http://angliaruskin.openrepository.com:80/arro ARRO captures, stores, indexes, preserves, and distributes digital research material. Thu, 15 Mar 2012 13:03:47 GMT 2012-03-15T13:03:47Z http://hdl.handle.net/10540/213610 Title: Bcl-xL deamidation in oncogenic tyrosine kinase signalling. Authors: Zhao, Rui Abstract: I have been interested in the molecular mechanisms of Haematopoietic malignant diseases such as leukaemia and lymphoma, especially those involving oncogenic tyrosine kinases. About 30 of the 90 tyrosine kinases in the human genome have been implicated in cancer (Blume-Jensen P, 2001). The oncogenic tyrosine kinases (OTKs), such as Bcr-Abl (product of chromosomal translocations of two genes bcr and abl) in Chronic Myelogenous Leukaemia, and Erythroblastic leukaemia viral oncogene homolog 2(Erb-B2) in mammary and other cancers, mediate their transforming effects via a diverse array of signalling pathways involved in DNA damage, cell survival and cell cycle regulation (Deutsch E, 2001; Skorski T, 2002; Kumar R, 1996). My work has been centred around the analysis of a mouse cancer model that is driven by an oncogenic tyrosine kinase – p56 Lck-F505 expressed on CD45 knock- out background (Baker M, 2000). The investigation of this mouse model has revealed that oncogenic inhibition of deamidation of the Bcl-xL survival protein plays a critical role in protecting thymocytes from DNA-damage induced apoptosis. Cells that would normally be eliminated due to accumulating DNA damage are instead preserved with an increasing load of double-stranded breaks, leading to genomic instability, chromosomal abnormalities and transformation. This work was published in Cancer Cell (An oncogenic tyrosine kinase inhibits DNA repair and DNA-damage-induced BclxL deamidation in T cell transformation. Zhao R, 2004). Following that I have tried to elucidate the different roles of the two deamidated species of Bcl-xL in apoptosis, and also the molecular mechanisms of DNA damage- induced Bcl-xL deamidation in order to understand the inhibition of Bcl-xL deamidation by oncogenic tyrosine kinases. Recently I have shown that Bcl-xL deamidation, whereby two critical Asn residues are converted to iso-Asp, cripples the ability of the protein to sequester pro-apoptotic BH3-only proteins such as Bim and p53- upregulated modulator of apoptosis (PUMA), thereby explaining its loss of pro-survival functionality. In vivo, DNA damage causes intracellular alkalinisation that is both necessary and sufficient to deamidate Bcl-xL, promoting apoptosis: no enzyme is necessary for this process. In pre-tumourigenic thymocytes alkalinisation is blocked, so preserving Bcl-xL in its pro-survival mode. Furthermore murine tumours are protected from genotoxic attack by native Bcl-xL, but enforced alkalinisation and consequent Bcl-xL deamidation promotes apoptosis. This part of work was published in Plos Biology (DNA damage-induced Bcl-xL deamidation is mediated by NHE-1 antiport regulated intracellular pH. Zhao R, 2007). Through collaboration with Prof AR Green’s research group at the Department of Haematology of the University of Cambridge, I have also analysed the Bcl-xL deamidation pathway in human myeloproliferative disorders, e.g. Polycythemia vera(PV) and Chronic Myelogenous Leukaemia (CML). We found that the oncogenic tyrosine kinases involved in these disorders, i.e. Jak2V617F and Bcr-Abl also inhibit the Bcl-xL deamidation pathway in DNA damage responses. These findings shed light on potential therapeutic application of the Bcl-xL deamidation pathway in human malignancies. This piece of work was recently published in the New England Journal of Medicine (Inhibition of the Bcl-xL deamidation pathway in myeloproliferative disorders. Zhao R, 2008). Overall the cited work has led to several important new insights into the molecular mechanisms involved in oncogenesis: first, that Bcl-xL deamidation is important in the cascade of events leading from DNA damage to apoptosis; second, that oncogenic tyrosine kinases inhibit these events in both the murine and human context; third, that up-regulation of the NHE-1 antiport and consequent intracellular alkalinisation are critical events in this DNA damage-induced cascade leading to apoptosis. In the process I have demonstrated the first in vivo mechanism for the deamidation of an internal protein Asn. Essentially, a completely new and unexpected signalling pathway has been uncovered that seems to pertain to all murine and human haematopoietic cell lineages that have been investigated so far. Sat, 01 Jan 2011 00:00:00 GMT http://hdl.handle.net/10540/213610 2011-01-01T00:00:00Z http://hdl.handle.net/10540/211749 Title: The impact of the new integrated older people's care services in Cambridgeshire on service users Authors: Hu, Mei Abstract: Social care and health services for older people in Cambridgeshire have been integrated since April 2004. This study examines the effect of the integration programme on service users. Previous research into health and social care integrations predominantly centre on process issues and pay much less attention to outcomes. No study has evaluated the impact of fully-integrated care services for the whole user group of older people. Theory-led programmatic approach was used in this study. Multi-method data collection and analysis were employed to uncover and examine the causal links, the contextual conditions, the implementation process, causal mechanisms, and intended and achieved outcomes of the integration programme. This study reveals an improvement in the physical functioning of one in three occupational equipment users; a rise in the level of satisfaction of 85% of occupational health and 82% of physiotherapy users; older people with complex problems and high-level needs were able to be helped to live at home; and waiting time for both assessment and for services within two weeks and four weeks were below the national achievement and the ministerial targets. It also reveals a lack of change outcomes in social care, and service users’ low level of satisfaction with social care services, which appear to be associated with the privatisation of long-term social care and the predominant aim in social