Thesis (M.Sc.)--Chinese University of Hong Kong, 1975. / Bibliography: l. 157-179.

published_or_final_version / Medicine / Master / Doctor of Medicine

published_or_final_version / abstract / Surgery / Master / Master of Philosophy

Made available in DSpace on 2016-09-27T13:40:04Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-05-27. Added 1 bitstream(s) on 2016-09-27T13:45:15Z : No. of bitstreams: 1 000869033_20170527.pdf: 824646 bytes, checksum: 00f5f8bbdd7abcbefcbd2d042d519568 (MD5) Bitstreams deleted on 2017-06-02T11:56:26Z: 000869033_20170527.pdf,. Added 1 bitstream(s) on 2017-06-02T11:57:14Z : No. of bitstreams: 1 000869033.pdf: 3301498 bytes, checksum: de14b09badf78ded8a950b747525f42b (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / O câncer de tireoide (CT) é a neoplasia mais comum do sistema endócrino. O carcinoma papilífero da tireoide (CPT) compreende 80-85% dos casos, seguido dos carcinomas foliculares (CFT), pouco diferenciados (CPDT) e anáplasicos (CAT). O diagnóstico dos CT, principalmente nos casos bem diferenciados, ainda é um desafio devido a semelhanças morfológicas compartilhadas por esses tumores e lesões benignas (LBT). O objetivo desse estudo foi avaliar o perfil de metilação do DNA para identificar marcadores epigenéticos envolvidos no desenvolvimento das lesões benignas e dos diferentes subtipos histológicos de carcinomas. Além disso, buscou-se identificar marcadores prognósticos nos CT. Foram incluídos nesse estudo 17 lesões benignas da tireoide (8 adenomas, 6 bócios tireoideanos e 3 tireoidites), 60 CPT, 8 CFT, 2 carcinomas de células de Hurthle (CCH), 1 CPDT e 3 CAT, além de 50 tecidos não neoplásicos (TN) obtidos dos pacientes que tiveram CPT. As análises de metilação diferencial foram realizadas utilizando a plataforma microarray Infinium® Human Methylation450 BeadChip (Illumina). Na primeira etapa do estudo, os resultados obtidos de sondas diferencialmente metiladas foram utilizados na construção de um algoritmo útil como classificador diagnóstico. Na segunda etapa, o perfil de metilação do DNA das lesões benignas e dos diferentes subtipos tumorais foi comparado aos dados de tecidos não neoplásicos. Somente sondas significativamente alteradas no presente estudo e aquelas confirmadas no GEO (Gene Expression Omnibus) foram selecionadas para a construção de algoritmos. Foram delineados três algoritmos diagnósticos baseados na metilação diferencial de nove sondas selecionadas a partir de área abaixo da curva de 0,75 para o classificador de LBT e 0,90 para os classificadores CFT e CPT além de análise multivariada. Foram também aplicados métodos lineares de classificação. A aplicação do algoritmo... / Thyroid cancer (TC) is the most prevalent type of endocrine cancer. Papillary thyroid carcinoma (PTC) comprises 80-85% of the diagnosed thyroid cancers, followed by follicular (FTC), poorly differentiated (PDTC) and anaplastic carcinomas (ATC). Diagnosis of thyroid carcinomas, especially of well-differentiated carcinomas is a challenge due to morphological similarities between these tumors and benign lesions. The aim of this study was to evaluate the methylation profile to identify diagnostic markers involved in benign lesions and in different histological subtypes of carcinomas. Moreover, a search for reliable molecular prognostic markers was also performed in TC. The study included 17 benign lesions (8 adenomas, 6 goiters and 3 thyroiditis), 60 PTCs, 8 FTCs, 2 Hürthle cell carcinomas (HCC), 1 PDTC and 3 ATC, as well as 50 non-neoplastic tissues (NT) obtained from patients who had PTC. Differential methylation analyzes were performed using the Infinium® Human Methylation450 BeadChip microarray (Illumina). In the first stage of the study, the results of differentially methylated probes were used in the development of diagnostic classifier algorithm. In second step, the methylation profile of benign lesions and tumor subtypes was compared to data from non-neoplastic tissues. Only probes significantly altered in the current study and those confirmed by GEO data (Gene Expression Omnibus) were selected for the development of the algorithms. Three diagnostic algorithms were developed based on differential methylation of nine probes selected from area under the curve of 0.75 for BTL classifier and 0.90 for FTC and PTC classifiers and multivariate analysis. It was also applied linear classification methods. Application of the algorithm diagnosis allowed the correct classification of non-neoplastic tissues, benign and malignant lesions (sensitivity: 91.9% and specificity: 76.5%). The same strategy was performed using the GEO database...

