Epigenetic priming targets tumor heterogeneity to shift transcriptomic phenotype of pancreatic ductal adenocarcinoma towards a Vitamin D susceptible state.

As a highly heterogeneous tumor, pancreatic ductal adenocarcinoma (PDAC) exhibits non-uniform responses to therapies across subtypes. Overcoming therapeutic resistance stemming from this heterogeneity remains a significant challenge. Here, we report that Vitamin D-resistant PDAC cells hijacked Vitamin D signaling to promote tumor progression, whereas epigenetic priming with glyceryl triacetate (GTA) and 5-Aza-2'-deoxycytidine (5-Aza) overcame Vitamin D resistance and shifted the transcriptomic phenotype of PDAC toward a Vitamin D-susceptible state. Increasing overall H3K27 acetylation with GTA and reducing overall DNA methylation with 5-Aza not only elevated the Vitamin D receptor (VDR) expression but also reprogrammed the Vitamin D-responsive genes. Consequently, Vitamin D inhibited cell viability and migration in the epigenetically primed PDAC cells by activating genes involved in apoptosis as well as genes involved in negative regulation of cell proliferation and migration, while the opposite effect of Vitamin D was observed in unprimed cells. Studies in genetically engineered mouse PDAC cells further validated the effects of epigenetic priming for enhancing the anti-tumor activity of Vitamin D. Using gain- and loss-of-function experiments, we further demonstrated that VDR expression was necessary but not sufficient for activating the favorable transcriptomic phenotype in respond to Vitamin D treatment in PDAC, highlighting that both the VDR and Vitamin D-responsive genes were prerequisites for Vitamin D response. These data reveal a previously undefined mechanism in which epigenetic state orchestrates the expression of both VDR and Vitamin D-responsive genes and determines the therapeutic response to Vitamin D in PDAC.

The Role of Self-Esteem in the Academic Performance of Rural Students in China.

The self-esteem of students may be significantly associated with their academic performance. However, past research in developing contexts on this issue is limited, particularly among early adolescents. Using a sample of 3101 students from rural primary and junior high schools in China, this study measured their self-esteem by the Rosenberg Self-Esteem Scale (RSES) and explored its association with academic performance. Our findings indicate that students in rural China had both significantly lower self-esteem and a higher prevalence of low self-esteem when compared to past studies of similarly aged students both from urban China and internationally. Furthermore, there was a strong positive correlation between a student's self-esteem and academic performance. A one-SD increase in RSES score (indicating better self-esteem) was associated with an increase of 0.12 SD in standardized math scores (p < 0.001), and students with low self-esteem (RSES score < 25) scored lower on math tests by 0.14 SD (p < 0.001), which were robust and consistent when employing the propensity score matching method. Our study expands the growing body of empirical evidence on the link between self-esteem and academic performance among rural youth in developing countries and emphasizes the need to improve their self-esteem with the aim of helping them achieve academically.