Disparity of ovarian cancer survival between urban and rural settings.

OBJECTIVE: To determine if there is a difference in overall survival of patients with epithelial ovarian cancer in rural, urban, and metropolitan settings in the United States. METHODS: We performed a retrospective cohort study using 2004-2016 National Cancer Database (NCDB) data including high and low grade, stage I-IV disease. Bivariate analyses used Student's t-test for continuous variables and χ2 test for dichotomous variables. Kaplan-Meier curves estimated survival of patients based on location of residence, and univariate analyses using Cox proportional HR assessed survival based on baseline characteristics. Multivariate analysis was performed to account for significant covariates. Propensity score matching was used to validate the multivariate survival model. For all tests, p<0.05 was considered statistically significant. RESULTS: A total of 111 627 patients were included with a mean age of 62.5 years for metroolitan (range 18-90), 64.0 years for rural (range 19-90) and 63.2 years for urban areas (range 18-90). Of all patients included, 94 290 were in a metropolitan area (counties >1 million population or 50 000-999 999), 15 386 were in an urban area (population of 10 000-49 999), and 1951 were in a rural area (non-metropolitan/non-core population). Univariate Cox proportional hazards models showed clinically significant differences in survival in patients from metropolitan, urban, and rural areas. Multivariate Cox proportional hazards models showed a clinically significant increase in HRs for patients in rural settings (HR 1.17; 95% CI 1.06 to 1.29). Increasing age and stage, non-insured status, non-white race, and comorbidity were also significant for poorer survival. CONCLUSION: Patients with ovarian cancer who live in rural settings with small populations and greater distance to tertiary care centers have poorer survival. These differences hold after controlling for stage, age, and other significant risk factors related to poorer outcomes. To improve clinical outcomes, we need further studies to identify which of these factors are actionable.

Activity Level and Sport Type in Adolescents Correlate with the Development of Cam Morphology.

BACKGROUND: The purpose of this study was to evaluate the influence of the volume and type of sport on the development of cam-type femoroacetabular impingement and acetabular dysplasia. METHODS: The Physical Activity Questionnaire for Adolescents (PAQ-A) was administered to Iowa Bone Development Study participants at the age of 17 years to identify those who had participated in at least 2 seasons of high school interscholastic sports. Based on relative peak strain and ground reaction forces, subjects were grouped as power sport athletes (basketball, cheerleading, football, gymnastics, soccer, and volleyball), non-power sport athletes (wrestling, baseball, cross-country or track and field, softball, or tennis), or non-athletes. Using anteroposterior views of the left hip formatted from dual x-ray absorptiometry (DXA) scans, the alpha angle, head-neck offset ratio (HNOR), and lateral center-edge angle (LCEA) were evaluated longitudinally at the ages of 17, 19, and 23 years. Logistic regression was used to evaluate the odds of hip cam morphology (alpha angle >55° and/or HNOR <0.17) or acetabular dysplasia (LCEA <24°) at the age of 23 years in all athlete groups. The relationships between physical activity level and hip measures (alpha angle, HNOR, and LCEA) from the ages of 17 to 23 years were examined using linear mixed models adjusted for sex. RESULTS: Compared with non-athletes at the age of 23 years, power sport athletes had significantly greater odds of cam morphology according to the alpha angle (odds ratio [OR], 2.93 [95% confidence interval (CI), 1.02 to 8.41]; p = 0.046) and HNOR (OR, 1.91 [95% CI, 1.01 to 3.60]; p = 0.047), but not greater odds of acetabular dysplasia (p > 0.05). There were no significant differences in the odds of cam morphology or acetabular dysplasia in non-power sport athletes compared with non-athletes (all p > 0.05). Higher physical activity levels were significantly associated with an increase in the alpha angle (beta and standard error, 0.77° ± 0.30°; p = 0.011) and a decrease in the HNOR (-0.003 ± 0.001; p = 0.003), but not the LCEA (-0.05 ± 0.15; p = 0.744). CONCLUSIONS: A higher volume of physical activity and participation in sports with higher peak strain and ground reaction forces during the process of skeletal maturation may increase the risk of developing cam morphology during late adolescence. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

The CBP KIX domain regulates long-term memory and circadian activity.

BACKGROUND: CREB-dependent transcription necessary for long-term memory is driven by interactions with CREB-binding protein (CBP), a multi-domain protein that binds numerous transcription factors potentially affecting expression of thousands of genes. Identifying specific domain functions for multi-domain proteins is essential to understand processes such as cognitive function and circadian clocks. We investigated the function of the CBP KIX domain in hippocampal memory and gene expression using CBPKIX/KIX mice with mutations that prevent phospho-CREB (Ser133) binding. RESULTS: We found that CBPKIX/KIX mice were impaired in long-term memory, but not learning acquisition or short-term memory for the Morris water maze. Using an unbiased analysis of gene expression in the dorsal hippocampus after training in the Morris water maze or contextual fear conditioning, we discovered dysregulation of CREB, CLOCK, and BMAL1 target genes and downregulation of circadian genes in CBPKIX/KIX mice. Given our finding that the CBP KIX domain was important for transcription of circadian genes, we profiled circadian activity and phase resetting in CBPKIX/KIX mice. CBPKIX/KIX mice exhibited delayed activity peaks after light offset and longer free-running periods in constant dark. Interestingly, CBPKIX/KIX mice displayed phase delays and advances in response to photic stimulation comparable to wildtype littermates. Thus, this work delineates site-specific regulation of the circadian clock by a multi-domain protein. CONCLUSIONS: These studies provide insight into the significance of the CBP KIX domain by defining targets of CBP transcriptional co-activation in memory and the role of the CBP KIX domain in vivo on circadian rhythms.

Reinstating plasticity and memory in a tauopathy mouse model with an acetyltransferase activator.

Chromatin acetylation, a critical regulator of synaptic plasticity and memory processes, is thought to be altered in neurodegenerative diseases. Here, we demonstrate that spatial memory and plasticity (LTD, dendritic spine formation) deficits can be restored in a mouse model of tauopathy following treatment with CSP-TTK21, a small-molecule activator of CBP/p300 histone acetyltransferases (HAT). At the transcriptional level, CSP-TTK21 re-established half of the hippocampal transcriptome in learning mice, likely through increased expression of neuronal activity genes and memory enhancers. At the epigenomic level, the hippocampus of tauopathic mice showed a significant decrease in H2B but not H3K27 acetylation levels, both marks co-localizing at TSS and CBP enhancers. Importantly, CSP-TTK21 treatment increased H2B acetylation levels at decreased peaks, CBP enhancers, and TSS, including genes associated with plasticity and neuronal functions, overall providing a 95% rescue of the H2B acetylome in tauopathic mice. This study is the first to provide in vivo proof-of-concept evidence that CBP/p300 HAT activation efficiently reverses epigenetic, transcriptional, synaptic plasticity, and behavioral deficits associated with Alzheimer's disease lesions in mice.

Modulation of neurogenesis by targeting epigenetic enzymes using small molecules: an overview.

Neurogenesis consists of a plethora of complex cellular processes including neural stem cell (NSC) proliferation, migration, maturation or differentiation to neurons, and finally integration into the pre-existing neural circuits in the brain, which are temporally regulated and coordinated sequentially. Mammalian neurogenesis begins during embryonic development and continues in postnatal brain (adult neurogenesis). It is now evident that adult neurogenesis is driven by extracellular and intracellular signaling pathways, where epigenetic modifications like reversible histone acetylation, methylation, as well as DNA methylation play a vital role. Epigenetic regulation of gene expression during neural development is governed mainly by histone acetyltransferases (HATs), histone methyltransferase (HMTs), DNA methyltransferases (DNMTs), and also the enzymes for reversal, like histone deacetylases (HDACs), and many of these have also been shown to be involved in the regulation of adult neurogenesis. The contribution of these epigenetic marks to neurogenesis is increasingly being recognized, through knockout studies and small molecule modulator based studies. These small molecules are directly involved in regeneration and repair of neurons, and not only have applications from a therapeutic point of view, but also provide a tool to study the process of neurogenesis itself. In the present Review, we will focus on small molecules that act predominantly on epigenetic enzymes to enhance neurogenesis and neuroprotection and discuss the mechanism and recent advancements in their synthesis, targeting, and biology.