DOCSLIB.ORG

(12) Patent Application Publication (10) Pub. No.: US 2012/0009177 A1 Platt Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

US 20120009177A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0009177 A1 Platt et al. (43) Pub. Date: Jan. 12, 2012 (54) GENE EXPRESSION MARKERS FOR Publication Classification PREDICTING RESPONSE TO INTERLEUKIN-6 RECEPTOR-INHIBITING (51) Int. Cl. MONOCLONAL ANTIBODY DRUG A 6LX 39/395 (2006.01) TREATMENT A6IP37/02 (2006.01) C40B 40/06 (2006.01) (75) Inventors: Adam Platt, Congleton (GB); CI2O I/68 (2006.01) Jianmei Wang, Welwyn Garden C40B 30/04 (2006.01) City (GB); Guiyuan Lei, Welwyn Garden City (GB); Laurent Essioux, Attenschwiller (FR): (52) U.S. Cl. .................... 424/130.1; 435/6.12: 435/6.11: Wei-min Liu, Dublin, CA (US); P. 506/9; 506/16 Mickey Williams, Great Falls, VA (US) (73) Assignee: Roche Molecular Systems, Inc., (57) ABSTRACT Pleasanton, CA (US) This invention provides methods, compositions, and kits relating to gene product biomarkers where gene expression (21) Appl. No.: 13/154,158 levels are correlated with therapeutic response of rheumatoid (22) Filed: Jun. 6, 2011 arthritis patients to treatment with an IL-6 receptor antago nist, Such as an IL6-R antibody. The methods, compositions, Related U.S. Application Data and kits of the invention can be used to identify rheumatoid (60) Provisional application No. 61/352.285, filed on Jun. arthritis patients who are likely, or not likely, to respond to 7, 2010. IL-6 receptor antagonist treatments. US 2012/00091 77 A1 Jan. 12, 2012 GENE EXPRESSION MARKERS FOR in some embodiments any one of from 2 to 20, 30, 40, 50, 60. PREDICTING RESPONSE TO 70, 80, or all of the genes set forth in Table 3. INTERLEUKIN-6 RECEPTOR-INHIBITING 0009. In some embodiments, the step of determining the MONOCLONAL ANTIBODY DRUG level of expression of the biomarker gene comprises measure TREATMENT the level of RNA expressed by the marker gene. The amount of RNA expressed may be determined, e.g., using an ampli CROSS-REFERENCE TO RELATED fication area reaction Such as qPCR, or by using a probe array. APPLICATIONS For example, a nucleic acid array forming a probe set may be used to detect RNA expressed of the biomarker gene. RNA 0001. This application claims benefit of U.S. provisional expression levels are typically determined by measuring the application No. 61/352.285, filed Jun. 7, 2010, which is level of cDNA transcribed from the RNA isolated from the herein incorporated by reference for all purposes. patient. RNA expression levels can be determined using known probesets to quantify expression level. As known in BACKGROUND OF THE INVENTION the art, Such probes sets may comprises multiple probes that 0002 Tocilizumab is the first humanized interleukin-6 hybridize to the target sequence of interest. Alternatively, receptor (IL-6R)-inhibiting monoclonal antibody that has expression of a marker gene can be determined by measuring been developed to treat rheumatoid arthritis. As with other the level of expression of a protein encoded by the gene. treatments, the antibody exhibits a range of therapeutic effi 0010. The levels of expression are compared to standard cacy in patients. Thus, there is a need to determine those control data, e.g., the expression data set generated in patients that are more likely to respond positively to treatment Example 1 and 2. An increased level of expression of the with tocilizumab and/or patients that are likely to not respond marker gene or decreased level of expression of the biomarker to treatment. The present invention addresses this need. gene may be determined by using statistical models for deter mining whether expression of the biomarker gene is indica BRIEF SUMMARY OF THE INVENTION tive of therapeutic response of a patient to treatment with an IL-6R antibody such as tocilizumab. In some the invention 0003. The invention is based, in part, on the discovery of provides an electronic device or computer Software that changes in gene expression that are associated with a positive employs the use of a statistical model to determine likelihood therapeutic response to treatment with an agent that modulate of therapeutic responses. IL-6-mediated signal transduction, Such as an anti-IL-6 anti body that inhibits transduction or an IL-6R-inhibiting mono 0011. In some embodiments, the levels of expression of clonal antibody Such as tocilizumab. genes set forth in Table 5 are evaluated to identify rheumatoid 0004 Thus, in one aspect, the invention provides a method arthritis patients that are likely to be responsive, or unrespon of identifying a rheumatoid arthritis patient that is likely to sive, to treatment with an IL-6R antagonist Such as tocili respond to treatment with