Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2017-10-02T22:09:38Z No. of bitstreams: 1 AndrezaConceicaoVerasDeAguiarGuerra_DISSERT.pdf: 2321373 bytes, checksum: b59795f8b1b8b454588a319240dc5f59 (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2017-10-06T19:31:20Z (GMT) No. of bitstreams: 1 AndrezaConceicaoVerasDeAguiarGuerra_DISSERT.pdf: 2321373 bytes, checksum: b59795f8b1b8b454588a319240dc5f59 (MD5) / Made available in DSpace on 2017-10-06T19:31:20Z (GMT). No. of bitstreams: 1 AndrezaConceicaoVerasDeAguiarGuerra_DISSERT.pdf: 2321373 bytes, checksum: b59795f8b1b8b454588a319240dc5f59 (MD5) Previous issue date: 2017-06-23 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior (CAPES) / O c?ncer colorretal tem se destacado por ser um dos tumores mais freq?entes, com taxas de morbidade e mortalidade expressivos. Na descoberta de novas drogas, produtos derivados de plantas se destacam por ser uma fonte segura e capaz de originar compostos de alta efici?ncia. Bastante conhecida na medicina popular brasileira, Libidibia ferrea (Mart. ex Tul.) L.P. Queiroz var. ferrea, tem sido utilizada no tratamento de um amplo espectro de condi??es e na preven??o do c?ncer. Nesse estudo, extratos etan?licos dos frutos de L. ferrea (a 20T, 40T, 60T e 80T) foram avaliados por 24 h e 48 h pela capacidade de inibi??o da prolifera??o celular; indu??o de apoptose atrav?s da avalia??o de Bcl-2, caspase-3 e Apaf-1; atividade antioxidante e efeito sobre alvos importantes relacionados a prolifera??o celular (EGFR e AKT) na linhagem colorretal humana HT-29, por meio de metodologias que envolveram ensaios de citometria de fluxo, espectrofotometria e RT-qPCR. Os resultados demostram que os extratos tiveram atividade antiproliferativa comparado ao controle, indu??o de apoptose atrav?s da via intr?nseca e a??o de inibi??o tumoral in vitro com a media??o de alvos importantes na tumorig?nese. Al?m disso, possui efeito antioxidante e anti-peroxida??o lip?dica, bem como quimioprotetor nas c?lulas saud?veis. Portanto, derivados de L. ferrea possuem importantes efeitos antic?ncer podendo ser considerados candidatos moleculares promissores para o tratamento do c?ncer colorretal. / Colorectal cancer is noted for being one of the most frequent of tumors, with expressive morbidity and mortality rates. In new drug discovery, plants stand out as a source capable of yielding safe and high-efficiency products. Well known in Brazilian popular medicine, Libidibia ferrea (Mart. Ex Tul.) L.P. Queiroz var. ferrea (better known as "ironwood" or "juc?"), has been used to treat a wide spectrum of conditions and to prevent cancer. Using methodologies that involved flow cytometry, spectrophotometry and RT-qPCR assays, ethanolic extracts of the fruits of L. ferrea (20T, 40T, 60T and 80T) were evaluated at 24 h and 48 h for: their ability to inhibit cell proliferation; induce apoptosis through Bcl-2, caspase-3 and Apaf-1; their antioxidant activity and effects on important targets related to cell proliferation (EGFR and AKT) in the HT-29 human colorectal cancer lineage. The results revealed antiproliferative activity as compared to the controls, induction of apoptosis through the intrinsic pathway, and in vitro tumor inhibition activity under the mediation of important targets in tumorigenesis. In addition, L. ferrea revealed antioxidant, lipid peroxidation and chemoprotective effects in healthy cells. Thus, L. ferrea derivatives have important anticancer effects, and may be considered promising candidate for colorectal cancer therapy.

Submitted by PPG Medicina e Ci?ncias da Sa?de (medicina-pg@pucrs.br) on 2018-10-24T17:02:58Z No. of bitstreams: 1 JULIANA_LORENZONI_ALTHOFF.pdf: 23099056 bytes, checksum: 2ebbb4db3683a55ddc1d12778cf36c64 (MD5) / Approved for entry into archive by Sheila Dias (sheila.dias@pucrs.br) on 2018-10-25T14:52:43Z (GMT) No. of bitstreams: 1 JULIANA_LORENZONI_ALTHOFF.pdf: 23099056 bytes, checksum: 2ebbb4db3683a55ddc1d12778cf36c64 (MD5) / Made available in DSpace on 2018-10-25T15:03:03Z (GMT). No. of bitstreams: 1 JULIANA_LORENZONI_ALTHOFF.pdf: 23099056 bytes, checksum: 2ebbb4db3683a55ddc1d12778cf36c64 (MD5) Previous issue date: 2009-03-23 / Background: The colon-rectal cancer is the third most frequent neoplasia in the western world with the highest mortality rates. The progression of normal colon tissue to invasiveness neoplasia is follow by several processes called carcinogenesis. Afterwards it converges to the cellular migration and metastasis of the tissue. The metabolic ways of the E26 (Ets) transcription factors, identified in a great variety of species, contributes in this process, by activating or repressing the DNA transcription. Specially, the prostate-derived Ets factor (PDEF) which prognosis and cancer colon-rectal relation action is not completely elucidating at the moment. Methods: A retrospective cohort of patients with pathologic stage I ? III colon-rectal cancer, diagnosed and treated in the same institution between 2002 and 2008, was study. Histological and clinical features as well as clinical outcomes and survival were reviewed. The tissue microarrays (TMA), immunohistochemical analysis and image capture quantification were carried out in representative blocks of tumor with antibodies for the detection of the PDEF expression and Ki-67. The endpoints were to determine the prevalence of the PDEF protein expression and its correlation with these population?s prognostic factors. Results: The sample was constituted 46 patients and the median follow-up was 23,2 months. There was a trend towards loss of PDEF protein expression according to the patients? clinical stage. PDEF expression values were 30,3%, 25,8% and 14,7% in stages I, II and III, respectively. There was not a significant correlation with the lost of PDEF protein expression and the clinical and pathological characteristics along with the proportion of Ki-67 proliferative marker and the patient?s global survival. Conclusions: These results suggest that the PDEF protein, member of the Ets family, act as a repression gene of cancer colon-rectal carcinogenesis. The PDEF expression analysis can be an interesting prognostic marker and a therapeutic target. New studies with more patients and a long follow-up are necessary to validate these results. / Base te?rica: O c?ncer colorretal ? a terceira neoplasia mais freq?ente no mundo ocidental com taxas de mortalidade ainda consideras altas. A progress?o do tecido epitelial do c?lon normal at? o est?gio de neoplasia invasiva ? acompanhada de uma s?rie de processos celulares chamados carcinog?nese que, ao fim, convergem para o potencial de migra??o celular e metastatiza??o. As vias metab?licas da fam?lia dos genes Ets (E26 - sequ?ncia espec?fica de transcri??o), identificada em uma grande diversidade de esp?cies, contribuem neste processo, ativando ou reprimindo transcri??es de DNA. Em especial o fator derivado prost?tico (PDEF) cujo progn?stico e mecanismo de a??o relacionado ao c?ncer colorretal, at? o momento, n?o est? claramente elucidado. M?todos: Uma coorte retrospectiva de pacientes com carcinoma colorretal est?gios de I a III, diagnosticados e tratados na mesma institui??o de 2002 a 2008, foi estudada. As caracter?sticas histol?gicas e cl?nicas, bem como os dados de evolu??o e a sobrevida foram revisados. A an?lise de imunoistoqu?mica com m?todo de matriz de amostras teciduais (TMA) e a quantifica??o por captura de imagem foram realizadas em blocos representativos do tumor com anticorpos para detec??o da express?o da prote?na PDEF e Ki-67. Os objetivos eram detectar a preval?ncia da express?o da prote?na PDEF e sua correla??o com fatores progn?sticos nesta popula??o. Resultados: A amostra foi constitu?da de 46 pacientes e tempo de seguimento mediano de 23,2 meses. Houve tend?ncia a perda da prote?na PDEF conforme o estadiamento dos pacientes sendo a express?o de 30,3%, 25,8% e 14,7% nos est?gio I, II e III, respectivamente, P=0,416. N?o encontrou-se associa??o significativa entre os achados cl?nico-patol?gicos, a dosagem do marcador de prolifera??o celular Ki-67 e a sobrevida global dos pacientes com a perda da express?o da prote?na PDEF. Conclus?es: Os resultados sugerem que a prote?na PDEF, membro da fam?lia Ets, atue como gene repressor da carcinog?nese do c?ncer colorretal. A an?lise de sua express?o pode se tornar um interessante marcador progn?stico e alvo terap?utico. S?o necess?rios novos estudos com amostras maiores e tempo de seguimento mais longo a fim de validar estes achados.

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2017-03-20T21:49:24Z No. of bitstreams: 1 DiegoMarquesDaCostaSantos_DISSERT.pdf: 2551094 bytes, checksum: 6ba7eac7b523f238609d30d5347a6556 (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2017-03-23T18:43:14Z (GMT) No. of bitstreams: 1 DiegoMarquesDaCostaSantos_DISSERT.pdf: 2551094 bytes, checksum: 6ba7eac7b523f238609d30d5347a6556 (MD5) / Made available in DSpace on 2017-03-23T18:43:15Z (GMT). No. of bitstreams: 1 DiegoMarquesDaCostaSantos_DISSERT.pdf: 2551094 bytes, checksum: 6ba7eac7b523f238609d30d5347a6556 (MD5) Previous issue date: 2016-08-30 / O c?ncer colorretal (CCR) ? um tipo de c?ncer que acomete a regi?o do intestino grosso e reto; sendo o terceiro c?ncer mais comum em homens e o segundo em mulheres no mundo. A maior parte da susceptibilidade ao CCR ? proveniente de variantes gen?ticas m?ltiplas, cada uma com um efeito individual que, quando combinada, causa a diversidade de risco para o desenvolvimento desse c?ncer. Dentre os tipos de muta??es encontrados no genoma humano, as inser??es e dele??es (INDEL) s?o a segunda classe mais comum; e o entendimento deste tipo de muta??o possui um potencial de impactar na express?o, na estrutura e at? mesmo fun??o da prote?na. Entretanto, sabe-se relativamente pouco sobre o impacto das INDEL no risco de CCR, especialmente na popula??o miscigenada do Brasil. Dessa forma o objetivo deste trabalho ? realizar um estudo do tipo caso-controle para determinar a associa??o de 16 INDEL com a susceptibilidade ao CCR na popula??o do Rio Grande do Norte. Al?m disso, foi tamb?m avaliado a distribui??o relativa da ancestralidade entre o grupo caso e controle. Os polimorfismos e os marcadores utilizado para a distribui??o da ancestralidade foram genotipados utilizando ABI PRISM 3130 e o GeneMapper ID v3.2. A an?lise estat?stica foi realizada utilizando o R v 3.1. Em rela??o ? ancestralidade gen?mica, foi observada diferen?a significativa na distribui??o da contribui??o Africana entre os grupos. Em rela??o ? an?lise de associa??o entre o polimorfismo e o risco de desenvolver CCR, foi observado que o alelo D do polimorfismo estudado no gene IL4, e o alelo I do polimorfismo do TYMS foram associados com o aumento do risco de desenvolver CCR. No presente trabalho, tamb?m foi avaliado o risco que a combina??o genot?pica do TYMS (rs151264360) e do IL4 (rs79071878) aumenta consideravelmente o risco de ter CCR; e foi observado que se faz necess?rio a presen?a de pelo menos 3 alelos de risco para conferir risco de ter CCR. / Colorectal cancer (CRC) is a type of cancer that affects large intestine and rectum region, and this is the third most common cancer worldwide in men and the second in women. The genetic susceptibility to CRC comes from multiple genetic variants. Individually, these genetic variants have modest effect. However, theses variants, when combined, cause a wide range of risk. Among all mutations types found in the human genome, insertion-deletions (INDEL) are the second most common class, which has a potential impact on the expression, structure and protein function. However, there are a few studies about INDEL impact on CRC risk. Thus the aim of this study is to evaluate the association of 16 INDEL with CRC susceptibility in Rio Grande do Norte population. Furthermore, it was also evaluated the relative ancestry distribution between case and control groups. Polymorphism and marker used for ancestry distribution were genotyped using ABI PRISM 3130 and GeneMapper ID v 3.2. Statistical analysis was performed using the R v 3.1. Regarding the genetic ancestry, there was significant difference in the distribution of the African contribution between groups. Regarding the polymorphism association in CRC risk, it was observed that the D allele of IL4 and I allele of TYMS polymorphisms were associated with increased CRC risk. In this study, it was also evaluated the combined effect of IL4 and TYMS polymorphism in CRC risk, and it was observed that at least 3 allelic risks were necessary to confer CRC risk.

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2016-06-03T23:19:48Z No. of bitstreams: 1 GeorgeAlexandreLira_DISSERT.pdf: 12487121 bytes, checksum: e5befba62b31cf9c0849235dd847b32c (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2016-06-06T23:43:09Z (GMT) No. of bitstreams: 1 GeorgeAlexandreLira_DISSERT.pdf: 12487121 bytes, checksum: e5befba62b31cf9c0849235dd847b32c (MD5) / Made available in DSpace on 2016-06-06T23:43:09Z (GMT). No. of bitstreams: 1 GeorgeAlexandreLira_DISSERT.pdf: 12487121 bytes, checksum: e5befba62b31cf9c0849235dd847b32c (MD5) Previous issue date: 2015-08-31 / Excluindo-se os tumores de pele n?o-melanoma, o c?ncer colorretal ? o segundo mais comum no sudeste do Brasil; o terceiro na regi?o sul e na regi?o Centro-Oeste. J? no norte do Brasil, ? o quarto e, na regi?o Nordeste, o quinto. Avaliar vari?veis clinico-patol?gicos do c?ncer colorretal ? de fundamental import?ncia para se conhecer poss?veis desfechos na sobrevida dos pacientes portadores e pontuar caracter?sticas na progress?o tumoral como o perfil da invas?o tumoral e angiog?nese. O objetivo desse trabalho ? estudar as caracter?sticas cl?nico-patol?gicas dos pacientes portadores do c?ncer colorretal (CCR) na Liga Norte Riograndense contra o c?ncer em Natal-RN/BR, analisando as vari?veis cl?nicas e patol?gicas como par?metros de progn?stico e determinando o n?vel de express?o de prote?nas, tais sejam: E-caderina (E-cad), Beta-catenina (?-cat), Galectina-3 (Gal-3), Metaloproteinases de matriz (MMP) 2 e 9 e o Fator alfa de crescimento v?sculo-endotelial (VEGF-?) nos tecidos tumorais. Foi realizado um estudo retrospectivo dos casos de c?ncer colorretal da Liga Norte-Riograndense contra o C?ncer no per?odo de 1995 a 2005 em Natal-RN / Brasil. As vari?veis cl?nico-patol?gicas, tais como: idade, sexo, etnia, h?bitos de vida, hist?ria familiar, local do tumor prim?rio, grau de diferencia??o, estadiamento TNM, Dukes? modificado, tratamento e sobrevida foram analisadas. Os dados cl?nico-patol?gicos foram coletados dos prontu?rios m?dicos atrav?s de um formul?rio espec?fico e os dados foram armazenados em uma planilha do Excel. Um total de 534 pacientes foi selecionado do arquivo do setor da patologia dessa institui??o, mas 176 pacientes foram exclu?dos. 358 pacientes foram inclu?dos para an?lise epidemiol?gica e suas correla??es cl?nico-patol?gicas foram realizadas. 180 pacientes foram selecionados para estudos histol?gicos e imunohistoqu?micos. Prote?nas participantes da progress?o tumoral E-caderina, Beta-catenina, Galectina-3, Metaloproteinases 2 e 9 e o Fator alfa de crescimento endotelial vascular foram analisadas. Os blocos de parafina dessas amostras foram tratados pela t?cnica de Tissue Microarray e suas l?minas submetidas a imunohistoqu?mica para avaliar a intensidade de marca??o dessas prote?nas nos tecidos tumorais. Os resultados dessa an?lise foram correlacionados ?s vari?veis cl?nico-patol?gicas dos pacientes. An?lise estat?stica pelo Teste de qui-quadro de Pearson e an?lise de sobrevida pela Curva de Kaplan-Meier foram utilizados. Valores de p<0,05 foram considerados estatisticamente significativos. A m?dia de idade da nossa amostra foi de 58,8 anos e 51,7% foram do sexo feminino. O consumo de ?lcool aumentou em 1,71 vezes o risco de morte pelo CCR (p=0,034). J? o tabaco aumentou 2,7 vezes a chance de desenvolver tumores de alto est?gio TNM (p=0,001). Os pacientes com hist?rico familiar de c?ncer teve 3,833 vezes a chance de desenvolver o CCR (p=0,002). A express?o da MMP-2 mostrou uma associa??o significativa com os tumores de alto est?gio TNM (p<0,046) e mortalidade (p=0,041). A express?o do ? VEGF teve correla??o estatisticamente significante com o alto est?gio TNM (p<0,009), grau de indiferencia??o celular (p<0,025) e mortalidade (p<0,035). As express?es da E-caderina e Beta-catetina mostraram associa??o do tumor com alto est?gio TNM (p=0,0001) e Dukes? modificado (p=0,05), les?o em reto (p=0,03 e p=0,007, respectivamente), tabaco (p=0,05) e indiferencia??o (p=0,001). A express?o das Gal-3 apresentou relev?ncia estat?stica com pacientes de alto est?gio TNM (p=0,01), fumantes (p=0,01), etilista (p=0,03), indiferencia??o (p=0,0001) e mortalidade (p=0,0001). Frente aos resultados, pode-se perceber que o estilo de vida e hist?rico familiar teve correla??o no progn?stico do CCR, assim como a express?o de MMP-2, MMP-9, VEGF alfa, E-caderina, Beta-catenina e Galectina-3 foram importantes marcadores de progn?stico na progress?o tumoral no c?ncer colorretal. / Except the non-melanoma skin tumors, colorectal cancer is the second most common in the Southeastern Region of Brazil, the third most common in the Southern and Central Regions. It is also the forth most common in the Northern Region and it is the fifth one in the Northeastern. To assess pathological and clinical variables of colorectal Cancer is crucial to know the possible conclusions for the survival of patients and point out the characteristics in the progress of tumor, such as the profile of tumor invasion and its angiogenesis. This work focuses on analyzing clinically and pathologically some settings in colorectal cancer patients (CRC) in the city of Natal and its countryside through those variables as parameters of prognosis and determine the level of protein expression, for instance: E-cadherin (E-cad), beta- -catenin (?-cat), galectin-3 (gal-3), matrix metalloproteinases (MMP) 2 and 9 and vascular-endothelial growth factor alpha (? VEGF) in the tumor tissues. A retrospective study was done in colorectal cancer cases in the regions of Rio Grande do Norte state from 1995 to 2005, specifically in Natal city/RN/Brazil. The pathological and clinical variables, such as: age, gender, ethnicity, lifestyle, family history, the location of the primary tumor, level of differentiation, TDM staging, modified Dukes?, treatment and survival were analyzed. The pathological and clinical data were collected from medical records through a specific form and were filed on Excel. A total of 534 patients were selected from the Pathology Department file in this institution, however, 176 patients were excluded. 358 patients were included for Epidemiological analysis and its clinical and pathological correlations were selected. 180 patients were also selected for histological and immunohistochemical studies. The tumor progression of these selected proteins mentioned before were analyzed. The Paraffin blocks of these samples were treated by Microarray Tissue technique and its blades subjected to immunohistochemistry to test the intensity of these proteins in tumor tissues. The results of this analysis were correlated with clinicopathologic variables of patients. Statistical analysis using the chi-frame Pearson test and analysis of midlife by Kaplan-Meier curve was also utilized. P values < 0.05 were considered statistically significant. The average age of our sample was 58.8 years and 51.7 % were female. Alcohol consumption has increased by 1.71 time the risk of death by CCR (p = 0.034) and tobacco consumption increased 2.7 times the chance of developing tumors of high TNM stage (p = 0.001). Cancer patients had a family history of 3,833 times the chance of developing the CCR (p = 0.002). The expression of MMP-2 showed a significant association with tumors of high TNM stage (p <0.046) and mortality (p = 0.041). The ? VEGF expression had statistically significant correlation with high TNM stage (p <0.009), degree of cell indifferentiation (p <0.025) and mortality (p <0.035). Expressions of E-cadherin and beta-catetina demonstrated tumor linked to high TNM stage (p = 0.0001) and Dukes? modified (p = 0.05), lesions in the rectum (p = 0.03 and p = 0.007, respectively), smoking (p = 0.05) and indifferentiation (p = 0.001). The expression of Gal-3 showed statistical significance with high TNM stage of patients (p = 0.01), smokers (p = 0.01), alcohol drinking (p = 0.03), indifferentiation (p = 0.0001) and mortality (p = 0.0001). Based on the results, therefore, we could realize that lifestyle and family history had correlation in the CCR prognosis, as well as MMP-2 expression, MMP-9, VEGF alpha, E-cadherin, Beta-catenin and Galectin-3 were important prognostic markers in tumor progression in colorectal cancer.