DOCSLIB.ORG

Final Version

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Final Version BONE AND PHOSPHATE IN RELATION TO HEALTH, SURVIVAL AND GENETIC FACTORS natalia campos obando Cover: Yuliana Cruz Zuñiga Lay-out: Marta Aguilar Díaz ISBN: 978-9968-48-518-9 Bone and phosphate in relation to health, survival and genetic factors Bot en fosfaat in relatie tot gezondheid, overleving en genetische factoren Proefschrift ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van der Rector Magnificus Prof. Dr. R.C.M.E. Engels en volgens het besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op donderdag 28 mei 2020 om 15:30 uur door natalia campos obando geboren te SAN JOSE, Costa Rica A DIOS, Origen de todo bien y Fuente insondable de Misericordia A la Inmaculada Virgen del Carmen y al Patriarca San José, por su generoso Auxilio y Protección en todo momento A mis padres, por su amor y apoyo incondicional y por estar a mi lado siempre To my Promotors, Prof. Dr. MC Zillikens & Prof. Dr. AG Uitterlinden, for allowing me to become part of your wonderful group and for all your teachings A mis queridos pacientes, por sus muestras de apoyo y sus Oraciones. Ustedes son la razón de ser de nosotros los médicos. PROMOTIECOMISSIE Promotoren: Prof. Dr. M.C. Zillikens Prof. Dr. A.G. Uitterlinden Overige leden: Prof. Dr. Ewout Hoorn Prof. Dr. Paul Lips Prof. Dr. Bruno Stricker CONTENTS Propositions of this thesis Chapter 1. Introduction of this thesis 1 PART I. Bone traits and phosphate in relation to health & survival Chapter 2. Bone mineral density and chronic lung disease mortality: 31 the Rotterdam Study Chapter 3. Bone health and coronary artery calcification: 57 the Rotterdam Study Chapter 4. Serum phosphate is associated with fracture risk: 83 the Rotterdam Study and MrOS Chapter 5. Serum phosphate levels are related to all-cause, 127 cardiovascular and COPD mortality in men Chapter 6. Genetic evidence for a causal role of serum phosphate in 165 coronary artery calcification: the Rotterdam Study PART II. Sex differences in calcium and phosphate levels Chapter 7. Influence of sex hormones on sexual dimorphism in calcium 213 and phosphate homeostasis Chapter 8. Age-dependent sex differences in calcium and phosphate 249 homeostasis PART III. Genetic studies in relation to bone and phosphate Chapter 9. PLS3 mutations in X-linked osteoporosis with fractures 275 Chapter 10. Osteoporotic vertebral fractures during pregnancy: 299 be aware of a potential underlying genetic cause Chapter 11. Genome-wide association study of human serum phosphate 317 levels: a large Biobanks approach Chapter 12. General discussion 381 Chapter 13. Summary / Samenvatting 441 Chapter 14. Acknowledgements / Publications 461 PROPOSITIONS OF THIS THESIS Bone and phosphate in relation to health, survival and genetic factors 1. The relation between low bone mineral density and increased mortality in men is in part explained by higher mortality from chronic obstructive pulmonary disease. [Looker, 2014 & this thesis] 2. Bone mineral density of the femoral neck, composed predominantly of cortical bone, is not causally related to arterial calcification. [Schulz et al, 2004; Chow et al, 2008 & this thesis] 3. Increased serum phosphate levels within the normal range are causally related to coronary artery calcification in the general population, and, as such, must be considered a cardiovascular risk factor. [Dhingra, 2007 & this thesis] 4. The associations we found between low bone mineral density and increased yet normal phosphate levels with decreased survival, lung emphysema, and coronary artery calcification (P), strongly resemble the premature ageing syndrome described in Fgf23-/- and kl/kl mouse phenocopies. [Kuro-o et al, 1997; Shimada et al, 2004 & this thesis] 5. Regardless of kidney function, increased phosphate levels are related to fracture risk in men, especially at trabecular-enriched bones (such as vertebral bodies and wrist); this finding is partly attributable to a predominant synthesis of FGF23 at trabecular osteocytes. [Pereira et al, 2009; Delgado-Calle et al, 2011 & this thesis] 6. In pregnancy and