Altered Glycosylation in Pancreatic Cancer: Development of New Tumor Markers and Therapeutic Strategies

Total Page:16

File Type:pdf, Size:1020Kb

Altered Glycosylation in Pancreatic Cancer: Development of New Tumor Markers and Therapeutic Strategies ALTERED GLYCOSYLATION IN PANCREATIC CANCER: DEVELOPMENT OF NEW TUMOR MARKERS AND THERAPEUTIC STRATEGIES Pedro Enrique Guerrero Barrado Per citar o enllaçar aquest document: Para citar o enlazar este documento: Use this url to cite or link to this publication: http://hdl.handle.net/10803/671007 ADVERTIMENT. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs. ADVERTENCIA. El acceso a los contenidos de esta tesis doctoral y su utilización debe respetar los derechos de la persona autora. Puede ser utilizada para consulta o estudio personal, así como en actividades o materiales de investigación y docencia en los términos establecidos en el art. 32 del Texto Refundido de la Ley de Propiedad Intelectual (RDL 1/1996). Para otros usos se requiere la autorización previa y expresa de la persona autora. En cualquier caso, en la utilización de sus contenidos se deberá indicar de forma clara el nombre y apellidos de la persona autora y el título de la tesis doctoral. No se autoriza su reproducción u otras formas de explotación efectuadas con fines lucrativos ni su comunicación pública desde un sitio ajeno al servicio TDR. Tampoco se autoriza la presentación de su contenido en una ventana o marco ajeno a TDR (framing). Esta reserva de derechos afecta tanto al contenido de la tesis como a sus resúmenes e índices. WARNING. Access to the contents of this doctoral thesis and its use must respect the rights of the author. It can be used for reference or private study, as well as research and learning activities or materials in the terms established by the 32nd article of the Spanish Consolidated Copyright Act (RDL 1/1996). Express and previous authorization of the author is required for any other uses. In any case, when using its content, full name of the author and title of the thesis must be clearly indicated. Reproduction or other forms of for profit use or public communication from outside TDX service is not allowed. Presentation of its content in a window or frame external to TDX (framing) is not authorized either. These rights affect both the content of the thesis and its abstracts and indexes. DOCTORAL THESIS Altered glycosylation in pancreatic cancer: development of new tumor markers and therapeutic strategies Pedro Enrique Guerrero Barrado 2020 DOCTORAL THESIS Altered glycosylation in pancreatic cancer: development of new tumor markers and therapeutic strategies Pedro Enrique Guerrero Barrado 2020 Doctoral Programme in Molecular Biology, Biomedicine and Health Thesis supervisors: Dr. Rosa Peracaula Miró Dr. Esther Llop Escorihuela Tutor: Dr. Rosa Peracaula Miró PhD thesis submitted in fulfilment of the requirement to for the title of doctor from the University of Girona Certificate of thesis direction Hereby, Dr. Rosa Peracaula Miró and Dr. Esther Llop Escorihuela from the University of Girona DECLARE: That the work entitled Altered glycosylation in pancreatic cancer: development of new tumor markers and therapeutic strategies, which presents Pedro Enrique Guerrero Barrado to obtain the title of doctor, has been carried out under our direction and that it meets the requirements to be eligible for an International Mention. And for the record and have the appropriate effects, we sign this document. For all intents and purposes, the following certification is signed: Dr. Rosa Peracaula Miró Dr. Esther Llop Escorihuela Girona, June 2020 Agradecimientos En primer lugar, me gustaría dar las gracias a mis dos directoras de tesis Esther y Rosa que han hecho posible que hoy pueda estar escribiendo esta tesis. Por todo lo que me han enseñado desde ese primer contacto de prácticas de empresa con nuestras columnas de SNA. Gracias por vuestra paciencia, por todo el apoyo científico y personal recibido en los momentos buenos y en los de ofuscación con la tesis. Agradeceros por todo lo enseñado, por las oportunidades que me habéis dado para continuar aprendiendo cosas nuevas en sitios tan diferentes. Gracias por hacer que en estos años fuera de casa estando en el trabajo me sintiera como en casa y por ponerle ruedas a la tesis aunque hubiera unos cuantos