Source: Masters Abstracts International, Volume: 47-06, page: 3551. Advisers: Florence J. Dallo; Raul Caetano. Includes bibliographical references.

Epidemiological evidence linking dietary folate deficiency and risk for colorectal cancer is conflicting. Studies using animal models indicate that timing, dose and presence of pre-malignant lesions will influence whether folate deficiency prevents or promotes tumor formation. In this thesis a new model of spontaneous tumor formation due to long-term dietary folate deficiency alone, in non-transgenic mice and without carcinogen induction, is developed. The mechanisms by which folate deficiency might influence cancer risk are also examined. / BALB/c mice, with or without a null allele in a key folate-metabolizing enzyme, Methylenetetrahydrofolate reductase (Mthfr ), develop intestinal tumors due to dietary folate deficiency alone. On folate-deficient (FD) diets, 12.5% of Mthfr+/+ mice and 28.1% of Mthfr+/- mice developed tumors; mice on control diet (CD) did not. C57B1/6 mice (a strain resistant to other methods of tumor induction) placed on the same diets for the same amount of time did not develop any tumors. To investigate possible mechanisms the levels of DNA damage (dUTP/dTTP ratio and p-H2AX staining) and DNA methylation (thin layer chromatography) were examined. FD BALB/c, but not C57B1/6 mice, had a trend towards increased dUTP/dTTP and DNA double-strand breaks and decreased global DNA methylation compared to CD mice. To determine why the FD diet affects the BALB/c and not the C57Bl/6 strain, the expression of genes involved in folate metabolism was examined. Several changes in gene expression were observed. In particular, BALB/c mice had increased Mthfr expression and MTHFR activity compared to C57Bl/6 mice. Increased MTHFR activity may deplete 5,10-methylenetetrahydrofolate supplies for the dTMP synthesis, increasing the dUMP levels and, possibly, DNA damage. The levels of several DNA repair genes were also examined. Two genes involved in base excision repair, Thymine DNA glycosylase (Tdg) and Apurinic/apyrimidinic endonuclease 1 (Apex1), were increased in FD C57B1/6 compared to FD BALB/c mice suggesting increased DNA repair capacity. / These results support the evidence that dietary folate deficiency promotes intestinal tumor formation possibly through increased DNA damage, with subsequent defects in DNA repair.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Thesis (Ph.D. in Toxicology) -- University of Colorado Denver, 2007. / Typescript. Includes bibliographical references (leaves 156-176). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;

Thesis (M.S.)--University of Texas Health Science Center at Houston, School of Public Health, 2007. / Source: Masters Abstracts International, Volume: 46-01, page: 0238. Adviser: Marsha Frazier. Includes bibliographical references.

Source: Dissertation Abstracts International, Volume: 70-07, Section: B, page: 4061. Advisers: Sally W. Vernon; Xianglin L. Du. Includes bibliographical references.

