Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma.

DNA methylation at the 5 position of cytosine (5-mC) is a key epigenetic mark that is critical for various biological and pathological processes. 5-mC can be converted to 5-hydroxymethylcytosine (5-hmC) by the ten-eleven translocation (TET) family of DNA hydroxylases. Here, we report that "loss of 5-hmC" is an epigenetic hallmark of melanoma, with diagnostic and prognostic implications. Genome-wide mapping of 5-hmC reveals loss of the 5-hmC landscape in the melanoma epigenome. We show that downregulation of isocitrate dehydrogenase 2 (IDH2) and TET family enzymes is likely one of the mechanisms underlying 5-hmC loss in melanoma. Rebuilding the 5-hmC landscape in melanoma cells by reintroducing active TET2 or IDH2 suppresses melanoma growth and increases tumor-free survival in animal models. Thus, our study reveals a critical function of 5-hmC in melanoma development and directly links the IDH and TET activity-dependent epigenetic pathway to 5-hmC-mediated suppression of melanoma progression, suggesting a new strategy for epigenetic cancer therapy.

The prevalence and risk factors of preterm small-for-gestational-age infants: a population-based retrospective cohort study in rural Chinese population.

BACKGROUND: Preterm birth and small for gestational age (SGA) are strong indicators of neonatal adverse outcomes. With the growing importance of preterm SGA infants, we aim to evaluate the prevalence and risk factors for preterm SGA in China. METHOD: We analyzed the data of parents and infants from a population-based cohort research of the free National Pre-pregnancy Checkups Project (NPCP) in rural China. Only singleton live births that occurred between 24 weeks +0 days and 36 weeks +6 days of pregnancy were included in this study. SGA was defined as birth weight less than the 10th percentile of the reference birth-weight-for-gestational-age population. A multiple logistic regression model was built using the statistically significant variables from the 371 variables in the questionnaire. RESULTS: A total of 11,474 singleton, preterm, live-birth infants were included. Of the total infants, 317 (2.77%) were preterm SGA infants. A higher risk of preterm SGA infants was observed among mothers who were on oral contraceptives (OR: 8.162, 95% CI: 1.622-41.072), mothers who had syphilis (OR: 12.800, 95% CI: 1.250-131.041), and mothers with a high eosinophil percentage (OR: 13.292, 95% CI: 1.282-135.796). Maternal intake of folic acid at least 3 months before pregnancy (OR: 0.284, 95% CI:0.124-0.654) and paternal intake of egg and meat (OR: 0.097,95% CI:0.030-0.315) were protective factors. Compared with North China, the incidence of preterm SGA infants was higher in South China. CONCLUSION: Preterm SGA infants were associated with both maternal and paternal factors.

Homozygous ALOXE3 Nonsense Variant Identified in a Patient with Non-Bullous Congenital Ichthyosiform Erythroderma Complicated by Superimposed Bullous Majocchi's Granuloma: The Consequences of Skin Barrier Dysfunction.

Non-bullous congenital ichthyosiform erythroderma (NBCIE) is a hereditary disorder of keratinization caused by pathogenic variants in genes encoding enzymes important to lipid processing and terminal keratinocyte differentiation. Impaired function of these enzymes can cause pathologic epidermal scaling, significantly reduced skin barrier function. In this study, we have performed a focused, genetic analysis of a probrand affected by NBCIE and extended this to his consanguineous parents. Targeted capture and next-generation sequencing was performed on NBCIE associated genes in the proband and his unaffected consanguineous parents. We identified a homozygous nonsense variant c.814C>T (p.Arg272*) in ALOXE3 (NM_001165960.1) in the proband and discovered that his parents are both heterozygous carriers of the variant. The clinical manifestations of the proband's skin were consistent with NBCIE, and detailed histopathological assessment revealed epidermal bulla formation and Majocchi's granuloma. Infection with Trichophyton rubrum was confirmed by culture. The patient responded to oral terbinafine antifungal treatment. Decreased skin barrier function, such as that caused by hereditary disorders of keratinization, can increase the risk of severe cutaneous fungal infections and the formation of Majocchi's granuloma and associated alopecia. Patients with NBCIE should be alerted to the possible predisposition for developing dermatophytoses and warrant close clinical follow-up.

Mineralocorticoid receptor blockade reverses obesity-related changes in expression of adiponectin, peroxisome proliferator-activated receptor-gamma, and proinflammatory adipokines.

BACKGROUND: In obesity, decreases in adiponectin and increases in proinflammatory adipokines are associated with heart disease. Because adipocytes express mineralocorticoid receptor (MR) and MR blockade reduces cardiovascular inflammation and injury, we tested the hypothesis that MR blockade reduces inflammation and expression of proinflammatory cytokines in adipose tissue and increases adiponectin expression in adipose tissue and hearts of obese mice. METHODS AND RESULTS: We determined the effect of MR blockade (eplerenone, 100 mg/kg per day for 16 weeks) on gene expression in retroperitoneal adipose and heart tissue from obese, diabetic db/db mice (n=8) compared with untreated obese, diabetic db/db mice (n=10) and lean, nondiabetic db/+ littermates (n=11). Expression of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, plasminogen activator inhibitor type 1, and macrophage protein CD68 increased, and expression of adiponectin and peroxisome proliferator-activated receptor-gamma decreased in retroperitoneal adipose tissue from obese versus lean mice. In addition, adiponectin expression in heart was reduced in obese versus lean mice. MR blockade prevented these obesity-related changes in gene expression. Furthermore, treatment of undifferentiated preadipocytes with aldosterone (10(-8) mol/L for 24 hours) increased mRNA levels of tumor necrosis factor-alpha and monocyte chemoattractant protein-1 and reduced mRNA and protein levels of peroxisome proliferator-activated receptor-gamma and adiponectin, supporting a direct aldosterone effect on gene expression. CONCLUSIONS: MR blockade reduced expression of proinflammatory and prothrombotic factors in adipose tissue and increased expression of adiponectin in heart and adipose tissue of obese, diabetic mice. These effects on adiponectin and adipokine gene expression may represent a novel mechanism for the cardioprotective effects of MR blockade.

Paternal exposure to medical-related radiation associated with low birthweight infants: A large population-based, retrospective cohort study in rural China.

Low birthweight (LBW) is closely associated with fetal and perinatal mortality and morbidity. We identified the risk factors of LBW and geographical differences in LBW incidence in 30 Chinese provinces in the present study.This study was a population-based, retrospective cohort study performed in 30 Chinese provinces. We used data from the free National Pre-pregnancy Checkups Project, which is a countrywide population-based retrospective cohort study. To identify regional differences in LBW incidence, we used the Qinling-Huaihe climate line to divide China into northern and southern sections and the Heihe-Tengchong economic line to divide it into eastern and western sections. Multivariate unconditional logistic regression analysis with SAS 9.4 was used for data analysis. P < .05 was considered statistically significant.LBW incidence was 4.54% in rural China. Southern China had a significantly higher incidence (4.65%) than northern China (4.28%). Our main risk factor for LBW is paternal exposure to radiation (odds ratio = 1.537), which has never been studied before.This study identifies multiple risk factors of couples giving birth to LBW babies including paternal risk factors.

Both maternal and paternal risk factors for term singleton low birthweight infants in rural Chinese population: a population-based, retrospective cohort study.

No large population-based study has focused on both maternal paternal risk factors for low birthweight (LBW) in China. We aimed to identify parental risk factors associated with LBW.A population-based, retrospective cohort study was conducted on 202,725 singleton infants at 37-42 weeks. These term singleton newborns were classified as LBW with birthweight ≤2500 g(TLBW) and normal birthweight between 50th to 97th percentile (TNBW 50th-97th) according to Chinese singleton norms. Multiple logistic regression analyses were used to find those parental risk factors of LBW by comparing two groups. TLBW and TNBW(50th-97th) occupied 4.8% and 70.8% of the study population, respectively. Logistic regression showed a significant association with positive maternal hepatitis B surface antigen (RR = 1.979, P = 0.047), irregular folic acid intake (RR = 1.152, P = 0.003), paternal history of varicocele (RR = 2.404, P = 0.003) and female babies (RR = 1.072, P = 0.046). Maternal smoking, hypertension and history of stillbirth were found related to LBW but no statistically significant. Positive maternal hepatitis B surface antigen, irregular folic acid intake, paternal history of varicocele had a negative effect on birth weight. Measures are necessarily taken to avoid them to improve pregnancy outcomes. Further studies should be done to investigate each detailed risk factors on LBW.

Correlation between preconception maternal non-occupational exposure to interior decoration or oil paint odour and average birth weight of neonates: findings from a nationwide cohort study in China's rural areas.

BACKGROUND: Birth weight is a critical indicator of neonatal health and foretells people's health in adolescence and even adulthood. Some researchers have warned against the adverse effects on babies' birth weight of exposure to pollutants in interior decoration or oil paint by odour intake. This study evaluated the effects of maternal exposure to such factors before conception on the birth weights of neonates. METHODS: Data on 213 461 cases in this study were from the database of the free National Pre-pregnancy Checkups Project. Defined as 'exposed' were those women exposed to oil paint odour or interior decoration at home or in the workplace within 6 months before their pregnancy. The study focused on revealing the correlation between such exposure and the birth weight of the neonates of these women, especially the incidence of macrosomia and low birth weight (LBW). Statistical analysis was conducted using the Kruskal-Wallis H test, the Mann-Whitney U test and logistic regression. RESULTS: The birth weight of babies from mothers non-occupationally exposed to such settings averaged 3465 g (range 3150-3650 g), whereas the birth weight of those from mothers free of such exposure averaged 3300 g (range 3000-3600g). Maternal exposure preconception to interior decoration or oil paint odour reduced the incidence of LBW in their babies (p=0.003, OR 0.749, 95% CI 0.617 to 0.909). Such exposure may also augment the probability of macrosomia (p<0.001, OR 1.297, 95% CI 1.133 to 1.484). CONCLUSION: Maternal exposure to interior decoration or oil paint odour preconception may increase the average birth weight of neonates, as well as the incidence of macrosomia.