The role of molecular, clinical and socioeconomic factors in the long-term survival of axillary node negative breast cancer patients

The overall objective of this study was to investigate factors associated with long-term survival in axillary node negative (ANN) breast cancer patients. Clinical and biological factors included stage, histopathologic grade, p53 mutation, Her-2/neu amplification, estrogen receptor status (ER), progesterone receptor status (PR) and vascular invasion. Census derived socioeconomic (SES) indicators included median individual and household income, proportions of university educated individuals, housing type, "incidence" of low income and an indicator of living in an affluent neighbourhood. The effects of these measures on breast cancer-specific survival and competing cause survival were investigated. A cohort study examining survival among axillary node negative (ANN) breast cancer patients in the greater Toronto area commenced in 1 989. Patients were followed up until death, lost-to-follow up or study termination in 2004. Data were collected from several sources measuring patient demographics, clinical factors, treatment, recurrence of disease and survival. Census level SES data were collected using census geo-coding of patient addresses' at the time of diagnosis. Additional survival data were acquired from the Ontario Cancer Registry to enhance and extend the observation period of the study. Survival patterns were examined using KaplanMeier and life table procedures. Associations were examined using log-rank and Wilcoxon tests of univariate significance. Multivariate survival analyses were perfonned using Cox proportional hazards models. Analyses were stratified into less than and greater than 5 year survival periods to observe whether known markers of short-tenn survival were also associated with reductions in long-tenn survival among breast cancer patients. The 15 year survival probabilities in this cohort were: for breast cancerspecific survival 0.88, competing causes survival 0.89 and for overall survival 0.78. Estrogen receptor (ER) and progesterone receptor (PR) status (Hazard Ratio (HR) ERIPR- versus ER+/PR+, 8.15,95% CI, 4.74, 14.00), p53 mutation (HR, 3.88, 95% CI, 2.00, 7.53) and Her-2 amplification (HR, 2.66, 95% CI, 1.36, 5.19) were associated with significant reductions in short-tenn breast cancer-specific survival «5 years following diagnosis), however, not with long-term survival in univariate analyses. Stage, histopathologic grade and ERiPR status were the clinicallbiologieal factors that were associated with short-term breast cancer specific survival in multivariate results. Living in an affluent neighbourhood (top quintile of median household income compared to the rest of the population) was associated with the largest significant increase in long-tenn breast cancer-specific survival after adjustment for stage, histopathologic grade and treatment (HR, 0.36, 95% CI, 0.12, 0.89).

Mechanisms of long-term modulation of synaptic transmission in crayfish

Please consult the paper edition of this thesis to read. It is available on the 5th Floor of the Library at Call Number: Z 9999 B56 M68 2007

The role of retinoic acid in long-term memory formation and synaptic plasticity in the mollusc Lymnaea stagnalis

The active metabolite of vitamin A, retinoic acid (RA), is involved in memory formation and hippocampal plasticity in vertebrates. A similar role for retinoid signaling in learning and memory formation has not previously been examined in an invertebrate species. However, the conservation of retinoid signaling between vertebrates and invertebrates is supported by the presence of retinoid signaling machinery in invertebrates. For example, in the mollusc Lymnaea stagnalis the metabolic enzymes and retinoid receptors have been cloned from the CNS. In this study I demonstrated that impairing retinoid signaling in Lymnaea by either inhibiting RALDH activity or using retinoid receptor antagonists, prevented the formation of long-term memory (LTM). However, learning and intermediate-term memory were not affected. An additional finding was that exposure to constant darkness (due to the light-sensitive nature of RA) itself enhanced memory formation. This memory-promoting effect of darkness was sufficient to overcome the inhibitory effects of RALDH inhibition, but not that of a retinoid receptor antagonist, suggesting that environmental light conditions may influence retinoid signaling. Since RA also influences synaptic plasticity underlying hippocampal-dependent memory formation, I also examined whether RA would act in a trophic manner to influence synapse formation and/or synaptic transmission between invertebrate neurons. However, I found no evidence to support an effect of RA on post-tetanic potentiation of a chemical synapse. Retinoic acid did, however, reduce transmission at electrical synapses in a cell-specific manner. Overall, these studies provide the first evidence for a role of RA in the formation of implicit long-term memories in an invertebrate species and suggest that the role of retinoid signaling in memory formation has an ancient origin.