Citations

Abstract The antimetabolite 5-fluorouracil (5-FU) is one of the most widely used chemotherapy drugs. Dihydropyrimidine dehydrogenase (DPD) is a major determinant of 5-FU response and toxicity. Although DPYD variants may affect 5-FU metabolism, they do not completely explain the reported variability in DPD function or the resultant differences in treatment response. Here, we report that H3K27 trimethylation (H3K27me3) at the DPYD promoter regulated by Ezh2 and UTX suppresses DPYD expression by inhibiting transcription factor PU.1 binding, leading to increased resistance to 5-FU. Enrichment of H3K27me3 at the DPYD promoter was negatively correlated with both DPYD expression and DPD enzyme activity in peripheral blood specimens from healthy volunteers. Lastly, tumor expression data suggest that DPYD repression by Ezh2 predicts poor survival in 5-FU–treated cancers. Collectively, the findings of the present article suggest that a previously uncharacterized mechanism regulates DPD expression and may contribute to tumor resistance to 5-FU. Cancer Res; 76(21); 6362–73. ©2016 AACR.

Pancreatic islet failure is a characteristic feature of impaired glucose control in diabetes mellitus. Circadian control of islet function is essential for maintaining proper glucose homeostasis. Circadian variations in transcriptional pathways have been described in diverse cell types and shown to be critical for optimization of cellular function in vivo. In the current study, we utilized Short Time Series Expression Miner (STEM) analysis to identify diurnally expressed transcripts and biological pathways from mouse islets isolated at 4 h intervals throughout the 24 h light-dark cycle. STEM analysis identified 19 distinct chronological model profiles, and genes belonging to each profile were subsequently annotated to significantly enriched Kyoto Encyclopedia of Genes and Genomes biological pathways. Several transcriptional pathways essential for proper islet function (e.g., insulin secretion, oxidative phosphorylation), cell survival (e.g., insulin signaling, apoptosis) and cell proliferation (DNA replication, homologous recombination) demonstrated significant time-dependent variations. Notably, KEGG pathway analysis revealed “protein processing in endoplasmic reticulum - mmu04141” as one of the most enriched time-dependent pathways in islets. This study provides unique data set on time-dependent diurnal profiles of islet gene expression and biological pathways, and suggests that diurnal variation of the islet transcriptome is an important feature of islet homeostasis, which should be taken into consideration for optimal experimental design and interpretation of future islet studies.

Both vitamin D deficiency and cognitive impairment are common in patients with chronic kidney disease (CKD). Vitamin D exerts neuroprotective and regulatory roles in the central nervous system. Hypovitaminosis D has been associated with muscle weakness and bone loss, cardiovascular diseases (hypertension, diabetes and hyperlipidemia), inflammation, oxidative stress, immune suppression and neurocognitive impairment. The combination of hypovitaminosis D and CKD can be even more debilitating, as cognitive impairment can develop and progress through vitamin D-associated and CKD-dependent/independent processes, leading to significant morbidity and mortality. Although an increasingly recognized comorbidity in CKD, cognitive impairment remains underdiagnosed and often undermanaged. Given the association of cognitive decline and hypovitaminosis D and their deleterious effects in CKD patients, determination of vitamin D status and when appropriate, supplementation, in conjunction with neuropsychological screening, should be considered integral to the clinical care of the CKD population.

Summary Background and Purpose Sprawling ( Swl ) is a radiation‐induced mutation which has been identified to have a nine base pair deletion in dynein heavy chain 1 (DYNC1H1: encoded by a single gene Dync1h1 ). This study is to investigate the phenotype and the underlying mechanism of the Dync1h1 mutant. Methods and Results To display the phenotype of Swl mutant mice, we examined the embryos of homozygous ( Swl/Swl ) and heterozygous ( Swl /+) mice and their postnatal dorsal root ganglion (DRG) of surviving Swl /+ mice. The Swl /+ mice could survive for a normal life span, while Swl/Swl could only survive till embryonic (E) 8.5 days. Excessive apoptosis of Swl/ + DRG neurons was revealed during E11.5–E15.5 days, and the peak rate was at E13.5 days. In vitro study of mutated DRG neurons showed impaired retrograde transport of dynein‐driven nerve growth factor (NGF). Mitochondria, another dynein‐driven cargo, demonstrated much slower retrograde transport velocity in Swl/+ neurons than in wild‐type (WT) neurons. Nevertheless, the Swl , Loa, and Cra mutations did not affect homodimerization of DYNC1H1. Conclusion The Swl/Swl mutation of Dync1h1 gene led to embryonic mal‐development and lethality, whereas the Swl/+ DRG neurons demonstrated deficient retrograde transport in dynein‐driven cargos and excessive apoptosis during mid‐ to late‐developmental stages. The underlying mechanism of the mutation may not be due to impaired homodimerization of DYNC1H1.

Alcohol consumption is associated with a modest increased risk of colon cancer, but its relationship with colon cancer survival has not been elucidated. Using data from a phase III randomized adjuvant trial, we assessed the association of alcohol consumption with colon cancer outcomes. Patients completed a risk factor questionnaire before randomization to FOLFOX or FOLFOX + cetuximab (N = 1984). Information was collected on lifestyle factors, including smoking, physical activity and consumption of different types of alcohol. Cox models assessed the association between alcohol consumption and outcomes of disease‐free survival (DFS), time‐to‐recurrence (TTR) and overall survival (OS), adjusting for age, sex, study arm, body mass, smoking, physical activity and performance status. No statistically significant difference in outcomes between ever and never drinkers were noted [hazard ratio (HR)DFS = 0.86, HRTTR = 0.87, HROS = 0.86, p‐values = 0.11–0.17]. However, when considering alcohol type, ever consumers of red wine (n = 628) had significantly better outcomes than never consumers (HRDFS = 0.80, HRTTR = 0.81, HROS = 0.78, p‐values = 0.01–0.02). Favorable outcomes were confirmed in patients who consumed 1‐30 glasses/month of red wine (n = 601, HR = 0.80–0.83, p‐values = 0.03–0.049); there was a suggestion of more favorable outcomes in patients who consumed >30 glasses/month of red wine (n = 27, HR = 0.33–0.38, p‐values = 0.05–0.06). Beer and liquor consumption were not associated with outcomes. Although alcohol consumption was not associated with colon cancer outcomes overall, mild to moderate red wine consumption was suggestively associated with longer OS, DFS and TTR in stage III colon cancer patients.

Numerical laboratory data at admission have been proposed for enhancement of inpatient predictive modeling from administrative claims. In this study, predictive models for inpatient/30-day postdischarge mortality and for risk-adjusted prolonged length of stay, as a surrogate for severe inpatient complications of care, were designed with administrative data only and with administrative data plus numerical laboratory variables. A comparison of resulting inpatient models for acute myocardial infarction, congestive heart failure, coronary artery bypass grafting, and percutaneous cardiac interventions demonstrated improved discrimination and calibration with administrative data plus laboratory values compared to administrative data only for both mortality and prolonged length of stay. Improved goodness of fit was most apparent in acute myocardial infarction and percutaneous cardiac intervention. The emergence of electronic medical records should make the addition of laboratory variables to administrative data an efficient and practical method to clinically enhance predictive modeling of inpatient outcomes of care.

Predictive modeling for postdischarge outcomes of inpatient care has been suboptimal. This study evaluated whether admission numerical laboratory data added to administrative models from New York and Minnesota hospitals would enhance the prediction accuracy for 90-day postdischarge deaths without readmission (PD-90) and 90-day readmissions (RA-90) following inpatient care for cardiac patients. Risk-adjustment models for the prediction of PD-90 and RA-90 were designed for acute myocardial infarction, percutaneous cardiac intervention, coronary artery bypass grafting, and congestive heart failure. Models were derived from hospital claims data and were then enhanced with admission laboratory predictive results. Case-level discrimination, goodness of fit, and calibration were used to compare administrative models (ADM) and laboratory predictive models (LAB). LAB models for the prediction of PD-90 were modestly enhanced over ADM, but negligible benefit was seen for RA-90. A consistent predictor of PD-90 and RA-90 was prolonged length of stay outliers from the index hospitalization.