Blood DNA methylation biomarkers for breast cancer risk

Breast cancer is the most common malignancy affecting women worldwide with an average lifetime risk of 12%. Risk is affected by age, family history, genetics, reproductive factors and environmental exposures, however many unknown risk factors may exist. Regular screening, lifestyle advice and preventative therapy may be offered to women at highest risk; however in the absence of high-penetrance mutations, personal breast cancer risk cannot be accurately estimated. Risk biomarkers are therefore required to help improve current risk prediction models. Epigenetic mechanisms control gene expression and genome function, and are influenced by both heritable and environmental factors. DNA methylation, the most widely studied epigenetic mark, is widely deregulated in cancer and cancer precursor lesions; however the contribution to disease risk of DNA methylation variability in normal tissue prior to disease is poorly understood. Several blood DNA methylation markers associated with cancer have been reported, including genome-wide hypomethylation and hypermethylation of the ATM gene associated with breast cancer, however, validation of these associations in samples collected prior to diagnosis (prospectively collected) are required to determine association with breast cancer risk. The aims of this thesis were to 1) validate ATM methylation as a breast cancer risk marker in three nested case-control studies from prospective cohorts; 2) To investigate hypomethylation of LINE1 in the same prospective cohorts and compare this in a metaanalysis with all other published LINE1 data; 3) To investigate potential mechanisms or modifiers of ATM methylation; 4) To perform discovery microarray studies to identify novel DNA methylation markers of breast cancer risk. Herein, we show that ATM hypermethylation showed a 1.9 fold increased risk of breast cancer limited to women in the highest quintile of methylation (OR =1.89 (1.36-2.64), p= 1.64x10-4). There was no evidence of LINE1 methylation associated with cancer risk in the prospective cohort studies. The meta-analysis 3 of LINE1 and other global methylation markers showed little evidence of association with cancer risk for surrogate assays of repetitive elements, but relatively consistent association with cancer risk using HPLC based total methyl-cytosine levels. Investigation of potential modifiers of ATM methylation revealed that methylation was independent of genetic haplotype, but independently associated with age, genotype of the one-carbon metabolism enzyme MTHFR, and serum levels of serum kynurenic acid levels in controls (p=0.02). Surprisingly, ATM methylation was reduced in controls (p= 5.707e-06) and cases (p= 0.008) that had fasted compared to those that had not. The effect of fasting on ATM methylation could be recapitulated by glucose restriction in ex-vivo PBMCs (p=0.046), independent of cell proliferation. Discovery studies to identify novel DNA methylation risk markers were conducted using differential methylation hybridisation and Illumina Infinium HumanMethylayion450 BeadChip microarrays; however, significant associations were not reproducible in validation sample sets. Discussed are prospects and caveats for epigenetics association studies, including the implications of temporal alteration of DNA methylation by environmental exposures, biases associated with genetic influences on DNA methylation, and the potential for investigation of these interactions to better understand the contribution of epigenetics to gene expression and cancer risk.Open Acces

Modernization and Cultural Change in China: Links to the 2008 Summer Olympics

In 2001, the International Olympic Committee awarded Beijing, China to be host of the 2008 Summer games. Though interesting for multiple reasons, the decision to pick Beijing is intriguing partially because it will be just the third city in the modern era of the Olympics to be located in a Third World country. It has long been argued that hosting the Olympics can lead to significant social and economic changes, especially in non-Western locations. This paper, however, examines a different set of changes linked to the upcoming Olympics in China--the cultural dynamics. The main argument is that the rapid modernization process in China that has occurred during the past three decades has led to both the decision to hold the 2008 Summer games in Beijing as well as efforts to alter certain cultural practices in the country. The decision to award the Olympics to Beijing has served as an intervening variable, as it is accelerating attempts to change various aspects of Chinese culture that are generally unacceptable by Western standards

A comparison of New Zealand police officers' perceptions of development practice within New Zealand development programmes : a research paper presented in partial fulfilment of the requirements for the degree of Master of International Development, School of People, Environment and Planning, Massey University, Manawatu, New Zealand

From the 1990s onwards, the New Zealand Police followed a global trend of progressively becoming involved in overseas peacekeeping and development deployments that over time changed from operational interventions to deployments that were more developmental in nature. While development concepts within these New Zealand Police development interventions have been committed to in principal, there has been little or no research undertaken as to how New Zealand police perceive and undertake their roles within these interventions. Using a post-development framework this research explores how these development interventions and the subsequent expectations for the role of the New Zealand police officer during development interventions overseas were created. A survey and interviews were conducted with a small number of New Zealand police officers who have deployed within these interventions to identify their perceptions of development practice so as to compare with the expectations of the development programmes. My research predominantly finds that New Zealand police officers place a high value on their prior New Zealand policing experiences. In implementing development programmes there was an overwhelming recognition by the research participants for the need to form positive relationships by listening and acknowledging another’s culture. This recognition of the benefits of positive working relationships has led this research to conclude that a recognition of the importance of the personal agency of New Zealand police officers could contribute to recognise and support the personal agency of their development partner to achieve realistic and desirable development outcomes for the intended beneficiary, provided programme design is constructed to incorporate this approach

Can I Have a Look?: A Formal Analysis of Hitchcock and the Art of Suspense in Rear Window

The legendary director Alfred Hitchcock has one goal, to make audiences squirm at the edges of their seats. Rear Window, one of his most critically acclaimed, studied and, according to Hitchcock himself, cinematic films. The way he shot this film and used the tools in his cinematic tool belt all enhance the suspense of his masterpiece. His use of sound, camera movement, scene set-up, actors, writing and more all come together to create a supreme work of suspense

GaInP

Issued as Progress report, and Report, Project no. E-21-672 (continues project no. E-21-F42

Memantine for prevention of migraine: a retrospective study of 60 cases.

The objective was to retrospectively characterise the efficacy of memantine as preventive therapy in a series of patients with frequent migraine. Patients in a university headache clinic completed a survey regarding their experience with memantine, and medical records were reviewed. All patients who received memantine as preventive therapy for migraine over a 15-month period were mailed surveys and consent forms for record review. Patients were treated with memantine beginning at a dose of 5 mg/day, increasing if needed by 5 mg/week up to 10 mg twice a day. The majority of patients (36 out of 54) treated with memantine for at least 2 months reported a significant reduction in estimated headache frequency, and improved function. Side effects were uncommon and generally mild. This limited retrospective case review suggests that memantine may be an effective preventive therapy for patients with frequent migraine. A prospective trial is warranted

An acoustic charge transport imager for high definition television applications

In this report we present the progress during the second six month period of the project. This includes both experimental and theoretical work on the acoustic charge transport (ACT) portion of the chip, the theoretical program modelling of both the avalanche photodiode (APD) and the charge transfer and overflow transistor and the materials growth and fabrication part of the program

The Evolution of a New Technological University in Terms of Policy Definition and Control of Implementation

This paper derives from a Doctoral case study completed in the Dublin Institute of Technology (DIT) in 2008. The main issues of the case study are still being addressed today as DIT prepares to amalgamate with the Institute of Technology Blanchardstown (ITB) and Institute of Technology Tallaght (ITT) in 2015. The combined new institute will become a university in 2016 and is in the process of a move to a green field site. The rate and scope of these changes are challenging for all concerned. Through a series of interviews and focus groups in 2008, a story of DIT emerged. The McNay model was used as a Conceptual Framework and Analytical Tool to examine various types of university model and compare them with the cultures, practices and understandings of stakeholders in DIT. The classic entrepreneurial model from the USA was shown to be unlikely to be successful, largely because of the Institute’s inability to raise money on the scale of the US model. The corporate model using managerialist practice was also rejected by stakeholders. It was concluded that a European style of University with Collegial Innovation was appropriate, that bureaucracy needed be greatly reduced and that the culture and power residing within the organisation must be acknowledged in the process of change

The Evolution of a New Technological University in Terms of Policy Definition and Control of Implementation

This paper derives from a doctoral case study completed in the Dublin Institute of Technology (DIT) in 2008. The main issues of the case study are still being addressed today as DIT prepares to amalgamate with the Institute of Technology Blanchardstown (ITB) and Institute of Technology Tallaght (ITT) in 2015. The combined new organisation will become a university in 2016 and is in the process of a move to a greenfield site. The rate and scope of these changes are challenging for all concerned. Through a series of interviews and focus groups in 2008 a story of DIT emerged. The McNay model was used as a Conceptual Framework and Analytical Tool to examine various types of university model and compare them with the cultures, practices and understandings of stakeholders in the DIT. The classic entrepreneurial model from the USA was shown to be unlikely to be successful, largely because of the Institute’s inability to raise money on the scale of the US model. The corporate model using managerialist practice was also rejected by stakeholders. It was concluded that a European style of University with Collegial Innovation was appropriate, that bureaucracy needed be greatly reduced and that the culture and power residing within the organisation must be acknowledged in the process of chang