S100A1 Deficiency Impairs Post-Ischemic Angiogenesis via Compromised Proangiogenic Endothelial Cell Function and Nitric Oxide Synthase Regulation
Authors: Carolin Lerchenmueller, Giuseppe Rengo, Hugo A Katus, Walter J Koch, Karsten Peppel, Patrick Most
Journal: Circulation (2012)

Background - Impaired NO homeostasis in endothelial cells (ECs) lacking the EF-hand calcium (Ca2+) sensor protein S100A1 prompted investigation of its pathophysiological role in regenerative angiog...
PS1471 MYELOPROLIFERATIVE NEOPLASMS IN KOREAN CHILDREN AND YOUNG ADULTS
Authors: H.S. Choi, J. Hong, J.H. Lee, S.M. Bang
Journal: HemaSphere (2019)

Background: Myeloproliferative neoplasms (MPNs) are a rare, heterogeneous group of clonal hematopoietic stem cell disorders, characterized by aberrant proliferation of one or more myeloid lineages leading to an overproduction of both mature and immature cells. Three major components of classical BCR‐ABL‐negative MPNs are polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (pMF). They may be transformed to either secondary MF (sMF) or secondary acute myeloid leukemia (sAML). In addition, they can have second cancers during follow up (FU). These classical MPNs primarily occur in middle and advanced age adults, and are exceptionally rare in pediatric age. Aims: We conducted an epidemiologic study to elucidate clinical course of MPNs in children and young adults under 30 years of age focusing on disease transformation as well as thromembolism and second cancers. Methods: We analyzing data from the Health Insurance Review and Assessment Service (HIRA) database which includes almost all hospital‐based patients’ information in Korea. Results: A total of 352 patients who were diagnosed as one of the three kinds of MPNs from Jan. 2008 to Dec. 2016 (242 patients for ET, 104 for PV, and 6 for pMF) were included. Six pMF patients were excluded from further analysis. The incidence was 0.148 per 100,000 for ET and 0.064 per 100,000 for PV. Among 242 ET patients, the male‐female ratio was 119 to 123, and median age at diagnosis was 22 years (range 13–29). Four ET patients (1.65%) underwent any transformation during the study period (median FU duration 49.5 months); ET→PV (i.e., initially diagnosed ET but changed to PV later; N = 2), and ET→sMF (N = 2). Among 104 PV patients, the male‐female ratio was 96 to 8, and median age at diagnosis was 24 years (range 11–29). No PV patients were transformed into sMF during the FU period (median 45.9 months). sAML did not develop in both ET and PV patients. Solid cancers occurred in 5 ET patients and 3 PV patients. Cumulative incidence of arterial and venous thromboembolism were 6.98% and 1.71% in ET, 16.69% and 4.77% in PV, respectively. Five‐year overall survival and transformation‐free survival (to PV, MF and cancer) were 98% and 96.12% in ET, 100% and 97.29% in PV, respectively. Summary/Conclusion: This is the first population‐based epidemiologic study in Korean children and young adults with MPNs. The incidence of MPNs is very low in this age group. ET is more common than PV, whereas pMF is very rare. Transformations of ET to PV or MF occurred in a small number of patients. Considering long latency to transformation in MPNs, continuous observation is needed. In addition, second solid tumors should also be carefully observed. Further research is necessary in this patient group, including studies involving other complications such as bleeding.
PB2216 ARTERIAL AND VENOUS THROMBOSIS IN TREATED PATIENTS WITH MYELOPROLIFERATIVE NEOPLASMS
Authors: A. Boban, M. Morić Perić, I. Zekanović, I. Horvat, M. Radić Antolić, P. Rončević, S. Zupančić‐Šalek, R. Serventi‐Seiwerth, S. Bašić Kinda, R. Vrhovac, N. Duraković, Z. Perić, D. Sertić, M. Mikulić, D. Pulanić, I. Aurer
Journal: HemaSphere (2019)

Background: Cardiovascular and thromboembolic events are the leading causes of morbidity and mortality for patients with myeloproliferative disorders (MPN). Aims: This retrospective study aimed to evaluate the incidence and the risk factors for the arterial and venous thrombosis in treated patients with MPN. Methods: The study included 329 adult MPN patients, 184 (56%) female, treated at University Hospital Center Zagreb, Department of Internal medicine, Division of Hematology and Zadar General Hospital, Hematology Unit. Patients were aged 24‐85 years (median 68), and were diagnosed as having essential thrombocythemia (ET) (n = 149, 45%), polycythaemia vera (PV)(n = 94, 29%), primary myelofibrosis (PMF)(n = 69, 21%) and unclassifiable MPN (n = 17, 5%). Diagnosis were made according to the 2008 WHO Classification. JAK‐2 mutation status was either established or revised in our center, but was unknown in 55 (17%) patients. Data about treatment and cardiovascular and thromboembolic incidents was retrieved from medical records. Results: Forty patients (12%) developed thrombosis after median of 36 (range 1‐240) months from the time of diagnosis. Fifteen (5%) patients developed venous thrombosis, twenty‐four (7%) arterial, while one (0,3%) patient both type of thrombosis. Regarding the disease type, thrombosis was described in 16 patients with ET (11%), 18 with PV (19%) and 6 with PMF (8%). The risk of thrombosis was the highest in patients with previous thrombotic events, but did not correlate with the type of therapy (cytoreductive and/or antiagreggation) nor the JAK‐2 status. Summary/Conclusion: The risk of both arterial and venous thrombosis was found to be increased in patients with MPN even after introducing appropriate treatment. The highest risk of post treatment thrombosis was found in patients with previously diagnosed thrombotic events.
PB2007 PRELIMINARY RESULTS OF USING BRENTUXIMAB VEDOTIN IN RELAPSE/REFRACTORY HODGKIN'S LYMPHOMA.
Authors: A. Jazyltayeva, S. Gabbasova, N. Kemelbekov, R. Karakulov, B. Nassypov, G. Sagyndikov, E. Ishkinin, A. Akanov, A. Taktybayeva, M. Mirzayeva, M. Seidlazym
Journal: HemaSphere (2019)

