Thesis (M.S.)--University of Wisconsin--Madison, 1984. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 69-78).

Thesis (M.S.)--University of Wisconsin--Madison, 1983. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 116-120).

Th.--Méd.--Montpellier, 1852-01-16. / Voyez tome 1 N ° 1 Montpellier 1852.

Methylation of histone lysine residues functions as a dynamic, reversible mechanism for regulating gene expression and aberrations in this process have been linked with the development of cancer. Members of the lysine demethylase (KDM) family remove methyl marks from histones. KDM5B removes methyl marks from histone H3 lysine 4 (H3K4) whereas KDM6A and KDM6B remove methyl marks from histone H3 lysine 27 (H3K27). In this thesis, GSK-J4, an inhibitor of KDM5B, KDM6A and KDM6B, is shown to impair viability in a range of cancers affecting bone including multiple myeloma, Ewing sarcoma and chordoma. GSK-J4 induces a biphasic transcriptional response, characterized by an early, massive rise in the expression of a number of cysteine-rich metallothionein genes followed by induction of ATF4 via phosphorylation of eIF2α by GCN2. Induction of ATF4 leads to apoptosis in myeloma cells and cell cycle arrest in Ewing sarcoma. Ectopic overexpression of metallothioneins is shown to be sufficient to induce the ATF4 response. GSK-J4 is shown to alters cellular metabolism by impairing glutaminolysis. ChIPseq demonstrates a global increased H3K27me3 in response to treatment with GSK-J4 with a decrease in H3K4me3 around transcription start sites of genes not involved in the ATF4 response. Combined knockdown of KDM6A and KDM6B recapitulates the cellular response to GSK-J4 whereas inhibition of KDM5B is not sufficient to reproduce the effect. A model is presented suggesting that the increased requirement for incorporation of cysteine into protein due to the expression of metallothioneins leads to the presence of uncharged cysteinyl-tRNA molecules that are sensed by GCN2 leading to activation of an ATF4-driven integrated stress response.

Orientador: Luiz Eduardo Blumer Rosa / Banca: Luiz Eduardo Blumer Rosa / Banca: Daniel Araki Ribeiro / Banca: João Ernesto de Carvalho / Banca: Adriana Aigotti Haberbek Brandão / Banca: Rosilene Fernandes da Rocha / Resumo: Os objetivos deste estudo foram avaliar o efeito da administração sistêmica de extrato liofilizado de Pfaffia glomerata em modelo de carcinogênese química em pele de camundongos hairless, bem como investigar a toxicidade hepática e renal das doses administradas. Foram utilizados 32 camundongos hairless, fêmeas com 5 semanas de vida, distribuídos em grupos controle (C) e experimentais (E1, E2 e E3). Os grupos E1, E2 e E3 receberam a administração sistêmica de extrato liofilizado de P. glomerata nas doses de 200, 400 e 1000 mg/Kg/dia, respectivamente, via oral, durante 15 semanas. O grupo C recebeu somente água filtrada. Duas semanas após o início da administração de extrato liofilizado de P. glomerata, os animais foram submetidos à carcinogênese química induzida pelo DMBA a 0,5% na região do dorso. Na 15ª semana foi realizada a avaliação clínica, biópsia das lesões de pele, coletada amostra de sangue e removidos fígado e rins dos animais. As lesões de pele seguiram para avaliação histopatológica e imunoistoquímica, os órgãos para análise histopatológica e as amostras de sangue para toxicológica. Nesta última, foram realizadas as análises da atividade enzimática de fosfatase alcalina, aspartato aminotransferase e da concentração de uréia. Comparados os grupos C e E o teste estatístico de Kruskal-Wallis não mostrou diferença estatística significativa em relação ao tipo, tamanho e graduação de malignidade das lesões. Não foi observada significância nas análises de fosfatase alcalina, aspartato aminotransferase e uréia. O teste de correlação de Spearman mostrou relação significativa para VEGF e PCNA e o qui-quadrado para infiltrado inflamatório em fígado e rins. Conclui-se que o tratamento com as doses de 200, 400 e 1000mg/kg/dia de extrato liofilizado de P. glomerata não apresentou ação quimiopreventiva e revelou indícios de toxicidade hepática e renal neste modelo experimental. / Abstract: The goals of this study were both to evaluate the effect of systemic administration of the extract of Pfaffia glomerata in the chemical carcinogenesis model on the skin of hairless mice, as well as to investigate the hepatic and renal toxicity of the administered doses. For that we have used 32 hairless mice, female, aged 5 weeks, distributed in control group (C) and experimental groups (E1, E2 e E3). The experimental groups E1, E2 e E3 received systemic administration of the lyofilized extract of P. glomerata in 200, 400 and 1000 mg/Kg/day doses, respectively, by oral means, during 15 weeks. Group C received only filtered water. Two weeks after the beginning of the lyophilized extract of P. glomerata administration, the animals were submitted to chemical carcinogenesis induced by the 0,5% DMBA brushed in the dorsal region. At the 15th week a clinical evaluation was conducted, skin biopsy made, blood sample collected and liver and kidneys of the animals removed. After that the following evaluation were conducted: histopathological and immunohistochemical evaluation of the skin lesions, histopatological evaluation of the organs, and toxicological evaluation of the blood samples. The blood samples went also thorough the following analysis: enzimatic activity of alkaline phosphatase, aspartate aminotransferase and urea concentration. When comparing C and E groups, the Kruskal-Wallis statistical analysis has not shown any statistically significant difference of type, size and malignancy grading. It has not been observed statistically significant difference in the alkaline phosphatase, aspartate aminotransferase and urea analysis. The Spearman correlation test showed significant relation for VEGF and PCNA and the c2 test for inflammatory infiltrate in the liver and kidneys. We therefore concluded that the treatment using 200, 400 and 1000mg/Kg/day of the lyophilized... (Complete abstract, click electronic access below) / Doutor

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Thesis (Ph. D.)--Ohio State University, 2004. / Title from first page of PDF file. Document formatted into pages; contains x, 133 p.; also includes graphics. Includes abstract and vita. Advisor: Carol Kennedy, School of Nursing. Includes bibliographical references (p. 122-133).

Thesis (Ph. D.)--University of Chicago, Department on Medical Physics, December 2003. / Includes bibliographical references. Also available on the Internet.

Thesis (Ph.D.)--Duquesne University, 2006. / Title from document title page. Abstract included in electronic submission form. Includes bibliographical references (p. 126-140) and index.