lactation associated osteoporosis, a persistent low bone mineral density should trigger investigation for secondary causes for osteoporosis, including potential underlying genetic factors. [this thesis] 7. Bone metabolism plays an important role in the anti-ageing FGF23/Klotho axis, as indicated by osteocytes being the main source of FGF23, Klotho being expressed also in osteocytes, and our findings of low bone mineral density being related to decreased survival. [Riminucci et al, 2003; Komaba et al, 2017; Kuro-o, 2018 & this thesis] 8. Additional evidence to support that bone metabolism plays an important role in ageing and survival is indicated by the findings of nitrogenated bisphosphonates being related to decreased mortality -mediated through a reduction in bone loss and independent of fracture prevention. [Reid et al, 2020 & Bliuc et al, 2019] 9. The sex difference in the association of serum phosphate with several clinical cardiovascular outcomes is not explained by sex dimorphism in its genetic factors. [Felsenfeld et al, 1999; Calvo et al, 1988; Kemi et al, 2006 & this thesis] 10. Entropy-based methods (ε) are required to disentangle the strong linkage disequilibrium of the Major Histocompatibility Complex (6p21.3) to identify causal variants in genetic association studies (such as in the GWAS of serum phosphate). [Nothnagel et al, 2002; Hirata et al, 2019 & this thesis] 11. Very early-on global collaboration and sharing of clinical, epidemiological, and genetic data in local infectious disease outbreaks, can limit societal and economic consequences for all countries in potential pan-epidemic outbreaks. PROPOSICIONES DE ESTA TESIS Hueso y fosfato en relación con salud, supervivencia y factores genéticos 1. La relación entre baja densidad mineral ósea y aumento en la mortalidad en los hombres se explica parcialmente por una mayor mortalidad por enfermedad pulmonar obstructiva crónica. [Looker, 2014 & esta tesis] 2. La densidad mineral ósea del cuello femoral, compuesta predominantemente de hueso cortical, no está causalmente relacionada con calcificación arterial. [Schulz y otros, 2004; Chow et al, 2008 & esta tesis] 3. El nivel elevado de fosfato sérico - aún dentro del rango normal - está causalmente relacionado con calcificación de las arterias coronarias en la población general, y como tal, debe ser considerado un factor de riesgo cardiovascular. [Dhingra, 2007 & esta tesis] 4. Las asociaciones que encontramos entre baja densidad mineral ósea y aumento en los niveles normales de fosfato - aún dentro del rango normal - con disminución de la supervivencia, enfisema pulmonar y calcificación de las arterias coronarias (P), se asemejan fuertemente al síndrome de envejecimiento prematuro descrito en fenocopias de ratones Fgf23-/- y kl/ kl. [Kuro-o et al, 1997; Shimada et al, 2004 & esta tesis] 5. Independientemente de la función renal, el aumento en los niveles de fosfato está asociado con riesgo de fractura en los hombres, especialmente en los huesos enriquecidos en componente trabecular (como los cuerpos vertebrales y el radio distal); este hallazgo es parcialmente atribuible a una síntesis predominante de FGF23 en los osteocitos trabeculares. [Pereira et al, 2009; Delgado-Calle et al, 2011 & esta tesis] 6. En la osteoporosis asociada a embarazo y lactancia, la persistencia de una densidad mineral ósea disminuida debe desencadenar la investigación de factores secundarios de osteoporosis, incluyendo potenciales factores genéticos subyacentes. [esta tesis] 7. El metabolismo óseo desempeña un papel importante en el eje anti- envejecimiento FGF23/Klotho, indicado por los siguientes hallazgos: los osteocitos son la fuente principal de FGF23, la expresión de Klotho también ocurre en osteocitos, y nuestros hallazgos de baja densidad mineral ósea asociados con disminución en la supervivencia. [Riminucci et al, 2003; Komaba et al, 2017; Kuro-o, 2018 & esta tesis] 8. La evidencia adicional para apoyar que el metabolismo óseo tiene un papel importante en el envejecimiento y la supervivencia está basada en el hallazgo que los bifosfonatos nitrogenados están relacionados con disminución de la mortalidad - mediada por una reducción en la pérdida ósea e independientemente de la prevención de fracturas. [Reid et al, 2020 y Bliuc et al, 2019] 9. La diferencia por sexo en la asociación de fosfato sérico con diversos resultados cardiovasculares clínicos no se explica por dimorfismo sexual en los factores genéticos del fosfato. [Felsenfeld et al, 1999; Calvo et al, 1988; Kemi et al, 2006 & esta tesis] 10. Se requieren métodos basados ​​en entropía (ε) para dilucidar el fuerte desequilibrio de ligamiento del Complejo Mayor de Histocompatibilidad (6p21.3) y así poder identificar las variantes causales en los estudios de asociación genética (como en el GWAS de fosfato sérico). [Nothnagel y et al, 2002; Hirata et al, 2019 & esta tesis] 11. La implementación de colaboración temprana a nivel global y el intercambio de datos clínicos, epidemiológicos y genéticos durante los brotes locales de enfermedades infecciosas, pueden limitar las consecuencias sociales y económicas para todos los países en potenciales brotes de pandemias. Some abbreviations implemented in this thesis: BMD: bone mineral density LS: lumbar spine P: serum phosphate levels CAC: coronary artery calcification FN: femoral neck COPD: chronic obstructive pulmonary disease HR: hazard ratio CVD: cardiovascular disease RS: Rotterdam Study
Load more

Recommended publications
  • Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model
    Downloaded from http://www.jimmunol.org/ by guest on September 25, 2021 T + is online at: average * The Journal of Immunology , 34 of which you can access for free at: 2016; 197:1477-1488; Prepublished online 1 July from submission to initial decision 4 weeks from acceptance to publication 2016; doi: 10.4049/jimmunol.1600589 http://www.jimmunol.org/content/197/4/1477 Molecular Profile of Tumor-Specific CD8 Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A. Waugh, Sonia M. Leach, Brandon L. Moore, Tullia C. Bruno, Jonathan D. Buhrman and Jill E. Slansky J Immunol cites 95 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html http://www.jimmunol.org/content/suppl/2016/07/01/jimmunol.160058 9.DCSupplemental This article http://www.jimmunol.org/content/197/4/1477.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 25, 2021. The Journal of Immunology Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A.
    [Show full text]
  • Replace This with the Actual Title Using All Caps
    UNDERSTANDING THE GENETICS UNDERLYING MASTITIS USING A MULTI-PRONGED APPROACH A Dissertation Presented to the Faculty of the Graduate School of Cornell University In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy by Asha Marie Miles December 2019 © 2019 Asha Marie Miles UNDERSTANDING THE GENETICS UNDERLYING MASTITIS USING A MULTI-PRONGED APPROACH Asha Marie Miles, Ph. D. Cornell University 2019 This dissertation addresses deficiencies in the existing genetic characterization of mastitis due to granddaughter study designs and selection strategies based primarily on lactation average somatic cell score (SCS). Composite milk samples were collected across 6 sampling periods representing key lactation stages: 0-1 day in milk (DIM), 3- 5 DIM, 10-14 DIM, 50-60 DIM, 90-110 DIM, and 210-230 DIM. Cows were scored for front and rear teat length, width, end shape, and placement, fore udder attachment, udder cleft, udder depth, rear udder height, and rear udder width. Independent multivariable logistic regression models were used to generate odds ratios for elevated SCC (≥ 200,000 cells/ml) and farm-diagnosed clinical mastitis. Within our study cohort, loose fore udder attachment, flat teat ends, low rear udder height, and wide rear teats were associated with increased odds of mastitis. Principal component analysis was performed on these traits to create a single new phenotype describing mastitis susceptibility based on these high-risk phenotypes. Cows (N = 471) were genotyped on the Illumina BovineHD 777K SNP chip and considering all 14 traits of interest, a total of 56 genome-wide associations (GWA) were performed and 28 significantly associated quantitative trait loci (QTL) were identified.
