Background: CCAAT/enhancer binding protein delta (C/EBPδ,CEBPD), a gene part of the highly conserved basicleucine zipper (b-ZIP) domain of transcriptional factors, is downregulated in 65% of high grade serous carcinomas of the ovary (HGSC). Overexpression of C/EBPδ in different tumours, such as glioblastoma and breast cancer either promotes tumour progression or inhibits growth and has low expression in normal tissue until activated by cytotoxic stressors. Methods: Higher overall expression of C/EBPδ in the luteal phase of the menstrual cycle prompted us to investigate the role of C/EBPδ in carcinogenesis. In vitro experiments were conducted in fallopian tube cell samples and cancer cell lines to investigate the role of C/EBPδ in proliferation, migration, and the epithelial to mesenchymal transition. Findings: Expression of C/EBPδ induced premature cellular arrest and decreased soft agar colony formation. Loss of C/EBPδ in epithelial cancer cell lines did not have significant effects on proliferation, yet overexpression demonstrated downregulation of growth, similar to normal fallopian tube cells. C/EBPδ promoted a partial mesenchymal to epithelial (MET) phenotype by upregulating E-cadherin and downregulating Vimentin and N-cadherin in FTE cells and increased migratory activity, which suggests a regulatory role in the epithelial-mesenchymal plasticity of these cells. Interpretation: Our findings suggest that C/EBPδ regulates the phenotype of normal fallopian tube cells by acting on downstream regulatory factors that are implicated in the development of ovarian serous carcinogenesis.

Epithelial ovarian cancer represents a group of heterogeneous diseases with high grade serous cancer (HGSC) representing the most common histotype. Molecular profiles of precancerous lesions found in the fallopian tube have implicated this tissue as the presumptive site of origin of HGSC. Precancerous lesions are primarily found in the distal fallopian tube (fimbria), near the ovary relative to the proximal tissue (ampulla), nearer to the uterus. The proximity of the fimbria to the ovary and the link between ovulation, through follicular fluid release, and ovarian cancer risk led us to examine transcriptional responses of fallopian tube epithelia (FTE) at the different anatomical sites of the human fallopian tube. Gene expression profiles of matched FTE from the fimbria and from premenopausal women resulted in differentially expressed genes (DEGs): CYYR1, SALL1, FOXP2, TAAR1, AKR1C2/C3/C4, NMBR, ME1 and GSTA2. These genes are part of the antioxidant, stem and inflammation pathways. Comparisons between the luteal phase (post-ovulation) to the follicular phase (pre-ovulation) demonstrated greater differences in DEGs than a comparison between fimbria and fallopian tube anatomical differences alone. This data suggests that cyclical transcriptional changes experienced in pre-menopause are inherent physiological triggers that expose the FTE in the fimbria to cytotoxic stressors. These cyclical exposures induce transcriptional changes reflective of genotoxic and cytotoxic damage to the FTE in the fimbria which are closely related to transcriptional and genomic alterations observed in ovarian cancer.

Objective: To determine whether cognition is associated with mortality among older US adults. Methods: We studied 5,989 National Health and Nutrition Examination Survey participants age 60+ in years 1999–2014 with mortality follow-up through 2015. Cognitive function was measured in one standard deviation decrements using the Digit Symbol Substitution Test (DSST), Animal Fluency (AnFl), and two Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) tests. Results: Each decrement in cognitive function was associated with increased risk of mortality overall (DSST HR: 1.36, 95% CI: 1.25, 1.48), among women only (AnFl: 1.51, 95% CI: 1.02, 2.24), and among those with less than a high school education only (AnFl HR: 1.46, 95% CI: 1.09, 1.97; CERAD-WL HR: 1.34, 95% CI: 1.07, 1.67; and CERAD-DR HR: 1.38, 95% CI: 1.05, 1.82). Discussion: Among US adults, lower cognitive functioning was associated with mortality; associations were stronger among women and those with less education.