Orientador: Silvia Regina Rogatto / Banca: Patricia Pintor dos Reis / Banca: Miriam Galvonas Jasiulionis / Banca: Janete Maria Cerutti / Banca: Sandra A. Drigo Linde / Resumo: O câncer de tireoide (CT) é a neoplasia mais comum do sistema endócrino. O carcinoma papilífero da tireoide (CPT) compreende 80-85% dos casos, seguido dos carcinomas foliculares (CFT), pouco diferenciados (CPDT) e anáplasicos (CAT). O diagnóstico dos CT, principalmente nos casos bem diferenciados, ainda é um desafio devido a semelhanças morfológicas compartilhadas por esses tumores e lesões benignas (LBT). O objetivo desse estudo foi avaliar o perfil de metilação do DNA para identificar marcadores epigenéticos envolvidos no desenvolvimento das lesões benignas e dos diferentes subtipos histológicos de carcinomas. Além disso, buscou-se identificar marcadores prognósticos nos CT. Foram incluídos nesse estudo 17 lesões benignas da tireoide (8 adenomas, 6 bócios tireoideanos e 3 tireoidites), 60 CPT, 8 CFT, 2 carcinomas de células de Hurthle (CCH), 1 CPDT e 3 CAT, além de 50 tecidos não neoplásicos (TN) obtidos dos pacientes que tiveram CPT. As análises de metilação diferencial foram realizadas utilizando a plataforma microarray Infinium® Human Methylation450 BeadChip (Illumina). Na primeira etapa do estudo, os resultados obtidos de sondas diferencialmente metiladas foram utilizados na construção de um algoritmo útil como classificador diagnóstico. Na segunda etapa, o perfil de metilação do DNA das lesões benignas e dos diferentes subtipos tumorais foi comparado aos dados de tecidos não neoplásicos. Somente sondas significativamente alteradas no presente estudo e aquelas confirmadas no GEO (Gene Expression Omnibus) foram selecionadas para a construção de algoritmos. Foram delineados três algoritmos diagnósticos baseados na metilação diferencial de nove sondas selecionadas a partir de área abaixo da curva de 0,75 para o classificador de LBT e 0,90 para os classificadores CFT e CPT além de análise multivariada. Foram também aplicados métodos lineares de classificação. A aplicação do algoritmo... / Abstract: Thyroid cancer (TC) is the most prevalent type of endocrine cancer. Papillary thyroid carcinoma (PTC) comprises 80-85% of the diagnosed thyroid cancers, followed by follicular (FTC), poorly differentiated (PDTC) and anaplastic carcinomas (ATC). Diagnosis of thyroid carcinomas, especially of well-differentiated carcinomas is a challenge due to morphological similarities between these tumors and benign lesions. The aim of this study was to evaluate the methylation profile to identify diagnostic markers involved in benign lesions and in different histological subtypes of carcinomas. Moreover, a search for reliable molecular prognostic markers was also performed in TC. The study included 17 benign lesions (8 adenomas, 6 goiters and 3 thyroiditis), 60 PTCs, 8 FTCs, 2 Hürthle cell carcinomas (HCC), 1 PDTC and 3 ATC, as well as 50 non-neoplastic tissues (NT) obtained from patients who had PTC. Differential methylation analyzes were performed using the Infinium® Human Methylation450 BeadChip microarray (Illumina). In the first stage of the study, the results of differentially methylated probes were used in the development of diagnostic classifier algorithm. In second step, the methylation profile of benign lesions and tumor subtypes was compared to data from non-neoplastic tissues. Only probes significantly altered in the current study and those confirmed by GEO data (Gene Expression Omnibus) were selected for the development of the algorithms. Three diagnostic algorithms were developed based on differential methylation of nine probes selected from area under the curve of 0.75 for BTL classifier and 0.90 for FTC and PTC classifiers and multivariate analysis. It was also applied linear classification methods. Application of the algorithm diagnosis allowed the correct classification of non-neoplastic tissues, benign and malignant lesions (sensitivity: 91.9% and specificity: 76.5%). The same strategy was performed using the GEO database... / Doutor

