Thesis (Ph. D.)--UCLA, 2007. / Vita. Includes bibliographical references (leaves 178-187).

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Gene expression profiles have identified five major molecular breast cancer subtypes (Luminal A, Luminal B, Basal-like, HER2+/estrogen receptor− , and Normal Breast-like) that show significant differences in survival. The cost and complexity of gene expression technology has impeded its clinical implementation. By comparison, immunohistochemistry is an economical technique applicable to the standard formalin-fixed, paraffin-embedded material commonly used in hospital labs, and has the advantage of simultaneously interpretation with histomorphology. In this thesis, I hypothesize that a surrogate panel of immunohistochemical biomarkers can be developed to discriminate the breast cancer biological subtypes. The main study cohort consists of over 4000 primary invasive breast tumors, assembled into tissue microarrays. These patients were referred to the British Columbia Cancer Agency between 1986-1992 and have staging, pathology, treatment and follow-up information. In summary, our results demonstrate that (1) the rabbit monoclonal antibody, SP1, is an improved standard for immunohistochemiscal estrogen receptor assessment in breast cancer; (2) the transcription factor, GATA-3, is almost exclusively expressed among estrogen receptor positive tumors but does not seem to predict for tamoxifen response among estrogen receptor positive patients; (3) the proliferation marker, Ki-67, together with HER2 can segregate Luminal A from Luminal B subtypes, which carry distinct risks for breast cancer relapse and death; and (4) the inclusion of the basal markers EGFR and ck5/6 to “triple negative” breast cancers provides a more specific definition of basal-like breast cancer that better predicts patient survival. These results consistently demonstrate that an immunopanel of six biomarkers (estrogen receptor, progesterone receptor, HER2, Ki-67, epidermal growth factor receptor and cytokeratin 5/6) can be readily applied to standard pathology specimens to subtype breast cancer samples based on their underlying molecular biology. These findings have been considered sufficient to justify application of this panel onto NCIC (MA5, MA12) and CALGB (9341 and 9741) clinical trials specimens. This followup work which is underway and will determine if the six marker immunopanel can guide decisions about which patients need aggressive systemic drug treatment, and thereby ensure patients get the most effective, individualized adjuvant systemic therapy for their breast tumor. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate

DNA micro-array technology is a new and powerful technology that could substantially increase the speed of forest tree breeding programmes. This thesis represents a compilation of investigations that focus on the exploitation of DNA micro-array technology for genetic marker analysis of Eucalyptus trees. The major focus of the studies presented in this thesis was on the assessment and development of micro-array-based DNA fingerprinting in Eucalyptus. A DNA chip for Eucalyptus was not available at start of the study. As a result of this study a 384-prototype chip was developed to evaluate the potential of micro-arrays for fingerprinting closely related Eucalyptus clones, species and hybrids. These studies show that micro-arrays are an efficient DNA marker technology for genome-wide fingerprinting of complex organisms for which no sequence data exist. However, cross-hybridisation and the lack of dedicated software products remain a challenge. The 384-probe array developed in this study was subsequently employed for the detection of putative markers associated with tolerance to Chrysoporthe austroafricana in Eucalyptus grandis. Putative tolerance-associated markers were identified by bulk segregant analysis (BSA) and converted to cleaved amplified polymorphic sequence markers for further characterization in segregating Eucalyptus populations. BSA revealed a total of 109 scorable, polymorphic loci, of which nine appeared to be associated with tolerance or susceptibility. Two DArT markers were converted to cleaved amplified polymorphic sequence (CAPS) markers, which discriminate susceptible and tolerant individuals. These PCR markers can be used for the rapid screening for disease tolerance in Eucalyptus planting and breeding stock. The collection of studies included in this thesis demonstrated that DArT is an efficient DNA marker technology for genome-wide genotyping, particularly for application in less-studies plant genomes. Whole-genome profiling using DArT raises significant opportunities for tree breeding programmes and for future genome analysis of Eucalyptus. / Thesis (PhD)--University of Pretoria, 2011. / Genetics / Unrestricted

The purposes of this study were 1) to investigate the release of cardiac biomarkers resulting from acute bouts of maximal intermittent exercise in a laboratory-based setting and set up an exercise-induced cardiac biomarker release (EICBR) model; 2) to compare the changes in cardiac biomarkers in normoxic and hypoxic environments and determine the effects of hypoxia; 3) to investigate the changes in oxidative stress biomarkers resulting from acute bouts of maximal intermittent exercise in normoxic and hypoxic environments at multiple time points; and 4) to observe the relationship between oxidative stress and EICBR and explore the hypothesis that lipid peroxidation triggers the release of cardiac biomarkers from the cytosolic pool. The maximal oxygen consumption (VO2max) and the corresponding velocity of VO2max (vVO2max) of ten well-trained male marathon runners (age 22.1±2.6 y, body mass 64.0±4.9 kg and height 177.3±3.9 cm) was determined under normoxic (FIO2=21.0%, VO2max_N=64.72±5.63 ml∙kg-1∙min-1 and vVO2max_N=18.2±1.0 km∙h-1) and hypoxic (FIO2=14.4%, VO2max_H=62.16±6.74 ml∙kg-1∙min-1 and vVO2max_H=16.7±0.7 km∙h-1) conditions in two experimental trials. One set of conditions was tested in each trial. The order in which each participant faced each trial was selected at random and the trials were separated by 72 h. The ten participants also completed three maximal intermittent exercise protocols, under normoxic (trial N, FIO2=21.0%), absolutely hypoxic (trial AH, FIO2=14.4%) and relatively hypoxic (trial RH, FIO2=14.4%) conditions. The order in which the participants faced the three conditions was once again selected at random and the protocols were separated by at least 7 d. Each bout of maximal intermittent exercise in trials N and AH consisted of a hard run of 16.4±0.9 km∙h-1 (90% vVO2max_N) for 2 min, followed by an easy run of 9.1±0.5 km∙h-1 (50% vVO2max_N) for 2 min with a 2% slope. In trial RH, each bout of exercise consisted of a hard run of 15.0±0.6 km∙h-1 (90% vVO2max_H) for 2 min, followed by an easy run of 8.4±0.3 km∙h-1 (50% vVO2max_H) for 2 min with a 2% slope. Each of the three trials consisted of 23 bouts of maximal intermittent exercise, performed over 92 min. Measurements of the serum of the antecubital venous blood were performed pre- and post- (0 h, 2 h, 4 h and 24 h) exercise. The measurements were taken at five time points for each of the three conditions. The cardiac damage biomarkers of high sensitivity cardiac troponin T (hs-cTnT) and cardiac troponin I (cTnI) and the oxidative stress biomarkers of malondialdehyde (MDA), lipid hydroperoxide (LH), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and total antioxidant capacity (TAOC) were analysed. Heart rate (HR) and arterial oxygen saturation (SaO2) were recorded before and during exercise. Due to the skewed distribution of the data (P<0.05), a non-parametric Friedman’s test was used to compare the differences in the levels of hs-cTnT and cTnI between pre- and post-exercise and at each time point for the three conditions. MDA, LH, SOD, CAT, GSH, TAOC and HR were normally distributed (P>0.05) and were analysed using one-way repeated ANOVA tests. Pearson’s product moment correlation coefficients were used to determine the degree of association between the peak levels of hs-cTnT and cTnI, and MDA, LH, SOD, CAT, GSH and TAOC. In trial N, the level of hs-cTnT was elevated 0 h post-exercise (9.628±3.797 pg∙ml-1 was significantly different from the pre-exercise level of 5.118±1.857 pg∙ml-1, P=0.005), reached its peak level 2 h post-exercise (24.290±18.628 pg∙ml-1 was significantly different from the pre-exercise level, P=0.005) and returned to the baseline level at 24 h post-exercise (5.978±1.849 pg∙ml-1). The peak levels of hs-cTnT (N, AH 37.001±31.995 pg∙ml-1, RH 28.614±23.628 pg∙ml-1) and cTnI (N 0.0375±0.0437 ng∙ml-1, AH 0.0475±0.0533 ng∙ml-1, RH 0.0345±0.0375 ng∙ml-1) did not significantly differ under the three conditions. In trial AH, the peak levels of hs-cTnT (2 h, 4 h) and cTnI (2 h, 4 h) were highly related to the MDA_0h and the TAOC_24h. In trial RH, the peak levels of hs-cTnT (2 h, 4 h) and cTnI (2 h, 4 h) were highly related to the TAOC_4h. It was concluded that maximal intermittent exercise can be used to trigger EICBR. The stimulus of hypoxia did not induce more cardiac damage in this exercise model. Maximal intermittent exercise potentially triggers EICBR through oxidative stress, especially lipid peroxidation. Keywords: cardiac biomarkers, hs-cTnT, cTnI, oxidative stress, hypoxia

The need for individual neural markers has been expressed in both basic and clinical neuroscience. To address this, we here designed a novel behavioural paradigm in which to test several measures as possible neural markers of individuality which distinguish participants from each other in how they perceive, feel and perform cognitive tasks. The individualized paradigm for consequentialist moral dilemmas was validated, showing variability across participants in thresholds and reaction times. Next, task-induced activity changes in EEG activity during the time interval of the Late Positive Potential (LPP) in alpha power, along with phase coherence early in the trial, correlated with reaction times and scores of subjective emotional distress. From these findings in study one, in study two we measured trial-to-trial variability (TTV) and found that the TTV index in the alpha and beta bands correlated with reaction time and prestimulus Lempel-Ziv Complexity. These findings, again in the alpha and beta bands, support alpha power during the LPP, variability quenching in these bands, and early intertrial coherence as markers of neural individuality. Finally, measures of scale-free activity in the resting state, along with others, and self-consciousness scale subscores as indices of the self were investigated. It was found that the power-law exponent, autocorrelation window, modulation index and electromagnetic tomography activity in two Default Mode Network areas correlated significantly with the Private subscore of the Self-Consciousness Scale only. These findings indicate that these resting state measures, along with activity in the DMN, may serve as markers of neural individuality in the brain’s spontaneous activity.

Rationale & Background: During pregnancy, cardiometabolic adaptations occur to sustain fetal growth. Disruptions in maternal cardiometabolic status may arise related to maternal adiposity, dietary deficiencies or excesses, or sedentary behaviours in pregnancy. Clinically, maternal cardiometabolic dysfunction is associated with adverse health outcomes in both mothers and their offspring. We aimed to determine: 1) the contribution of maternal adiposity, diet and physical activity to maternal cardiometabolic status in early pregnancy using biomarkers of lipid and glucose profiles; 2) whether maternal adiposity measured by 4-site sum of skinfold thickness (SFT) or bioelectrical impedance analysis (BIA) yielded similar strength of association with cardiometabolic status. Study Design: Maternal blood samples, anthropometric and body adiposity, dietary and physical activity measures were collected from a subset of pregnant women in early pregnancy (12-17 wk gestation) prior to randomization to the Be Healthy in Pregnancy RCT. Blood samples were analyzed for fasting glucose, insulin, triglycerides, leptin, adiponectin, and C-reactive protein (CRP). Maternal adiposity was assessed by pre- pregnancy body mass index (pBMI) and two indirect quantitative measures of % body fat (BIA and 4-site SFT). Results: Of the 91 subjects (mean age= 31 ± 4 y), 46.2% were overweight/obese by pBMI. For both SFT and BIA, % body fat was positively associated with fasting glucose, insulin, triglyceride, leptin, and CRP concentrations, and negatively associated with adiponectin concentration, although the strength of the associations was greater for SFT than BIA. After adjustment for confounders, maternal adiposity remained significantly associated with all cardiometabolic biomarkers, except for adiponectin and CRP. Dietary polyunsaturated: saturated fat ratio, energy expenditure, high activity level, age, ethnicity and parity were significantly associated with some of the biomarkers. Conclusion: Maternal adiposity was predominantly associated with leptin, insulin, and glucose status in early pregnancy although dietary fat, energy, activity level, age, ethnicity and parity were also significantly associated with some biomarkers. Body fat estimated by SFT or BIA are generally comparable for use as a screening tool for cardiometabolic dysfunction in early pregnancy. In the clinical setting, BIA may be more easily adopted as it is faster and requires fewer technical skills by the operator than SFT measures. / Thesis / Master of Science (MSc)

abstract: Yaʕni ‘lit. he/it signifies/means/intends’ is an arising linguistic and discourse-pragmatic phenomenon in many varieties and speech situations of spoken Arabic. Yet, the few scholarly investigations yaʕni has received come from restricted and limited contexts of language use. The primary aims of this dissertation were to, first, expand and broaden research on Arabic yaʕni into novel contexts of language use and to, second, explore the linguistic and the discourse-pragmatic functions of yaʕni. Therefore, the data used for this dissertation were collected, selected, and analyzed from a sample of spoken data brought from two episodes of a Saudi sports TV show Alkurah Tatakallam ‘lit. the ball speaks.’ The analytical procedures and discussions showed that yaʕni had the following types of linguistic and discourse-pragmatic functions: as (a) a verb, (b) elaboration and turn expansion, (c) repair organization, (d) managing the turn-taking system, (e) alleviation and hedging, (f) marking concessive/contrastive relations, and (g) emphatic yaʕni. The discussions seemed to suggest the gradual solidification of three views: First, there is a suggestion that the categorical status ranging from verb yaʕni to the discourse marker yaʕni can be understood in terms of scalarity, gradience, and prototypicality. Second, there is another suggestion that gradations can also be located between the discourse-pragmatic functions of yaʕni. Third, there is a suggestion that, synchronically and diachronically, yaʕni as a form has been wildly drifting from its categorical verb status, lexical source, propositional meaning, and even its discourse-pragmatic markerhood. The analysis, discussions, and suggestions invoked the idea of bridging context(s) related to the categorical status and the discourse-pragmatic functions of yaʕni. This categorical status of yaʕni puts the binary distinction between conceptual meaning and procedural meaning of relevance theory, and the studies of yaʕni following such a binary distinction, into question since this distinction seemed blurry. The bridging context(s) seemed to support the gradualness and the directionality of the evolution of DMs. Therefore, the categorical and discourse-pragmatic behavior of yaʕni seems to have support from the hypothesis and theories such as grammaticalization and pragmaticalization. It seems also that the historical development of yaʕni can be discussed in terms of the hypothesis and theories of idiomaticization and phraseology. / Dissertation/Thesis / Doctoral Dissertation Linguistics and Applied Linguistics 2018