bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of Gadd45b Accelerates BCR-ABL-Driven CML
Authors: Sha Xiaojin , Liebermann Dan , Hoffman Barbara 
Published: October 2019

Abstract
Gadd45b is a member of Gadd45 stress sensor protein family that also includes Gadd45a & Gadd45g. To investigate the effect of Gadd45b in bcr-abl oncogene driven chronic myeloid leukemia (CML) development, syngeneic wild type lethally irradiated mice were reconstituted with either wild type or Gadd45b null myeloid progenitors transduced with a retroviral vector expressing BCR-ABL. Loss of Gadd45b was observed to accelerate BCR-ABL driven CML development with shortened median mouse survival time. BCR-ABL Gadd45b deficient CML progenitors exhibited increased proliferation and decreased apoptosis, associated with hyper-activation of c-Jun NH2-terminal kinase and Stat5. These results provide novel evidence that gadd45b, like gadd45a, functions as a suppressor of BCR-ABL driven leukemia, albeit via a different mechanism.

Disclosures
No relevant conflicts of interest to declare.
Developing the Next Generation of iPSC Cell-Based Immunotherapies
Authors: Vizcardo Raul , Klemen Nicholas Donald , Islam Rafiqul , Gurusamy Devikala , Tamaoki Naritaka , Jia Li , Yu Zhiya , Hennings Amanda N , Maeda Takuya , Bosch-Marce Marta , Good Meghan L , Pack Svetlana , Stroncek David F. , Flomerfelt Francis A , Kruhlak Michael J , Restifo Nicholas Phillip 
Published: October 2019

Abstract
T cells are potentially curative for patients with metastatic cancer, but many patients with cancer have T cells that are 'terminally differentiated', a condition associated with treatment failure. We have observed that less differentiated T cells have a greater capacity to proliferate, persist and destroy large cancer deposits. Advances in regenerative medicine might allow the generation of rejuvenated T cells from induced pluripotent stem cells (iPSC). We have previously reported that T cells can be generated from iPSC in vitro by co-culturing them OP9 stromal cells expressing Notch-1 ligand, Delta-like-1 (OP9/DLL1). These cells have limited tumor-specificity but also exhibit unconventional and NK cell-like properties demonstrating lineage diversion into alternative lymphoid development pathways, with unknown consequences for their safety and efficacy. To generate iPSC-derived T cells with more naturalistic tumor-specific T cell programs, we sought to restore physiologic signals for selection, maturation and survival. We employed a novel 3D thymic culture system using fetal thymic tissue and generated a novel type of T cell, 'iPSC-derived thymic emigrants' (iTE). Antigen-specific CD8αβ+ iTE exhibited functional properties in vitro that were almost indistinguishable from natural naïve CD8αβ+ T cells, including vigorous expansion and robust anti-tumor activity. iPSC-derived immature T cells generated using OP9/DLL1 and 'educated' in fetal thymic organoids in a 3D culture system resembled naturally-occurring 'young' T cells, as analyzed using whole genome RNA-seq techniques. iTE recapitulated many of the transcriptional programs of naïve T cells in vivo and revealed a striking capacity for engraftment, memory formation and efficient tumor destruction. Although many milestones remain, our data show that 'Next-Gen' autologous tumor-specific T cells can realistically be generated from iPSC using 3D thymic organ tissue. Our next goal is now to employ these cells to treat patients with metastatic cancer because iPSC-derived T cells have a potentially unlimited capacity for proliferation, engraftment and anti-tumor activity.

Disclosures
Vizcardo: NCI: Patents & Royalties: International Patent Application PCT/US2017/65986. Klemen:NIH/NCI: Patents & Royalties: International Patent Application PCT/US2017/65986. Restifo:NIH/NCI: Patents & Royalties: International Patent Application PCT/US2017/65986.
The Diagnostic Value of Kappa/Lambda Ratios Determined By Flow Cytometric Analysis of Peripheral Blood and Bone Marrow Specimens in B-Cell Chronic Proliferative Disease
Authors: Paiva Aldair Sousa , Jardim Alessandra Suelen , Soares Victor lima , Paiva Hugo Diogenes De Oliveira , Bahia Frank , Sales Valéria SF , Leão Marcos Dias , Silva Antonia Eduarda Martins Oliveira Elói , Lima João Pedro Andrade , Cavalcanti Geraldo Barroso 
Published: October 2019

