La surveillance syndromique est un concept récent en épidémiologie. Fondée sur le suivi automatisé d’indicateurs de santé non spécifiques, cette nouvelle approche offre des perspectives intéressantes pour la détection de phénomènes pathologiques émergents. Nous nous sommes basés sur les données actuellement collectées en France sur la mortalité bovine pour évaluer la faisabilité et la pertinence d’un système de surveillance syndromique basé sur cet indicateur. Nous avons d’abord modélisé le niveau de référence de la mortalité bovine en France puis proposé des méthodes pour identifier et quantifier d’éventuels excès de mortalité. Nous avons d’abord analysé des données réelles pour estimer rétrospectivement les conséquences sur la mortalité de l’épizootie de fièvre catarrhale ovine qui a touché le cheptel bovin français en 2007 et 2008. Nous avons ensuite proposé une méthode visant à identifier des regroupements d’unités spatiales présentant des augmentations inhabituelles de mortalité, et évalué ses performances pour détecter des foyers d’une maladie infectieuse dont nous avons simulé la propagation dans le cheptel bovin. Sur la base de ces travaux, nous discutons finalement de l’intérêt pour la protection de la santé animale d’un système de surveillance non spécifique basé sur la mortalité, et émettons des propositions pour la mise en place opérationnelle d’un tel système. / Syndromic surveillance is a recent concept in epidemiology. Based on automated monitoringof non-specific health indicators, this new approach offers interesting prospects for the detection of various health events. We analyzed data on cattle mortality routinely collected inFrance to assess the feasibility and relevance of a syndromic surveillance system based on this indicator. We modeled the baseline of cattle mortality in France and proposed methods to identify and quantify excess mortality. First we analyzed real data to retrospectively estimate the effects on mortality of the bluetongue outbreak which affected the French cattle in 2007 and 2008. We then proposed a method to detect unusual increases mortality, and evaluated its performance for the detection of outbreaks of an infectious disease of which we simulated the spread in the cattle population. We finally discuss the interest of a surveillance system based on non-specific mortality for the protection of animal health, and make proposals for the operational implementation of such a system.

Deux tests sérologiques (test de fixation de complément (CFT) et l'ELISA de compétition (cELISA)) sont recommandés par l'OIE et utilisés couramment au Laboratoire Central Vétérinaire de Bamako parfois en parallèle dans le diagnostic et le dépistage de la péripneumonie contagieuse bovine (PPCB). La performance de ces tests a été estimée différemment par plusieurs auteurs dans des contextes épidémiologiques différents à partir de méthodes statistiques standards avec un statut sanitaire réel des animaux partiellement ou totalement connu. Dans un milieu où la PPCB est endémique avec différents stades d'évolution de la maladie, sachant que les tests sérologiques sont non parfaits (non gold standards), l'utilisation d'une approche bayésienne semblait appropriée pour une appréciation précise des paramètres de performance de tests qui sont la sensibilité et la spécificité, afin de mieux apprécier la prévalence de la maladie dans le cheptel bovin du delta central du Niger au Mali. Les résultats d'analyse de laboratoire des échantillons de terrain ont servi de bases de données importantes pour une analyse descriptive de la situation épidémiologique par appréciation des patrons de variations des principaux paramètres pouvant exercer une influence majeure sur la propagation de la PPCB. Ceci, dans le but d'aider à la réflexion sur la recherche d'outils et stratégies nouvelles dans le processus de prévention et d'éradication de la PPCB par le développement des modalités d'implantation d'une méthodologie innovante, pratique et efficace comme la qualification sanitaire troupeau concernant la PPCB dans un environnement d'élevage extensif. Cette thèse a permis de mieux définir les corrélations entre les deux tests, d'observer une meilleure sensibilité de cELISA par rapport à CFT permettant de justifier son utilisation seule dans un programme de dépistage à large échelle de la PPCB dans un milieu endémique. La démonstration dans l'étude de l'existence d'agrégation des animaux séropositifs à l'échelle du troupeau et aussi géographique montre qu'un système de qualification sanitaire troupeau pourrait jouer en collaboration avec le réseau national de surveillance épidémiologique vétérinaire, un rôle prépondérant dans la lutte ciblée et la maîtrise de la propagation de la PPCB au Mali. Mots clefs : PPCB-cELISA-CFT-Approche bayésienne-Agrégation-qualification sanitaire-Bovin / Two serological tests (complement fixation test (CFT) and competitive ELISA (cELISA)) are recommended by the OIE and commonly