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Studies Of angiogenesis in osteocytes: implications for pathogenic mechanisms of osteonecrosis in children with acute lymphoblastic leukaemia

Adams, Madeleine Ruth 2015. Studies Of angiogenesis in osteocytes: implications for pathogenic mechanisms of osteonecrosis in children with acute lymphoblastic leukaemia. MD Thesis, Cardiff University.
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The work presented in this thesis is the result of 2 years of investigation into pathogenic mechanisms resulting in the development of osteonecrosis in children and young people treated for acute lymphoblastic leukaemia (ALL). This was a study using in vitro methods to investigate the effects of corticosteroids (namely dexamethasone which is used in the treatment of ALL) on osteocyte angiogenesis with particular focus on vascular endothelial growth factor (VEGF) and markers of bone remodelling. Interactions between dexamethasone and vitamin D were investigated in order to identify potential preventative or therapeutic strategies for osteonecrosis that could be studied in vivo. The actions of sex steroids on osteocyte biology and their interactions with dexamethasone were also studied in order to begin to explain the increased susceptibility to osteonecrosis that is exists in both adolescent and female patients. Results demonstrate a number of novel findings including; i) significant interactions between dexamethasone and vitamin D on osteocyte VEGF gene expression and protein secretion as well as the RANKL: OPG ratio which is crucial to bone remodelling, ii) dexamethasone treatment leading to significant alterations in expression levels of an array of genes expressed by osteocytes that are involved in angiogenesis pathways and iii) significant effects of sex steroids on osteocyte VEGF production and modulation of the effects of dexamethasone by oestradiol. Osteonecrosis is an extremely disabling side effect of the treatment for ALL which in the vast majority of cases is now a curable disease. The results of this thesis contribute to the current understanding of the pathogenesis and have identified a number of potential therapeutic pathways to target.

Item Type: Thesis (MD)
Status: Unpublished
Schools: Medicine
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RJ Pediatrics
Date of First Compliant Deposit: 30 March 2016
Last Modified: 30 Oct 2017 09:30

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