tbuckley/cabot-search huggingface dataset:
PB2329 THE IMPACT OF VITAMIN D LEVELS ON PERIPHERAL STEM CELL MOBILIZATION IN ALLOGENEIC HEMATOPOIETIC STEM CELL DONORS
Authors: E. Hocaoğlu, Z. A. Yegin, F. Can, Z. N. Özkurt, M. Yağcı
Journal: HemaSphere (2019)

Background: Vitamin D is a steroid hormone which has an essential role in many physiological conditions including bone metabolism, immune regulation and hematopoiesis. Vitamin D was indicated to have a favourable impact on hematopoietic stem cell (HSC) production in in‐vitro studies. Additionally, animal experiments designated a potential for vitamin D receptor in HSC mobilization. Despite these advances, the possible role of vitamin D in peripheral HSC mobilization remains to be defined. Aims: The aim of this study was to evaluate the impact of pre‐mobilization serum vitamin D levels on peripheral HSC mobilization in allogeneic donors. Methods: We investigated the impact of pre‐mobilization serum vitamin D levels of 112 allogeneic donors [median age: 39(18‐69) years; male/female: 62/50] on peripheral HSC mobilization. All donors had received granulocyte colony stimulating factor (G‐CSF) at a dose of 10 mcg/kg/day for 4 days. First HSC apheresis was performed on the fourth day of G‐CSF. Serum 25‐hydroxy vitamin D levels were measured with immunoassay method before G‐CSF administration. Results: M edian vitamin D level was found to be 15.8(3‐63.2) μg/L in the study population. On the first apheresis day, median peripheral and product CD34(+) cell counts were 36.5(7‐206) × 10 6 /kg and 5.3(0.5‐22.8) × 10 6 /kg respectively. Median vitamin D levels were significantly lower in donors with low peripheral CD34(+) cell count which was defined as &lt;20 × 10 6 /kg, compared to donors with CD34 level≥20 × 10 6 /kg [13.5(7‐27.4) μg/L vs 17(3‐63.2) μg/L; p = 0.035] (Figure 1). When we divide the study group into two subgroups based on median vitamin D levels, peripheral CD34(+) cell counts were found to be significantly lower in low‐vitamin D group compared to high‐vitamin D group [35(7‐135) × 10 6 vs 41.4(10‐206) × 10 6 ; p = 0.038]. Any significant association was not observed between vitamin D levels and product CD34(+) cell counts. In logistic regression analysis, serum vitamin D level was considered to be correlated with peripheral CD34(+) cell count [p = 0.042; SE: 0.034; 95% Cl Exp(B): 1.003‐1.145]. Summary/Conclusion: Mobilization failure still remains to be a critical issue for HSC transplantation. In this study, the significant association between vitamin D levels and peripheral CD34(+) cell counts, lacking a similar correlation with product CD34(+) cell counts, requires further evaluation with larger study populations and more standardized procedures including product processing and collection. In these circumstances, the possible role of vitamin D in HSC mobilization deserves further consideration as vitamin D replacement before mobilization would be an easy, safe and cost‐effective approach to improve mobilization success. image
Abstract P127: Dose-dependent Effects of Comprehensive Lifestyle Changes on Blood Lipid Levels: Results From the PREMIER Trial
Authors: Ramzi Dudum, Stephen P Juraschek, Lawrence J Appel
Journal: Circulation (2017)