used in Central Veterinary Laboratory of Bamako sometimes in parallel, in the diagnosis and screening for contagious (CBPP). The performance of these tests has been estimated differently by several authors in different epidemiological settings using standard statistical methods with a real status of animals partially or completely known. In an environment where CBPP is endemic and where different stages of disease are available, given that serological tests are not perfect (not gold standard), the use of Bayesian approach seemed appropriate for an accurate assessment of the performance parameters of tests which are the sensitivity, specificity and predictive values to better assess the prevalence of the disease in cattle in the central Niger delta in Mali. The results of laboratory analysis of field samples were used as large database for epidemiological analysis of the geographical distribution of seroprevalence and the influence of major risk factors for the spread of CBPP. This, in order to aid reflection on tools research and new strategies in the process of prevention and eradication of CBPP by developing for implementation of an innovative, practical and effective methodology as sanitary qualification of cattle. This thesis has helped define the correlations between the two tests, observing a better sensitivity of cELISA compared to CFT to justify its use only in a program of widespread testing of CBPP in an endemic environment. In this study, the proof of the existence of aggregation of seropositive animals across herds and geographical level shows that a sanitary qualification system of cattle can play in collaboration with the national network of veterinary epidemiological surveillance a leadership role in targeted control and mastery of the spread of CBPP in Mali.Keys words: CBPP- cELISA - CFT- Bayesian approach -Aggregation- Sanitary qualification –Bovine

L'objectif du principe de gouvernance d'entreprise de l'OCDE défini des recommandations en matière d'organisation et de transparence des entreprises afin d'obtenir le meilleur équilibre entre le surveillance, l'efficacité de la direction et la participation des parties prenantes. Aujourd'hui, ce principe est un ligne directrice essentielle pour gagner la confiance des investisseurs et constitue le standard minimum de la gestion des entreprises. L'efficacité de ce principe est non seulement dépend de la politique, l'économie et la connaissance des législation, mais aussi, dépend d'application des loi en Thaïlande, en France et en Chine. Notre étudie analyser les différences qui amènera pour créer une connaissance qui peut permettre l'adaptation d'un nouveau système de gestion d'entreprise afin d'améliorer le meilleur développement d'économique durable. / The principe of corporate governance of the OECD define recommendations for the organization and transparency of companies to obtain the best balance between the surveillance, the effective of leadership and the participation of stakeholder. Today, this principe is a guideline essential to gain the confidence of investors and its the minimum standard of corporate governance. However, the effectiveness of this principle depend on the politics, the economy and the legislation. And the varies according in Thailand, in France and in China. The study of these differences will lead then to create knowledge that may enable the adaptation of a new business management for better sustainable economy development in each country.

La surveillance de l’activité physique et des comportements sédentaires, et la question de leur mesure, sont primordiales dans un contexte où les sociétés modernes favorisent l’augmentation de l’incidence de nombreuses maladies associées à un mode de vie sédentaire. Objectif : L’objectif de cette thèse était d’approfondir les connaissances sur la surveillance et la mesure de l’activité physique et des comportements sédentaires. Méthodes : Quatre études ont été réalisées. Deux travaux analysent et discutent le système français de surveillance de l’activité physique et des comportements sédentaires des adultes et des jeunes. Une étude teste les propriétés psychométriques du questionnaire mondial sur la pratique d’activités physiques (GPAQ). Enfin, une revue de la littérature analyse le contenu des questionnaires disponibles pour mesurer les comportements sédentaires. Résultats : Les deux études portant sur la surveillance observent un manque d’homogénéité et de constance dans le choix des outils de mesure qui limite le suivi de l’évolution des pratiques. L’étude sur le GPAQ révèle des résultats, en termes de reproductibilité et de validité, similaires aux valeurs habituellement observées. Enfin, la revue de littérature a mis en évidence que les questionnaires mesurant les comportements sédentaires présentent des différences en termes de population cible, période de rappel, nombre d’item, et caractéristiques des comportements sédentaires mesurés. Conclusion : Des