The role of prenatal maternal stress in child development

ABSTRACT-The notion that a woman's psychological state during pregnancy affects the fetus is a persistent cultural belief in many parts of the world. Recent results indicate that prenatal maternal distress in rodents and nonhuman primates negatively influences long-term learning, motor development, and behavior in their offspring. The applicability of these findings to human pregnancy and child development is considered in this article. Potential mechanisms through which maternal psychological functioning may alter development of the fetal nervous system are being identified by current research, but it is premature to conclude that maternal prenatal stress has negative consequences for child development. Mild stress may be a necessary condition for optimal development

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Long-Term Associations Between Prenatal Maternal Cortisol and Child Neuroendocrine-Immune Regulation.

BACKGROUND: Advancing understanding of the developmental origins of neuroendocrine-immune (NEI) functioning is key to elucidating the biological mechanisms involved in health and disease risk across the lifespan. This study examined whether prenatal maternal hypothalamic-pituitary-adrenal (HPA) activity moderates child NEI relations and explored the consistency of this moderating effect across gestation. METHODS: Pregnant women participated in five prenatal study visits from 24 to 38 weeks gestation. At each visit, women provided a saliva sample. In a 5-year follow-up study, children (nfemale = 25, nmale=20) provided four saliva samples and participated in behavioral assessments and challenge tasks. Prenatal maternal saliva samples were assayed for cortisol. Child saliva samples were assayed for cortisol and cytokines (IL-1β, IL-6, IL-8, TNFα) as indices of HPA and inflammatory activity. Multilevel mixed-effects models examined the moderation of child NEI relations by prenatal maternal cortisol. RESULTS: Among males, average prenatal maternal cortisol did not moderate child NEI relations. Among females, average prenatal maternal cortisol moderated some child NEI relations with higher prenatal cortisol associated with more positive cortisol-cytokine relations at age five. When examined by gestational time point, there were more significant NEI moderation effects by maternal cortisol from later gestation (≥ 30 weeks) than earlier. CONCLUSIONS: The findings suggest prenatal maternal HPA activity may moderate child NEI functioning. Additional research conducted with more heterogeneous and larger samples is needed to fully understand these relations. Furthering our knowledge of NEI development has important research and clinical implications, particularly for understanding and addressing conditions with inflammatory pathophysiologies, such as depression and cardiovascular disease

The bloom is (slightly) off the rose: the motherhood effect on psychological functioning in successive pregnancies

Objective: To examine the maternal psychological state during the course of two successive pregnancies. Methods: The sample consisted of 73 women drawn from a larger maternal–fetal cohort that participated during two pregnancies. Women completed self-report psychological questionnaires at 24, 30, and 36 weeks gestation to index maternal depressive symptoms, trait anxiety, and pregnancy hassles and uplifts. Analyses examined stability of maternal symptoms across successive pregnancies in the same women. Results: Antenatal symptoms of depression and anxiety exhibited strong intra-individual stability between successive pregnancies. Mean differences in maternal symptoms were not detected for either at 24, 30, or 36 weeks gestation, excepting elevated anxiety symptoms at the mid-point due to greater fluctuation in maternal anxiety during the prior pregnancy. Subsequent pregnancies were associated with less intense uplifting feelings about the pregnancy on each measurement occasion. Conclusions: Findings suggest marked consistency in maternal psychological orientation across subsequent pregnancies, though parity also plays a role in the maternal experience