kilómetros o una cuarentena por medio. ¡¡Lo de hacer frases más cortas todavía lo tengo que practicar más Esther!! Pero por lo demás, he aprendido mucho de vosotras. Por supuesto agradecer a todos los miembros que forman o han formado parte de Bioquímica del cáncer (BQ-105 para los amigos) con l@s cuales he coincidido estos años. A Rafa, mil gracias por acabar siempre consiguiéndome las firmas antes del deadline por muy justos que fuéramos y por darme la oportunidad de poder ver como han ido creciendo cosas del TFG e involucrarme en ellas y la ilusión que me ha hecho! Que nada te quite tú buen humor y esas risas que se escuchaban desde el pasillo que animan a todos. A Mª Ángeles porque gracias a ella tuve la oportunidad de colaborar con el grupo, Silvia por esos consejillos con las 2D, Anna por la ayuda por cultivos y por supuesto especialmente dar gracias a Montse, por esa actitud y alegría que transmites, por todos esos consejos, por la de veces que me has ayudado, por todas las charlas y las horas de laboratorio mano a mano que he tenido la suerte de pasar como compi de poyata. Txell que no me olvido tampoco!!! por ser la alegría de la huerta, nuestro radiopatio y nuestra social manager de los congresos. Ni que decir de mis compis de despacho,,,,, que han tenido la paciencia de aguantar mis tonterías todos estos años, hasta el punto de colgar un ola k ase del techo incluso con outfit navideño, por dejarme llenar el despacho de telarañas en Halloween e ir colonizando la mesa a modo de vivero privado. Muchísimas Gracias Adrià, Anna y Laura por hacer tan ameno todos estos años, por todas nuestras tonterías y el buen rollo que transmitís, por todos esos momentazos que solo recordar te sacan la risa tonta, como nuestra traicionera, nuestros paseos en unicornio XXL por la playa, las bromas saliendo de las cajas, nuestro cultivo in vitro de orquídeas y algún que otro petardo con hielo seco siempre en el momento mas inoportuno del mundo por supuesto. Gracias a nuestros vecinos Bioquímicos, Alex por el buen rollo que transmites, Jess, Santi, Imma por ese buen carácter y estar siempre ahí para echar una mano. Gracias a todo el granja team por hacer las comidas tan amenas, por todos esos escape rooms de los cuales hemos salido a tiempo y todas esas experiencias y cenitas de becarios, por ponerle banda sonora a la barca de rafting o nuestros ataques a la máquina de hielo para las escapadas playeras. Micro team, Elianita por ser siempre tan detallista y compartir las penas y estrés estos últimos meses con todos los papeleos de la tesis y la burocracia; ¡¡¡Qué por fin vemos la luz!!! Mireia, gracias por siempre estar dispuesta a echar una mano en lo que haga falta y ser el SOS de las dudas ya sean del sepe, protocolos, papeleo o lo que haga falta, ni Wikipedia puede competir,,,, Eli, Elena, Queralt, Sara, Nuria, Paola, Carla y Pau en el pack por ese buen rollo y risas que hemos compartido, Pau siempre tan sarcástico y sacándole punta a todo animando el cotarro. Siempre me acordare con cariño de ese san Juan tan especial en los tipis con Carla sufriendo con mi hoguera. Biocels y neuro, Irene y Sandra, daros las gracias por vuestra paciencia con mi nivel de catalán y las risas que me habéis sacado, por ir muchas más veces a la playa con cervezas con limón sin alcohol Sandrita. Iker y sus chupitos de licor de oso consiguiendo que te lo pases bien hasta encerrados en un ascensor y a las genéticas Judith y Melania y a todos los miembros del departamento que en algún momento u otro me han ayudado todos estos años. Agradecer también a todo el equipo del IMIM, Carlos, Joan, Héctor, Mireia y con especial cariño a Pilar y Neus por todo lo que me habéis enseñado, las innumerables ayudas y las bases que me habéis brindado, Snails incluidos. Gemma, Aida por la ayuda siempre con los protocolos y las becas. Ni que decir de la mejor científica que ha pisado el IMIM y mi corresponsal de Barcelona, Mrs galectina la doctora Vinaixa, por la de veces que me ha tenido que ayudar de emergencia y mandar pantallazos de su libreta, por tu carácter, por ser la alegría de la huerta, por esas risas que siempre sacas a quien te rodea, por ese apoyo en los momentos mas flojos, por las anécdotas, por esas invitaciones a valencia con Paella de verdad incluida y alguna que otra noche de fiesta. Muchas gracias es quedarse corto.