    [Show full text]
  • Transcriptional Control of Tissue-Resident Memory T Cell Generation
    Transcriptional control of tissue-resident memory T cell generation Filip Cvetkovski Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2019 © 2019 Filip Cvetkovski All rights reserved ABSTRACT Transcriptional control of tissue-resident memory T cell generation Filip Cvetkovski Tissue-resident memory T cells (TRM) are a non-circulating subset of memory that are maintained at sites of pathogen entry and mediate optimal protection against reinfection. Lung TRM can be generated in response to respiratory infection or vaccination, however, the molecular pathways involved in CD4+TRM establishment have not been defined. Here, we performed transcriptional profiling of influenza-specific lung CD4+TRM following influenza infection to identify pathways implicated in CD4+TRM generation and homeostasis. Lung CD4+TRM displayed a unique transcriptional profile distinct from spleen memory, including up-regulation of a gene network induced by the transcription factor IRF4, a known regulator of effector T cell differentiation. In addition, the gene expression profile of lung CD4+TRM was enriched in gene sets previously described in tissue-resident regulatory T cells. Up-regulation of immunomodulatory molecules such as CTLA-4, PD-1, and ICOS, suggested a potential regulatory role for CD4+TRM in tissues. Using loss-of-function genetic experiments in mice, we demonstrate that IRF4 is required for the generation of lung-localized pathogen-specific effector CD4+T cells during acute influenza infection. Influenza-specific IRF4−/− T cells failed to fully express CD44, and maintained high levels of CD62L compared to wild type, suggesting a defect in complete differentiation into lung-tropic effector T cells.
    [Show full text]
  • Disease-Related Cellular Protein Networks Differentially Affected
    www.nature.com/scientificreports OPEN Disease‑related cellular protein networks diferentially afected under diferent EGFR mutations in lung adenocarcinoma Toshihide Nishimura1,8*, Haruhiko Nakamura1,2,8, Ayako Yachie3,8, Takeshi Hase3,8, Kiyonaga Fujii1,8, Hirotaka Koizumi4, Saeko Naruki4, Masayuki Takagi4, Yukiko Matsuoka3, Naoki Furuya5, Harubumi Kato6,7 & Hisashi Saji2 It is unclear how epidermal growth factor receptor EGFR major driver mutations (L858R or Ex19del) afect downstream molecular networks and pathways. This study aimed to provide information on the infuences of these mutations. The study assessed 36 protein expression profles of lung adenocarcinoma (Ex19del, nine; L858R, nine; no Ex19del/L858R, 18). Weighted gene co-expression network analysis together with analysis of variance-based screening identifed 13 co-expressed modules and their eigen proteins. Pathway enrichment analysis for the Ex19del mutation demonstrated involvement of SUMOylation, epithelial and mesenchymal transition, ERK/mitogen- activated protein kinase signalling via phosphorylation and Hippo signalling. Additionally, analysis for the L858R mutation identifed various pathways related to cancer cell survival and death. With regard to the Ex19del mutation, ROCK, RPS6KA1, ARF1, IL2RA and several ErbB pathways were upregulated, whereas AURK and GSKIP were downregulated. With regard to the L858R mutation, RB1, TSC22D3 and DOCK1 were downregulated, whereas various networks, including VEGFA, were moderately upregulated. In all mutation types, CD80/CD86 (B7), MHC, CIITA and IFGN were activated, whereas CD37 and SAFB were inhibited. Costimulatory immune-checkpoint pathways by B7/CD28 were mainly activated, whereas those by PD-1/PD-L1 were inhibited. Our fndings may help identify potential therapeutic targets and develop therapeutic strategies to improve patient outcomes.
