Mutagenicity of tamoxifen DNA adducts in human endometrial cells and in silico prediction of p53 mutation hotspots

Tamoxifen elevates the risk of endometrial tumours in women and α-(N2-deoxyguanosinyl)-tamoxifen adducts are reportedly present in endometrial tissue of patients undergoing therapy. Given the widespread use of tamoxifen there is considerable interest in elucidating the mechanisms underlying treatment-associated cancer. Using a combined experimental and multivariate statistical approach we have examined the mutagenicity and potential consequences of adduct formation by reactive intermediates in target uterine cells. pSP189 plasmid containing the supF gene was incubated with α-acetoxytamoxifen or 4-hydroxytamoxifen quinone methide (4-OHtamQM) to generate dG-N2-tamoxifen and dG-N2-4-hydroxytamoxifen, respectively. Plasmids were replicated in Ishikawa cells then screened in Escherichia coli. Treatment with both α-acetoxytamoxifen and 4-OHtamQM caused a dose-related increase in adduct levels, resulting in a damage-dependent increase in mutation frequency for α-acetoxytamoxifen; 4-OHtamQM had no apparent effect. Only α-acetoxytamoxifen generated statistically different supF mutation spectra relative to the spontaneous pattern, with most mutations being GC→TA transversions. Application of the LwPy53 algorithm to the α-acetoxytamoxifen spectrum predicted strong GC→TA hotspots at codons 244 and 273. These signature alterations do not correlate with current reports of the mutations observed in endometrial carcinomas from treated women, suggesting that dG-N2-tam adduct formation in the p53 gene is not a prerequisite for endometrial cancer initiation in women

Higher education commercialisation and its implications in England - the views of university stakeholders

This thesis was submitted for the award of Master of Philosophy and was awarded by Brunel University LondonEngland’s higher education landscape has changed dramatically over the last decade, especially in terms of the level of funding and how it is delivered. The funding for higher education has been declining and this is having a severe impact on university activities. This may be as a result of the increasing number of people going into Higher Education (HE) and the government paying more attention to other sectors, for example the National Health Service. There is now a more entrepreneurial element in university operations to increase income. This study critically analyses the implications of the changing funding policy on students and the university. The epistemology, i.e. how to obtain information from those affected by the changes, is an analysis of the perceptions of people, and the methodology is administering a self-completion on-line questionnaire to higher education stakeholders i.e. all categories of staff of four universities taken as a sample. The reason for collecting the views of stakeholders is because university income is affected by the changes. This study covers the period 2008-2017. It is a qualitative study and the analysis of the data collected using open-ended and close-ended questions suggests a number of implications for higher education governance and management. The analysis of the open-ended responses reveals an overwhelming opposition to market mechanism for higher education and an increase in tuition fees. The responses from the close questions also paint a very strong picture of disapproval of the public funding policy and university commercialization. On average, about 80% of the open-ended responses expressed stiff opposition. However, the findings of this study should be treated with caution as it was only 4 universities that were studied and a small percentage of the staff in each university responded to the survey. The result of the analysis answers the research questions including: “How does higher education fee structures impact on student numbers?” The theory of demand and supply is used in an attempt to answer the research question. Demand and supply is used to project higher education demand for the next 10 years. The projection indicates that higher education tuition fees may rise and that could cause a decrease in demand for higher education. Already UCAS figures indicate a fall in student registration in 2012, the first year of the introduction of £9,000 tuition fees. However, the figures for 2013 indicate a 1% increase in student registration for the 18 and 19 year olds but a decrease of about 9-10% in registration for the older age group. There was a 3% increase in 2014-15 and 3% increase in 2015-16. In addition to the application of the theory of demand and supply, the study applied critical theory to the new market agenda for higher education in England where there is a dichotomy in the provision of HE. The system encourages social exclusion and this was expressed strongly in the survey responses. The link between demand and supply and the applied critical theory is that demand and supply creates a situation where those well off will demand quality products while the less well off will demand low quality products creating a class system as in the case of HE provision. Critical theory is a against such a class system where the rich dominate and have the best in society. The study would say it is too early to make any conclusions as to the full impact of the introduction of the fee payment and the high fees on student application numbers