DOCSLIB.ORG

Maturation, Playing Position and Genetic Variation

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Maturation, Playing Position and Genetic Variation MATURATION, PLAYING POSITION AND GENETIC VARIATION: INJURY RISK FACTORS IN HIGH-LEVEL YOUTH SOCCER ELLIOTT C R HALL A thesis submitted in partial fulfilment of the requirements of Liverpool John Moores University for the degree of Doctor of Philosophy September 2019 ACKNOWLEDGEMENTS I wish to thank all those who have helped me in completing this PhD thesis, particularly my supervisory team. It has been a privilege to work with and learn from you all, and I am extremely grateful for the opportunity. I would like to express sincere gratitude to my Director of Studies, Dr. Rob Erskine, firstly for considering me for this PhD, and secondly for the exceptional guidance and support throughout the project. The work ethic, passion and drive you have displayed has motivated me to perform to the best of my ability, and my development has been guided by your valuable knowledge and experience. I hope the faith you displayed in nominating me for this project has been in some way repaid by the work we have achieved. I would like to thank Professor Barry Drust. I feel very fortunate to have had the opportunity to work under your guidance, particularly as this project involves a sport to which you have contributed so much invaluable knowledge and passion. Importantly, you have helped me to see things differently than I did at the start of this journey, and to see the ‘bigger picture’ in academic and personal life. It is also imperative to mention your support during participant recruitment, which contributed significantly to the success of this project. I would like to thank Professor James Morton. I am extremely lucky to have had your valued input throughout my PhD in relation to this project and my own professional development. Your knowledge, ambition and enthusiasm are inspiring to both researchers and practitioners, and you have helped me to appreciate the value of being able to function as both. I would also like to thank Dr Alun Williams. It has been a privilege to have your contribution throughout the entire PhD, though particularly in 2 relation to our investigation of genetic variability. Your expertise and knowledge in the field has inspired me to study and understand key concepts of research in this area, particularly how our work may benefit real world settings, but also the limitations and ethical considerations of such research. Thank you to all fellow PGRs and students I have worked with during my PhD, and to those who contributed to the research described in this thesis. Importantly, thanks to all players, parents/guardians and staff of participating clubs. I would like to thank my parents and family for their love and support, and my friends for providing distraction when needed. I must express my love, thanks and gratitude to my girlfriend Christy, who has supported me from day one and has made sacrifices for me to complete this PhD. Finally, I would like to thank my daughter Ayla for happiness and entertainment. You showed me in your first few weeks of life that determination and persistence eventually overcomes any challenge. 3 ABSTRACT The negative impact of injury on the development of youth soccer players (YSP) means that efforts must be made to prevent and control their occurrence. Although a range of risk factors have been investigated in YSP, they remain poorly understood due to limitations with previous studies (as discussed in Chapter Two). Greater understanding of the factors affecting injury risk could help identify and improve management of ‘at risk’ players, thus improving the likelihood of them reaching their full potential of a professional contract. Accordingly, the overriding aim of this thesis was to investigate the association of potentially key risk factors with injury risk in a large cohort of high-level YSP from academies within eight professional clubs from four different countries, across two continents. For all four experimental chapters in this thesis, injuries were prospectively recorded over the course of a single season in high-level YSP to determine (i) whether the rate of these injuries varied in YSP between different nations; (ii) if maturation status, playing position and/or genetic variation were associated with injury risk in YSP. The injury audit (Chapter Three) revealed that non-contact injuries to skeletal muscle were amongst those frequently recorded, with most injuries located in the lower limb. The Under-14 (U14) and U16 age groups suffered relatively more severe injuries, with minimal differences in injury rate between nations. Thus, Chapter Three indicated that more severe injuries occurred around the timing of biological maturation, suggesting an association of maturation status with injury in YSP. When this hypothesis was tested directly in Chapter Four, maturation status (pre-, mid- and post- peak height velocity [PHV], estimated by maturity offset) 4 was indeed associated with injury risk, where soft-tissue, ligament/tendon and thigh injuries were more prevalent in post-PHV than pre- and mid-PHV, and muscle injuries were more prevalent in post- than pre-PHV. With all injuries combined, post-PHV missed more days in the season than pre-PHV. Thus, the results from this chapter strongly suggest that post-PHV are at greatest risk of injury, and miss more of the season due to injury than pre- and mid- PHV. Having identified a maturation-dependent link with injury risk in YSP, Chapter Five investigated whether there was an association between playing positon and injuries solely in post-PHV YSP (due to the greater prevalence and severity of injuries in post- vs. pre-PHV, and the fact that playing position is more firmly defined at post-PHV). Prevalence and severity did not differ between outfield positions, but relatively fewer goalkeepers suffered thigh injuries than lateral and forward players combined. These data indicate injury prevention strategies should be similar for outfield players in post-PHV, but should focus on preventing thigh injuries particularly for lateral and forward players. Finally, the results from Chapter Six showed that three single nucleotide polymorphisms (SNPs), i.e. COL5A1 rs12722, EMILIN1 rs2289360 and VEGFA rs2010963, were associated with injury prevalence in pre- and post-PHV combined, and that more SNPs were individually associated with injury risk in post- vs. pre-PHV. When combining those SNPs that were individually associated with injury risk, injured YSP demonstrated a worse polygenic profile (in terms of more ‘at risk’ genotypes) than uninjured YSP regarding non-contact and non-contact soft-tissue injuries, while pre- and post-PHV YSP had similar polygenic profiles. These data indicate a maturation-dependent influence of individual SNPs on injury, i.e. the 5 environment likely interacts with genetic predisposition for injury more so in post-PHV YSP, when the intensity of training/match-play is greater than it is for pre-PHV YSP. The results from this thesis clearly identify post-PHV as being at higher risk of injury than their biologically younger counterparts, and that injury risk is similar between countries in this under-researched and important population. The results also show that playing position in physically mature YSP has minimal influence on injury risk but that genetic variation appears to be linked with the likelihood of suffering certain injuries, as well as the severity of those injuries. These novel findings could be used to help identify and manage ‘at risk’ YSP in order to reduce the burden of injury, thus increasing the chance of talented YSP reaching their full potential of a professional playing career. 6 TABLE OF CONTENTS ACKNLOWEDGEMENTS ............................................................................ 2 ABSTRACT ................................................................................................. 4 TABLE OF CONTENTS .............................................................................. 7 LIST OF ABBREVIATIONS ....................................................................... 13 LIST OF FIGURES .................................................................................... 15 LIST OF TABLES ...................................................................................... 17 CHAPTER ONE 19 GENERAL INTRODUCTION ....................................................................... 19 1.0 INTRODUCTION ................................................................................. 20 1.1 AIMS AND OBJECTIVES OF THE THESIS ........................................ 25 CHAPTER TWO 26 LITERATURE REVIEW ............................................................................... 26 2.1 INTRODUCTION ................................................................................. 27 2.2 PHYSIOLOGICAL DEMANDS AND INJURY IN YOUTH SOCCER .... 30 2.3 THE EFFECT OF MATURATION ON INJURY INCIDENCE IN YOUTH SOCCER ................................................................................................... 34 2.3.1 Skeletal maturation in youth soccer players ................................... 34 2.3.2 The contribution of biological age to injury incidence ..................... 39 2.4 THE EFFECT OF PLAYING POSITION ON INJURY INCIDENCE IN YOUTH SOCCER ..................................................................................... 42 2.4.1 Physiological demands of different playing positions in youth soccer ................................................................................................................ 42 2.4.2 Effect of playing position on injury incidence in
