The Poly (ADP-ribose) polymerase (PARP) family has numerous essential functions in cellular processes such as transcription, chromatin remodelling, DNA damage response and repair as well as apoptosis. PARP inhibition blocks base excision repair and results in conversion of SSBs to DNA double-strand break (DSBs), the most deleterious form of DNA damage. DSBs can be repaired by homologous recombination repair (HRR) or non-homologous end joining (NHEJ). The physiological importance of HRR is underscored by the observation of genomic instability in HRR-deficient (HRD+) cells and, importantly, the association of cancer predisposition and developmental defects with mutations in HRR genes. PARP1 and PARP2 are required for SSB repair, while PARP1 is also involved in the repair of DNA double-strand breaks (DSBs) and replication fork damage. AZD9574 is a novel brain penetrant PARP1 inhibitor that acts by selectively inhibiting and trapping PARP1 at the sites of SSBs. While AZD9574 inhibited PARP1 enzymatic activity in all tested cell lines irrespective of the HRR status (IC50 range between 0.3 – 2 nM), colony formation assay in isogenic cell lines pairs confirmed higher potency and selectivity towards HRD+ models. In vivo, AZD9574 demonstrated dose-dependent efficacy in a BRCA1 mutant MDA-MB-436 subcutaneous xenograft model. Anti-tumour effects of AZD9574 were manifested by significant growth regressions that were durable after treatment withdrawal. An intracranial xenograft model of breast cancer brain metastases was developed to assess the efficacy of AZD9574 in the context of blood-brain barrier penetrance. Treatment of animals with established intracranial lesions showed sustained tumour growth suppression resulting in a significantly extended survival of tumour-bearing mice. Collectively, we believe that our data support the development of AZD9574 as a potential therapy for patients with HRD+ breast cancer whose disease has spread to the brain.This abstract was previously presented at AACR 2022 (Hamerlik et al, AACR 2022, Abs #3880)
Sommaire: À partir d'une analyse de la littérature, puis d'une étude empirique auprès d'un échantillon homogène de fonctionnaires fédéraux, l'article examine les liens entre, d'une part, les principaux indicateurs psychologiques et attitudinaux au travail (indicateurs souvent utilisés pour prédire la propension à quitter des employés) et d'autre part, les étapes de carrière de ces mêmes employés. En établissant les étapes de carrière en fonction des préoccupations de carrière actuelles des employés, les résultats démontrent que les répondants aux périodes d'exploration et de désengagement de leur carrière rapportent ceci: de façon généale, leurs attitudes au travail sont plus négatives que ceux qui se situent aux périodes d'établissement et de maintien. Les constats de l'étude soulèvent des enjeux importants pour la gestion des ressources humaines dans le secteur public et laissent entrevoir des pistes pratiques d'intervention pour une plus grande mobilisation et rétention des employés.
Abstract: Through an analytical review of the literature, followed by an empirical study conducted among a homogeneous sampling of federal public servants, the article examines the relationships between, on the one hand, the key psychological and attitudinal indicators in the workplace (indicators that are often used to predict an employee's propensity to quit his or her employment) and, on the other hand, the career steps of these same employees. When the career steps are established on the basis of the employees' actual concerns in terms of their careers, the results demonstrate that respondents who are either in the exploration or disengagement phase of their careers report the following: in general, their attitudes towards work are more negative than the attitudes of those who are in the middle of establishing or maintaining their careers. The study's findings raise important issues with respect to human resources management in the public sector, and suggest practical avenues for action aimed at ensuring greater employee mobilization and retention.
Le modèle transactionnel du stress est l'un des modèles explicatifs les mieux connus. Par un mécanisme de double évaluation, cette perspective cognitivo-phénoménologique propose que l'état de stress émane d'une inadéquation entre les demandes contextuelles et les ressources personnelles. Peu de validations intégrales de ce modèle ont été effectuées jusqu’à maintenant. Cette étude propose une vérification de l’ensemble de la dynamique transactionnelle du stress en contexte professionnel au moyen d’une étude transversale auprès de 420 enseignants. L'étude cherche à vérifier la séquence sous-jacente au modèle transactionnel ainsi que divers effets médiateurs/modérateurs issus de l'intervention de certaines caractéristiques individuelles. Les résultats des analyses statistiques permettent globalement de considérer que la perspective transactionnelle est une façon efficace de conceptualiser le stress au travail en milieu scolaire.
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