Made available in DSpace on 2014-06-11T19:31:09Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-11-27Bitstream added on 2014-06-13T20:01:43Z : No. of bitstreams: 1 guimaraes_gc_dr_jabo.pdf: 4022989 bytes, checksum: 55bb5e0b9e5da66256e886dd7c8f6782 (MD5) / Universidade Estadual Paulista (UNESP) / Com este trabalho objetivou-se descrever o comportamento do centro tendíneo, pericárdio e peritônio bovinos, submetidos a ensaios mecânicos de tração a fresco e conservados em glicerina a 98% durante 30, 60 e 90 dias, bem como, analisar suas características histológicas, utilizando técnicas de microscopia de luz e ultraestrutural. Utilizou-se para tanto dez bovinos com idade entre 30 e 36 meses, mestiços, machos e fêmeas, coletando-se de cada animal fragmentos dessas membranas. Não se observou diferenças marcantes quanto à integridade estrutural e ultraestrutural dos elementos que constituem tanto as amostras do material a fresco quanto àqueles conservados em glicerina a 98%, que exibiram células mesoteliais e fibras conjuntivas sem alterações intensas. O centro tendíneo e o peritônio não sofreram alteração significativa (p>0,05) para os valores de tensão quando comparados os testes de resistência à tração do material a fresco com os conservados em glicerina. Entretanto, todos os tecidos avaliados exibiram aumento significativo (p£0,05) para os valores de alongamento quando conservados em glicerina 98% por até 90 dias. Verificou-se que o pericárdio é a membrana que suporta as maiores tensões, ou seja, maior força de tração por área de secção. Assim, conclui-se que a glicerina é eficaz para conservação de membranas biológicas, além de alterar suas propriedades mecânicas. / With this study, it was objectified to describe the comportment of fresh and 98% glycerin conserved for periods of 30, 60 and 90 days tendinous center, pericardium and peritoneum of bovines submitted to mechanical tests of traction as well as to analyze the histological characteristics, utilizing optical microscopy and ultrastructural techniques. It was utilized ten bovines between 30 and 36 months of age, crossbreeds, males and females, collecting fragments of this membranes in each animal. There was no significant difference as for structural and ultrastrucutural integrity of the elements that constitutes the samples of fresh and 98% glycerin conserved material, evidencing mesothelial cells and connective tissue without intense alterations. The tendinous center and peritoneum didnþt suffered significant modification (p>0.05) in the values of tension when compared the resistance tests to traction in fresh with 98% glycerin conserved membranes. However, all the evalueted tissues showed significant increase (p£0.05) for the elongation values when conserved in 98% glycerin for until 90 days. It was observed that pericardium is the one which supports greaters tensions. So, it can be concluded, that glycerin is efficient to the conservation of biological membranes besides to modify its mechanical properties.

Orientador: Márcia Rita Fernandes Machado / Banca: André Luiz Quagliatto Santos / Banca: Antônio Carlos Marconi Stipp / Banca: Carlos Roberto Daleck / Banca: Maria Rita Pacheco / Resumo: Com este trabalho objetivou-se descrever o comportamento do centro tendíneo, pericárdio e peritônio bovinos, submetidos a ensaios mecânicos de tração a fresco e conservados em glicerina a 98% durante 30, 60 e 90 dias, bem como, analisar suas características histológicas, utilizando técnicas de microscopia de luz e ultraestrutural. Utilizou-se para tanto dez bovinos com idade entre 30 e 36 meses, mestiços, machos e fêmeas, coletando-se de cada animal fragmentos dessas membranas. Não se observou diferenças marcantes quanto à integridade estrutural e ultraestrutural dos elementos que constituem tanto as amostras do material a fresco quanto àqueles conservados em glicerina a 98%, que exibiram células mesoteliais e fibras conjuntivas sem alterações intensas. O centro tendíneo e o peritônio não sofreram alteração significativa (p>0,05) para os valores de tensão quando comparados os testes de resistência à tração do material a fresco com os conservados em glicerina. Entretanto, todos os tecidos avaliados exibiram aumento significativo (p£0,05) para os valores de alongamento quando conservados em glicerina 98% por até 90 dias. Verificou-se que o pericárdio é a membrana que suporta as maiores tensões, ou seja, maior força de tração por área de