Load more

Recommended publications
  • Human Periprostatic Adipose Tissue: Secretome from Patients With
    CANCER GENOMICS & PROTEOMICS 16 : 29-58 (2019) doi:10.21873/cgp.20110 Human Periprostatic Adipose Tissue: Secretome from Patients With Prostate Cancer or Benign Prostate Hyperplasia PAULA ALEJANDRA SACCA 1, OSVALDO NÉSTOR MAZZA 2, CARLOS SCORTICATI 2, GONZALO VITAGLIANO 3, GABRIEL CASAS 4 and JUAN CARLOS CALVO 1,5 1Institute of Biology and Experimental Medicine (IBYME), CONICET, Buenos Aires, Argentina; 2Department of Urology, School of Medicine, University of Buenos Aires, Clínical Hospital “José de San Martín”, Buenos Aires, Argentina; 3Department of Urology, Deutsches Hospital, Buenos Aires, Argentina; 4Department of Pathology, Deutsches Hospital, Buenos Aires, Argentina; 5Department of Biological Chemistry, School of Exact and Natural Sciences, University of Buenos Aires, Buenos Aires, Argentina Abstract. Background/Aim: Periprostatic adipose tissue Prostate cancer (PCa) is the second most common cancer in (PPAT) directs tumour behaviour. Microenvironment secretome men worldwide. While most men have indolent disease, provides information related to its biology. This study was which can be treated properly, the problem consists in performed to identify secreted proteins by PPAT, from both reliably distinguishing between indolent and aggressive prostate cancer and benign prostate hyperplasia (BPH) disease. Evidence shows that the microenvironment affects patients. Patients and Methods: Liquid chromatography-mass tumour behavior. spectrometry-based proteomic analysis was performed in Adipose tissue microenvironment is now known to direct PPAT-conditioned media (CM) from patients with prostate tumour growth, invasion and metastases (1, 2). Adipose cancer (CMs-T) (stage T3: CM-T3, stage T2: CM-T2) or tissue is adjacent to the prostate gland and the site of benign disease (CM-BPH). Results: The highest number and invasion of PCa.
    [Show full text]
  • The EMILIN/Multimerin Family
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE REVIEW ARTICLE published: 06 Januaryprovided 2012 by Frontiers - Publisher Connector doi: 10.3389/fimmu.2011.00093 The EMILIN/multimerin family Alfonso Colombatti 1,2,3*, Paola Spessotto1, Roberto Doliana1, Maurizio Mongiat 1, Giorgio Maria Bressan4 and Gennaro Esposito2,3 1 Experimental Oncology 2, Centro di Riferimento Oncologico, Istituto di Ricerca e Cura a Carattere Scientifico, Aviano, Italy 2 Department of Biomedical Science and Technology, University of Udine, Udine, Italy 3 Microgravity, Ageing, Training, Immobility Excellence Center, University of Udine, Udine, Italy 4 Department of Histology Microbiology and Medical Biotechnologies, University of Padova, Padova, Italy Edited by: Elastin microfibrillar interface proteins (EMILINs) and Multimerins (EMILIN1, EMILIN2, Uday Kishore, Brunel University, UK Multimerin1, and Multimerin2) constitute a four member family that in addition to the Reviewed by: shared C-terminus gC1q domain typical of the gC1q/TNF superfamily members contain a Uday Kishore, Brunel University, UK Kenneth Reid, Green Templeton N-terminus unique cysteine-rich EMI domain. These glycoproteins are homotrimeric and College University of Oxford, UK assemble into high molecular weight multimers. They are predominantly expressed in *Correspondence: the extracellular matrix and contribute to several cellular functions in part associated with Alfonso Colombatti, Division of the gC1q domain and in part not yet assigned nor linked to other specific regions of the Experimental Oncology 2, Centro di sequence. Among the latter is the control of arterial blood pressure, the inhibition of Bacil- Riferimento Oncologico, Istituto di Ricerca e Cura a Carattere Scientifico, lus anthracis cell cytotoxicity, the promotion of cell death, the proangiogenic function, and 33081 Aviano, Italy.
