Exposure to ambient temperature and heat index in relation to DNA methylation age: A population-based study in Taiwan.

BACKGROUND: Climate change caused an increase in ambient temperature in the past decades. Exposure to high ambient temperature could result in biological aging, but relevant studies in a warm environment were lacking. We aimed to study the exposure effects of ambient temperature and heat index (HI) in relation to age acceleration in Taiwan, a subtropical island in Asia. METHODS: The study included 2,084 participants from Taiwan Biobank. Daily temperature and relative humidity data were collected from weather monitoring stations. Individual residential exposure was estimated by ordinary kriging. Moving averages of ambient temperature and HI from 1 to 180 days prior to enrollment were calculated to estimate the exposure effects in multiple time periods. Age acceleration was defined as the difference between DNA methylation age and chronological age. DNA methylation age was calculated by the Horvath's, Hannum's, Weidner's, ELOVL2, FHL2, phenotypic (Pheno), Skin & blood, and GrimAge2 (Grim2) DNA methylation age algorithms. Multivariable linear regression models, generalized additive models (GAMs), and distributed lag non-linear models (DLNMs) were conducted to estimate the effects of ambient temperature and HI exposures in relation to age acceleration. RESULTS: Exposure to high ambient temperature and HI were associated with increased age acceleration, and the associations were stronger in prolonged exposure. The heat stress days with maximum HI in caution (80-90°F), extreme caution (90-103°F), danger (103-124°F), and extreme danger (>124°F) were also associated with increased age acceleration, especially in the extreme danger days. Each extreme danger day was associated with 571.38 (95 % CI: 42.63-1100.13), 528.02 (95 % CI: 36.16-1019.87), 43.9 (95 % CI: 0.28-87.52), 16.82 (95 % CI: 2.36-31.28) and 15.52 (95 % CI: 2.17-28.88) days increase in the Horvath's, Hannum's, Weidner's, Pheno, and Skin & blood age acceleration, respectively. CONCLUSION: High ambient temperature and HI may accelerate biological aging.

Development of a Novel Endometrial Signature Based on Endometrial microRNA for Determining the Optimal Timing for Embryo Transfer.

Though tremendous advances have been made in the field of in vitro fertilization (IVF), a portion of patients are still affected by embryo implantation failure issues. One of the most significant factors contributing to implantation failure is a uterine condition called displaced window of implantation (WOI), which refers to an unsynchronized endometrium and embryo transfer time for IVF patients. Previous studies have shown that microRNAs (miRNAs) can be important biomarkers in the reproductive process. In this study, we aim to develop a miRNA-based classifier to identify the WOI for optimal time for embryo transfer. A reproductive-related PanelChip® was used to obtain the miRNA expression profiles from the 200 patients who underwent IVF treatment. In total, 143 out of the 167 miRNAs with amplification signals across 90% of the expression profiles were utilized to build a miRNA-based classifier. The microRNA-based classifier identified the optimal timing for embryo transfer with an accuracy of 93.9%, a sensitivity of 85.3%, and a specificity of 92.4% in the training set, and an accuracy of 88.5% in the testing set, showing high promise in accurately identifying the WOI for the optimal timing for embryo transfer.

Letter to editor 'Non-invasive model for predicting high-risk esophageal varices based on liver and spleen stiffness'.

This letter to the editor relates to the study entitled "Non-invasive model for predicting high-risk esophageal varices based on liver and spleen stiffness". Acute bleeding caused by esophageal varices is a life-threatening complication in patients with liver cirrhosis. Due to the discomfort, contraindications, and associated complications of upper gastrointestinal endoscopy screening, it is crucial to identify an imaging-based non-invasive model for predicting high-risk esophageal varices in patients with cirrhosis.

Non-invasive model for predicting high-risk esophageal varices based on liver and spleen stiffness.