Introduction: Low-density lipoprotein (LDLc) is a major risk factor for cardiovascular (CV) disease. While comprehensive lifestyle change (CLC) lowers LDLc, little is known about how CLC adherence affects LDLc levels. Hypothesis: The PREMIER trial demonstrated CLC reduced LDLc levels. We hypothesized those undergoing CLC will exhibit dose dependent reductions in LDLc proportional to the number of intervention sessions attended. Methods: PREMIER was a multicenter randomized trial in adults with pre-hypertension or stage 1 hypertension. The current analyses were limited to participants randomized to CLC interventions, excluding those who were assigned to control, those on lipid-lowering medication, or those missing follow-up lipid data. One intervention, “Established” (Est.), was a CLC that emphasized increased physical activity, weight reduction, reduced sodium intake, and a reduced fat/calorie diet. A second CLC intervention, “Established+DASH” (Est.+DASH), also included counseling on the DASH diet. Behavioral counseling was delivered via 18 sessions in the first 6 months and 15 sessions in the following 12 months (total 33 sessions). Results: Among the 450 participants, mean age was 50.4, 63% were women, and 31% were black. Baseline LDLc was 134 mg/dL in Est. and 134.8 mg/dL in Est.+DASH. Mean attendance in the first 6 months was 14.2 sessions in Est. and 14.6 in Est.+DASH, and in the last 12 months was 9.6 sessions in Est. and 10.1 sessions in Est.+DASH. There was no difference in attendance by intervention. After adjustment for factors associated with LDLc, every 10 CLC sessions were associated with a 6 mg/dL (P=0.003) lower LDLc ( Table ). This association was attenuated when adjusted for weight change. Similar patterns were noted for triglycerides and total cholesterol. Conclusions: Better attendance at CLC sessions was associated with larger reductions in LDLc over an 18 month period with evidence that weight loss mediated this relationship.
Abstract MP005: Do Worksite Wellness Programs Improve Dietary Behaviors and Adiposity? A Systematic Review and Meta-analysis
Authors: Jose L Penalvo, Renata Micha, Jessica D Smith, Colin D Rehm, Eve Bishop, Jennifer A Onopa, Irina Uzhova, Jason H Wu, Dariush Mozaffarian
Journal: Circulation (2017)

Introduction: Worksites are promising venues for promoting health, given considerable time spent at work and opportunities for environmental change. Yet, the impact of worksite wellness programs (WWPs) on diet and adiposity, as well as the most relevant WWP components, are not established. Methods: Following MOOSE and PRISMA guidelines, we conducted a systematic review and meta-analysis of the impact of multi-component WWP trials (RCT or quasi-experimental) on diet and adiposity. Data were extracted in duplicate and pooled using inverse variance random effects meta-analysis. Pre-specified sources of heterogeneity (study design, world region, worksite type, duration, WWP components) were analyzed by meta-regression and subgroup analysis. Funnel plots, Begg’s, and Egger’s tests evaluated potential publication bias. Results: From 6612 abstracts, we identified 48 studies assessing WWPs and diet or adiposity. Most were in the US (54%) or Europe (23%), with diet (64%) and exercise/weight loss (20%) as main targets. Intervention components were variable (Figure). Most common outcomes were intakes of fruits and vegetables (F&amp;V) (19 studies), total fat or fat subtypes (18), and dietary fiber (4); and BMI (35) and waist circumference (WC) (10). Median duration was 12 months (range: 1-48 mo). In pooled analyses, WWP increased intake of F&amp;V, especially fruits (Figure). Significant effects were not identified for dietary fiber, total fat, or fat subtypes. WWP also reduced BMI (Figure) and WC (-2.03 cm, 95% CI:-3.88,-0.20). Trial duration significantly modified effects on BMI (&lt;12 mo duration: -0.64 kg/m 2 ; 12+ mo: -0.16 kg/m 2 ; P-interaction=0.046); but not WC or F&amp;V intake. Additional findings for heterogeneity, including WWP components, and publication bias will be presented. Conclusions: These novel findings support effectiveness of WWP for increasing F&amp;V and reducing BMI and WC.
What Physicians and Health Organizations Should Know About Mandated Imaging Appropriate Use Criteria
Authors: Keith D. Hentel, Andrew Menard, John Mongan, Jeremy C. Durack, Pamela T. Johnson, Ali S. Raja, Ramin Khorasani
Journal: Annals of Internal Medicine (2019)

