DOCSLIB.ORG

Solving the Glucocorticoid Paradox in Cancer Using Expression Data

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Solving the Glucocorticoid Paradox in Cancer Using Expression Data ADVERTIMENT. Lʼaccés als continguts dʼaquesta tesi queda condicionat a lʼacceptació de les condicions dʼús establertes per la següent llicència Creative Commons: http://cat.creativecommons.org/?page_id=184 ADVERTENCIA. El acceso a los contenidos de esta tesis queda condicionado a la aceptación de las condiciones de uso establecidas por la siguiente licencia Creative Commons: http://es.creativecommons.org/blog/licencias/ WARNING. The access to the contents of this doctoral thesis it is limited to the acceptance of the use conditions set by the following Creative Commons license: https://creativecommons.org/licenses/?lang=en Solving The Glucocorticoid Paradox In Cancer Using Expression Data Mario Huerta Casado 2016 Solving the Glucocorticoid Paradox In Cancer Using Expression Data Mario Huerta Casado 2016 Submitted for the Degree of Doctor of Philosophy in Biotechnology by Mario Huerta Casado The work was supervised by Dr. Enric Querol Murillo of the Institut de Biotecnologia i de Biomedicina- Universitat Autònoma de Barcelona and Dr. Juan Cedano Rodriguez of CENUR Litoral Norte-Salto, Universidad de la República, Uruguay Mario Huerta Casado Enric Querol Murillo Juan Cedano Rodriguez Universitat Autònoma de Barcelona, 2016 Don’t let the trees stop you from seeing the forest. Unknown author Abstract Glucocorticoids are commonly used as an adjuvant treatment for side-effects and have anti- proliferative activity in several tumours. Inspite of this fact, there has been reported a proliferative effect in several studies, that some of them involving the spread of cancer. These paradoxes are common in cancer research. Usually the same genes seem to be promoter and inhibitor of cancer. We shall attempt to reconcile these incongruities from the transcriptomic and tissue-physiology perspectives with our procedures and findings. An accurate phenotype analysis of expression data can help to solve multiple paradoxes derived from tumour-progression models. We have developed several strategies, tools and databases to facilitate the study of interdependences among the phenotypes hidden inside expression data. These phenotypes can be identified by the sample clusters obtained by common clustering methods (HC, SOTA, SOM, PAM), but clustering methods do not provide information about their interdependence. We study these interdependences by the detection of non-linear expression- relationships where each fluctuation in the relationship implies a phenotype change and each relationship typology implies specific phenotype interdependence. In this way different strategies and tools have been developed to study phenotypic changes and the paradoxes subjected to them. Using the tools developed we have studied the non-linear expression relationships related to glucocorticoid activity. The result is that we have found the possible reason for opposite effects of some stressor agents like dexamethasone on tumour progression as it has been confirmed by literature. This hidden reason has resulted in being linked with the type of tumour progression of the tissues. In the first type of tumour progression found, new cells can be stressed during proliferation and stressor agents increase tumour proliferation. In the second type, cell stress and tumour proliferation are antagonists so, therefore, stressor agents stop tumour proliferation in order to stress the cells. Resum Els glucocorticoides s'utilitzen comunament com a tractament adjuvant per tractar efectes secundaris i tenen una activitat antiproliferativa en diversos tumors però, d'altra banda, el seu efecte proliferatiu s’ha documentat en diversos estudis i en alguns d'ells implica la propagació del càncer. Aquestes paradoxes són comuns en l’investigació del càncer. Molt sobint, els mateixos gens semblen ser a l’hora promotors i inhibidors del càncer. Amb el present treball pretenem conciliar aquestes incongruències des de la perspectiva de la genética i de la fisiologia del teixit amb els nostres procediments i troballes. Un anàlisi precís dels fenotips presents a les dades d'expressió gènica pot ajudar a resoldre múltiples paradoxes derivades dels models de progressió de tumors. En aquest sentit hem desenvolupat diverses estratègies, eines i bases de dades, per facilitar l'estudi de les interdependències entre els fenotips ocults dins de les dades d'expressió. Aquests fenotips poden ser identificats pels grups de mostres obtinguts mitjançant mètodes comuns d'agrupament (HC, SOTA, SOM, PAM), però els mètodes d'agrupament no proporcionen informació sobre la seva interdependència. Nosaltres estudiem aquestes interdependències per la detecció de relacions d'expressió no lineals, on cada fluctuació en la relació implica un canvi fenotípic i cada