INTRODUÇÃO: Enquanto a análise de sobrevida tradicional estima inadequadamente o prognóstico futuro dada alguma sobrevida inicial, a sobrevida condicional ajusta a sobrevida futura pela já observada, permitindo a compreensão da distribuição temporal do impacto dos preditores. OBJETIVOS: Estimar e analisar as sobrevidas global e livre de doença até o décimo ano pós-operatório; identificar preditores independentes destes desfechos; estimar e analisar as sobrevidas condicionais global e livre de doença de cinco anos dada a sobrevida até o quinto ano pós-operatório; analisar o comportamento dos preditores dos desfechos ao longo do tempo. MÉTODOS: Estudo retrospectivo envolvendo 13 centros brasileiros. Dados clínicos, radiológicos e anatomopatológicos foram considerados. Utilizou-se o método de Kaplan-Meier com o teste log-rank para comparar fatores e a regressão de Cox obteve a razão de riscos. A sobrevida condicional foi calculada a partir das tábuas de sobrevida e a diferença padronizada reavaliou as variáveis consideradas significativas. RESULTADOS: 1157 pacientes foram incluídos. A sobrevida global de 1, 3, 5, 7 e 10 anos foi 78,6%, 72,3%, 66,0%, 61,3% e 59,4%, respectivamente. Foram preditoras de sobrevida global: idade [HR 1,04 (IC 95% 1,02-1,06), p 0.000], sexo feminino [HR 1,35 (IC 95% 1,02-1,79), p 0.038], recidiva pós-operatória do CHC [HR 1,35 (IC 95% 1,08-1,79), p 0.003], diâmetro do maior nódulo viável no explante [HR 1,01 (IC95% 1,01-1,02), p 0.006], invasão vascular não discriminada [HR 3,18 (IC95% 1,48-6,85), p 0.004], invasão micro [HR 1,65 (IC 95% 1,27-2,15), p 0.001] e macrovascular [HR 2,25 (IC 95% 1,30-3,89), p 0.000]. A sobrevida condicional global de 5 anos ao final do 1°, 3° e 5° anos foi 79,5%, 82,2% e 90,0%, respectivamente. As variáveis preditoras na análise univariada tiveram comportamento errático ao longo do tempo. A sobrevida atuarial livre de doença em 1, 3, 5, 7 e 10 anos foi 94,2%, 90,1%, 89,8%, 87,5% e 87,5%, respectivamente. Foram preditoras de sobrevida livre de doença: nível sérico de alfa-fetoproteína no diagnóstico [HR 1,0 (IC 95% 1,01-1,02), p 0.000], CHC dentro do critério de Milão no diagnóstico [HR 0,42 (IC 95% 0,22-0,80), p 0.008], explante dentro do critério de Milão [HR 0,34 (IC 95% 0,17-0,68), p 0.002], explante com neoplasia pouco diferenciada ou hepatocolangiocarcinoma [HR 3,04 (IC 95% 1,75-5,30), p 0.000], invasão vascular não discriminada [HR 15,72 (IC 95% 3,44-71,83), p 0.000], invasão micro [HR 3,40 (IC 95% 1,83-6,28), p 0.000] e macrovascular [HR 11,96 (IC 95% 5,20-27,47), p 0.000]. A sobrevida condicional livre de doença de 5 anos ao final do 1°, 3° e 5° anos foi 94,1%, 97,1% e 97,4%, respectivamente. Variáveis preditoras na análise univariada em geral tem maior impacto no primeiro ou segundo ano. CONCLUSÕES: Os resultados do transplante no Brasil foram comparáveis àqueles observados nos EUA e Europa. Considerando-se as perdas precoces, as curvas de sobrevida pelo método Kaplan-Meier foram pessimistas e a análise de sobrevida condicional fornece outra perspectiva para estes dados. O comportamento das variáveis determinantes de prognóstico não é uniforme ao longo do tempo / INTRODUCTION: Traditional survival analysis provides inadequate estimates of the future prognosis for patients with accrued survival. Conversely, conditional survival adjusts future survival by the already accrued survival. It provides insights into the temporal distribution of the effect of predictors. OBJECTIVES: To estimate and to analyse overall and disease free survival until the 10th post-operative year; to identify independent predictors of these outcomes; to estimate and to analyse 5-year overall and disease free conditional survival until the 5th post-operative year; to analyse the behaviour of the predictors of outcomes during follow-up. METHODS: Retrospective cohort from 13 Brazilian transplantation centers. Clinical, radiological, and anatomopathological data were considered. The Kaplan-Meier method with the longrank test for the comparison of factors was applied and the Cox proportional hazards model provided the hazard ratios. Conditional survival was calculated through life tables, while differences between significative variables were reassessed by the standardized difference. RESULTS: 1157 patients were included. Overall survival in 1, 3, 5, 7 and 10 years was 78.6%, 72.3%, 66.0%, 61.3%, and 59.4%, respectively. 