The Appropriate Use Criteria Program, enacted by the Centers for Medicare & Medicaid Services in response to the Protecting Access to Medicare Act of 2014 (PAMA), aims to reduce inappropriate and unnecessary imaging by mandating use of clinical decision support (CDS) by all providers who order advanced imaging examinations (magnetic resonance imaging; computed tomography; and nuclear medicine studies, including positron emission tomography). Beginning 1 January 2020, documentation of an interaction with a certified CDS system using approved appropriate use criteria will be required on all Medicare claims for advanced imaging in all emergency department patients and outpatients as a prerequisite for payment. The Appropriate Use Criteria Program will initially cover 8 priority clinical areas, including several (such as headache and low back pain) commonly encountered by internal medicine providers. All providers and organizations that order and provide advanced imaging must understand program requirements and their options for compliance strategies. Substantial resources and planning will be needed to comply with PAMA regulations and avoid unintended negative consequences on workflow and payments. However, robust evidence supporting the desired outcome of reducing inappropriate use of advanced imaging is lacking.
Hepatocyte TNF Receptor–Associated Factor 6 Aggravates Hepatic Inflammation and Fibrosis by Promoting Lysine 6–Linked Polyubiquitination of Apoptosis Signal‐Regulating Kinase 1
Authors: Yutao Wang, Huan Wen, Jiajun Fu, Lin Cai, Peng‐Long Li, Chang‐Ling Zhao, Zhu‐feng Dong, Jun‐peng Ma, Xi Wang, Han Tian, Yan Zhang, Ye Liu, Jingjing Cai, Zhi‐Gang She, Zan Huang, Wenhua Li, Hongliang Li
Journal: Hepatology (2019)

Activation of apoptosis signal-regulating kinase 1 (ASK1) is a key driving force of the progression of nonalcoholic steatohepatitis (NASH) and represents an attractive therapeutic target for NASH treatment. However, the molecular and cellular mechanisms underlying ASK1 activation in the pathogenesis of NASH remain incompletely understood. In this study, our data unequivocally indicated that hyperactivated ASK1 in hepatocytes is a potent inducer of hepatic stellate cell (HSC) activation by promoting the production of hepatocyte-derived factors. Our previous serial studies have shown that the ubiquitination system plays a key role in regulating ASK1 activity during NASH progression. Here, we further demonstrated that tumor necrosis factor receptor-associated factor 6 (TRAF6) promotes lysine 6 (Lys6)-linked polyubiquitination and subsequent activation of ASK1 to trigger the release of robust proinflammatory and profibrotic factors in hepatocytes, which, in turn, drive HSC activation and hepatic fibrosis. Consistent with the in vitro findings, diet-induced liver inflammation and fibrosis were substantially attenuated in Traf6+/- mice, whereas hepatic TRAF6 overexpression exacerbated these abnormalities. Mechanistically, Lys6-linked ubiquitination of ASK1 by TRAF6 facilitates the dissociation of thioredoxin from ASK1 and N-terminal dimerization of ASK1, resulting in the boosted activation of ASK1-c-Jun N-terminal kinase 1/2 (JNK1/2)-mitogen-activated protein kinase 14(p38) signaling cascade in hepatocytes. Conclusion: These results suggest that Lys6-linked polyubiquitination of ASK1 by TRAF6 represents a mechanism underlying ASK1 activation in hepatocytes and a key driving force of proinflammatory and profibrogenic responses in NASH. Thus, inhibiting Lys6-linked polyubiquitination of ASK1 may serve as a potential therapeutic target for NASH treatment.
Granatum: a graphical single-cell RNA-Seq analysis pipeline for genomics scientists
Authors: Xun Zhu, Thomas K. Wolfgruber, Austin Tasato, Cédric Arisdakessian, David G. Garmire, Lana X. Garmire
Journal: Genome Medicine (2017)