Recommended publications
  • Analysis of Trans Esnps Infers Regulatory Network Architecture
    Analysis of trans eSNPs infers regulatory network architecture Anat Kreimer Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2014 © 2014 Anat Kreimer All rights reserved ABSTRACT Analysis of trans eSNPs infers regulatory network architecture Anat Kreimer eSNPs are genetic variants associated with transcript expression levels. The characteristics of such variants highlight their importance and present a unique opportunity for studying gene regulation. eSNPs affect most genes and their cell type specificity can shed light on different processes that are activated in each cell. They can identify functional variants by connecting SNPs that are implicated in disease to a molecular mechanism. Examining eSNPs that are associated with distal genes can provide insights regarding the inference of regulatory networks but also presents challenges due to the high statistical burden of multiple testing. Such association studies allow: simultaneous investigation of many gene expression phenotypes without assuming any prior knowledge and identification of unknown regulators of gene expression while uncovering directionality. This thesis will focus on such distal eSNPs to map regulatory interactions between different loci and expose the architecture of the regulatory network defined by such interactions. We develop novel computational approaches and apply them to genetics-genomics data in human. We go beyond pairwise interactions to define network motifs, including regulatory modules and bi-fan structures, showing them to be prevalent in real data and exposing distinct attributes of such arrangements. We project eSNP associations onto a protein-protein interaction network to expose topological properties of eSNPs and their targets and highlight different modes of distal regulation.
    [Show full text]
  • Collagen and Elastin Fibres
    J Clin Pathol: first published as 10.1136/jcp.s3-12.1.49 on 1 January 1978. Downloaded from J. clin. Path., 31, Suppl. (Roy. Coll. Path.), 12, 49-58 Collagen and elastin fibres A. J. BAILEY From the Agricultural Research Council, Meat Research Institute, Langford, Bristol Although an understanding of the intracellular native collagen was generated from type I pro- biosynthesis of both collagen and elastin is of collagen. Whether this means that the two pro- considerable importance it is the subsequent extra- collagens are converted by different enzyme systems cellular changes involving fibrogenesis and cross- and the type III enzyme was deficient in these linking that ensure that these proteins ultimately fibroblast cultures, or that the processing of pro become the major supporting tissues of the body. type III is extremely slow, is not known. The latter This paper summarises the formation and stability proposal is consistent with the higher proportion of collagen and elastin fibres. of soluble pro type III extractable from tissue (Lenaers and Lapiere, 1975; Timpl et al., 1975). Collagen Basement membrane collagens, on the other hand, do not form fibres and this property may be The non-helical regions at the ends of the triple due to the retention of the non-helical extension helix of procollagen probably provide a number of peptides (Kefalides, 1973). In-vivo biosynthetic different intracellular functions-that is, initiating studies showing the absence of any extension peptide rapid formation of the triple helix; inhibiting intra- removal support this (Minor et al., 1976), but other cellular fibrillogenesis; and facilitating transmem- workers have reported that there is some cleavage brane movement.
