published_or_final_version / abstract / toc / Zoology / Doctoral / Doctor of Philosophy

published_or_final_version / Pathology / Doctoral / Doctor of Philosophy

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Background: In 2007, the International Agency for Research on Cancer (IARC) classified long-term shift work as a probable human carcinogen; however, the mechanism through which shift work potentially increases cancer risk is not known. One hypothesis is that diminished melatonin production may be involved, possibly as a result of exposure to light during night work. Experimental studies suggest a link between melatonin and peptides in the insulin-like growth factor (IGF) family, also implicated in carcinogenesis. This research aimed to describe the distributions of circulating concentrations of insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-3 (IGFBP-3) and their associations with urinary melatonin as possible intermediates in the pathway between work at night and breast cancer. Methods: A cross-sectional study was conducted among 85 premenopausal nurses working a rotating shift pattern of two 12-hour days, two 12-hour nights, and five days off. Once during both the summer and winter seasons, melatonin metabolites were measured in urine samples and circulating concentrations of IGF-I and IGFBP-3 were determined from serum samples. Weight and height were measured by the study coordinator, while a questionnaire and study diaries were used to collect all other covariate information. Predictors of IGF levels were identified using multivariate mixed effects modeling and relationships between melatonin and the IGFs were investigated using Spearman’s rank correlation and multivariate mixed effects modeling. Results: Both age (β = -3.6, p < 0.0001) and current OC use (β = -40.8, p = 0.003) were associated with decreases in circulating IGF-I, while levels of IGF-I were increased in the winter months (β = 26.3, p = 0.02). A positive relationship between recent alcohol consumption and serum IGFBP-3 was also suggested (β = 197.8, p = 0.05). Neither Spearman’s rank correlations nor mixed effects modeling indicated that urinary melatonin was a determinant of serum IGFs. Conclusions: Age, season, and current OC use were observed to predict circulating IGF-I, while recent alcohol consumption was a determinant of IGFBP-3 levels. A relationship between melatonin and IGFs, theorized as a component of the mechanism linking shift work and cancer, was not supported by the results of this project. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2012-05-30 15:29:31.253

Biodegradable polymer materials, specifically poly(lactic-co-glycolide) (PLGA) can be used as bone replacements for bone regeneration. Scaffolds can be prepared to be porous to induce bone growth into a scaffold so that it is replaced with natural tissue as the polymer degrades. However, simply using PLGA will result in formation of scar tissue rather than regeneration of natural bone. Therefore focus has turned to attaching growth factors to the PLGA molecules to elicit a specific cellular response when the implant is placed in the body. Site-directed immobilization utilizes specific groups on both the biomaterial and biomolecule so that growth factors can be oriented in a specific manner for increased cellular response. In this research, exposed carboxyl groups on a non end-capped PLGA were modified with bishydrazide spacer molecules of varying length for the eventual attachment of a biomolecule via carbodiimide chemistry. The number of hydrazide groups attached to the surface could be controlled to investigate the effects of the spacer length on protein immobilization. Both vascular endothelial growth factor (VEGF) and parathyroid hormone (PTH) were used in these studies. These two molecules have different target cells and actions, although both can play a role in bone formation. Both molecules have carbohydrate residues that were oxidized with periodate to form aldehyde moieties that were able to react with the hydrazide spacers to form a stable bond between the spacer and protein. The use of a spacer enhanced the binding accessibility of the protein as compared to randomly adsorbed protein. The shortest and longest of the spacers resulted in the highest amount of protein, with corresponding results for antibody binding. The modification of PLGA functional groups with a spacer molecule indicates that this material could be used for site-directed immobilization for any application, simply by tailoring the reaction between the biomaterial and biomolecule.

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Angiogenesis has a crucial influence on tumour development and identification of microvessels in malignant breast cancer tissue is an indicator for worse prognosis. Angiogenesis is partially governed by the family of vascular endothelial growth factors (VEGF) and their receptors, by which the VEGF-A-protein seems to be the most important factor.     The aims of this work were to first establish a method for immunohistological (IH)-staining of the VEGF-A-protein for clinical use and then to label and evaluate the expression of this protein in 31 Nottingham Histology Graded (NHG I-III) breast carcinoma.      Formaldehyde-fixated tissues from invasive breast neoplasms and control tissues were labelled with monoclonal antibodies against VEGF-A and CD31-proteins using a semi-automated IH-system from Ventana BenchMark. Positively stained vessels were counted from digital copies of microscopic pictures related to mm2 tissue.     A method of IH-labelling with VEGF-A protein was successfully established before staining of the breast tissue and in 19 of the 31 breast cancers. Vessels were counted for both antibodies. The VEGF-A-antibody stained 2.7 ± 2.3 (mean ± SD) vessels/mm2 and the CD31-antibody stained 27.3 ± 19.3 in the breast carcinoma tissue. The percent of VEGF-A-stained vessels in relation to CD31-stained were 7.6% in the NHG-I- (n=3), 7.8% in the NHG-II- (n=10) and 15.0% in the NHG-III-group (n=6).     The results demonstrate that increased NHG-grade and lower differentiation can be associated with higher percent of vessels expressing VEGF-A-protein. The result was not statistically certified because of the small number of stained breast cancers and additional investigations are recommended before clinical use.