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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.

Role of p53 in Adaptation to the Tumor Microenvironment

Mendoza, Erin January 2010 (has links)
Tumors cells grow in nutrient and oxygen-deprived microenvironments and adapt to the suboptimal growth conditions by altering their metabolic pathways. The adaptation process commonly creates a tumor phenotype of high glycolytic potential and aggressive growth characteristics which facilitate metastasis and confer resistance to radiation and chemotherapy. Understanding the mechanisms that allow tumors to adapt and survive in their microenvironment is crucial to cancer prevention and control. It was hypothesized that the tumor microenvironment would induce signaling and enzymatic changes, which if manipulated could improve treatment outcome. The results presented here demonstrate that exposure of tumor cells to chronic low pH or hypoxic conditions induced signaling cascades and altered enzyme profiles which resulted in a pro-survival phenotype. Three key adaptation events were observed and included 1) the up regulation of the metabolic stress and glycolytic proteins AMP-activated protein kinase (AMPK) and 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 (PFKFB3), respectfully. 2) The upregulation of p53 and 3) changes in the ratios of the bioreductive enzymes were also found to be important in the adaptation. The tumor suppressor p53 played a central role in adaptation because it induced the transcription of anti-glycolytic proteins to control glycolysis and minimize tumor cell acidosis. The ratio of bioreductive enzymes was also altered by changes to the microenvironment. Hypoxia had the greatest effect on protein levels and caused a decrease in the ratio of NAD(P)H:quinone oxidoreductase 1 (NQO1): cytochrome p450 reductase. The increase in cytochrome p450 reductase, a one electron bioreduction enzyme, has been shown to increase toxicity of bioreductive drugs in hypoxic tumors. Micronutrients also had an effect on p53 homeostasis because increasing NQO1 activity by riboflavin supplementation induced a p53-stabilizing effect by enhancing binding of p53 to NQO1, protecting the tumor suppressor from degradation. Taken together, these results indicate the changes that occur in tumor adaptation to the microenvironment require signaling and enzymatic changes that work in concert to regulate metabolism and apoptosis. Many of these changes present therapeutic targets that could be exploited to enhance therapy or prevent adaptation and subsequent tumor growth.

Signatures of mutational processes in human cancer

Alexandrov, Ludmil January 2014 (has links)
No description available.

Avaliação da ação sistêmica de extrato liofilizado de Pfaffia glomerata na carcinogênese quimicamente induzida pelo DMBA em pele de camundongos hairless /

Carmo, Elaine Dias do. January 2007 (has links)
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

The role of the lysine demethylases KDM5 and KDM6 in bone malignancies

Hookway, Edward January 2016 (has links)
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.

Registered nurse knowledge of the early warning signs of childhood cancer

Raymond, Naseerah January 2014 (has links)
The global burden of cancer has more than doubled in the past 30 years. It is estimated that in 2008, 7 million people worldwide died of cancer. Although the majority of deaths were in adults, 90 000 deaths related to childhood cancers. Childhood cancer comprises all cancers arising in children under the age of 15 years. Cancer in children is fairly rare and globally it is estimated that 160 000 children will be diagnosed with cancer each year (World Health Organization, 2008). Early detection is a fundamental goal in oncology nursing as it provides for early treatment of cancers. The onset in children’s cancers is generally short and if not detected early can grow fast and aggressively. Children’s tumours tend to be more invasive but have a better response to treatment in comparison to adults’ cancer. The purpose of this study is to explore the knowledge of registered nurses practicing at primary health clinics situated in the Johannesburg metropolis regarding the early warning signs of childhood cancer. An exploratory research strategy would be used and a contextual study will be done. The context of the study will be Johannesburg and specifically the primary health clinics in the metropolis. A quantitative survey will be conducted. The population targeted is all registered nurses practicing in the 35 primary health clinics in the Johannesburg Metropolis Region B, D, E, F and D. A census will be done and a self- administered questionnaire will be used to gather self-report data. The data will be analyzed by means of descriptive statistics.

Characterization of germline deletions in MLHJ and MSH2 that cause hereditary nonpolyposis colorectal cancer

McVety, Susan January 2005 (has links)

Mathematical models in two-step cancer chemotherapy /

Jackson, Trachette L. January 1998 (has links)
Thesis (Ph. D.)--University of Washington, 1998. / Vita. Includes bibliographical references (p. [102]-107).

Chemical transformation and chromosomal analysis of fibroblasts from patients genetically predisposed to cancer

Danielson, Donna Mary, January 1976 (has links)
Thesis--Wisconsin. / Includes bibliographical references (leaves 60-72).

An inaugural essay on carcinoma or cancer

O'Connor, John, January 1812 (has links)
Thesis (M.D.)--College of Medicine of Maryland, 1812. / Microform version available in the Readex Early American Imprints series.

Separate and joint analysis of longitudinal and survival data /

Rajeev, Deepthi, January 2007 (has links) (PDF)
Project (M.S.)--Brigham Young University. Dept. of Statistics, 2007. / Includes bibliographical references (p. 31-34).

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