secção. Assim, conclui-se que a glicerina é eficaz para conservação de membranas biológicas, além de alterar suas propriedades mecânicas. / Abstract: With this study, it was objectified to describe the comportment of fresh and 98% glycerin conserved for periods of 30, 60 and 90 days tendinous center, pericardium and peritoneum of bovines submitted to mechanical tests of traction as well as to analyze the histological characteristics, utilizing optical microscopy and ultrastructural techniques. It was utilized ten bovines between 30 and 36 months of age, crossbreeds, males and females, collecting fragments of this membranes in each animal. There was no significant difference as for structural and ultrastrucutural integrity of the elements that constitutes the samples of fresh and 98% glycerin conserved material, evidencing mesothelial cells and connective tissue without intense alterations. The tendinous center and peritoneum didnþt suffered significant modification (p>0.05) in the values of tension when compared the resistance tests to traction in fresh with 98% glycerin conserved membranes. However, all the evalueted tissues showed significant increase (p£0.05) for the elongation values when conserved in 98% glycerin for until 90 days. It was observed that pericardium is the one which supports greaters tensions. So, it can be concluded, that glycerin is efficient to the conservation of biological membranes besides to modify its mechanical properties. / Doutor

Orientador: Luiz Antonio Vane / Resumo: A melatonina foi isolada em 1958 e múltiplas funções desta molécula passaram a ser esclarecidas. As ações em receptores específicos de membrana, ligados à proteína G são responsáveis pelo controle do ciclo circadiano e do ritmo sazonal, no entanto a atividade como varredor dos radicais livres de oxigênio e outros mediadores do metabolismo oxidativo não são mediadas por receptores. A geração de EROS está diretamente ligada ao dano celular e tecidual, sendo a isquemia e a reperfusão (I/R), os mecanismos fisiopatológicos que mais contribuem para o desequilíbrio entre moléculas oxidantes e antioxidantes, resultando no estresse oxidativo. A insuflação da cavidade peritoneal com gás carbônico promove I/R causando desfechos deletérios ao paciente. Com o objetivo de estudar os efeitos da melatonina sobre a inflamação e o estresse oxidativo peritoneal e a expressão gênica das proteínas MTNR1A e MTNR1B entre os pacientes submetidos à laparoscopia cirúrgica, que receberam ou não a melatonina, foram randomizados 80 pacientes em 2 grupos de 40 pacientes cada para receber melatonina (GMEL) - 20mg via oral 12 horas antes e 1 hora antes do procedimento, respectivamente - e 40 pacientes para receber placebo (GPLA) - 12 horas antes e 1 hora antes do procedimento, respectivamente. Amostras de peritônio parietal foram coletadas 10 minutos após o início do pneumoperitônio e 3 minutos após o final do mesmo. A morfologia tecidual foi avaliada no exame histopatológico de lâminas coradas com hematox... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Melatonin was isolated in 1958 and multiple functions of this molecule have been clarified. The actions on specific receptors of membrane, attached to the G protein-coupled receptors are responsible for the control of circadian and seasonal rhythm cycle, however the activity as free radical oxygen scavenger and other mediators of oxidative metabolism are not mediated by receptors. The generation of EROS is directly linked to cellular damage and tissue ischemia and reperfusion being (I/R), the pathophysiological mechanisms that contribute most to the imbalance between oxidants and antioxidants molecules, resulting in oxidative stress. The peritoneal cavity insufflation with carbon gas promotes I/R causing deleterious outcomes for the patient. In order to study the effects of melatonin on the peritoneal inflammation and oxidative stress and genic expression of the proteins MTNR1A and MTNR1B among patients undergoing surgical laparoscopy who received or not melatonin, 80 patients were randomized into 2 groups of 40 patients each to receive melatonin (GMEL) - 20 mg orally 12 hours before and 1 hour before the procedure, respectively -and 40 patients to receive placebo (GPLA) - 12 hours before and 1 hour before the procedure, respectively. Parietal peritoneum samples were collected 10 minutes after the beginning of the pneumoperitoneum and 3 minutes after the end of it. Tissue morphology was evaluated on histopathological examination of slides stained with hematoxylin-eosin fo... (Complete abstract click electronic access below) / Doutor

