No description available.

OBJECTIVES: Veterans of the armed forces, like most population groups, have a high prevalence of vitamin D deficiency, which may be associated with adverse outcomes in several types of cancer. Ultraviolet irradiation is inversely linked with the risk of bladder cancer, presumably through enhanced vitamin D synthesis. We hypothesized that variations in vitamin D status and monitoring predict adverse outcomes in bladder cancer among veterans. METHODS: A retrospective analysis of data in the Veterans Integrated Service Network-9 (southeastern United States) was performed for patients diagnosed between October 1, 1999 and February 29, 2008. Age, tobacco exposure, body mass index, and latitude and seasonality of sampling were included as variables in addition to serum vitamin 25(OH)D levels. RESULTS: Monitoring of vitamin D and vitamin D levels and status were closely linked to survival in bladder cancer. Both the chances of survival and longevity improved with enhanced vitamin D status and monitoring. Veterans with bladder cancer had better outcomes if the initial vitamin D level was higher and had more monitoring of the vitamin. Initial vitamin D levels were more strongly related to outcomes than follow-up levels. The link between vitamin D and outcomes remained after adjusting for background variables such as age, body mass index, latitude, seasonality, and tobacco exposure. CONCLUSIONS: Findings suggest that adequate vitamin D levels early in the course of the disease provide the best opportunity to improve outcomes. Ensuring that veterans with bladder cancer have adequate vitamin D reserves with appropriate monitoring may play a role in improving outcomes in bladder cancer.

OBJECTIVES: Veterans of the armed forces, like most population groups, have a high prevalence of vitamin D deficiency, which may be associated with adverse outcomes in several types of cancer. Ultraviolet irradiation is inversely linked with the risk of bladder cancer, presumably through enhanced vitamin D synthesis. We hypothesized that variations in vitamin D status and monitoring predict adverse outcomes in bladder cancer among veterans. METHODS: A retrospective analysis of data in the Veterans Integrated Service Network-9 (southeastern United States) was performed for patients diagnosed between October 1, 1999 and February 29, 2008. Age, tobacco exposure, body mass index, and latitude and seasonality of sampling were included as variables in addition to serum vitamin 25(OH)D levels. RESULTS: Monitoring of vitamin D and vitamin D levels and status were closely linked to survival in bladder cancer. Both the chances of survival and longevity improved with enhanced vitamin D status and monitoring. Veterans with bladder cancer had better outcomes if the initial vitamin D level was higher and had more monitoring of the vitamin. Initial vitamin D levels were more strongly related to outcomes than follow-up levels. The link between vitamin D and outcomes remained after adjusting for background variables such as age, body mass index, latitude, seasonality, and tobacco exposure. CONCLUSIONS: Findings suggest that adequate vitamin D levels early in the course of the disease provide the best opportunity to improve outcomes. Ensuring that veterans with bladder cancer have adequate vitamin D reserves with appropriate monitoring may play a role in improving outcomes in bladder cancer.

No description available.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13466号 / 論医博第2253号 / 新制||医||1055(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 村川 泰裕, 教授 中島 貴子, 教授 藤田 恭之 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Reprinted from Cancer Biomarkers, 15(4), Nakashima et al., Urine CXCL1 as a biomarker for tumor detection and outcome prediction in bladder cancer, 357-364, Copyright (2015), with permission from IOS Press. / 京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19596号 / 医博第4103号 / 新制||医||1014(附属図書館) / 32632 / 京都大学大学院医学研究科医学専攻 / (主査)教授 椛島 健治, 教授 武田 俊一, 教授 川村 孝 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

Arsenic is a toxic metalloid that continues to contaminate the water and food sources of millions of people globally. Among the numerous health effects of arsenic exposure are urothelial toxicity and cancer. In recent years, small extracellular vesicles (SEVs) have been shown to be vital in intracellular communication and have been used in clinical studies as biomarkers of disease. The overall goal of this thesis is to understand the mechanisms of cell communication during arsenic exposure and to develop minimally invasive biomarkers for the toxic responses. The specific objectives are to: a) determine if SEVs released from arsenic exposed urothelial cells are responsible for mediating urothelial toxicity; and b) assess the application of urinary SEVs as novel biomarkers of arsenic exposure in an exposed population. The hypothesis leading this research is that the biology and protein packaging profile of urothelial SEVs are altered following arsenic exposure because of the induction of cell stress signaling pathways. I also hypothesize that urinary SEV proteins can be used as biomarkers of arsenic exposure because they are positively correlated with urinary arsenic concentrations in an exposed population. SVHUC1 human urothelial cells were dosed with sodium meta arsenite (1, 2, and 5 uM) for 48 hours. T24 urothelial carcinoma cells were also grown in parallel to compare for carcinogenicity. A label-free quantitative proteomics approach was used to assess the differentially expressed proteins in the cell lysate and the SEVs extracted from the culture media to determine the mechanistic pathways involved and how well the protein profiles in SEVs correlate with those in the cell lysate. SEVs were isolated from the archived urine samples of participants (n=36) enrolled in the Yellow Knife Health Effects Monitoring Program (YKHEMP) and two potential biomarkers, transforming growth factor beta receptor 1 (TGFBR1) and ribonuclease inhibitor 1 (RNH1), were measured by an enzyme linked immunosorbent assay (ELISA). SEVs in all samples were successfully characterized based on their size (50-200 nm) and positive antibody array for eight protein markers indicating their endosomal biogenesis. The total number of SEVs was not shown to increase following arsenic exposure in the in vitro study. However, the cancerous T24 cells had nearly four times higher numbers of SEVS compared to the non-cancerous SVHUC1 cells. The changes in the protein profiles in SEVs released following arsenic dosage indicated activation of pathways important for cell survival, viability, and migration and inactivation of pathways related to cell death and necrosis which were also observed in the paired cell lysate samples. Comparison between paired SEV and cell lysate samples, however, indicated selective SEV packaging of proteins which may be for the purpose of intracellular communication. Comparative assessment of SEVs from T24 and arsenic exposed SVHUC1 cells showed similar activation of cancer related pathways including those responsible for malignant tumors and increased proliferation rates. From the in vitro study results, we identified 8 potential SEV biomarkers. Of which, TGFBR1 showed the most promising association, having been positively associated with both inorganic arsenic and cadmium concentrations in urine samples. This thesis showed that SEVs are important mediators of arsenic exposure in urothelial cells and highlighted the comparability of SEV and cell lysate analysis. Furthermore, TGFBR1 was identified as a promising biomarker of arsenic exposure for its positive association with increased arsenic both in vitro and in human biomonitoring analysis.

No description available.

No / The indolequinone EO9 demonstrated good preclinical activity but failed to show clinical efficacy against a range of tumours following intravenous drug administration. A significant factor in EO9's failure in the clinic has been attributed to its rapid pharmacokinetic elimination resulting in poor drug delivery to tumours. Intravesical administration of EO9 would circumvent the problem of drug delivery to tumours and the principal objective of this study is to determine whether or not bladder tumours have elevated levels of the enzyme NQO1 (NAD(P)H:quinone oxidoreductase) which plays a key role in activating EO9 under aerobic conditions. Elevated NQO1 levels in human bladder tumour tissue exist in a subset of patients as measured by both immunohistochemical and enzymatic assays. In a panel of human tumour cell lines, EO9 is selectively toxic towards NQO1 rich cell lines under aerobic conditions and potency can be enhanced by reducing extracellular pH. These studies suggest that a subset of bladder cancer patients exist whose tumours possess the appropriate biochemical machinery required to activate EO9. Administration of EO9 in an acidic vehicle could be employed to reduce possible systemic toxicity as any drug absorbed into the blood stream would become relatively inactive due to an increase in pH.