350 (30.3%) deaths were observed, 240 (68.6%) in the 1st year. Overall survival was independently predicted by age [HR 1.04 (95% CI 1.02-1.06), p 0.000], female sex [HR 1.35 (95% CI 1.02-1.79), p 0.038], post-operative HCC recurrence [HR 1.35 (95% CI 1.08-1.79), p 0.003], diameter of the largest viable nodule on the explant [HR 1.01 (95% CI 1.01-1.02), p 0.006], non-discriminated vascular invasion [HR 3.18 (95% CI 1.48-6.85), p 0.004], micro [HR 1.65 (95% CI 1.27-2.15), p 0.001] and macrovascular invasion [HR 2.25 (95% CI 1.30-3.89), p 0.000]. 5-year overall conditional survival at the end of the 1st, 3rd and 5th post-operative years was 79.5%, 82.2%, and 90.0%, respectively. Predictors of overall survival identified on univariate analysis presented an erratic behaviour over time. Disease free survival in 1, 3, 5, 7 and 10 years was 94.2%, 90.1%, 89.8%, 87.5%, and 87.5%, respectively. 97 (8.4%) reccurrences occurred. Disease free survival was independently predicted by serum alpha-fetoprotein upon diagnosis [HR 1.0 (95% CI 1.01-1.02), p 0.000], HCC within the Milan criteria upon diagnosis [HR 0.42 (95% CI 0.22-0.80), p 0.008], explant within the Milan criteria [HR 0.34 (95% CI 0.17-0.68), p 0.002], undifferentiated tumor or hepatocholangiocarcinoma on the explant [HR 3.04 (95% CI 1.75-5.30), p 0.000], non-discriminated vascular invasion [HR 15.72 (95% CI 3.44-71.83), p 0.000], micro [HR 3.40 (95% CI 1.83-6.28), p 0.000], and macrovascular invasion [HR 11.96 (95% CI 5.20-27.47), p 0.000]. 5-year disease free conditional survival at the end of the 1st, 3rd and 5th post-operative years was 94.1%, 97.1%, and 97.4%, respectively. Predictors of recurrence on the univariate analysis usually presented with greater impact during the 1st or 2nd post-operative year. CONCLUSIONS: Outcomes of liver transplantation in Brazil were comparable to those from the US and Europe. Survival estimates through the Kaplan-Meier method were pessimistic due to greater early losses. Conditional survival offers a different perspective for the same data. The behaviour of predictive values varies over time

Leung, Jackie. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 117-131). / Abstract also in Chinese. / Abstract --- p.i / 論文摘要 --- p.iii / Acknowledgement --- p.iv / List of publications --- p.vi / List of Tables --- p.vi / List of Figures --- p.vi / Table of Contents --- p.ix / Chapter Chapter 1: --- Introduction --- p.1 / Chapter 1.1. --- Liver cancer --- p.1 / Chapter 1.1.1. --- Hepatocellular Carcinoma (HCC) --- p.2 / Chapter 1.2. --- Lung Cancer --- p.5 / Chapter 1.3. --- Pteris semipinnata L --- p.8 / Chapter 1.4. --- Extract of PsL: 5F --- p.10 / Chapter 1.5. --- Animal models in chemotherapy researches --- p.13 / Chapter 1.5.1. --- Model of HCC --- p.13 / Chapter 1.5.2. --- Model of lung cancer --- p.15 / Chapter 1.6. --- Apoptosis: Significance of programmed cell death --- p.17 / Chapter 1.6.1. --- The extrinsic pathway --- p.18 / Chapter 1.6.2. --- The intrinsic pathway --- p.19 / Chapter 1.7. --- Apoptotic molecules related to this study --- p.22 / Chapter 1.7.1. --- Bcl-2 family --- p.22 / Chapter 1.7.1.1. --- Bax --- p.22 / Chapter 1.7.1.2. --- Bcl-2 --- p.23 / Chapter 1.7.2. --- Nuclear factor kappa B --- p.25 / Chapter 1.7.3. --- Inducible nitric oxide synthase --- p.27 / Chapter 1.8. --- Side-effects