In our republic, occupational exposure to asbestos has been restricted to jobs concerned with disposal of products, materials and buildings containing asbestos, and research work studying asbestos fibres. The reason consists in health risks as all kinds of asbestos belong to high-risk carcinogens. The asbestos fibre related diseases should be reported. All data connected are kept in the National Institute of Public Health (NIPH) in Prague. The purpose of this study was to find out how much people are aware of the risks related to asbestos and find people who suffered from asbestos dust-induced disease, i.e. mesothelioma of pleura. The quantitative method was used to summarise information on asbestos-induced disease occurence in 1970-2010 available in the National Institute of Public Health in Prague. Along with that, the work maps the population awareness of asbestos risks. The thesis itself can be divided into two parts. The first one contains information based on data collection while the other part deals with data of NIPH in Prague. Two hypotheses were predicted: Hypothesis H1: People are aware of the material containing asbestos. Hypothesis H2: People are aware of negative impact of asbestos on human health. Both hypotheses were proved. Three hypotheses were suggested in the other part: Hypothesis H3: Latency, the time between first exposure to manifestation of disease, is never less than 20 years. Hypothesis H4: Incidence of mesothelioma of pleura and peritoneum is higher in people aged 60-69. Hypothesis H5: Smoking affects the course of the disease negatively. Hypotheses H3 and H4 were proved. Hypothesis H5 cannot be neither proved or disproved. Although the number of smokers among mesothelioma patients was higher, there is no evidence of negative effect of smoking on the disease. To prove this hypothesis, the data colllection should be larger. Findings of the study proved the time of exposure to asbestos fibres does not affect the occurence of this disease. The findings can be used in further research studies.

Submitted by Jaqueline Silva (jtas29@gmail.com) on 2014-10-21T19:57:29Z No. of bitstreams: 2 Tese - Apóstolo Ferreira Martins - 2013.pdf: 3484742 bytes, checksum: 39684f9f07bf15cacff9b0c7f509d87c (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Jaqueline Silva (jtas29@gmail.com) on 2014-10-21T19:57:49Z (GMT) No. of bitstreams: 2 Tese - Apóstolo Ferreira Martins - 2013.pdf: 3484742 bytes, checksum: 39684f9f07bf15cacff9b0c7f509d87c (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2014-10-21T19:57:49Z (GMT). No. of bitstreams: 2 Tese - Apóstolo Ferreira Martins - 2013.pdf: 3484742 bytes, checksum: 39684f9f07bf15cacff9b0c7f509d87c (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2013-08-16 / Abdominal wall defects may require anatomical and functional reconstruction, what is usually achieved with the use of meshes. However these materials can trigger the formation of adhesions. To minimize or abolish this process one side of the mesh can be coated with a product that stands between this material and the visceral peritoneum forming a composite. The present study evaluated the systemic and tissue response to the implantation of composite polypropylene mesh-based film of chitosan 2QM (PQ group), compared to promoted by polypropylene mesh alone (group PP), intraperitoneally implanted in the abdominal cavity of pigs. After 28 days evaluation was performed by ultrasonography and video-laparoscopy. No significant difference was observed between the two groups of animals with respect to the formation of adhesions (P> 0.05). Systemic reactions were evaluated by means of the leukocyte count, C-reactive protein dosage, seric total protein, albumin and globulins which also showed no significant difference between groups (P1> 0.05). The systemic response was proportional to the composite response promoted by polypropylene mesh. However, the tissue inflammatory response was higher in the PP group (P = 0.0033). The number of polymorphonuclear cells increased statistically in the region of the implant in PQ group (P = 0.0068). Type I collagen and total collagen predominated in the implant regions in PP group (P = 0.0154 and P = 0.0037 respectively). It was concluded that the composite polypropylene mesh-chitosan based film