tipolologia de la relació diferent implica una interdependència fenotípica específica. D'aquesta manera, s'han desenvolupat diferents estratègies i eines per estudiar els canvis fenotípics i les paradoxes sotmeses a ells. Utilitzant les eines desenvolupades s'han estudiat les relacions d'expressió no lineals relacionades amb l'activitat dels glucocorticoides. Estudiant-les, hem trobat la possible raó dels efectes oposats d'alguns agents estressants com la dexametasona sobre la progressió tumoral, com ha estat confirmat per la literatura. Aquesta raó oculta ha resultat estar vinculada amb el tipus de progressió del tumor en cada teixit. En el primer tipus de progressió tumoral trobat, les noves cèl·lules poden ser estressades durant la proliferació i els agents estressants augmenten la proliferació tumoral. En el segon tipus, l'estrès cel·lular i la proliferació del tumor són antagonistes així, per tant, els agents estressants aturen la proliferació tumoral amb la finalitat d’estressar les cèl·lules. Resumen Los glucocorticoides se utilizan comúnmente como tratamiento adyuvante para tratar efectos secundarios y tienen una actividad antiproliferativa en varios tumores, pero, por otra parte, su efecto proliferativo se ha documentado en varios estudios que en algunos de ellos implica la propagación del cáncer. Estas paradojas son comunes en la investigación del cáncer. A menudo los mismos genes parecen ser promotores e inhibidores del cáncer. En el presente trabajo vamos a tratar de conciliar estas incongruencias desde la perspectiva genética y de la fisiologicaa del tejido con nuestros procedimientos y hallazgos. Un análisis preciso de los fenotipos presentes en los datos de expresión génica puede ayudar a resolver múltiples paradojas derivadas de los modelos de progresión de tumores. Con ese fin hemos desarrollado diversas estrategias, herramientas y bases de datos para facilitar el estudio de las interdependencias entre los fenotipos ocultos dentro de los datos de expresión. Estos fenotipos pueden ser identificados por los grupos de muestras obtenidos mediante métodos comunes de agrupación (HC, SO, SOM, PAM), pero los métodos de agrupación no proporcionan información sobre su interdependencia. Estudiamos estas interdependencias mediante la detección de relaciones de expresión no lineales, dónde cada fluctuación en la relación implica un cambio fenotípico y cada tipología de la relación implica una interdependencia fenotípica específica. De este modo, se han desarrollado diferentes estrategias y herramientas para estudiar los cambios fenotípicos y las paradojas sometidas a ellos. Utilizando las herramientas desarrolladas se han estudiado las relaciones de expresión no lineales relacionadas con la actividad de los glucocorticoides. Estudiándolas, hemos encontrado la posible razón de los efectos opuestos de algunos agentes estresantes como la dexametasona sobre la progresión tumoral, como ha sido confirmado por la literatura. Esta razón oculta resultó estar vinculada con el tipo de progresión del tumor de los diferentes tejidos. En el primer tipo de progresión tumoral encontrado, las nuevas células pueden ser estresadas durante la proliferación y los agentes estresantes aumentan la proliferación tumoral. En el segundo tipo, el estrés celular y la proliferación del tumor son antagonistas así, por tanto, los agentes estresantes detienen la proliferación tumoral con el fin de estresar las células. Table of Contents 1. Background ........................................................................................................................................................................... 21 1.1. The glucocorticoid paradox .................................................................................................................................................................................... 24 1.2. What is the hidden reason for this dual behaviour of glucocorticoids? ............................................................................................................... 24 1.3. To search for the hidden reason for glucocorticoids' dual behaviour we need tools to study dual behaviours in cancer findings................. 25 1.4. Studying phenotypes from expression data using sample clustering ................................................................................................................. 26 1.5. Studying phenotypic changes from expression data ............................................................................................................................................ 29 1.6. Using non-linear expression relationships to study phenotypes and phenotypic changes ............................................................................... 30 2. Objectives ............................................................................................................................................................................