recommandations ont été formulées afin d’améliorer la mesure et la surveillance de l’activité physique et des comportements sédentaires en France / Physical activity and sedentary behaviors are major health determinants and are being surveyed worldwide. Objective: The aim of this thesis was to contribute to the surveillance and measurement of physical activity and sedentary behaviors. Method: This thesis includes four studies. The first study analyzes and discusses the present situation of French national surveillance studies. The second study presents the results from the first French report card on physical activity for children and adolescents. The third study discusses the validity and reliability properties of the French version of the Global Physical Activity Questionnaire (GPAQ). The fourth study examines the content of questionnaires measuring sedentary behaviors. Results: Studies 1 and 2 reported measurement issues impairing the overall data quality, inter-study comparisons and survey of changes over time. The study of GPAQ reported limited but acceptable reliability and validity for the measurement of physical activity and sedentary time in France. Finally, the systematic review on sedentary behaviors questionnaires reported large differences in the population targeted (ex: adults, youth, elderly), recall frame (ex: previous day, last 7 days, last month), the number of item (from 1 to more than 100), and the sedentary behaviors characteristics measured (from only sitting time to up to 27 sedentary behaviors). Conclusion: The work realized during this thesis allows the formulation of recommendations to improve the surveillance of physical activity and sedentary behaviors in France

Les maladies infectieuses demeurent l'une des causes majeures de décès dans le monde. Au Gabon, on estime que plus de la moitié des données disponibles ne sont pas collectées, et que plus de la moitié des données potentiellement collectées ne sont pas transmises au niveau central expliquant ainsi la lenteur à la réactivité du système de santé. Un réseau de surveillance syndromique des maladies infectieuses à potentiel épidémique (SuSyMIPE) a pu être mis en place dans quatre sites (Gamba, Koulamoutou, Libreville et Oyem) sentinelles. Pour chaque syndrome, un groupe de maladies était évoqué. Les notifications journalières de cas codifiées par "Short Message Service" (SMS) étaient transmis en fin d'après-midi. De janvier et octobre 2016, 5348 cas suspects des syndromes surveillés ont été enregistré, 28,1% (n = 1502) de Koulamoutou 24,5% (n = 1310) de Libreville, 24% (n = 1284) Gamba et 23,4% (n = 1252) d' Oyem. 71,3% (n = 3816) des cas étaient des fièvres, 19,7% (n = 1053) des syndromes respiratoires et les cas des syndromes diarrhéiques représentaient 9% (n = 479). Ce réseau nous a permis de détecter assez précocement l'épidémie de rougeole dans deux chefs-lieux de provinces (Libreville et Oyem) en 2016. Au total, entre les semaines 13 et 19, 79 cas suspects ont été notifiés, principalement 82,3% (n = 65) à Oyem et 17,7% (n = 14) à Libreville. Le sex-ratio M / F était de 0,88 (37/42), et l'âge moyen était de 49,37 ± 72.82 mois. Cependant, 53,3% (n = 16/30) seulement ont été confirmés pour la rougeole. La mise en place de ce système de surveillance syndromique nous a permis de répondre de manière plus rapide et plus efficiente aux épisodes de rougeole qui se sont manifestés. / Infectious diseases remain one of the leading causes of death in the world. In Gabon, it is estimated that more than half of the available data are not collected, and that more than half of the potentially collected data are not transmitted centrally, thus explaining the slowness of the responsiveness of the health system. A syndromic surveillance network for infectious diseases with epidemic potential (SuSyMIPE) has been set up in four sites (Gamba, Koulamoutou, Libreville and Oyem) sentinels. For each syndrome, a group of diseases was mentioned. The daily notifications of cases coded by "Short Message Service" (SMS) were transmitted at the end of the afternoon. From January to October 2016, 5348 cases of suspected syndromes were recorded, 28.1% (n = 1502) of Koulamoutou 24.5% (n = 1310) of Libreville, 24% (n = 1284) Gamba and 23, 4% (n = 1252) from Oyem. 71.3% (n = 3816) of the cases were fevers, 19.7% (n = 1053) of the respiratory syndromes and the cases of diarrheal syndromes accounted for 9% (n = 479). This network enabled us to detect the measles epidemic early in two provincial capitals (Libreville and Oyem) in 2016. In total, between weeks 13 and 19, 79 suspected cases were reported, mainly 82.3. % (n = 65) in Oyem and 17.7% (n = 14) in Libreville. The sex ratio M / F was 0.88 (37/42), and the mean age was 49.37 ± 72.82 months. However, only 53.3% (n = 16/30) were confirmed for measles. The implementation of this syndromic surveillance system allowed us to respond more quickly and more efficiently to the measles episodes that occurred.