Abstract
Background. Previous studies have suggested that analysis of the distribution of surface immunoglobulin light chain kappa and lambda by flow cytometry (FC) provides evidence for monoclonality of B cell tumors in patients with persistent lymphocytosis. The objective is this study is to investigate the efficiency of FC in determination of monoclonality in patients with persistent lymphocytosis through the analysis of kappa and lambda light chain of immunoglobulin expression (kappa/lambda tests). Methods: Samples of peripheral blood from 43 patients with B-CLD were analyzed. They were analyzed by FC with monoclonal antibody panel as: CD3, CD4, CD5, CD8, CD10, CD19, CD22, CD20; CD103; FMC7; CD23, CD25, CD38, CD45, CD16/CD56, HLADR, anti- heavy chain of immunoglobulin (IgH), anti-heavy chain m and d of immunoglobulin (IgM/IgD) and anti-light chains (kappa and lambda) of immunoglobulin. In addition, information about sex, age and clinical and hematological data from the patients were also evaluated. Results. A relation between kappa / lambda higher than 10:1 was found in all samples, suggesting a monoclonal B cells proliferation with 86% of the samples displayed kappa light chain of immunoglobulin expression and 14% displayed lambda light chain of immunoglobulin expression. The immunophenotyping data associated with the hematological and clinical ones, confirmed 35 cases of B-cell chronic lymphocytic leukemia, 3 cases of B-cell prolymphocytic leukemia, 3 of hairy cell leukemia, one case of Waldenstrong macroglobulinemia and mantle cell lymphoma. Conclusions. The results showed that the kappa and lambda light chain of immunoglobulin expression analysis by FC is a simple and effective methodology in the malignant B- cell proliferation.

Disclosures
No relevant conflicts of interest to declare.
Prognostic Value of DNA Index By Flow Cytometry for Minimal Residual Disease in Childhood B-Cell Acute Lymphoblastic Leukemia
Authors: Cervantes Elizabeth , Enriquez Daniel J , Vidal Judith , Retamozo Rosario 
Published: October 2019

Abstract
Background: Prognostic factors in B-ALL represent a critical role for treatment stratification. High hyperdiploids (>50 chromosomes) have been related to better outcomes, and hypodiploids to worse prognosis. DNA Index (DI) quantifies the DNA from leukemic blast by flow cytometry and has been correlated to the number of chromosomes. Our aim was to demonstrate the prognostic value of DI for minimal residual disease in childhood B-ALL.
Methods: 26 blood samples from newly diagnosed childhood B-ALL cases were analyzed between November 2017 and February 2018. DI was evaluated by flow cytometry in samples with Propidium Iodide and leukemic blasts were identified by CD19/CD22/CD10/CD20 antibodies. DI was calculated as the ratio of mean fluorescence of pathologic B blasts and normal cells (T, NK lymphocytes, neutrophils and monocytes) in G0/G1 phase. We stablished three categories: diploid (0.95 - 1.05, 46 chromosomes), hypodiploid (<0.95) and hyperdiploid (>1.05). 8-colors FacsCanto II BD flow cytometer was also used to evaluate minimal residual disease with 0.0025% threshold of detection.
Results: 26 cases were evaluated and 2 died during induction treatment. Median age was 8 years (4mo - 16years) and 54% were males. At diagnosis, 62% showed DI diploid and 38% DI hyperdiploid, no hypodiploids cases were detected. Clinical characteristics were similar between both groups. Median DI in the hyperdiploids cases was 1.25 (R: 1.12 - 1.64). We only detected two hyperdiploids cases by conventional karyotype. All patients received the same BFM-based protocol. After induction, all cases achieved complete remission and 46% had MRD negative at the 28th day. DI diploid and hyperdiploid cases achieved 47% and 44% MRD negative, respectively. At the end of consolidation (R: 6-8 Mo), 77% cases achieved MRD negative, and between categories, 62% of DI diploid cases had MRD negative and 100% of DI hyperdiploid cases were negative for MRD detection by flow (p=0.02).
Conclusions: The hyperdiploid DNA index by flow cytometry is associated with minimal residual disease negative at the end of consolidation.Flow cytometry offers an alternative over the conventional karyotype to detect good prognosis groups among B-ALL cases.

