Submitted by Setor de Tratamento da Informa??o - BC/PUCRS (tede2@pucrs.br) on 2017-03-10T15:09:55Z No. of bitstreams: 1 TES_JULIANO_SARTORI_COMPLETO.pdf: 9083435 bytes, checksum: 6cadde5ff4cace9cc886d4131547c873 (MD5) / Made available in DSpace on 2017-03-10T15:09:55Z (GMT). No. of bitstreams: 1 TES_JULIANO_SARTORI_COMPLETO.pdf: 9083435 bytes, checksum: 6cadde5ff4cace9cc886d4131547c873 (MD5) Previous issue date: 2016-12-02 / Despite the advances resulting from the molecular characterization of breast cancer that allowed the use of more selective therapeutic targets, the disease still causes different clinical outcomes with high rates of recurrence and mortality. In this context of complexity and heterogeneity of breast cancer, are important the investigations of new biomolecular markers related to breast oncogenesis that may contribute to know the prognosis and improve the clinical management of patients. The sirtuin-1 (SIRT-1) is a histone deacetylase implicated in various epigenetic critical functions into cells, among these, the maintenance of genomic stability, proliferation and cell aging. The aim of this study was to investigate the grade of expression of the sirtuin- 1 (SIRT-1) in a cohort of 457 women with breast cancer and verify the effect, independent or in combination with other variables in the prognosis of these patients. It is a survival analysis study based on hospital medical records of women with breast cancer undergoing treatment in Erechim-RS from 2003 to 2013 and followed until 31 July 2015. The analysis of the grade of SIRT-1 expression was performed by immunohistochemistry in 123 patients (26.9%) of the total cohort. Overall survival specific disease (OS) was estimated by the Kaplan-Meier method and the risk of death from breast cancer by the method of Cox proportional hazards. The research was approved by the Research Ethics Committee of PUC-RS as reported number 465.362. The median age was 57.4 years and the median estimate of breast cancer survival was 79.6% at 5 years and 69.1% at 10 years, with median follow-up time of 61.9 months. Risk factors associated with worse prognosis were: age between 60 and 69 years (HR = 1.88; 95% CI 1.02 - 3.44; p = 0.042); older than 70 years (HR = 2.92; CI 95% 1.70 - 5.01; p = 0.000); tumor size greater than 2 cm (HR = 1.86; CI 95% 1.04 -3.36; p = 0.038); metastasis in 4 or more axillary lymph nodes (HR = 2.37; CI 95% 1.38 - 4.08; p = 0.002); located clinical staging (CS II, TNM) (HR = 3.39; CI 95% 1.35 - 8.51; p = 0.009); advanced clinical staging (CS III, TNM) (HR = 6.32; CI 95% 2.49-16.08; p = 0.000); high histologic grade (HR = 6.32; CI 95% 1.63 - 29.99; p = 0.008); triple negative molecular profile (HR = 2.33; CI 95% 1.19 - 4.58; p = 0.014) and radical surgery (HR = 2.10; CI 95% 1.31 - 3.36; p = 0.002). The positive expression of progesterone receptor (HR = 0.52, CI 95% 0.34 - 0.79; p = 0.002) was a better prognostic factor for patients. The grade of overexpression of SIRT-1, defined as nuclear expression of SIRT-1 greater than 80% was observed in 6.5% of cases. The SIRT-1 overexpression characterized a subgroup of women who had a worse prognosis with shorter survival and increased risk of death from breast cancer (HR = 2.66; CI 95% 1.03 - 6.86; p = 0.043). Multivariate regressive models (Cox) were constructed and the overexpression of SIRT-1 remained significant statistic demonstrating independent factor associated with worse prognostic in breast