    [Show full text]
  • Synthetic Polynucleotides Synthetische Polynukleotide Polynucleotides Synthetiques
    Europäisches Patentamt *EP000960192B1* (19) European Patent Office Office européen des brevets (11) EP 0 960 192 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.7: C12N 9/02, C12N 15/53, of the grant of the patent: A61K 38/43, C12N 9/06 09.11.2005 Bulletin 2005/45 (86) International application number: (21) Application number: 97933592.4 PCT/AU1997/000505 (22) Date of filing: 11.08.1997 (87) International publication number: WO 1998/006830 (19.02.1998 Gazette 1998/07) (54) SYNTHETIC POLYNUCLEOTIDES SYNTHETISCHE POLYNUKLEOTIDE POLYNUCLEOTIDES SYNTHETIQUES (84) Designated Contracting States: • SHARP P M ET AL: "The codon Adaptation AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC Index--a measure of directional synonymous NL PT SE codon usage bias, and its potential applications." NUCLEIC ACIDS RESEARCH. (30) Priority: 09.08.1996 AU PO156596 ENGLAND 11 FEB 1987, vol. 15, no. 3, 11 February 1987 (1987-02-11), pages 1281-1295, (43) Date of publication of application: XP001122356 ISSN: 0305-1048 01.12.1999 Bulletin 1999/48 • DATABASE SWISSPROT [Online] 1 December 1992 (1992-12-01) MARIANI T.J. ET AL.: (60) Divisional application: "Protein-lysine 6-oxidase precursor (EC 05000327.6 1.4.3.13) (Lysyl oxidase)." Database accession no. P28300 XP002229125 (73) Proprietor: THE UNIVERSITY OF SYDNEY • DATABASE EMBL [Online] EBI; 16 May 1992 Sydney, New South Wales 2006 (AU) (1992-05-16) MARIANI T.J. ET AL.: "Human lysyl oxidase (LOX) mRNA, complete cds." Database (72) Inventor: WEISS, Anthony, Steven accession no. M94054 XP002229126 Randwick, NSW 2031 (AU) • DATABASE EMBL [Online] EBI; 26 November 1993 (1993-11-26) HAMALAINEN E.R.
    [Show full text]
  • Urinary Biomarkers for the Detection of Prostate Cancer in Patients with High-Grade Prostatic Intraepithelial Neoplasia
    The Prostate Urinary Biomarkers for the Detection of Prostate Cancer in Patients With High-Grade Prostatic Intraepithelial Neoplasia Tamara Sequeiros,1 Juan M. Bastaros, 2 Milagros Sanchez, 1 Marina Rigau,1 Melania Montes,1 Jose Placer,2 Jaques Planas,2 Ines de Torres,3 Jaume Reventos, 1,4,5 D. Michiel Pegtel,6 Andreas Doll,1,4 Juan Morote,1,2 and Mireia Olivan1* 1Group of Biomedical Research in Urology, Vall d’Hebron Research Institute (VHIR) and Universitat Autonoma de Barcelona (UAB), Barcelona, Spain 2Department of Urology, Vall d’Hebron University Hospital and Universitat Autonoma de Barcelona (UAB), Barcelona, Spain 3Department of Pathology, Vall d’Hebron University Hospital and Universitat Autonoma de Barcelona (UAB), Barcelona, Spain 4Departament de Ciencies Basiques, Universitat Internacional de Catalunya, Barcelona, Spain 5IDIBELL- Bellvitge Biomedical Research Institute, Barcelona, Spain 6Department of Pathology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands INTRODUCTION. High-grade prostatic intraepithelial neoplasia (HGPIN) is a recognized precursor stage of PCa. Men who present HGPIN in a first prostate biopsy face years of active surveillance including repeat biopsies. This study aimed to identify non-invasive prognostic biomarkers that differentiate early on between indolent HGPIN cases and those that will transform into actual PCa. METHODS. We measured the expression of 21 candidate mRNA biomarkers using quantitative PCR in urine sediment samples from a cohort of 90 patients with initial diagnosis of HGPIN and a posterior follow up of at least two years. Uni- and multivariate statistical analyses were applied to analyze the candidate biomarkers and multiplex models using combinations of these biomarkers.