    [Show full text]
  • Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
    BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in
    [Show full text]
  • Rab27a and Rab27b Control Different Steps of the Exosome Secretion Pathway
    ARTICLES Rab27a and Rab27b control different steps of the exosome secretion pathway Matias Ostrowski1,2, Nuno B. Carmo3,12, Sophie Krumeich1,2,12, Isabelle Fanget10,12, Graça Raposo4,2, Ariel Savina1,2, Catarina F. Moita3, Kristine Schauer4,2, Alistair N. Hume5, Rui P. Freitas3, Bruno Goud4,2, Philippe Benaroch1,2, Nir Hacohen8,9, Mitsunori Fukuda11, Claire Desnos10, Miguel C. Seabra5,6,7, François Darchen10, Sebastian Amigorena1,2, Luis F. Moita3,13 and Clotilde Thery1,2,13 Exosomes are secreted membrane vesicles that share structural and biochemical characteristics with intraluminal vesicles of multivesicular endosomes (MVEs). Exosomes could be involved in intercellular communication and in the pathogenesis of infectious and degenerative diseases. The molecular mechanisms of exosome biogenesis and secretion are, however, poorly understood. Using an RNA interference (RNAi) screen, we identified five Rab GTPases that promote exosome secretion in HeLa cells. Among these, Rab27a and Rab27b were found to function in MVE docking at the plasma membrane. The size of MVEs was strongly increased by Rab27a silencing, whereas MVEs were redistributed towards the perinuclear region upon Rab27b silencing. Thus, the two Rab27 isoforms have different roles in the exosomal pathway. In addition, silencing two known Rab27 effectors, Slp4 (also known as SYTL4, synaptotagmin-like 4) and Slac2b (also known as EXPH5, exophilin 5), inhibited exosome secretion and phenocopied silencing of Rab27a and Rab27b, respectively. Our results therefore strengthen the link between MVEs and exosomes, and introduce ways of manipulating exosome secretion in vivo. Exosomes are membrane vesicles secreted into the extracellular space membrane of MVEs into the lumen of these endosomes14.
    [Show full text]
  • Downloaded from Here
    bioRxiv preprint doi: https://doi.org/10.1101/017566; this version posted November 19, 2015. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 1 Testing for ancient selection using cross-population allele 2 frequency differentiation 1;∗ 3 Fernando Racimo 4 1 Department of Integrative Biology, University of California, Berkeley, CA, USA 5 ∗ E-mail: [email protected] 6 1 Abstract 7 A powerful way to detect selection in a population is by modeling local allele frequency changes in a 8 particular region of the genome under scenarios of selection and neutrality, and finding which model is 9 most compatible with the data. Chen et al. [2010] developed a composite likelihood method called XP- 10 CLR that uses an outgroup population to detect departures from neutrality which could be compatible 11 with hard or soft sweeps, at linked sites near a beneficial allele. However, this method is most sensitive 12 to recent selection and may miss selective events that happened a long time ago. To overcome this, 13 we developed an extension of XP-CLR that jointly models the behavior of a selected allele in a three- 14 population tree. Our method - called 3P-CLR - outperforms XP-CLR when testing for selection that 15 occurred before two populations split from each other, and can distinguish between those events and 16 events that occurred specifically in each of the populations after the split.
    [Show full text]
  • 1 1 2 3 Cell Type-Specific Transcriptomics of Hypothalamic
    1 2 3 4 Cell type-specific transcriptomics of hypothalamic energy-sensing neuron responses to 5 weight-loss 6 7 Fredrick E. Henry1,†, Ken Sugino1,†, Adam Tozer2, Tiago Branco2, Scott M. Sternson1,* 8 9 1Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, VA 10 20147, USA. 11 2Division of Neurobiology, Medical Research Council Laboratory of Molecular Biology, 12 Cambridge CB2 0QH, UK 13 14 †Co-first author 15 *Correspondence to: [email protected] 16 Phone: 571-209-4103 17 18 Authors have no competing interests 19 1 20 Abstract 21 Molecular and cellular processes in neurons are critical for sensing and responding to energy 22 deficit states, such as during weight-loss. AGRP neurons are a key hypothalamic population 23 that is activated during energy deficit and increases appetite and weight-gain. Cell type-specific 24 transcriptomics can be used to identify pathways that counteract weight-loss, and here we 25 report high-quality gene expression profiles of AGRP neurons from well-fed and food-deprived 26 young adult mice. For comparison, we also analyzed POMC neurons, an intermingled 27 population that suppresses appetite and body weight. We find that AGRP neurons are 28 considerably more sensitive to energy deficit than POMC neurons. Furthermore, we identify cell 29 type-specific pathways involving endoplasmic reticulum-stress, circadian signaling, ion 30 channels, neuropeptides, and receptors. Combined with methods to validate and manipulate 31 these pathways, this resource greatly expands molecular insight into neuronal regulation of 32 body weight, and may be useful for devising therapeutic strategies for obesity and eating 33 disorders.