tocilizumab; or of identifying a Zumab. In typical embodiments, anywhere from 2 to 10, 20, patient that is likely not to respond to treatment with tocili 30, 40, 50, 60, 70, 80, or 90, or all of the genes in column C, Zumab; wherein the method comprises identifying the levels column D, column E. column F. column G, column H. column of expression of a gene set forth in Table 1, Table 2, or Table I, or column J are analyzed to determined likelihood of a 3. Such genes can be identified using a variety of techniques, therapeutic response. including array probe sets and amplification techniques. The level of expression of the marker gene is then compared to the DETAILED DESCRIPTION OF THE INVENTION expression level shown in the data set used to establish a 0012. As used herein, a “positive therapeutic response' or correlation. “therapeutic benefit” refers to an improvement in, and/or 0005. In a further aspect, the invention provides, a kit for delay in the onset of any symptom of rheumatoid arthritis. predicting the therapeutic response of a rheumatoid arthritis 0013 As used herein “negative therapeutic response' patient to a treatment regimen that comprises administration refers to a lack of improvement of one or more symptoms of of an IL-6R antibody such as tocilizumab. In some embodi rheumatoid arthritis. ments, the kit also includes an electronic device or computer 0014. An “interleukin-6 receptor (IL-6R) inhibiting anti Software to compare the marker gene expression level of a body” refers to an antibody to IL-6 receptor where the anti biomarker gene set forth in Table 1, Table 2, or Table 3 from body binds to IL-6 receptor and antagonizes (i.e., inhibits) the patient to a dataset. The endpoint for evaluating therapeu IL-6 receptor activity. An example of Such an antibody is tic response can be any symptom of rheumatoid arthritis, e.g., tocilizumab, a humanized IL-6R monoclonal antibody (see, the endpoints evaluated in Example 1. e.g., Sato et al., Cancer Res 1993:53: 851-6; and U.S. Pat. No. 0006. In some embodiments, the marker gene is any one of 7,479.543) that is used for the treatment of rheumatoid arthri the genes set forth in Table 1. In some embodiments, the tis. marker genes are at least two genes set forth in Table 1. Thus, 0015. In the current invention, a “gene set forth in Table 1 in some embodiments any one of from 2 to 20, 30, 40, 50, 60. refers to the gene that corresponds to the probesets annotated 70, 80, or all of the genes set forth in Table 1. in Table 1. Similarly, a “gene set forth in Tables 2, 3, or 5 0007. In some embodiments, the marker gene is any one of refers to the gene that corresponds to the probesets annotated the genes set forth in Table 2. In some embodiments, the in the respective Table. For Tables 1-3, the “Representative marker genes are at least two genes set forth in Table 2. Thus, Public ID' is listed as the accession number Table 1. The in some embodiments any one of from 2 to 20, 30, 40, 50, 60. “Representative Public ID is the accession number of a 70, 80, or all of the genes set forth in Table 2. representative sequence. For consensus-based probe sets, the 0008. In some embodiments, the marker gene is any one of representative sequence is only one of several sequences (se the genes set forth in Table 3. In some embodiments, the quence Sub-clusters) used to build the consensus sequence in marker genes are at least two genes set forth in Table 3. Thus, the probe set used in the Examples and it is not directly used US 2012/00091 77 A1 Jan. 12, 2012 to derive the probe sequences. The representative sequence is 0021. The expression levels of any gene expression prod chosen during array design as a sequence that is best associ uct of one of the genes set forth in Table 1, Table 2, or Table ated with the transcribed region being interrogated by the 3 may be measured, however, typically expression of multiple probe set. As understood in the art, there are naturally occur genes is assessed. Gene expression levels may be measured ring polymorphisms for many gene sequences. Genes that are using any number of methods known in the art. In typical naturally occurring allelic variations for the purposes of this embodiments, the method involves measuring the level of invention are those genes encoded by the same genetic locus. RNA. RNA expression can be quantified using any method, The proteins encoded by allelic variations of a gene set forth e.g., employing a quantitative amplification method Such as in Table 1, Table 2, or Table 3 typically have at least 95% qPCR. In other embodiments, the methods employ array amino acid sequence identity to one another, i.e., an allelic based assays.
Recommended publications
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus

    A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus

    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD

    Supplementary Table S4. FGA Co-Expressed Gene List in LUAD

    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
  • A Common Analgesic Enhances the Anti-Tumour Activity of 5-Aza-2’- Deoxycytidine Through Induction of Oxidative Stress

    A Common Analgesic Enhances the Anti-Tumour Activity of 5-Aza-2’- Deoxycytidine Through Induction of Oxidative Stress

    bioRxiv preprint doi: https://doi.org/10.1101/2020.03.31.017947; this version posted April 1, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. A common analgesic enhances the anti-tumour activity of 5-aza-2’- deoxycytidine through induction of oxidative stress Hannah J. Gleneadie1,10, Amy H. Baker1, Nikolaos Batis2, Jennifer Bryant2, Yao Jiang3, Samuel J.H. Clokie4, Hisham Mehanna2, Paloma Garcia5, Deena M.A. Gendoo6, Sally Roberts5, Alfredo A. Molinolo7, J. Silvio Gutkind8, Ben A. Scheven1, Paul R. Cooper1, Farhat L. Khanim9 and Malgorzata Wiench1, 5,*. 1School of Dentistry, Institute of Clinical Studies, College of Medical and Dental Sciences, The University of Birmingham, Birmingham, B5 7EG, UK; 2Institute of Head and Neck Studies and Education (InHANSE), The University of Birmingham, Birmingham, B15 2TT, UK; 3School of Biosciences, The University of Birmingham, Birmingham, B15 2TT, UK; 4West Midlands Regional Genetics Laboratory, Birmingham Women’s and Children’s Hospital, Birmingham, B15 2TG, UK; 5Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, The University of Birmingham, Birmingham, B15 2TT, UK; 6Centre for Computational Biology, Institute of Cancer and Genomic Sciences, The University of Birmingham, Birmingham, B15 2TT, UK; 7Moores Cancer Center and Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA; 8Department of Pharmacology and Moores Cancer
  • (12) Patent Application Publication (10) Pub. No.: US 2014/0304845 A1 Loboda Et Al

    (12) Patent Application Publication (10) Pub. No.: US 2014/0304845 A1 Loboda Et Al