A Constituição da República Federativa do Brasil de 1988 elevou a saúde como direito social fundamental e constituiu o Sistema Único de Saúde com competência para as ações e serviços de saúde, incluídas as de vigilância sanitária. As ações e serviços da área formulam-se e implementam-se por intermédio de políticas públicas adotadas pelo Poder Público. As referidas políticas são programas de ação governamental que se valem de normas jurídicas e têm estimulado a reflexão dos juristas, em vista, especialmente, de frequentes decisões judiciais sobre políticas públicas, mais notadamente, nas de caráter social. Em vigilância sanitária há o estabelecimento de políticas públicas, por parte da União, que tem na Agência Nacional de Vigilância Sanitária (Anvisa) seu órgão executor, em nível federal. A Anvisa, para executar a política pública de vigilância sanitária, formula atos que regulam essa atividade. Tais atos, muitas vezes, são questionados judicialmente. Esta pesquisa analisou as decisões judiciais federais, entre os anos de 1999 e 2007, em que a Anvisa figurou no pólo passivo da relação processual, com o intuito de observar se o Poder Judiciário, ao decidir sobre essa importante matéria, leva em conta o código binário Direito Sanitário/Não Direito Sanitário da Teoria dos Sistemas Sociais de Niklas Luhmann ou o ignora, formulando sentenças baseadas em outras fontes que não o Direito Sanitário e a política pública de vigilância sanitária. Concluiu-se que o Poder Judiciário federal, embora pouco versado em matéria de saúde pública, deixa-se influenciar pela compreensão de vigilância sanitária e de risco sanitário e tem julgado, em maioria, a favor da saúde / The 1988 Constitution of the Federative Republic of Brazil has given health a fundamental social right status and also has created a centralized health system called SUS which is responsible, among other subjects, for health surveillance services. In Brazil, actions and health services are created and implemented as public policies. Those are government actions and programs supported by laws that have been stimulating lawyers to speculate about the subject, notably because of numerous court decisions in public policies, especially those with a social character. In Brazil, health surveillance is jurisdiction of federal government through the National Health Surveillance Agency (Anvisa). This agency in order to implement public policies in health surveillance enforces acts to regulate such activities. However, such acts are often challenged in court. In order to determine if Judiciary decisions takes into account Health Law / Not Health law Niklas Luhmann\'s binary system or simply ignores the subject resulting in sentences based on other sources but Health Law and health surveillance public policy. The conclusion was that Federal Judiciary has decided mostly in favor of health, although not much experienced in public health matters they are influenced by health surveillance and health hazard notions

A hemovigilância é considerada uma importante ferramenta para a segurança transfusional. Os primeiros sistemas nacionais de hemovigilância, no mundo, foram implantados na década de 1990. No Brasil, o Sistema Nacional de Hemovigilância (SNH), que é coordenado pela Agência Nacional de Vigilância Sanitária (Anvisa), iniciou sua implantação, em 2002, com foco nas reações transfusionais (RT), em uma rede restrita de hospitais. No final de 2006, a possibilidade de notificar RT foi estendida aos demais serviços de saúde e os gestores de saúde da esfera estadual também foram inseridos nesse processo. O estado de São Paulo (SP), onde funciona um subsistema do SNH (SNH-SP), colaborou com 41% do total de RT notificadas, no período de 2002 a 2014, segundo a Anvisa. Contudo, apesar de decorridos cerca de 10 anos, o SNH-SP nunca foi avaliado. O objetivo desse trabalho foi avaliar a implantação do SNH-SP, a fim de obter subsídios para sua melhoria. Trata-se de um estudo avaliativo, utilizando-se metodologia de avaliação baseada no Updated Guidelines for Evaluating Public Health Systems do Centers for Disease Control and Prevention (CDC). Foram utilizadas duas bases de dados secundários: das transfusões e das notificações das RT. Foram também utilizados três questionários concebidos para identificar fatores que contribuem ou não com a adesão e com a implantação do SHN-SP, pelos hospitais, serviços de hemoterapia (SH) e pela vigilância sanitária (Visa). Eles foram respondidos por 81 hospitais, 61 SH e 22 das 28 regionais de Visa. Verificou-se que o SNH-SP tem adesão crescente dos hospitais, especialmente os de maior porte, embora a aceitabilidade destes seja baixa, quando comparada com a dos SH. Foram realizadas 12.182.981 transfusões em 947 serviços de saúde, entre 2008 a 2015, mais de 55% delas, de concentrado de hemácias. O número de notificações de RT aumenta a cada ano, mas há subnotificação geral e de alguns tipos específicos de RT. Foram notificadas 23.942 RT, por 353 serviços de saúde. As 23.734 RT ocorridas nesse período se caracterizaram, predominantemente, como imediatas (97,96%), dos tipos febril não hemolítica (51,81%) e alérgica (38,20%). Apresentaram gravidade leve (87,62%), contudo, houve 35 (0,15%) óbitos. Concentraram-se nos maiores de 50 anos (51,49%). A incidência de RT nesse período variou entre 3,44 e 4,55/1.000, sendo mais elevada nas transfusões de concentrados de granulócitos, chegando a 53,06 RT/1.000. O SNH-SP tem gestão centralizada e tanto ele quanto o sistema de informação utilizado para notificação ainda são desconhecidos de parte dos hospitais. Há déficit de pessoal para trabalhar na área, tanto nos hospitais quanto nas Visa. Há falta de integração com outros sistemas de saúde afins, sugerindo a subnotificação de doenças transmitidas pelo sangue no SNH-SP, como as hepatites B e C. A estruturação do SNH apresenta simplicidade, porém, seu funcionamento atual, em SP, prejudica a avaliação desse atributo. Ao se analisar as RT definidas como eventos sentinela, a oportunidade e a qualidade dos dados foram consideradas insatisfatórias. O SNH-SP foi considerado útil, mas ajustes são recomendados para seu efetivo funcionamento. / Haemovigilance is considered an important tool for transfusion safety. The first national hemovigilance systems in the world were implemented in the 1990s. The Brazilian Hemovigilance System (BHS), which is managed by Agência Nacional de Vigilância Sanitária (Anvisa), began in 2002, focusing on the transfusion reactions (TR) in a limited hospital network. At the end of 2006, the possibility of reporting TR was extended to all health services and state health managers were also included in this process. The state of São Paulo (SP), where a BHS subsystem (BHS-SP) operates, contributed with 41% of the total reported RTs, from 2002 to 2014, according to Anvisa. However, after about 10 years, the BHS-SP has never been evaluated. The objective of this study was to evaluate the implementation of the BHS-SP, in order to obtain inputs for its improvement. This is an evaluative study, using an evaluation methodology based on the Updated Guidelines for Evaluating Public Health Systems of the Centers for Disease Control and Prevention (CDC). Two secondary databases were used: transfusions and reported TR. Three questionnaires designed to identify factors that whether or not contribute to the adherence and to the implementation of the SHN-SP, by hospitals, blood banks (BB) and by health surveillance (Visa) were also used. 81 hospitals, 61 BB and 22 out of 28 regional Visa answered them. It was verified that the BHS-SP has an increasing adherence of the hospitals, especially of the larger ones, although the acceptability of these is low, when compared with the BB. 12,182,981 transfusions were performed in 947 health services, from 2008 to 2015, more than 55% of them, of red blood cells. The number of reported TR increases each year, but there is underreporting, in general and in some specific types of RT. 23,942 TRs were reported from 353 health services. The 23,734 TR occurred in this period were characterized as immediate (97.96%), non-haemolytic (51.81%) and allergic (38.20%). They were classified as non-severe (87.62%), however, there were 35 (0.15%) fatalities. They concentrated on those over 50 years old (51.49%). The incidence of TR in this period varied between 3.44 and 4.55/1,000, higher in granulocyte concentrates transfusions, reaching 53.06 TR/1,000. The BHS-SP has centralized management. Both, the BHS-SP and the information system used for reporting TR are still unknown by the hospitals. There is a shortage of staff to work in the area, in hospitals and in Visa. There is a lack of integration with other related health systems, suggesting the underreporting of bloodborne diseases in BHS-SP, such as hepatitis B and C. The organizational structure of the BHS demonstrates simplicity, but its current functioning in SP impairs the evaluation of this attribute. When RTs defined as sentinel events were analyzed, the timeliness and the quality of the data were considered unsatisfactory. The BHS-SP was considered useful, but adjustments are recommended for its effective functioning.

