RESUMEN
Aberrant gene-silencing through dysregulation of polycomb protein activity has emerged as an important oncogenic mechanism in cancer, implicating polycomb proteins as important therapeutic targets. Recently, an inhibitor targeting EZH2, the methyltransferase component of PRC2, received U.S. Food and Drug Administration approval following promising clinical responses in cancer patients. However, the current array of EZH2 inhibitors have poor brain penetrance, limiting their use in patients with central nervous system malignancies, a number of which have been shown to be sensitive to EZH2 inhibition. To address this need, we have identified a chemical strategy, based on computational modeling of pyridone-containing EZH2 inhibitor scaffolds, to minimize P-glycoprotein activity, and here we report the first brain-penetrant EZH2 inhibitor, TDI-6118 (compound 5). Additionally, in the course of our attempts to optimize this compound, we discovered TDI-11904 (compound 21), a novel, highly potent, and peripherally active EZH2 inhibitor based on a 7 member ring structure.
RESUMEN
The federal health portfolio has conducted surveillance on child maltreatment as a public health issue since the 1990s. The Public Health Agency of Canada (PHAC) is now releasing the Child Maltreatment Indicator Framework, to take its place alongside other PHAC frameworks, such as the Suicide Surveillance Indicator Framework. Based on a scoping review of existing reviews and meta-analyses, this Framework, along with the online interactive data tool, presents child maltreatment outcome indicators and risk and protective factors at the individual, family, community and societal levels, disaggregated by sex, age and other sociodemographic variables. This Framework will function as a valuable resource pertaining to an issue that affects at least one in three Canadian adults.
The Child Maltreatment Surveillance Indicator Framework complements other indicator frameworks released by the Public Health Agency of Canada and presents available data on child maltreatment outcomes and risk and protective factors at the individual, family, community and societal level. One-third (34.1%) of the Canadian population aged 15 years and older have experienced at least one type of childhood maltreatment. Physical abuse was experienced most often (27.4%), followed by exposure to intimate partner violence (10.6%) and sexual abuse (8.1%). Factors such as parental mental illness, substance use and past experience of family violence can put children at higher risk of child maltreatment.
Le Cadre d'indicateurs de la maltraitance envers les enfants vient compléter d'autres cadres d'indicateurs publiés par l'Agence de la santé publique du Canada et présente des données sur les résultats et les facteurs de risque et de protection de la violence envers les enfants, aux échelles individuelle, familiale, communautaire et sociétale. Le tiers (34,1 %) de la population canadienne âgée de 15 ans et plus a été victime d'au moins un type de maltraitance durant l'enfance. La violence physique est le type de maltraitance le plus répandu (27,4 %), suivie de l'exposition à la violence entre partenaires intimes (10,6 %) et de l'abus sexuel (8,1 %). Des facteurs présents chez les parents tels que la maladie mentale, la consommation de substances et le fait d'avoir été victime de violence familiale peut exposer les enfants à un risque plus élevé de maltraitance.