Load more

Recommended publications
  • Single Nucleotide Polymorphisms in DKK3 Gene Are Associated with Prostate Cancer Risk and Progression ______
    ORIGINAL ARTICLE Vol. 41 (5): 869-897, September - October, 2015 doi: 10.1590/S1677-5538.IBJU.2014.0041 Single nucleotide polymorphisms in DKK3 gene are associated with prostate cancer risk and progression _______________________________________________ Min Su Kim 1, Ha Na Lee 2, Hae Jong Kim 3,4, Soon Chul Myung 5 1Department of Urology, Seoul Medical Center, Seoul, Korea; 2Department of Urology, Seoul Seonam Hospital, EwhaWomans University, Seoul, Korea; 3Research Institue for Biomedical and Pharmaceutical Sciences, Chung-Ang University, Seoul, Korea; 4Advanced Urogenital Diseas Research Center, Chung-Ang University, College of Medicine, Seoul, Korea; 5Department of Urology, Chung-Ang University, College of Medicine, Seoul, Korea ABSTRACT ARTICLE INFO ______________________________________________________________ ______________________ We had investigated whether sequence variants within DKK3 gene are associated with Key words: the development of prostate cancer in a Korean study cohort. We evaluated the asso- Biological Markers; Genetic ciation between 53 single nucleotide polymorphisms (SNPs) in the DKK3 gene and Variation; Prostatic Neoplasms; prostate cancer risk as well as clinical characteristics (PSA, clinical stage, pathological Polymorphism, Single Nucleotide stage and Gleason score) in Korean men (272 prostate cancer subjects and 173 benign prostate hyperplasia subjects) using unconditional logistic regression analysis. Of the Int Braz J Urol. 2015; 41: 869-97 53 SNPs and 25 common haplotypes, 5 SNPs and 4 haplotypes were
    [Show full text]
  • Short Bowel Syndrome Results in Increased Gene Expression
    Schall et al. BMC Genomics (2017) 18:23 DOI 10.1186/s12864-016-3433-4 RESEARCH ARTICLE Open Access Short bowel syndrome results in increased gene expression associated with proliferation, inflammation, bile acid synthesis and immune system activation: RNA sequencing a zebrafish SBS model Kathy A. Schall1, Matthew E. Thornton2, Mubina Isani1, Kathleen A. Holoyda1, Xiaogang Hou1, Ching-Ling Lien3, Brendan H. Grubbs2 and Tracy C. Grikscheit1,4* Abstract Background: Much of the morbidity associated with short bowel syndrome (SBS) is attributed to effects of decreased enteral nutrition and administration of total parenteral nutrition (TPN). We hypothesized that acute SBS alone has significant effects on gene expression beyond epithelial proliferation, and tested this in a zebrafish SBS model. Methods: In a model of SBS in zebrafish (laparotomy, proximal stoma, distal ligation, n = 29) or sham (laparotomy alone, n = 28) surgery, RNA-Seq was performed after 2 weeks. The proximal intestine was harvested and RNA isolated. The three samples from each group with the highest amount of RNA were spiked with external RNA controls consortium (ERCC) controls, sequenced and aligned to reference genome with gene ontology (GO) enrichment analysis performed. Gene expression of ctnnb1, ccnb1, ccnd1, cyp7a1a, dkk3, ifng1-2, igf2a, il1b, lef1, nos2b, saa1, stat3, tnfa and wnt5a were confirmed to be elevated in SBS by RT-qPCR. Results: RNA-seq analysis identified 1346 significantly upregulated genes and 678 significantly downregulated genes in SBS zebrafish intestine compared to sham with Ingenuity analysis. The upregulated genes were involved in cell proliferation, acute phase response signaling, innate and adaptive immunity, bile acid regulation, production of nitric oxide and reactive oxygen species, cellular barrier and coagulation.
    [Show full text]
  • Distant Bystander Effect of REIC/DKK3 Gene Therapy Through Immune System Stimulation in Thoracic Malignancies
    ANTICANCER RESEARCH 37 : 301-308 (2017) doi:10.21873/anticanres.11321 Distant Bystander Effect of REIC/DKK3 Gene Therapy Through Immune System Stimulation in Thoracic Malignancies KEN SUZAWA 1* , KAZUHIKO SHIEN 1,2* , HUANG PENG 3, MASAKIYO SAKAGUCHI 4, MASAMI WATANABE 5,6,7 , SHINSUKE HASHIDA 1,2 , YUHO MAKI 1, HIROMASA YAMAMOTO 1, SHUTA TOMIDA 8, JUNICHI SOH 1, HIROAKI ASANO 1, KAZUNORI TSUKUDA 1, YASUTOMO NASU 5,6,7 , HIROMI KUMON 3,5,7 , SHINICHIRO MIYOSHI 1 and SHINICHI TOYOOKA 1,2 Departments of 1Thoracic Surgery, 2Clinical Genomic Medicine and 4Cell Biology, 5Urology, 3Collaborative Research Center for Okayama Medical Innovation Center, and 8Biobank, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; 6Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan; 7Innovation Center Okayama for Nanobio-Targeted Therapy, Okayama University, Okayama, Japan Abstract. Background: Reduced expression in immortalized Both advanced-stage non-small cell lung cancer (NSCLC) cell (REIC)/Dickkoph-3 (DKK3) is a tumor-suppressor gene, and malignant mesothelioma (MM) are aggressive tumors and and its overexpression by adenovirus vector (Ad-REIC) present a dismal prognosis. Despite advances in treatment exhibits a remarkable therapeutic effect on various human regimens for both diseases, such as surgical resection, cancer types through a mechanism triggered by endoplasmic chemotherapy, molecular-targeted therapy and radiotherapy, reticulum stress. Materials and Methods: We examined the treatment outcome is still unsatisfactory. Gene therapy for direct anti-tumor effect of Ad-REIC gene therapy on lung thoracic malignancies represents a novel therapeutic approach cancer and malignant mesothelioma cell lines in vitro, and and has been evaluated in a number of clinical trials over the the distant bystander effect using immunocompetent mouse last two decades (1).
    [Show full text]
  • Meta-Analysis of Nasopharyngeal Carcinoma
    BMC Genomics BioMed Central Research article Open Access Meta-analysis of nasopharyngeal carcinoma microarray data explores mechanism of EBV-regulated neoplastic transformation Xia Chen†1,2, Shuang Liang†1, WenLing Zheng1,3, ZhiJun Liao1, Tao Shang1 and WenLi Ma*1 Address: 1Institute of Genetic Engineering, Southern Medical University, Guangzhou, PR China, 2Xiangya Pingkuang associated hospital, Pingxiang, Jiangxi, PR China and 3Southern Genomics Research Center, Guangzhou, Guangdong, PR China Email: Xia Chen - [email protected]; Shuang Liang - [email protected]; WenLing Zheng - [email protected]; ZhiJun Liao - [email protected]; Tao Shang - [email protected]; WenLi Ma* - [email protected] * Corresponding author †Equal contributors Published: 7 July 2008 Received: 16 February 2008 Accepted: 7 July 2008 BMC Genomics 2008, 9:322 doi:10.1186/1471-2164-9-322 This article is available from: http://www.biomedcentral.com/1471-2164/9/322 © 2008 Chen et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Epstein-Barr virus (EBV) presumably plays an important role in the pathogenesis of nasopharyngeal carcinoma (NPC), but the molecular mechanism of EBV-dependent neoplastic transformation is not well understood. The combination of bioinformatics with evidences from biological experiments paved a new way to gain more insights into the molecular mechanism of cancer. Results: We profiled gene expression using a meta-analysis approach. Two sets of meta-genes were obtained. Meta-A genes were identified by finding those commonly activated/deactivated upon EBV infection/reactivation.
    [Show full text]
  • 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.