INTRODUÇÃO: A doença diarréica aguda é ainda importante causa de morbidade no mundo. Sua elevada incidência e a aceitação de sua ocorrência como fato "normal" impõem desafios para seu registro e implantação de seus sistemas de vigilância. OBJETIVOS: Conhecer as características epidemiológicas da diarréia aguda e avaliar a capacidade de detecção de surtos pelo Programa de Monitorização da Doença Diarréica Aguda, no município de Avaré. MÉTODOS: De 27 de fevereiro a 16 de julho 2005, realizou-se estudo prospectivo da diarréia em unidade sentinela do programa. Os surtos identificados foram investigados por estudos descritivos e analíticos. Amostras de fezes foram coletadas para os casos envolvidos nos surtos. A avaliação dos propósitos do programa embasou-se em indicadores de utilidade, sensibilidade e oportunidade. RESULTADOS: Foram identificados 408 casos (Coeficiente de Incidência = 4,7/1000 habitantes); idade mediana de 7 anos (variação de 1 mês a 89 anos) e 54% do sexo masculino. Dos quatro surtos de diarréia confirmados, dois ocorreram em uma creche e em um orfanato, devido à Giárdia lamblia e Cryptosporidum spp.; um intradomiciliar de origem alimentar, sem identificação do agente, e uma epidemia na comunidade associada ao rotavírus. Dos casos atendidos, 63 (15,5%) pertenciam a surtos, identificando-se mais 56 casos, em um total de 119 casos (Coeficiente de Incidência de Surtos=1,4/1000 habitantes). CONCLUSÕES: O estudo mostrou que o programa responde ao seu principal propósito, respeitando-se as condições de regularidade na informação, análises dos padrões da diarréia e investigação criteriosa. Intensificar treinamentos para aumentar a habilidade das equipes locais nas avaliações e investigações é uma das principais recomendações deste estudo. / BACKGROUND: Acute diarrheal illness remains an important cause of morbidity worldwide. Its high incidence and the acceptance of its occurrence as “normal" fact impose challenges for its report and implantation of its surveillance systems. OBJECTIVES: To describe the epidemiologic characteristics of the acute diarrhea and to evaluate the capacity of the Monitoring Program of the Acute Diarrheal Illness for early detection of outbreaks, in the city of Avaré, State of São Paulo, Brazil. METHODS: From February 16 to July 28, 2005, was a prospective study of the diarrhea in a sentinel health service of the program. Descriptive and analytical studies were developed to investigate the potential outbreaks identified in this period. Stool samples were collected from the involved cases in the outbreaks. The evaluation of purpose of the program was based on indicators of usefulness, sensitivity and timeliness. RESULTS: A total of 408 cases were identified (incidence rate=4.7/1000 inhabitants). The median age was 7 years (range 1-89 years) and 54% were male. Among four confirmed diarrhea outbreaks, two occurred in a day nursery and orphanage, due to Giardia lamblia and Cryptosporidum spp., respectively; one was caused by food in dwelling-house, without identification of the agent, and one caused by rotavirus spread citywide. Of all monitored cases, 63 (15.5%) were involved in outbreaks, linked to more 56 cases, in a total of 119 cases (outbreaks incidence rate=1.4/1000 inhabitants). CONCLUSIONS: The study showed that the program enables prompt detection and investigation of outbreaks, respected the conditions of reliability of the information, evaluation of the acute diarrhea trends and careful inquiry. To intensify training to increase the ability of local professionals to recognize patterns of possible outbreaks and for suitable investigations is one of the major recommendations of this study.

Considéré comme un cancer de l'âge mûr, l'incidence du cancer colorectal ne cesse d'augmenter avec l'allongement de la vie. Dans la majorité des cas, le cancer colique est associé à une mutation du gène suppresseur de tumeur Apc, contrôlant l’activation de la signalisation Wnt/β-caténine. Afin, d'identifier de nouveaux acteurs de la tumorigenèse colique, notre laboratoire a développé des modèles murins de mutation du gène Apc qui ont pour avantage de mimer la pathologie humaine (Colnot et al, 2004 ; Andreu et al, 2005). La création de ces modèles a permis à l’équipe de démontrer i) qu’une activation physiologique de cette voie contrôle la prolifération des cellules souches et des progéniteurs ainsi que leur différenciation et ii) qu’une activation aigüe est suffisante pour déclencher l’initiation tumorale intestinale (Andreu et al, 2005; Andreu et al, 2008). Les travaux antérieurs à mon arrivée ont permis d’identifier différents évènements moléculaires et cellulaires induits en cascade suite à l’activation pathologique de la voie Wnt/β-caténine. Parmi ceux-ci, une induction transcriptionnelle de gènes impliqués dans l'autophagie a été mise en évidence. Ce processus d'auto-cannibalisme cellulaire est associé à de nombreuses pathologies telles que les maladies neurodégénératives ou infectieuses. Cependant, le rôle de l'autophagie dans le cancer reste ambivalent et son implication dans le cancer colique demeure inconnue.Dans ce contexte, mon travail de doctorat a consisté à répondre aux questions suivantes :L’induction transcriptionnelle de gène Atg s’accompagne-t-elle d’une activation du processus d’autophagie à tous les stades de la progression tumorale intestinale murine et humaine?Des études de transcriptomique à haut débit nous ont permis d’identifier une induction transcriptionnelle de gènes clés du processus d’autophagie tels qu’Atg7. Cependant, l’activation fonctionnelle de l’autophagie n’est pas toujours associée à une augmentation de la transcription des acteurs de ce processus. Nous nous sommes donc intéressés aux marqueurs couramment décris dans la littérature et permettant d’établir l’état d’activation du flux autophagique. Ainsi, nous avons étudié le niveau d’expression de ces marqueurs par des expériences de western-blot et d’immuno-marquages sur des échantillons tumoraux humains et murins à différents stades de la progression du CRC. L’inhibition de l’autophagie impacte-t-elle la carcinogénèse colorectale?Dans ce contexte, nous avons généré un modèle murin de délétion conditionnelle et simultanée d'un allèle du gène Apc et des deux allèles du gène Atg7 (gène clé de l'autophagie) spécifiquement dans les cellules épithéliales intestinales. Afin de suivre l'apparition et l'évolution des tumeurs au cours du temps, nous avons mis au point une nouvelle méthode non-invasive de reconstruction tridimensionnelle de côlons de souris, issue d'imagerie échographique à haute résolution. Dans le but de caractériser l’impact de l’inhibition de l’autophagie, les modifications propres à la cellule déficiente en autophagie ont été explorées, notamment le statut énergétique ainsi que les changements dans l’environnement immunitaire et microbien de l’épithélium intestinal. Finalement, l’inhibition génétique de l’autophagie dans notre modèle murin, prédisposé au développement de tumeurs intestinales, nous a permis de caractériser l’implication de l’autophagie dans la carcinogénèse colique, ainsi que les mécanismes moléculaires et cellulaires liant l’auto-cannibalisme cellulaire à la pathologie tumorale. / Colorectal cancer is one of the major causes of cancer-related deaths. We took advantage of Apc mutant mice that mimic the adenomatous polyps that affect humans with an inactivated Apc gene, to gain insight into the critical events that affect the development of colorectal cancer. We show that autophagy, a catabolic pathway involved in the degradation of intracellular proteins and organelles, is activated in intestinal murine and human cancer and its inhibition has a crucial role in controlling tumorigenesis. We report that the in vivo conditional deletion of the essential autophagy gene Atg7 in intestinal epithelial cells inhibits the formation of pre-cancerous lesions resulting from Apc loss by enhancing immunosurveillance. The antibody-mediated depletion of CD8+ T cells demonstrated a critical role for CD8+ T cells in antitumoral responses resulting from the inhibition of autophagy. We used a broad-spectrum antibiotics treatment to show that the expansion of IFN-producing CD8+ T cells following the deletion of Atg7 is dependent on the intestinal microbiota and is associated with Paneth and goblet cell defects. In addition, the inhibition of autophagy affected tumor cell growth and restrained cancer growth for extended time periods. We demonstrate that the inhibition of autophagy in Apc tumor cells results in a stress response accompanied by metabolic defects, characterized by AMPK activation and p53 cell cycle arrest. This study suggests that autophagy inhibitors may suppress tumorigenesis in patients at high risk of developing colorectal cancer.

L’essor des transports à une échelle globale s’inscrit dans un phénomène de mondialisation et 90% des biens échangés au travers le monde sont effectués par voie maritime. La maritimisation se définit comme un processus de dépendance économique des états au trafic maritime due à ce phénomène de mondialisation (Vigarié 1983). Ce phénomène transforme les territoires, et principalement les espaces côtiers mais a également comme conséquence une territorialisation des espaces maritimes, à savoir une utilisation et gestion des espaces pour les activités humaines. L'utilisation de cet espace a augmenté depuis 1970 et principalement le transport, que ce soit via porte-conteneurs ou tanker (Rodrigue, Comtois, and Slack 2013). Cela forme ainsi un réseau de transport maritime et d’approvisionnement lié à l’emplacement des ports dans le monde et des routes maritimes les reliant. Cependant ce réseau s’étend sur un espace vaste et dynamique, l’espace maritime, qui peut générer des risques pour l’usage de l’espace à des fins de transports.Ce réseau d’approvisionnement est vulnérable face à certains événements (perturbations) pouvant affecter la performance du réseau d’approvisionnement (Achurra-Gonzalez et al. 2016) : les tempêtes, les pénuries, la piraterie maritime, les fermetures de canaux sont des événements ayant une influence sur l’efficacité d’un réseau d’approvisionnement. Cette vulnérabilité est liée à plusieurs facteurs (Wagner and Neshat 2010) : les variations de l’offre et de la demande, les risques économiques, et à la structure du réseau et de l’espace maritime, les risques géographiques. L’ensemble de ces risques peuvent être mesurés et quantifiés dans les caractéristiques topologiques, géométriques et relationnelles des graphes. Un graphe est un ensemble de noeuds relié par un ensemble de lien. Les graphes sont utilisés pour la formalisation des réseaux, notamment des réseaux de transports (Ducruet and Lugo 2013).Afin de tester les perturbations sur les caractéristiques du réseau, un système de simulation est mis en place. Pour cela, les perturbations sont modélisées par des objets spatio-temporels ayant une influence sur l’accessibilité à l’espace des navires. Au travers d’un système multi-agents (Ferber 1997), ces navires prennent des décisions face aux perturbations (changement de route, de destination, report ou annulation du voyage). Ces comportements individuels, une fois agrégés, par la pondération des noeuds et des liens du graphe, permettent d’évaluer les variations topologiques et géométriques du graphe en fonction des perturbations dans l’espace maritime, grâce à des indicateurs utilisés pour mesurer la vulnérabilité des réseaux (Gleyze 2005). Ainsi cette recherche permet de mieux comprendre l’influence de ces perturbations sur le fonctionnement d’un réseau d’approvisionnement dans un espace maritime. / Transportation on a global scale is due to the globalization process. Today, 90% of goods in the world are traded by sea. Maritimization is defined as a process of increased economic dependence of states on maritime traffic (Vigarié 1983). This phenomenon transforms territories, mainly the coastal areas, but also results in a territorialization of maritime spaces, which means a use and a management of maritime space for human activities. The use of this space for transportation has increased since 1970, whether through container ships or tanker (Rodrigue, Comtois, and Slack 2013). These trips have created a network which linked the locations of the ports in the world by the sea routes of shipping. However, this network extends over a vast and dynamic space, maritime space, which can generate risks for the use of space for transportation.This supply network is vulnerable to certain events (disruptions) that may affect the performance of the supply network (Achurra-Gonzalez et al., 2016): storms, shortages or maritime piracy have an influence on the efficiency of a supply network. This vulnerability is linked to several factors (Wagner and Neshat 2010): variations in supply and demand, which are economical risks, and the structure of the network and maritime space, which are geographical risks. All these can be measured and quantified by the topological, geometric and relational properties of graphs. A graph is a set of nodes connected by a link set. The graphs are used for the formalization of networks, notably transport networks (Ducruet and Lugo 2013).To test the disruptions on the characteristics of the network, a simulation system is used. In the simulations, disruptions are modeled by space-time objects having an influence on the accessibility of the vessels. Through a multi-agent system (Ferber 1997), these ships make decisions about disruptions (change of route, destination, postponement or cancellation of the trip). These individual behaviors, once aggregated by the weighting of the nodes and links of the graph, allow evaluating the topological and geometric variations which represent the influence of disruptions on the martitime network. Theses variations can be measured by indicators of the vulnerability of network (Gleyze 2005). This research allows us to improve the understanding on the influence of these disruptions on a network within a dynamic space.