work of achieving maintenance and prevention outcomes. The integration programme’s goals—unifying the care system, easier and simpler access to services and a single and quick assessment—were not fully reached, mainly because of users’ low awareness of the integration, incompatible ICT systems and lack of funding. This study contributes to knowledge on how the total integration in Cambridgeshire has benefited users and how theory-led programmatic approach can be used in this area and in the study of this kind of complex social programme. Fri, 01 Jul 2011 00:00:00 GMT http://hdl.handle.net/10540/211749 2011-07-01T00:00:00Z http://hdl.handle.net/10540/211745 Title: British banking-halls as a property investment Authors: Tipping, Malvern Abstract: This research is related to British banking-halls as a class of real estate investment. Sale-and-leaseback has become an increasingly common approach during the last two decades for the holding of British banking-halls. One measure used in making property investment decisions is the all risks yield (ARY). Investors and their advisors have a need for a predictive framework which they can use for predicting those retail bank premises likely to achieve the highest ARY when assembling investment portfolios of such properties. A predictive framework necessitates the identification of those factors significantly influencing the yields of British banking-halls. This research aims to develop such a framework. Triangulation methodology was adopted to establish and test the predictive framework. A literature review established theory before a qualitative study, based upon semi-structured interviews and a questionnaire, was used to establish the influencing factors. A cross-sectional study of auction data then formed the basis of the quantitative regression study. The qualitative and quantitative studies validated that four factors were significant in influencing yield. These were tenant banking company, lot size, super-region and the macro-economic cycle index. A toolkit comprising a predictive framework for those banking-halls likely to produce the highest ARY was produced. This is capable of being used by professional practitioners and investors in predicting high yield for portfolio building purposes. The predictive framework was developed based upon the quantitative data from those three banks with the most premises sold by sale-and-leaseback. It formed a baseline from which further studies can build to test its significance for other banks. Consequently, a more robust predictive framework can be developed for banking-hall investments. Further research can also be conducted to develop predictive frameworks forecasting yields for investment in other commercial retail sectors, based upon the findings of this research. Fri, 01 Jul 2011 00:00:00 GMT http://hdl.handle.net/10540/211745 2011-07-01T00:00:00Z http://hdl.handle.net/10540/211744 Title: A critical comparative analysis of racial integration laws and its impact on professional team sports Authors: Khoo, Teng Guan Abstract: The following research aims to examine the interaction of law, either hard law (legislation) or soft law (governing body regulation), on achieving a balance between racial equality and success in sport. Nearly all national jurisdictions have legislated to some degree in an attempt to affect equality or equality of opportunity for its citizens. This might be based on achieving equality of opportunity or by means of affirmative action. The research aim is to ascertain how far racial discrimination laws have positive or negative impacts on the success of sports in different countries. The research also has a series of supplementary objectives: to ascertain and consider critically the extent to which the law in various jurisdictions (Malaysia, South Africa, England and the United States) has been used to promote equality; to develop a sequential model to describe general trends to predict the influence of affirmative action and equal opportunity legislation upon the potential success of countries’ sporting achievements; to review tensions inherent in reconciling the equality of citizens at a national level and their impacts upon the international sporting success of that nation; to establish a correlative relationship between the types of anti-discrimination law within nations and the impact of these upon the degree of international sporting success of those nations. The research conducted concentrates primarily on qualitative methods by first adopting a doctrinal approach in a comparative legal study of four jurisdictions (Malaysia, South Africa, England and the United States). A non-doctrinal approach is then adopted and a qualitative intrinsic case study completed, including interviews concerning the subject area. Thus, the research has used multi-method qualitative approaches. The research indicated different anti-discrimination approaches taken in achieving equality. This can be typified by countries such as the United States or England based primarily on meritocracy and countries such as South Africa and Malaysia based primarily on preferential treatment. There is evidence to suggest that these approaches do have a certain correlation, albeit not similar in the outcome of achieving equality for selection. From the evidence presented, the overall study illustrates that racial discrimination laws in the four jurisdictions produced a mixed outcome in relation to the success of professional team sports. Specifically, England and the United States witnessed a positive impact in terms of achieving international success in sports even though there are inherent difficulties in reconciling the equality of citizens at a national level. For Malaysia and South Africa, the result tends to be positive in general at this stage although it is equally recognised that this approach might result in some negative impacts in the long run. The research however is subject to certain limitations which are outside the scope of this thesis, but it is recognised that these might affect the overall success of professional team sports within those countries. Mon, 01 Aug 2011 00:00:00 GMT http://hdl.handle.net/10540/211744 2011-08-01T00:00:00Z