    [Show full text]
  • Microgenomics of Ameloblastoma
    RESEARCH REPORTS Biological P. DeVilliers1, C. Suggs2, D. Simmons2, V. Murrah3, and J.T. Wright2* Microgenomics of 1Department of Pathology, University of Alabama at Ameloblastoma Birmingham; 2Department of Pediatric Dentistry, CB #7450, and 3Department of Oral Pathology, University of North Carolina at Chapel Hill, NC 27599, USA; *corresponding author, [email protected] J Dent Res 90(4):463-469, 2011 ABSTRACT INTRODUCTION Gene expression profiles of human ameloblastoma microdissected cells were characterized with the meloblastoma is an aggressive tumor of odontogenic epithelial origin, purpose of identifying genes and their protein Awith devastating morbidity if left untreated, due to its unlimited growth products that could be targeted as diagnostic and potential. It is characterized by a high rate of recurrence (up to 70%, depend- prognostic markers as well as for potential thera- ing on the treatment modality) and potential to undergo malignant transfor- peutic interventions. Five formalin-fixed, decalci- mation and to metastasize (up to 2% of cases). Malignant ameloblastoma is fied, paraffin-embedded samples of ameloblastoma defined as a histologically benign-appearing ameloblastoma with metastasis were subjected to laser capture microdissection, (Goldenberg et al., 2004; Cardoso et al., 2009). Surgical resection is the treat- linear mRNA amplification, and hybridization to ment of choice, which can cause further morbidity to the craniofacial com- oligonucleotide human 41,000 RNA arrays and plex, with loss of function and esthetics (Olasoji and Enwere, 2003). compared with universal human reference RNA, Gene expression profiling of tumor cell populations has advanced our to determine the gene expression signature. understanding of the pathogenesis of human tumors (Naderi et al., 2004).
    [Show full text]
  • 4-6 Weeks Old Female C57BL/6 Mice Obtained from Jackson Labs Were Used for Cell Isolation
    Methods Mice: 4-6 weeks old female C57BL/6 mice obtained from Jackson labs were used for cell isolation. Female Foxp3-IRES-GFP reporter mice (1), backcrossed to B6/C57 background for 10 generations, were used for the isolation of naïve CD4 and naïve CD8 cells for the RNAseq experiments. The mice were housed in pathogen-free animal facility in the La Jolla Institute for Allergy and Immunology and were used according to protocols approved by the Institutional Animal Care and use Committee. Preparation of cells: Subsets of thymocytes were isolated by cell sorting as previously described (2), after cell surface staining using CD4 (GK1.5), CD8 (53-6.7), CD3ε (145- 2C11), CD24 (M1/69) (all from Biolegend). DP cells: CD4+CD8 int/hi; CD4 SP cells: CD4CD3 hi, CD24 int/lo; CD8 SP cells: CD8 int/hi CD4 CD3 hi, CD24 int/lo (Fig S2). Peripheral subsets were isolated after pooling spleen and lymph nodes. T cells were enriched by negative isolation using Dynabeads (Dynabeads untouched mouse T cells, 11413D, Invitrogen). After surface staining for CD4 (GK1.5), CD8 (53-6.7), CD62L (MEL-14), CD25 (PC61) and CD44 (IM7), naïve CD4+CD62L hiCD25-CD44lo and naïve CD8+CD62L hiCD25-CD44lo were obtained by sorting (BD FACS Aria). Additionally, for the RNAseq experiments, CD4 and CD8 naïve cells were isolated by sorting T cells from the Foxp3- IRES-GFP mice: CD4+CD62LhiCD25–CD44lo GFP(FOXP3)– and CD8+CD62LhiCD25– CD44lo GFP(FOXP3)– (antibodies were from Biolegend). In some cases, naïve CD4 cells were cultured in vitro under Th1 or Th2 polarizing conditions (3, 4).
    [Show full text]
  • S41467-020-18249-3.Pdf
    ARTICLE https://doi.org/10.1038/s41467-020-18249-3 OPEN Pharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain Lei Zhao1,2,17, Zhongqi Li 1,2,17, Joaquim S. L. Vong2,3,17, Xinyi Chen1,2, Hei-Ming Lai1,2,4,5,6, Leo Y. C. Yan1,2, Junzhe Huang1,2, Samuel K. H. Sy1,2,7, Xiaoyu Tian 8, Yu Huang 8, Ho Yin Edwin Chan5,9, Hon-Cheong So6,8, ✉ ✉ Wai-Lung Ng 10, Yamei Tang11, Wei-Jye Lin12,13, Vincent C. T. Mok1,5,6,14,15 &HoKo 1,2,4,5,6,8,14,16 1234567890():,; The molecular signatures of cells in the brain have been revealed in unprecedented detail, yet the ageing-associated genome-wide expression changes that may contribute to neurovas- cular dysfunction in neurodegenerative diseases remain elusive. Here, we report zonation- dependent transcriptomic changes in aged mouse brain endothelial cells (ECs), which pro- minently implicate altered immune/cytokine signaling in ECs of all vascular segments, and functional changes impacting the blood–brain barrier (BBB) and glucose/energy metabolism especially in capillary ECs (capECs). An overrepresentation of Alzheimer disease (AD) GWAS genes is evident among the human orthologs of the differentially expressed genes of aged capECs, while comparative analysis revealed a subset of concordantly downregulated, functionally important genes in human AD brains. Treatment with exenatide, a glucagon-like peptide-1 receptor agonist, strongly reverses aged mouse brain EC transcriptomic changes and BBB leakage, with associated attenuation of microglial priming. We thus revealed tran- scriptomic alterations underlying brain EC ageing that are complex yet pharmacologically reversible.