Made available in DSpace on 2015-07-22T20:50:30Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-05-27 / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Fundo de Auxílio aos Docentes e Alunos (FADA) / Durante a metastase, as celulas perdem seu contato tecidual original, movem-se pela matriz extracelular (MEC), invadem o sistema linfatico e/ou sanguineo, extravasam e formam novos tumores. Devido a isso, essas celulas tumorais precisam modificar sua adesao celula-MEC. Receptores de adesao exercem papeis cruciais na transformacao neoplasica de celulas normais atraves da inducao de comportamentos celulares e morfologicos especificos do cancer. Isto implica que celulas tumorais provavelmente expressam e utilizam um conjunto distinto de receptores de adesao celular durante e carcinogenese. Sindecam-2 e um proteoglicano transmembranico de heparam sulfato (HS) que participa da formacao de dominios especializados na membrana plasmatica e funciona diretamente como um vinculo entre o ambiente extracelular e a organizacao do citoplasma cortical. Em diversas linhagens celulares de cancer colorretal, a expressao de sindecam-2 encontra-se aumentada, quando comparada com linhagens normais, e este aumento parece ser critico para o comportamento das celulas cancerosas, uma vez que regula sua adesao e proliferacao, e, portanto, sua atividade tumorigenica. Os resultados obtidos neste trabalho demonstraram que em celulas de carcinoma colorretal altamente metastaticas, pertencentes a linhagem HCT-116, a expressao e a sintese de sindecam-2 sao intensificadas na presenca de MEC produzida por fibroblastos. Os demais sindecans sofrem diminuicao, assim como o HS presente na MEC produzida pelas celulas tumorais. Entre os componentes da MEC estromal, a fibronectina mostrou-se como principal responsavel pelo aumento de sindecam-2. Houve co-localizacao entre sindecam-2, integrina ƒÑ5ƒÒ1 e fibronectina, o que sugere a participacao destas moleculas no mecanismo de adesao em celulas HCT-116. Alem disso, o bloqueio de sindecam-2 resultou na nao formacao de fibras de estresse durante a adesao celular, indicando seu importante papel na regulacao de filamentos de actina. Fica claro, portanto, o papel fundamental da MEC estromal na regulacao da expressao de proteinas de superficie celular e provavelmente na sinalizacao para o interior de celulas cancerosas, modificando sua proliferacao, adesao e seu formato. / During metastasis cells lose their original tissue contacts, move through the extracellular matrix (ECM), enter the lymphatic and/or blood system, extravasate and subsequently form new tumors. Therefore, these tumor cells must experience changes in cell-ECM adhesion. Adhesion receptors play crucial roles in the neoplastic transformation of normal cells through the induction of cancer-specific cellular behavior and morphology. This implies that cancer cells likely express and utilize a distinct set of adhesion receptors during carcinogenesis. Syndecan-2 is a transmembrane heparan sulfate (HS) proteoglycan which has been implicated in the formation of specialized membrane domains and functions as a direct link between the extracellular environment and the organization of the cortical cytoplasm. In several colon-rectal cancer cell lines, syndecan-2 is highly expressed compared to normal cell lines. This increase appears to be critical for cancerous cell behavior since it regulates adhesion and proliferation and therefore the tumorigenic activity. The results of this study showed that in a highly metastatic colon-rectal cancer cell line, HCT-116, both expression and synthesis of syndecan-2 are enhanced when grown on ECM produced by fibroblasts. The expression of the others syndecans decreased, as did HS in the ECM produced by the cancer cells. Among the stromal components of ECM, the fibronectin was shown to be important for the increase of syndecan-2. Co-localization between syndecan-2, integrin ƒÑ5ƒÒ1 and fibronectin, suggests the involvement of these molecules in the adhesion mechanism of HCT-116 cells. Furthermore, blocking syndecan-2 with an antibody resulted in the absence of stress fibers during cell adhesion, indicating its important role in the regulation of actin filaments. Thus, the stromal ECM has a fundamental role in regulating the expression of cell surface proteins and probably signaling to the interior of cancer cells by altering their proliferation and adhesion, and its format. / TEDE / BV UNIFESP: Teses e dissertações

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / O cÃncer colorretal(CCR) à altamente prevalente nos paÃses mais ricos e industrializados. As metaloproteinases de matriz (MMPs) sÃo importantes enzimas que facilitam a invasÃo e disseminaÃÃo do tumor em vÃrios tipos de cÃncer, inclusive o colorretal. Os inibidores teciduais de metaloproteinases (TIMPs) sÃo os principais inativadores fisiolÃgicos destas enzimas. Este estudo avaliou a expressÃo de metaloproteinase-2 (MMP-2), metaloproteinase-14 (MMP-14) e inibidor tecidual de metaloproteinases-2 (TIMP-2) no cÃncer colorretal. O imunomarcador CD68 foi utilizado para caracterizar a natureza das cÃlulas mononucleadas do estroma. Amostras teciduais de 50 casos de colectomias, devido ao cÃncer colorretal no perÃodo de 2004 a 2010, obtidas dos arquivos do Departamento de Patologia e Medicina Legal (DPML), Faculdade de Medicina da Universidade Federal do Cearà (UFC), foram analisadas. Realizou-se tissue microarrays e a seguir imuno-histoquÃmica para avaliar a expressÃo de MMP-2, MMP-14 e TIMP-2 de acordo com os seguintes escores baseados em outros relatos: 0= sem imunomarcaÃÃo ou raras cÃlulas marcadas (<5%); 1 = discreta marcaÃÃo na maioria (> 50%) das cÃlulas tumorais ou cÃlulas mononucleares do estroma, ou moderada marcaÃÃo em uma minoria de cÃlulas (<50 %); 2 =marcaÃÃo moderada na maioria (> 50%) de cÃlulas tumorais ou cÃlulas mononucleares ou intensa marcaÃÃo em minoria de cÃlulas (<50%); 3 = marcaÃÃo intensa na maioria (> 50%) de cÃlulas tumorais ou cÃlulas mononucleares. Observou-se relaÃÃo entre a expressÃo aumentada de MMP-14 em mononucleares de tumor primÃrio e casos sem metÃstases linfonodais (MMP-14, escores 2 e 3/N0 : 23/24 = 95%; N1-N3: 14/20 = 70%, p = 0,0353). No entanto, nenhuma relaÃÃo significativa foi encontrada entre a expressÃo de MMP-14, MMP-2 e TIMP-2 nos tumores primÃrios em cÃlulas cancerosas ou mononucleares e outros parÃmetros clÃnico-patolÃgicos. A imunoexpressÃo de MMP-2 foi negativa nas cÃlulas neoplÃsicas, em tumores primÃrios (47/47=100%) e metastÃticos (12/12 = 100%). A imunorreatividade de MMP-14 em cÃlulas neoplÃsicas foi frequentemente positiva em tumores primÃrios (50/50 = 100%) e metastÃticos (7/8= 88%). Em mononucleares, a maioria dos quais macrÃfagos (corados pelo CD68), a expressÃo positiva de MMP-14 tambÃm predominou marcadamente, tanto em tumores primÃrios (46/47 = 98%) como em carcinomas metastÃticos (9/10 = 90%). A expressÃo de TIMP-2 em cÃlulas neoplÃsicas, discreta, ocorreu em 70% de tumores primÃrios (35/50 casos) e 100% dos metastÃticos (8/8). A imunocoloraÃÃo para TIMP-2 em macrÃfagos associados ao tumor (TAMs) foi ainda mais elevada do que nas cÃlulas neoplÃsicas. Em conclusÃo, a MMP-14 e TIMP-2 sÃo frequentemente expressas em carcinomas colo-retais em ambas localizaÃÃes anatÃmicas, principalmente nas metÃstases para linfonodos , sugerindo que estas proteases desempenham papel importante na invasÃo local e na progressÃo tumoral neste tipo de cÃncer. A predominÃncia destes marcadores nas cÃlulas mononucleares (sobretudo macrÃfagos) , claramente evidentes na positividade para a MMP-2, enfatiza a importÃncia do microambiente tumoral no desenvolvimento de neoplasias. / The colorectal cancer (RCC) is highly prevalent in richer and industrialized countries. The matrix metalloproteinases (MMPs) are regarded as important for facilitating tumor invasion and spread in various cancers, including colorectal. Tissue inhibitors of metalloproteinases (TIMPs) are the major physiological inhibitors of MMPs. The expression of metalloproteinase-2 (MMP-2), metalloproteinase 14 (MMP-14) and tissue inhibitor of metalloproteinases-2 ( TIMP-2) in colorectal cancer was assessed. CD68 immunostaininig was utilized to the characterization of mononuclear cells nature. Paraffin-embedded tissues from patients undergoing colectomy for colorectal cancer in the period 2004 to 2010, were selected from the files of the Department of Pathology and Forensic Medicine (DPML), Medical School , Federal University of Cearà (UFC). Tissue microarrays were performed and slides were obtained for immunohistochemical detection of the expression of MMP-2, MMP-14 and TIMP-2 and the tissue samples analyzed. The following scores were applied: 0 = no immunostaining or rare labeled cells (<5%), 1 = slight marking the majority (> 50%) of tumor cells or stromal mononuclear cells, or moderate marking in a minority of cells (<50%) 2 = moderate labeling in the majority (> 50%) of tumor or mononuclear cells or intense marking in the minority of cells (<50%) and 3 = intense labeling in the majority (> 50%) of tumor cells or mononuclear cells. In this study, the relationship between increased expression of MMP-14 in mononuclear primary tumor cells and cases without lymph node metastases (MMP-14, 2 and 3/N0 scores: 23/26 = 88%; N1-N3: 14/21 = 67%, p = 0.0353) was stablished . However, no significant relationship was found between the immunohistochemical expression of MMP-14, MMP-2 and TIMP-2 in primary tumors in cancer cells and mononuclear cells and other clinico-pathological parameters. The expression of MMP-2 were negative in the neoplastic cells both in primary tumors (47/47 = 100%) and in metastatic ones (12/12 = 100%). The immunoreactivity of MMP-14 in neoplastic cells in primary tumors was positive (50/50 = 100%) and in all cases except one of metastatic carcinoma (7/8 = 88%). In mononuclear cells, most of them characterized as macrophages (CD68 stained), MMP-14 positive expression also predominated markedly, both in primary tumors (46/47 = 98%) and in metastatic carcinomas (9/10 = 90%). TIMP-2 expression in neoplastic cells of primary tumors occurred in 35/50 cases (70%) and lymph nodes showed positive immunostaining in all cases (8/8 = 100%). In both sites there were no cases with high expression. The TIMP-2 immunoreactivity in tumour associated macrophages (TAMs) was even higher than in the neoplastic cells. In conclusion, MMP-14 and TIMP-2 are frequently expressed in colorectal carcinomas in both anatomical sites , mainly in lymph node metastasis, suggesting that these proteases play an important role in local invasion and tumor progression of these cancers. The predominance of these biomarkers in mononuclear cells, clearly evident in the positivity for MMP-2, emphasizes the importance of tumor microenvironment in the development of neoplasms.

O câncer colorretal (CCR) é o quarto tipo mais incidente mundialmente e a taxa de mortalidade ocupa a terceira posição. Apresenta desenvolvimento lento e bom prognóstico quando diagnosticado em estadio inicial. Apesar de ser um câncer que pode ter rastreamento populacional, as políticas públicas não têm conseguido estabelecer estratégicas efetivas de prevenção e diagnóstico precoce. Este estudo teve como objetivo geral caracterizar o perfil epidemiológico da coorte dos pacientes diagnosticados com CCR, atendidos no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo (HCFMRP-USP), no período de janeiro de 2000 a dezembro de 2010. Estudo de coorte retrospectivo, longitudinal, baseado em dados secundários do Registro Hospitalar de Câncer (RHC) do HCFMRP-USP. As análises foram realizadas com o auxílio do Programa Excel 2010 da Microsoft e o Software R 3.0.1. Para análise da sobrevida, foi utilizado o método não paramétrico de Kaplan-Meier e para as associações foi aplicado o teste de Fisher e Qui-quadrado. Estudo aprovado pelo Comitê de Ética da Escola de Enfermagem de Ribeirão Preto- USP, nº 224.448/2012, Resolução CNS 466/2012. A população foi composta por 926 pacientes e os resultados evidenciaram prevalência do sexo masculino, com idade de 70 anos ou mais, 38,9% analfabetos/baixa escolaridade, 54,2% foram diagnosticados com o estadio III e IV e a localização predominante do tumor foi cólon e reto. O tempo médio entre a primeira consulta e o diagnóstico foi de 19,8 dias e entre o diagnóstico e o tratamento, foi de 27,8 dias. Observou-se igual sobrevida para homens e mulheres, sendo que o tempo médio entre o início do tratamento