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Depression in the perinatal period is common in mothers worldwide. Emerging research indicates that fathers are also at risk of developing perinatal depression. However, knowledge regarding biological risk factors and pathophysiological mechanisms of perinatal depression is still scarce, particularly in fathers. It has been suggested that the neurotrophin BDNF may play a role in maternal perinatal depression; however, there is currently no data regarding paternal perinatal depression. For this pilot study, 81 expecting parents were recruited and assessed at several time points. We screened for depression using EPDS and MADRS, investigated several psychosocial variables, and took blood samples for BDNF val66met genotyping, epigenetic, and protein analysis. Between pregnancy and 12 months postpartum (pp), we found that 3.7 to 15.7% of fathers screened positive for depression, and 9.6 to 24% of mothers, with at least a twofold increased prevalence in both parents using MADRS compared with EPDS. We also identified several psychosocial factors associated with perinatal depression in both parents. The data revealed a trend that lower BDNF levels correlated with maternal depressive symptoms at 3 months pp. In the fathers, no significant correlations between BDNF and perinatal depression were found. Pregnant women demonstrated lower BDNF methylation and BDNF protein expression compared with men; however, these were found to increase postpartum. Lastly, we identified correlations between depressive symptoms and psychosocial/neurobiological factors. The data suggest that BDNF may play a role in maternal perinatal depression, but not paternal.
Chemotherapy, the standard treatment for pancreatic ductal adenocarcinoma (PDAC), has only a modest effect on the outcome of patients with late-stage disease. Investigations of the genetic features of PDAC have demonstrated a frequent occurrence of mutations in genes involved in homologous recombination (HR), especially in the breast cancer susceptibility gene 2 (BRCA2). Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, is approved as a maintenance treatment for patients with advanced PDAC with germline BRCA1/2 mutations following a platinum-containing first-line regimen. Limitations to the use of PARP inhibitors are represented by the relatively small proportion of patients with mutations in BRCA1/2 genes and the modest capability of these substances of inducing objective response. We have previously shown that pancreatic cancer with BRCA2 mutations exhibits a remarkably enhanced sensitivity towards tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) receptor-stimulating agents. We thus aimed to investigate the effect of combined treatment with PARP inhibitors and TRAIL receptor-stimulating agents in pancreatic cancer and its dependency on the BRCA2 gene status. The respective effects of TRAIL-targeting agents and the PARP inhibitor olaparib or of their combination were assessed in pancreatic cancer cell lines and patient-derived organoids. In addition, BRCA2-knockout and -complementation models were investigated. The effects of these agents on apoptosis, DNA damage, cell cycle, and receptor surface expression were assessed by immunofluorescence, Western blot, and flow cytometry. PARP inhibition and TRAIL synergized to cause cell death in pancreatic cancer cell lines and PDAC organoids. This effect proved independent of BRCA2 gene status in three independent models. Olaparib and TRAIL in combination caused a detectable increase in DNA damage and a concentration-dependent cell cycle arrest in the G2/M and S cell cycle phases. Olaparib also significantly increased the proportion of membrane-bound death receptor 5. Our results provide a preclinical rationale for the combination of PARP inhibitors and TRAIL receptor agonists for the treatment of pancreatic cancer and suggest that the use of PARP inhibitors could be extended to patients without BRCA2 mutations if used in combination with TRAIL agonists.