Worldwide the incidence rate of melanoma has risen while other cancer trends decrease. Late stages of melanoma carry a severe prognosis and the cancer is one that afflicts young adults relatively frequent. Treatment options are very few and survival rates remain low in metastatic disease. Models for evaluating new treatments, chemoprevention and melanoma progression are needed. The first model system described here involves the use of chemical carcinogenesis to induce melanoma in a transgenic mouse system, the TPras mouse. The analysis of tumors that developed on these mice demonstrates that this model system has genetic alterations that are much like the human disease, namely the loss or alteration of the tumor suppressor p16 protein, increase in Ras protein and altered PKC expression. The in vitro system from the TP-ras mouse is also used to compliment the in vivo studies for the effectiveness of perillyl alcohol (POH) as a chemoprevention agent of melanoma in the TPras mice. The mechanisms of POH activity are a decrease in Ras protein levels as well as ras downstream effectors, Akt and MAPK. POH causes only a slight increase in apoptosis while it greatly diminishes the production of UV induced reactive oxygen species (ROS). The activity of POH in vitro suggests a mechanism for the chemopreventive effect seen with POH in the TPras mice. The second model described herein mimics the human risk factor for melanoma of light pigmentation. An increase in UV induced tumors is demonstrated in the Avy mice, which are a lighter pigmented mouse than the TPras mice. Thymine dimer production in vitro demonstrated only a mild sunscreen effect of the darker pigmented melanocytes. However the evaluation of ROS production induced by UV indicated that the melanocytes from the lighter pigmented mouse were able to produce much greater levels of ROS both from UVB and UVA induction. These studies suggest that oxidative damage may contribute to melanoma susceptibility in lighter pigmented individuals. In summary, this work has validated the Avy and TPras mouse models for studying risk factors and testing chemoprevention agents, respectively, in melanoma.

<p> Colorectal cancer is one of the most common cancers in the United States and confronting its challenges has remained a problem to the United States health sector, especially among outpatient clinics. Guided by health belief model, the purpose of this needs assessment was to identify patients age 50 and older in outpatient clinic located in a large metropolitan city in Texas who should receive information on the need for colorectal cancer screening based on their risk for developing colorectal cancer as outlined by American Cancer Society. A sample of 70 charts of patients age 50-75 years was randomly selected and audited using descriptive statistics. Among the patients aged 50-75 years attending the outpatient clinic, 25.7% were African Americans, 71.4% were Hispanic, and 2.9% were Caucasians; 42.9% were male and 57.1% were female. The rate of colorectal cancer screening was 12.9%, a rate that is lower than the rate for all Texans, which was 54.1% - 59.2%. CRC screening was ordered for 62.9% of all patients; 24.2% of clinic patients were identified as being at high risk for colorectal cancer. The low rate of screening may hamper early detection of colorectal cancer in outpatient clinics setting. It is recommended that the outpatient clinic develop intensive campaign to increase patient awareness about the need for and benefits of colorectal cancer screening, especially for those at high risk for developing colorectal cancer. The findings of this study may raise awareness on the chasm in quality of health care availability and provide insight on colorectal cancer and its prevention.</p>

<p> Prostate cancer is stimulated to grow in response to testosterone. Androgen deprivation therapy (ADT) leads to chemical castration and suppression of prostate cancer cell production. Testosterone levels less then 300ng/ml decreases bone mineral density and could result in osteoporosis. Studies have shown that during the first year of ADT, fracture risk, mainly in hips and spine increases about 50%. In men, 40% of hip fractures result in death. Exercise may reduce the risk of osteoporosis and thus contribute to the prevention of hip and other fractures. There is limited data regarding whether exercise is associated with a reduced risk of osteoporosis in men treated with ADT. </p><p> Purpose of this study was to evaluate the relationship between self-reported exercise and bone mineral density measured by dual-energy x-ray absorptiometry (DEXA) and 25 hydroxy vitamin D levels in prostate cancer patients receiving ADT. </p><p> A convenience sample of 96 men with prostate cancer treated with ADT for a minimum of nine months or longer and up to the time of inclusion in the study completed the Canadian Fitness Survey questionnaire to assess the amount and types of exercise performed. In addition, questions from a section of the NHANES survey about cigarette and alcohol use, history of non traumatic fracture, diseases causing fracture, and use of medication including calcium supplementation were asked. A serum vitamin D level and DEXA scan were completed within a specified time period based on length of time receiving ADT. Subjects were recruited from eight urology practices and one cancer center in Clark County, Nevada. </p><p> The relationships between total duration of exercise, intensity, frequency, bone density T-scores, and serum vitamin D were examined using correlation analysis, as was the relationship between specific types of exercise, measured the same way and bone density T-scores. Furthermore, regression analysis was used to examine for potential confounders. Confounders identified for this study include age, body mass index, cigarette smoking, alcohol use, history of non-traumatic fracture or disease causing fracture, and use of medication, including calcium supplementation. Regression analysis was conducted to determine if there was an independent association between exercise and bone mineral density and serum vitamin D. This study provides evidence associating exercise with reduced risk of osteoporosis in patients receiving ADT. </p><p> The second study looked at determinants of 25 OH vitamin D. We found that the only independent modifiable determinant was vitamin D supplementation of &ge;800 IU/day. Avoiding osteoporosis by increasing exercise in this group of patients is a practical measure that preventive care specialists could institute.</p>

This thesis considers the use of Bayesian sequential decision theory for the diagnosis of pre-cancerous lesions of the cervix otherwise known as cervical intraepithelial neoplasia (CIN). We consider a sequence of n diagnostic tests where the ordering of the tests is predetermined. After each test in the sequence, the clinician must either make a treatment decision based on available information or continue testing. Our method allows the use of the previously collected information along with the new information collected at each level. In addition, we apply Bayesian sequential decision theory in a setting where the observations are not independent and identically distributed. Before this theory can be applied to the medical setting, a satisfactory method of attaining the costs of diagnostic tests and losses associated with treatment decisions must be specified. These costs and losses must be in the same units of measurement and they should include monetary considerations and both positive and negative patient outcomes. This thesis provides a method to determine bounds on relative costs and losses for medical decisions. First the medical decision process is modelled as a Bayesian sequential decision problem. Then we assume the current standard of care for detection of CIN is optimal, and use the model to determine bounds for the costs associated with testing and the losses associated with treatment. Unlike several other approaches, the costs and losses from our analysis potentially incorporate both monetary considerations and patient outcomes associated with testing and treatment or non-treatment. We estimate the probabilities necessary for the model from data collected at the University of Texas M. D. Anderson Cancer Center. We use both maximum likelihood estimates and Bayesian posterior mean estimates, with a prior developed from the literature. We also randomly sampled from the posterior distribution and compared our empirical bounds on the losses to values for the bounds on the losses reported in the cancer literature. The implications are discussed further in the thesis.

TTumor hypoxia (poor oxygenation) adversely affects patient prognosis by promoting therapeutic resistance and an aggressive tumor phenotype. We aimed to understand how urokinase plasminogen activator receptor (uPAR), a cysteine-rich protein implicated in the malignant phenotype and poor patient prognosis, matures in hypoxia. We hypothesized that secretion of uPAR during hypoxia is conferred by a superior ability to form disulfide bonds without oxygen. A model and assay was established to monitor the oxygen-dependency of suPAR (a soluble secreted isoform of uPAR) folding and secretion. We found that suPAR maturation involves disulfide formation and N-linked glycosylation in normoxia. In anoxia, suPAR disulfide formation was impaired, but suPAR was nevertheless secreted. We propose that suPAR has low dependency on disulfide formation for efficient secretion in comparison to other disulfide-containing proteins. Mechanisms supporting protein expression during hypoxia may potentially be targeted to mitigate the adverse effects of tumor hypoxia and ultimately improve cancer therapy.

No description available.

No description available.

Renal Cell Carcinoma (RCC) has a very high rate of mortality since it does not respond to conventional therapies such as chemotherapy and radiation therapy. Furthermore, in the majority of cases, metastases are already present at the time of diagnosis. The objective of our study is to develop a noval treatment for RCC, using a dendritic cell (DC) vaccine. An animal model of RCC, RENCA, was used to develop the vaccine.

The objective of this thesis was to determine whether altered transport of a novel sarcosinamide analog of chloroethylnitrosourea (SarCNU) may account for its increased antitumor activity in primary and established glioma cells as compared to BCNU, the agent of choice for chemotherapy of brain tumors. These studies were done in the SarCNU-sensitive SK-MG-1 glioma cells and the 20-fold more resistant SKI-1 cells. Indirect evidence for a sarcosinamide-related uptake for SarCNU was obtained by using cytotoxicity as an indicator for transport in SK-MG-1 cells. The transport of radiolabelled sarcosinamide was shown to proceed via facilitated diffusion, an energy-independent, carrier-mediated process which also accommodates SarCNU. Epinephrine was identified as the native substrate for this uptake which is similar to the catecholamine uptake 2. The source of resistance to SarCNU in SKI-1 cells was also examined. The decreased steady-state accumulation of SarCNU shown in SKI-1 cells was not secondary to the observed alterations in the kinetics of SarCNU transport in these cells. The decrease in SarCNU-induced DNA crosslinks noted in SKI-1 cells was neither a result of increased expression of ERCC-1 RNA nor repair by the O$ sp6$-alkylguanine DNA transferase nor the 3-methyladenine DNA glycosylase activity. The slight elevation of glutathione transferase (GST) mu RNA in SKI-1 cells suggests that detoxification may contribute to resistance. These results indicate that resistance to SarCNU may be mediated by increased drug efflux and/or alternative DNA repair in SKI-1 cells.

In search of thyroid carcinoma biomarkers, proteins secreted by thyroid cancer cell lines, papillary-derived TPC-1 and anaplastic-derived CAL62, were analyzed using liquid chromatography-tandem mass spectrometry. Of forty six high-confidence identifications, six proteins were considered for verification in thyroid cancer patients’ tissues and blood. The localization of two proteins, nucleolin and prothymosin-alpha (PTMA), was confirmed in TPC-1 and CAL62 by confocal microscopy and immunohistochemically in xenografts of TPC-1 cells and human thyroid carcinomas. Increased nuclear and cytoplasmic expression of PTMA was observed in anaplastic carcinomas compared to normal thyroid tissues, papillary and poorly differentiated carcinomas. Importantly, six proteins were detected in thyroid cancer patients’ sera, warranting future analysis to confirm their potential as blood-based thyroid cancer markers. Herein we demonstrate the ability of secretome analysis of thyroid cancer cell lines to identify proteins that may be studied for application in management of thyroid carcinomas upon future validation.