    [Show full text]
  • Discovery of the First Genome-Wide Significant Risk Loci for Attention Deficit/Hyperactivity Disorder
    ARTICLES https://doi.org/10.1038/s41588-018-0269-7 Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder Ditte Demontis 1,2,3,69, Raymond K. Walters 4,5,69, Joanna Martin5,6,7, Manuel Mattheisen1,2,3,8,9,10, Thomas D. Als 1,2,3, Esben Agerbo 1,11,12, Gísli Baldursson13, Rich Belliveau5, Jonas Bybjerg-Grauholm 1,14, Marie Bækvad-Hansen1,14, Felecia Cerrato5, Kimberly Chambert5, Claire Churchhouse4,5,15, Ashley Dumont5, Nicholas Eriksson16, Michael Gandal17,18,19,20, Jacqueline I. Goldstein4,5,15, Katrina L. Grasby21, Jakob Grove 1,2,3,22, Olafur O. Gudmundsson13,23,24, Christine S. Hansen 1,14,25, Mads Engel Hauberg1,2,3, Mads V. Hollegaard1,14, Daniel P. Howrigan4,5, Hailiang Huang4,5, Julian B. Maller5,26, Alicia R. Martin4,5,15, Nicholas G. Martin 21, Jennifer Moran5, Jonatan Pallesen1,2,3, Duncan S. Palmer4,5, Carsten Bøcker Pedersen1,11,12, Marianne Giørtz Pedersen1,11,12, Timothy Poterba4,5,15, Jesper Buchhave Poulsen1,14, Stephan Ripke4,5,27, Elise B. Robinson4,28, F. Kyle Satterstrom 4,5,15, Hreinn Stefansson 23, Christine Stevens5, Patrick Turley4,5, G. Bragi Walters 23,24, Hyejung Won 17,18, Margaret J. Wright 29, ADHD Working Group of the Psychiatric Genomics Consortium (PGC)30, Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium30, 23andMe Research Team30, Ole A. Andreassen 31, Philip Asherson32, Christie L. Burton 33, Dorret I. Boomsma34,35, Bru Cormand36,37,38,39, Søren Dalsgaard 11, Barbara Franke40, Joel Gelernter 41,42, Daniel Geschwind 17,18,19, Hakon Hakonarson43, Jan Haavik44,45, Henry R.
    [Show full text]
  • In Prostate Cancer
    l ch cina em di is e tr M y Shen et al., Med chem 2014, 4:11 Medicinal chemistry DOI: 10.4172/2161-0444.1000220 ISSN: 2161-0444 Revie Article Open Access Roles of Serine Protease Inhibitor Kazal type 1 (SPINK1) in Prostate Cancer Chengwu Shen1, Jing Zhang1, Mei Qi2, Yannicca WYChang3 and Bo Han2,4* 1Department of Pharmacy, Shandong Provincial Hospital, Jinan 250021 China 2Department of Pathology, School of Medicine, Shandong University, Jinan 250012, China 3Department of Health and Disease and Psychology, University of Tornoto, Markham, Canada 4Department of Pathology, Qilu Hospital, Shandong University, Jinan 250012, China Abstract Altered genes that play a driving role in cancer development can often serve as specific diagnostic markers, criteria of molecular classification and therefore potential therapeutic targets. Serine protease inhibitor Kazal type 1 (SPINK1), also known as pancreatic secretory trypsin inhibitor or tumor-associated trypsin inhibitor, encodes a 56 amino acid secreted peptide, and its normal function is thought to be the inhibition of serine proteases such as trypsin. Recent studies have indicated marked overexpression of SPINK1 defines an aggressive molecular subtype of ETS (erythroblastosis virus E26 transformation-specific) fusion-negative prostate cancer ((PCa) patients. SPINK1 may act as an autocrine growth factor and promotes PCa growth and invasion. Most recently, we suggested that SPINK1 induces epithelial-mesenchymal transition (EMT) through EGFR signaling pathway in PCa. The association between SPINK1 overexpression and poor prognosis in PCa has been reported. Notably, SPINK1 might be a novel extracellular therapeutic target in a subset of high-grade PCa patients. In this review, we will summarize the current understanding of SPINK1 involving its role in PCa biology, association with prognosis as well as perspective in therapy from the pathologist's point of view.