Background: Hodgkin disease (HL) is curable disease in up to 80% of patients, but for the remaining relapse/refractory patients no standard salvage therapy exists. Brentuximab vedotin comprises an anti CD30 antibody conjugated by a protease‐cleavable linker to a microtubule‐disrupting agent. Aims: The aim of the study is to evaluate the outcome of patients with relapse/refractory form of HL, who received Brentuximab vedotin. Methods: In our Institute 21 patients with HL were treated, from 2015 till 2018 years. 17 (81%) patients had a primary‐resistant form, four (19%) patients had relapse of the disease. The average age was 34.5 years (from 20 to 69 years), the average number of courses of therapy is 5.38 (from 3 to 8 courses). The mean follow‐up period was 17.9 months (from 4.1 to 38.1 months). Results: We have analyzed the survival of patients who received treatment. 21 patients who entered the study at the time of collection of information, 15 (71.4%) patients were alive. Median survival was 33.2 months. The standard error (SE) is 3.3 months, with 95% CI (26.8 ‐ 39.6). Among patients with a primary resistant form, 13 (76.5%) patients were alive, with a median survival of 28.1 months, a SE of 2.3 months of 95% CI (23.6–32.6). Among patients with a non‐primary resistant form, two (50%) patients were alive, while the median survival was 9.1 months, SE 2.4 months 95% CI (4.5–13.7). Eleven patients had a partial response to treatment (52, 4%), ten of them (90.9%) were alive, while the median survival was 27.9 months, SE 2.3 months 95% CI (23.5 ‐ 32.4). In three (14.3%) patients, a complete response to treatment was noted, of which three (100%) patients were alive. Cancer progression was noted in seven (33.3%) patients, two of them (28.6%) were alive, while the median survival was 27.9 months, SE 2.3 months 95% CI (23.5 ‐ 32.4). In analyzing six (28.6%) patients had AutoSCT, and 15 (71.4%) patients did not, due to low stem cell growth. Among patients, which didn’t have AutoSCT 11 (73.3%) patients were alive, with a median survival of 30.4 months, a SE of 2.7 months of 95% CI (25.1 ‐ 35.7). When analyzing the causes of mortality, all patients indicated the cause of death from the progression of cancer. Summary/Conclusion: The analysis of the results using Brentuximab Vedotin showed good results in treatment of relapse and refractory forms of HL. In patients who failed to perform autologous stem cell transplantation, showed median survival of 30.4 months. This indicates the possibility of using the drug as an alternative to this procedure for the primary resistant form of the disease or further therapy options.
AB0605 SERUM NEOPTERIN AND ISCHEMIA MODIFIED ALBUMIN LEVELS ARE ASSOCIATED WITH THE DISEASE ACTIVITY OF ADULT IMMUNOGLOBULIN A VASCULITIS (HENOCH-SCHONLEIN PURPURA)
Authors: Ahmet Omma, Seda Colak, Sevinc Can Sandikci, Cigdem Yucel, Abdulsamet Erden, Erdim Sertoglu, Taner Özgürtaş
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Immunoglobulin a vasculitis (IgAV) [formerly called Henoch– Schönlein purpura (HSP)] is an IgA mediated systemic vasculitis which primarily affects skin, gastrointestinal system and small vessels of kidneys. Exact pathogenesis of IgAV remains unknown. A fewclinicalstudiesevaluatedthe role of oxidativeinjury in thepathogenesis of vasculitis. Ischemia modified albumine (IMA) and Neopterin increased status of oxidative stress. <h3>Objectives</h3> The aims of the study are to investigate serum neopterin and IMA levels in patients with IgAV and evaluate the association of these markers with disease activity and relapse. <h3>Methods</h3> Thirty-four consecutive adult patients (24 males and 10 females) admitted to the rheumatology clinic of ankara Numune Training and Research Hospital meeting the IgAVAmerican College of Rheumatology (ACR) criteria were enrolled in this cross-sectional study. Demographic and clinical features of IgAV and control group were recorded into a predefined protocol. Disease activity was categorized as "remission" or "active" according to BVAS. BVAS ≥1 was accepted "active".Serum neopterin levels, hsCRP and IMA were evaluated according to BVAS and compared to healthy control group. <h3>Results</h3> Serum median (IQR) neopterin, IMA levelsandhsCRPwerehigher in thestudygroupthan in controlgroup [2.01 (12.5) ng/mL vs. 1.77 (1.37) ng/mL, 0.67 (0.2) ng/mL vs. 0.43 (0.17) ng/mL, 5.6 (17.1) mg/L vs. 1.55 (1.6) mg/L, p=0.095, p&lt;0.001and p=0.002,respectively). When evaluated according to BVAS, IMA and hsCRP levels were significantly higher in the group with active disease [0.77 (0.12) vs. 0.61 (0.13) and 14.85 (4.6), p=0.009 and p=0.03, respectively]. Serum neopterin levels were significantly higher in the active group compared to BVAS [18.95 (32.36) vs. 1.63 (1.48), p&lt;0.001]. <h3>Conclusion</h3> Oxidative stress is important in HSP pathogenesis. Roles of hsCRP,Neopterin and IMA as potential markers of diagnosis and disease activity seem to be worth studying in the future studies with larger study groups. <h3>Disclosure of interests</h3> None declared