of chemotherapy --- p.29 / Chapter 1.8.1. --- Chemotherapy and liver dysfunction --- p.30 / Chapter 1.8.2. --- Nephrotoxicity of chemotherapeutic agents --- p.31 / Chapter 1.9. --- Aim of study --- p.33 / Chapter Chapter 2: --- Materials and Methodology --- p.34 / Chapter 2.1. --- Animals --- p.34 / Chapter 2.1.1. --- HCC model --- p.34 / Chapter 2.1.2. --- Lung cancer model --- p.35 / Chapter 2.2. --- Tumors induction --- p.36 / Chapter 2.2.1. --- HCC induction in C3H/HeJ mice --- p.36 / Chapter 2.2.2. --- Lung cancer induction in A/J mice --- p.37 / Chapter 2.3. --- 5F preparation --- p.38 / Chapter 2.4. --- 5F treatment --- p.39 / Chapter 2.5. --- Harvest of samples and tissues --- p.41 / Chapter 2.6. --- Tumor assessment --- p.43 / Chapter 2.7. --- Investigation of apoptosis and cell proliferation --- p.44 / Chapter 2.8. --- Immunohistochemistry --- p.47 / Chapter 2.9. --- Biochemical test --- p.51 / Chapter 2.9.1. --- Liver Function Tests (LFT) --- p.52 / Chapter 2.9.1.1. --- Aspartate aminotransferase (AST) & Alanine aminotransferase (ALT) --- p.52 / Chapter 2.9.2. --- Renal Function Test (RFT) --- p.53 / Chapter 2.9.2.1. --- Serum creatinine level (CRE) --- p.53 / Chapter 2.9.2.2. --- Blood Urea Nitrogen index (BUN) --- p.54 / Chapter 2.10. --- Statistical analysis --- p.55 / Chapter Chapter 3: --- Results --- p.56 / Chapter 3.1. --- Anti-tumor effect of 5F is dose- dependent --- p.56 / Chapter 3.2. --- 5F reduces cell proliferation and induces apoptosis in-vivo --- p.60 / Chapter 3.3. --- Effects of 5F on apoptotic signaling molecules --- p.68 / Chapter 3.3.1. --- 5F up-regulates pro-apoptotic Bax and Bak --- p.68 / Chapter 3.3.2. --- 5F down-regulates anti-apoptotic NF-kappa B and Bcl-2 --- p.76 / Chapter 3.3.3. --- 5F up-regulated iNOS in HCC but not in lung cancer --- p.88 / Chapter 3.3.4. --- Regulation on Erk1/2 was associated with treatment of 5F --- p.93 / Chapter 3.4. --- Side-effect studies of 5F --- p.97 / Chapter Chapter 4: --- Discussion --- p.105 / Chapter Chapter 5: --- Conclusion --- p.116 / Bibliography --- p.117

Chau, Kin Fan. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 106-119). / Abstract also in Chinese. / Abstract --- p.II / 摘要 --- p.VI / Acknowledgements --- p.IX / List of figures --- p.X / List of Abbreviations --- p.XII / Table of Contents --- p.XV / Chapter Chapter 1: --- Introduction / Chapter 1.1 --- Incidence and etiology of hepatocellular carcinoma (HCC) --- p.1 / Chapter 1.2 --- Structure of Hepatitis B Virus (HBV) --- p.2 / Chapter 1.3 --- Hepatitis B X protein (HBx) and HCC --- p.5 / Chapter 1.4 --- HBx and Apoptosis --- p.8 / Chapter 1.5 --- The role of Bcl-2 family in apoptosis and cell survival --- p.10 / Chapter 1.6 --- "Bid, the BH3-domain only protein" --- p.14 / Chapter 1.7 --- Dual Functions of Bid --- p.16 / Chapter 1.8 --- The relationship between Bid and HBx --- p.19 / Chapter 1.9 --- Hypoxia and HCC --- p.21 / Chapter 1.10 --- Hypoxia and HBx --- p.25 / Chapter 1.11 --- Hypoxia and Bid --- p.28 / Chapter 1.12 --- Aim of study --- p.29 / Chapter Chapter 2: --- Methods and materials / Chapter 2.1 --- Confirmation of the culture of the stable cell lines --- p.30 / Chapter 2.2 --- Doxorubicin treatment to the cell lines --- p.34 / Chapter 2.3 --- Culture of the cell lines under hypoxic conditions --- p.35 / Chapter 2.4 --- Protein sample preparations --- p.37 / Chapter 2.5 --- Determination of protein samples --- p.38 / Chapter 2.6 --- Sodium dodecyl sulfate 226}0ؤ polyacrylamide gel electrophoresis (SDS- PAGE) --- p.39 / Chapter 2.7 --- Transfer of protein to nitrocellulose membranes --- p.39 / Chapter 2.8 --- Western blot analysis of proteins --- p.41 / Chapter 2.8.1. --- Antibodies --- p.41 / Chapter 2.8.2. --- Determination of expression profiles of desired proteins by immunoblotting --- p.45 / Chapter 2.9 --- "Measurement of cell viability