    [Show full text]
  • Association of SPINK1 Expression and TMPRSS2:ERG Fusion with Prognosis in Endocrine-Treated Prostate Cancer
    Published OnlineFirst May 4, 2010; DOI: 10.1158/1078-0432.CCR-09-2505 Clinical Imaging, Diagnosis, Prognosis Cancer Research Association of SPINK1 Expression and TMPRSS2:ERG Fusion with Prognosis in Endocrine-Treated Prostate Cancer Katri A. Leinonen1, Teemu T. Tolonen1,3, Hazel Bracken1, Ulf-Håkan Stenman4, Teuvo L.J. Tammela2, Outi R. Saramäki1, and Tapio Visakorpi1 Abstract Purpose: The aim of the study was to examine whether TMPRSS2:ERG fusion or SPINK1 protein expres- sion is associated with hormone responsiveness of prostate cancer and can thus be used as a biomarker. Experimental Design: Diagnostic needle biopsies from prostate cancer patients primarily treated by endocrine therapy were evaluated for TMPRSS2:ERG fusion with fluorescence in situ hybridization and SPINK1 protein expression with immunohistochemistry. Results: The frequency of TMPRSS2:ERG fusion in 178 biopsies of hormonally treated patients was 34%. Of the fusion-positive cases, 71% showed deletion between the two genes, and 23% showed gain of the fusion. The fusion was associated with high Ki-67 staining (P = 0.001), age at diagnosis (P = 0.024), and tumor area (P = 0.006), but not with Gleason score, T stage, M stage, prostate-specific antigen (PSA), or progression-free survival. Strong positive SPINK1 expression was found in 11% (21 of 186) of the biopsies. SPINK1-positive cases had significantly shorter progression-free survival compared with SPINK1-negative cases (P = 0.001). The expression was not associated with any other clinicopathologic variables studied. In a multivariate analysis, SPINK1 expression showed independent prognostic value, with a relative risk of 2.3 (95% confidence interval, 1.1-4.6).
    [Show full text]
  • Multiplexed Engineering Glycosyltransferase Genes in CHO Cells Via Targeted Integration for Producing Antibodies with Diverse Complex‑Type N‑Glycans Ngan T
    www.nature.com/scientificreports OPEN Multiplexed engineering glycosyltransferase genes in CHO cells via targeted integration for producing antibodies with diverse complex‑type N‑glycans Ngan T. B. Nguyen, Jianer Lin, Shi Jie Tay, Mariati, Jessna Yeo, Terry Nguyen‑Khuong & Yuansheng Yang* Therapeutic antibodies are decorated with complex‑type N‑glycans that signifcantly afect their biodistribution and bioactivity. The N‑glycan structures on antibodies are incompletely processed in wild‑type CHO cells due to their limited glycosylation capacity. To improve N‑glycan processing, glycosyltransferase genes have been traditionally overexpressed in CHO cells to engineer the cellular N‑glycosylation pathway by using random integration, which is often associated with large clonal variations in gene expression levels. In order to minimize the clonal variations, we used recombinase‑mediated‑cassette‑exchange (RMCE) technology to overexpress a panel of 42 human glycosyltransferase genes to screen their impact on antibody N‑linked glycosylation. The bottlenecks in the N‑glycosylation pathway were identifed and then released by overexpressing single or multiple critical genes. Overexpressing B4GalT1 gene alone in the CHO cells produced antibodies with more than 80% galactosylated bi‑antennary N‑glycans. Combinatorial overexpression of B4GalT1 and ST6Gal1 produced antibodies containing more than 70% sialylated bi‑antennary N‑glycans. In addition, antibodies with various tri‑antennary N‑glycans were obtained for the frst time by overexpressing MGAT5 alone or in combination with B4GalT1 and ST6Gal1. The various N‑glycan structures and the method for producing them in this work provide opportunities to study the glycan structure‑and‑function and develop novel recombinant antibodies for addressing diferent therapeutic applications.
    [Show full text]
  • INVESTIGATION INTO POSSIBLE MUTATIONS of the SPINK1 GENE AS a CAUSE of HEREDITARY PANCREATITIS in the MINIATURE SCHNAUZER a Diss
    INVESTIGATION INTO POSSIBLE MUTATIONS OF THE SPINK1 GENE AS A CAUSE OF HEREDITARY PANCREATITIS IN THE MINIATURE SCHNAUZER A Dissertation by MICAH ANDREW BISHOP Submitted to the Office of Graduate and Professional Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Chair of Committee, Jörg Steiner Committee Members, Jan Suchodolski Audrey Cook Roy Pool David Twedt Head of Department, Roger Smith December 2015 Major Subject: Veterinary Microbiology Copyright 2015 Micah Bishop ABSTRACT The Miniature Schnauzer has been anecdotally reported to have a hereditary predisposition to the development of pancreatitis. The aims of this study were to establish a true breed predisposition for the disease and to investigate a potential genetic etiology. The first part of this study investigated breed predisposition for the development of pancreatitis. Miniature Schnauzers were found to have an odds ratio of 1.23 (P = 0.0240) for having an increased cPLI (as measured by an in-house ELISA or by Spec cPL®) serum concentration compared to the population as a whole. The second part of this study investigated the SPINK1 gene in Miniature Schnauzers with and without evidence of pancreatitis. Three variants were found in the gene and Miniature Schnauzers that were homozygous for the variants had an odds ratio of 25 (P = 0.0067) for having clinical and biochemical evidence of pancreatitis compared to healthy individuals. The third part of the study examined the entire canine genome using SNP scanning to investigate other genes or regions that may be associated with pancreatitis in the Miniature Schnauzer.
    [Show full text]
  • Methods, Compounds, Compositions and Vehicles for Delivering 3-Amino-1-Propanesulfonic Acid
    (19) TZZ _ T (11) EP 2 862 581 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 22.04.2015 Bulletin 2015/17 A61K 47/48 (2006.01) C07K 5/06 (2006.01) C07K 5/08 (2006.01) C07C 309/15 (2006.01) (2006.01) (2006.01) (21) Application number: 14200552.9 C07D 207/16 C07D 209/20 C07D 217/24 (2006.01) C07D 233/64 (2006.01) (2006.01) (2006.01) (22) Date of filing: 12.10.2007 C07D 291/02 C07D 333/24 C12P 11/00 (2006.01) A61K 38/07 (2006.01) A61K 38/08 (2006.01) A61P 25/28 (2006.01) (84) Designated Contracting States: (72) Inventor: The designation of the inventor has not AT BE BG CH CY CZ DE DK EE ES FI FR GB GR yet been filed HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR (74) Representative: Hoffmann Eitle Patent- und Rechtsanwälte PartmbB (30) Priority: 12.10.2006 US 851039 P Arabellastraße 30 12.04.2007 US 911459 P 81925 München (DE) (62) Document number(s) of the earlier application(s) in Remarks: accordance with Art. 76 EPC: This application was filed on 30-12-2014 as a 07875176.5 / 2 089 417 divisional application to the application mentioned under INID code 62. (71) Applicant: BHI Limited Partnership Laval, QC H7V 4A7 (CA) (54) Methods, compounds, compositions and vehicles for delivering 3- amino-1-propanesulfonic acid (57) The invention relates to methods, compounds, that will yield or generate 3APS, either in vitro or in vivo.
    [Show full text]
  • Markers for Detection of Prostate Cancer
    Cancers 2010, 2, 1125-1154; doi:10.3390/cancers2021125 OPEN ACCESS cancers ISSN 2072-6694 www.mdpi.com/journal/cancers Review Markers for Detection of Prostate Cancer Raymond A. Clarke 1, Horst J. Schirra 2, James W. Catto 3, Martin F. Lavin 4,5 and Robert A. Gardiner 5,* 1 Prostate Cancer Institute, Cancer Care Centre, St George Hospital Clinical School of Medicine, University of New South Wales, Kogarah, NSW 2217, Australia; E-Mail: [email protected] 2 School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane QLD, 4072, Australia; E-Mail: [email protected] 3 Academic Urology Unit and Institute for Cancer Studies, University of Sheffield, Royal Hallamshire Hospital, Sheffield S10 2JF, UK; E-Mail: [email protected] 4 Queensland Institute of Medical Research, Radiation Biology and Oncology, Brisbane, QLD 4029, Australia; E-Mail: [email protected] 5 University of Queensland Centre for Clinical Research, Brisbane, Australia * Author to whom correspondence should be addressed; E-Mail: [email protected]. Received: 22 March 2010; in revised form: 2 June 2010 / Accepted: 3 June 2010 / Published: 4 June 2010 Abstract: Early detection of prostate cancer is problematic, not just because of uncertainly whether a diagnosis will benefit an individual patient, but also as a result of the imprecise and invasive nature of establishing a diagnosis by biopsy. Despite its low sensitivity and specificity for identifying patients harbouring prostate cancer, serum prostate specific antigen (PSA) has become established as the most reliable and widely-used diagnostic marker for this condition. In its wake, many other markers have been described and evaluated.
    [Show full text]
  • An Integrative Systems Approach Identifies Novel Candidates in Marfan Syndrome-Related Pathophysiology
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by The Jackson Laboratory: The Mouseion at the JAXlibrary The Jackson Laboratory The Mouseion at the JAXlibrary Faculty Research 2019 Faculty Research 2019 An integrative systems approach identifies novel candidates in Marfan syndrome-related pathophysiology. Raghu Bhushan Lukas Altinbas Marten Jäger Marcin Zaradzki Daniel Lehmann See next page for additional authors Follow this and additional works at: https://mouseion.jax.org/stfb2019 Part of the Life Sciences Commons, and the Medicine and Health Sciences Commons Recommended Citation Bhushan, Raghu; Altinbas, Lukas; Jäger, Marten; Zaradzki, Marcin; Lehmann, Daniel; Timmermann, Bernd; Clayton, Nicholas P; Zhu, Yunxiang; Kallenbach, Klaus; Kararigas, Georgios; and Robinson, Peter N, "An integrative systems approach identifies novel candidates in Marfan syndrome-related pathophysiology." (2019). Faculty Research 2019. 76. https://mouseion.jax.org/stfb2019/76 This Article is brought to you for free and open access by the Faculty Research at The ousM eion at the JAXlibrary. It has been accepted for inclusion in Faculty Research 2019 by an authorized administrator of The ousM eion at the JAXlibrary. For more information, please contact [email protected]. Authors Raghu Bhushan, Lukas Altinbas, Marten Jäger, Marcin Zaradzki, Daniel Lehmann, Bernd Timmermann, Nicholas P Clayton, Yunxiang Zhu, Klaus Kallenbach, Georgios Kararigas, and Peter N Robinson This article is available at The ousM eion at the JAXlibrary: https://mouseion.jax.org/stfb2019/76 Received: 20 May 2018 | Revised: 11 December 2018 | Accepted: 13 December 2018 DOI: 10.1111/jcmm.14137 ORIGINAL ARTICLE An integrative systems approach identifies novel candidates in Marfan syndrome‐related pathophysiology Raghu Bhushan1,2 | Lukas Altinbas1 | Marten Jäger1,3 | Marcin Zaradzki4 | Daniel Lehmann1 | Bernd Timmermann5 | Nicholas P.
    [Show full text]