BACKGROUND: Acute bleeding due to esophageal varices (EVs) is a life-threatening complication in patients with cirrhosis. The diagnosis of EVs is mainly through upper gastrointestinal endoscopy, but the discomfort, contraindications and complications of gastrointestinal endoscopic screening reduce patient compliance. According to the bleeding risk of EVs, the Baveno VI consensus divides varices into high bleeding risk EVs (HEVs) and low bleeding risk EVs (LEVs). We sought to identify a non-invasive prediction model based on spleen stiffness measurement (SSM) and liver stiffness measurement (LSM) as an alternative to EVs screening. AIM: To develop a safe, simple and non-invasive model to predict HEVs in patients with viral cirrhosis and identify patients who can be exempted from upper gastrointestinal endoscopy. METHODS: Data from 200 patients with viral cirrhosis were included in this study, with 140 patients as the modelling group and 60 patients as the external validation group, and the EVs types of patients were determined by upper gastrointestinal endoscopy and the Baveno VI consensus. Those patients were divided into the HEVs group (66 patients) and the LEVs group (74 patients). The effect of each parameter on HEVs was analyzed by univariate and multivariate analyses, and a non-invasive prediction model was established. Finally, the discrimination ability, calibration ability and clinical efficacy of the new model were verified in the modelling group and the external validation group. RESULTS: Univariate and multivariate analyses showed that SSM and LSM were associated with the occurrence of HEVs in patients with viral cirrhosis. On this basis, logistic regression analysis was used to construct a prediction model: Ln [P/(1-P)] = -8.184 -0.228 × SSM + 0.642 × LSM. The area under the curve of the new model was 0.965. When the cut-off value was 0.27, the sensitivity, specificity, positive predictive value and negative predictive value of the model for predicting HEVs were 100.00%, 82.43%, 83.52%, and 100%, respectively. Compared with the four prediction models of liver stiffness-spleen diameter to platelet ratio score, variceal risk index, aspartate aminotransferase to alanine aminotransferase ratio, and Baveno VI, the established model can better predict HEVs in patients with viral cirrhosis. CONCLUSION: Based on the SSM and LSM measured by transient elastography, we established a non-invasive prediction model for HEVs. The new model is reliable in predicting HEVs and can be used as an alternative to routine upper gastrointestinal endoscopy screening, which is helpful for clinical decision making.

Zinc finger protein 671 has a cancer-inhibiting function in colorectal carcinoma via the deactivation of Notch signaling.

Zinc finger protein 671 (ZNF671) has been described as a vital cancer inhibitor in multiple neoplasms, yet the functional roles of ZNF671 in colorectal carcinoma (CRC) remain unresolved. This project examined the possible link between ZNF671 and CRC. Lower levels of ZNF671 were observed in CRC tissue compared with noncancerous tissue, which were related to a worse survival rate in CRC patients. High methylation levels at the ZNF671 gene promoter region were shown in CRC tissue, which were inversely correlated with ZNF671 expression. Treatment with demethylation agents restored ZNF671 levels in CRC cell lines. Up-regulation of ZNF671 resulted in suppressive effects on the proliferative ability and metastatic potency of CRC cells. Moreover, the up-regulation of ZNF671 reinforced the chemosensitivity of CRC cells. A mechanism study determined ZNF671 to be a vital mediator of Notch signaling. The up-regulation of ZNF671 decreased the expression of Notch1 and lowered the levels of NICD, HES1, and HEY1. The overexpression of NICD1 diminished ZNF671-mediated antitumor effects. ZNF671 depletion reinforced Notch signaling, and Notch suppression reversed ZNF671-depletion-elicited protumor effects. Moreover, the overexpression of ZNF671 weakened the tumorigenicity of CRC cells in a xenograft model in vivo. In summary, ZNF671 exerts a cancer-inhibiting function in CRC via the deactivation of Notch signaling. Low ZNF671 levels caused by gene promoter hypermethylation contribute to the malignant transformation of CRC. This work underlines the interest of ZNF671 as a target candidate for exploiting novel anti-CRC therapies.

The developmentally timed decay of an essential microRNA family is seed-sequence dependent.

MicroRNA (miRNA) abundance is tightly controlled by regulation of biogenesis and decay. Here, we show that the mir-35 miRNA family undergoes selective decay at the transition from embryonic to larval development in C. elegans. The seed sequence of the miRNA is necessary and largely sufficient for this regulation. Sequences outside the seed (3' end) regulate mir-35 abundance in the embryo but are not necessary for sharp decay at the transition to larval development. Enzymatic modifications of the miRNA 3' end are neither prevalent nor correlated with changes in decay, suggesting that miRNA 3' end display is not a core feature of this mechanism and further supporting a seed-driven decay model. Our findings demonstrate that seed-sequence-specific decay can selectively and coherently regulate all redundant members of a miRNA seed family, a class of mechanism that has great biological and therapeutic potential for dynamic regulation of a miRNA family's target repertoire.

Specific Amino Acid Substitutions in OXA-51-Type ß-Lactamase Enhance Catalytic Activity to a Level Comparable to Carbapenemase OXA-23 and OXA-24/40.

The chromosomal blaOXA-51-type gene encodes carbapenem-hydrolyzing class D ß-lactamases (CHDLs), specific variants shown to mediate carbapenem resistance in the Gram-negative bacterial pathogen Acinetobacter baumannii. This study aims to characterize the effect of key amino acid substitutions in OXA-51 variants of carbapenem-hydrolyzing class D ß-lactamases (CHDLs) on substrate catalysis. Mutational and structural analyses indicated that each of the L167V, W222G, or I129L substitutions contributed to an increase in catalytic activity. The I129L mutation exhibited the most substantial effect. The combination of W222G and I129L substitutions exhibited an extremely strong catalytic enhancement effect in OXA-66, resulting in higher activity than OXA-23 and OXA-24/40 against carbapenems. These findings suggested that specific arrangement of residues in these three important positions in the intrinsic OXA-51 type of enzyme can generate variants that are even more active than known CHDLs. Likewise, mutation leading to the W222M change also causes a significant increase in the catalytic activity of OXA-51. blaOXA-51 gene in A. baumannii may likely continue to evolve, generating mutant genes that encode carbapenemase with extremely strong catalytic activity.

Precise delivery of multi-stimulus-responsive nanocarriers based on interchangeable visual guidance.

Cancer treatment is imminent, and controlled drug carriers are an important development direction for future clinical chemotherapy. Visual guidance is a feasible means to achieve precise treatment, reduce toxicity and increase drug efficacy. However, the existing visual control methods are limited by imaging time-consuming, sensitivity and side effects. In addition, the ability of the carrier to respond to environmental stimuli in vivo is another difficulty that limits its application. Here, we propose a highly stimulus-responsive GC liposome with precise tracing and sensitive feedback capabilities. It combines magnetic resonance imaging and fluorescence imaging, and addresses the need for precise visualization by alternating imaging modalities. More importantly, GC liposomes are a carrier that can accumulate stimuli. In this paper, by tracking the fragmentation process of empty GC and drug-loaded D-GC liposomes, we confirm the synergistic effect between multiple stimuli, which can result in a more efficient drug release performance. Finally, in mice models we examined the GC liposome imaging approach and the D-GC + UV group guided by this visualization exhibited the highest tumor inhibition efficiency (6.85-fold). This study highlights the advantages of alternate visualization-guided and co-stimulation treatment strategies, and provides design ideas and potential materials for efficient and less toxic cancer treatments.

Associations between prenatal exposure to perfluoroalkyl substances, hypomethylation of MEST imprinted gene and birth outcomes.

Prenatal perfluoroalkyl substance (PFAS) exposure has been linked to adverse birth outcomes, but the underlying mechanism has yet to be elucidated. DNA methylation changes in mesoderm-specific transcript (MEST) imprinted gene may be a mechanism of the prenatal exposure effects of PFASs on fetal growth. The aim was to investigate the prenatal PFASs exposure effects on DNA methylation changes in MEST imprinted gene involved in fetal growth. Among 486 mother-infant pairs from the Taiwan Birth Panel Study, PFASs and DNA methylation levels at 5 CpG sites of MEST promoter region were measured in cord blood. Univariable and multivariable linear regressions were performed to estimate the associations between prenatal PFAS exposure, MEST DNA methylation levels, and child birth outcomes. Mediation analysis was performed to examine the potential pathway of MEST methylation between PFASs and birth outcomes. We found that higher prenatal perfluorooctyl sulfonate (PFOS) exposure was significantly associated with lower methylation levels at 5 CpG sites of MEST promoter region (an adjusted ß range: -1.56, -2.22). Significant negative associations were also found between MEST methylation levels and child birth weight. Furthermore, the associations between PFOS and perfluorooctanoic acid (PFOA) exposure and MEST methylation levels were more profound in girls than in boys. The mediated effect of average MEST methylation level between PFOS exposure and birth weight was 18.3 (95% CI = 2.1, 40.2; p = 0.014). The direct effect of PFOS exposure to birth weight independent to average MEST methylation level was -93.2 (95% CI = -170.5, -17.8; p = 0.018). In conclusion, our results suggest that prenatal PFAS exposure, especially PFOS, is associated with lower methylation levels at MEST promoter region, which not only leverages the role of imprinted gene in ensuring the integrity of fetal growth but also provides a potential mechanism for evaluating the prenatal exposure effect.