e a ocorrência do óbito foi de 626,3 dias. Conclui-se que há necessidade de investir na prevenção primária do CCR, com ações que minimizem os fatores de riscos conhecidos e na prevenção secundária com testes efetivos, como a pesquisa de sangue oculto nas fezes. Destaca-se ainda a urgente necessidade de políticas públicas mais direcionadas e investimento na educação permanente dos profissionais de saúde, principalmente o enfermeiro, que tem papel primordial na geração de conhecimento para esta população / Colorectal cancer (CCR) is the fourth most incident cancer worldwide and is the third leading cause of cancer-related deaths. It develops slowly and has a good prognosis when identified in early stages. Even though it can be screened in the population, public policies have not established effective preventive measures or early diagnosis strategies. This study\'s general objective was to characterize the epidemiological profile of a cohort of patients diagnosed with CCR cared for by the Hospital das Clinicas at University of São Paulo at Ribeirão Preto, Medical School (HCFMRP-USP) from January 2000 to December 2010. This longitudinal, retrospective cohort was based on secondary data from the Cancer Hospital Record from HCFMRP-USP. Analyses were performed using Excel 2010, Microsoft and R software 3.0.1. For the analysis of survival, Kaplan-Meier non-parametric method was used and the Fisher\'s test and Chi-square were used for associations. The study was approved by the Institutional Review Board at the College of Nursing at Ribeirão Preto, USP according to CNS Resolution 466/2012 (No. 224,448/2012). The population was composed of 926 patients and the results show a prevalence of 70 years old or older males, 38.9% were illiterate or had low level of education, 54.2% were diagnosed at stages III and IV, while the predominant sites were colon and rectum. The average time between the first consultation and diagnosis was 19.8 days and 27.8 days between diagnosis and treatment. Equal survival rates were observed for both men and women while the average time between the beginning of treatment and death was 626.3 days. There is a need to invest in CCR primary prevention with actions that minimize known risks and secondary prevention with effective tests such as fecal occult blood test. We also highlight the urgent need of public policies focused on this condition and investment on the permanent education of healthcare professionals, especially nurses who play an essential role in transmitting knowledge to this population

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-10-18T12:19:11Z No. of bitstreams: 1 anapaulatellespiresdias.pdf: 1519258 bytes, checksum: 115fa6d893019191b30393d181c96383 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-10-25T12:07:25Z (GMT) No. of bitstreams: 1 anapaulatellespiresdias.pdf: 1519258 bytes, checksum: 115fa6d893019191b30393d181c96383 (MD5) / Made available in DSpace on 2016-10-25T12:07:26Z (GMT). No. of bitstreams: 1 anapaulatellespiresdias.pdf: 1519258 bytes, checksum: 115fa6d893019191b30393d181c96383 (MD5) Previous issue date: 2008-02-29 / O carcinoma colorretal (CCR) é a segunda neoplasia mais freqüente na população mundial. A alta incidência do CCR e a diferença nos resultados do tratamento desta neoplasia, de acordo com o estádio da doença, justificam os esforços para o rastreamento, prevenção e detecção precoce. Objetiva-se neste estudo descrever os aspectos: epidemiológicos, endoscópicos e anatomopatológicos das neoplasias colorretais em uma série de casos e avaliar o papel da colonoscopia na prevenção do CCR. Trata-se de estudo descritivo de série de casos atendida em centro especializado em endoscopia digestiva, no período de janeiro de 2002 a dezembro de 2006. Foram coletados dados sobre 1.962 colonoscopias realizadas em 1.491 indivíduos e, em 492 (33%) foram identificadas lesões polipóides. 408 indivíduos foram considerados para fins de análise. Na série de casos 70% dos indivíduos eram assintomáticos. A prevalência de neoplasias colorretais foi de 50% (60/120) em homens e de 42,4% em mulheres (122/288). As neoplasias foram detectadas em 138 dos 287 indivíduos (48%), com 50 anos ou mais, e a sua prevalência foi significantemente maior do que naqueles com menos de 50 anos (44/121) 36,3% (p=0,01). Verificou-se que 58,9% dos indivíduos com neoplasia e neoplasia avançada apresentavam história familiar positiva para câncer de mama, útero, ovário e/ou colorretal. Nos 408 indivíduos, foram realizadas 679 colonoscopias, com retirada de 959 lesões polipóides; destas, 463 (48,3%) eram neoplásicas, incluindo 13(1,35%) adenocarcinomas. Nas lesões menores que 5 mm, foi evidenciado displasia em 36% (346/959). No colon proximal, 21% (85/408) dos indivíduos apresentavam lesões neoplásicas e 2% (8/408), neoplasias avançadas, incluindo seis casos de adenocarcinoma sem qualquer evidência de lesão em colon distal. Dentre os 232 indivíduos que apresentavam lesões neoplásicas (benignas e ou avançadas), 130 (56%) apresentavam apenas lesões em colon proximal. Se o rastreamento fosse realizado apenas com a retossigmoidoscopia, a perda diagnóstica de lesões neoplásicas benignas seria de 76(62,3%) nas mulheres e 29(48,3%) nos homens. Em relação ao adenocarcinoma, a perda diagnóstica seria de 50% para ambos os sexos. Neoplasias colorretais são comuns em indivíduos assintomáticos. Sexo masculino, idade avançada e história familiar para câncer são fatores de risco para a detecção de lesões. A colonoscopia consiste em método eficaz de rastreamento para o CCR, a remoção de lesões neoplásicas colorretais interfere diretamente na história natural desta forma de câncer. / The colorectal carcinoma (CRC) is the second most frequent cancer in the world population. The high incidence of CRC and the difference in the results of the treatment of cancer, according to the stage of disease justify the efforts for screening, prevention and early detection. The objective of this study was to describe the epidemiological, endoscopic and pathological of polypoid lesions and colorectal cancers and assess the role of colonoscopy in preventing the CRC. This is a descriptive study of number of cases addressed in centre specializing in gastrointestinal endoscopy. In the period January 2002 to December 2006, colonoscopies were performed in 1962 and 1,491 individuals in 492 (33%) of these have been identified polypoid lesions; 408 individuals were considered for analysis. The data were included and analyzed in the Epi Info-2000. In a series of cases studied, 60% of the subjects were asymptomatic. The prevalence of colorectal cancers was 50% (60/120) in men and 42.4% in women (122/288). The cancers were detected on 138 of the 287 individuals (48%) with 50 years or more, and their prevalence was significantly higher than those with less than 50 years (44/121) 36.3% (p = 0.01). It was found that 58.9% of individuals with advanced cancer and cancer had positive family history for cancer of the breast, uterus, ovary, or colorectal. In 408 individuals, 679 colonoscopies were performed, with withdrawal of 959 polypoid lesions; these, 463 (48.3%) were neoplasms, included 13 adenocarcinomas. In lesions smaller than 5 mm, was shown dysplasia in 36% (346/959). In the proximal colon, 21% (85/408) of the subjects had neoplastic lesions in 2% (8 / 408), advanced malignancies, including six cases of adenocarcinoma without any evidence of damage in distal colon. The indication of colonoscopy only by the presence of lesions in the distal colon is controversial. Among the 232 individuals who had neoplastic lesions (benign, or advanced), 130 (56%) had only injuries in proximal colon. If the screening was done only with the retossigmoidoscopy, loss diagnosis of benign neoplastic lesions would be 76 (62.3%) in women and 29 (48.3%) in men. Regarding adenocarcinoma, the loss would be diagnostic of 50% for both sexes. Colorectal neoplasms are common even in asymptomatic subjects. Male, age and family history for cancer are risk factors for the detection of lesions. A colonoscopy is the most effective method of screening for the CRC, indicated for all individuals over 50 years old because, by identifying and removing neoplastic lesions, the colonoscopist have the ability to interfere directly in the natural history of this form of cancer.