    [Show full text]
  • Análise Integrativa De Perfis Transcricionais De Pacientes Com
    UNIVERSIDADE DE SÃO PAULO FACULDADE DE MEDICINA DE RIBEIRÃO PRETO PROGRAMA DE PÓS-GRADUAÇÃO EM GENÉTICA ADRIANE FEIJÓ EVANGELISTA Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas Ribeirão Preto – 2012 ADRIANE FEIJÓ EVANGELISTA Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas Tese apresentada à Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo para obtenção do título de Doutor em Ciências. Área de Concentração: Genética Orientador: Prof. Dr. Eduardo Antonio Donadi Co-orientador: Prof. Dr. Geraldo A. S. Passos Ribeirão Preto – 2012 AUTORIZO A REPRODUÇÃO E DIVULGAÇÃO TOTAL OU PARCIAL DESTE TRABALHO, POR QUALQUER MEIO CONVENCIONAL OU ELETRÔNICO, PARA FINS DE ESTUDO E PESQUISA, DESDE QUE CITADA A FONTE. FICHA CATALOGRÁFICA Evangelista, Adriane Feijó Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas. Ribeirão Preto, 2012 192p. Tese de Doutorado apresentada à Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo. Área de Concentração: Genética. Orientador: Donadi, Eduardo Antonio Co-orientador: Passos, Geraldo A. 1. Expressão gênica – microarrays 2. Análise bioinformática por module maps 3. Diabetes mellitus tipo 1 4. Diabetes mellitus tipo 2 5. Diabetes mellitus gestacional FOLHA DE APROVAÇÃO ADRIANE FEIJÓ EVANGELISTA Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas.
    [Show full text]
  • Role of RUNX1 in Aberrant Retinal Angiogenesis Jonathan D
    Page 1 of 25 Diabetes Identification of RUNX1 as a mediator of aberrant retinal angiogenesis Short Title: Role of RUNX1 in aberrant retinal angiogenesis Jonathan D. Lam,†1 Daniel J. Oh,†1 Lindsay L. Wong,1 Dhanesh Amarnani,1 Cindy Park- Windhol,1 Angie V. Sanchez,1 Jonathan Cardona-Velez,1,2 Declan McGuone,3 Anat O. Stemmer- Rachamimov,3 Dean Eliott,4 Diane R. Bielenberg,5 Tave van Zyl,4 Lishuang Shen,1 Xiaowu Gai,6 Patricia A. D’Amore*,1,7 Leo A. Kim*,1,4 Joseph F. Arboleda-Velasquez*1 Author affiliations: 1Schepens Eye Research Institute/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, 20 Staniford St., Boston, MA 02114 2Universidad Pontificia Bolivariana, Medellin, Colombia, #68- a, Cq. 1 #68305, Medellín, Antioquia, Colombia 3C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114 4Retina Service, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, 243 Charles St., Boston, MA 02114 5Vascular Biology Program, Boston Children’s Hospital, Department of Surgery, Harvard Medical School, 300 Longwood Ave., Boston, MA 02115 6Center for Personalized Medicine, Children’s Hospital Los Angeles, Los Angeles, 4650 Sunset Blvd, Los Angeles, CA 90027, USA 7Department of Pathology, Harvard Medical School, 25 Shattuck St., Boston, MA 02115 Corresponding authors: Joseph F. Arboleda-Velasquez: [email protected] Ph: (617) 912-2517 Leo Kim: [email protected] Ph: (617) 912-2562 Patricia D’Amore: [email protected] Ph: (617) 912-2559 Fax: (617) 912-0128 20 Staniford St. Boston MA, 02114 † These authors contributed equally to this manuscript Word Count: 1905 Tables and Figures: 4 Diabetes Publish Ahead of Print, published online April 11, 2017 Diabetes Page 2 of 25 Abstract Proliferative diabetic retinopathy (PDR) is a common cause of blindness in the developed world’s working adult population, and affects those with type 1 and type 2 diabetes mellitus.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2006/0088532 A1 Alitalo Et Al