Selective Synthesis of Carbon Nanorings via Asymmetric Intramicellar Phase-Transition-Induced Tip-to-Tip Assembly.

The selective synthesis of energetically less favorable ring-shaped nanostructures by liquid phase synthetic chemistry is a huge challenge. Herein, we report a precise synthesis of carbon nanorings with a well-defined morphology and tunable thickness based on asymmetric intramicellar phase-transition-induced tip-to-tip assembly via mixing hydrophobic long-chain octadecanol and block copolymer F127. This orientational self-assembly depends on the hydrophobicity difference of the intermediate's surface, which triggers directional interactions that surpass the entropy cost of undesired connections and help assemble intermediates into defined ringlike structures. Based on a ringlike template, carbon nanorings with adjustable sizes can be attained by changing synthetic variables. More importantly, diverse units including crescentlike, podlike, and garlandlike nanostructures can also be created through controlling the kinetics of the self-assembly process. This discovery lays a solid foundation for the challenging construction of such a precise configuration on the nanoscale, which would not only promote fundamental studies but also pave the way for the development of advanced nanodevices with unique properties.

Association of Ambient Fine Particulate Matter (PM2.5) with Elevated Fecal Hemoglobin Concentration and Colorectal Carcinogenesis: A Population-Based Retrospective Cohort Study.

The roles of ambient fine particulate matter (PM2.5) in the prevention of colorectal cancer (CRC) have been scarcely highlighted as there is short of empirical evidence regarding the influences of PM2.5 on multistep carcinogenic processes of CRC. A retrospective cohort design with multistate outcomes was envisaged by linking monthly average PM2.5 concentrations at 22 city/county level with large-scale cohorts of cancer-screened population to study the influences of PM2.5 on short-term inflammatory process and multistep carcinogenic processes of CRC. Our study included a nationwide CRC screening cohort of 4,628,995 aged 50-69 years who attended first screen between 2004 and 2009 and continued periodical screens until 2016. We aimed to illustrate the carcinogenesis of PM2.5 related to CRC by applying both hierarchical logistical and multistate Markov regression models to estimate the effects of air pollution on fecal immunochemical test (FIT) positive (a proxy of inflammatory marker) and pre-clinical and clinical states of CRC in the nationwide cohort. We found a significant association of high PM2.5 exposure and FIT-positive by an increased risk of 11% [95% confidence interval (CI), 10-12]. PM2.5 enhanced the risk of being preclinical state by 14% (95% CI, 10-18) and that of subsequent progression from pre-clinical to clinical state by 21% (95% CI, 14-28). Furthermore, the elevated risks for CRC carcinogenesis were significantly higher for people living in high PM2.5 pollution areas in terms of yearly averages and the number days above 35 µg/m3 than those living in low PM2.5 pollution areas. We concluded that both short-term and long-term PM2.5 exposure were associated with multistep progression of CRC, which were useful to design precision primary and secondary prevention strategies of CRC for people who are exposed to high PM2.5 pollution.

M1BP cooperates with CP190 to activate transcription at TAD borders and promote chromatin insulator activity.

Genome organization is driven by forces affecting transcriptional state, but the relationship between transcription and genome architecture remains unclear. Here, we identified the Drosophila transcription factor Motif 1 Binding Protein (M1BP) in physical association with the gypsy chromatin insulator core complex, including the universal insulator protein CP190. M1BP is required for enhancer-blocking and barrier activities of the gypsy insulator as well as its proper nuclear localization. Genome-wide, M1BP specifically colocalizes with CP190 at Motif 1-containing promoters, which are enriched at topologically associating domain (TAD) borders. M1BP facilitates CP190 chromatin binding at many shared sites and vice versa. Both factors promote Motif 1-dependent gene expression and transcription near TAD borders genome-wide. Finally, loss of M1BP reduces chromatin accessibility and increases both inter- and intra-TAD local genome compaction. Our results reveal physical and functional interaction between CP190 and M1BP to activate transcription at TAD borders and mediate chromatin insulator-dependent genome organization.

Prenatal chlorpyrifos exposure in association with PPARγ H3K4me3 and DNA methylation levels and child development.

BACKGROUND: Chlorpyrifos, one of the most widely used pesticides, can penetrate the placenta and affect fetal growth and neurodevelopment. Epigenetic regulation of peroxisome proliferator-activated receptor gamma (PPARγ), such as DNA methylation and trimethylation of lysine 4 of H3 (H3K4me3), may provide a potential mechanism for how fetal growth and development are impacted by chlorpyrifos exposure. The aims of the study were to investigate whether prenatal chlorpyrifos exposure was associated with H3K4me3 and DNA methylation levels of the PPARγ gene in the placenta and the related effects on birth outcomes and neurodevelopment. METHODS: Among 425 mother-infant pairs from the Taiwan Birth Panel Study, chlorpyrifos levels were measured in cord blood by using online SPE-LC/HESI/MS/MS; placental PPARγ H3K4me3 and DNA methylation levels were measured by ChIP-qPCR and pyrosequencing, respectively; the neonates' health outcomes were extracted from the medical records; and childhood neurodevelopment was evaluated by using the Comprehensive Developmental Inventory for Infants and Toddlers in 2-year-old children. Multivariable regression models were used to adjust for potential confounders. RESULTS: After controlling for potential confounders, each unit increase in the natural log-transformed prenatal chlorpyrifos exposure level was associated with an increase in the PPARγ DNA methylation level (adjusted ß (aß) = 0.77, p = 0.032) and poorer performance in the cognitive and language domains at 2 years old, especially in boys (aß = -1.66, p = 0.016, and aß = -1.79, p = 0.023, respectively). PPARγ H3K4me3 levels were positively associated with gestational age (aß = 0.16, p = 0.011), birth weight (aß = 30.52, p = 0.013), birth length (aß = 0.18, p = 0.003 and aß = 0.15, p = 0.042), and gross-motor performance (aß = 1.67, p = 0.036). CONCLUSIONS: Our findings suggested that prenatal chlorpyrifos exposure affected PPARγ DNA methylation levels and performance in the cognitive and language domains.

FIGLA, LHX8 and SOHLH1 transcription factor networks regulate mouse oocyte growth and differentiation.

Germ-cell transcription factors control gene networks that regulate oocyte differentiation and primordial follicle formation during early, postnatal mouse oogenesis. Taking advantage of gene-edited mice lacking transcription factors expressed in female germ cells, we analyzed global gene expression profiles in perinatal ovaries from wildtype, FiglaNull, Lhx8Null and Sohlh1Null mice. Figla deficiency dysregulates expression of meiosis-related genes (e.g. Sycp3, Rad51, Ybx2) and a variety of genes (e.g. Nobox, Lhx8, Taf4b, Sohlh1, Sohlh2, Gdf9) associated with oocyte growth and differentiation. The absence of FIGLA significantly impedes meiotic progression, causes DNA damage and results in oocyte apoptosis. Moreover, we find that FIGLA and other transcriptional regulator proteins (e.g. NOBOX, LHX8, SOHLH1, SOHLH2) are co-expressed in the same subset of germ cells in perinatal ovaries and Figla ablation dramatically disrupts KIT, NOBOX, LHX8, SOHLH1 and SOHLH2 abundance. In addition, not only do FIGLA, LHX8 and SOHLH1 cross-regulate each other, they also cooperate by direct interaction with each during early oocyte development and share downstream gene targets. Thus, our findings substantiate a major role for FIGLA, LHX8 and SOHLH1 as multifunctional regulators of networks necessary for oocyte maintenance and differentiation during early folliculogenesis.

Children's environmental health based on birth cohort studies of Asia (2) - air pollution, pesticides, and heavy metals.

The life style and child raising environment in Asia are quite different compared with Western countries. Besides, the children's environmental threats and difficulties in conducting studies could be different. To address children's environmental health in Asia area, the Birth Cohort Consortium of Asia (BiCCA) was co-established in 2011. We reviewed the mercury, polychlorinated biphenyls, perfluoroalkyl substances, phthalates, and environmental tobacco smoke in pervious based on birth cohort studies in Asia. The aim of this study was to summarize the traditional environmental pollution and the target subjects were also based on the birth cohort in Asia area. Environmental pollutants included air pollutants, pesticides focusing on organochlorine pesticides, diakylphosphates, and pyrethroid, and heavy metals including lead, arsenic, cadmium, manganese, vanadium, and thallium. Fetal growth and pregnancy outcomes, childhood growth and obesity, neurodevelopment and behavioral problems, and allergic disease and immune function were classified to elucidate the children's health effects. In total, 106 studies were selected in this study. The evidences showed air pollution or pesticides may affect growth during infancy or childhood, and associated with neurodevelopmental or behavioral problems. Prenatal exposure to lead or manganese was associated with neurodevelopmental or behavioral problems, while exposure to arsenic or cadmium may influence fetal growth. In addition to the harmonization and international collaboration of birth cohorts in Asia; however, understand the whole picture of exposure scenario and consider more discipline in the research are necessary.

