Replication stress identifies novel molecular classification associated with treatment outcomes in pancreatic cancer.

BACKGROUND: Replication stress is a prominent hallmark of tumor cells, which is crucial for maintaining genomic integrity. However, it remains poorly understood whether replication stress can serve as a surrogate biomarker to indicate prognosis and treatment response of pancreatic cancer. METHODS: Transcriptomic and clinical data were obtained from The Cancer Genome Atlas and literature. An integrated signature of 18 replication-stress associated genes (termed as REST18) was established using the cox proportional hazards regression analysis. Tumors were sorted into REST18-low and REST18-high groups. Survival analysis, gene set enrichment analysis and composition of immune cells were compared between these tumors. RESULTS: Patients with REST18-high tumors showed worse prognoses than those with REST18-low tumors in the TCGA database and the finding is validated in an independent cohort of pancreatic cancer. Comparison of REST18 model and other molecular classifications showed that REST18-high tumors are positively correlated to basal-like or squamous phenotypes, which have higher metastasis potential. DNA repair pathway is enriched in the REST18-high tumors. Analysis of tumor immune microenvironment found that REST18-high tumors are characterized with "immune-cold" features. Univariate and multivariate analysis show that REST18 is an independent risk factor for overall survival and predicts outcomes of chemotherapy in pancreatic cancer. CONCLUSION: REST18 is a novel biomarker to indicate prognosis and treatment response of chemotherapy in pancreatic cancer.

Differential effects of gram-positive and gram-negative bacterial products on morphine induced inhibition of phagocytosis.

Opioid drug abusers have a greater susceptibility to gram positive (Gram (+)) bacterial infections. However, the mechanism underlying opioid modulation of Gram (+) versus Gram (-) bacterial clearance has not been investigated. In this study, we show that opioid treatment resulted in reduced phagocytosis of Gram (+), when compared to Gram (-) bacteria. We further established that LPS priming of chronic morphine treated macrophages leads to potentiated phagocytosis and killing of both Gram (+) and Gram (-) bacteria in a P-38 MAP kinase dependent signaling pathway. In contrast, LTA priming lead to inhibition of both phagocytosis and bacterial killing. This study demonstrates for the first time the differential effects of TLR4 and TLR2 agonists on morphine induced inhibition of phagocytosis. Our results suggest that the incidence and severity of secondary infections with Gram (+) bacteria would be higher in opioid abusers.