Search

DNA methyltransferase inhibitors (DNMTI) like 5-Azacytidine (5-Aza) are the only disease-modifying drugs approved for the treatment of higher-risk myelodysplastic syndromes (MDS), however less than 50% of patients respond, and there are no predictors of response with clinical utility. Somatic mutations in the DNA methylation regulating gene tet-methylcytosine dioxygenase 2 (TET2) are associated with response to DNMTIs, however the mechanisms responsible for this association remain unknown. Using bisulfite padlock probes, mRNA sequencing, and hydroxymethylcytosine pull-down sequencing at several time points throughout 5-Aza treatment, we show that TET2 loss particularly influences DNA methylation (5mC) and hydroxymethylation (5hmC) patterns at erythroid gene enhancers and is associated with downregulation of erythroid gene expression in the human erythroleukemia cell line TF-1. 5-Aza disproportionately induces expression of these down-regulated genes in TET2KO cells and this effect is related to dynamic 5mC changes at erythroid gene enhancers after 5-Aza exposure. We identified differences in remethylation kinetics after 5-Aza exposure for several types of genomic regulatory elements, with distal enhancers exhibiting longer-lasting 5mC changes than other regions. This work highlights the role of 5mC and 5hmC dynamics at distal enhancers in regulating the expression of differentiation-associated gene signatures, and sheds light on how 5-Aza may be more effective in patients harboring TET2 mutations. IMPLICATIONS: TET2 loss in erythroleukemia cells induces hypermethylation and impaired expression of erythroid differentiation genes which can be specifically counteracted by 5-Azacytidine, providing a potential mechanism for the increased efficacy of 5-Aza in TET2-mutant patients with MDS. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/3/451/F1.large.jpg.

Glucose variability (GV)—the degree of fluctuation in glucose levels over a certain period of time—is emerging as an important parameter of dynamic glycemic control. Repeated glycemic oscillations have been reported to be the link to diabetes complications. This prospective observational study aims to: (1) identify multilevel risk factors (personal and social‐built environmental factors) associated with high GV; (2) identify "within‐person predictors" of high GV leveraging the intra‐person data to inform future personalized diabetes interventions; and (3) examine which lifestyle factors either mediate or moderate the relationship between emotional well‐being and GV among diverse adults with type 2 diabetes (T2D). We will recruit 200 adults with T2D from the community. All participants will complete baseline surveys assessing demographics, lifestyle, social‐built environmental, and clinical factors. Real‐time dynamic glucose levels will be measured using continuous glucose monitoring (CGM). Sleep, physical activity, diet/eating, and emotional well‐being will be measured with an actigraphy device and a real‐time self‐report tool (ecological momentary assessment [EMA]) across 14 days. Two 24‐h dietary recall data will be collected by online video calls. Generalized linear models, multilevel models, and structural equation models will be developed to achieve the study aims. The findings from the study will identify high‐risk groups of high GV who would benefit from CGM to improve diabetes outcomes and inform the future development of personalized just‐in‐time interventions targeting lifestyle behaviors with an increased understanding of GV and by supporting healthcare providers' clinical decisions. [ABSTRACT FROM AUTHOR]

Floor impact noise is a significant social concern to secure a quiescent living space for multi-story building residents in South Korea. The floating floor, consisting of a concrete structure on resilient pads, is a specifically designed system to minimize noise transmission. This floating structure employs polymeric pads as the resilient materials. In this study, we investigated the utilization of helically shaped machining scraps as a resilient material for an alternative approach to floor noise reduction. The dynamic elastic modulus and loss factor of the scrap pads were measured using the vibration test method. The scrap pads exhibited a low dynamic elastic modulus and a high loss factor compared to the polymeric pads. Heavyweight impact sound experiments in an actual building were conducted to evaluate the noise reduction performance. The proposed pads showed excellent performance on the reduction in the structure-borne vibration of the concrete slab and resulting sound generation. The analytical model was used to simulate the response of the floating floor structure, enabling a parametric study to examine the effects of the resilient layer viscoelastic properties. Both experimental and analytical evidence confirmed that the proposed scrap pads contribute to the development of sustainable solutions for the minimization of floor impact noise. [ABSTRACT FROM AUTHOR]

Public response to the COVID-19 pandemic provides a unique opportunity to study how lay people's risk perception involves their emotive responses. We investigated how outrage factors as emotional responses to risk influence levels of risk perception in the context of the pandemic disease. Furthermore, how media use influences the perception of outrage factors is also examined. A nationwide online survey (n = 1,000) was conducted in South Korea. The survey results indicated that pandemic risk perception was connected to the generic intensity of perceived outrage factors as measured by averaging the perception of multiple outrage factors. Individual outrage factors such as personal stake, effect on children, dread, and controllability directly influenced risk perception regarding COVID-19. When the intensity of media use was considered, individuals with heavy media use perceived outrage factors more intensely than those who used media less frequently. Media use also moderated the outrage effect of catastrophic potential and moral nature on the perception of risk associated with the pandemic disease. For heavy media users, the outrage effect of moral nature was increased, while that of catastrophic potential decreased. The implications of the outrage effect on the pandemic disease risk perception are addressed. Finally, we discuss the meaning of heavy media users' varying levels of vulnerability to outrage effect by moral nature and catastrophic potential. [ABSTRACT FROM AUTHOR]

We estimate relative hazards and absolute risks (or cumulative incidence or crude risk) under cause-specific proportional hazards models for competing risks from double nested case-control (DNCC) data. In the DNCC design, controls are time-matched not only to cases from the cause of primary interest, but also to cases from competing risks (the phase-two sample). Complete covariate data are available in the phase-two sample, but other cohort members only have information on survival outcomes and some covariates. Design-weighted estimators use inverse sampling probabilities computed from Samuelsen-type calculations for DNCC. To take advantage of additional information available on all cohort members, we augment the estimating equations with a term that is unbiased for zero but improves the efficiency of estimates from the cause-specific proportional hazards model. We establish the asymptotic properties of the proposed estimators, including the estimator of absolute risk, and derive consistent variance estimators. We show that augmented design-weighted estimators are more efficient than design-weighted estimators. Through simulations, we show that the proposed asymptotic methods yield nominal operating characteristics in practical sample sizes. We illustrate the methods using prostate cancer mortality data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Study of the National Cancer Institute. [ABSTRACT FROM AUTHOR]