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Background and Aims: Coronary heart disease (CHD) and stroke have common risk factors, but some of these differ in the magnitude or direction of associations between CHD and stroke. We assessed whether the impact of each risk factor differed between CHD and stroke mortality in Asians., Methods: In total, 104 910 subjects aged 40-79 years without histories of cancer, CHD and stroke at baseline were followed between 1988 and 2009. Competing-risks analysis was used to test for differences in the associations of each risk factor with two endpoints (CHD and stroke). Population attributable fractions (PAFs) were also calculated for these endpoints to estimate the population impact of each risk factor., Results: During a median 19.1-year follow-up, 1554 died from CHD and 3163 from stroke. The association of hypertension with CHD was similar to that with stroke in terms of the magnitude and direction (multivariable-adjusted hazard ratio for CHD: 1.63 vs. stroke: 1.73 in men and 1.70 vs. 1.66 in women). Conversely, the magnitude of these associations differed for smoking (CHD: 1.95 vs. stroke: 1.23 in men and 2.45 vs. 1.35 in women) and diabetes (1.49 vs. 1.09 in men and 2.08 vs. 1.39 in women). The highest PAF for CHD was caused by smoking in men and by hypertension in women; that for stroke was caused by hypertension in both sexes., Conclusions: Hypertension associations and PAFs were consistent between CHD and stroke, but not for other risk factors. These findings may be useful to optimize public health intervention strategies., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The rise of noncommunicable diseases is a serious health burden for Palau. This study described the prevalence of hypertension, and assessed its association with obesity. Surveys following the WHO STEPwise approach to surveillance were conducted in 2529 adults. Multivariate prevalence ratios (PR) of hypertension for body mass index (BMI) categories were calculated by logistic regression models using conditional standardization procedure. Age- and sex-specified analyses were performed. Overall prevalence of obesity and hypertension were 40.4% and 46.8%, respectively. Prevalence of hypertension was positively associated with BMI. However, overweight men had as high prevalence of hypertension as the obese (multivariable-adjusted PR was 1.84 for overweight and 1.91 for obese compared with nonoverweight). The association between hypertension and BMI was similar across age groups. The prevalence of hypertension in women increased gradually with the increase of BMI whereas that in men reached a plateau already in the overweight.

In this report, an ultrasensitive electrochemical biosensor for miR-21 detection was designed on the basis of a padlock exponential rolling circle amplification (P-ERCA) assay and CoFe 2 O 4 magnetic nanoparticles (CoFe 2 O 4 MNPs) by nanoelectrocatalysis without a substrate for signal amplification. Here, to improve catalytic efficiency, nanocatalyst (CoFe 2 O 4 MNPs) and redox molecule (Tb) were co-immobilized onto the graphene (Gra) surface and formed Au@CoFe 2 O 4 /Tb-Gra probe. The obtained probe exhibits high-performance Tb catalysis by reducing the interaction distance between CoFe 2 O 4 MNPs and Tb, and importantly, the detection sensitivity is significantly improved even in the absence of substrate (H 2 O 2 ). Simultaneously, to further improve the sensitivity and specificity of the biosensor, P-ERCA assay was introduced. After multiple polymerization and nicking reactions, plenty of P-ERCA amplification product was produced and circular exponential signal amplification was achieved, giving an extreme sensitivity for miR-21 assay. The as-prepared biosensor shows a wide dynamic range of 1 fM to 2 nM with a low detection limit of 0.3 fM for miR-21 detection and exhibits high specificity and sensitivity., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: The extremely high incidence of esophageal cancer in certain rural areas of China has prompted significant intellectual curiosity and research efforts both in China and abroad., Methods: We summarize the research progress over the past several decades in high-risk areas (Linxian, Cixian, Shexian, and Yanting) based on literature research and our field trip (2012-2013)., Results: Considerable progress in clarifying the environmental risk factors and pathogenesis of esophageal cancer in high-risk areas has been achieved over the past several decades. Epidemiologic evidence suggests that carcinogen exposure and nutritional deficiency, rather than smoking and drinking, may be the major risk factors for esophageal cancer in the Taihang Mountains region, where the incidence of esophageal cancer is among the highest in the world. Two genome-wide association studies have identified variants in PLCE1 at 10q23 that are significantly associated with esophageal cancer risk. Recent whole-exome studies have revealed a comprehensive mutation pattern, in which the C>T transition is the predominant mutation type., Conclusions: Despite extensive research, the main causative factors that contribute to esophageal cancer in high-risk areas have not yet been elucidated. Challenges in this research area include determining the causative role of nitrosamine, identifying other potential carcinogens, and conducting fruitful international collaborative studies based on a multidisciplinary approach. Increased international collaboration will contribute to a better understanding of the etiology of esophageal cancer., (Copyright © 2016 Elsevier Inc. All rights reserved.)

We aimed to investigate the prevalence and predictors of diabetes and prediabetes among adults in Palau. We used data of 1915 adults, aged 25 to 64 years, who participated in the World Health Organization's (WHO) STEPwise Approach to Risk Factor Surveillance (STEPS) study in Palau. Information on behavioral risk factors of NCDs and physical and biochemical measurements were obtained using standard methods of the WHO. The diagnosis of diabetes and prediabetes was based on the recent American Diabetes Association criteria. Predictors of the prevalence of diabetes and prediabetes were identified using multinomial logistic regression analysis. The overall age-standardized prevalence of prediabetes and diabetes were 40.4% (43.6% for men, 37.4% for women) and 17.7% (18.6% for men, 17% for women), respectively. Old age, overall obesity (high BMI), central obesity (large waist circumference or waist-hip ratio), hypertension and hypertriglyceridemia were significant predictors of prediabetes and/or diabetes. Diabetes occurred at a younger age in "obese" individuals than that of their "non-obese" counterparts. We confirmed that prediabetes and diabetes are highly prevalent in Palau affecting 40% and 18% adults, respectively. Introducing public health interventions to reduce and prevent obesity as early as possible could prove useful to curb the problem.

Transcriptional enhancers control cell-type-specific gene expression. Primed enhancers are marked by histone H3 lysine 4 (H3K4) mono/di-methylation (H3K4me1/2). Active enhancers are further marked by H3K27 acetylation (H3K27ac). Mixed-lineage leukemia 4 (MLL4/KMT2D) is a major enhancer H3K4me1/2 methyltransferase with functional redundancy with MLL3 (KMT2C). However, its role in cell fate maintenance and transition is poorly understood. Here, we show in mouse embryonic stem cells (ESCs) that MLL4 associates with, but is surprisingly dispensable for the maintenance of, active enhancers of cell-identity genes. As a result, MLL4 is dispensable for cell-identity gene expression and self-renewal in ESCs. In contrast, MLL4 is required for enhancer-binding of H3K27 acetyltransferase p300, enhancer activation, and induction of cell-identity genes during ESC differentiation. MLL4 protein, rather than MLL4-mediated H3K4 methylation, controls p300 recruitment to enhancers. We also show that, in somatic cells, MLL4 is dispensable for maintaining cell identity but essential for reprogramming into induced pluripotent stem cells. These results indicate that, although enhancer priming by MLL4 is dispensable for cell-identity maintenance, it controls cell fate transition by orchestrating p300-mediated enhancer activation., Competing Interests: The authors declare no conflict of interest.

Excess intake of iodine is a suspected risk factor for thyroid cancer. Previous epidemiological research from Japan reported that daily intake of seaweed was associated with a four-fold higher risk in postmenopausal women, whereas others reported a null association. A major source of iodine intake in Japan is from edible seaweeds, and it is reported to be among the highest in the world. We examined the association between seaweed intake frequency and the risk of thyroid cancer in women in the Japan Collaborative Cohort Study followed from 1988 to 2009. Seaweed intake, together with other lifestyle-related information was collected using a self-administered questionnaire at baseline. Seaweed intake frequency was categorized as follows: 1-2 times/week or less, 3-4 times/week, and almost daily. Hazard ratios and the 95% confidence intervals of thyroid cancer incidence according to seaweed intake frequency were estimated using Cox proportional hazards regression. During 447 876 person-years of follow-up (n=35 687), 94 new cases of thyroid cancer were identified. The crude incidence rate was 20.9 per 100 000 person-years. The hazard ratio of thyroid cancer in women who consumed seaweed daily compared with women who ate it 1-2 times/week or less was 1.15 (95% confidence interval: 0.69-1.90, P for trend=0.59). Further analyses did not indicate any association between seaweed intake and the risk of thyroid cancer on statistically adjusting for potential confounding variables as well as on stratification by menopausal status. The present study did not find an association between seaweed intake and thyroid cancer incidence in premenopausal or in postmenopausal women.

The X chromosome-encoded histone demethylase UTX (also known as KDM6A) mediates removal of repressive trimethylation of histone H3 lysine 27 (H3K27me3) to establish transcriptionally permissive chromatin. Loss of UTX in female mice is embryonic lethal. Unexpectedly, male UTX-null mice escape embryonic lethality due to expression of UTY, a paralog that lacks H3K27 demethylase activity, suggesting an enzyme-independent role for UTX in development and thereby challenging the need for active H3K27 demethylation in vivo. However, the requirement for active H3K27 demethylation in stem cell-mediated tissue regeneration remains untested. Here, we employed an inducible mouse KO that specifically ablates Utx in satellite cells (SCs) and demonstrated that active H3K27 demethylation is necessary for muscle regeneration. Loss of UTX in SCs blocked myofiber regeneration in both male and female mice. Furthermore, we demonstrated that UTX mediates muscle regeneration through its H3K27 demethylase activity, as loss of demethylase activity either by chemical inhibition or knock-in of demethylase-dead UTX resulted in defective muscle repair. Mechanistically, dissection of the muscle regenerative process revealed that the demethylase activity of UTX is required for expression of the transcription factor myogenin, which in turn drives differentiation of muscle progenitors. Thus, we have identified a critical role for the enzymatic activity of UTX in activating muscle-specific gene expression during myofiber regeneration and have revealed a physiological role for active H3K27 demethylation in vivo.

Signal Transducers and Activators of Transcription (STATs) are principal transcription factors downstream of cytokine receptors. Although STAT5A is expressed in most tissues it remains to be understood why its premier, non-redundant functions are restricted to prolactin-induced mammary gland development and function. We report that the ubiquitously expressed Stat5a/b locus is subject to additional lineage-specific transcriptional control in mammary epithelium. Genome-wide surveys of epigenetic status and transcription factor occupancy uncovered a putative mammary-specific enhancer within the intergenic sequences separating the two Stat5 genes. This region exhibited several hallmarks of genomic enhancers, including DNaseI hypersensitivity, H3K27 acetylation and binding by GR, NFIB, ELF5 and MED1. Mammary-specific STAT5 binding was obtained at two canonical STAT5 binding motifs. CRISPR/Cas9-mediated genome editing was used to delete these sites in mice and determine their biological function. Mutant animals exhibited an 80% reduction of Stat5 levels in mammary epithelium and a concomitant reduction of STAT5-dependent gene expression. Transcriptome analysis identified a class of mammary-restricted genes that was particularly dependent on high STAT5 levels as a result of the intergenic enhancer. Taken together, the mammary-specific enhancer enables a positive feedback circuit that contributes to the remarkable abundance of STAT5 and, in turn, to the efficacy of STAT5-dependent mammary physiology., (Published by Oxford University Press on behalf of Nucleic Acids Research 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Objective: To investigate differences in the association of parental history of diabetes with the risk of type 2 diabetes mellitus (T2DM) in the offspring according to the sex of the parent and the offspring's body weight., Methods: A prospective cohort study of 4446 middle-aged non-diabetic Japanese men and women were followed in Aichi Prefecture, central Japan, from 2002 to 2011. Subjects were categorized by their self-reported parental history of diabetes ("no parental history," "father only," "mother only," and "both"). The association of parental history of diabetes and incidence in the offspring was examined according to overweight status adjusted for age, sex, birth weight, smoking, alcohol consumption, physical activity, total energy intake, body mass index, and number of metabolic syndrome components., Results: During follow-up (median 8.9 years), 277 subjects developed T2DM. Parental history of diabetes was positively associated with T2DM incidence. However, stratified analysis by overweight status revealed that only maternal history was associated with increased T2DM incidence in non-overweight subjects (hazard ratio=2.35, 95% confidence interval: 1.41-3.91). While in overweight subjects, paternal history was significantly associated with higher T2DM incidence (hazard ratio=1.98, 95% confidence interval: 1.19-3.28)., Conclusions: Our results suggest that parental history of diabetes mellitus is associated with the incidence of T2DM in offspring differently according to the sex of the affected parent and the offspring's body weight., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The touch dome is a highly patterned mechanosensory structure in the epidermis composed of specialized keratinocytes in juxtaposition with innervated Merkel cells. The touch dome epithelium is maintained by tissue-specific stem cells, but the signals that regulate the touch dome are not known. We identify touch dome stem cells that are unique among epidermal cells in their activated Hedgehog signaling and ability to maintain the touch dome as a distinct lineage compartment. Skin denervation reveals that renewal of touch dome stem cells requires a perineural microenvironment, and deleting Sonic hedgehog (Shh) in neurons or Smoothened in the epidermis demonstrates that Shh is an essential niche factor that maintains touch dome stem cells. Up-regulation of Hedgehog signaling results in neoplastic expansion of touch dome keratinocytes but no Merkel cell neoplasia. These findings demonstrate that nerve-derived Shh is a critical regulator of lineage-specific stem cells that maintain specialized sensory compartments in the epidermis.

Background: To examine the association of intrahepatic fat with homeostasis model assessment-insulin resistance (HOMA-IR), a marker of insulin resistance, in Japanese adults, and whether intrahepatic fat is associated with insulin resistance independent of waist circumference and other measures of obesity., Methods: Fifty-three individuals aged 37-69 were studied. Spectrum obtained using a 3-T magnetic resonance imager was analysed with LCModel to quantify intrahepatic fat. Blood levels of insulin, glucose and other biochemical markers were obtained after 8h or more fasting. Percent body fat was estimated by a bioelectrical impedance analyzer. HOMA-IR and intrahepatic fat content were log-transformed in the analysis., Results: We found a positive correlation between intrahepatic fat and HOMA-IR, which was independent of the anthropometric measures of obesity. In contrast, significant and positive correlations of body mass index, percent body fat, and waist circumference with HOMA-IR were largely explained by their associations with intrahepatic fat. Intrahepatic fat was positively associated with alanine transaminase and triglycerides even after adjustment for HOMA-IR., Conclusion: Intrahepatic fat was associated with insulin resistance independent of age, sex, and measures of obesity in Japanese adults. Hypertriglyceridemia and liver injury may directly occur subsequent to intrahepatic fat accumulation., (Copyright © 2013 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.)