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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Melanoma models for chemoprevention and ultraviolet radiation susceptibility

Lluria-Prevatt, Maria del Carmen January 2001 (has links)
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.
2

Applications of Bayesian sequential decision theory to medical decision-making

Swartz, Richard J. January 2003 (has links)
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.
3

Immunocytochemical detection of estrogen receptors in human breast cancer and in non-neoplastic lesions

Al-Kana, Randah January 1988 (has links)
No description available.
4

Insertional mutagenesis by provirus integration in Moloney murine leukemia virus-induced rat thymomas

Villeneuve, Luc January 1988 (has links)
No description available.
5

A dendritic cell vaccine for murine renal cell carcinoma

Chagnon, Fanny January 2003 (has links)
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.
6

Cytotoxicity and transport of sarcosinamide chloroethyl-nitrosourea (SarCNU) in sensitive and resistant human glioma cells

Skalski, Violetta January 1989 (has links)
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.
7

Study of two putative prostate cancer tumor markers

Shun, Kitty. January 2006 (has links)
The following thesis is based on my study of two candidate prostate cancer tumor markers, namely telomerase and CD9. Accordingly, the thesis will be divided in two main chapters describing the results obtained for each protein. Although these proteins are de-regulated in prostate cancer cells, little is known about their regulation and function in prostate cells. For example, telomerase is generally inactive in normal cells and reactivated in cancer cells and CD9 is a transmembrane protein that is lost as prostate cancer progresses. In chapter 2, I will show that introduction of normal human chromosomes into mouse melanoma cells can shut down its telomerase activity by inhibiting hTERT transcription and that the gene encoding this regulator is likely located on human chromosome 17p11.1. Additionally, following further characterization of CD9 partners in chapter 3, we will learn more about the likely mechanism by which CD9 induces mitotic catastrophe when over-expressed in prostate cancer cells.
8

The use of rat glutathione S-transferase A3 for hematopoietic chemoprotection from nitrogen mustards in cancer therapy /

Létourneau, Sylvain. January 1999 (has links)
The effectiveness of anti-cancer chemotherapy is limited by acute dose limiting toxicities, principally myelosuppression. The introduction of drug resistance genes into hematopoietic cells may increase the bone marrow (BM) tolerance to chemotherapy and may permit safer dose escalation, and thus increase clinical efficacy. Conferring chemoprotection to nitrogen mustards would be clinically relevant because of their broad spectrum of anti-tumor activity and their predominant, dose-limiting hematotoxicity. The glutathione S-transferase (GST) alpha isoenzymes, particularly the rat GSTA3, have been implicated in resistance to nitrogen mustards. To determine if retrovirus-mediated gene transfer of the rat GSTA3 (previously called GST-Yc) could be used to confer resistance to nitrogen mustards, we studied the expression of rat GSTA3 and the sensitivity to nitrogen mustards in mouse NIH 3T3 fibroblasts following either transfection or transduction of GSTA3 with a Moloney-based retrovirus vector (N2Yc). Populations of GSTA3-transduced cells and single cell-derived clones demonstrated increased glutathione (GSH) peroxidase activity (associated with the A3 subunit) and moderate in vitro resistance to chlorambucil and mechlorethamine. To address the feasibility of using rat GSTA3 gene transfer to confer chemoprotection to the hematopoietic system, we then transduced human leukemia K-562 cells and primary murine hematopoietic progenitor cells with the N2Yc retrovirus vector, Similarly to N2Yc-expressing fibroblasts, K-562 cells and clonogenic primary murine hematopoietic cells transduced with the N2Yc retrovirus vector demonstrated increased GSH peroxidase activity and moderate in vitro resistance to melphalan, chlorambucil and mechlorethamine. We next explored the possibility of conferring chemoprotection against nitrogen mustards in vivo following transplantation of mice with GSTA3-transduced BM cells. Unfortunately, we did not observed chemoprotection from chlorambucil in
9

The catecholamine extraneuronal uptake, transporter is associated with the increased sensitivity of gliomas to sarcosinamide chloroethylnitrosourea /

Marcantonio, Daniela. January 1997 (has links)
SarCNU, a novel chloroethylnitrosourea analogue, is transported by the extraneuronal uptake2 transporter (uptake2). SK-MG-1 human glioma cells are sensitive to SarCNU cytotoxicity and express uptake 2 whereas SKI-1 glioma cells have no detectable transporter, and are relatively resistant. To clone uptake2, we detected differences in RNA expression utilizing differential display. With differential display, we detected a novel sequence expressed in SK-MG-1 cells but not in SKI-1 cells, having 62% homology to an expressed sequence tag clone from human brain, and could be a partial sequence of uptake2. In the treatment of SF-295 glioma xenografts in athymic mice, SarCNU had superior activity than 1,3-bis-(2-chloroethyl)-1-nitrosourea. This suggested that SF-295 cells express uptake2. We determined if expression of uptake2 in the established SF-295 cell line correlated with the enhanced activity of SarCNU in vivo. Transport of [3H]SarCNU was not decreased by inhibitors of uptake2 in the SF-295 cell line and its steady state accumulation was similar to that of SKI-1. The increased stability of SarCNU versus BCNU may account for its enhanced activity in vivo or the expression of uptake2 in vivo may differ from its expression in vitro.
10

Malignancy in systemic lupus erythematosus

Bernatsky, Sasha. January 2001 (has links)
Objectives. (1) To estimate cancer incidence in systemic lupus erythematosus (SLE) as compared to the general population. (2) To estimate the sensitivity and specificity of methods of cancer ascertainment. (3) To determine the prevalence of malignancy risk factors in SLE. Methods. (1) We determined the incidence of malignancy in the Montreal General Hospital (MGH) lupus cohort, through linkage with the Quebec tumor registry. Standardized incidence ratios (SIRS) were generated, using Quebec population rates. In addition, a meta-analysis was performed by pooling data from eight cohort studies of malignancy in SLE. (2) We administered a postal survey to cohort members to determine risk factors for cancer and self-report of cancer occurrence. For dead or lost-to-follow-up patients, data was abstracted from charts. We calculated the sensitivity and specificity of self-report and chart review for cancer ascertainment, compared to registry linkage results. (3) Using the data collected on self-report and chart review, we compared risk factor prevalence within the MGH cohort to that of the Quebec population. Results. (1) Observed cancers in our cohort were greater than what would be expected; for all cancers, the SIR was 1.8 (95% Confidence Interval 1.2--2.6). The meta-analysis SIR (for all malignancies) was 1.67 (1.42--1.94). Postal survey and chart review methods demonstrated high specificity. Sensitivity was imperfect, but did not greatly effect estimation of the SIR estimate. (2) Our lupus cohort had a distinct profile of risk factors for malignancy compared to the general population; differences included more prevalent nulliparity, obesity, and use of hormone replacement therapy. Conclusions. The risk of malignancy in SLE patients is increased. Risk factor profiles could influence the incidence of certain malignancies in SLE.

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