4. Electronic Theses and Dissertations (ETDs) - Faculties submissions
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Item Life History Trade-offs associated with Evolution of Cancer(University of the Witwatersrand, Johannesburg, 2023-07) Worsley, Catherine Mary; Durand, Pierre; Mayne, Elizabeth; Veale, RobThe evolution of multicellularity requires cooperation between single cells to form new multicellular individuals. Changes in levels of selection occur during this process, with selection at the multicellular level overriding that at the single cell level. For a multicellular individual to function, somatic mutations and selection must be under tight regulation. Nevertheless, mutations and selective environmental pressures can select for cells with fitness advantages relative to normal cells, resulting in cancer. Therapeutic drugs and radiation are forms of artificial selection that can drive the development and selection of cell populations that are resistant to treatment. Cancer occurs because of the failure of multicellular systems to suppress somatic evolution. This somatic evolution results in tumour cells with a wide range of phenotypes with either fast (proliferating) or slow (quiescent) life history strategies. Evolutionary theory provides a framework for understanding what drives the formation of these phenotypes and the ecological niche that supports them, and helps in predicting tumour progression and response to therapy. The key hypothesis of this study was that selective pressures in the tumour microenvironment drive trade-offs between tumour cell survival, proliferation, and apoptosis. An extensive literature review was conducted to identify key selective pressures affecting tumour progression. Low extracellular pH was identified as a component of the tumour microenvironment that affects life history trade-offs, and particularly drives escape from immune-mediated destruction. A protocol was then developed to expose cancer cells to low pH in cell culture. Breast carcinoma and oesophageal squamous cell carcinoma cell lines were selected for these experiments based on the prevalence of these cancers and because of their different anatomical locations. Exposure to low pH induced different levels of apoptosis in each cell line. This also affected cell cycle progression and the secretion of growth factors and immunomodulatory cytokines. The oesophageal cell line, WHCO6, adapted to moderate acidity levels with some cells undergoing apoptosis. Factors released by these cells supported the growth and survival of related cells. In contrast, in the breast carcinoma MCF-7 cell line, low pH induced high rates of apoptosis, and factors released by dying cells stimulated death in related cells. This study highlights that different life history strategies are employed by different cancer types. It also shows the importance of the tumour microenvironment, and acidity in particular, in driving tumour cell adaptation and survival. This study also identifies apoptosis as a pro-tumorigenic driver of cancer progression which has important therapeutic implications.Item The effect of two modalities of sleep disruption on immunity in healthy young female participants(University of the Witwatersrand, Johannesburg, 2023-07) Ajlan, Zuha; Scheuermaier, Karine; Iacovides, StellaStudies have shown that sleep deprivation leads to an inappropriate immune response by elevating pro-inflammatory markers, including interleukin (IL-)1, IL-6, and tumour necrosis factor (TNF-)α. This inappropriate immune activation increases the risk of developing autoimmune disorders. Despite women representing 80% of patients with autoimmune disorders and having a greater prevalence of poor sleep quality and sleep disorders, most experimental human studies investigating sleep and immunity focused on men. Therefore, this study assessed the effect of sleep fragmentation vs sleep restriction on sleep parameters. I then compared the immune response after the two types of sleep disruptions relative to a normal sleep episode and I investigated the association between sleep architecture and immune markers in healthy young women in the follicular phase of their menstrual cycle. Fourteen healthy females underwent a randomised-crossover controlled study consisting of one adaptation night and three randomised, non-consecutive sleep conditions, namely: baseline night (BN, uninterrupted 8 hours of sleep); restriction night (RN, sleep was limited to the first 4 hours of their habitual sleep episode); fragmentation night (FN, eight randomised forced awakenings through an 8-hour sleep opportunity night). Polysomnographic (PSG) sleep recordings were obtained for each condition, and plasma was collected 2.5 hours after their habitual waketime following each condition. A multiplex Luminex assay was used to measure the concentration of nine cytokines. I compared PSG-extracted sleep variables between the three experimental nights. I ran mixed models analyses testing cytokine levels in each sleep condition (RN vs. FN vs. BN) in unadjusted analyses and then adjusting for order of the condition (first vs. second vs. third experimental night), day of follicular phase of the menstrual cycle and age. I also used an unadjusted mixed model analysis to test the association between cytokine levels and each sleep variable. Total sleep time, non-rapid eye movement (NREM) and rapid eye movement (REM) were reduced in FN and RN but were lowest during RN (p<0.001). I found an effect of sleep condition on IL-8 (F = 3.40, P = 0.05) with IL-8 being lower in RN vs FN or BN. There was no effect of condition on the other cytokines in unadjusted or adjusted analyses. Lower wake after sleep onset (WASO) and higher NREM were associated with higher IL-8 concentration regardless of the sleep condition. Lower stage 2 (N2) (F = 6.28, β = -0.001, P = 0.02) and higher stage 3 (N3) (F = 7.01, β = 0.004, P = 0.01) was associated with a higher TNF-α regardless of the sleep condition. In conclusion, the study shows that acute sleep disruption alters sleep architecture and leads to an inappropriate immune activity in young healthy women. Future studies should try and investigate chronic sleep fragmentation vs chronic sleep restriction on the immune system.