has not promoted systemic response in animals, but the tissue inflammatory response was represented by a slow influx of polimornucleares. It can be inferred that the thickness of the chitosan based film was a factor that hindered the incorporation the composite by tissue receptor along with the slow degradation of the polysaccharide in vivo. / Defeitos de parede abdominal podem requerer a reconstrução anatômica e funcional, o que normalmente é conseguido com emprego de telas. Entretanto, esses materiais podem desencadear a formação de aderências. Para minimizar, ou impedir, esse processo uma das faces da tela pode ser revestida por um produto que se interponha entre este material e o peritônio visceral. O presente estudo avaliou a resposta sistêmica e tecidual ao implante do compósito tela de polipropileno-filme à base de quitosana 2QM (grupo PQ), comparado à promovida pela tela de polipropileno isolada (grupo PP), implantada intraperitonialmente na cavidade abdominal de suínos. Após 28 dias procedeu-se a avaliação por ultrassonografia, videolaparoscopia e não se observou diferença significativa entre os dois grupos de animais com relação à formação de aderências (P > 0,05). As reações sistêmicas foram avaliadas por meio da contagem de leucócitos, dosagem de proteína C-reativa, proteínas totais séricas, albumina e globulinas, que também não mostraram diferença significativa entre os grupos (P1 > 0,05). A resposta sistêmica ao compósito foi proporcional à resposta promovida pela tela de polipropileno. Entretanto, a resposta inflamatória tecidual foi maior no grupo PP (P = 0,0033). Os polimorfonucleares apresentaram-se estatisticamente aumentados na região do implante no grupo PQ (P = 0,0068). O colágeno tipo I e o colágeno total predominaram nas regiões de implante do grupo PP (P = 0,0154 e P = 0,0037 respectivamente). Concluiu-se que o compósito tela de polipropileno-filme à base de quitosana não promoveu resposta sistêmica nos animais, mas a resposta inflamatória tecidual foi representada por um influxo tardio de polimornucleares. Pode-se inferir que a elevada espessura do filme à base de quitosana e seu longo tempo de degradação in vivo (>28 dias) foram fatores que dificultaram a incorporação do compósito no tecido receptor.

A artrite induzida por pristane (PIA) em camundongos HIII (resistentes) e LIII (suscetíveis) foi usada para estudar mecanismos inflamatórios e imunes atuantes na fase pré-clínica da doença, os quais são pouco conhecidos. Estudos anteriores mostraram diferenças significativas na produção de citocinas nos animais HIII e LIII na fase pré-clínica da PIA, sugerindo forte influênica no fenótipo de PIA. A PIA foi induzida apenas por via intraperitoneal nos animais LIII, com intensa infiltração de neutrófilos, linfócitos, monócitos e macrófagos, altos níveis de IL-12p40 e maior expressão de genes de citocinas inflamatórias após a injeção de pristane. Por outro lado, na linhagem HIII houve aumento de eosinófilos e neutrófilos, mas redução de monócitos e linfócitos. Não observamos diferenças nos níveis de TNF-<font face=\"Symbol\">&#945;, IFN-<font face=\"Symbol\">g, IL-12p70, IL-17, IL-10. Concluímos que a intensidade e o tipo de resposta inflamatória na fase inicial da PIA podem ser mecanismos envolvidos na diferença de resistência/ susceptibilidade entre as linhagens HIII e LIII. / Pristane-induced arthritis (PIA) in HIII (resistant) and LIII (susceptible) mice was used in this work to characterize the cellular and molecular alterations of the pre-clinical phase of the disease, of which little is known. Previous reports showed significant differences in cytokine production of HIII and LIII mice in the pre-clinical phase of PIA, suggesting a strong influence on PIA phenotype. PIA was induced only by the intraperitoneal route in LIII animals, which showed intense infiltration of neutrophils, lymphocytes, monocytes and macrophages, with high levels of IL-12p40 after pristane injection. Inflammatory cytokine genes were also upregulated in LIII mice. On the other hand, HIII strain had increased eosinophils and neutrophils, but reduced monocytes and lymphocytes. No significant differences were found in TNF-<font face=\"Symbol\">&#945;, IFN-<font face=\"Symbol\">g, IL-12p70, IL-17, IL-10 levels. We conclude that the intensity and type of inflammatory response in the initial phase of PIA may be different mechanisms involved in resistance / susceptibility between HIII and LIII mice.

Os macrófagos (M<font face=\"Symbol\">&#934;s) compõem uma população celular altamente heterogênea, e são extensivamente adotados como ferramenta experimental, em especial os M<font face=\"Symbol\">&#934;s peritoneais murinos. O objetivo desse trabalho foi revisitar o peritônio dando ênfase à heterogeneidade dos M<font face=\"Symbol\">&#934;s. Duas populações distintas compõem os M<font face=\"Symbol\">&#934; peritoneais residentes: LPM (Large Peritoneal Macrophage) e SPM (Small Peritoneal Macrophage). Todas as condições proporcionadas in vivo resultam no desaparecimento de LPM, aumento de SPM e influxo de monócitos. Em paralelo, ocorre uma diminuição na marcação para <font face=\"Symbol\">b-galactosidase (marcador de senescência) e um aumento na produção de Óxido Nítrico (NO) e na frequência de células F4/80+IL-12+ após a subseqüente estimulação com LPS e IFN-<font face=\"Symbol\">g, que parece ser às custas da SPM. Além disso, parece haver uma especialização onde LPM assume um perfil M2 após inoculação de zimosan, e SPM um perfil M1 após reestimulo com LPS ou IFN-<font face=\"Symbol\">g.Esses dados sugerem que renovação celular que ocorre no peritônio após estimulação, parece ser benéfica para a resposta celular frente a estímulos infecciosos. / Macrophages (M<font face=\"Symbol\">&#934;) are a heterogeneous population extensively adopted as experimental model, especially peritoneal M<font face=\"Symbol\">&#934;. Then, the aim of this work was to revisit peritoneal cavity looking for M<font face=\"Symbol\">&#934; heterogeneity. Peritoneal M<font face=\"Symbol\">&#934; comprise two distinct subpopulations: LPM (Large Peritoneal Macrophage) and SPM (Small Peritoneal Macrophage). The different conditions proporcioned in vivo, resulted in the disappearance of LPM and the accumulation of SPM and monocytes. In parallel, adherent cells isolated from stimulated mice displayed reduced staining for <font face=\"Symbol\">b-galactosidase (senescence marker). Further, an increase in nitric oxide (NO) production and IL-12-producing cells frequency was observed in response to LPS/FN-<font face=\"Symbol\">g re-stimulation. In addition, there was a specialization of activation profile marked by a M2 activation profile after zymosan administered in vivo assumed by LPM, and SPM showed a bias to M1 after re-stimulation with LPS/IFN-<font face=\"Symbol\">g. Then, the substitution of LPM by a robust SPM and monocytes in response to infectious stimuli greatly improves peritoneal effector activity.

De nouvelles approches sont possibles en imagerie par résonance magnétique (IRM) pour répondre aux principaux enjeux diagnostiques et thérapeutiques liés aux maladies péritonéales. Cette technique implique l'utilisation de protocoles dédiés et une courbe d'apprentissage. Après une revue de la littérature sur l'imagerie péritonéale mettant en perspective la place de l'IRM et sa potentielle sous utilisation, l'objectif de ce travail a été d'étudier l'apport de cette technique dans deux modèles de maladies péritonéales diffuses. Le premier modèle concernait l'endométriose. En utilisant des protocoles adaptés, les études sur les atteintes digestives et diaphragmatiques ont démontré qu'une cartographie lésionnelle utile au diagnostic et à la prise en charge chirurgicale gynécologique pouvait être obtenue avec de hauts niveaux de performance. Le second modèle concernait la carcinose. La problématique était d'évaluer l'apport de l'IRM dans la sélection des patients candidats à une chirurgie menée à visée curative. La première étude menée sur une grande cohorte a démontré un très faible impact des différentes techniques d'imagerie dans la sélection des patients non résécables. La seconde étude, proposant une nouvelle approche de la quantification des lésions en combinant l'IRM au scanner, a rapporté une amélioration relative du bilan lésionnel, bien qu'encore infra optimale. Avec une approche qualitative centrée sur la recherche de signes de non résécabilité, la troisième étude a démontré que l'IRM avait une meilleure sensibilité que le scanner pour détecter les atteintes non résécables de l'intestin grêle dans le pseudomyxome péritonéal. L'IRM, grâce à sa haute résolution en contraste, offre des informations uniques. Utilisée comme technique de référence ou en complément des autres techniques en fonction de la nature des lésions à explorer, elle permet d'optimiser la prise en charge des patients / Magnetic resonance imaging (MRI) allows news approaches to improve diagnostic and therapeutic issues related to peritoneal diseases. This technique requires using dedicated protocols and has a learning curve. After a literature review on peritoneal imaging highlighting the role of MRI and its potential underutilization, the purpose of this work was to study the contribution of MRI in two models of diffuse peritoneal diseases. The first model concerned endometriosis. Using dedicated protocols, studies on digestive and diaphragmatic involvements reported high performance for providing a useful mapping of lesions for both diagnosis and surgical planning. The second model concerned peritoneal carcinomatosis. The purpose was to assess the contribution of MRI in selecting patients for curative surgery. The first study, performed in a large cohort, reported a very low impact of the different imaging techniques in the selection of non-resectable patients. Using a new approach combining MRI and computed tomography (CT), the second study demonstrated a substantial improvement in quantitative lesion assessment, although remaining sub optimal. With a qualitative approach evaluating signs of non-resectability, the third study showed MRI had better sensitivity than CT for the detection of non-resecable small bowel involvements in pseudomyxoma peritonei. MRI, thanks to its high contrast resolution, provides unique information. Used as reference technique or in addition to other techniques, MRI optimizes patient management

Les cancers de l’ovaire constituent la cinquième cause de cancer chez la femme et la principale cause de décès pour cancer gynécologique. Ce mauvais pronostique est lié à un diagnostic tardif de la maladie et à l’acquisition de la résistance au sel de platine. L’individualisation thérapeutique est nécessaire compte tenu de l’évolution très clinique hétérogène malgré une histologie et un stade similaire. Les facteurs pronostiques classiques comme l’âge, le stade FIGO, le type histologique, le grade et le résultat chirurgical, ne sont pas suffisants pour prédire la réponse thérapeutique et le pronostique. Cette hétérogénéité clinique est probablement expliqué par l’existence des formes biologiques différentes. La réponse clinique initiale à la chimiothérapie chez la plupart des patientes suivi d’une récidive dans plus de la moitié des cas suggère l’existence d’une subpopulation des cellules qui développe des mécanismes de résistance et survivent. Le TGCA a retrouvé des mutations au niveau de TP53 dans plus de 95% des patientes avec un cancer séreux de l’ovaire à haut grade. Ils ont trouvé une prévalence élevé de mutations somatiques mais peu récurrentes, avec un nombre important des variations du nombre de copies. La recombinaison homologue est défectueuse dans la moitié des tumeurs analysées et les voies de signalisation NOTCH et FOXM1 sont également impliqués. La mutation TP53 et les défets de réparation d’ADN provoquent une instabilité génétique et favorisent une diversité génétique. Il y a des données dans la littérature sur l’hétérogénéité existante entre différentes localisations des cancers de l’ovaire en fonction du moment de la maladie chez la même patiente et chez des patientes différentes avec la même histologie. Nous avons centré notre étude sur la caractérisation de l´expression génique des métastases péritonéales sur une série de patientes avec un cancer sereux de haut grade de l’ovaire en carcinose péritonéale. Nous avons montré des profils géniques différents entre les localisations péritonéales et la tumeur primitive. Nous avons mis en évidence que les gènes présentant des variations d’expression génique les plus marquées au niveau du péritoine codaient pour des protéines impliquées dans les voies de signalisation des principales cytokines intervenant dans l’oncogenèse dont la voie JAK/STAT. Ces voies de signalisation sont probablement impliquées dans la réponse des tumeurs à leur microenvironnement au niveau du péritoine (J Translational medicine 2012). Nous avons réalisé une deuxième étude pour combiner le séquençage génomique et transcriptomique au niveau des prelevements multi-site des patientes avec un cancer de haut grade de l´ovaire afin d’évaluer s’il existe des différences d’expression allélique. 43 gènes montrent des variants alléliques communs à tous les patients. La majorité des gènes presentent une expresión preferentielle par site mais les voies de sigalisation sont similaires pour les localisations peritoneales et pour les tumeurs primitives. Ces produits codent des protéines impliquées dans les voies de signalisation impliquées dans l’adhésion, la migration cellulaire, la réparation de l’ADN ou la croissance cellulaire et peuvent être des cibles thérapeutiques éventuelles (PLOS Genetics under final review). / Ovarian cancer is the fifth most common cause of cancer in women and the leading cause of death in gynaecological cancer. This low survival rate is due to the frequent diagnosis of epithelial ovarian cancer at an advanced stage, and to intrinsic and acquired resistance to platinum-based chemotherapy. Individualisation of treatment is necessary since EOC is a heterogeneous disease. Patients with morphologically similar, advanced-stage tumours display a broad range of clinical outcomes. Prognostic features, including patient’s age, performance status, FIGO stage, histological tumour grade and subtype, and initial surgery results, are insufficient to capture the important individual variations in response to chemotherapy and survival. This heterogeneous outcome suggests the existence of biologically different forms. The Cancer Genome Atlas (TCGA) found that TP53 mutations are present in more than 95% of HGSOC. They found a high prevalence of somatic mutations, but there is a low prevalence of recur¬rent mutations; and there are large-scale copy number aberrations. Initial analyses also suggest that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in ovarian cancer pathogenesis. However, TP53 mutation and frequent germline and somatic DNA repair defects lead to genetic instability with the potential to generate genetic diversity. Indeed, genetic heterogeneity by different mutational profiles throughout time among different tumor localisations within the same patient, and between patients have been reported.We have focused our research on the charecterisation of peritoneal gene expression profiles compared to primary ovarian lesions. High-density gene expression arrays demonstrate significant different gene expression profiles compared to theirs matched ovarian primary tumors. Differentially expressed genes are enriched in specific pathways, including cell adhésion, cytokine signaling and specifically JAK-STAT pathway. Underlying copy number variation significantly affect gene expression, and patients with copy number alterations displayed greater gene expression différences between their peritoneal and matched primary ovarian lesions (J Translational medicine 2012). In a second study, we performed a combined genome and transcriptome analysis form multi-site samples form ovarian cancer patients to identify preferentially expressed alleles. 43 genes shared across all patients presented significant allele variants. Patients clustered together but every sample and site clustered independently at the variant level. Most genes seemed site-specific but there were similar pathways in the primary and metastatic sites. Preferentially expressed alleles could act as cancer drivers and therefore they can constitute a new therapeutic target (PLOS Genetics under final review).

Le mésothéliome est une tumeur maligne rare des séreuses, au pronostic sombre, dont le facteur de risque principal connu est l’exposition à l’amiante. Il se déclare avec un temps de latence d’environ 30 ans après le début de l’exposition, atteint principalement la plèvre et touche majoritairement les hommes. L’analyse de cette pathologie, reconnue comme une maladie professionnelle et pour laquelle une Déclaration Obligatoire de maladie a été instituée en janvier 2012, s’est focalisée jusqu’alors essentiellement sur l’homme, tant sur le plan épidémiologique que sur le plan biologique. Il apparaît pourtant dans la littérature internationale des différences notables par sexe.Ces constations posent la question d’investiguer d’autres facteurs de risque, en particulier l’hypothèse d’une prédisposition génétique, les mécanismes biologiques intervenant dans les voies de la carcinogenèse du mésothéliome étant partiellement connus. Ceci incite à étudier les facteurs épidémiologiques, cliniques, biologiques et immunohistochimiques, prédisposant chez la femme au développement du mésothéliome pleural et péritonéal, et d’évaluer leurs impacts pronostiques, à partir des cas diagnostiqués entre 1998 et 2013, issus de la plus importante base de données française. Elle incite également à établir un état des lieux épidémiologique actualisé par sexe en France pour le mésothéliome pleural et péritonéal ; ces données étant inexistantes pour la France pour le péritoine. / Mesothelioma is a rare malignant serous tumor with a poor prognosis of which asbestos exposure is the major known risk factor. It occurs with a latent period about 30 years after exposure, reaches mainly the pleura and affects mainly the men. The study of this pathology, recognized as an occupationnal disease and for which a Mandatory Declaration of Disease was introduced in January 2012, focused until then mainly on men, both epidemiologically and biologically. However, there are significant gender differences in the international literature.These results raise the question of investigating other risk factors, in particular the hypothesis of genetic predisposition, the biological mechanisms involved in mesothelioma carcinogenesis pathways being partially known. This encourages the study of epidemiological, clinical, biological and immunohistochemical factors predisposing women to the development of pleural and peritoneal mesothelioma, and to evaluate their prognostic impacts, based on cases diagnosed between 1980 and 2015, from the largest French database. It also encourages the establishment of an updated epidemiological inventory by gender in France for pleural and peritoneal mesothelioma; these data are non-existent for peritoneum.