    [Show full text]
  • TSPAN9 and EMILIN1 Synergistically Inhibit the Migration and Invasion Of
    Qi et al. BMC Cancer (2019) 19:630 https://doi.org/10.1186/s12885-019-5810-2 RESEARCHARTICLE Open Access TSPAN9 and EMILIN1 synergistically inhibit the migration and invasion of gastric cancer cells by increasing TSPAN9 expression Yaoyue Qi1, Jing Lv2, Shihai Liu3, Libin Sun2, Yixuan Wang1, Hui Li1, Weiwei Qi2* and Wensheng Qiu2* Abstract Background: Globally, the incidence and mortality rates of gastric cancer are high, and its poor prognosis is closely related to tumor recurrence and metastasis. Therefore, the molecular mechanisms associated with the migration and invasion of gastric cancer cells are important for gastric cancer treatment. Previously, TSPAN9 has been reported to inhibit gastric cancer cell migration; however, the underlying molecular mechanism remains unclear. Methods: Human gastric adenocarcinoma cell lines, SGC7901 and AGS, were cultured in vitro. TSPAN9 expression was determined by RT-PCR, western blot analysis, and immunohistochemistry in gastric cancer and tumor-adjacent tissues. Following the over-expression and knockdown of TSPAN9, wound healing and cell invasion assays were performed and EMT-related protein expression was evaluated to analyze the invasion and migration of gastric cancer cells. TSPAN9 expression and the invasion and metastasis of gastric cancer cells were observed by the functional assays following EMILIN1 over-expression. Results: Inhibiting TSPAN9 expression significantly promoted the migration and invasion of gastric cancer cells. In addition, immunofluorescence co-localization and co-immunoprecipitation analysis revealed closely related expression of EMILIN1 and TSPAN9. Moreover, EMILIN1 can synergistically boost the tumor suppressive effect of TSPAN9, which may be produced by promoting TSPAN9 expression. Conclusions: We have demonstrated that EMILIN1 induces anti-tumor effects by up-regulating TSPAN9 expression in gastric cancer.
    [Show full text]
  • Inactivation of EMILIN-1 by Proteolysis and Secretion in Small Extracellular Vesicles Favors Melanoma Progression and Metastasis
    International Journal of Molecular Sciences Article Inactivation of EMILIN-1 by Proteolysis and Secretion in Small Extracellular Vesicles Favors Melanoma Progression and Metastasis Ana Amor López 1, Marina S. Mazariegos 1, Alessandra Capuano 2 , Pilar Ximénez-Embún 3, Marta Hergueta-Redondo 1, Juan Ángel Recio 4 , Eva Muñoz 5,Fátima Al-Shahrour 6 , Javier Muñoz 3, Diego Megías 7, Roberto Doliana 2, Paola Spessotto 2 and Héctor Peinado 1,* 1 Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain; [email protected] (A.A.L.); [email protected] (M.S.M.); [email protected] (M.H.-R.) 2 Unit of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO), Department of Advanced Cancer Research and Diagnostics, IRCCS, I-33081 Aviano, Italy; [email protected] (A.C.); [email protected] (R.D.); [email protected] (P.S.) 3 Proteomics Unit—ProteoRed-ISCIII, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain; [email protected] (P.X.-E.); [email protected] (J.M.) 4 Biomedical Research in Melanoma-Animal Models and Cancer Laboratory, Vall d’Hebron Research Institute VHIR-Vall d’Hebron Hospital Barcelona-UAB, 08035 Barcelona, Spain; [email protected] 5 Clinical Oncology Program, Vall d’Hebron Institute of Oncology-VHIO, Vall d’Hebron Hospital, Barcelona-UAB, 08035 Barcelona, Spain; [email protected] Citation: Amor López, A.; 6 Bioinformatics Unit, Structural Biology Programme, Spanish National Cancer Research Centre (CNIO), Mazariegos, M.S.; Capuano, A.; 28029 Madrid, Spain; [email protected] Ximénez-Embún, P.; Hergueta- 7 Confocal Microscopy Unit, Biotechnology Programme, Spanish National Cancer Research Center (CNIO), Redondo, M.; Recio, J.Á.; Muñoz, E.; 28029 Madrid, Spain; [email protected] Al-Shahrour, F.; Muñoz, J.; Megías, D.; * Correspondence: [email protected] et al.