    US 20060O88532A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0088532 A1 Alitalo et al. (43) Pub. Date: Apr. 27, 2006 (54) LYMPHATIC AND BLOOD ENDOTHELIAL Related U.S. Application Data CELL GENES (60) Provisional application No. 60/363,019, filed on Mar. (76) Inventors: Kari Alitalo, Helsinki (FI); Taija 7, 2002. Makinen, Helsinki (FI); Tatiana Petrova, Helsinki (FI); Pipsa Publication Classification Saharinen, Helsinki (FI); Juha Saharinen, Helsinki (FI) (51) Int. Cl. A6IR 48/00 (2006.01) Correspondence Address: A 6LX 39/395 (2006.01) MARSHALL, GERSTEIN & BORUN LLP A6II 38/18 (2006.01) 233 S. WACKER DRIVE, SUITE 6300 (52) U.S. Cl. .............................. 424/145.1: 514/2: 514/44 SEARS TOWER (57) ABSTRACT CHICAGO, IL 60606 (US) The invention provides polynucleotides and genes that are (21) Appl. No.: 10/505,928 differentially expressed in lymphatic versus blood vascular endothelial cells. These genes are useful for treating diseases (22) PCT Filed: Mar. 7, 2003 involving lymphatic vessels, such as lymphedema, various inflammatory diseases, and cancer metastasis via the lym (86). PCT No.: PCT/USO3FO6900 phatic system. Patent Application Publication Apr. 27, 2006 Sheet 1 of 2 US 2006/0088532 A1 integrin O9 integrin O1 KIAAO711 KAAO644 ApoD Fig. 1 Patent Application Publication Apr. 27, 2006 Sheet 2 of 2 US 2006/0088532 A1 CN g uueleo-gº US 2006/0O88532 A1 Apr. 27, 2006 LYMPHATIC AND BLOOD ENDOTHELLAL CELL lymphatic vessels, such as lymphangiomas or lymphang GENES iectasis. Witte, et al., Regulation of Angiogenesis (eds. Goldber, I. D. & Rosen, E. M.) 65-112 (Birkauser, Basel, BACKGROUND OF THE INVENTION Switzerland, 1997).
    [Show full text]
  • Aneuploidy: Using Genetic Instability to Preserve a Haploid Genome?
    Health Science Campus FINAL APPROVAL OF DISSERTATION Doctor of Philosophy in Biomedical Science (Cancer Biology) Aneuploidy: Using genetic instability to preserve a haploid genome? Submitted by: Ramona Ramdath In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Science Examination Committee Signature/Date Major Advisor: David Allison, M.D., Ph.D. Academic James Trempe, Ph.D. Advisory Committee: David Giovanucci, Ph.D. Randall Ruch, Ph.D. Ronald Mellgren, Ph.D. Senior Associate Dean College of Graduate Studies Michael S. Bisesi, Ph.D. Date of Defense: April 10, 2009 Aneuploidy: Using genetic instability to preserve a haploid genome? Ramona Ramdath University of Toledo, Health Science Campus 2009 Dedication I dedicate this dissertation to my grandfather who died of lung cancer two years ago, but who always instilled in us the value and importance of education. And to my mom and sister, both of whom have been pillars of support and stimulating conversations. To my sister, Rehanna, especially- I hope this inspires you to achieve all that you want to in life, academically and otherwise. ii Acknowledgements As we go through these academic journeys, there are so many along the way that make an impact not only on our work, but on our lives as well, and I would like to say a heartfelt thank you to all of those people: My Committee members- Dr. James Trempe, Dr. David Giovanucchi, Dr. Ronald Mellgren and Dr. Randall Ruch for their guidance, suggestions, support and confidence in me. My major advisor- Dr. David Allison, for his constructive criticism and positive reinforcement.
    [Show full text]