    US 201403.04845A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0304845 A1 Loboda et al. (43) Pub. Date: Oct. 9, 2014 54) ALZHEMIERS DISEASE SIGNATURE Publicationublication ClassificatiClassification MARKERS AND METHODS OF USE (51) Int. Cl. (71) Applicant: MERCKSHARP & DOHME CORP, CI2O I/68 (2006.01) Rahway, NJ (US) AOIK 67/027 (2006.01) (52) U.S. Cl. (72) Inventors: SIES yet.sS); CPC .......... CI2O I/6883 (2013.01); A0IK 67/0275 Icnaei NepoZnyn, Yeadon, (2013.01) le.East,Italia; David J. Stone, Wyncote, USPC .............. 800/12:536/23.5:536/23.2:506/17 (US); Keith Tanis, Quakertown, PA (US); William J. Ray, Juniper, FL (US) (57) ABSTRACT (21) Appl. No.: 14/354,622 Methods, biomarkers, and expression signatures are dis 1-1. closed for assessing the disease progression of Alzheimer's (22) PCT Filed: Oct. 26, 2012 disease (AD). In one embodiment, BioAge (biological age), NdStress (neurodegenerative stress), Alz (Alzheimer), and (86). PCT No.: PCT/US12A62218 Inflame (inflammation) are used as biomarkers of AD pro S371 (c)(1), gression. In another aspect, the invention comprises a gene (2), (4) Date: Apr. 28, 2014 signature for evaluating disease progression. In still another Related U.S. Application Data abiliticises in (60) Provisional application No. 61/553,400, filed on Oct. used to identify animal models for use in the development and 31, 2011. evaluation of therapeutics for the treatment of AD. Patent Application Publication Oct. 9, 2014 Sheet 1 of 16 US 2014/0304845 A1 Y : : O O O O O O O O D O v v CN On cy Patent Application Publication Oct.
  • Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways

    Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways

    biomolecules Article Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways Aayushi Srivastava 1,2,3,4 , Abhishek Kumar 1,5,6 , Sara Giangiobbe 1, Elena Bonora 7, Kari Hemminki 1, Asta Försti 1,2,3 and Obul Reddy Bandapalli 1,2,3,* 1 Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany; [email protected] (A.S.); [email protected] (A.K.); [email protected] (S.G.); [email protected] (K.H.); [email protected] (A.F.) 2 Hopp Children’s Cancer Center (KiTZ), D-69120 Heidelberg, Germany 3 Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), D-69120 Heidelberg, Germany 4 Medical Faculty, Heidelberg University, D-69120 Heidelberg, Germany 5 Institute of Bioinformatics, International Technology Park, Bangalore 560066, India 6 Manipal Academy of Higher Education (MAHE), Manipal, Karnataka 576104, India 7 S.Orsola-Malphigi Hospital, Unit of Medical Genetics, 40138 Bologna, Italy; [email protected] * Correspondence: [email protected]; Tel.: +49-6221-42-1709 Received: 29 August 2019; Accepted: 10 October 2019; Published: 13 October 2019 Abstract: Evidence of familial inheritance in non-medullary thyroid cancer (NMTC) has accumulated over the last few decades. However, known variants account for a very small percentage of the genetic burden. Here, we focused on the identification of common pathways and networks enriched in NMTC families to better understand its pathogenesis with the final aim of identifying one novel high/moderate-penetrance germline predisposition variant segregating with the disease in each studied family.
  • Supplementary Table 1

    Supplementary Table 1

    Supplementary Table 1. 492 genes are unique to 0 h post-heat timepoint. The name, p-value, fold change, location and family of each gene are indicated. Genes were filtered for an absolute value log2 ration 1.5 and a significance value of p ≤ 0.05. Symbol p-value Log Gene Name Location Family Ratio ABCA13 1.87E-02 3.292 ATP-binding cassette, sub-family unknown transporter A (ABC1), member 13 ABCB1 1.93E-02 −1.819 ATP-binding cassette, sub-family Plasma transporter B (MDR/TAP), member 1 Membrane ABCC3 2.83E-02 2.016 ATP-binding cassette, sub-family Plasma transporter C (CFTR/MRP), member 3 Membrane ABHD6 7.79E-03 −2.717 abhydrolase domain containing 6 Cytoplasm enzyme ACAT1 4.10E-02 3.009 acetyl-CoA acetyltransferase 1 Cytoplasm enzyme ACBD4 2.66E-03 1.722 acyl-CoA binding domain unknown other containing 4 ACSL5 1.86E-02 −2.876 acyl-CoA synthetase long-chain Cytoplasm enzyme family member 5 ADAM23 3.33E-02 −3.008 ADAM metallopeptidase domain Plasma peptidase 23 Membrane ADAM29 5.58E-03 3.463 ADAM metallopeptidase domain Plasma peptidase 29 Membrane ADAMTS17 2.67E-04 3.051 ADAM metallopeptidase with Extracellular other thrombospondin type 1 motif, 17 Space ADCYAP1R1 1.20E-02 1.848 adenylate cyclase activating Plasma G-protein polypeptide 1 (pituitary) receptor Membrane coupled type I receptor ADH6 (includes 4.02E-02 −1.845 alcohol dehydrogenase 6 (class Cytoplasm enzyme EG:130) V) AHSA2 1.54E-04 −1.6 AHA1, activator of heat shock unknown other 90kDa protein ATPase homolog 2 (yeast) AK5 3.32E-02 1.658 adenylate kinase 5 Cytoplasm kinase AK7
  • Qt38n028mr Nosplash A3e1d84

