Each cancer is unique: it reflects the underlying genetic make-up of the patient and the stochastic mutational processes that occur within the tumour. This uniqueness suggests that each patient should receive a personalized type of therapy. Current predictions of a cancer patient’s outcome or prognosis are highly inaccurate. To aid in the prediction of patient prognosis based on highthroughput molecular datasets I have worked to optimize each step of the experimental pipeline: platform annotation, experimental design, consideration of tumour heterogeneity, data pre-processing and statistical analysis, and feature selection. First, a 12k CpG Island clone library was sequenced and annotated using a BLAT analysis. Second, microarrays built using this library were used in a fully-saturated study to evaluate the importance of ChIP-chip experimental design parameters. Third, intra-tumour heterogeneity was shown to influence specific pathways in a large fraction of genes. Fourth, a systematic empirical evaluation of 19,446 combinations of microarray analysis methods identified key steps of the analysis process and provided insight into their optimization. Finally, the combination of a two-stage experimental design and a novel semi-supervised algorithm yielded a six-gene, mRNA abundance-based classifier that could divide non-small cell lung cancer patients into two groups with significantly different outcomes in four independent validation cohorts. Further, a permutation study showed that millions of six-gene markers exist, but that ours ranked amongst the top 99.98% of all six-gene markers. The knowledge gained from these studies provides a key foundation for the development of personalized therapies for cancer patients.

BACKGROUND: Glioblastoma multiforme (GBM) is a highly heterogeneous tumor of the central nervous system (CNS) that exhibits considerable variation in its clinical course. Recently, the World Health Organization (WHO) published a classification system for tumors of the CNS that combines histological features with molecular parameters to determine tumor grade. The incorporation of molecular biomarkers that carry both prognostic and predictive value adds another level of objectivity to the glioma grading system and will help guide clinical decision. As such, the assessment of biomarkers has become an integral part of tumor evaluation in neuro-oncology. This curriculum will discuss the clinical relevance of the most recently studied biomarkers with prognostic and predictive value in the evaluation of GBM. Biomarkers regularly used for the assessment of GBM include the IDH mutations, MGMT methylation status, and EGFRvIII. Furthermore, this review will offer a perspective on experimental approaches currently under investigation for treatment of GBM. LITERATURE REVIEW FINDINGS: MGMT methylation of the promoter region is associated with better treatment response from temozolomide (TMZ), an alkylating therapeutic. Treatment benefit was most prominent in the elderly population and therapy should be individualized for that age group. Patients with GBM characterized by IDH1/IDH2 mutations carry a better overall prognosis primarily due to their higher sensitivity to chemo- and radiotherapy. The prognostic value of EGFRvIII remains controversial, although it may be associated with a worse prognosis. Nonetheless, EGFRvIII provides an ideal target for targeted molecular therapies as it is only found on tumor cells. PROPOSED METHODS: A curriculum aimed at educating primary care providers (PCPs) about the most clinically significant biomarkers in GBM will be developed. The curriculum will be in a PowerPoint format, and the hour-long lecture will be presented at continuing medical education national conferences. A pre- and post-test consisting of the same 10 multiple- choice questions will be administered on a voluntary basis to help evaluate knowledge acquisition from the curriculum. Results will be evaluated with a paired t-test analysis. The tests will be will be administered through Poll Everywhere, a smartphone survey application. CONCLUSION: There is increasing evidence to suggest that therapies should be individualized according to specific biomarkers with predictive value. PCPs are in a position where they are often the first providers to suspect the diagnosis of a brain tumor. Therefore, it is imperative for PCPs to be aware of the latest development in the field of neuro-oncology so that they may appropriately counsel patients.

The Gleason Score (GS) is a powerful predictor of outcome among prostate cancer patients. Patients with tumours graded with a GS of 2 to 6 have a much greater chance of survival compared to those with a GS of 8 to 10. A significant proportion (~40%) of men present with early stage GS 7 tumours (indicating intermediate risk) for whom prognosis is highly variable. Three gene signatures were derived from publicly available gene expression profiles of prostate cancers from the Swedish Watchful Waiting cohort: 1) The Genomic Grade Index consisted of the top 24 genes discriminating between high (8, 9 & 10) and low (≤ 6) GS tumours, 2) The Lethal Gene Score consisted of the top 24 genes discriminating between lethal and indolent disease within GS 7 tumours only, and 3) The network-based gene signature consisted of 88 genes. When these gene signatures were tested in silico on the gene expression profiles of GS 7 patients in both the SWW and the Mayo cohort, patients were stratified into high and low risk for recurrence. These results demonstrate that gene signatures are capable of differentiating low risk and high risk patients within GS 7 tumours. The prognostic capacity of our gene signature will be tested prospectively in a retrospective collection of archived prostate cancer tissue blocks from a phase 3 clinical trial, and it is hypothesized that the patients can be stratified into good and poor outcome groups. NanoString Technology will be used to quantify mRNA values for the signature genes on selected paraffin blocks. Expression values of candidate genes will be correlated with patients’ long-term follow-up information to derive a clinically meaningful signature. Outcome will be defined as biochemical recurrence or metastatic event. The goal of this study is to identify multiple genes whose expression could be formulated into a clinically applicable assay, the implementation of which could serve to better stratify intermediate risk prostate cancer patients for appropriate treatment. / Thesis / Master of Science (MSc) / The over-treatment of prostate cancer patients is a significant concern, as recent clinical trials has shown that it can lead to significant patient morbidity. Although the Gleason Scoring system is a powerful predictor of lethal or indolent disease, a significant proportion of men who present with early stage Gleason Score 7 tumours experience poorer prognosis than expected. The goal of this study is to develop and optimize a gene signature that can be utilized on Gleason Score 7, intermediate risk prostate cancer patients to differentiate them into good and poor outcome groups. We hypothesize that this signature will be able to accurately predict outcome in a separate retrospective cohort of prostate cancer patients. In short, our study hopes to provide proof-of-principle that through the use of gene signatures, it is possible to better differentiate prostate cancer patients into different outcome groups so that they may receive more appropriate treatment specific to their disease type.

No description available.

In this project stroke data were analyzed with the use of survival techniques and incomplete principal component cox analysis. The data set resulted from a multi-center randomised controlled trial coordinated by investigators from the Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton with 438 patients. It was found that among stroke survivors, congestive heart failure along with other cardiac impairments post the major risks. Other factors found to be important were patient age, previous TIAs, presence of ulcers, diabetes and sex. / Thesis / Master of Science (MS)

ITC/USA 2012 Conference Proceedings / The Forty-Eighth Annual International Telemetering Conference and Technical Exhibition / October 22-25, 2012 / Town and Country Resort & Convention Center, San Diego, California / The U.S. Air Force's next generation reusable booster (NGRSB) offers the opportunity for the Space Command to use intelligent equipment for decision making replacing personnel, increasing safety and mission assurance by removing decisions from program management personnel who may not have had any flight-test experience. Adding intelligence to launch vehicle and spacecraft equipment may include requiring the builder to use a prognostic and health management (PHM) program. The PHM was added to NASA's aircraft programs in 2009 and we have requested NASA HQ and NASA Marshal Space Flight Center adopt the NASA PHM in the procurement contracts used on the new Space Launch Systems, NASA's congressionally mandated replacement for the Space Shuttle. Space Vehicle Program managers often make decisions for on-orbit spacecraft without ever having on-orbit space flight experience. Intelligent equipment would have eliminated the catastrophic failures on the NASA Space Shuttle Challenger and Columbia. These accidents occurred due to the lack of space vehicle subsystem engineering personnel analyzing real-time equipment telemetry presented on strip chart and video data prior to lift off during pre-launch checkout for the Space Shuttle Challenger and the lack of space vehicle real-time equipment telemetry for Columbia. The PHM requires all equipment to include analog telemetry for measuring the equipment performance and usable life determination in real-time and a prognostic analysis completed manually will identify the equipment that will fail prematurely for replacement before launch preventing catastrophic equipment failures that may cause loss of life.

Launch vehicle equipment reliability is driven by infant mortality failures, which can be eliminated using a prognostic analysis prior, during and/or after the exhaustive and comprehensive dynamic environmental factory acceptance testing. Measuring and confirming equipment performance is completed to increase equipment reliability by identifying equipment that fails during test for repair/replacement. To move to the 100% reliability domain, equipment dynamic environmental factory testing should be followed by a prognostic analysis to measure equipment usable life and identify the equipment that will fail prematurely. During equipment testing, only equipment performance is measured and equipment performance is unrelated to equipment reliability making testing alone inadequate to produce equipment with 100% reliability. A prognostic analysis converts performance measurements into an invasive usable life measurement by sharing test data used to measure equipment performance. Performance data is converted to usable life data provides a time-to-failure (TTF) in minutes/hours/days/months for equipment that will fail within the first year of use, allowing the production of equipment with 100% reliability.

Motivation In South Africa, various transitional changes parallel detrimental modifications in lifestyle behaviour of especially the lower socio-economic communities. We are currently double-burdened by a high prevalence of communicable and noncommunicable diseases such as diabetes, chronic respiratory and cardiovascular diseases, which is accompanied by a high cardiovascular mortality rate. Healthcare and treatment resources are limited and low-cost intervention strategies to lower this burden are urgently needed. Unhealthy lifestyle behaviours, such as excessive alcohol consumption and tobacco use, are known to augment inflammation as reflected by inflammatory markers such as C-reactive protein and interleukin-6, which are well-known risk factors for cardiovascular disease and mortality. Several studies showed the prognostic value of soluble urokinase plasminogen activator receptor (suPAR) in advanced disease states and that suPAR associates with different types of cancers, infectious diseases, diabetes, coronary artery disease and all-cause mortality. Since the discovery of suPAR in 1991, the role of this less known inflammatory marker in various diseases has been under debate. It was further reported that black individuals have higher suPAR levels than whites. However, whether an unhealthy lifestyle and cardiometabolic risk factors are related to suPAR, whether suPAR plays a role in the development of cardiovascular disease such as hypertension, and whether suPAR could predict all-cause and cardiovascular mortality, especially among the understudied black South African population, remain to be established. Aim The central aim of this thesis was to determine if suPAR associates with cardiovascular disease development in a black South African population. We therefore explored whether suPAR relates to lifestyle and cardiometabolic risk factors, associates with the development of hypertension and has prognostic value for cardiovascular and all-cause mortality over five years. Methodology This five-year prospective sub-study, which is embedded in the international Prospective Urban and Rural Epidemiology study, included black South African volunteers of ages older than 35 years from the North West province, South Africa. Baseline data collection took place in 2005 during which 2 010 men and women from urban and rural areas were examined. A total of 1 292 participants returned for examination and were followed-up for the first time in 2010. Of these participants, 214 were newly identified as being infected with the human immunodeficiency virus (HIV), while 233 died during the five year period. Standardised methods were used to capture all data and included health questionnaires (lifestyle factors, medication use, disease status and history, mortality outcome), cardiovascular and anthropometric measurements, as well as biochemical analyses of inflammatory markers (suPAR, C-reactive protein, interleukin-6), HIV status and relevant metabolic markers. In preparation for statistical analyses, non-Gaussian variables were logarithmically transformed. We compared means and proportions with independent t-tests, analysis of variance, analysis of covariance (for adjustments) and Chi-square tests, while dependent t-tests and McNemar tests were used for analysis of longitudinal data within individual groups. We determined relationships between variables with Pearson’s correlation coefficients. Independent relationships were determined with logistic regression, forward stepwise multiple regression and proportional Cox-regression analyses. Mortality rates were calculated using Kaplan-Meier survival function estimates and log-rank tests. In all cases, p≤0.05 were used to indicate statistical significance. Results and conclusions of each manuscript Three manuscripts were written in order to achieve the aim of this thesis. In the first manuscript we explored the cross-sectional relationships of suPAR with lifestyle and cardiometabolic risk factors in a black South African population. We showed that suPAR was independently associated with lifestyle behaviours, including alcohol consumption, as indicated by gamma-glutamyltransferase levels (β=0.24; p<0.001), tobacco use (β=0.13; p<0.001) and unemployment (β=0.07; p=0.039), despite no direct links with cardiometabolic factors such as blood pressure, dyslipidaemia, glycaemia or adiposity. These findings emphasise the important need to address lifestyle behaviours in order to limit the detrimental effect of modifiable risk factors on the health and mortality rate of this population. Secondly, we determined whether suPAR was associated with the development of hypertension over five years. We found that suPAR was higher and increased more prominently (14.2% vs. 6.94%; p=0.007) in participants that developed hypertensio than in those that remained normotensive. Change in systolic blood pressure was independently associated with baseline suPAR (β=0.14; p=0.043), while becoming hypertensive was associated with an increase in suPAR (odds ratio=1.41; p=0.015). Whether inflammation leads to the development of hypertension or vice versa, remains unclear. Our findings emphasise the need to acknowledge the role of inflammation in hypertension and may permit further investigation of the use of suPAR as a potential marker for early risk identification and intervention. The third manuscript investigated the prognostic value of suPAR, compared to other inflammatory markers C-reactive protein and interleukin-6, in all-cause and cardiovascular mortality. We showed for the first time in a black population that suPAR predicted both all-cause (hazard ratio=1.27; p=0.003) and cardiovascular mortality (hazard ratio=1.40; p=0.026), independent of interleukin-6. Future research is needed to clarify the mechanisms behind the association of suPAR with cardiovascular mortality and to explore the possibility of a suPAR cut-off value for early identification of those with increased risk for cardiovascular morbidity and mortality in this population. General conclusion In this thesis we showed for the first time that suPAR has potential as a marker of cardiovascular disease development in black South Africans. SuPAR associated with hypertension and independently predicted all-cause and cardiovascular mortality over five years. Our findings, that suPAR is independently associated with adverse health behaviours such as alcohol and tobacco use, lend support for the use of suPAR as a novel approach for early risk identification and intervention strategies, which may be effective in combatting the high cardiovascular disease burden among the black South African community. / PhD (Physiology), North-West University, Potchefstroom Campus, 2015

