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The competition between two molecules of similar polarity for adsorption sites on the stationary phase is discussed in light of rapid kinetics of adsorption and desorption, and of the effects of temperature, acetonitrile, surfactant (cyclohexylaminopropane sulfonic acid, CAPS) and salt concentrations on the retention of the thyroid hormones (3,5-diiodothyronine, T2; 3,3',5-triiodothyronine, T3 and thyroxine, T4). A three parameter equation relates the surfactant concentration and ionic strength to the retention of the hormones and is analyzed in terms of the Stern-Gouy-Chapman theory. A second order polynomial describes the temperature dependency and permits the evaluation of the enthalpy, entropy and heat capacity, demonstrating a reduction in the molecular motion of the analyte with increasing surfactant and acetonitrile concentrations. The equation parameters for linear or non-linear equations, using data sets with or without homogeneous variances, are evaluated using a Simplex optimization procedure that uses one of two proposed optimization criteria. The construction and operation of a computer based gradient programmer for HPLC is described. A surfactant mediated gradient elution with electrochemical detection is examined for the analysis of serum thyroid hormones.

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Adult mammopoiesis occurs in close synchronization with reproductive development when the hypothalamic-pituitary-ovarian axis delivers integral systemic hormone cues to propel mammary morphogenesis during puberty, remodeling during reproductive cycles and functional differentiation following pregnancy. While hormones remain the driving force behind normal glandular development, increased life-time hormone exposure is a strong risk factor for breast cancer. Breast cancer heterogeneity has been attributed to different cells of origin and/or different mutation repertoires. Stem/progenitor cells are intensely investigated as cells of origin given their regenerative and self-renewal properties that provide conceivable advantage in cancer. Although hormones have a fundamental influence in breast cancer, their capacity to regulate stem/progenitor cells was unknown, and presents the central directive in this thesis. Employing mouse models, we show that mammary epithelial subpopulations and in particular, stem cells, are highly responsive to ovarian hormones and depend on key molecular events. A progesterone peak during the luteal phase of reproductive cycles results in a significant increase in stem cell-enriched basal cells and an expansion of stem cells measured by in vivo transplantation assays, with rapid development of lobuloalveoli. Progesterone was found to stimulate expression of mitogenic ligands, RANKL and Wnt4, in ER+PR+ luminal epithelial niche cells concomitant with increased expression of their receptors and target genes in the ER-PR- basal stem cell population, suggesting a cross-talk between luminal and basal cells that elicits stem cell expansion within the niche. The requirement of RANKL signaling for hormone-induced mammary stem cell dynamics was further explored utilizing mice deficient for its receptor, RANK, and by pharmacological inhibition of RANKL. Disruption of RANKL/RANK signaling resulted in abrogated activation of the basal stem cell-enriched population and alveolar progenitor cells in response to progesterone. This was accompanied by a marked reduction in cell proliferation, cell cycle regulators, alveolar lineage determinants and notably, in epithelial Wnt responsiveness. Thus, progesterone orchestrates a series of molecular events in the mammary stem cell niche where RANK is effectively positioned to deliver instructive signals to stem cells, culminating in stem cell recruitment and alveolar regeneration, processes which when deregulated have considerable potential to promote breast cancer pathogenesis.

Background: In 2007, the International Agency for Research on Cancer classified shift-work involving circadian disruption as a “probable carcinogen.” One proposed pathway for this relationship involves nighttime light exposure and subsequent decreases in melatonin production. It is postulated that melatonin, a cancer-protective hormone, may influence patterns of sex hormone production that in turn influence breast cancer risk. The purpose of this study was to investigate the relationships between night shift-work history, melatonin and sex hormone levels among shift-working women. Methods: 82 pre-menopausal nurses who work a rotating shift pattern of two days (7AM-7PM), two nights (7PM-7AM), followed by five days off participated in two study periods approximately six months apart (in summer and winter), each taking place during a day shift of the normal rotating shift pattern. Creatinine-adjusted melatonin metabolite concentrations were measured from morning void urine samples, and estradiol, estrone, progesterone and prolactin concentrations were measured from fasting blood samples taken at the same time. Other pertinent information was collected by measurement (weight, height) and by self-report via questionnaire. We examined melatonin-sex hormone relationships within each of two seasons, and across seasons, to investigate two hypothesized latency periods for influences of melatonin levels on sex hormones. Multivariate linear regression was used to explore relationships, with adjustment for confounders including age and body mass index. Results: An inverse relationship between melatonin and estradiol was suggested in winter (β = -0.13, p = 0.11), and a positive relationship was suggested for increasing estrone with increasing melatonin tertile in summer (p = 0.07), after multivariate adjustments. Melatonin was not associated with other hormones in either season. On investigation of a longer latency period, melatonin in the first season was not associated with sex hormones in the second season. While those working night shifts for 20 years or more had higher mean levels of estradiol, estrone and progesterone, results were not statistically different from those with a shorter history of night work. Conclusions: The results of this study do not provide evidence to support the proposed biological pathway involving altered melatonin and sex hormone levels as intermediates between shift-work and breast cancer risk. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2010-09-14 11:42:06.201

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