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This Thesis Has Been Submitted in Fulfilment of the Requirements for a Postgraduate Degree (E.G This thesis has been submitted in fulfilment of the requirements for a postgraduate degree (e.g. PhD, MPhil, DClinPsychol) at the University of Edinburgh. Please note the following terms and conditions of use: This work is protected by copyright and other intellectual property rights, which are retained by the thesis author, unless otherwise stated. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author. The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author. When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given. PHENOTYPES AND GENETIC MARKERS OF CANCER CACHEXIA Neil Johns MD Thesis presented to The University of Edinburgh – 2015 Table of Contents Acknowledgements ....................................................................................... i Declaration of originality ............................................................................. iii List of publications arising from this thesis .............................................. iv Abbreviations ................................................................................................ v Abstract ........................................................................................................ xi Chapter 1 – Introduction .............................................................................. 1 1.1 Background ........................................................................................ 2 1.2 Definition of cancer cachexia ............................................................. 2 1.3 Epidemiology and incidence of cancer cachexia ................................ 3 1.4 Staging of cancer cachexia as a spectrum ......................................... 6 1.5 Mechanisms of tissue loss ................................................................. 7 1.5.1 Anorexia / decreased food intake ...............................................................7 1.5.2 Increased enery expenditure ......................................................................9 1.5.3 Other aspects of abnormal metabolism associated with cachexia ......... 12 1.6 Mediators of tissue loss .................................................................... 14 1.6.1 Changes in muscle and adipose tissue mass ......................................... 15 1.7 Fat loss ............................................................................................ 23 1.8 Muscle loss ...................................................................................... 23 1.9 Biomarkers of cancer cachexia ........................................................ 24 1.9.1 Plasma biomarkers of cancer cachexia .................................................. 25 1.9.2 Muscle biomarkers of cancer cachexia ................................................... 25 1.9.3 Urinary biomarkers of cancer cachexia ................................................... 26 1.9.4 Genetic biomarkers of cancer cachexia .................................................. 27 1.9.5 Candidate gene association analysis in cachexia ................................... 29 1.10 Clinical consequences and management of cachexia ...................... 32 1.11 Hypothesis ....................................................................................... 36 1.12 Aims ................................................................................................. 36 1.13 Plan ................................................................................................. 37 Chapter 2 – Muscle wasting in cancer ...................................................... 39 2.1 Summary ......................................................................................... 40 2.2 Introduction ...................................................................................... 40 2.3 Heterogeneity .................................................................................. 41 2.4 Skeletal muscle morphology in cancer associated myopenia: murine models ............................................................................................. 43 2.4.1 Fibre size and type in cancer associated myopenia ............................... 44 2.4.2 Fibre RNA, DNA, and protein content in cancer associated myopenia .. 45 2.4.3 Dystrophin glycoprotein complex (DGC) ................................................. 46 2.5 Mediators of cancer associated myopenia: murine models .............. 46 2.5.1 Pro-inflammatory mediators .................................................................... 46 2.5.2 Catabolic mediators ................................................................................. 48 2.5.3 Anabolic mediators .................................................................................. 48 2.6 Mechanisms of cancer associated myopenia: murine models .......... 49 2.6.1 Protein degradation pathways ................................................................. 49 2.6.2 Protein synthesis pathways ..................................................................... 55 2.6.3 Fat-muscle cross talk .............................................................................. 55 2.7 Skeletal muscle morphology and function in cancer associated myopenia: clinical data ..................................................................... 56 2.8 Mediators of cancer associated myopenia: clinical data ................... 57 2.8.1 Systemic mediators of cachexia .............................................................. 58 2.8.2 Pro-inflammatory cytokines ..................................................................... 58 2.8.3 Other circulating mediators ..................................................................... 59 2.9 Mechanisms of cancer associated myopenia: clinical data ............... 62 2.9.1 UPP / E3 ubiquitin ligases ....................................................................... 62 2.9.2 Autophagy / Lysosomal pathway ............................................................ 64 2.9.3 Calpains................................................................................................... 64 2.9.4 Caspases ................................................................................................ 64 2.9.5 Myogenesis ............................................................................................. 65 2.10 Future prospects .............................................................................. 65 Chapter 3 – Materials and methods ........................................................... 66 3.1 Ethical approval ............................................................................... 67 3.2 Study participants ............................................................................ 67 3.2.1 Clinical Classification of Cancer Cachexia: Phenotypic Correlates in Human Skeletal Muscle (Chapter 4) ....................................................... 67 3.2.2 Genetic signatures associated with susceptibility to cancer cachexia vary according to weight-loss or low muscle mass phenotype (Chapter 6) .... 68 3.3 Clinical and pathological data collection (Chapter 4 and 6) .............. 70 3.4 Nutritional assessment (Chapter 4 and 6) ........................................ 70 3.5 Collection of biological samples (Chapter 4 and 6) ........................... 70 3.5.1 Blood collection (Chapter 4 and 6) .......................................................... 70 3.5.2 Rectus abdominis muscle biopsy and storage for biochemical analysis (Chapter 4 and 6) .................................................................................... 71 3.5.3 Rectus abdominis muscle sample preparation for cryo-section (Chapter 4) .............................................................................................. 71 3.6 Blood assays (Chapter 4 and 6) ....................................................... 71 3.6.1 Measurement of C-reactive protein (CRP) .............................................. 71 3.7 Body composition analysis ............................................................... 72 3.7.1 Estimation of total body skeletal and adipose tissue using computed tomography (CT) scans ........................................................................... 72 3.8 Cellular methods (Chapter 4 and 6) ................................................. 74 3.8.1 Immunohistochemistry (Chapter 4) ......................................................... 74 3.8.2 Tissue Preparation for DNA, RNA and Protein extractions (Chapter 4) . 75 3.8.3 DNA and RNA extraction and linearity of the extraction method (Chapter 4) .............................................................................................. 75 3.8.4 Protein extractions (Chapter 4) ............................................................... 76 3.8.5 Western blots (Chapter 4) ....................................................................... 76 3.8.6 DNA extraction from blood (Chapter 6) ................................................... 77 3.8.7 Quantification of DNA (Chapter 6) .......................................................... 78 3.9 Single nucleotide polymorphism (SNP) genotyping (Chapter 6) ....... 78 3.10 Microarray analysis (Chapter 6) ....................................................... 80 3.11 Statistics
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