Single-cell RNA sequencing (scRNA-Seq) is an increasingly popular platform to study heterogeneity at the single-cell level. Computational methods to process scRNA-Seq data are not very accessible to bench scientists as they require a significant amount of bioinformatic skills. We have developed Granatum, a web-based scRNA-Seq analysis pipeline to make analysis more broadly accessible to researchers. Without a single line of programming code, users can click through the pipeline, setting parameters and visualizing results via the interactive graphical interface. Granatum conveniently walks users through various steps of scRNA-Seq analysis. It has a comprehensive list of modules, including plate merging and batch-effect removal, outlier-sample removal, gene-expression normalization, imputation, gene filtering, cell clustering, differential gene expression analysis, pathway/ontology enrichment analysis, protein network interaction visualization, and pseudo-time cell series construction. Granatum enables broad adoption of scRNA-Seq technology by empowering bench scientists with an easy-to-use graphical interface for scRNA-Seq data analysis. The package is freely available for research use at http://garmiregroup.org/granatum/app
PB2411 DETECTION OF PATERNALLY INHERITED MUTATION (IVS‐II‐I G → A) OF THALASSEMIA IN MATERNAL PLASMA BY USING DHPLC METHODS
Authors: M. Zafari
Journal: HemaSphere (2019)

Background: β‐ Thalassemia is the most common inheritable disease in the world. About 3% of populations (150 million persons) are β‐thalassemi carriers’, and they run 25% risk of having Thalassemia major baby in each pregnancy. Prenatal diagnosis (PND) if offered in many country for prevent Thalassemia, and it is a part of national prevention program by invasive methods, such as; chorionic villus sampling (CVS) at 11‐14 weeks gestation or amniocentesis (AC) from 15 weeks gestation. Aims: the purpose of this study was detection of paternally inherited mutation (IVS‐II‐I G → A) of Thalassemia in maternal plasma by using DHPLC methods with its assessments via sensitivity and specificity determinations for prenatal diagnosis of thalassemia major. Methods: Subjects included Iranian pregnant women who at risk of having fetuses with β‐thalassemia major. We focused exclusively on samples in which the father was carrier for IVS II‐I G → A mutation and the mother had been genotyped to carry another β‐globin gene mutation. 10 ml peripheral blood sample were obtained from 50 pregnant women. The CVS sample was obtained Trans abdominal puncture with a 23‐gauge needle under ultrasound guidance. The samples were analyzed by reveres dot blot analysis. We were masked as to the identity the samples with numerical coding system, so, these were examined in a blinded manner. Circulatory DNA was extracted from 200 μl of peripheral blood plasma with QIAamp DNA mini and blood kit (QIAGEN‐USA) according to the manufacture s instructions. The genomic DNA concentration was measured by NanoDrpe system (ND1000, USA) and electrophoresis. They stored at ‐20 c until used. At firs beta‐Globin gene fragments containing IVSII‐1(G &gt; A) mutation was amplified with HRM real time PCR, also by using specific primers. DHPLC was performed on the WAVW fragment analysis system (Transgenomic Inc, USA) to detect the variants of beta globins’ gene mutation of Thalassemia. In order to generate the hetro&amp; homoduplexes, we mixed an equal amount of HRM Real time PCR product of wild type and patients. Results: the sensivity, specifity of this method was 40. 62 and 61.12; also the PPV and NPV was 65% and 36.67% respectively. Summary/Conclusion: the specifity and NPV of DHPLC method is higher than specifity and PPV.
Abstract 15249: Phosphoinositide 3-Kinase p110α Gene Therapy Ameliorates Diabetic Cardiomyopathy in Mice
Authors: Darnel Prakoso, Miles J De Blasio, Chengxue Qin, Sarah Rosli, Helen Kiriazis, Hongwei Qian, Xiao-Jun Du, Kate L Weeks, Paul Gregorevic, Julie R McMullen, Rebecca H Ritchie
Journal: Circulation (2016)

Diabetic cardiomyopathy is characterised by left ventricular (LV) diastolic dysfunction accompanied by LV fibrosis and increases in levels of both cardiomyocyte apoptosis and reactive oxygen specie...
A novel independence test for somatic alterations in cancer shows that biology drives mutual exclusivity but chance explains most co-occurrence
Authors: Sander Canisius, John W. M. Martens, Lodewyk F. A. Wessels
Journal: Genome biology (2016)