cancer. Therefore, the evaluation of the grade of expression of the SIRT-1, in the cohort of Erechim-RS, proved to be an independent prognostic marker for analysis of the risk of death from breast cancer. / Apesar dos avan?os decorrentes da caracteriza??o molecular do c?ncer de mama que permitiram o emprego de alvos terap?uticos mais seletivos, a doen?a ainda ocasiona diferentes desfechos cl?nicos, com elevadas taxas de recidiva e mortalidade. Neste contexto de complexidade e heterogeneidade do c?ncer de mama, s?o importantes as investiga??es de novos marcadores biomoleculares relacionados ? oncog?nese mam?ria que possam contribuir para conhecer o progn?stico e aprimorar o manejo cl?nico das pacientes. A Sirtu?na-1 (SIRT-1) ? uma histona desacetilase implicada em diversas fun??es epigen?ticas cr?ticas para as c?lulas, dentre estas, a manuten??o da estabilidade gen?mica, a prolifera??o e o envelhecimento celular. O objetivo deste estudo foi investigar o grau de express?o da Sirtu?na-1 (SIRT-1) em uma coorte de 457 mulheres portadoras de c?ncer de mama e verificar o seu efeito, independente ou em associa??o a outras vari?veis, no progn?stico destas pacientes. Trata-se de um estudo de an?lise de sobrevida com base em registros de mulheres portadoras de c?ncer de mama submetidas a tratamento em Erechim-RS no per?odo de 2003 a 2013 com seguimento at? 31 de julho de 2015. A an?lise do grau de express?o de SIRT-1 foi realizada por t?cnica de imuno-histoqu?mica em 123 pacientes (26,9%) do total da coorte. A sobrevida global doen?a espec?fica foi estimada pelo m?todo de Kaplan-Meier e, o risco de morte, por c?ncer de mama, pelo m?todo de riscos proporcionais de Cox. A pesquisa foi aprovada no Comit? de ?tica e Pesquisa da PUC-RS, sob n? 465.362. A idade mediana foi de 57,4 anos e a estimativa mediana de sobrevida por c?ncer de mama foi de 79,6% em 5 anos e 69,1% em 10 anos, com tempo mediano de seguimento de 61,9 meses. Os fatores de risco associados a pior progn?stico foram: faixa et?ria entre 60 e 69 anos (HR=1,88; IC95% 1,02-3,44; p=0,042); faixa et?ria maior que 70 anos (HR=2,92; IC95% 1,70-5,01; p=0,000); tamanho tumoral acima de 2 cm (HR=1,86; IC95% 1,04-3,36; p=0,038); presen?a de met?stase em 4 linfonodos axilares ou mais (HR=2,37; IC95% 1,38-4,08; p=0,002); estadiamento cl?nico localizado (EC II,TNM) (HR=3,39; IC95% 1,35-8,51; p=0,009); estadiamento cl?nico avan?ado (EC III,TNM) (HR=6,32; IC95% 2,49-16,08; p=0,000); grau histol?gico alto (HR=6,32; IC95% 1,63-29,99; p=0,008); perfil molecular triplo negativo (HR=2,33; IC95% 1,19-4,58; p=0,014) e a cirurgia radical (HR=2,10; IC95% 1,31-3,36; p=0,002). A express?o positiva do receptor de progesterona (HR=0,52; IC95% 0,34- 0,79; p=0,002) foi um fator de melhor progn?stico para as pacientes. O grau de hiperexpress?o da SIRT-1, definida como express?o nuclear da SIRT-1 maior que 80%, foi verificada em 6,5% dos casos. A hiperexpress?o da SIRT-1 caracterizou um subgrupo de mulheres que apresentaram pior progn?stico, com menor sobrevida e maior risco de morte por c?ncer de mama (HR=2,66; IC95% 1,03-6,86; p=0,043). Foram elaborados modelos regressivos multivariados (Cox) e a hiperexpress?o de SIRT-1 manteve signific?ncia estat?stica demonstrando fator independente associado a pior progn?stico no c?ncer de mama. Portanto, a avalia??o do grau de express?o da SIRT-1, na coorte de Erechim-RS, demonstrou ser um marcador independente para determinar o progn?stico no c?ncer de mama.

Submitted by Rodrigo Martins Cruz (rodrigo.cruz@ufvjm.edu.br) on 2015-01-23T16:14:44Z No. of bitstreams: 5 lopes.pdf: 4584389 bytes, checksum: 490508b2570ae9d7329524ffc42068ef (MD5) license_url: 52 bytes, checksum: 3d480ae6c91e310daba2020f8787d6f9 (MD5) license_text: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) license_rdf: 23898 bytes, checksum: e363e809996cf46ada20da1accfcd9c7 (MD5) license.txt: 2109 bytes, checksum: aa477231e840f304454a16eb85a9235f (MD5) / Approved for entry into archive by Rodrigo Martins Cruz (rodrigo.cruz@ufvjm.edu.br) on 2015-02-10T10:36:20Z (GMT) No. of bitstreams: 5 lopes.pdf: 4584389 bytes, checksum: 490508b2570ae9d7329524ffc42068ef (MD5) license_url: 52 bytes, checksum: 3d480ae6c91e310daba2020f8787d6f9 (MD5) license_text: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) license_rdf: 23898 bytes, checksum: e363e809996cf46ada20da1accfcd9c7 (MD5) license.txt: 2109 bytes, checksum: aa477231e840f304454a16eb85a9235f (MD5) / Made available in DSpace on 2015-02-10T10:36:20Z (GMT). No. of bitstreams: 5 lopes.pdf: 4584389 bytes, checksum: 490508b2570ae9d7329524ffc42068ef (MD5) license_url: 52 bytes, checksum: 3d480ae6c91e310daba2020f8787d6f9 (MD5) license_text: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) license_rdf: 23898 bytes, checksum: e363e809996cf46ada20da1accfcd9c7 (MD5) license.txt: 2109 bytes, checksum: aa477231e840f304454a16eb85a9235f (MD5) Previous issue date: 2013 / A presente disserta??o consiste em dois artigos cient?ficos, sendo um artigo original e outro de revis?o. Em um dos artigos, os autores fizeram uma revis?o da literatura sobre c?ncer e pr?polis, abordando a carcinog?nese experimental induzida quimicamente pelo 9,10-dimetil-1,2-benzantraceno (DMBA), a composi??o qu?mica da pr?polis e seus efeitos quimiopreventivos. O objetivo do artigo de pesquisa foi avaliar a rea??o tecidual da mucosa lingual de hamsters, submetida ? aplica??o di?ria e alternada de DMBA e extrato etan?lico de pr?polis (EEP) de uma apresenta??o comercial. Materiais e m?todos: 60 hamsters foram divididos em tr?s grupos, com dois per?odos experimentais, 13 e 20 semanas. A borda lateral da l?ngua foi submetida ? aplica??o t?pica, di?ria e alternada de DMBA 0,5 % e EEP 30 % (grupo EEP, n = 20), DMBA 0,5 % e extrato aquoso de pr?polis (EAP) (grupo EAP, n = 20), DMBA 0,5 % e soro fisiol?gico (grupo DMBA, n = 20). Realizou-se an?lise da ocorr?ncia dos tipos de altera??es cl?nicas e histol?gicas. Mensurou-se a ?rea e volume das altera??es cl?nicas, a ocorr?ncia das altera??es estruturais (AE) e citol?gicas (AC) do tecido epitelial escamoso com atipias e a ?rea histol?gica dos carcinomas de c?lulas escamosas (CCE). Para a an?lise estat?stica, aplicaram-se os testes ANOVA, qui-quadrado, Kruskal-Wallis e Mann-Whitney. Resultados: Para todas as vari?veis analisadas, n?o houve diferen?as significativas na compara??o entre os grupos nos dois tempos experimentais. Em 13 semanas ocorreu uma ?nica les?o de CCE no grupo EEP. Em 20 semanas, a maior ocorr?ncia de CCE tamb?m foi no grupo EEP. Conclus?o: o EEP, com teor alco?lico de 30 %, favoreceu a rea??o tecidual da inicia??o e da promo??o da carcinog?nese, por mecanismos ainda n?o elucidados. / ABSTRACT This dissertation consists of two papers, the first one is a review and the second is an original paper. In the first article, the authors reviewed the literature on cancer and propolis, addressing experimental carcinogenesis, chemically induced by 9,10-dimethyl-1,2-benzanthracene (DMBA), the chemical composition of propolis and its chemopreventive effects. The aim of the research paper was to evaluate the?tissue response?of tongue mucosa of hamsters, subjected to daily and alternating application of ethanolic extract of propolis (EEP) of a commercial presentation. Materials and methods: 60 hamsters were divided into three groups, and two experimental periods, 13 and 20 weeks. The lateral edge of the tongue underwent daily and alternate topical application of DMBA 0.5% and 30% EEP (EEP group, n = 20), DMBA and 0.5% aqueous extract of propolis (EAP) (EAP group; n = 20), and DMBA 0.5%?saline (DMBA?group, n =?20). The occurrence of types of clinical and histological changes was analysed. The area and volume of clinical changes, the occurrence of structural (AE) and cytological (CA) changes of squamous epithelial tissue with atypia and the histological area of squamous cell carcinoma (SCC) were measured. For statistical analysis, ANOVA, chi-square and Kruskal-Wallis and Mann-Whitney test were applied. Results: For all variables, there were no significant differences when comparing the groups in the two experimental periods. In 13 weeks, a single lesion of SCC in EEP group was observed. At 20 weeks, the highest occurrence of SCC was also in the group EEP. Conclusion: the EEP, with an alcohol content of 30% favored tissue reaction of initiation and promotion of carcinogenesis by mechanisms not yet elucidated.