    Qt38n028mr Nosplash A3e1d84

    ! ""! ACKNOWLEDGEMENTS I dedicate this thesis to my parents who inspired me to become a scientist through invigorating scientific discussions at the dinner table even when I was too young to understand what the hippocampus was. They also prepared me for the ups and downs of science and supported me through all of these experiences. I would like to thank my advisor Dr. Elizabeth Blackburn and my thesis committee members Dr. Eric Verdin, and Dr. Emmanuelle Passegue. Liz created a nurturing and supportive environment for me to explore my own ideas, while at the same time teaching me how to love science, test my questions, and of course provide endless ways to think about telomeres and telomerase. Eric and Emmanuelle both gave specific critical advice about the proper experiments for T cells and both volunteered their lab members for further critical advice. I always felt inspired with a sense of direction after thesis committee meetings. The Blackburn lab is full of smart and dedicated scientists whom I am thankful for their support. Specifically Dr. Shang Li and Dr. Brad Stohr for their stimulating scientific debates and “arguments.” Dr. Jue Lin, Dana Smith, Kyle Lapham, Dr. Tet Matsuguchi, and Kyle Jay for their friendships and discussions about what my data could possibly mean. Dr. Eva Samal for teaching me molecular biology techniques and putting up with my late night lab exercises. Beth Cimini for her expertise with microscopy, FACs, singing, and most of all for being a caring and supportive friend. Finally, I would like to thank Dr. Imke Listerman, my scientific partner for most of the breast cancer experiments.
  • Estudo De Associação Genética Em Larga Escala Identifica Potenciais Regiões Candidatas Para O Bruxismo Do Sono

    Estudo De Associação Genética Em Larga Escala Identifica Potenciais Regiões Candidatas Para O Bruxismo Do Sono

    Rosalvo Amaral Junior Estudo de associação genética em larga escala identifica potenciais regiões candidatas para o bruxismo do sono Dissertação apresentada à Universidade Federal de São Paulo – Escola Paulista de Medicina, para obtenção do Título de Mestre em Ciências São Paulo 2017 Rosalvo Amaral Junior Estudo de associação genética em larga escala identifica potenciais regiões candidatas para o bruxismo do sono Dissertação apresentada à Universidade Federal de São Paulo – Escola Paulista de Medicina, para obtenção do Título de Mestre em Ciências Orientadora: Profa. Dra. Monica Levy Andersen Coorientadora: Dra. Camila Hirotsu São Paulo 2017 Amaral Junior, Rosalvo Estudo de associação genética em larga escala identifica potenciais regiões candidatas para o bruxismo do sono/ Rosalvo Amaral Junior. São Paulo, 2017. xxiii, 100f. Dissertação (Mestrado) – Universidade Federal de São Paulo. Escola Paulista de Medicina. Programa de Pós -graduação em Psicobiologia. Título em inglês: Genome-wide association study identifies potential candidate gene regions for sleep bruxism. 1. Bruxismo do sono. 2. Genética. 3. Polimorfismo. 4. Polissonografia. Rosalvo Amaral Junior UNIVERSIDADE FEDERAL DE SÃO PAULO ESCOLA PAULISTA DE MEDICINA DEPARTAMENTO DE PSICOBIOLOGIA Chefe do Departamento: Prof. Dr. José Carlos Fernandes Galduróz Coordenadora do Curso de Pós-graduação: Profa. Dra. Débora Cristina Hipólide iii Rosalvo Amaral Junior Estudo de associação genética em larga escala identifica potenciais regiões candidatas para o bruxismo do sono Presidente da
  • Implantation Period Using the Affymetrix Genechip Mirna 4.0 Array

    Implantation Period Using the Affymetrix Genechip Mirna 4.0 Array

    Characterization of miRNAs in the spent media throughout the pre- implantation period using the Affymetrix Genechip miRNA 4.0 array by Paul Del Rio A Thesis presented to The University of Guelph In partial fulfilment of requirements for the degree of Master of Science in Biomedical Science Guelph, Ontario, Canada © Paul Del Rio, January, 2021 ABSTRACT CHARACTERIZATION OF MIRNAS IN THE SPENT MEDIA THROUGHOUT THE PRE- IMPLANTATION PERIOD USING THE AFFYMETRIX GENECHIP MIRNA 4.0 ARRAY Paul Del Rio Advisor(s): University of Guelph, 2021 Dr. Pavneesh Madan Distinct miRNA populations have only been detected in spent media (SM) cultured with blastocyst-stage embryos. Therefore, the aim of the study was to globally profile the extracellular microRNA (miRNA) population throughout the pre-implantation period in bovine embryos. Briefly, embryos were in-vitro produced in group culture and SM was collected at the 2-cell, 8-cell, and blastocyst stage of development. Total RNA was extracted from SM and hybridized onto a miRNA microarray. Results show that distinct miRNA populations can be detected in the SM at the 2-cell, 8-cell, and blastocyst stage of development with miRNAs showing stage-dependant and stage-independent expression in SM. In addition, distinct miRNA populations can be identified in the SM cultured with slow-growing and fast-growing embryos at the 2-cell, 8-cell, and blastocyst stage of development. Overall, the findings contribute to the growing body of evidence supporting the use of miRNAs in SM as non-invasive biomarkers of early embryo development. DECLARATION OF WORK PERFORMED I declare that all work presented in this thesis was performed by me with the exception of the procedures mentioned below: Stephan Botha, Saeid Ghiasi, and Stephanie Hookey collected cattle ovaries from a government inspected commercial abattoir (Cargill Meat Solutions, Guelph, Ontario, Canada).
  • Analysis of the Impact of Pufas on Placental Gene Expression V2.28 Uploadx

    Analysis of the Impact of Pufas on Placental Gene Expression V2.28 Uploadx

    TECHNISCHE UNIVERSITÄT MÜNCHEN Lehrstuhl für Ernährungsmedizin Analysis of the Impact of Polyunsaturated Fatty Acids (PUFAs) on Placental Gene Expression Eva-Maria Sedlmeier Vollständiger Abdruck der von der Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation. Vorsitzender: Univ.-Prof. Dr. M. Klingenspor Prüfer der Dissertation: 1. Univ.-Prof. Dr. J. J. Hauner 2. Univ.-Prof. Dr. H. Daniel Die Dissertation wurde am 17.10.2013 bei der Technischen Universität München eingereicht und durch die Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt am 12.12.2013 angenommen. Table of contents Table of contents Table of contents ....................................................................................................... I Summary .................................................................................................................. VI Zusammenfassung ................................................................................................ VIII 1. Introduction ........................................................................................................ 1 1.1. Fetal programming - a strategy to prevent the obesity epidemic? ...........................................1 1.1.1. The obesity epidemic ........................................................................................................1 1.1.2. Fetal programming
  • 1 SUPPLEMENTAL DATA Figure S1. Poly I:C Induces IFN-Β Expression

    1 SUPPLEMENTAL DATA Figure S1. Poly I:C Induces IFN-Β Expression

    SUPPLEMENTAL DATA Figure S1. Poly I:C induces IFN-β expression and signaling. Fibroblasts were incubated in media with or without Poly I:C for 24 h. RNA was isolated and processed for microarray analysis. Genes showing >2-fold up- or down-regulation compared to control fibroblasts were analyzed using Ingenuity Pathway Analysis Software (Red color, up-regulation; Green color, down-regulation). The transcripts with known gene identifiers (HUGO gene symbols) were entered into the Ingenuity Pathways Knowledge Base IPA 4.0. Each gene identifier mapped in the Ingenuity Pathways Knowledge Base was termed as a focus gene, which was overlaid into a global molecular network established from the information in the Ingenuity Pathways Knowledge Base. Each network contained a maximum of 35 focus genes. 1 Figure S2. The overlap of genes regulated by Poly I:C and by IFN. Bioinformatics analysis was conducted to generate a list of 2003 genes showing >2 fold up or down- regulation in fibroblasts treated with Poly I:C for 24 h. The overlap of this gene set with the 117 skin gene IFN Core Signature comprised of datasets of skin cells stimulated by IFN (Wong et al, 2012) was generated using Microsoft Excel. 2 Symbol Description polyIC 24h IFN 24h CXCL10 chemokine (C-X-C motif) ligand 10 129 7.14 CCL5 chemokine (C-C motif) ligand 5 118 1.12 CCL5 chemokine (C-C motif) ligand 5 115 1.01 OASL 2'-5'-oligoadenylate synthetase-like 83.3 9.52 CCL8 chemokine (C-C motif) ligand 8 78.5 3.25 IDO1 indoleamine 2,3-dioxygenase 1 76.3 3.5 IFI27 interferon, alpha-inducible
  • Adrenomedullin and Receptor for Urokinase Plasminogen Activator Are Involved

    Adrenomedullin and Receptor for Urokinase Plasminogen Activator Are Involved

    Adrenomedullin and Receptor for Urokinase Plasminogen Activator are involved in Hereditary Angioedema attacks: a transcriptomic study Giuseppe Castellano*1, Chiara Divella*1, Fabio Sallustio*1, Vincenzo Montinaro1, Claudia Curci1, Andrea Zanichelli2, Erika Bonanni2, Chiara Suffritti2, Sonia Caccia2, Anna Gallone3, Francesco Paolo Schena4, Loreto Gesualdo MD1, Marco Cicardi2 (1) Nephrology Unit ; Department of Emergency and Organ Transplantation, University “Aldo Moro” Bari, Italy, and Center for Diagnosis and Treatment of Hereditary Angioedema. (2) Department of Biomedical and Clinical Sciences, Luigi Sacco Hospital, University of Milan, Milan, Italy. (3) Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari "Aldo Moro", Bari, 70124, Italy. (4) University of Bari and Fondazione Schena, Valenzano, Bari, Italy. Corresponding author: Giuseppe Castellano, M.D., PhD; Nephrology Unit ; Department of Emergency and Organ Transplantation, University “Aldo Moro” Bari, Italy, and Center for Diagnosis and Treatment of Hereditary Angioedema. Piazza G. Cesare,11 70124 Bari, Italy; Tel./Fax : 0039 080 5478878; Email: [email protected] * Giuseppe Castellano and Chiara Divella and Fabio Sallustio equally contributed to the present study. Loreto Gesualdo, Francesco Paolo Schena and Marco Cicardi shared senior authorship Acknowledgments 1 Supported by The Telethon Foundation (Telethon Grant number: GGP08223 granted to GC, SC and MC). Disclosure of potential conflict of interest The rest of the authors declare that they have no relevant conflicts of interest. 2 Abstract Background: Hereditary Angioedema (HAE) due to C1-inhibitor deficiency is a lifelong illness characterized by recurrent acute attacks of localized skin or mucosal edema. An activation of the kallikrein/bradykinin pathway at endothelial cell level has a relevant pathogenetic role in acute HAE attacks.