    [Show full text]
  • Flavone Effects on the Proteome and Transcriptome of Colonocytes in Vitro and in Vivo and Its Relevance for Cancer Prevention and Therapy
    TECHNISCHE UNIVERSITÄT MÜNCHEN Lehrstuhl für Ernährungsphysiologie Flavone effects on the proteome and transcriptome of colonocytes in vitro and in vivo and its relevance for cancer prevention and therapy Isabel Winkelmann Vollständiger Abdruck der von der Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation. Vorsitzender: Univ.-Prof. Dr. D. Haller Prüfer der Dissertation: 1. Univ.-Prof. Dr. H. Daniel 2. Univ.-Prof. Dr. U. Wenzel (Justus-Liebig-Universität Giessen) 3. Prof. Dr. E.C.M. Mariman (Maastricht University, Niederlande) schriftliche Beurteilung Die Dissertation wurde am 24.08.2009 bei der Technischen Universität München eingereicht und durch die Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt am 25.11.2009 angenommen. Die Forschung ist immer auf dem Wege, nie am Ziel. (Adolf Pichler) Table of contents 1. Introduction .......................................................................................................... 1 1.1. Cancer and carcinogenesis .................................................................................. 2 1.2. Colorectal Cancer ............................................................................................... 3 1.2.1. Hereditary forms of CRC ........................................................................................ 4 1.2.2. Sporadic forms of CRC ..........................................................................................
    [Show full text]
  • The Pdx1 Bound Swi/Snf Chromatin Remodeling Complex Regulates Pancreatic Progenitor Cell Proliferation and Mature Islet Β Cell
    Page 1 of 125 Diabetes The Pdx1 bound Swi/Snf chromatin remodeling complex regulates pancreatic progenitor cell proliferation and mature islet β cell function Jason M. Spaeth1,2, Jin-Hua Liu1, Daniel Peters3, Min Guo1, Anna B. Osipovich1, Fardin Mohammadi3, Nilotpal Roy4, Anil Bhushan4, Mark A. Magnuson1, Matthias Hebrok4, Christopher V. E. Wright3, Roland Stein1,5 1 Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 2 Present address: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 3 Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 4 Diabetes Center, Department of Medicine, UCSF, San Francisco, California 5 Corresponding author: [email protected]; (615)322-7026 1 Diabetes Publish Ahead of Print, published online June 14, 2019 Diabetes Page 2 of 125 Abstract Transcription factors positively and/or negatively impact gene expression by recruiting coregulatory factors, which interact through protein-protein binding. Here we demonstrate that mouse pancreas size and islet β cell function are controlled by the ATP-dependent Swi/Snf chromatin remodeling coregulatory complex that physically associates with Pdx1, a diabetes- linked transcription factor essential to pancreatic morphogenesis and adult islet-cell function and maintenance. Early embryonic deletion of just the Swi/Snf Brg1 ATPase subunit reduced multipotent pancreatic progenitor cell proliferation and resulted in pancreas hypoplasia. In contrast, removal of both Swi/Snf ATPase subunits, Brg1 and Brm, was necessary to compromise adult islet β cell activity, which included whole animal glucose intolerance, hyperglycemia and impaired insulin secretion. Notably, lineage-tracing analysis revealed Swi/Snf-deficient β cells lost the ability to produce the mRNAs for insulin and other key metabolic genes without effecting the expression of many essential islet-enriched transcription factors.
    [Show full text]
  • Supplementary Table S9
    IlluminaID H1 H2 H3 U1 U2 U3 Molecules Description ILMN_10020 0.50 0.00 0.54 1.08 0.68 0.63 TRPC1 transientreceptorpotential ILMN_10028 0.81 1.25 2.13 0.73 1.47 1.10 LOC149134 hypotheticalLOC149134 ILMN_10044 0.21 0.30 0.47 1.02 1.07 1.25 LXN latexin ILMN_100511 1.53 2.14 1.43 1.56 1.03 0.09 ILMN_10137 0.35 0.73 0.42 2.55 2.07 2.51 IL18R1 interleukin18receptor1 ILMN_10181 1.26 1.86 1.86 3.57 2.54 0.38 INHA inhibin,alpha ILMN_102294 2.68 1.07 5.55 7.64 6.02 5.93 ILMN_1031 0.33 0.85 1.27 0.70 0.44 0.92 EAPP E2Fassociatedphosphoprotein ILMN_103432 1.32 1.78 0.74 1.94 1.55 1.44 ILMN_103704 1.54 1.43 3.09 1.89 2.29 2.37 ILMN_10377 0.65 0.76 0.70 1.60 1.81 1.44 ILMN_10382 1.46 1.29 1.49 0.79 0.78 0.61 TCEA2 transcriptionelongationfactorA ILMN_103984 1.89 1.73 2.23 1.19 1.62 2.77 ILMN_104055 0.88 0.88 R1.04 1.63 1.03 1.67 ILMN_10521 1.37 1.25 1.79 0.93 1.16 1.62 HES1 hairyandenhancerofsplit1, ILMN_105895 2.53 0.42 2.70 1.05 0.64 1.33 ILMN_10640 0.46 0.21 0.83 0.71 1.04 0.85 LOC492311 similartobovineIgAregulatory ILMN_10738 0.30 0.33 0.39 1.58 1.64 1.63 ACSM3 acylCoAsynthetasemedium ILMN_107390 0.73 2.89 2.33 0.58 1.83 2.14 ILMN_10759 0.75 2.09 1.31 1.42 1.58 1.73 ZNF763 zincfingerprotein763 ILMN_108061 3.83 5.16 0.55 1.31 3.20 1.86 ILMN_108133 1.28 3.32 1.70 0.76 1.09 1.07 ILMN_10842 0.62 0.41 0.50 0.75 0.69 1.13 TMIGD2 transmembraneand ILMN_10850 1.06 0.24 0.60 0.95 0.71 0.66 CREB3L4 cAMPresponsiveelement ILMN_11001 2.02 0.96 0.96 1.56 1.57 1.05 C12ORF5 chromosome12openreading ILMN_11038 0.84 0.82 0.64 1.48 1.77 1.49 C11ORF82 chromosome11openreading
    [Show full text]
  • Chromosomal Instability Is Associated with Higher Expression of Genes
    Volume 10 Number 11 November 2008 pp. 1222–1230 1222 www.neoplasia.com Anna V. Roschke*, Oleg K. Glebov*, Chromosomal Instability Is † Samir Lababidi , Kristen S. Gehlhaus*, † Associated with Higher John N. Weinstein and Ilan R. Kirsch* Expression of Genes Implicated *Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20889-5105, USA; in Epithelial-Mesenchymal † Laboratory of Molecular Pharmacology, Center for Transition, Cancer Invasiveness, Cancer Research, National Cancer Institute, Bethesda, and Metastasis and with MD 20889-5105, USA Lower Expression of Genes Involved in Cell Cycle Checkpoints, DNA Repair, and Chromatin Maintenance1 Abstract Chromosomal instability—a hallmark of epithelial cancers—is an ongoing process that results in aneuploidy and karyotypic heterogeneity of a cancer cell population. Previously, we stratified cancer cell lines in the NCI-60 drug discovery panel based on their karyotypic complexity and heterogeneity. Using this stratification in conjunction with drug response data for the cell lines allowed us to identify classes of chemical compounds whose growth- inhibitory activity correlates with karyotypic complexity and chromosomal instability. In this article, we asked the question: What are the biological processes, pathways, or genes associated with chromosomal instability of can- cer cells? We found that increased instability of the chromosomal content in a cancer cell population, particularly, persistent gains and losses of chromosomes, is associated with elevated expression of genes involved with aggressive cellular behavior, including invasion- and metastasis-associated changes in cell communication, ad- hesion, motility, and migration. These same karyotypic features are negatively correlated with the expression of genes involved in cell cycle checkpoints, DNA repair, and chromatin maintenance.
    [Show full text]