PPM1D mutations silence NAPRT gene expression and confer NAMPT inhibitor sensitivity in glioma.

Pediatric high-grade gliomas are among the deadliest of childhood cancers due to limited knowledge of early driving events in their gliomagenesis and the lack of effective therapies available. In this study, we investigate the oncogenic role of PPM1D, a protein phosphatase often found truncated in pediatric gliomas such as DIPG, and uncover a synthetic lethal interaction between PPM1D mutations and nicotinamide phosphoribosyltransferase (NAMPT) inhibition. Specifically, we show that mutant PPM1D drives hypermethylation of CpG islands throughout the genome and promotes epigenetic silencing of nicotinic acid phosphoribosyltransferase (NAPRT), a key gene involved in NAD biosynthesis. Notably, PPM1D mutant cells are shown to be sensitive to NAMPT inhibitors in vitro and in vivo, within both engineered isogenic astrocytes and primary patient-derived model systems, suggesting the possible application of NAMPT inhibitors for the treatment of pediatric gliomas. Overall, our results reveal a promising approach for the targeting of PPM1D mutant tumors, and define a critical link between oncogenic driver mutations and NAD metabolism, which can be exploited for tumor-specific cell killing

Collective identity and well-being of Bulgarian Roma adolescents and their mothers

In Europe and specifically in Bulgaria, Roma represent the largest indigenous ethnic minority exposed to severe discrimination, social exclusion, poverty, and compromised well-being. To improve their conditions, identifying sources of psychological well-being for Roma is theoretically relevant and practically important. This study investigated the relation between ethnic, familial, and religious identities as salient collective identity components for psychological well-being among 194 Roma adolescents (age: M = 16.11 years, SD = 1.36) and their mothers (age: M = 35.95 years, SD = 3.54). The results indicated that in line with marginalization models of acculturation, Roma youth and their mothers showed a low endorsement of both Bulgarian mainstream and Roma ethnic identity. The average scores of well-being were also low. For both groups, familial identity was stronger compared to Roma, Bulgarian, and religious identity. A path model showed that collective identity was a positive predictor of well-being in both adolescents and mothers and that the mothers' collective identity was a predictor of adolescent well-being. Bulgarian mainstream identity had the strongest relationship with collective identity. It is concluded that, for Roma youth and their mothers, family is an important identity domain as it represents the most salient identification source that is not challenged in their environment