In cancer, mutually exclusive or co-occurring somatic alterations across genes can suggest functional interactions. Existing tests for such patterns make the unrealistic assumption of identical gene alteration probabilities across tumors. We present Discrete Independence Statistic Controlling for Observations with Varying Event Rates (DISCOVER), a novel test that is more sensitive than other methods and controls its false positive rate. A pan-cancer analysis using DISCOVER finds no evidence for widespread co-occurrence, and most co-occurrences previously detected do not exceed expectation by chance. Many mutual exclusivities are identified involving well-known genes related to cell cycle and growth factor signaling, as well as lesser known regulators of Hedgehog signaling.
PB1976 MICROANGIOPATHIC HEMOLYTIC ANEMIA DUE TO HEART VALVE PROSTHESIS
Authors: D. Andrade Luís, S. Afonso, B. Loureiro, J. Silva Gomes, R. Barreira, T. Maia Magalhães, M.L. Ribeiro
Journal: HemaSphere (2019)

Background: Microangiopathic hemolytic anemias (MAHA) are characterized by the presence of hemolytic anemia (HA), related to red blood cell (RBC's) fragmentation, thrombocytopenia and hemosiderinuria due the intravascular hemolysis. The term thrombotic microangiopathy (TMA) is also used to describe syndromes characterized by AHMA, thrombocytopenia, and thrombotic lesions in small blood vessels such as Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic uremic syndrome (HUS). Although TTP and HUS are the prototypes of TMA / MAHA, there are other causes that should not be forgotten, such as MAHA by valvular leak. Aims: Perform the casuistry of the Hematology Service of a Central Hospital for a rare cause of hemolytic anemia. Methods: Parameterized search for the data of patients with MAHA and hemosiderinuria evaluated at a Hematology out patients clinic at a Central Hospital between January 2007 and March 2018. Results: 9 patients with MAHA were identified with valvular leak, the mean age at diagnosis was 68 years and 6 were men (66%). All patients had mechanical heart valves: 66% mitral valve, 22% aortic valve and 11% both valves. The time from surgery to diagnosis of AHMA was ∼ 2 years. The mean Hb value was 8.4 mg/dL. All patients had RBC fragmentation. The mean value of DLH was 3773U/L, total bilirubin (TBil) was 1.9 mg/dL. 88% patients were supplemented with oral iron. Only 3 patients increase ∼ 1.5 g of Hb after 3 months of therapy. 1/3 patients were supplemented with EV iron; 1/3 needed blood transfusion. 66% underwent valvular leakage correction and of these 50% significantly improved Hb and hemolysis. Summary/Conclusion: A careful clinical history and the RBC morphology play a central role in the diagnosis of anemia. The MAHA due to leak valvular is a rare entity, but with a tendency to increase. Despite the small number of patients, the authors consider pertinent to present these data because this is a potentially reversible cause of anemia. The disproportionate high DHL level in relation to the TBilis a possible clue to the differential diagnosis of HA.
PF647 THE PROGNOSTIC IMPACT OF PATHOLOGIC FRACTURE AS MYELOMA-DEFINING EVENT IN NEWLY DIAGNOSED MULTIPLE MYELOMA
Authors: R. Ríos-Tamayo, M.J. Sánchez Pérez, D. Sánchez Rodríguez, A. García Ruiz, P. Garrido Collado, G. Salas, J. Muñoz Ballester, F. Hernández Mohedo, Z. Mesa, R. Leyva Ferrer, J. Sainz Pérez
Journal: HemaSphere (2019)

Background: Multiple myeloma (MM) is characterized by osteolytic bone disease which is present in 70%>80% of patients at diagnosis, increasing the risk of skeletal-related events. The initial clinical presentation in MM has been associated with overall survival (OS) (Greenberg AJ et al.2013) showing that bone disease-only as myeloma-defining event (MDE) had good outcome. However, a subgroup of patients with bone disease having pathologic fracture (PF) as the initial clinical presentation may have poorer OS and they are the focus of the study. Aims: To assess the prognostic impact of PF as the initial MDE in newly diagnosed MM (NDMM) patients (pts). Methods: All NDMM pts with PF as the MDE have been selected from the Granada population-based MM Registry (Ríos-Tamayo R et al.2015). The epidemiologic, clinical and cytogenetic baseline prognostic variables have been analyzed. Progression free-survival (PFS) and OS curves were estimated in months (m) by the Kaplan-Meier method and compared with the log-rank test. Comparisons for categorical variables among different groups were made with the x2-test. Comparisons of means of quantitative continuous variables between two groups were made with the t-test. Results: Until the end of 2018, 505 NDMM pts included in our registry had the information about their MDE. 35 of them (6.93 %) showed a PF as their MDE. Pts with PF at clinical presentation had a statistically significant poorer median OS [21.3; 95% confidence interval (95% CI), 7.8–34.8 versus 38.5 m; 95% CI, 30.3–46.7; p = 0.036] (Figure 1). The median PFS were 14;95% CI, 5.5–22.5 versus 21 m; 95% CI, 16.5–25.5; p = ns. No statistically differences between groups were detected for age, sex, ISS3, High Risk FISH, serum creatinine, diagnostic delay, bone marrow plasma cells or weight loss. In the PF group there was a trend to high mean LDH (347.6 versus 263.4; p = 0.068), lower mean BMI (26.4 versus 28.2; p = 0.056) and higher percentage of ECOG4 (18.5% versus 5.6%; p = 0.096).Summary/Conclusion: Despite the characteristic finding of bone disease, the presence of PF as MDE is only detected in approximately 7% of NDMM pts. This specific clinical presentation is associated with a trend to present more clinical aggressiveness evidenced by higher LDH and higher percentage of ECOG4, conditioning finally worse OS.
Safe Start of Ibrutinib in Patients with Chronic Lymphocytic Leukemia and Uncontrolled Autoimmune Hemolytic Anemia
Authors: Alejandro Garcia-Horton, Rosanne St. Bernard, Alejandro Lazo-Langner, Anargyros Xenocostas, Joy Mangel, Kang Howson-Jan, Selay Lam, Cyrus C. Hsia
Journal: Blood (2018)
Evaluating Fast Maximum Likelihood-Based Phylogenetic Programs Using Empirical Phylogenomic Data Sets
Authors: Xiaofan Zhou, Xing-Xing Shen, Chris Todd Hittinger, Antonis Rokas
Journal: Molecular Biology and Evolution (2017)

The sizes of the data matrices assembled to resolve branches of the tree of life have increased dramatically, motivating the development of programs for fast, yet accurate, inference. For example, several different fast programs have been developed in the very popular maximum likelihood framework, including RAxML/ExaML, PhyML, IQ-TREE, and FastTree. Although these programs are widely used, a systematic evaluation and comparison of their performance using empirical genome-scale data matrices has so far been lacking. To address this question, we evaluated these four programs on 19 empirical phylogenomic data sets with hundreds to thousands of genes and up to 200 taxa with respect to likelihood maximization, tree topology, and computational speed. For single-gene tree inference, we found that the more exhaustive and slower strategies (ten searches per alignment) outperformed faster strategies (one tree search per alignment) using RAxML, PhyML, or IQ-TREE. Interestingly, single-gene trees inferred by the three programs yielded comparable coalescent-based species tree estimations. For concatenation-based species tree inference, IQ-TREE consistently achieved the best-observed likelihoods for all data sets, and RAxML/ExaML was a close second. In contrast, PhyML often failed to complete concatenation-based analyses, whereas FastTree was the fastest but generated lower likelihood values and more dissimilar tree topologies in both types of analyses. Finally, data matrix properties, such as the number of taxa and the strength of phylogenetic signal, sometimes substantially influenced the programs' relative performance. Our results provide real-world gene and species tree phylogenetic inference benchmarks to inform the design and execution of large-scale phylogenomic data analyses.