Motivation In South Africa, various transitional changes parallel detrimental modifications in lifestyle behaviour of especially the lower socio-economic communities. We are currently double-burdened by a high prevalence of communicable and noncommunicable diseases such as diabetes, chronic respiratory and cardiovascular diseases, which is accompanied by a high cardiovascular mortality rate. Healthcare and treatment resources are limited and low-cost intervention strategies to lower this burden are urgently needed. Unhealthy lifestyle behaviours, such as excessive alcohol consumption and tobacco use, are known to augment inflammation as reflected by inflammatory markers such as C-reactive protein and interleukin-6, which are well-known risk factors for cardiovascular disease and mortality. Several studies showed the prognostic value of soluble urokinase plasminogen activator receptor (suPAR) in advanced disease states and that suPAR associates with different types of cancers, infectious diseases, diabetes, coronary artery disease and all-cause mortality. Since the discovery of suPAR in 1991, the role of this less known inflammatory marker in various diseases has been under debate. It was further reported that black individuals have higher suPAR levels than whites. However, whether an unhealthy lifestyle and cardiometabolic risk factors are related to suPAR, whether suPAR plays a role in the development of cardiovascular disease such as hypertension, and whether suPAR could predict all-cause and cardiovascular mortality, especially among the understudied black South African population, remain to be established. Aim The central aim of this thesis was to determine if suPAR associates with cardiovascular disease development in a black South African population. We therefore explored whether suPAR relates to lifestyle and cardiometabolic risk factors, associates with the development of hypertension and has prognostic value for cardiovascular and all-cause mortality over five years. Methodology This five-year prospective sub-study, which is embedded in the international Prospective Urban and Rural Epidemiology study, included black South African volunteers of ages older than 35 years from the North West province, South Africa. Baseline data collection took place in 2005 during which 2 010 men and women from urban and rural areas were examined. A total of 1 292 participants returned for examination and were followed-up for the first time in 2010. Of these participants, 214 were newly identified as being infected with the human immunodeficiency virus (HIV), while 233 died during the five year period. Standardised methods were used to capture all data and included health questionnaires (lifestyle factors, medication use, disease status and history, mortality outcome), cardiovascular and anthropometric measurements, as well as biochemical analyses of inflammatory markers (suPAR, C-reactive protein, interleukin-6), HIV status and relevant metabolic markers. In preparation for statistical analyses, non-Gaussian variables were logarithmically transformed. We compared means and proportions with independent t-tests, analysis of variance, analysis of covariance (for adjustments) and Chi-square tests, while dependent t-tests and McNemar tests were used for analysis of longitudinal data within individual groups. We determined relationships between variables with Pearson’s correlation coefficients. Independent relationships were determined with logistic regression, forward stepwise multiple regression and proportional Cox-regression analyses. Mortality rates were calculated using Kaplan-Meier survival function estimates and log-rank tests. In all cases, p≤0.05 were used to indicate statistical significance. Results and conclusions of each manuscript Three manuscripts were written in order to achieve the aim of this thesis. In the first manuscript we explored the cross-sectional relationships of suPAR with lifestyle and cardiometabolic risk factors in a black South African population. We showed that suPAR was independently associated with lifestyle behaviours, including alcohol consumption, as indicated by gamma-glutamyltransferase levels (β=0.24; p<0.001), tobacco use (β=0.13; p<0.001) and unemployment (β=0.07; p=0.039), despite no direct links with cardiometabolic factors such as blood pressure, dyslipidaemia, glycaemia or adiposity. These findings emphasise the important need to address lifestyle behaviours in order to limit the detrimental effect of modifiable risk factors on the health and mortality rate of this population. Secondly, we determined whether suPAR was associated with the development of hypertension over five years. We found that suPAR was higher and increased more prominently (14.2% vs. 6.94%; p=0.007) in participants that developed hypertensio than in those that remained normotensive. Change in systolic blood pressure was independently associated with baseline suPAR (β=0.14; p=0.043), while becoming hypertensive was associated with an increase in suPAR (odds ratio=1.41; p=0.015). Whether inflammation leads to the development of hypertension or vice versa, remains unclear. Our findings emphasise the need to acknowledge the role of inflammation in hypertension and may permit further investigation of the use of suPAR as a potential marker for early risk identification and intervention. The third manuscript investigated the prognostic value of suPAR, compared to other inflammatory markers C-reactive protein and interleukin-6, in all-cause and cardiovascular mortality. We showed for the first time in a black population that suPAR predicted both all-cause (hazard ratio=1.27; p=0.003) and cardiovascular mortality (hazard ratio=1.40; p=0.026), independent of interleukin-6. Future research is needed to clarify the mechanisms behind the association of suPAR with cardiovascular mortality and to explore the possibility of a suPAR cut-off value for early identification of those with increased risk for cardiovascular morbidity and mortality in this population. General conclusion In this thesis we showed for the first time that suPAR has potential as a marker of cardiovascular disease development in black South Africans. SuPAR associated with hypertension and independently predicted all-cause and cardiovascular mortality over five years. Our findings, that suPAR is independently associated with adverse health behaviours such as alcohol and tobacco use, lend support for the use of suPAR as a novel approach for early risk identification and intervention strategies, which may be effective in combatting the high cardiovascular disease burden among the black South African community. / PhD (Physiology), North-West University, Potchefstroom Campus, 2015

No description available.