published_or_final_version / Medicine / Master / Doctor of Medicine

Thesis (M.Sc.)--University of Alberta, 2010. / A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Master of Science in Environmental Health Sciences, School of Public Health. Title from pdf file main screen (viewed on April 27, 2010). Includes bibliographical references.

Made available in DSpace on 2014-06-11T19:23:07Z (GMT). No. of bitstreams: 0 Previous issue date: 2013-02-22Bitstream added on 2014-06-13T20:29:56Z : No. of bitstreams: 1 carvalho_ma_me_botfm.pdf: 295836 bytes, checksum: a1b7b838d81f747f5c015856484d4256 (MD5) / Este estudo teve como objetivo avaliar o comportamento do clareamento global do Iodo-131, em pacientes que fazem radioiodoterapia para o tratamento do Câncer Diferenciado da Tireoide. Nós tivemos a intenção de promover uma ferramenta de organização dos leitos disponíveis para restrição durante o tratamento, e avaliar o resultado da dose efetiva através de um programa computacional da estimativa de dose interna - OLINDA/EXM. O estudo foi realizado no Departamento de Medicina Nuclear do Hospital de Câncer de Barretos, no período de agosto de 2011 a janeiro de 2012. A população do estudo foi constituída por 72 sujeitos, dentre eles 60 do sexo feminino e 12 do sexo masculino. As atividades administradas foram: n=16, 3,70GBq; n=35, 5,55GBq; n=18, 7,40GBq e n=3; ≥9,25GBq. Foram realizadas 3 monitorações diárias da taxa de dose externa a uma distância de 3 metros do paciente, durante todo o período de restrição. Após cada monitoração foi realizado o cálculo de fração de atividade administrada e uma hora após a administração, sem excreção do paciente, foram realizados os cálculos de constante de taxa de dose no ar (6,15 ± 0,65) nSvMBq-1 h-1 a 3 metros e de taxa de dose para a liberação da fonte (6,83 ± 0,72) μSv h-1. Após a alta hospitalar de cada paciente foi realizado o cálculo do tempo de meia vida efetiva global do Iodo-131 (13,12 ± 4,09) h, assim como simulações das estimativas de dose efetiva (509,39 ± 255,05) mSv e equivalente de dose para medula óssea (34,27 ± 19,18) mSv. A partir das variáveis atividade administrada, massa corpórea e idade foi construído um nomograma para dimensionar a ocupação dos leitos destinados a restrição da fonte radioativa. Concluímos, portanto, que o nomograma proposto pode melhorar o gerenciamento dos leitos destinados a radioiodoterapia, agrupando pacientes pelas... / This study aimed to evaluate the behavior of the global clearance of the Iodine-131 in patients submitted to treatment for differentiated thyroid cancer. We had the intention to promote an organizing tool for restriction of available beds during treatment and evaluate the results of effective dose using a computer program to estimate internal dose known as OLINDA/EXM. The study was conducted in the Department of Nuclear Medicine at Hospital de Câncer de Barretos, from August 2011 to January 2012. The population consisted of 72 subjects, including 60 females and 12 males. The doses administered were as follow: n=16, 3,7GBq; n=35, 5,55GBq; n=18, 7,4GBq and n=3, ≥9,25GBq. We performed three monitoring daily assessments at a distance of 3 meters from the patient throughout the period of restriction. Immediately after iodine-131 administration, and an hour after, it was calculated the fraction of administered activity without excretion of the patient; the calculations were performed for constant dose rate in the air (6.15 ± 0.65) nSvMBq-1 h-1 to 3 meters and dose rate for the release of the source (6.83 ± 0.72) μSv h-1. After hospital discharge of each patient it was calculated the global effective half-life of iodine-131(13.12 ± 4.09) h, as well as simulations of estimated effective doses (509.39 ± 255.05) mSv and dose equivalent to bone marrow (34.27 ± 19.18) mSv. From the variables administered activity, body mass and age, a nomogram was constructed to scale occupation of hospital beds for the restriction of the radioactive source. We conclude, therefore, that the nomogram proposed can improve the management of beds intended for radioiodine therapy, grouping patients by characteristics of excretion of iodine-131 and not only by the administered dose. Monitoring the external dose rate at a distance... (Complete abstract click electronic access below)

Orientador: Euclides Timoteo da Rocha / Banca: Marco Antônio Rodrigues Fernandes / Banca: Maria Ines Calil Cury Guimarães / Resumo: Este estudo teve como objetivo avaliar o comportamento do clareamento global do Iodo-131, em pacientes que fazem radioiodoterapia para o tratamento do Câncer Diferenciado da Tireoide. Nós tivemos a intenção de promover uma ferramenta de organização dos leitos disponíveis para restrição durante o tratamento, e avaliar o resultado da dose efetiva através de um programa computacional da estimativa de dose interna - OLINDA/EXM. O estudo foi realizado no Departamento de Medicina Nuclear do Hospital de Câncer de Barretos, no período de agosto de 2011 a janeiro de 2012. A população do estudo foi constituída por 72 sujeitos, dentre eles 60 do sexo feminino e 12 do sexo masculino. As atividades administradas foram: n=16, 3,70GBq; n=35, 5,55GBq; n=18, 7,40GBq e n=3; ≥9,25GBq. Foram realizadas 3 monitorações diárias da taxa de dose externa a uma distância de 3 metros do paciente, durante todo o período de restrição. Após cada monitoração foi realizado o cálculo de fração de atividade administrada e uma hora após a administração, sem excreção do paciente, foram realizados os cálculos de constante de taxa de dose no ar (6,15 ± 0,65) nSvMBq-1 h-1 a 3 metros e de taxa de dose para a liberação da fonte (6,83 ± 0,72) μSv h-1. Após a alta hospitalar de cada paciente foi realizado o cálculo do tempo de meia vida efetiva global do Iodo-131 (13,12 ± 4,09) h, assim como simulações das estimativas de dose efetiva (509,39 ± 255,05) mSv e equivalente de dose para medula óssea (34,27 ± 19,18) mSv. A partir das variáveis atividade administrada, massa corpórea e idade foi construído um nomograma para dimensionar a ocupação dos leitos destinados a restrição da fonte radioativa. Concluímos, portanto, que o nomograma proposto pode melhorar o gerenciamento dos leitos destinados a radioiodoterapia, agrupando pacientes pelas... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: This study aimed to evaluate the behavior of the global clearance of the Iodine-131 in patients submitted to treatment for differentiated thyroid cancer. We had the intention to promote an organizing tool for restriction of available beds during treatment and evaluate the results of effective dose using a computer program to estimate internal dose known as OLINDA/EXM. The study was conducted in the Department of Nuclear Medicine at Hospital de Câncer de Barretos, from August 2011 to January 2012. The population consisted of 72 subjects, including 60 females and 12 males. The doses administered were as follow: n=16, 3,7GBq; n=35, 5,55GBq; n=18, 7,4GBq and n=3, ≥9,25GBq. We performed three monitoring daily assessments at a distance of 3 meters from the patient throughout the period of restriction. Immediately after iodine-131 administration, and an hour after, it was calculated the fraction of administered activity without excretion of the patient; the calculations were performed for constant dose rate in the air (6.15 ± 0.65) nSvMBq-1 h-1 to 3 meters and dose rate for the release of the source (6.83 ± 0.72) μSv h-1. After hospital discharge of each patient it was calculated the global effective half-life of iodine-131(13.12 ± 4.09) h, as well as simulations of estimated effective doses (509.39 ± 255.05) mSv and dose equivalent to bone marrow (34.27 ± 19.18) mSv. From the variables administered activity, body mass and age, a nomogram was constructed to scale occupation of hospital beds for the restriction of the radioactive source. We conclude, therefore, that the nomogram proposed can improve the management of beds intended for radioiodine therapy, grouping patients by characteristics of excretion of iodine-131 and not only by the administered dose. Monitoring the external dose rate at a distance... (Complete abstract click electronic access below) / Mestre

Abnormal thyroid cell proliferation causes human diseases, such as goiter, thyroid adenoma or carcinoma and primary hypothyroidism resulting from hypoplasia. Thyrotropin (TSH), mainly acting through cAMP and cAMP-dependent protein kinases (PKA), is considered the main regulator of thyrocyte proliferation and differentiation. The general aim of this thesis was to get new mechanistic insights in the regulatory action of the cAMP pathway on various functions of thyrocytes, including proliferation.<p><p>During the first part of this thesis work, we have collaborated to a study of the effects of the TSH/cAMP pathway on small G proteins of the Rho family and their impact on the actin cytoskeleton and thyroid cell function. This study, performed in canine thyrocytes, showed for the first time, that the TSH/cAMP/PKA pathway inactivates the three small G proteins RhoA, Rac1 and Cdc42 and the RhoA/ROCK/LIMK/cofilin pathway. Inactivation of the latter appeared both necessary and sufficient to mediate the action of TSH and PKA on the reorganization of actin microfilaments and its morphological impact. Moreover, this inactivation by PKA of Rho-mediated actin polymerization also played an important role in the cAMP-dependent expression of thyroid differentiation genes. On the other hand, a residual RhoA activity appeared to be required for mitogenesis. This dependence of DNA synthesis on RhoA activity was not mediated by ROCK-dependent events nor by the integrity of the actin cytoskeleton. Indeed, DNA synthesis induction was unexpectedly resistant to actin depolymerisation in canine thyrocytes, which explains how it could be compatible with the cAMP-dependent microfilament disruption. <p><p>This first study did not provide new insights on how the cAMP/PKA-dependent mitogenic stimulus can trigger cell cycle progression, which, in thyrocytes, depends on the phosphorylation of pRb by the cyclin D3-CDK4 complex. In the various in vitro thyroid models, the only convergent early signaling event found in response to TSH/cAMP, insulin and growth factors was the phosphorylation and activation of p70 S6K1 which largely depends on mTOR (mammalian Target Of Rapamycin). The main part of the work in this thesis has been devoted to investigation of the action of TSH/cAMP on the mTOR pathway. mTOR is a therapeutic target for a wide variety proliferative disorders and rapamycin derivates are now considered in anti-cancer treatments.<p><p>We have shown for the first time in PC Cl3 rat thyroid cells that TSH, through cAMP, activates mTORC1, leading to phosphorylation of S6K1 and 4E-BP1. mTORC1-dependent S6K1 phosphorylation in response to both insulin and cAMP required amino acids, whereas inhibition of AMPK and GSK3 enhanced insulin but not cAMP effects. Unlike insulin, TSH/cAMP did not activate PKB, nor induce TSC2 phosphorylation at Thr1462 and Tyr1571. However, like insulin, TSH/cAMP produced a stable increase in mTORC1 kinase activity associated with augmented 4E-BP1 binding to raptor. This could be caused in part by Thr246-phosphorylation of PRAS40, which was found as an in vitro substrate of PKA, but other regulatory events likely remain to be uncovered. Both in PC Cl3 cells and primary dog thyrocytes, rapamycin inhibited DNA synthesis and pRb phosphorylation induced by TSH and insulin. Rapamycin reduced cyclin D3 accumulation but not the abundance of cyclin D3-CDK4 complexes. However, rapamycin inhibited the activity of these complexes and the activating Thr172-phosphorylation of CDK4 stimulated by both TSH and insulin. We propose that mTORC1 activation by TSH, at least in part through PKA-dependent phosphorylation of PRAS40, crucially contributes to mediate cAMP-dependent mitogenesis by regulating CDK4 Thr172-phosphorylation. / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished