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Malignant pleural mesothelioma (MPM) is an aggressive cancer of the pleura mainly caused by asbestos fibers exposure. MPM is notably characterized by a very poor prognosis and current treatments, including radiation and chemotherapy, are unsatisfactory. As genomic analyzes show that the major mutations occurring in MPM cells pertain to checkpoint control and DNA repair, a first part of this thesis addresses the DNA damage response and the mechanisms of DNA repair in several MPM cell lines. In this study, we show that gamma ionizing radiation (IR) induces cell cycle arrest of MPM cells at the G2-M checkpoint. We also demonstrate that MPM cells are driven prematurely towards mitosis following the abrogation of IR-induced G2 arrest by the checkpoint inhibitor UCN-01, however without a significant induction of cell death. To avoid excessive genomic instability, DNA repair mechanisms are likely to play a key role in such DNA-damaging conditions. We therefore evaluate here the efficiencies of the two main DNA double-strand break repair mechanisms, non-homologous end-joining (NHEJ) and homologous recombination (HR) and highlight differences in such repair activities among MPM cell lines and in comparison to control mesothelial cells. We underline an efficient HR repair in MPM cells, opening the door to additional investigations that might reveal an addiction to activated DNA repair pathways and thereby render MPM cells hypersensitive to targeted combination therapies. In the second part of this thesis, we perform a pre-clinical study investigating the resistance of MPM to a particular epigenetic-based therapy associating the histone deacetylase (HDAC) inhibitor valproic acid (VPA) and doxorubicin. By comparing MPM cell lines with a differential sensitivity to this combination chemotherapy, this study suggests a correlation between transforming growth factor-alpha (TGF-α) expression and resistance to treatment. We further confirm the role of TGF-α in chemoresistance by modulating its expression in highly- and poorly responsive MPM cell lines. In addition, pharmacological inhibition of TGF-α's receptor (EGFR or epidermal growth factor receptor) by tyrosine kinase inhibitors gefitinib and erlotinib improves the efficacy of VPA+doxorubicin in vitro. Dual HDAC-EGFR inhibitor CUDC-101 furthermore synergizes with doxorubicin to induce apoptosis in vitro and to slow down tumor growth in two different MPM mouse models, emphasizing its therapeutic potential and opening new prospects for combination therapies associating HDAC and EGFR inhibition against MPM. With two different approaches, this thesis provides a better understanding of MPM resistance to chemo- and radiotherapies and offers clues for new therapeutic strategies based on DNA repair pathways and dual HDAC-EGFR/TGF-α inhibition.

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Childhood obesity and overweight have become one of the most serious health issues in the 21st century. While obesity in children can be associated with dramatic health and social consequences, developing new ways and tools to prevent childhood obesity and overweight is much needed. Dietary intake characteristics and food choices are being part of the risk factors contributing to the development of obesity in children and adolescents. Trying to influence people’s thoughts and behaviors, such as promoting good dietary habits, is the objective of several social marketing programs. In this study, we aimed to evaluate how the humanizing of food products (i.e. the anthropomorphization of two vegetables), along with the level of familiarity with those products, can influence attitudes and behaviors of children, such as the attitude toward the ad and the purchase intention. 
With this aim, we designed a well-controlled school-based study with a 7 to 12-year-old children-targeted questionnaire. While children clearly showed a better knowledge and preference of one vegetable over the other, our study highlighted that attitudes and behaviors of children are influenced by the level of familiarity with these products. On the other hand, although the vegetables’ anthropomorphization was well perceived by children, only low or moderate effects of food humanizing have been observed. However, this study opens the door for further investigation and research, including food anthropomorphization, in order to develop the best intervention strategies, also targeting parental behavior and physical activity, and thereby significantly improve the prevention of childhood obesity.

childhood obesity --- social marketing --- food anthropomorphization --- eating behavior --- Sciences économiques & de gestion > Marketing