DOCSLIB.ORG

Preclinical Activity of LBH589 Alone Or in Combination with Chemotherapy in a Xenogeneic Mouse Model of Human Acute Lymphoblastic Leukemia

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Preclinical Activity of LBH589 Alone Or in Combination with Chemotherapy in a Xenogeneic Mouse Model of Human Acute Lymphoblastic Leukemia Leukemia (2012) 26, 1517 --1526 & 2012 Macmillan Publishers Limited All rights reserved 0887-6924/12 www.nature.com/leu ORIGINAL ARTICLE Preclinical activity of LBH589 alone or in combination with chemotherapy in a xenogeneic mouse model of human acute lymphoblastic leukemia A Vilas-Zornoza1,13, X Agirre1,13, G Abizanda1,2, C Moreno3, V Segura4, A De Martino Rodriguez5, ES Jose´ -Eneriz1, E Miranda1, JI Martı´n-Subero6, L Garate1, MJ Blanco-Prieto7, JA Garcı´a de Jalo´n5, P Rio8, J Rifo´n2, JC Cigudosa9, JA Martinez-Climent1, J Roma´n-Go´ mez10, MJ Calasanz11, JM Ribera12 and F Pro´ sper1,2 Histone deacetylases (HDACs) have been identified as therapeutic targets due to their regulatory function in chromatin structure and organization. Here, we analyzed the therapeutic effect of LBH589, a class I--II HDAC inhibitor, in acute lymphoblastic leukemia (ALL). In vitro, LBH589 induced dose-dependent antiproliferative and apoptotic effects, which were associated with increased H3 and H4 histone acetylation. Intravenous administration of LBH589 in immunodeficient BALB/ c-RAG2À/ÀgcÀ/À mice in which human-derived T and B-ALL cell lines were injected induced a significant reduction in tumor growth. Using primary ALL cells, a xenograft model of human leukemia in BALB/c-RAG2À/ÀgcÀ/À mice was established, allowing continuous passages of transplanted cells to several mouse generations. Treatment of mice engrafted with T or B-ALL cells with LBH589 induced an in vivo increase in the acetylation of H3 and H4, which was accompanied with prolonged survival of LBH589-treated mice in comparison with those receiving vincristine and dexamethasone. Notably, the therapeutic efficacy of LBH589 was significantly enhanced in combination with vincristine and dexamethasone. Our results show the therapeutic activity of LBH589 in combination with standard chemotherapy in pre-clinical models of ALL and suggest that this combination may be of clinical value in the treatment of patients with ALL. Leukemia (2012) 26, 1517--1526; doi:10.1038/leu.2012.31 Keywords: LBH589; acute lymphoblastic leukemia; epigenetics; histone; mouse model INTRODUCTION ALL suggests that several genetic lesions need to act in concert 1 Although it is tempting to consider acute lymphoblastic leukemia to induce overt leukemia. (ALL) as a curable disease because of the remarkable improve- The classical view of cancer as a genetic disease has been ment in the cure rates observed in recent years, the prognosis of challenged by the clear demonstration that epigenetic modifica- relapsed patients is still dismal.1 Almost 80% of children tions can alter gene expression by mechanisms that do not affect diagnosed with ALL become cured with modern risk-adapted the DNA sequence itself. Epigenetics has an important role in the therapies. However, 460% of adult patients will eventually pathogenesis and prognosis of various tumors. The hypermethyla- relapse and most of them will succumb to their disease. This tion of DNA promoters and changes in histone modification underlies the need for new therapeutic options for resistant patterns are the most frequently described abnormalities in tumor patients. The role of recurrent chromosomal translocations in the cells.6 Along with others, we have extensively demonstrated that pathogenesis of ALL has been clearly established2 providing not patients with ALL frequently show an abnormal hypermethylation only important prognostic information but also guiding the of DNA promoter of tumor-suppressor genes, microRNAs (miRNAs) development of new treatments such as the use of tyrosine- or genes involved in tumorigenic pathways such as WNT or kinase inhibitors (imatinib or dasatinib) in patients with t(9;22).3 Ephrin-Eph pathway, and that these changes are associated with Other genetic alterations such as the overexpression of FLT3 prognosis of the disease.7--12 receptor tyrosine kinase in mixed-lineage leukemia gene-rear- Among the various epigenetic modifiers, histone deacetylases ranged or hyperdiploid B-ALL4 or the presence of NOTCH1- inhibitors (HDACi) have emerged as promising drugs for the activating mutations in T-cell ALL are attractive candidates for treatment of a number of tumors.13 HDACis are a class of targeted therapies with FLT3 or NOTCH inhibitors (g-secretase anticancer agents that inhibit deacetylation of histones and inhibitors).5 Indeed, the current view of the pathogenesis of non-histone cellular proteins, inducing hyperacetylation and an 1Oncology Division, University of Navarra, Pamplona, Spain; 2Hematology Service, Clı´nica Universidad de Navarra, University of Navarra, Pamplona, Spain; 3Department of Immunology, University of Navarra, Pamplona, Spain; 4Department of Bioinformatics, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain; 5Department of Animal Pathology, Veterinary Faculty, University of Zaragoza, Zaragoza, Spain; 6Department of Anatomic Pathology, Pharmacology and Microbiology, University of Barcelona, Barcelona, Spain; 7Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain; 8Centro de Investigaciones Energe´ticas, Medioambientales y Tecnolo´gicas (CIEMAT), Madrid, Spain; 9Molecular Cytogenetics Group, Centro Nacional Investigaciones Oncolo´gicas (CNIO), Madrid, Spain; 10Hematology Department, Reina Sofia Hospital, Maimonides Institute for Biomedical Research, Cordoba, Spain; 11Department of Genetics, University of Navarra, Pamplona, Spain and 12Hematology Service, Institut Catala` d’Oncologia, Hospital Universitari Germans Trias i Pujol, Universitat Auto`noma de Barcelona, Badalona, Barcelona, Spain. Correspondence: Dr F Pro´sper, Hematology and Cell Therapy, Clı´nica Universidad de Navarra, Avda, Pı´o XII 36, Pamplona 31008, Spain. E-mail: [email protected] 13These authors are equal first authors. Received 25 April 2011; revised 12 December 2011; accepted 30 January 2012; accepted article preview online 6 February 2012; advance online publication, 16 March 2012 LBH589 in ALL A Vilas-Zornoza et al 1518 ‘open chromatin’ configuration. In cancer, such hyperacetylation analyzed on Affymetrix GeneChip Human mapping 250K SNP arrays (Santa is associated with a greater transcriptional activity of silenced Clara, CA, USA) capable of genotyping on average 250 000 single- tumor-suppressor genes. LBH589 (also called Panobinostat) is an nucleotide polymorphisms according to the manufacturer’s protocol. HDACi characterized as a pan-deacetylase inhibitor with activity Microarray data were analyzed for determination of both total and against both class I and II HDACs. This drug has demonstrated a allelic-specific copy numbers using the Genotyping Console software significant activity against different tumors such as myeloma, (Affymetrix, Santa Clara, CA, USA) as previously described.17 acute myelogenous leukemia and T-cell lymphomas as well as 14,15 breast, prostate, colon and pancreatic cancer. DNA methylation array analysis In this study, we investigate the role of the HDACi LBH589 using A HumanMethylation27 BeadChip (Illumina, Inc., San Diego, CA, USA) was in vitro and in vivo models of ALL, and demonstrate that treatment used to quantify DNA methylation. The panel is developed to quantify the of ALL cells with LBH589 induces a prolonged survival in a mouse methylation status of 27 578 CpG sites located within the proximal model of human ALL. Also, we show that this effect is significantly promoter of 14 475 well-annotated genes from the consensus coding improved when combined with currently active drugs used to sequence project as well as known cancer genes and miRNAs. The protocol treat ALL, providing the basis for using this combination in was performed according to the manufacturer’s instructions. The patients with ALL. methylation status of a CpG was determined by the beta value calculation, which ranges from 0 for unmethylated CpGs to 1 for completely methylated CpGs. MATERIALS AND METHODS Human samples and cell lines Gene expression array analysis Six ALL-derived cell lines TOM-1, REH, 697, s.e.m., TANOUE and MOLT-4, Total RNA from primary cells and tissues was extracted with Ultraspec were purchased from the DSMZ (Deutche Sammlung von Microorganis- (Biotecx, Houston, TX, USA) following the manufacturer’s instructions after men und Zellkulturen GmbH, Braunschweig, Germany). Cell lines were tissue lysates were prepared using a mechanical tissue homogenization by maintained in culture in RPMI 1640 medium supplemented with 10% fetal ultraturrax (IKA, Wilmington, DE, USA). RNA was quantified using NanoDrop bovine serum and with 1% penicillin--streptomycin and 2% HEPES (Gibco- Specthophotometer (NanoDrop Technologies). Gene expression analysis BRL, Verviers, Belgium) at 37 1C in a humid atmosphere containing 5% CO . 2 was performed using GeneChip Human Gene 1.0 ST array (Affymetrix) To generate the mouse model, bone marrow (BM) or peripheral blood (PB) following the manufacturer’s instructions. Microarray data were normalized mononuclear cells were obtained at diagnosis from patients with ALL after and analyzed as previously described.18 signed informed consent had been obtained from the patient or the patient’s guardians, in accordance with the Declaration of Helsinki. TaqMan low-density arrays Reagent and cell drug treatment A TaqMan Low-Density Array A v2.1 (Applied Biosystems, Foster City, CA, USA) was used for 377 human miRNA expression assays after treatment. A The HDACi LBH589 was provided by Novartis Pharmaceuticals (East total concentration of 500 ng of
Load more

Recommended publications
  • Downloaded from Ftp://Ftp.Uniprot.Org/ on July 3, 2019) Using Maxquant (V1.6.10.43) Search Algorithm
    bioRxiv preprint doi: https://doi.org/10.1101/2020.11.17.385096; this version posted November 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. The proteomic landscape of resting and activated CD4+ T cells reveal insights into cell differentiation and function Yashwanth Subbannayya1, Markus Haug1, Sneha M. Pinto1, Varshasnata Mohanty2, Hany Zakaria Meås1, Trude Helen Flo1, T.S. Keshava Prasad2 and Richard K. Kandasamy1,* 1Centre of Molecular Inflammation Research (CEMIR), and Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, N-7491 Trondheim, Norway 2Center for Systems Biology and Molecular Medicine, Yenepoya (Deemed to be University), Mangalore, India *Correspondence to: Professor Richard Kumaran Kandasamy Norwegian University of Science and Technology (NTNU) Centre of Molecular Inflammation Research (CEMIR) PO Box 8905 MTFS Trondheim 7491 Norway E-mail: [email protected] (Kandasamy R K) Tel.: +47-7282-4511 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.11.17.385096; this version posted November 17, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. Abstract CD4+ T cells (T helper cells) are cytokine-producing adaptive immune cells that activate or regulate the responses of various immune cells.
    [Show full text]
  • Mouse Lbh Knockout Project (CRISPR/Cas9)
    https://www.alphaknockout.com Mouse Lbh Knockout Project (CRISPR/Cas9) Objective: To create a Lbh knockout Mouse model (C57BL/6J) by CRISPR/Cas-mediated genome engineering. Strategy summary: The Lbh gene (NCBI Reference Sequence: NM_029999 ; Ensembl: ENSMUSG00000024063 ) is located on Mouse chromosome 17. 3 exons are identified, with the ATG start codon in exon 1 and the TAG stop codon in exon 3 (Transcript: ENSMUST00000024857). Exon 2 will be selected as target site. Cas9 and gRNA will be co-injected into fertilized eggs for KO Mouse production. The pups will be genotyped by PCR followed by sequencing analysis. Note: Mice homozygous for a knock-out allele exhibit impaired mammary gland development and decreased litter size. Exon 2 starts from about 8.57% of the coding region. Exon 2 covers 32.7% of the coding region. The size of effective KO region: ~103 bp. The KO region does not have any other known gene. Page 1 of 8 https://www.alphaknockout.com Overview of the Targeting Strategy Wildtype allele gRNA region 5' gRNA region 3' 1 2 3 Legends Exon of mouse Lbh Knockout region Page 2 of 8 https://www.alphaknockout.com Overview of the Dot Plot (up) Window size: 15 bp Forward Reverse Complement Sequence 12 Note: The 2000 bp section upstream of Exon 2 is aligned with itself to determine if there are tandem repeats. Tandem repeats are found in the dot plot matrix. The gRNA site is selected outside of these tandem repeats. Overview of the Dot Plot (down) Window size: 15 bp Forward Reverse Complement Sequence 12 Note: The 2000 bp section downstream of Exon 2 is aligned with itself to determine if there are tandem repeats.
    [Show full text]
  • POGLUT1, the Putative Effector Gene Driven by Rs2293370 in Primary
    www.nature.com/scientificreports OPEN POGLUT1, the putative efector gene driven by rs2293370 in primary biliary cholangitis susceptibility Received: 6 June 2018 Accepted: 13 November 2018 locus chromosome 3q13.33 Published: xx xx xxxx Yuki Hitomi 1, Kazuko Ueno2,3, Yosuke Kawai1, Nao Nishida4, Kaname Kojima2,3, Minae Kawashima5, Yoshihiro Aiba6, Hitomi Nakamura6, Hiroshi Kouno7, Hirotaka Kouno7, Hajime Ohta7, Kazuhiro Sugi7, Toshiki Nikami7, Tsutomu Yamashita7, Shinji Katsushima 7, Toshiki Komeda7, Keisuke Ario7, Atsushi Naganuma7, Masaaki Shimada7, Noboru Hirashima7, Kaname Yoshizawa7, Fujio Makita7, Kiyoshi Furuta7, Masahiro Kikuchi7, Noriaki Naeshiro7, Hironao Takahashi7, Yutaka Mano7, Haruhiro Yamashita7, Kouki Matsushita7, Seiji Tsunematsu7, Iwao Yabuuchi7, Hideo Nishimura7, Yusuke Shimada7, Kazuhiko Yamauchi7, Tatsuji Komatsu7, Rie Sugimoto7, Hironori Sakai7, Eiji Mita7, Masaharu Koda7, Yoko Nakamura7, Hiroshi Kamitsukasa7, Takeaki Sato7, Makoto Nakamuta7, Naohiko Masaki 7, Hajime Takikawa8, Atsushi Tanaka 8, Hiromasa Ohira9, Mikio Zeniya10, Masanori Abe11, Shuichi Kaneko12, Masao Honda12, Kuniaki Arai12, Teruko Arinaga-Hino13, Etsuko Hashimoto14, Makiko Taniai14, Takeji Umemura 15, Satoru Joshita 15, Kazuhiko Nakao16, Tatsuki Ichikawa16, Hidetaka Shibata16, Akinobu Takaki17, Satoshi Yamagiwa18, Masataka Seike19, Shotaro Sakisaka20, Yasuaki Takeyama 20, Masaru Harada21, Michio Senju21, Osamu Yokosuka22, Tatsuo Kanda 22, Yoshiyuki Ueno 23, Hirotoshi Ebinuma24, Takashi Himoto25, Kazumoto Murata4, Shinji Shimoda26, Shinya Nagaoka6, Seigo Abiru6, Atsumasa Komori6,27, Kiyoshi Migita6,27, Masahiro Ito6,27, Hiroshi Yatsuhashi6,27, Yoshihiko Maehara28, Shinji Uemoto29, Norihiro Kokudo30, Masao Nagasaki2,3,31, Katsushi Tokunaga1 & Minoru Nakamura6,7,27,32 Primary biliary cholangitis (PBC) is a chronic and cholestatic autoimmune liver disease caused by the destruction of intrahepatic small bile ducts. Our previous genome-wide association study (GWAS) identifed six susceptibility loci for PBC.
    [Show full text]
  • Colorectal Cancer Risk Genes Are Functionally Enriched in Regulatory
    www.nature.com/scientificreports OPEN Colorectal cancer risk genes are functionally enriched in regulatory pathways Received: 07 January 2016 Xi Lu1,*, Mingming Cao2,*, Su Han3, Youlin Yang1 & Jin Zhou4 Accepted: 12 April 2016 Colorectal cancer (CRC) is a common complex disease caused by the combination of genetic variants Published: 05 May 2016 and environmental factors. Genome-wide association studies (GWAS) have been performed and reported some novel CRC susceptibility variants. However, the potential genetic mechanisms for newly identified CRC susceptibility variants are still unclear. Here, we selected 85 CRC susceptibility variants with suggestive association P < 1.00E-05 from the National Human Genome Research Institute GWAS catalog. To investigate the underlying genetic pathways where these newly identified CRC susceptibility genes are significantly enriched, we conducted a functional annotation. Using two kinds of SNP to gene mapping methods including the nearest upstream and downstream gene method and the ProxyGeneLD, we got 128 unique CRC susceptibility genes. We then conducted a pathway analysis in GO database using the corresponding 128 genes. We identified 44 GO categories, 17 of which are regulatory pathways. We believe that our results may provide further insight into the underlying genetic mechanisms for these newly identified CRC susceptibility variants. Colorectal cancer (CRC) is the third most common form of cancer and the second leading cause of cancer-related death in the western world and1,2. CRC is a leading cause of cancer-related deaths in the United States, and its lifetime risk in the United States is about 7%1,3. CRC is a common complex disease caused by the combination of genetic variants and environmental factors1.
    [Show full text]
  • A Framework for Exploring Associations Between Biomedical Terms in Pubmed
    www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 61), pp: 103100-103107 Research Paper A framework for exploring associations between biomedical terms in PubMed Haixiu Yang1,*, Lingling Zhao2,*, Ying Zhang3, Hong Ju4, Dong Wang5, Yang Hu6, Jun Zhang3 and Liang Cheng1 1College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, PR China 2School of Computer Science and Technology, Harbin Institute of Technology, Harbin 150001, PR China 3Department of Rehabilitation and Pharmacy, Heilongjiang Province Land Reclamation Headquarters General Hospital, Harbin 150088, PR China 4Department of Information Engineering, Heilongjiang Biological Science and Technology Career Academy, Harbin 150001, PR China 5Department of Academic Research, Heilongjiang University of Science & Technology, Harbin 150022, PR China 6School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, PR China *These authors contributed equally to this work Correspondence to: Liang Cheng, email: [email protected] Jun Zhang, email: [email protected] Yang Hu, email: [email protected] Keywords: co-occurrence relationship, text mining, framework, term association Received: June 12, 2017 Accepted: September 08, 2017 Published: October 05, 2017 Copyright: Yang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Co-occurrence relationships in PubMed between terms accelerate the recognition of term associations. The lack of manually curated relationships in vocabularies and the rapid increase of biomedical literatures highlight the importance of co-occurrence relationships. Here we proposed a framework to explore term associations based on a standard procedure that comprises multiple tools of text mining and relationship degree calculation methods.
    [Show full text]
  • Integrating Autoimmune Risk Loci with Gene-Expression Data Identifies Specific Pathogenic Immune Cell Subsets
    Integrating Autoimmune Risk Loci with Gene-Expression Data Identifies Specific Pathogenic Immune Cell Subsets The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Hu, Xinli et al. “Integrating Autoimmune Risk Loci with Gene- Expression Data Identifies Specific Pathogenic Immune Cell Subsets.” The American Journal of Human Genetics 89 (2011): 496-506. As Published http://dx.doi.org/10.1016/j.ajhg.2011.09.002 Publisher Elsevier B.V. Version Final Published Version Citable link http://hdl.handle.net/1721.1/66693 Terms of Use Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. ARTICLE Integrating Autoimmune Risk Loci with Gene-Expression Data Identifies Specific Pathogenic Immune Cell Subsets Xinli Hu,1,2,3,4 Hyun Kim,1,2 Eli Stahl,1,2,3 Robert Plenge,1,2,3 Mark Daly,3,5 and Soumya Raychaudhuri1,2,3,6,* Although genome-wide association studies have implicated many individual loci in complex diseases, identifying the exact causal alleles and the cell types within which they act remains greatly challenging. To ultimately understand disease mechanism, researchers must carefully conceive functional studies in relevant pathogenic cell types to demonstrate the cellular impact of disease-associated genetic variants. This challenge is highlighted in autoimmune diseases, such as rheumatoid arthritis, where any of a broad range of immunological cell types might potentially be impacted by genetic variation to cause disease. To this end, we developed a statistical approach to identify potentially pathogenic cell types in autoimmune diseases by using a gene-expression data set of 223 murine-sorted immune cells from the Immunological Genome Consortium.
    [Show full text]
  • Molecular Characterization of Cell-Free Eccdnas in Human Plasma
    www.nature.com/scientificreports OPEN Molecular characterization of cell- free eccDNAs in human plasma Jing Zhu1,2, Fan Zhang3, Meijun Du2, Peng Zhang2, Songbin Fu1 & Liang Wang 2 Extrachromosomal circular DNAs (eccDNAs) have been reported in most eukaryotes. However, little Received: 9 February 2017 is known about the cell-free eccDNA profles in circulating system such as blood. To characterize Accepted: 23 August 2017 plasma cell-free eccDNAs, we performed sequencing analysis in 26 libraries from three blood donors Published: xx xx xxxx and negative controls. We identifed thousands of unique plasma eccDNAs in the three subjects. We observed proportional eccDNA increase with initial DNA input. The detected eccDNAs were also associated with circular DNA enrichment efciency. Increasing the sequencing depth in an additional sample identifed many more eccDNAs with highly heterogenous molecular structure. Size distribution of eccDNAs varied signifcantly from 31 bp to 19,989 bp. We found signifcantly higher GC content in smaller eccDNAs (<500 bp) than the larger ones (>500 bp) (p < 0.01). We also found an enrichment of eccDNAs at exons and 3′UTR (enrichment folds from 1.36 to 3.1) as well as the DNase hypersensitive sites (1.58–2.42 fold), H3K4Me1 (1.23–1.42 fold) and H3K27Ac (1.33–1.62 fold) marks. Junction sequence analysis suggested fundamental role of nonhomologous end joining mechanism during eccDNA formation. Further characterization of the extracellular eccDNAs in peripheral blood will facilitate understanding of their molecular mechanisms and potential clinical utilities. Extrachromosomal DNA, also called extrachromosomal elements (EEs), is the DNA elements physically sepa- rated from the chromosomes, which refects the plasticity of the genome and may be related to genome evolution and genomic disorders.
    [Show full text]
  • An Online System for Identifying Significant Relationships Between Genetic Sequences and Diseases
    RESEARCH ARTICLE BLAT2DOLite: An Online System for Identifying Significant Relationships between Genetic Sequences and Diseases Liang Cheng1*, Shuo Zhang2, Yang Hu3* 1 College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, PR China, 2 School of Management, Harbin University of Commerce, Harbin 150028, PR China, 3 School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, PR China * [email protected] (LC); [email protected] (YH) a11111 Abstract The significantly related diseases of sequences could play an important role in understand- ing the functions of these sequences. In this paper, we introduced BLAT2DOLite, an online system for annotating human genes and diseases and identifying the significant relation- OPEN ACCESS ships between sequences and diseases. Currently, BLAT2DOLite integrates Entrez Gene Citation: Cheng L, Zhang S, Hu Y (2016) database and Disease Ontology Lite (DOLite), which contain loci of gene and relationships BLAT2DOLite: An Online System for Identifying Significant Relationships between Genetic between genes and diseases. It utilizes hypergeometric test to calculate P-values between Sequences and Diseases. PLoS ONE 11(6): genes and diseases of DOLite. The system can be accessed from: http://123.59.132. e0157274. doi:10.1371/journal.pone.0157274 21:8080/BLAT2DOLite. The corresponding web service is described in: http://123.59.132. Editor: Quan Zou, Tianjin University, CHINA 21:8080/BLAT2DOLite/BLAT2DOLiteIDMappingPort?wsdl. Received: April 4, 2016 Accepted: May 26, 2016 Published: June 17, 2016 Copyright: © 2016 Cheng et al. This is an open Introduction access article distributed under the terms of the Creative Commons Attribution License, which permits Identifying significantly related diseases of genes has drawn more and more attention in inter- unrestricted use, distribution, and reproduction in any preting molecular functions [1–13].
    [Show full text]
  • UC San Diego Electronic Theses and Dissertations
    UC San Diego UC San Diego Electronic Theses and Dissertations Title Cardiac Stretch-Induced Transcriptomic Changes are Axis-Dependent Permalink https://escholarship.org/uc/item/7m04f0b0 Author Buchholz, Kyle Stephen Publication Date 2016 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA, SAN DIEGO Cardiac Stretch-Induced Transcriptomic Changes are Axis-Dependent A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Bioengineering by Kyle Stephen Buchholz Committee in Charge: Professor Jeffrey Omens, Chair Professor Andrew McCulloch, Co-Chair Professor Ju Chen Professor Karen Christman Professor Robert Ross Professor Alexander Zambon 2016 Copyright Kyle Stephen Buchholz, 2016 All rights reserved Signature Page The Dissertation of Kyle Stephen Buchholz is approved and it is acceptable in quality and form for publication on microfilm and electronically: Co-Chair Chair University of California, San Diego 2016 iii Dedication To my beautiful wife, Rhia. iv Table of Contents Signature Page ................................................................................................................... iii Dedication .......................................................................................................................... iv Table of Contents ................................................................................................................ v List of Figures ...................................................................................................................
    [Show full text]
  • Content Based Search in Gene Expression Databases and a Meta-Analysis of Host Responses to Infection
    Content Based Search in Gene Expression Databases and a Meta-analysis of Host Responses to Infection A Thesis Submitted to the Faculty of Drexel University by Francis X. Bell in partial fulfillment of the requirements for the degree of Doctor of Philosophy November 2015 c Copyright 2015 Francis X. Bell. All Rights Reserved. ii Acknowledgments I would like to acknowledge and thank my advisor, Dr. Ahmet Sacan. Without his advice, support, and patience I would not have been able to accomplish all that I have. I would also like to thank my committee members and the Biomed Faculty that have guided me. I would like to give a special thanks for the members of the bioinformatics lab, in particular the members of the Sacan lab: Rehman Qureshi, Daisy Heng Yang, April Chunyu Zhao, and Yiqian Zhou. Thank you for creating a pleasant and friendly environment in the lab. I give the members of my family my sincerest gratitude for all that they have done for me. I cannot begin to repay my parents for their sacrifices. I am eternally grateful for everything they have done. The support of my sisters and their encouragement gave me the strength to persevere to the end. iii Table of Contents LIST OF TABLES.......................................................................... vii LIST OF FIGURES ........................................................................ xiv ABSTRACT ................................................................................ xvii 1. A BRIEF INTRODUCTION TO GENE EXPRESSION............................. 1 1.1 Central Dogma of Molecular Biology........................................... 1 1.1.1 Basic Transfers .......................................................... 1 1.1.2 Uncommon Transfers ................................................... 3 1.2 Gene Expression ................................................................. 4 1.2.1 Estimating Gene Expression ............................................ 4 1.2.2 DNA Microarrays ......................................................
    [Show full text]
  • Microarray Bioinformatics and Its Applications to Clinical Research
    Microarray Bioinformatics and Its Applications to Clinical Research A dissertation presented to the School of Electrical and Information Engineering of the University of Sydney in fulfillment of the requirements for the degree of Doctor of Philosophy i JLI ··_L - -> ...·. ...,. by Ilene Y. Chen Acknowledgment This thesis owes its existence to the mercy, support and inspiration of many people. In the first place, having suffering from adult-onset asthma, interstitial cystitis and cold agglutinin disease, I would like to express my deepest sense of appreciation and gratitude to Professors Hong Yan and David Levy for harbouring me these last three years and providing me a place at the University of Sydney to pursue a very meaningful course of research. I am also indebted to Dr. Craig Jin, who has been a source of enthusiasm and encouragement on my research over many years. In the second place, for contexts concerning biological and medical aspects covered in this thesis, I am very indebted to Dr. Ling-Hong Tseng, Dr. Shian-Sehn Shie, Dr. Wen-Hung Chung and Professor Chyi-Long Lee at Change Gung Memorial Hospital and University of Chang Gung School of Medicine (Taoyuan, Taiwan) as well as Professor Keith Lloyd at University of Alabama School of Medicine (AL, USA). All of them have contributed substantially to this work. In the third place, I would like to thank Mrs. Inge Rogers and Mr. William Ballinger for their helpful comments and suggestions for the writing of my papers and thesis. In the fourth place, I would like to thank my swim coach, Hirota Homma.
    [Show full text]
  • Program Book
    The Genetics Society of America Conferences 15th International Xenopus Conference August 24-28, 2014 • Pacific Grove, CA PROGRAM GUIDE LEGEND Information/Guest Check-In Disabled Parking E EV Charging Station V Beverage Vending Machine N S Ice Machine Julia Morgan Historic Building W Roadway Pedestrian Pathway Outdoor Group Activity Area Program and Abstracts Meeting Organizers Carole LaBonne, Northwestern University John Wallingford, University of Texas at Austin Organizing Committee: Julie Baker, Stanford Univ Chris Field, Harvard Medical School Carmen Domingo, San Francisco State Univ Anna Philpott, Univ of Cambridge 9650 Rockville Pike, Bethesda, Maryland 20814-3998 Telephone: (301) 634-7300 • Fax: (301) 634-7079 E-mail: [email protected] • Web site: genetics-gsa.org Thank You to the Following Companies for their Generous Support Platinum Sponsor Gold Sponsors Additional Support Provided by: Carl Zeiss Microscopy, LLC Monterey Convention & Gene Tools, LLC Visitors Bureau Leica Microsystems Xenopus Express 2 Table of Contents General Information ........................................................................................................................... 5 Schedule of Events ............................................................................................................................. 6 Exhibitors ........................................................................................................................................... 8 Opening Session and Plenary/Platform Sessions ............................................................................
    [Show full text]