by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay" --- p.46 / Chapter 2.10 --- Determination of cell proliferation by BrdU proliferation assay --- p.47 / Chapter 2.11 --- Detection of apoptosis of the cell lines by TUNEL (Terminal deoxynucleotidyl transferase mediated dUTP Nick End Labeling) --- p.50 / Chapter 2.12 --- Determination of the involvement of p38 MAPK in the generation of truncated Bid by p38 MAPK inhibitor SB203580 --- p.52 / Chapter Chapter 3: --- Results / Chapter 3.1 --- Confirmation of plasmids and the stable cell lines --- p.53 / Chapter 3.2 --- Morphology and the basic parameters of the cells with full-length HBx or mutant HBx --- p.53 / Chapter 3.3 --- Cell viability under doxorubicin treatment with or without hypoxia --- p.59 / Chapter 3.4 --- Determination of cell proliferation under stress --- p.70 / Chapter 3.5 --- Expression profiles of various proteins in the stable cell lines under doxorubicin treatment with or without hypoxia --- p.74 / Chapter 3.5.1. --- Verification of hypoxia --- p.74 / Chapter 3.5.2. --- Pro-apoptotic proteins --- p.74 / Chapter 3.5.3. --- Anti-apoptotic proteins --- p.74 / Chapter 3.6 --- Determination of apoptosis of various cell lines under stress --- p.82 / Chapter 3.7 --- "p38 MAPK, but not Akt, was activated by doxorubicin" --- p.87 / Chapter 3.8 --- The p38 MAPK inhibitor SB203580 could attenuate the cleavage of Bid --- p.89 / Chapter Chapter 4: --- Discussion --- p.92 / Chapter Chapter 5: --- Conclusion and future prospective --- p.103 / Chapter Chapter 6: --- References --- p.106

O aumento na incidência do carcinoma hepatocelular (CHC) tem sido atribuído ao aumento da obesidade, diabetes e doença hepática gordurosa não alcoólica. (DHGNA), estando ainda por ser melhor esclarecidos vários aspectos histopatológicos e imuno-histoquímicos. O objetivo deste estudo é avaliar aspectos clínicos e patológicos de pacientes com CHC secundário a DHGNA, assim como relacionar a marcadores imuno-histoquímicos de classe proliferativa. Avaliamos 35 espécimes de CHC de 21 pacientes diagnosticados com DHGNA submetidos a ressecção hepática (12 pacientes) ou a transplante hepático (8 pacientes) ou ambos (1 paciente), de 2005 a 2015. Dados demográficos, clínicos e bioquímicos foram relacionados a características histológicas e reatividade imuno-histoquímica para K19, marcando características de células progenitoras e Ki-67, marcando as células em ciclo celular. Um total de 35 nódulos foram detectados em 21 pacientes. A cirrose estava presente em 12 casos (7 F4A x 4F4B x 1F4C de acordo com estadiamento de Laennec) e 9 pacientes não apresentavam cirrose (estadiamento DHGNA: F2: 6pts, F3 = 3pts). A idade variou de 50 a 77 anos e 16 pacientes eram do sexo masculino (76%). Dezesseis pacientes (76%) apresentavam diabetes mellitus, 17 pacientes (81%) apresentavam hipertensão arterial e 19 pacientes (90%) tinham IMC superior a 25 kg / m2. O CHC ocorreu em 8 pacientes CHILD A, 4 CHILD B e em 9 pacientes sem cirrose. O nível de alfa-fetoproteína foi normal em 13 (62%) pacientes. Dentre os critérios histológicos, 25 (70%) nódulos foram diagnosticados como \"CHC esteatohepatítico\". Embora 63% tenham sido pouco diferenciados (G.3/G.4) de acordo com Edmondson & Steiner (1954), apenas 21% apresentaram níveis elevados de Ki-67 ( > 10%). No caso da K19, também 21% dos pacientes apresentaram expressão positiva ( > 5%), e foi associado a maior inflamação intratumoral (G 2/3). Curiosamente, 75% dos pacientes com alta expressão de Ki-67 ( > 10%) não eram cirróticos. Em conclusão: 1. Nesta casuística cirúrgica, o CHC relacionado com DHGNA foi encontrado em não cirróticos em 42% dos casos, com nível normal de alfafetoproteína em 62%. 2. Os marcadores histológicos de \"CHC esteatohepatítico\" estiveram altamente prevalentes. 3. A imunoexpressão positiva de K19 e Ki-67 ocorreu em apenas 21% dos pacientes, o que pode sugerir que o CHC na síndrome metabólica pode ser preferencialmente \"um subtipo inflamatório e não proliferativo de CHC\" / The increase incidence of hepatocellular carcinoma (HCC) has been attributed to the increase in obesity, diabetes and non-alcoholic fatty liver disease. (NAFLD), and several histopathological and immunohistochemical aspects are still to be better clarified. The aim of this study is to assess clinical and pathological aspects of patients with HCC secondary to NAFLD as well as to related to immunohistochemical markers of proliferative class. We evaluated 35 HCC specimens from 21 patients diagnosed with NAFLD undergoing liver resection (12 patients) or liver transplantation (8 patients) or both (1 patient) from 2005 to 2015. Demographic, clinical and biochemical data were related to histological features and immunohistochemical reactivity for K19, marking characteristics of progenitor cells and Ki-67, marking the cells in cell cycle. A total of 35 nodules were detected from 21 patients. Cirrhosis was present in 12 cases (7 F4A x 4F4B x 1F4C according to Laennec Staging) and 9 patients did not have cirrhosis (NAFLD staging: F2: 6pts, F3=3pts). Ages ranged from 50 to 77 years and 16 patients were male (76%). Sixteen patients (76%) had diabetes mellitus, 17 patients (81%) had arterial hypertension and 19 patients (90%) had BMI above 25kg/m2. HCC occurred in 8 patients Child A, 4 Child B and in 9 patients without cirrhosis. Alpha-fetoprotein level was normal in 13 (62%) patients. Among the histological criteria, 25 (70%) nodules were diagnosed as \"steatohepatitic HCC\". Although 63% were poorly differentiated (G.3/ G.4) according to Edmondson & Steiner (1954), only 21% presented high levels of Ki-67 ( > 10%). In the case of K19, 21% of patients presented positive expression (> 5%), and was associated with greater intratumoral inflammation (G 2/3). Interestingly, 75% of the patients with high Ki67 expression ( > 10%) were non-cirrhotic. In conclusion: 1. In this surgical series, HCC related to NAFLD was found in non-cirrhotic patients in 42% of cases, with a normal level of alpha-fetoprotein in 62%. 2. Histological markers of \"steatohepatitic HCC\" were highly prevalent. 3. Positive immunoexpression of K19 and Ki-67 occurred in only 21% of patients, which might suggest that HCC in metabolic syndrome might be preferentially \"an inflammatory, non-proliferative subtype of HCC\"

A cascade of metabolomic studies have been developed in the recent decade. The application of metabolomics in the clinical field has been shown to be promising since even subtle physiological changes can be revealed by a metabolomic study which determines variations in the metabolome.Personalized clinical care is currently proposed for almost all the diseases, however, it is still difficultto be executed for the scarce of clinical biomarkers. This thesis work concerns the applications of both ¹H NMR-based and MS-based metabolomics in the determination of potential serumbiomarkers which help to improve personalized diagnosis and prognosis. It is composed by twoprincipal parts. The first part of the work aims to find out metabolite biomarkers predicting themortality of septic shock before clinical intervention and first 12 hours after hospitalization using NMR-based and LC-MS-based metabolomic methods respectively. The goal of the second part of the work is to seek potential biomarkers predicting the recurrence of HCC before and after RFA treatment. Our findings not only show that both the two applied techniques were useful for the discovery of novel clinical biomarkers, but also show that the two techniques are complementary / De nombreuses études métabolomiques a été développée au cours de la dernière dizaine année.L'application de la métabolomique dans le traitement clinique s'est révélée prometteuse puisque même des faibles modifications physiologiques peuvent être révélées par une étude métabolomique. Des soins cliniques personnalisés sont actuellement proposés pour presque toutes les maladies, mais il est encore difficile de les réaliser à cause du manque de biomarqueurs cliniques. Ce travail de thèse a pour le but de la détermination de biomarqueurs cliniques par la spectroscopie RMN et par la spectrométrie de masse. Il est composé de deux parties : la première partie du travail vise à déterminer les biomarqueurs des métabolites prédisant la mortalité du choc septique avant l'intervention clinique et les 12 premières heures après l'hospitalisation en utilisant respectivement des méthodes métaboliques basées sur la RMN et la LC-MS. L'objectif de la deuxième partie du travail est de rechercher des biomarqueurs potentiels prédisant la récidive du CHC avant et après le traitement RFA. Nos résultats montrent non seulement que les deux techniques appliquées ont été utiles pour la découverte de nouveaux biomarqueurs cliniques, maismontrent également que les deux techniques sont complémentaires.

Abstrakt Bei Frauen wurde der Zusammenhang zwischen berufsbedingten Expositionen und dem primären Leberzellkarzinom (HCC) bisher nur sehr eingeschränkt diskutiert, das heißt, es gibt bisher kaum Forschungsergebnisse. Diese Arbeit zeigt die Ergebnisse einer internationalen Fall-Kontroll-Studie bei Frauen. Es wurden 317 HCC-Fälle und 1789 Kontrollen ohne diese Erkrankung untersucht. Grenzwertig signifikant erhöhte, adjustierte Risikoschätzer (Odds Ratio=OR)konnten für Beschäftigte in der Landwirtschaft (OR=2.50, 95% Konfidenzintervall: 1.28-4.88) und der chemischen Industrie (2.37 (1.04-5.41)) gefunden werden. Andere, nicht-signifikant erhöhte Werte fanden sich bei Frauen, die in der pharmazeutischen Industrie, in der Plastik- und PVC-Produktion, in der Schlachterei und in der Textilindustrie beschäftigt waren. Allerdings zeigten die jeweiligen Risikoschätzer nur eine geringe Konsistenz zwischen drei verschiedenen Analyseverfahren. Desweiteren zeigte keine der Analysen einen linearen Trend mit zunehmender Zeitdauer der Exposition. Die Anzahl der exponierten Fälle und Kontrollen waren aber in vielen der Berufsgruppen sehr klein, und damit auch die Studien-Power und die Präzision. Wir konnten keinen ernstzunehmenden und konsistenten Beleg für eine Beziehung zwischen HCC bei Frauen und berufsbedingten Expositionen aufzeigen. Nichtsdestotrotz, auch schwache Hinweise auf berufsbedingte Risiken rechtfertigen weitere sorgfältige Betrachtungen in zukünftigen Studien. / Abstract The association of occupational variables and hepatocellular cancer (HCC) is discussed with particular reference to women, as little research has been undertaken on their behalf. This paper reports the results of an international case-control study concerning women and involves 317 cases of HCC and 1789 controls without HCC. Working in the chemical industry and in farming was shown to have only a marginally significant risk associated with HCC: adjusted occupational risk (OR) and 95% confidence interval 2.37 (1.04-5.41) for the chemical industry and 2.50 (1.28-4.88) for farming. Other non-significantly elevated ORs were observed in the pharmaceutical, plastics, PVC-producing, textile-producing and butchery industries. Little consistency was found among the risk estimates for HCC, based on three different analytical approaches. None of the analyses showed a linear trend of risk with increasing duration of exposure. However, the numbers of exposed cases and controls were small for many of the occupations and therefore the study power and precision were low. We failed to find important and consistent evidence for a relationship between HCC in women and occupational variables. However, even weak evidence of occupational risk warrants careful consideration in future studies.