    [Show full text]
  • Data Supplement
    Cell-specific ablation of Hsp47 defines the collagen producing cells in the injured heart Hadi Khalil,1 Onur Kanisicak,1,2 Ronald J. Vagnozzi,1Anne Katrine Johansen,1 Bryan D. Maliken,1 Vikram Prasad,1 Justin G. Boyer,1 Matthew J. Brody,1 Tobias Schips,1 Katja K. Kilian,1 Robert N. Correll,1,3 Kunito Kawasaki,4 Kazuhiro Nagata,4 Jeffery D. Molkentin1,5 1Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA 2Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA 3Department of Biological Sciences, University of Alabama, Tuscaloosa, Alabama, USA 4Institute for Protein Dynamics, Kyoto Sangyo University, Kyoto, Japan 5Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA Data Supplement -Supplemental Figures 1-7 -Supplemental Tables 1-3 Culture A Adβgal AdCre 100 µm CHP eGFP R26eGFP; Postn-MCM B 0.05 Hearts # R26eGFP; Hsp47fl/fl-Postn-MCM 0.04 * Supplemental Figure 1. Deletion of Hsp47 leads to collagen 0.03 aggregates in cultured fibroblasts and cell death in vivo. (A) Adult primary heart fibroblasts were isolated from R26eGFP Hsp47-loxP 0.02 TUNEL (%) TUNEL * targeted mice and infected with Adβgal or AdCre. Seventy-two hours later cells were processed for collagen-hybridizing peptide 0.01 immunofluorescence (red), showing collagen aggregates when Hsp47 was deleted, which was not observed in Adβgal controls. Fibroblast 0 Sham identity was shown by eGFP staining in the AdCre infected conditions. TAC Three separate experiments gave similar results. (B) TUNEL staining showing cell death levels in hearts of the indicated mice after 4 weeks post TAC.
    [Show full text]
  • An EMILIN1-Negative Microenvironment Promotes Tumor Cell Proliferation and Lymph Node Invasion
    Published OnlineFirst July 24, 2012; DOI: 10.1158/1940-6207.CAPR-12-0076-T Cancer Prevention Research Article Research An EMILIN1-Negative Microenvironment Promotes Tumor Cell Proliferation and Lymph Node Invasion Carla Danussi1, Alessandra Petrucco1, Bruna Wassermann1, Teresa Maria Elisa Modica1, Eliana Pivetta1, Lisa Del Bel Belluz1, Alfonso Colombatti1,2,3, and Paola Spessotto1 Abstract À À The evidence that EMILIN1 (Elastic Microfibril Interface Located proteIN) deficiency in Emilin1 / mice caused dermal and epidermal hyperproliferation and an abnormal lymphatic phenotype prompted us to hypothesize the involvement of this extracellular matrix component in tumor development and in lymphatic metastasis. Using the 12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate À À (DMBA/TPA) two-stage model of skin carcinogenesis, we found that Emilin1 / mice presented an accelerated formation, a higher incidence, and the development of a larger number of tumors compared with their wild-type littermates. EMILIN1-negative tumors showed more Ki67-positive proliferating cells and higher levels of pErk1/2.Inthesetumors,PTENexpressionwaslower. À À Emilin1 / mice displayed enhanced lymphangiogenesis both in the tumor and in the sentinel lymph nodes. Accordingly, tumor growth and lymph node metastasis of transplanted syngenic tumors À À were also increased in Emilin1 / mice. In vitro transmigration assays through lymphatic endothelial cells showed that EMILIN1 deficiency greatly facilitated tumor cell trafficking. Overall, these data established that EMILIN1 exerts a protective role in tumor growth, in tumor lymphatic vessel formation, as well as in metastatic spread to lymph nodes and reinforced the importance of its presence in the microenvironment to determine the tumor phenotype. Cancer Prev Res; 5(9); 1131–43.
    [Show full text]
  • Multi-Omic Single Cell Analysis Resolves Novel Stromal Cell
    www.nature.com/scientificreports OPEN Multi‑omic single cell analysis resolves novel stromal cell populations in healthy and diseased human tendon Adrian R. Kendal1,2*, Thomas Layton1, Hussein Al‑Mossawi1, Louise Appleton1, Stephanie Dakin1, Rick Brown2, Constantinos Loizou2, Mark Rogers2, Robert Sharp2 & Andrew Carr1 Tendinopathy accounts for over 30% of primary care consultations and represents a growing healthcare challenge in an active and increasingly ageing population. Recognising critical cells involved in tendinopathy is essential in developing therapeutics to meet this challenge. Tendon cells are heterogenous and sparsely distributed in a dense collagen matrix; limiting previous methods to investigate cell characteristics ex vivo. We applied next generation CITE‑sequencing; combining surface proteomics with in‑depth, unbiased gene expression analysis of > 6400 single cells ex vivo from 11 chronically tendinopathic and 8 healthy human tendons. Immunohistochemistry validated the single cell fndings. For the frst time we show that human tendon harbours at least fve distinct COL1A1/2 expressing tenocyte populations in addition to endothelial cells, T‑cells, and monocytes. These consist of KRT7/SCX+ cells expressing microfbril associated genes, PTX3+ cells co‑expressing high levels of pro‑infammatory markers, APOD+ fbro–adipogenic progenitors, TPPP3/PRG4+ chondrogenic cells, and ITGA7+ smooth muscle‑mesenchymal cells. Surface proteomic analysis identifed markers by which these sub‑classes could be isolated and targeted in future. Chronic tendinopathy was associated with increased expression of pro‑infammatory markers PTX3, CXCL1, CXCL6, CXCL8, and PDPN by microfbril associated tenocytes. Diseased endothelium had increased expression of chemokine and alarmin genes including IL33. Musculoskeletal disorders are responsible for the second largest number of years lived with disability worldwide1.
    [Show full text]
  • Identification of Human Tendon Cell Populations in Healthy and Diseased Tissue Using Combined Single Cell Transcriptomics and Pr
    bioRxiv preprint doi: https://doi.org/10.1101/2019.12.09.869933; this version posted December 17, 2019. 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. Identification of human tendon cell populations in healthy and diseased tissue using combined single cell transcriptomics and proteomics Kendal AR1,2, Layton T1, Al-Mossawi H1, Brown R2, Loizou C2, Rogers M2, Sharp M2, Dakin S1, Appleton L1, Carr A1 1 Botnar Research Centre The Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences Windmill Road, Oxford, OX3 7LD, UK 2 Nuffield Orthopaedic Centre, Windmill Road, Oxford OX3 7LD UK Keywords: tenocyte; tendon fibroblast; human tendon; single-cell RNA sequencing; CITE-Seq; transcriptomic; tendinopathy bioRxiv preprint doi: https://doi.org/10.1101/2019.12.09.869933; this version posted December 17, 2019. 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. Abstract The long-term morbidity of tendon disease in an increasingly active and ageing population represents a growing area of unmet clinical need. Tendon disorders commonly affect the lower limb, ranging from isolated tendon rupture to degenerative joint deformity. In the absence of valid animal models of chronic tendinopathy, traditional methods to isolate and identify crucial sub types involved in disease are limited by the heterogeneity of tendon cells, by their relative paucity in tissue and by the density of the surrounding collagen matrix. To overcome this, we have used next generation CITE-sequencing to combine surface proteomics with in-depth, unbiased gene expression analysis of single cells derived ex vivo from healthy and diseased tendon.
    [Show full text]
  • Proteomic Analyses of ECM During Pancreatic Ductal Adenocarcinoma Progression Reveal Different Contributions by Tumor and Stromal Cells
    Proteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells Chenxi Tiana, Karl R. Clauserb,1, Daniel Öhlundc,d,e,1, Steffen Rickelta, Ying Huanga, Mala Guptaf, D. R. Manib, Steven A. Carrb, David A. Tuvesonc, and Richard O. Hynesa,g,2 aKoch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; bBroad Institute of MIT and Harvard, Cambridge, MA 02142; cCold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724; dDepartment of Radiation Sciences, Umeå University, 901 87 Umeå, Sweden; eWallenberg Centre for Molecular Medicine, Umeå University, 901 85 Umeå, Sweden; fNew York University Winthrop Hospital, Mineola, NY 11501; and gHoward Hughes Medical Institute, Chevy Chase, MD 20815 Contributed by Richard O. Hynes, August 6, 2019 (sent for review May 28, 2019; reviewed by Wilhelm Haas and Lynn Matrisian) Pancreatic ductal adenocarcinoma (PDAC) has prominent extracellular hand, a phase 2 clinical trial of PEGPH20 showed improvement in matrix (ECM) that compromises treatments yet cannot be nonselec- progression-free survival of HA-high patients (10). Together, these tively disrupted without adverse consequences. ECM of PDAC, despite clinical findings suggest that a more detailed understanding of the recognition of its importance, has not been comprehensively stromal components could provide potential biomarkers for patient studied in patients. In this study, we used quantitative mass spec- stratification, and targets for more focused interventions. trometry (MS)-based proteomics to characterize ECM proteins in Extracellular matrix (ECM), as a major component of PDAC normal pancreas and pancreatic intraepithelial neoplasia (PanIN)- and stroma, provides both biophysical and biochemical cues that reg- PDAC-bearing pancreas from both human patients and mouse genetic ulate malignant cell behavior.
    [Show full text]
  • Molecular Mechanisms of Adipogenesis in Obesity and the Metabolic Syndrome
    Research Collection Doctoral Thesis Molecular mechanisms of adipogenesis in obesity and the metabolic syndrome Author(s): Meissburger, Bettina Publication Date: 2010 Permanent Link: https://doi.org/10.3929/ethz-a-006214330 Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library DISS. ETH Nr. 19107 Molecular mechanisms of adipogenesis in obesity and the metabolic syndrome A dissertation submitted to the ETH Zurich for the degree of Doctor of Sciences Dr. sc. ETH Zürich presented by Bettina Meissburger Diplom-Biologin (t.o.), Universität Stuttgart born May 19th 1981 Citizen of Germany Accepted on recommendation of Prof. Dr. Christian Wolfrum Prof. Dr. Markus Stoffel Prof. Dr. Christoph Meier 2010 Table of Contents Abstract 3 Zusammenfassung 5 Chapter 1 7 General introduction Chapter 2 33 Retinoid-related orphan receptor gamma controls adipocyte hyperplasia and insulin sensitivity in obesity Chapter 3 66 Tissue inhibitor of metalloproteinase 1 (TIMP1) inhibits adipocyte differentiation in obesity Chapter 4 91 Regulation of adipogenesis by paracrine factors from adipose stromal-vascular cells- a link to fat depot-specific differences Chapter 5 121 Conclusions and Outlook Appendix Chapter 2 125 Appendix Chapter 4 132 Acknowledgements 142 Curriculum vitae 143 2 Abstract Abstract Adipose tissue is a key player in whole body metabolism and excess adipose tissue poses a major risk factor for the development of metabolic disorders such as type 2 diabetes. In response to nutritional overload, de novo adipocyte differentiation can serve as an adaptive mechanism by increasing the storage capacity of adipose tissue and maintaining normal adipocyte function.
    [Show full text]
  • An EMILIN1-Negative Microenvironment Promotes Tumor Cell Proliferation and Lymph Node Invasion
    Published OnlineFirst July 24, 2012; DOI: 10.1158/1940-6207.CAPR-12-0076-T Cancer Prevention Research Article Research An EMILIN1-Negative Microenvironment Promotes Tumor Cell Proliferation and Lymph Node Invasion Carla Danussi1, Alessandra Petrucco1, Bruna Wassermann1, Teresa Maria Elisa Modica1, Eliana Pivetta1, Lisa Del Bel Belluz1, Alfonso Colombatti1,2,3, and Paola Spessotto1 Abstract À À The evidence that EMILIN1 (Elastic Microfibril Interface Located proteIN) deficiency in Emilin1 / mice caused dermal and epidermal hyperproliferation and an abnormal lymphatic phenotype prompted us to hypothesize the involvement of this extracellular matrix component in tumor development and in lymphatic metastasis. Using the 12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate À À (DMBA/TPA) two-stage model of skin carcinogenesis, we found that Emilin1 / mice presented an accelerated formation, a higher incidence, and the development of a larger number of tumors compared with their wild-type littermates. EMILIN1-negative tumors showed more Ki67-positive proliferating cells and higher levels of pErk1/2.Inthesetumors,PTENexpressionwaslower. À À Emilin1 / mice displayed enhanced lymphangiogenesis both in the tumor and in the sentinel lymph nodes. Accordingly, tumor growth and lymph node metastasis of transplanted syngenic tumors À À were also increased in Emilin1 / mice. In vitro transmigration assays through lymphatic endothelial cells showed that EMILIN1 deficiency greatly facilitated tumor cell trafficking. Overall, these data established that EMILIN1 exerts a protective role in tumor growth, in tumor lymphatic vessel formation, as well as in metastatic spread to lymph nodes and reinforced the importance of its presence in the microenvironment to determine the tumor phenotype. Cancer Prev Res; 1–13.
    [Show full text]
  • A Role for TNMD in Adipocyte Differentiation and Adipose Tissue Function: a Dissertation
    University of Massachusetts Medical School eScholarship@UMMS GSBS Dissertations and Theses Graduate School of Biomedical Sciences 2016-06-30 A Role for TNMD in Adipocyte Differentiation and Adipose Tissue Function: A Dissertation Ozlem Senol-Cosar University of Massachusetts Medical School Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/gsbs_diss Part of the Cell Biology Commons, Cellular and Molecular Physiology Commons, and the Developmental Biology Commons Repository Citation Senol-Cosar O. (2016). A Role for TNMD in Adipocyte Differentiation and Adipose Tissue Function: A Dissertation. GSBS Dissertations and Theses. https://doi.org/10.13028/M2PC7S. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/837 This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in GSBS Dissertations and Theses by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. A ROLE FOR TNMD IN ADIPOCYTE DIFFERENTIATION AND ADIPOSE TISSUE FUNCTION A Dissertation Presented By OZLEM SENOL-COSAR Submitted to the Faculty of the University of Massachusetts Graduate School of Biomedical Sciences, Worcester In partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY JUNE 30, 2016 Interdisciplinary Graduate Program A ROLE FOR TNMD IN ADIPOCYTE DIFFERENTIATION AND ADIPOSE TISSUE FUNCTION A Dissertation Presented By OZLEM SENOL-COSAR This work was undertaken in the Graduate School of Biomedical Sciences Interdisciplinary Graduate Program The signature of the Thesis Advisor signifies validation of Dissertation content __________________________________ Michael P. Czech, Ph.D., Thesis Advisor The signatures of the Dissertation Defense Committee signify completion and approval as to style and content of the Dissertation __________________________________ David A.
    [Show full text]