Thesis (Ph. D.)--University of Washington, 2006. / Vita. Includes bibliographical references (p. 98-109).

Summary Thyroid carcinomas are the most common endocrine tumors in humans. There are three major types of carcinomas of thyrocyte origin, including papillary, follicular, and anaplastic carcinomas. Papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancy accounting 80% of thyroid cancer cases, and present several histologic variants, namely classical (45%), follicular (18%), solid, diffuse-sclerosing, cribriform, … . Specific genetic events represent early initiating and late triggering events. Several genetic lesions have been identified in various thyroid carcinomas and some of them are specifically associated to one type thyroid cancer. For instance, RET/PTC is the most common molecular event in the radiation-associated PTC in childhood. In the first part of the work, we studied two transgenic mouse models: the Tg-RET/PTC3 (Tg-RP3) mouse and the Tg-E7 mouse. Both strains express the human origin transgene (RET/PTC3 rearrangement or E7) exclusively in the thyroid under the control of the bovine thyroglobulin promoter. Our study of these two models showed: In both E7 and RET/PTC3 mouse models, the thyroids exhibited hyperplasia with own 'oncogene-dependent' follicular cell characteristics. Small follicular cells with hyperchromatic nuclei with an increased nucleus/cytoplasm ratio were numerous in the E7 mice, and large cells with convex apical border, a decreased nucleus/cytoplasm ratio, a pale nucleus and dispersed chromatin were found in the RET/PTC3 mice. At 6, 10 months and later on, E7 mice developed huge heterogeneous, normal functional thyroid goiter, with no tumor formation. As in previous studies on transgenic RET/PTC3 mouse models, the generally encountered features such as solid tumours were present. We also observed conventional variant of human PTC at late age (since 11 month-old) with quite low incidence (4%). In addition to solid and conventional variant PTCs, 28% of mice developed a peculiar big size thyroid tumor pattern with “proliferative papillary cystic changes with spindle cells and remodelling” and macrophage infiltration in the cysts at as early as 2 month of age; this kind of tumor histologically resembles the rare human young age 'diffused sclerosing' variant PTC (DSVP), but disappeared after 6 month. The other peculiar tumor exhibits morphological similarity with another rare human FAP-associated (Familial Adenomatous colonic polyposis) cribriform PTC, which showed a mixed architecture of several histological patterns (solid, follicular, cribriform). At 6 months, 26% of mice presented the cribriform tumor pattern. From the analyse of the proliferation index in the two models, we conclude that RET/PTC3 fusion protein over stimulates MAPK and Akt/PKB-signalling pathways, through Ras-Raf-Mek-Erk, Ras-PI3-K/Akt/PKB, particularly in the large cells which were strongly positive for three proliferation markers. E7 bypasses these two pathways, by directly binding to Rb1 protein and releasing the E2F transcription factor which induces cell proliferation. So RET/PTC3 and E7 mice present several morphologic features which mimic human PTC tumors; RET/PTC3 could therefore be used as a partial model for human PTCs. Further investigation of gene expression will allow the characterization of the molecular phenotype of the observed variants. In the second part of the work, we attempted to generate by xenobiotic administration an in vivo model of thyroid carcinoma. Chronic exposure of CD1 mice to acrylamide in the drinking water during 6 and 8 months at doses of 3mg/kg per day similar to those causing thyroid tumorigenesis after 2 years in rats, did not induce any thyroid tumors whatever the level of thyroid stimulation.

Thesis (M.S.)--Bowling Green State University, 2008. / Document formatted into pages; contains 40 p. Includes bibliographical references.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1980. / Typescript. Vita. Description based on print version record. Includes bibliographical references (leaves 170-183).

Thesis--University of Wisconsin--Madison. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (M.S.)--Wisconsin. / Includes bibliographical references.

Thesis (M.S.)--University of Wisconsin--Madison, 1964. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Several epidemiological studies .have demonstrated the importance of diet in the development of gastro-intestinal carcinomas in man. This study examines the role of plant phenolics, major components of the human diet. Employing a CHO cell test system, it was observed that phenolics with at least two hydroxyl groups in the ortho position, relative to each other were particularly clastogenic. This activity was abolished by the addition of S9, a rat liver microsomal preparation. The clastogenic activity of these compounds was found to increase with time, alkaline pH, and the presence of transition metals. It was therefore deduced that the source of activity might be an oxidative by-product. High' pressure liquid chromatography was used to separate out these oxidative products. No activity was found to reside in any of the separated components or combinations of components. Further study therefore centred on oxidative products not retained by chromatography and on those labile to this.process. Under oxidative conditions, the presence of hydrogen peroxide was detected. Levels measured were sufficient to explain the clastogenic activity of completely oxidized solutions of phenolic acids. Addition of the enzyme, catalase, appeared to abolish all activity of completely oxidized solutions. Hydrogen peroxide could not, however, account for the genotoxic effects measured in freshly prepared solutions. The presence of superoxide was detected in actively oxidizing solutions of plant phenolics. Its production appeared to be pH-dependent. Addition of superoxide dismutase increased the clastogenic activity of compounds tested, presumably by converting superoxide to peroxide, a more stable oxidative by-product. Addition of tyrosinase, a monophenol oxidase, also increased the clastogenic activity of freshly prepared solutions. Since this enzyme catalyzes the oxidation of several phenolics without subsequent generation of peroxide, it was deduced that phenolic free radicals must also be present which could be at least partially responsible for the enhanced biological activity. Electron spin resonance proved this was the case. Using electron spin resonance, the primary oxidative products were characterized both at high pH and by enzymatic activation. The results obtained agree with those published in the literature. Several reports in the literature have suggested that phenolics may also act as free radical scavengers. The importance of plant phenolics in diet may therefore depend on the oxidative conditions of the system to be tested. Under oxidative conditions, free radicals appear to be generated, which are capable of causing mutations and chromosomal rearrangements. Phenolic oxidation products may therefore play a role as initiators and promotors of carcinogenesis. However, under alternate conditions, phenolics may also act to scavenge free radicals, and could therefore be classed as inhibitors of carcinogenesis. / Science, Faculty of / Zoology, Department of / Graduate

Thesis (M.S.) in Biochemistry--University of Maine, 2007. / Includes vita. Includes bibliographical references (leaves 50-54).

Thesis (Ph.D.)--Kent State University, 2008. / Title from PDF t.p. (viewed Dec. 22, 2009). Advisor: Nywana Sizemore. Includes bibliographical references (p. 125-145).