Disclosures
No relevant conflicts of interest to declare.
A Retrospective Case Series Describing the Efficacy of Ketotifen in Systemic Mastocytosis
Authors: Slapnicar Calum Anthony , Scullion Smeenk Conrad , Hicks Lisa K. , Petrucci Jessica , Vadas Peter , Trinkaus Martina 
Published: October 2019

Abstract
Introduction
Systemic Mastocytosis (SM) represents a heterogeneous group of disorders characterized by the accumulation of neoplastic mast cells (MCs) in one or more organ systems. Patients with SM present with a broad range of symptoms resulting from excessive mast cell mediator release, especially histamine that frequently overlap with those of allergic disease. Episodes of life-threatening anaphylaxis are a recognized feature of SM. Here at St. Michael's Hospital, we currently follow more than 50 SM patients, the largest patient cohort in Canada. Ketotifen is a dual action mast cell stabilizer used to treat asthma, anaphylaxis and other mast cell, allergic-type disorders. Along with cromolyn, another mast cell stabilizer, ketotifen is known to be the most effective at controlling mast cell activation. At St. Michael's Hospital, ketotifen is used as an add-on, off-label therapy in SM patients at risk for recurrent anaphylaxis. The literature has yet to confirm the efficacy of using ketotifen to treat SM. Few centres besides St. Michael's use ketotifen as a potential therapy.
Objectives
Our primary objective was to describe the response to treatment by ketotifen in patients with SM in a tertiary care centre.
Methods
This is an observational, retrospective study (n=10) of SM patients treated with ketotifen at St. Michael's Hospital from January 2015 to June 2018. Electronic medical records were reviewed for mastocytosis treatment and symptom progression. All patients included in the study were diagnosed with SM according to the 2016 WHO criteria by undergoing a bone marrow biopsy. Symptoms were assessed at baseline (2-5 months pre-ketotifen initiation) and again at follow-up (4-8 months post initiation). An independent statistician produced binomial proportion confidence intervals for each reported symptom.
Results
Our study consisted of 7 females and 3 males, with an average age of 49 years old [IQR 33-67]. 5 of the 10 patients were diagnosed with indolent SM, the more moderate of the six SM subtypes. Table 1 demonstrates the 5 most frequently reported symptoms at baseline.
(Refer to Table 1) For nausea/vomiting, presyncope/syncope and urticaria, 100% of patients who reported these symptoms responded to treatment. For diarrhea and flushing, 86% and 67% of patients who reported these symptoms responded to treatment.
Conclusions
Ketotifen appears to be an effective therapy for patients with SM with anaphylaxis. It should be readily considered in the management of this population. Further investigation is warranted given our small sample size and single centre recruitment. Next steps include following these patients prospectively to better capture the efficacy of ketotifen within this population.
Disclosures
No conflicts of interest to declare

Disclosures
No relevant conflicts of interest to declare.
Methamphetamine use association with pulmonary diseases: a retrospective investigation of hospital discharges in California from 2005 to 2011
Authors: Tsai Halley , Lee Justin , Hedlin Haley , Zamanian Roham T. , de Jesus Perez Vinicio A. 
Published: October 2019

BackgroundMethamphetamine can have acute and long-term adverse health consequences. Our objective was to determine whether methamphetamine use is associated with more hospitalisation codes for asthma exacerbation, chronic obstructive pulmonary disease (COPD) exacerbation, pneumonia and acute respiratory failure (ARF).MethodsThe Health Care Utilization Project (HCUP) database includes retrospective inpatient discharge abstracts from 2005 through 2011 from the California state inpatient databases (SIDs). ICD-9 codes were used to identify hospitalisations for asthma exacerbation, COPD exacerbation, acute pneumonia, ARF and methamphetamine use from discharges with complete demographic data and ages 18 to 75 years. Adjusted rate ratios comparing methamphetamine users with nonusers were estimated separately for each pulmonary disease diagnosis by sex using negative binomial regression models.ResultsWe included 21 125 249 inpatient discharges from 2005 through 2011 in California in our analysis; 182 766 (0.87%) had methamphetamine use. The rate ratio comparing pneumonia in discharges with methamphetamine useversusthose without were 1.40 (95% CI 1.18, 1.67) for women and 1.18 (95% CI 1.04, 1.35) for men; comparing ARF 1.77 (95% CI 1.59, 1.98) for women and 1.24 (95% CI 1.12, 1.37) for men; and comparing COPD exacerbation 1.40 (95% CI 1.18, 1.67) for women and 0.90 (95% CI 0.79, 1.02) for men.ConclusionsA positive association was found when comparing inpatient hospital discharge diagnoses for methamphetamine use and those for pneumonia and ARF in both sexes. This association was not seen when comparing discharge diagnoses for methamphetamine and those for asthma exacerbation in both sexes or COPD exacerbation in men. While future investigation for is warranted, this finding may help to further characterise the pulmonary toxicity of methamphetamine.
The Initiation of Inferior Grain Filling is Affected by Sugar Translocation Efficiency in Large Panicle Rice
Authors: Chen Lin , Deng Yao , Zhu Honglei , Hu Yuxiang , Jiang Zhengrong , Tang She , Wang Shaohua , Ding Yanfeng 
Published: October 2019

Abstract

Background
Large panicle rice has a large sink capacity, but inferior spikelet filling is poor in this variety of rice due to asynchronous grain filling. The understanding of the factors that cause asynchronous grain filling will help to propose a model for how to regulate the rice inferior spikelets grain filling.

Results
In this study, two large panicle rice varieties, W1844 and CJ03, with the same sink capacity but with differences in asynchronous grain filling were used. The difference in the grain filling rate between superior and inferior spikelets in W1844 was much smaller than that in CJ03. We found that superior spikelet filling was initiated earlier in W1844 than in CJ03. The source-to-sink translocation rate of sucrose during the grain filling stage was more efficient in W1844 than in CJ03, and the gene expression levels of sucrose transporters (OsSUTs) were higher in W1844 functional leaves than in those of CJ03. In addition, carbon output, the transport ratio, and the contribution rate from the stem and sheath to the panicle were much higher at the early filling stage than at later filling stages in W1844.

Conclusion
Efficient sugar translocation can satisfy high sink strength, and also the strong sink activity can facilitate the sugar unloading in spikelets. All the above results indicate that an efficient sugar translocation rate at the early grain filling stage can improve sink strength and inferior grain filling initiation. Strategies to limit asynchronous grain filling in rice were also discussed based on our findings.
Comprehensive Transcriptomic Analysis of Mouse Gonadal Development Involving Sexual Differentiation, Meiosis and Gametogenesis
Authors: Wang Jian , Tian Geng G. , Zheng Zhuxia , Li Bo , Xing Qinghe , Wu Ji 
Published: October 2019

Abstract

Background
Mammalian gonadal development is crucial for fertility. Sexual differentiation, meiosis and gametogenesis are critical events in the process of gonadal development. Abnormalities in any of these events may cause infertility. However, owing to the complexity of these developmental events, the underlying molecular mechanisms are not fully understood and require further research.

Results
In this study, we employed RNA sequencing to examine transcriptome profiles of murine female and male gonads at crucial stages of these developmental events. By bioinformatics analysis, we identified a group of candidate genes that may participate in sexual differentiation, including Erbb3, Erbb4, and Prkg2. One hundred and two and 134 candidate genes that may be important for female and male gonadal development, respectively, were screened by analyzing the global gene expression patterns of developing female and male gonads. Weighted gene co-expression network analysis was performed on developing female gonads, and we identified a gene co-expression module related to meiosis. By alternative splicing analysis, we found that cassette-type exon and alternative start sites were the main forms of alternative splicing in developing gonads. A considerable portion of differentially expressed and alternatively spliced genes were involved in meiosis.

Conclusion
Taken together, our findings have enriched the gonadal transcriptome database and provided novel candidate genes and avenues to research the molecular mechanisms of sexual differentiation, meiosis, and gametogenesis.
doepipeline: a systematic approach to optimizing multi-level and multi-step data processing workflows
Authors: Svensson Daniel , Sjögren Rickard , Sundell David , Sjödin Andreas , Trygg Johan 
Published: October 2019

AbstractBackgroundSelecting the proper parameter settings for bioinformatic software tools is challenging. Not only will each parameter have an individual effect on the outcome, but there are also potential interaction effects between parameters. Both of these effects may be difficult to predict. To make the situation even more complex, multiple tools may be run in a sequential pipeline where the final output depends on the parameter configuration for each tool in the pipeline. Because of the complexity and difficulty of predicting outcomes, in practice parameters are often left at default settings or set based on personal or peer experience obtained in a trial and error fashion. To allow for the reliable and efficient selection of parameters for bioinformatic pipelines, a systematic approach is needed.ResultsWe presentdoepipeline, a novel approach to optimizing bioinformatic software parameters, based on core concepts of the Design of Experiments methodology and recent advances in subset designs. Optimal parameter settings are first approximated in a screening phase using a subset design that efficiently spans the entire search space, then optimized in the subsequent phase using response surface designs and OLS modeling.Doepipelinewas used to optimize parameters in four use cases; 1) de-novo assembly, 2) scaffolding of a fragmented genome assembly, 3) k-mer taxonomic classification of Oxford Nanopore Technologies MinION reads, and 4) genetic variant calling. In all four cases,doepipelinefound parameter settings that produced a better outcome with respect to the characteristic measured when compared to using default values. Our approach is implemented and available in the Python packagedoepipeline.ConclusionsOur proposed methodology provides a systematic and robust framework for optimizing software parameter settings, in contrast to labor- and time-intensive manual parameter tweaking. Implementation indoepipelinemakes our methodology accessible and user-friendly, and allows for automatic optimization of tools in a wide range of cases. The source code ofdoepipelineis available athttps://github.com/clicumu/doepipelineand it can be installed through conda-forge.
Identification of differentially expressed genes and pathways between intramuscular and abdominal fat-derived preadipocyte differentiation of chickens in vitro
Authors: Zhang Meng , Li Fang , Ma Xiang-fei , Li Wen-ting , Jiang Rui-rui , Han Rui-li , Li Guo-xi , Wang Yan-bin , Li Zi-yi , Tian Ya-dong , Kang Xiang-tao , Sun Gui-rong 
Published: October 2019

AbstractBackgroundThe distribution and deposition of fat tissue in different parts of the body are the key factors affecting the carcass quality and meat flavour of chickens. Intramuscular fat (IMF) content is an important factor associated with meat quality, while abdominal fat (AbF) is regarded as one of the main factors affecting poultry slaughter efficiency. To investigate the differentially expressed genes (DEGs) and molecular regulatory mechanisms related to adipogenic differentiation between IMF- and AbF-derived preadipocytes, we analysed the mRNA expression profiles in preadipocytes (0d, Pre-) and adipocytes (10d, Ad-) from IMF and AbF of Gushi chickens.ResultsAbF-derived preadipocytes exhibited a higher adipogenic differentiation ability (96.4% + 0.6) than IMF-derived preadipocytes(86.0% + 0.4) (p < 0.01). By Ribo-Zero RNA sequencing, we obtained 4403 (2055 upregulated and 2348 downregulated) and 4693 (2797 upregulated and 1896 downregulated) DEGs between preadipocytes and adipocytes in the IMF and Ad groups, respectively. For IMF-derived preadipocyte differentiation, pathways related to the PPAR signalling pathway, ECM-receptor interaction and focal adhesion pathway were significantly enriched. For AbF-derived preadipocyte differentiation, the steroid biosynthesis pathways, calcium signaling pathway and ECM-receptor interaction pathway were significantly enriched. A large number of DEGs related to lipid metabolism, fatty acid metabolism and preadipocyte differentiation, such asPPARG,ACSBG2,FABP4,FASN,APOA1andINSIG1, were identified in our study.ConclusionThis study revealed large transcriptomic differences between IMF- and AbF-derived preadipocyte differentiation. A large number of DEGs and transcription factors that were closely related to fatty acid metabolism, lipid metabolism and preadipocyte differentiation were identified in the present study. Additionally, the microenvironment of IMF- and AbF-derived preadipocyte may play a significant role in adipogenic differentiation. This study provides valuable evidence to understand the molecular mechanisms underlying adipogenesis and fat deposition in chickens.