Activation de la voie oncogénique mTOR par les formes mutées de l'isocitrate déshydrogénase 1/2 retrouvées chez les gliomes

Une des caractéristiques principales des cellules cancéreuses est la reprogrammation de leur métabolisme énergétique. Des mutations d’enzymes impliquées dans différentes voies métaboliques sont récurrentes chez plusieurs tumeurs, contribuant ainsi à la dérégulation de ces cellules et à l’oncogénèse. C’est le cas de l’isocitrate déshydrogénase 1 (IDH1) et 2 (IDH2), responsables de la conversion de l’isocitrate en α-kétoglutarate dans le cycle de l’acide citrique. Ces enzymes sont fréquemment mutées chez les gliomes, acquérant ainsi la capacité de convertir l’α-kétoglutarate en 2-hydroxyglutarate (2HG), un oncométabolite inhibant les oxygénases α-kétoglutarate dépendantes parmi lesquelles figure notamment KDM4A, une déméthylase de lysines. À la recherche de nouvelles voies oncogéniques potentiellement régulées par les formes mutées de IDH1/2, nous avons initialement observé que les mutations de ces deux enzymes et de PTEN, un régulateur négatif de la voie mTOR, étaient mutuellement exclusives chez les gliomes. Ceci suggère que les mutations de IDH1/2 reproduiraient certains effets engendrés par les mutations de PTEN, créant ainsi un environnement oncogénique similaire. Nous avons observé que les formes mutées de IDH1/2 stimulent l’activation de mTOR grâce à la production et l’accumulation de 2HG. Cette activation repose en partie sur l’inhibition de KDM4A par cet oncométabolite. KDM4A est impliqué dans la stabilisation de DEPTOR, un inhibiteur de mTOR. Ainsi, l’inhibition de KDM4A par le 2HG entraîne la déstabilisation de DEPTOR et, par conséquent, l’activation de mTOR. Nos travaux ont donc permis l’identification d’un nouveau mécanisme oncogénique régulé par les formes mutées de IDH1/2 retrouvées chez les gliomes, soit l’activation de mTOR.One hallmark of cancer cells is the reprogramming of their energy metabolism. Tumors often have mutations in the enzymes regulating the different metabolic pathways, which contribute to dysregulation of the cells and oncogenesis. Among these enzymes is the isocitrate deshydrogenase 1 (IDH1) and 2 (IDH2), converting isocitrate to α-ketoglutarate in the citric acid cycle. They are frequently mutated in gliomas, which alters their function. In fact, once mutated, IDH1/2 acquire the capacity to convert α-ketoglutarate to 2-hydroxyglutarate (2HG), an oncometabolite inhibiting α-ketoglutarate dependant enzyme such as KDM4A, a lysine demethylase. Looking towards new oncogenic pathways potentially regulated by mutations of IDH1/2, we first observed that these mutations and mutations in PTEN, which is a negative regulator of the mTOR signaling pathway, are mutually exclusive in gliomas. This suggests that mutations of these enzymes could mimic some effects of PTEN mutations and thus create a similar oncogenic environment. We found that IDH1/2 mutations could activate the mTOR pathway through 2HG production and accumulation. This activation relies in part on KDM4A inhibition by the oncometabolite. KDM4A is involved in stabilizing DEPTOR, an mTOR inhibitor. Thus, KDM4A inhibition by 2HG leads to DEPTOR destabilisation, resulting in mTOR activation. Overall, this work defines mTOR activation as a new mechanism regulated by IDH1/2 mutations in gliomas

The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway

The identification of cancer-associated mutations in the tricarboxylic acid (TCA) cycle enzymes isocitrate dehydrogenases 1 and 2 (IDH1/2) highlights the prevailing notion that aberrant metabolic function can contribute to carcinogenesis. IDH1/2 normally catalyse the oxidative decarboxylation of isocitrate into α-ketoglutarate (αKG). In gliomas and acute myeloid leukaemias, IDH1/2 mutations confer gain-of-function leading to production of the oncometabolite R-2-hydroxyglutarate (2HG) from αKG. Here we show that generation of 2HG by mutated IDH1/2 leads to the activation of mTOR by inhibiting KDM4A, an αKG-dependent enzyme of the Jumonji family of lysine demethylases. Furthermore, KDM4A associates with the DEP domain-containing mTOR-interacting protein (DEPTOR), a negative regulator of mTORC1/2. Depletion of KDM4A decreases DEPTOR protein stability. Our results provide an additional molecular mechanism for the oncogenic activity of mutant IDH1/2 by revealing an unprecedented link between TCA cycle defects and positive modulation of mTOR function downstream of the canonical PI3K/AKT/TSC1-2 pathway

Profiles of Parental Burnout Around the Globe: Similarities and Differences Across 36 Countries

Parental burnout (PB) is a pervasive phenomenon. Parenting is embedded in cultural values, and previous research has shown the role of individualism in PB. In this paper, we reanalyze previously collected data to identify profiles based on the four dimensions of PB, and explore whether these profiles vary across countries’ levels of collectivistic-individualistic (COL-IND) values. Our sample comprised 16,885 individuals from 36 countries (73% women; 27% men), and we used a latent profile approach to uncover PB profiles. The findings showed five profiles: Fulfilled, Not in PB, Low risk of PB, High risk of PB and Burned out. The profiles pointed to climbing levels of PB in the total sample and in each of the three country groups (High COL/Low IND, Medium COL-IND, Low COL/High IND). Exploratory analyses revealed that distinct dimensions of PB had the most prominent roles in the climbing pattern, depending on the countries’ levels of COL/IND. In particular, we found contrast to be a hallmark dimension and an indicator of severe burnout for individualistic countries. Contrary to our predictions, emotional distance and saturation did not allow a clear differentiation across collectivistic countries. Our findings support several research avenues regarding PB measurement and intervention

Médias et printemps étudiant au Québec 2012

Un mouvement de contestation étudiante d’envergure a secoué le Québec de février à septembre 2012 suite à l’annonce d’une importante hausse des frais universitaires. Connu comme le «Printemps érable» , ce conflit a bénéficié d’une considérable couverture médiatique qui a été critiquée par plusieurs observateurs pour son manque d’impartialité. Cet article se penche sur les biais du travail journalistique à l’aide de la notion de cadrage de l’information. À cet effet, un corpus d’articles provenant de quotidiens montréalais a été analysé pour y débusquer les éventuelles traces d’interventions journalistiques sur le contenu de l’information en fonction d’intérêts idéologiques propres à ce conflit.Carbonneau Jean-Rémi, Desrochers Mélissa. Médias et printemps étudiant au Québec 2012. In: Recherches Internationales, n°111, 2017. L’enseignement supérieur marchandisé et mondialisé. pp. 111-131

Profiles of Parental Burnout Around the Globe: Similarities and Differences Across 36 Countries

Parental burnout (PB) is a pervasive phenomenon. Parenting is embedded in cultural values, and previous research has shown the role of individualism in PB. In this paper, we reanalyze previously collected data to identify profiles based on the four dimensions of PB, and explore whether these profiles vary across countries’ levels of collectivistic-individualistic (COL-IND) values. Our sample comprised 16,885 individuals from 36 countries (73% women; 27% men), and we used a latent profile approach to uncover PB profiles. The findings showed five profiles: Fulfilled, Not in PB, Low risk of PB, High risk of PB and Burned out. The profiles pointed to climbing levels of PB in the total sample and in each of the three country groups (High COL/Low IND, Medium COL-IND, Low COL/High IND). Exploratory analyses revealed that distinct dimensions of PB had the most prominent roles in the climbing pattern, depending on the countries’ levels of COL/IND. In particular, we found contrast to be a hallmark dimension and an indicator of severe burnout for individualistic countries. Contrary to our predictions, emotional distance and saturation did not allow a clear differentiation across collectivistic countries. Our findings support several research avenues regarding PB measurement and intervention

Three reasons why parental burnout is more prevalent in individualistic countries: A 36-country study

Abstract Purpose The prevalence of parental burnout, a condition that has severe consequences for both parents and children, varies dramatically across countries and is highest in Western countries characterized by high individualism. Method In this study, we examined the mediators of the relationship between individualism measured at the country level and parental burnout measured at the individual level in 36 countries (16,059 parents). Results The results revealed three mediating mechanisms, that is, self-discrepancies between socially prescribed and actual parental selves, high agency and self-directed socialization goals, and low parental task sharing, by which individualism leads to an increased risk of burnout among parents. Conclusion The results confirm that the three mediators under consideration are all involved, and that mediation was higher for self-discrepancies between socially prescribed and actual parental selves, then parental task sharing, and lastly self-directed socialization goals. The results provide some important indications of how to prevent parental burnout at the societal level in Western countries.</jats:p

Gender Equality and Maternal Burnout : A 40-Country Study

In Western countries, recent decades have witnessed a revolution toward gender equality. Inequalities have been greatly reduced in areas such as education or employment. Because inequalities lead to distress, this development has largely benefited women. One notable exception is the realm of parenting, which has remained rife with inequalities even in the most egalitarian countries. We hypothesized that experiencing inequality in parenting when one holds egalitarian values and raising a child in a country characterized by a high level of gender equality in other areas, increases mothers’ psychological distress in the specific area of parenting. Multilevel modeling analyses computed among 11,538 mothers from 40 countries confirmed this prediction: high egalitarian values at the individual level and high gender equality at the societal level are associated with higher burnout levels in mothers. The associations hold beyond differences in sociodemographic characteristics at the individual level and beyond economic disparities at the societal level. These findings show the importance of egalitarian values and gender equality and their paradoxical effect when inequalities are still present in specific areas as parenting. This study reveals the crucial need to act not only at the micro level but also at the macro level to promote gender equality in parenting and prevent parental burnout.peerReviewe

Parental burnout around the globe: A 42-country study

High levels of stress in the parenting domain can lead to parental burnout, a condition that has severe consequences for both parents and children. It is not yet clear, however, whether parental burnout varies by culture, and if so, why it might do so. In this study, we examined the prevalence of parental burnout in 42 countries (17,409 parents; 71% mothers; Mage = 39.20) and showed that the prevalence of parental burnout varies dramatically across countries. Analyses of cultural values revealed that individualistic cultures, in particular, displayed a noticeably higher prevalence and mean level of parental burnout. Indeed, individualism plays a larger role in parental burnout than either economic inequalities across countries, or any other individual and family characteristic examined so far, including the number and age of children and the number of hours spent with them. These results suggest that cultural values in Western countries may put parents under heightened levels of stress

Parental Burnout Around the Globe : a 42-Country Study.

High levels of stress in the parenting domain can lead to parental burnout, a condition that has severe consequences for both parents and children. It is not yet clear, however, whether parental burnout varies by culture, and if so, why it might do so. In this study, we examined the prevalence of parental burnout in 42 countries (17,409 parents; 71% mothers; Mage = 39.20) and showed that the prevalence of parental burnout varies dramatically across countries. Analyses of cultural values revealed that individualistic cultures, in particular, displayed a noticeably higher prevalence and mean level of parental burnout. Indeed, individualism plays a larger role in parental burnout than either economic inequalities across countries, or any other individual and family characteristic examined so far, including the number and age of children and the number of hours spent with them. These results suggest that cultural values in Western countries may put parents under heightened levels of stress. Supplementary Information: The online version contains supplementary material available at 10.1007/s42761-020-00028-4