Le foie est un organe qui exerce un rôle majeur dans le contrôle de l’homéostasie métabolique et énergétique de l’organisme en maintenant la glycémie à un taux constant. LKB1 est une sérine-thréonine kinase qui joue un rôle clef dans la physiologie cellulaire en couplant le contrôle du métabolisme au statut énergétique de la cellule. A l’aide de modèles murins ayant une délétion de LKB1 dans les hépatocytes adultes, nous avons identifié un rôle complexe pour LKB1 au sein de l’homéostasie énergétique. L’objectif de ma thèse était de caractériser ce phénotype et d’en comprendre les bases physiologiques. Nos résultats montrent une hyperglycémie à jeun chez les animaux mutants, associée à une perte de masse maigre (muscle), une accumulation du glycogène à jeun et une activation constitutive de la voie de l’insuline, qui, à long terme, conduit à une cachexie. Nos résultats suggèrent que Lkb1 hépatique exercerait un dialogue complexe avec la signalisation insuline dans le contrôle de la gluconéogenèse avec une dépendance énergétique aux acides aminés. Nous avons aussi montré qu’il existait un dialogue complexe entre LKB1 et la voie Wnt/β-caténine dans le foie. En effet, les carcinomes hépatocellulaires (CHC) mutés CTNNB1 ont des caractéristiques phénotypiques en termes de polarité et de métabolisme (absence de stéatose). Nous avons émis l’hypothèse que ce phénotype pouvait être secondaire à l’activation du gène suppresseur de tumeurs LKB1. Les mutations CTNNB1 sont en effet capable d’induire l’expression protéique de LKB1 dans les lignées hépatomateuses humaines, et les CHC mutés CTNNB1 présentent une expression protéique accrue de LKB1. De plus, dans deux modèles murins d’invalidation hépatospécifique de Lkb1, LKB1 est apparu comme requis pour l’activation du programme transcriptionnel de β-caténine mais de façon dépendante du stade de développement et du contexte nutritionnel. / The liver plays a major role in the control of both metabolic and energetic homeostasis in the body by maintaining glycemia. LKB1 is a serine-threonine kinase that plays a crucial role in cell physiology by controlling cell metabolism and cell energetic status. Using murine model with LKB1 hepatospecific deletion, we identified a complex role for LKB1 in energy homeostasis. The aim of my thesis was to characterize this phenotype and to understand its physiological basis. Our results show a hyperglycemia at fasted state in mutants animals, associated with a loss of dry mass, a glycogen accumulation and a constitutive activation of insulin signaling, which leads to a cachexia at long term. Our results suggest that hepatic Lkb1 is involved in a cross talk with insulin signaling in the control of neoglucogenesis with amino acid dependence. We also showed a cross talk between LKB1 and Wnt/β-catenin signaling in the liver. Indeed, CTNNB1-mutated hepatocellular carcinoma (HCC) have phenotypic features in terms of polarity and metabolism (lack of lipid accumulation). Our hypothesis is that this phenotype would be secondary to the activation of the tumour suppressor gene LKB1. CTNNB1 mutations induce LKB1 proteic expression in human hepatoma cell lines and CTNNB1-mutated HCC show an increased proteic LKB1 expression. In two murine models of Lkb1 hepatospecific invalidation, LKB1 seems to be necessary for the activation of the β-catenin transcriptional program in a way that is dependent on developpemental state and nutritional context.

No description available.

No description available.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal