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Chemotherapy resistance is a primary reason of ovarian cancer therapy failure; hence it is important to investigate the underlying mechanisms of chemotherapy resistance and develop novel potential therapeutic targets.RNA sequencing of cisplatin-resistant and -sensitive (chemoresistant and chemosensitive, respectively) ovarian cancer organoids was performed, followed by detection of the expression level of fibrillin-1 (FBN1) in organoids and clinical specimens of ovarian cancer. Subsequently, glucose metabolism, angiogenesis, and chemosensitivity were analyzed in structural glycoprotein FBN1-knockout cisplatin-resistant ovarian cancer organoids and cell lines. To gain insights into the specific functions and mechanisms of action of FBN1 in ovarian cancer, immunoprecipitation, silver nitrate staining, mass spectrometry, immunofluorescence, Western blotting, and Fӧrster resonance energy transfer-fluorescence lifetime imaging analyses were performed, followed by in vivo assays using vertebrate model systems of nude mice and zebrafish.FBN1 expression was significantly enhanced in cisplatin-resistant ovarian cancer organoids and tissues, indicating that FBN1 might be a key factor in chemoresistance of ovarian cancer. We also discovered that FBN1 sustained the energy stress and induced angiogenesis in vitro and in vivo, which promoted the cisplatin-resistance of ovarian cancer. Knockout of FBN1 combined with treatment of the antiangiogenic drug apatinib improved the cisplatin-sensitivity of ovarian cancer cells. Mechanistically, FBN1 mediated the phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) at the Tyr1054 residue, which activated its downstream focal adhesion kinase (FAK)/protein kinase B (PKB or AKT) pathway, induced the phosphorylation of signal transducer and activator of transcription 2 (STAT2) at the tyrosine residue 690 (Tyr690), promoted the nuclear translocation of STAT2, and ultimately altered the expression of genes associated with STAT2-mediated angiogenesis and glycolysis.The FBN1/VEGFR2/STAT2 signaling axis may induce chemoresistance of ovarian cancer cells by participating in the process of glycolysis and angiogenesis. The present study suggested a novel FBN1-targeted therapy and/or combination of FBN1 inhibition and antiangiogenic drug for treating ovarian cancer.

Background Although programmed cell death‐ligand 1 (PD‐L1) plays a well‐known function in immune checkpoint response by interacting with programmed cell death‐1 (PD‐1), the cell‐intrinsic role of PD‐L1 in tumors is still unclear. Here, we explored the molecular regulatory mechanism of PD‐L1 in the progression and metastasis of ovarian cancer. Methods Immunohistochemistry of benign tissues and ovarian cancer samples was performed, followed by migration, invasion, and angiogenesis assays in PD‐L1‐knockdown ovarian cancer cells. Immunoprecipitation, mass spectrometry, and chromatin immunoprecipitation were conducted along with zebrafish and mouse experiments to explore the specific functions and mechanisms of PD‐L1 in ovarian cancer. Results Our results showed that PD‐L1 induced angiogenesis, which further promoted cell migration and invasion in vitro and in vivo of ovarian cancer. Mechanistically, PD‐L1 was identified to directly interact with vascular endothelial growth factor receptor‐2 (VEGFR2) and then activated the FAK/AKT pathway, which further induced angiogenesis and tumor progression, leading to poor prognosis of ovarian cancer patients. Meanwhile, PD‐L1 was found to be regulated by the oncogenic transcription factor c‐JUN at the transcriptional level, which enhanced the expression of PD‐L1 in ovarian cancer. Furthermore, we demonstrated that PD‐L1 inhibitor durvalumab, combined with the antiangiogenic drug, apatinib, could enhance the effect of anti‐angiogenesis and the inhibition of cell migration and invasion. Conclusion Our results demonstrated that PD‐L1 promoted the angiogenesis and metastasis of ovarian cancer by participating in the c‐JUN/VEGFR2 signaling axis, suggesting that the combination of PD‐L1 inhibitor and antiangiogenic drugs may be considered as a potential therapeutic approach for ovarian cancer patients., This manuscript demonstrated that PD‐L1 promoted the angiogenesis and metastasis of ovarian cancer by participating in the c‐JUN/VEGFR2 signaling axis, and suggested that the combination of PD‐L1 inhibitor and antiangiogenic drugs may be considered as a potential therapeutic approach for ovarian cancer patients.

Background Stanniocalcin 1 (STC1) plays an integral role in ovarian cancer (OC). However, the functional role of STC1 in metastasis, lipid metabolism and cisplatin (DDP) chemoresistance in OC is not fully understood. Methods Single-cell sequencing and IHC analysis were performed to reveal STC1 expression profiles in patient tissues. Metastasis, lipid metabolism and DDP chemoresistance were subsequently assessed. Cell-based in vitro and in vivo assays were subsequently conducted to gain insight into the underlying mechanism of STC1 in OC. Results Single-cell sequencing assays and IHC analysis verified that STC1 expression was significantly enhanced in OC tissues compared with para-carcinoma tissues, and it was further up-regulated in peritoneal metastasis tissues compared with OC tissues. In vitro and in vivo experiments demonstrated that STC1 promoted metastasis, lipid metabolism and DDP chemoresistance in OC. Simultaneously, STC1 promoted lipid metabolism by up-regulating lipid-related genes such as UCP1, TOM20 and perilipin1. Mechanistically, STC1 directly bound to integrin β6 (ITGB6) to activate the PI3K signaling pathway. Moreover, STC1 was directly regulated by Forkhead box C2 (FOXC2) in OC. Notably, targeting STC1 and the FOXC2/ITGB6 signaling axis was related to DDP chemoresistance in vitro. Conclusions Overall, these findings revealed that STC1 promoted metastasis, lipid metabolism and DDP chemoresistance via the FOXC2/ITGB6 signaling axis in OC. Thus, STC1 may be used as a prognostic indicator in patients with metastatic OC. Meanwhile, STC1 could be a therapeutic target in OC patients, especially those who have developed chemoresistance to DDP.

Rationale: Cisplatin derivatives are first-line chemotherapeutic agents for epithelial ovarian cancer. However, chemoresistance remains a major hurdle for successful therapy and the underlying molecular mechanisms are poorly understood at present. Methods: RNA sequencing of organoids (PDO) established from cisplatin-sensitive and -resistant ovarian cancer tissue samples was performed. Glucose metabolism, cell senescence, and chemosensitivity properties were subsequently examined. Immunoprecipitation, mass spectrometry, Fӧrster resonance energy transfer-fluorescence lifetime imaging (FRET-FLIM), luciferase reporter assay, ChIP and animal experiments were conducted to gain insights into the specific functions and mechanisms of action of the serine/threonine kinase, Aurora-A, in ovarian cancer. Results: Aurora-A levels were significantly enhanced in cisplatin-resistant PDO. Furthermore, Aurora-A promoted chemoresistance through suppression of cell senescence and induction of glucose metabolism in ovarian cancer organoids and cells. Mechanistically, Aurora-A bound directly to the transcription factor sex determining region Y-box 8 (SOX8) and phosphorylated the Ser327 site, in turn, regulating genes related to cell senescence and glycolysis, including hTERT, P16, LDHA and HK2, through enhancement of forkhead-box k1 (FOXK1) expression. Conclusions: Aurora-A regulates cell senescence and glucose metabolism to induce cisplatin resistance by participating in the SOX8/FOXK1 signaling axis in ovarian cancer. Our collective findings highlight a novel mechanism of cisplatin resistance and present potential therapeutic targets to overcome chemoresistance in ovarian cancer.

Background Resistance to oxaliplatin is a major obstacle for the management of locally advanced and metastatic colon cancer (CC). Although long noncoding RNAs (lncRNAs) play key roles in CC, the relationships between lncRNAs and resistance to oxaliplatin have been poorly understood yet. Methods Chemo-sensitive and chemo-resistant organoids were established from colon cancer tissues of the oxaliplatin-sensitive or -resistant patients. Analysis of the patient cohort indicated that lnc-RP11-536 K7.3 had a potential oncogenic role in CC. Further, a series of functional in vitro and in vivo experiments were conducted to assess the effects of lnc-RP11-536 K7.3 on CC proliferation, glycolysis, and angiogenesis. RNA pull-down assay, luciferase reporter and fluorescent in situ hybridization assays were used to confirm the interactions between lnc-RP11-536 K7.3, SOX2 and their downstream target HIF-1α. Results In this study, we identified a novel lncRNA, lnc-RP11-536 K7.3, was associated with resistance to oxaliplatin and predicted a poor survival. Knockout of lnc-RP11-536 K7.3 inhibited the proliferation, glycolysis, and angiogenesis, whereas enhanced chemosensitivity in chemo-resistant organoids and CC cells both in vitro and in vivo. Furthermore, we found that lnc-RP11-536 K7.3 recruited SOX2 to transcriptionally activate USP7 mRNA expression. The accumulative USP7 resulted in deubiquitylation and stabilization of HIF-1α, thereby facilitating resistance to oxaliplatin. Conclusion In conclusion, our findings indicated that lnc-RP11-536 K7.3 could promote proliferation, glycolysis, angiogenesis, and chemo-resistance in CC by SOX2/USP7/HIF-1α signaling axis. This revealed a new insight into how lncRNA could regulate chemosensitivity and provide a potential therapeutic target for reversing resistance to oxaliplatin in the management of CC.

The relations of polycyclic aromatic hydrocarbons (PAHs) exposure with platelet indices remain unclear. Based on the baseline data from the Wuhan-Zhuhai Cohort Study, we used generalized linear model, multivariate logistic regression analysis and restricted cubic splines (RCS) to assess linear and nonlinear relationship of PAHs exposure with platelet indices. The results showed that among Wuhan individuals, there were the non-linear relations between total hydroxynaphthalene (ΣOHNa) and mean platelet volume (MPV) or ratio of mean platelet volume to platelet count (MPVP), total hydrophenanthrene (ΣOHPh) and MPV or platelet distribution width (PDW), the sum concentration of urinary monohydroxylated metabolites of PAHs (ΣOH-PAHs) and ratio of platelet count to lymphocyte count (PLR) or MPVP, 1-hydropyrene (1-OHP) and PLR or PDW. But among Zhuhai individuals, neither linear nor non-linear relations were found between each of OH-PAHs or ΣOH-PAHs and platelet indices. The findings indicate that serum MPV and MPVP may be independent biomarkers of effects of exposing to environmental PAHs on human bodies.

Background Ovarian cancer is highly lethal and has a poor prognosis due to metastasis. Long non-coding RNAs (lncRNAs) are key regulators of tumor development, but their role in ovarian cancer metastasis remains unclear. Methods The expression of lnc-CTSLP8 in ovarian cancer was analyzed in public databases (TCGA and GEO) and validated via qRT-PCR. Lnc-CTSLP8 overexpression and knockout cell lines were constructed using a lentiviral vector and the CRISP/Cas9 system. Cell proliferation, colony formation, migration, and invasion were analyzed. An ovarian orthotopic tumor mouse model was used for the in vivo study. Changes in autophagosomes, autolysosomes, and mitochondria in ovarian cancer cells were observed via transmission electron microscopy. EMT markers were detected by immunoblotting and immunofluorescence assays. RNA immunoprecipitation, RNA pull-down, and dual luciferase reporter assays were performed to confirm the interaction between lnc-CTSLP8 and miR-199a-5p. Results A novel pseudogene, lnc-CTSLP8, was identified in ovarian cancer, with significantly elevated expression in metastatic tumor tissues compared to primary ovarian tumors. When overexpressed, lnc-CTSLP8 promoted ovarian cancer in vitro and in vivo by acting as a sponge for miR-199a-5p. Autophagy and EMT in ovarian cancer were also enhanced by lnc-CTSLP8. Mechanistically, lnc-CTSLP8 upregulated CTSL1 as a competitive endogenous RNA and exhibited oncogenic effects. Moreover, CTSL1 inhibitor treatment and miR-199a-5p overexpression abrogated the effects of lnc-CTSLP8 overexpression. Conclusions lnc-CTSLP8 acts as a ceRNA in ovarian cancer and represents a potential therapeutic target for metastatic ovarian cancer.

Background So far, the prevalence of human T-lymphotropic virus (HTLV) type 1 and 2 in some highly populated countries such as China is still unknown. In this study, a multi-center nationwide serological survey was designed and performed, to reveal the seroprevalence of HTLV infection among Chinese blood donors. Results Among 8,411,469 blood donors from 155 blood establishments, 435 were finally confirmed as HTLV carriers. The prevalence of HTLV infection in China varied in different provinces: Fujian had the highest prevalence of 36.240/100,000 (95% CI 31.990–41.050) and eleven provinces did not find HTLV-seropositive donors in the three years. no HTLV-2 infection was found. The overall prevalence of HTLV-1 in China decreased from 2016 to 2018. Female was identified as an independent risk factor of HTLV infection in China. Besides, seroconversion was observed in two of seven seroindeterminate donors 85 and 250 days after their last donation, respectively. Conclusions The seroprevalence of HTLV infection in most areas of China among blood donors is quite low, but it varies significantly in different geographic areas. Screening anti-HTLV-1/2 antibody and follow-up of serointederminate donors are essential to ensure blood safety especially in areas where we have found HTLV infected donors.

Quantitative PCR (qPCR) assay using TaqMan™ probe was widely used in the detection of different nucleic acids. However, this technology has several drawbacks, including false negative results caused by primer-dimer (PD) and false positive issues due to primer-probe aggregations. Here, we designed a modified TaqMan™-Molecular Beacon probe by adding an antisense base and a new type of primer pair named central-homo primer pairs bearing 5-10 bases homologous sequence on the 3' end. Using the HBV qPCR assay as a proof of concept, the new design significantly improved the accuracy of the TaqMan™ qPCR assay for HBV detection. Application of the central-homo primer pair led to significantly delayed Ct values by 5-10 cycles compared with conventional primer design. The modified probe containing an antisense base did not produce any detectable signal in repeating primer-probe aggregation experiments. Furthermore, the use of the central-homo primer pair and the non-competitive internal control could solve the false negative problem caused by PD formation. We validated this customized duplex qPCR system using 208 clinical samples collected from patients in clinic showing accuracy was higher than that of the conventional qPCR method.

Exposure to Polycyclic aromatic hydrocarbons (PAHs) has been associated with inflammatory responses. Fractional exhaled nitric oxide (FeNO) and exhaled carbon monoxide (eCO) are both important inflammatory mediators especially in airways. However, few studies have investigated associations of PAH exposures with FeNO or eCO. Therefore, we aimed to quantify the associations of urinary PAH metabolites with FeNO and eCO levels, and investigate their potential effect modifiers by linear mixed models among 4133 participants from the Wuhan-Zhuhai cohort in China. We further performed stratified analyses to estimate effect modification. We found significant associations of increased urinary PAH metabolites with elevated eCO and FeNO. Among all participants, each 1% increase of 1-hydroxynaphthalene, 2-hydroxynaphthalene, 2-hydroxyfluorene, 4-hydroxyphenanthrene, 3-hydroxyphenanthrene, and total PAH metabolites was significantly associated with a 12.6% (95% confidence interval: 9.3%, 15.9%), 9.7% (6.5%, 12.9%), 7.5% (4.1%, 10.9%), 3.2% (0.2%, 6.2%), 2.7% (0.1%, 5.3%), and 6.5% (2.7%, 10.4%) increased eCO level, respectively; while each 1% increase of urinary 1-hydroxynaphthalene, 9-hydroxyphenanthrene, 3-hydroxyphenanthrene, and 2-hydroxyphenanthrene was associated with a -3.0% (-5.8%, -0.2%), 2.9% (0.3%, 5.6%), 3.2% (1.0%, 5.4%), and 4.5% (2.2%, 6.9%) change of FeNO level, respectively. Positive associations between certain urinary PAH metabolites and eCO were observed among both ever-smokers and non-smokers, and the associations were stronger among ever-smokers than that among non-smokers. Increased urinary PAH metabolites were associated with decreased FeNO among ever-smokers and elevated FeNO levels among non-smokers. Our findings suggest that PAH exposures may impair airway through inducing inflammatory response, especially among ever-smokers.

Background Inflammation may play an important role in the association between exposure to polycyclic aromatic hydrocarbons (PAHs) and atherosclerotic cardiovascular disease (ASCVD) risk. However, the underlying mechanisms remain unclear. Objectives To investigate the association of PAHs exposure with ASCVD risk and effects of mean platelet volume (MPV) or Club cell secretory protein (CC16) on the association. Methods A total of 2022 subjects (689 men and 1333 women) were drawn from the baseline Wuhan residents of the Wuhan-Zhuhai Cohort study. Data on demography and the physical examination were obtained from each participant. Urinary monohydroxy PAH metabolites (OH-PAHs) levels were measured by a gas chromatography-mass spectrometry. We estimated the association between each OH-PAHs and the 10-year ASCVD risk or coronary heart disease (CHD) risk using logistic regression models, and further analyze the mediating effect of MPV or plasma CC16 on the association by using structural equation modeling. Results The results of multiple logistic regression models showed that some OH-PAHs were positively associated with ASCVD risk but not CHD risk, including 2-hydroxyfluoren (β = 1.761; 95% CI: 1.194–2.597), 9-hydroxyfluoren (β = 1.470; 95% CI: 1.139–1.898), 1-hydroxyphenanthrene (β = 1.480; 95% CI: 1.008–2.175) and ΣOH-PAHs levels (β = 1.699; 95% CI: 1.151–2.507). The analysis of structural equation modeling shows that increased MPV and increased plasma CC16 levels contributed 13.6% and 15.1%, respectively, to the association between PAHs exposure and the 10-year ASCVD risk (p Conclusions Exposure to PAHs may increase the risk of atherosclerosis, which was partially mediated by MPV or CC16.

Association of exposure to polycyclic aromatic hydrocarbons (PAHs) with increased urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation has been reported in occupational population and children. However, studies on the association between them in general population are limited. A total of 1864 eligible subjects from the baseline Wuhan participants of the Wuhan-Zhuhai Cohort Study (n = 3053) were included in this study, after excluding individuals with certain disease and missing data on urinary monohydroxy PAHs (OH-PAHs) and 8-OHdG levels. Urinary monohydroxy PAHs and 8-OHdG levels were measured by gas chromatography-mass spectrometry and high performance liquid chromatography-electrochemical detection, respectively. Association of urinary OH-PAHs with urinary 8-OHdG was analyzed by multiple linear regression analysis. We found a dose-dependent relationship between urinary PAHs metabolites and urinary 8-OHdG (p 0.05 for all). Furthermore, more evidence for the association of total concentrations of urinary OH-PAHs with 8-OHdG levels were observed in individuals with normal body mass index or central obesity (p 0.01 for all). There was a dose-dependent relationship between urinary OH-PAHs levels and urinary 8-OHdG levels among a general Chinese population. Exposure to background PAHs may have a greater influence on urinary 8-OHdG levels in individuals with central obesity.

Neurensin-2 (NRSN2) is a 24KD protein, which is reported located in the membrane, while its biological functions remain unknown, not to mention in the field of tumor biology. In current study, we aimed to analyze the functions of NRSN2 in ovarian cancer. We screened TCGA database and surprisingly found that its copy number and mRNA level are gained and heightened respectively in parts of serous ovarian cancer patients. In current study, both loss- and gain- function assays found that NRSN2 is associated with the malignant phenotype in ovarian cancer cells, because NRSN2 plays a remarkable role in anchorage-independent colony formation, subcutaneous tumor formation, cell invasion, and chemoresistance. Furthermore, we found that the level of NRSN2 was positively correlated with the expression of stem cell marker CD133. In addition, Wnt canonical signaling and Twist/Akt/Erk axis were also regulated by NRSN2. In conclusion, we found that a poorly studied protein, NRSN2, which is associated with the malignant phenotype of serous ovarian cancer and as a membrane protein; it could be a target for serous ovarian cancer treatment.

Background: Smoking is a risk factor for many human diseases. DNA methylation has been related to smoking, but genome-wide methylation data for smoking in Chinese populations is limited. Objectives: We aimed to investigate epigenome-wide methylation in relation to smoking in a Chinese population. Methods: We measured the methylation levels at > 485,000 CpG sites (CpGs) in DNA from leukocytes using a methylation array and conducted a genome-wide meta-analysis of DNA methylation and smoking in a total of 596 Chinese participants. We further evaluated the associations of smoking-related CpGs with internal polycyclic aromatic hydrocarbon (PAH) biomarkers and their correlations with the expression of corresponding genes. Results: We identified 318 CpGs whose methylation levels were associated with smoking at a genome-wide significance level (false discovery rate < 0.05), among which 161 CpGs annotated to 123 genes were not associated with smoking in recent studies of Europeans and African Americans. Of these smoking-related CpGs, methylation levels at 80 CpGs showed significant correlations with the expression of corresponding genes (including RUNX3, IL6R, PTAFR, ANKRD11, CEP135 and CDH23), and methylation at 15 CpGs was significantly associated with urinary 2-hydroxynaphthalene, the most representative internal monohydroxy-PAH biomarker for smoking. Conclusion: We identified DNA methylation markers associated with smoking in a Chinese population, including some markers that were also correlated with gene expression. Exposure to naphthalene, a byproduct of tobacco smoke, may contribute to smoking-related methylation. Citation: Zhu X, Li J, Deng S, Yu K, Liu X, Deng Q, Sun H, Zhang X, He M, Guo H, Chen W, Yuan J, Zhang B, Kuang D, He X, Bai Y, Han X, Liu B, Li X, Yang L, Jiang H, Zhang Y, Hu J, Cheng L, Luo X, Mei W, Zhou Z, Sun S, Zhang L, Liu C, Guo Y, Zhang Z, Hu FB, Liang L, Wu T. 2016. Genome-wide analysis of DNA methylation and cigarette smoking in Chinese. Environ Health Perspect 124:966–973; http://dx.doi.org/10.1289/ehp.1509834

Exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with adverse effects on the respiratory system. However, the association between internal levels of PAH metabolites and lung function levels remains unclear.We investigated the relationships between urinary PAH metabolite concentrations and lung function levels in a general Chinese population.Lung function and 12 urinary PAH metabolites were measured in 2,747 participants from the Wuhan-Zhuhai cohort in China. Associations between urinary PAH metabolites and lung function were analyzed by linear mixed models. We also investigated associations among urinary PAH metabolite concentrations, traffic exposure time, and dietary PAH exposure.We found significant associations between increased levels of urinary PAH metabolites and reduced lung function. Each 1-U increase in log-transformed levels of 2-hydroxynaphthalene, 9-hydroxyfluorene, 2-hydroxyfluorene, 4-hydroxyphenanthrene, 9-hydroxyphenanthrene, 3-hydroxyphenanthrene, 1-hydroxyphenanthrene, 2-hydroxyphenanthrene, 1-hydroxypyrene, or total urinary PAH metabolites was associated with a 23.79-, 19.36-, 41.76-, 36.87-, 33.47-, 27.37-, 39.53-, 34.35-, 25.03-, or 37.13-ml reduction in FEV1, respectively (all P 0.05). Each 1-U increase in 2-hydroxynaphthalene, 2-hydroxyfluorene, 4-hydroxyphenanthrene, 1-hydroxyphenanthrene, 2-hydroxyphenanthrene, or total urinary PAH metabolites was associated with a 24.39-, 33.90-, 27.15-, 28.56-, 27.46-, or 27.99-ml reduction in FVC, respectively (all P 0.05). The total urinary PAH metabolites concentration was positively associated with both traffic exposure time and dietary PAH exposure among nonsmokers.Total and specific urinary PAH metabolites were associated with lung function reduction in a general Chinese population. Further studies are needed to investigate the potential mechanism by which PAHs induces lung function reduction.

Exposure to polycyclic aromatic hydrocarbons (PAHs) is linked with increased risk of diabetes, whereas socioeconomic status (SES) may contribute to the development of diabetes. However, the mechanisms underlying the relationships between them are unclear. We used structural equation modeling (SEM) to identify mediating factors in the associations of PAHs exposure, low SES with diabetes risk. Data were collected from 2751 Wuhan participants at baseline from the Wuhan-Zhuhai Cohort Study (n = 3053). They answered the questionnaires regarding socio-demographic, participated physical examinations and provided urine samples for measurements of urinary monohydroxy-polycyclic aromatic hydrocarbons (OH-PAHs) levels. SEM was used to identify the mediating factors (such as hypertension, body mass index (BMI), triglycerides (TG) and total cholesterol (TCHO)) in the associations of low SES or PAHs exposure with diabetes risk. We observed that partial effect of PAHs exposure (β = 0.281, p = 0.034), BMI (β = 0.182, p = 0.000), TG (β = 0.358, p = 0.000), TCHO (β = 0.203, p = 0.009) or hypertension (β = 0.385, p = 0.000) on diabetes was directive. Moreover, low SES also exhibited a directive effect on PAHs exposure (β = −0.084, p = 0.000), BMI (β = 0.301, p = 0.000), hypertension (β = 0.134, p = 0.003) and TG (β = 0.087, p = 0.001). PAHs exposure directly affected TCHO levels (β = 0.080, p = 0.002) and TG (β = 0.076, p = 0.017). The proportion of the effect of PAHs exposure on diabetes mediated by TG and TCHO was 15.6%. The proportion of the effect of low SES on diabetes mediated by BMI, hypertension and TG was 89.1%. The results suggested that low SES increased diabetes risk, which may be partially explained by BMI, hypertension and triglycerides, and exposure to high levels of PAHs may have indirect contribution to increased risk for diabetes with dyslipidemia.

Background: Aging is related to an increased risk of morbidity and mortality and is affected by environmental factors. Exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with adverse health outcomes; but the association of such exposure with DNA methylation aging, a novel aging marker, is unclear. Objectives: Our aim was to investigate the association of PAH exposure with methylation aging. Methods: We trained and validated a methylation age predictor suitable for Chinese populations using whole blood methylation data in 989 Chinese and 160 Caucasians. We defined two aging indicators: Δage, as methylation age minus chronological age; and aging rate, the ratio of methylation to chronological age. The association of PAH exposure with aging indicators was evaluated using linear regressions in three panels of healthy Chinese participants (N=539, among the aforementioned 989 Chinese participants) whose exposure levels were assessed by 10 urinary monohydroxy-PAH metabolites. Results: We developed a methylation age predictor providing accurate predictions in both Chinese individuals and Caucasian persons (R=0.94–0.96, RMSE=3.8–4.3). Among the 10 urinary metabolites that we measured, 1-hydroxypyrene and 9-hydroxyphenanthrene were associated with methylation aging independently of other OH-PAHs and risk factors; 1-unit increase in 1-hydroxypyrene was associated with a 0.53-y increase in Δage [95% confidence interval (CI): 0.18, 0.88; false discovery rate (FDR) FDR=0.004] and 1.17% increase in aging rate (95% CI: 0.36, 1.98; FDR=0.02), whereas for 9-hydroxyphenanthrene, the increase was 0.54-y for Δage (95% CI: 0.17, 0.91; FDR=0.004), and 1.15% for aging rate (95% CI: 0.31, 1.99; FDR=0.02). The association direction was consistent across the three Chinese panels with the association magnitude correlating with the panels’ exposure levels; the association was validated by methylation data of purified leukocytes. Several cytosine-phosphoguanines, including those located on FHL2 and ELOVL2, were found associated with both aging indicators and monohydroxy-PAH levels. Conclusions: We developed a methylation age predictor specific for Chinese populations but also accurate for Caucasian populations. Our findings suggest that exposure to PAHs may be associated with an adverse impact on human aging and epigenetic alterations in Chinese populations. https://doi.org/10.1289/EHP2773

Previous studies have reported an association of exposure to polycyclic aromatic hydrocarbons (PAHs) with lung function decline or cardiovascular diseases, or reduced lung function with 10-year cardiovascular (CV) risk. We analyzed risk factors for the 10-year Framingham CV risk using multiple logistic regression, and examined the mediational effect of reduced lung function on the association between exposure to PAHs and FRS using the post-exploratory structural equation modeling. Participants (n = 2268) were drawn from the Wuhan residents at baseline from the Wuhan-Zhuhai Cohort Study. They completed the physical examination, measurements of lung function and urinary monohydroxylated-PAHs (OH-PAHs). In all individuals, we found a dose-response relationship of PAHs exposure, forced expiratory volume in 1 s (FEV1) or forced vital capacity (FVC) with the 10-year CV risk. The proportions of FEV1 and FVC mediation effects in association of PAH exposure with the10-year CV risk were 35% and 24%, respectively. The findings indicated that PAHs exposure or reduced lung function increased the 10-year CV risk. Impaired lung function may partly contribute to increase in the 10-year CV risk regarding exposure to PAHs.

Some studies have shown an association between obesity or exposure to polycyclic aromatic hydrocarbons (PAHs) and the risk of diabetes. This study aimed to investigate the interaction of obesity and urinary monohydroxy-PAHs (OH-PAHs) on diabetes. Individuals (n = 2716) were drawn from the baseline survey of the Wuhan-Zhuhai Cohort Study. They completed the physical examination, measurements of lung function, biochemical indices and urinary OH-PAHs levels. Additive effect of obesity and urinary ΣOH-PAHs levels on diabetes was assessed by calculating the relative excess risk due to interaction (RERI) and the attributable proportion (AP) due to interaction. Several urinary OH-PAHs were positively associated with diabetes in individuals with central obesity or normal weight (p 0.05 for all). Among individuals with poor lung function, the RERI between urinary ΣOH-PAHs and waist circumstance (WC, RERI: 0.866, 95% CI: -0.431, 2.164, p = 0.192) or waist-to-height ratio (WHtR, RERI: 1.091, 95% CI: -0.124, 2.305, p = 0.078) was found; the AP due to the interaction between urinary ΣOH-PAHs and WC or WHtR was 0.383 (95% CI: -0.07, 0.80, p = 0.086) or 0.465 (95% CI: 0.019, 0.912, p = 0.04). The results indicated that central obesity may enhance the effect of exposure to background PAHs on diabetes in individuals with poor lung function.

The incidence of diabetes is increasing rapidly in Chinese population, and it has been postulated that environmental factors may play a role in the etiology of diabetes. Therefore, we aimed to investigate the association between PAHs exposure and risk of diabetes in a community-based population of 2824 participants with completed questionnaires, measurements of biochemical indices, and urinary PAHs metabolites. We found that elevated urinary PAHs metabolites were associated, in a dose-dependent manner, with increased risk of diabetes. Particularly, these associations were more evident in subjects who were female, less than 55 years old, nonsmokers, and normal weight. In addition, there was a modest improvement in diabetes discrimination of prediction models when incorporating certain PAHs metabolites into conventional risk factors (CRF). Overall, our data suggested that there may be a dose-dependent relationship between PAHs metabolites and risk of diabetes among general Chinese population.

High expression of Aurora kinase A (Aurora-A) has been found to confer cancer cell radio- and chemoresistance, however, the underlying mechanism is unclear. In this study, by using Aurora-A cDNA/shRNA or the specific inhibitor VX680, we show that Aurora-A upregulates cell proliferation, cell cycle progression, and anchorage-independent growth to enhance cell resistance to cisplatin and X-ray irradiation through dysregulation of DNA damage repair networks. Mechanistic studies showed that Aurora-A promoted the expression of ATM/Chk2, but suppressed the expression of BRCA1/2, ATR/Chk1, p53, pp53 (Ser15), H2AX, γH2AX (Ser319), and RAD51. Aurora-A inhibited the focus formation of γH2AX in response to ionizing irradiation. Treatment of cells overexpressing Aurora-A and ATM/Chk2 with the ATM specific inhibitor KU-55933 increased the cell sensitivity to cisplatin and irradiation through increasing the phosphorylation of p53 at Ser15 and inhibiting the expression of Chk2, γH2AX (Ser319), and RAD51. Further study revealed that BRCA1/2 counteracted the function of Aurora-A to suppress the expression of ATM/Chk2, but to activate the expression of ATR/Chk1, pp53, γH2AX, and RAD51, leading to the enhanced cell sensitivity to irradiation and cisplatin, which was also supported by the results from animal assays. Thus, our data provide strong evidences that Aurora-A and BRCA1/2 inversely control the sensitivity of cancer cells to radio- and chemotherapy through the ATM/Chk2-mediated DNA repair networks, indicating that the DNA repair molecules including ATM/Chk2 may be considered for the targeted therapy against cancers with overexpression of Aurora-A.

To investigate the effects of the urinary metabolite profiles of background exposure to the atmospheric pollutants polycyclic aromatic hydrocarbon (PAH) and Framingham risk score (FRS), which assesses an individual's cardiovascular disease risk, on heart rate variability (HRV).The study conducted from April to May 2011 in Wuhan, China, included 1978 adult residents with completed questionnaires, physical examinations, blood and urine samples, and 5-min HRV indices (including SD of all normal to normal intervals (SDNN), root mean square successive difference (rMSSD), low frequency (LF), high frequency (HF) and their ratio (LF/HF), and total power) obtained from 3-channel Holter monitor. 12 urinary PAH metabolites were measured by gas chromatography-mass spectrometry. FRS was calculated by age, sex, lipid profiles, blood pressure, diabetes and smoking status. Linear regression models were constructed after adjusting for potential confounders.Elevated total concentration of hydroxynaphthalene (ΣOHNa) was significantly associated, in a dose-responsive manner, with decreased SDNN and LF/HF (ptrend=0.014 and 0.007, respectively); elevated total concentration of hydroxyfluorene (ΣOHFlu) was significantly associated with reduced SDNN, LF and LF/HF (ptrend=0.027, 0.003, and0.0001, respectively); and elevated total concentration of all PAH metabolites (ΣOH-PAHs) was associated with decreased LF and LF/HF (ptrend=0.005 and0.0001, respectively). Moreover, increasing quartiles of FRS were significantly associated with decreased HRV indices, except LF/HF (all ptrend0.0001). Interestingly, individuals in low-risk subgroups had greater decreases in SDNN, LF and LF/HF in relation to ΣOH-PAHs, ΣOHNa and ΣOHFlu than those in high-risk subgroups (all p0.05).Environmental PAH exposure may differentially affect HRV based on individual coronary risk profiles.

Rationale: Acute coronary syndrome (ACS) is a leading cause of death worldwide. Immune functions play a vital role in ACS development; however, whether epigenetic modulation contributes to the regulation of blood immune cells in this disease has not been investigated. Objective: We conducted an epigenome-wide analysis with circulating immune cells to identify differentially methylated genes in ACS. Methods and Results: We examined genome-wide methylation of whole blood in 102 ACS patients and 101 controls using HumanMethylation450 array, and externally replicated significant discoveries in 100 patients and 102 controls. For the replicated loci, we further analyzed their association with ACS in 6 purified leukocyte subsets, their correlation with the expressions of annotated genes, and their association with cardiovascular traits/risk factors. We found novel and reproducible association of ACS with blood methylation at 47 cytosine-phosphoguanine sites (discovery: false discovery rate P + T cells, CD4 + T cells, and B cells. Blood methylation of 26 replicated cytosine-phosphoguanine sites showed significant correlation with expressions of annotated genes (including IL6R , FASLG , and CCL18 ; P −4 ), and differential gene expression in case versus controls corroborated the observed differential methylation. The replicated loci suggested a role in ACS-relevant functions including chemotaxis, coronary thrombosis, and T-cell–mediated cytotoxicity. Functional analysis using the top ACS-associated methylation loci in purified T and B cells revealed vital pathways related to atherogenic signaling and adaptive immune response. Furthermore, we observed a significant enrichment of the replicated cytosine-phosphoguanine sites associated with smoking and low-density lipoprotein cholesterol ( P enrichment ≤1×10 −5 ). Conclusions: Our study identified novel blood methylation alterations associated with ACS and provided potential clinical biomarkers and therapeutic targets. Our results may suggest that immune signaling and cellular functions might be regulated at an epigenetic level in ACS.

Epidemiological studies have suggested associations between polycyclic aromatic hydrocarbons (PAHs) and heart rate variability (HRV). However, the roles of plasma cytokines in these associations are limited. In discovery stage of this study, we used Human Cytokine Antibody Arrays to examine differences in the concentrations of 280 plasma cytokines between 8 coke-oven workers and 16 community residents. We identified 19 cytokines with significant different expression (fold change ≥2 or ≤−2 and q-value p 16% BDNF decreases. Additionally, OH-PAHs were positively associated with activated leukocyte cell adhesion molecule (ALCAM) and C-reactive protein (CRP) (p 20% increases in CRP. We also found significant associations between these cytokines and HRV (p 8% decreases in HRV. Our results indicated PAH exposure was associated with plasma cytokines and higher cytokines were associated with decreased HRV, but additional human and potential mechanistic studies are needed.

Background: This study was to explore the expression profile of endometrial carcinoma (EC) and identify the potential molecular mechanism and therapeutic targets. Methods: Differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) were identified in EC using mRNA and miRNA sequencing data released by the Cancer Genome Atlas database; then, gene function and pathway of DEGs were analyzed based on the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway databases; finally, the transcription factors (TFs) latently regulating the DEGs and DEMs were predicted and a TF-miRNA-Gene network was then established to summarize the regulatory links between TFs, DEMs and DEGs. Results: One thousand five hundred and forty two upregulated and 1,885 downregulated DEGs, 34 upregulated and 12 downregulated DEMs were identified. The principal DEGs-enriched functions were cell differentiation, cell migration, and cell surface receptor signaling pathway. The DEGs-enriched cell signaling pathways including the MAPK, Wnt signaling pathway, and the p53 signaling pathway. As shown in the TF-miRNA-Gene network, TFs such as CPBP and GKLF, miRNAs such as miR-141-3p and miR-130b-3p, regulated most of DEGs and DEMs. Conclusion: These results may contribute to the study of the molecular mechanism and therapeutic targets in EC, and facilitate the discovery of new biomarkers for screening, diagnosis and monitoring.

Health conditions may greatly modify the association between particulate matter (PM) and heart rate variability (HRV), but whether the modification of PM effect by coronary artery disease (CAD) risk status depends on the PM levels remains unknown. We investigated the associations between personal exposures to PM with aerodynamic diameter of ≤10μm (PM10) and ≤2.5μm (PM2.5) and concurrent HRV, and whether the effect of PM on HRV was modified by Framingham risk score (FRS) in healthy subjects with different PM exposure levels. Personal exposures to PM10 and PM2.5 were measured for 24h in 152 volunteers of community residents who were free of cardiovascular disease in two cities (Zhuhai and Wuhan) that differ in air quality. Simultaneously, 24h HRV indices were obtained from 3-channel Holter monitor. FRS was calculated based on age, sex, lipid profiles, blood pressure, diabetes, and smoking status. Linear regression models were constructed after adjusting for potential confounders. We found significant decrease in total power (TP) and low power (LF) with increased PM10 concentrations (P for trend

OBJECTIVE To investigate indoor factors affecting fractional exhaled nitric oxide (FeNO) in community residents. METHODS A total of 2404 adults (865 men, 1539 women, mean age 51.7 ± 13.3 years) were recruited to the study. Factors affecting FeNO were analyzed by multiple linear regression analysis. RESULTS Participants without a kitchen exhaust fan/hood had higher FeNO (GM: 10.21%, 95% CI: 4.18%-16.59%). Participants engaged in home cooking who used only liquefied petroleum gas had higher FeNO (GM: 5.75%, 95% CI: 0.10%-11.73%) compared to those using natural gas for residential (home) cooking. CONCLUSION Nonuse of a kitchen exhaust fan/hood and use of liquefied petroleum gas among persons engaged in home cooking were associated with higher FeNO levels.

Background Particulate air pollution has been recognized to be associated with a wide range of adverse health effects, including increased mortality, morbidity, exacerbation of respiratory conditions. However, earlier physiological or pathological changes or long-term bodies’ reaction to air pollutants have not been studied in depth in China. The Wuhan-Zhuhai (WHZH) cohort study is designed to investigate the association between air pollutants exposure and physiological or pathological reactions on respiratory and cardiovascular system. Methods/Design The cohort is a community-based prospective study that includes 4812 individuals aged 18–80 years. The collections of data were conducted from April to May 2011 in Wuhan city and in May 2012 in Zhuhai city. At baseline, data on demographic and socioeconomic information, occupational history, family disease history, lifestyle, cooking mode, daily travel mode, physical activity and living condition have been collected by questionnaires. Participants underwent an extensive physical examination, including anthropometry, spirometry, electrocardiography, and measurements of blood pressure, heart rate, exhaled nitric oxide and carbon monoxide. Potential conditions in the lung, heart, liver, spleen, and skin were synchronously performed. In addition, samples of morning urine, fasting blood serum and plasma were collected during physical health examination. DNA were extracted and were stored at -80°C. Environment concentrations of particulate matter and chemicals were determined for 15 days in each of four seasons. Participants are followed for physiological or pathological changes or incidence of cardiopulmonary diseases every 3 years. Discussion The results obtained in WHZH cohort study may increase a better understanding of the relationship between particulate air pollution and its components and possible health damages. And the potential mechanisms underlying the development of cardiopulmonary diseases has implications for the development of prevention and treatment strategies.

Small ribosomal protein subunit S7 (RPS7) has been reported to be associated with various malignancies, but the role of RPS7 in ovarian cancer remains unclear. In this study, we found that silencing of RPS7 by a specific shRNA promoted ovarian cancer cell proliferation, accelerated cell cycle progression, and slightly reduced cell apoptosis and response to cisplatin treatment. Knockdown of RPS7 resulted in increased expression of P85α, P110α, and AKT2. Although the basal levels of ERK1/2, MEK1/2, and P38 were inconsistently altered in ovarian cancer cells, the phosphorylated forms of MEK1/2 (Ser217/221), ERK1/2 (Thr202/Tyr204), JNK1/2 (Thr183/Tyr185), and P38 (Thr180/Tyr182) were consistently reduced after RPS7 was silenced. Both the in vitro anchorage-independent colony formation and in vivo animal tumor formation capability of cells were enhanced after RPS7 was depleted. We also showed that silencing of RPS7 enhanced ovarian cancer cell migration and invasion. In sum, our results suggest that RPS7 suppresses ovarian tumorigenesis and metastasis through PI3K/AKT and MAPK signal pathways. Thus, RPS7 may be used as a potential marker for diagnosis and treatment of ovarian cancer.