Prenatal Perfluorooctyl Sulfonate Exposure and Alu DNA Hypomethylation in Cord Blood.

BACKGROUND: Perfluoroalkyl substances (PFASs) are stable and persistent in the environment, animals, and humans. PFASs can penetrate placenta and affect fetal growth. We investigated associations between prenatal exposure to perfluorooctanoic acid (PFOA), perfluorooctyl sulfonate (PFOS), perfluorononanoic acid (PFNA), and perfluoroundecanoic acid (PFUA) and global methylation levels. Specific Aims and Methods: The study used the subjects from Taiwan Birth Panel birth cohort study, including all pregnant women who gave birth between July 2004 and June 2005 in four hospitals in Taipei city and New Taipei City. A total of 363 mother-infant pairs were included in the final analyses. PFOA, PFOS, PFNA, and PFUA were measured by UPLC-MS/MS in cord blood. LINE-1 and Alu repeated elements from cord blood was used to represent global DNA methylation levels. Multivariable regression models were used to adjust potential confounders. RESULTS: After controlling for potential confounders, each unit increase in the natural log-transformed PFOS exposure was associated with an adjusted OR of 1.72 (95% CI: 1.03, 2.88) for low Alu methylation level when dichotomized methylation level by medium. No significant effects between PFOA, PFNA, PFUA and methylation levels in the multivariable regression models were observed. CONCLUSIONS: Our findings suggest that prenatal PFOS exposure may be associated with low Alu methylation level.

Children's environmental health based on birth cohort studies of Asia.

Numerous studies have explored the associations between environmental pollutants and pediatric health. Recent studies have investigated the issue in Asia, but no systematic review has been published to date. This study aims to elucidate the issue by summarizing relevant epidemiologic evidence for cohorts in Asia, using information from the Birth Cohort Consortium of Asia (BiCCA). Environmental pollutants include mercury, environmental tobacco smoke (ETS), polychlorinated biphenyls (PCB), perfluoroalkyl substances (PFAS) and phthalates. This study sought to classify the effects of such compounds on fetal growth and pregnancy outcomes, neurodevelopment and behavioral problems, allergic disease and immune function and the endocrine system and puberty. These evidences showed ETS has been associated with infant birth weight, children's neurodevelopment and allergy disease; mercury and PCB have been shown to affect children's neurodevelopment; phthalate has effects on endocrine function; PFAS alters children's neurodevelopment, the endocrine system, and the allergic response. However, more consistent and coordinated research is necessary to understand the whole picture of single environmental and/or co-exposure and children's health. Therefore, harmonization and international collaboration are also needed in Asia.

Particle Size Influences on the Coating Microstructure through Green Chromia Inclusion in Plasma Electrolytic Oxidation.

In an effort to color the aluminum alloy surface green via plasma electrolytic oxidation (PEO), two alkaline solutions have been employed with particulate inclusions and sodium aluminate. Electrolyte I comprises a self-made chromia pigment with a mean particle size 69 nm, whereas electrolyte II contains a commercially available pigment, GN-M, with a larger particle size 351 nm. Both pigments are oxygen deficient Cr2O3-δ of corundum-type structure before coating, the oxidative environment of PEO converts them into stoichiometric Cr2O3. In electrolyte I and II, the oxides of chromium and aluminum deposit simultaneously under analogous PEO conditions, yet resulting in very different microstructures. The GN-M inclusion of large size amasses on top of the coating, while the self-made inclusion goes deep, and closely associates with alumina and pores. The oxide coating, grown in electrolyte II, consists of a top Cr2O3-rich layer and a dense alumina layer underneath, delineated by the boundary marked with microdischarge burns. On the other hand, the self-made particulate inclusion appears to bring the electric microdischarges inside the coating and create inner pores and damages. The structure difference, caused by the difference in microdischarge locations, is attributed to shifting of the Cr2O3-Al2O3 interface where p-type and n-type semiconductors meet.

Genome-wide Gene-Asbestos Exposure Interaction Association Study Identifies a Common Susceptibility Variant on 22q13.31 Associated with Lung Cancer Risk.

BACKGROUND: Occupational asbestos exposure has been found to increase lung cancer risk in epidemiologic studies. METHODS: We conducted an asbestos exposure-gene interaction analyses among several Caucasian populations who were current or ex-smokers. The discovery phase included 833 Caucasian cases and 739 Caucasian controls, and used a genome-wide association study (GWAS) to identify single-nucleotide polymorphisms (SNP) with gene-asbestos interaction effects. The top ranked SNPs from the discovery phase were replicated within the International Lung and Cancer Consortium (ILCCO). First, in silico replication was conducted in those groups that had GWAS and asbestos exposure data, including 1,548 cases and 1,527 controls. This step was followed by de novo genotyping to replicate the results from the in silico replication, and included 1,539 cases and 1,761 controls. Multiple logistic regression was used to assess the SNP-asbestos exposure interaction effects on lung cancer risk. RESULTS: We observed significantly increased lung cancer risk among MIRLET7BHG (MIRLET7B host gene located at 22q13.31) polymorphisms rs13053856, rs11090910, rs11703832, and rs12170325 heterozygous and homozygous variant allele(s) carriers (P < 5 × 10(-7) by likelihood ratio test; df = 1). Among the heterozygous and homozygous variant allele(s) carriers of polymorphisms rs13053856, rs11090910, rs11703832, and rs12170325, each unit increase in the natural log-transformed asbestos exposure score was associated with age-, sex-, smoking status, and center-adjusted ORs of 1.34 [95% confidence interval (CI), 1.18-1.51], 1.24 (95% CI, 1.14-1.35), 1.28 (95% CI, 1.17-1.40), and 1.26 (95% CI, 1.15-1.38), respectively, for lung cancer risk. CONCLUSION: Our findings suggest that MIRLET7BHG polymorphisms may be important predictive markers for asbestos exposure-related lung cancer. IMPACT: To our knowledge, our study is the first report using a systematic genome-wide analysis in combination with detailed asbestos exposure data and replication to evaluate asbestos-associated lung cancer risk.

Polymorphisms in ERCC1 and ERCC2/XPD genes and carcinogen DNA adducts in human lung.

OBJECTIVES: In this exploratory study, we aimed to investigate whether polymorphisms in excision repair cross-complementing group 1 (ERCC1) and excision repair cross-complementing group 2/xeroderma pigmentosum group D (ERCC2/XPD) in the nucleotide excision repair (NER) pathways associated with DNA adducts in human lung tissue. We also analyzed the association stratified by the major histologic subtypes of non-small cell lung cancer (NSCLC): adenocarcinoma (ADC) and squamous cell carcinoma (SQCC). METHODS: The study population consisted of 107 early stage NSCLC patients from the Massachusetts General Hospital (MGH) in Boston who underwent curative surgical resection. Genotyping was completed for SNPs in ERCC1 [C8092A (rs3212986) and C118T (rs11615)] and ERCC2/XPD [Asp312Asn (rs1799793) and Lys751Gln (rs1052559)] using a PCR-RFLP method and the PCR with fluorescent allele-specific oligonucleotide probes (Taqman). DNA adduct levels were measured as relative adduct levels per 10(10) nucleotides by (32)P-postlabeling in non-tumor lung tissue. RESULTS: After adjusting for potential confounders, lung DNA adduct levels increased by 103.2% [95% confidence interval (CI), -11.5 to 366.6] for ERCC2/XPD rs1799793AA genotype compared with their corresponding wild type homozygous genotypes in overall NSCLC, but the difference did not reach statistical significance. When we stratified by the subtypes of NSCLC, we found that DNA adducts levels in lung increased by 204.9% (95% CI, 0.8 to 822.2, P=0.059) for ERCC2/XPD rs1799793AA genotype in subjects with SQCC and the trend was statistically significant (P for trend=0.0489). CONCLUSIONS: Polymorphisms in ERCC2/XPD Asp312Asn may be associated with increased DNA adduct levels in the lung, especially among subjects with SQCC. Further large scale studies are needed to confirm our findings.