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Thesis (M. Med. Sc.)--University of Hong Kong, 2007.

Thesis (Ph. D.)--Electrical and Computer Engineering, Georgia Institute of Technology, 2009. / Committee Chair: William Hunt; Committee Member: Alfred Merrill, Jr.; Committee Member: John Petros; Committee Member: Peter Hesketh; Committee Member: Robert Butera. Part of the SMARTech Electronic Thesis and Dissertation Collection.

published_or_final_version / Pathology / Master / Master of Medical Sciences

Historically, diagnosis has relied on clinical signs of disease, microscopy and serological testing. However, these approaches have a number of drawbacks for example, differential diagnosis, low sensitivity (microscopy) and the inability to differentiate past from current infections (serology). In the past decade the use of molecular techniques, such as the polymerase chain reactions (PCR) have gained favour. Many research groups have used these techniques to study the molecular epidemiology of diseases in sub-Saharan Africa. Such methodologies rely on the detection of genetic materials and as such are reliant on the specificity of their components and the quality of the starting materials. It is the aim of this thesis is to demonstrate improvements that can be made to sample collection that will help to enhance the reliability of these tests and highlight the importance of the diagnostic parameters. The model that I will use to demonstrate these improvements are African trypanosomes, these are the causative agents of sleeping sickness in humans and nagana in animals, and are wide spread across much of sub-Saharan Africa. My work will be presented as three main sections: Firstly, a comparison of the suitability of various different approaches to cattle blood sample collection – including the genetic materials prepared directly in the field and the use of Whatman FTA®cards – in terms of the provision of appropriate materials for molecular screening will be presented. It was found that uneven distribution of genetic materials occurs across the surface of the FTA®cards due to the matrix chemistry. Therefore suggestions for improvements for the preparation of materials to be stored on these cards and their downstream application are made. Secondly, a comparison between the specificity of the pan-Trypanosoma ITS-PCR reaction and the species-specific reactions is made. The ITS-PCR has gained favour in recent years as it is reported to be capable of identifying a wide range of trypanosomes, as this is a single nested PCR reaction the reduction in time and cost has been very appealing to researchers in this field. My work suggests that this test is not reliable in terms of the accurate detection of trypanosomes species, and in fact on a direct comparison of 969 samples, 37 parasitic events where identified by this approach compared to 197 when species-specific tests were applied. Thirdly, based on my findings from the previous two chapters I present two case studies, the first of which looks to evaluate the impact on the prevalence of trypanosome species in cattle after drug treatment during the Ugandan, Stamp Out Sleeping sickness (www.sleepingsickness.com) campaign. The results of this case study highlight the importance of understanding the relationship that occurs between trypanosome species in mixed infections, my second case study therefore looks to quantifying the infection load of Trypanosoma brucei and T. congolense within the midgut of their insect vector (Glossina morsitans morsitans) using qPCR.

published_or_final_version / abstract / Civil Engineering / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Surgery / Master / Master of Philosophy

Head and neck cancers account for 3% of all newly diagnosed cancers, of which 90% are squamous cell carcinomas (SCC). Improvements in surgery, radiotherapy and chemotherapy have done little to improve the mortality of this disease over the past 20 years while current clinicopathological predictors of disease outcome are sub-optimal. Identifying molecular targets of prognostic and therapeutic significance in head and neck squamous cell carcinomas (HNSCC) may help direct novel therapies to patients whom it is most likely to benefit. Accrued knowledge of the biology of HNSCC has highlighted specific aberrations in pRb and p53 pathways which warrant further study. An immunohistochemical analysis (IHC) in a cohort of 145 patients with SCC of the anterior tongue was performed. Protein expression of the pRb and p53 pathways and related molecules that directly or indirectly influence cell cycle progression at the G1/S phase checkpoint was assessed. We determined that over-expression of E2F-1 occurred in &gt35% of these cancers and associated with improved overall survival on univariate analysis. The strongest multivariate model included: regional lymph node status, tumour grade, p16INK4A, cyclin D1 and p14ARF. This is the first study to determine that p14ARF is an independent marker of both improved diseasefree survival and overall survival in a cohort of SCC of the anterior tongue. Unrecognized molecular heterogeneity is thought to account for the unpredictable clinical response to ZD1839, an EGFR tyrosine kinase inhibitor. We explored the anti-proliferative effects following ZD1839 treatment alone or in combination with radiotherapy in cyclin D1 and E2F-1 over-expressing SCC9 HNSCC cells. SCC9 cells over-expressing cyclin D1 or E2F-1 were highly resistant to ZD1839 treatment, while E2F-1 clones were also radioresistant. Combined therapy in SCC9 controls had a greater anti-proliferative effect than each individual treatment. These data showed that cyclin D1 and E2F-1 may have utility as markers of ZD1839 resistance. The data in this thesis contribute to our knowledge of the clinical behaviour and molecular pathology of HNSCC. Specifically the molecular data identifies novel markers of outcome in SCC of the anterior tongue such as p14ARF, and therapeutic response to ZD1839 such as cyclin D1 and E2F-1. This study addresses in part, the current issues and limitations of management in HNSCC and has the potential to contribute to strategies that may be developed to improve the outcome for patients who develop HNSCC in the future.

Thesis (Ph. D.)--University of Hong Kong, 2007. / Title proper from title frame. Also available in printed format.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences