PDX1 DNA methylation distinguishes two subtypes of pancreatic neuroendocrine neoplasms with a different prognosis

DNA methylation is a crucial epigenetic mechanism for gene expression regulation and cell differentiation. Furthermore, it was found to play a major role in multiple pathological processes, including cancer. In pancreatic neuroendocrine neoplasms (PNENs), epigenetic deregulation is also considered to be of significance, as the most frequently mutated genes have an important function in epigenetic regulation. However, the exact changes in DNA methylation between PNENs and the endocrine cells of the pancreas, their likely cell-of-origin, remain largely unknown. Recently, two subtypes of PNENs have been described which were linked to cell-of-origin and have a different prognosis. A difference in the expression of the transcription factor PDX1 was one of the key molecular differences. In this study, we performed an exploratory genome-wide DNA methylation analysis using Infinium Methylation EPIC arrays (Illumina) on 26 PNENs and pancreatic islets of five healthy donors. In addition, the methylation profile of the PDX1 region was used to perform subtyping in a global cohort of 83 PNEN, 2 healthy alpha cell and 3 healthy beta cell samples. In our exploratory analysis, we identified 26,759 differentially methylated CpGs and 79 differentially methylated regions. The gene set enrichment analysis highlighted several interesting pathways targeted by altered DNA methylation, including MAPK, platelet-related and immune system-related pathways. Using the PDX1 methylation in 83 PNEN, 2 healthy alpha cell and 3 healthy beta cell samples, two subtypes were identified, subtypes A and B, which were similar to alpha and beta cells, respectively. These subtypes had different clinicopathological characteristics, a different pattern of chromosomal alterations and a different prognosis, with subtype A having a significantly worse prognosis compared with subtype B (HR 0.22 [95% CI: 0.051–0.95], p = 0.043). Hence, this study demonstrates that several cancer-related pathways are differently methylated between PNENs and normal islet cells. In addition, we validated the use of the PDX1 methylation status for the subtyping of PNENs and its prognostic importance

Avian predators transmit fear along the air-water interface influencing prey and their parental care

The nonconsumptive consequences of predators on prey behavior, survival, and demography have recently garnered significant attention by ecologists. However, the impacts of top predators on free-ranging prey are challenging to evaluate because the most common fright response for prey is to leave the area of risk. Additionally, the top-down impacts of avian predators on aquatic environments are surprisingly overlooked. Here we investigated the nonconsumptive effects of avian predators on parental care in pumpkinseed (Lepomis gibbosus (L., 1758)) through use of a realistic model of a predatory bird, the Osprey (Pandion haliaetus (L., 1758)). Our predator model exacted dramatic metabolic fright responses and inducible defenses in experimental fish resulting in significant behavioral changes with respect to their parental care. Key parental behaviors including in-nest rotations and egg and nest maintenance were noticeably altered by predator treatments demonstrating as much as an order of magnitude difference in parental performance, suggesting that even transient predation risk might decrease reproductive fitness. Our data provide important new insights on how the landscape of fear operates along the air-water interface and suggests that avian predators may have greater controlling effects on fish populations than previously thought