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Background Epidemiological evidence remains conflicting regarding diet and risk of lung cancer. Objectives We sought to systematically investigate whether dietary factors are associated with the risk of incident lung cancer in the UK Biobank. Methods A total of 416,588 participants (54% women) from the UK Biobank were included in the present study. Based on baseline data from FFQs, 3 main dietary patterns were identified by using principal component analysis. Cox proportional hazards models were used to investigate the association of individual food groups and dietary patterns with lung cancer risk. Results During a median follow-up of 7.13 y, 1782 incident lung cancer cases were documented. The association analysis showed high intake of red meat and processed meat was associated with an increased risk of lung cancer (HRper 50 g/d: 1.36; 95% CI: 1.13, 1.65 for red meat; HRper 25 g/d: 1.30; 95% CI: 1.10, 1.53 for processed meat). However, the consumption of fruits (HRper 100 g/d: 0.90; 95% CI: 0.84, 0.95), vegetables (HRper 100 g/d: 0.89; 95% CI: 0.81, 0.99), breakfast cereals (HRper 50 g/d: 0.81; 95% CI: 0.74, 0.89), and dietary fiber (HRper 5 g/d: 0.76; 95% CI: 0.69, 0.84) was inversely associated with the risk of lung cancer. For the dietary pattern analysis [quartile (Q) comparison], high adherence to the Prudent pattern (HRQ4 compared with Q1: 0.84; 95% CI: 0.73, 0.96) was associated with a lower risk of lung cancer, whereas the Western pattern (HRQ4 compared with Q1: 1.27; 95% CI: 1.11, 1.46) was associated with a higher risk of lung cancer. Conclusions Our study indicated that a diet characterized by high intake of fruits, vegetables, breakfast cereals, and dietary fiber, as well as low intake of red meat and processed meat, was associated with a lower risk of lung cancer. [ABSTRACT FROM AUTHOR]

Background Many cohort studies have explored the relation between tea consumption and stroke risk; however, the conclusions have been inconsistent. In addition, evidence is lacking in China, where the patterns of tea consumption and main types of tea consumed differ substantially from those in high-income countries. Objective We aimed to systematically assess the association of tea consumption with the risk of stroke based on a Chinese large-scale cohort study. Methods A total of 487,377 participants from the China Kadoorie Biobank were included in the present study. Detailed information about tea consumption (including frequency, duration, amount, and tea type) was self-reported at baseline. After ∼4.3 million person-years of follow-up, 38,727 incident cases of stroke were recorded, mainly through linkage with mortality and morbidity registries and based on the national health insurance system. Results Overall, 128,280 adults (26.3%) reported drinking tea almost daily (41.4% men, 15.9% women), predominantly green tea (86.7%). Tea consumption had an inverse and dose–response relation with the risk of stroke (P trend < 0.001). Compared with nonconsumers, those who consumed tea occasionally, weekly, and daily had adjusted HRs and 95% CIs of 0.96 (0.94, 0.99), 0.94 (0.90, 0.98), and 0.92 (0.89, 0.95) respectively, with little difference by stroke type. Among those who consumed tea daily, the HRs for stroke decreased with the increasing duration and amount of tea consumed (all P  < 0.001). These inverse associations were significant for green tea but not for other types of tea. Among men, but not women, the inverse relations could be detected, and similar inverse associations could be found for male noncurrent alcohol-consumers and noncurrent smokers as well. Conclusions Among Chinese adults, higher consumption of tea, especially green tea, was associated with a lower risk of ischemic and hemorrhagic stroke. [ABSTRACT FROM AUTHOR]

Background Coffee consumption has been linked to lower risk of various health outcomes. However, the biological pathways mediating the associations remain poorly understood. Objectives The aim of this study was to assess the association between coffee consumption and concentrations of plasma biomarkers in key metabolic and inflammatory pathways underlying common chronic diseases. Methods We investigated the associations of total, caffeinated, and decaffeinated coffee consumption with 14 plasma biomarkers, including C-peptide, insulin-like growth factor 1 (IGF-1), IGF binding protein (IGFBP) 1, IGFBP-3, estrone, total and free estradiol, total and free testosterone, sex hormone–binding globulin (SHBG), total adiponectin, high-molecular-weight (HMW) adiponectin, leptin, C-reactive protein (CRP), interleukin 6 (IL-6), and soluble tumor necrosis factor receptor 2 (sTNFR-2). Data were derived from 2 cohorts of 15,551 women (Nurses' Health Study) and 7397 men (Health Professionals Follow-Up Study), who provided detailed dietary data before blood draw and were free of diabetes, cardiovascular disease, or cancer at the time of blood draw. Multivariable linear regression was used to calculate the percentage difference of biomarker concentrations comparing coffee drinkers with nondrinkers, after adjusting for a variety of demographic, clinical, and lifestyle factors. Results Compared with nondrinkers, participants who drank ≥4 cups of total coffee/d had lower concentrations of C-peptide (−8.7%), IGFBP-3 (−2.2%), estrone (−6.4%), total estradiol (−5.7%), free estradiol (−8.1%), leptin (−6.4%), CRP (−16.6%), IL-6 (−8.1%), and sTNFR-2 (−5.8%) and higher concentrations of SHBG (5.0%), total testosterone (7.3% in women and 5.3% in men), total adiponectin (9.3%), and HMW adiponectin (17.2%). The results were largely similar for caffeinated and decaffeinated coffee. Conclusion Our data indicate that coffee consumption is associated with favorable profiles of numerous biomarkers in key metabolic and inflammatory pathways. This trial was registered at clinicaltrials.gov as NCT03419455. [ABSTRACT FROM AUTHOR]

Over the last few years, social recommendation has attracted tremendous attention due to the ever-growing online social platform such as Twitter and Facebook. However, as the number of users increases rapidly, recommendation efficiency has become the bottleneck of many existing social recommender systems due to the computation and storage of real-valued models. For addressing the efficiency problem, recent researches resolve it by introducing hashing technique into social recommender systems. By mapping real values to discrete values, the computational speed is guaranteed as well as the storage cost is reduced. Nevertheless, these methods suffer from two critical limitations: (1) The inevitable quantization loss brought by hash function decreases recommendation accuracy to a certain extent. (2) The original social relations contain massive noise that may result in sub-optimal accuracy of recommendation without considering the fact that people can only pay attention to a small number of their friends. Therefore, to tackle the above limitations and have a better tradeoff between accuracy and efficiency, in this paper, we propose a novel social recommendation method called Discrete Limited Attentional Collaborative Filtering (DLACF), which models recommendation objective with limited attention as a constrained mix-integer optimization problem. Since the original problem is NP-hard, we further devise a computationally efficient optimization algorithm to learn the binary codes as well as to estimate the best influential friends. Experimental results conducted on two real-world datasets demonstrate the effectiveness of our proposed model, achieving the averaged improvement of 118.7% and 54.7% compared to state-of-the-art discrete methods. [ABSTRACT FROM AUTHOR]

Previous studies have shown that Lactobacillus species play a role in ameliorating colorectal cancer (CRC) in a mouse model. However, the underlying mechanisms remain largely unknown. Here, we found that administration of a probiotic strain, Lactobacillus plantarum L168 and its metabolite, indole-3-lactic acid, ameliorated intestinal inflammation, tumor growth, and gut dysbiosis. Mechanistically, we indicated that indole-3-lactic acid accelerated IL12a production in dendritic cells by enhancing H3K27ac binding at the enhancer regions of IL12a that contributed to priming CD8+ T cell immunity against tumor growth. Furthermore, indole-3-lactic acid was found to transcriptionally inhibit Saa3 expression related to cholesterol metabolism of CD8+ T cells through changing chromatin accessibility and subsequent enhancing function of tumor-infiltrating CD8+ T cells. Together, our findings provide new insights into the epigenetic regulation of probiotics-mediated anti-tumor immunity and suggest the potential of L. plantarum L168 and indole-3-lactic acid to develop therapeutic strategies for patients with CRC. [Display omitted] • L. plantarum L168 and its derived ILA ameliorate colorectal tumorigenesis • ILA accelerates IL12a production in DCs to prime anti-tumor immunity of CD8+ T cells • ILA enhances function of CD8+ T cells through epigenetic mechanisms • ILA inhibits expression of Saa3 in CD8+ T cells to reduce tumor growth of CRC The underlying anti-tumor immune mechanisms for probiotics preventing colorectal cancer remain largely unknown. Zhang et al. report that a strain of probiotics, L. plantarum L168 and its derived metabolite, indole-3-lactic acid, ameliorate colorectal tumorigenesis through contributing to anti-tumor immunity of CD8+ T cell via epigenetic regulation. [ABSTRACT FROM AUTHOR]

Hepatitis B (HBV) infection is the leading cause of hepatocellular carcinoma (HCC) in Asia.1 Hepatitis B surface antigen (HBsAg) seroclearance is considered to be one of the most important end points of chronic HBV infection and is associated with a reduced risk of HCC. [ABSTRACT FROM AUTHOR]

• Proposing a member based single step optimization method for seismic design. • Establishing equivalent SDOF system through composite mode. • Design method based on reference structure rather than uncontrolled structure. • The proposed method is suitable for multiple BRB damped outrigger structure. Using the passive control performance curve and the idea of mapping, a single step seismic optimal design method for damped outrigger structure with buckling-restrained brace (BRB) was proposed in this paper. In order to consider the influence of high order modes on earthquake responses, composite modes were used to establish equivalent single-degree-of-freedom (SDOF) system of uncontrolled structure and reference structure. The passive control performance curve based on SDOF reference structure was established through the simplified mapping method. According to the performance point determined on the passive control performance curve, seismic mitigation design based on reference structure was conducted using single step optimization method. The proposed method can accurately and simply determine the parameters of BRB and is quite practical as only the response spectrum analysis is needed. Moreover, it can be used for seismic mitigation design of multiple damped outrigger structure and breaks the limitation of the single outrigger structure. Numerical examples show that the damped outrigger structure designed by this method can achieve the desired performance objectives. [ABSTRACT FROM AUTHOR]

• The increasing appreciation of the key roles played by the innate immune system in sensing vaccines and tuning immune responses. • The genetic mechanisms underlying the invalid immune response of EV71 vaccine remain largely unknown. • Whole exome sequencing and bioinformatics analyses reveal the different responsiveness to enterovirus 71 vaccination. • A meaningful attempt on the comparison of genomic profiles between potent and invalid immune responders induced by EV71 vaccine, and several candidate potentially detrimental genes were identified. To explore the molecular genetic mechanisms underlying different responsiveness to Enterovirus 71 (EV71) vaccine. We recruited 10,245 healthy children into a phase 3 clinical trial to evaluate the efficacy of EV71 vaccine in 2012. Fifty subjects from the trial were divided into the potent immune response group (20 subjects) and the ineffective immune response group (30 subjects). Whole-exome sequencing was performed for these 50 samples and we conducted bioinformatics analyses based on online public database. A total of 222,180 germline variants were detected across 50 subjects. Single nucleotide variant (SNV)-based screening of the subjects with potent or ineffective immune response allowed the identification of a potentially detrimental heterozygous missense variant (c.3784C>T) in EEA1. We also retained TRIM59 and ABCA7 genes that contain different loss of function (LoF) variants shared in two cases and involved in the immune response process. Then, we conducted high-resolution typing of 9 classical HLA genes, HLA-DRB1*03:01 , HLA-DQA1*05:01 and HLA-DQB1*02:01 alleles were frequently (recurrence ≥5) observed only in ineffective immune responders. Our study is a meaningful attempt on the comparison of genomic profiles between potent and ineffective immune responders induced by EV71 vaccine, and several candidate potentially detrimental genes were identified. [ABSTRACT FROM AUTHOR]

Objective: To investigate the association between genetic variants in the major histocompatibility complex (MHC) region and nonobstructive azoospermia (NOA) susceptibility.Design: MHC region fine-mapping analysis based on previous NOA genome-wide association study (GWAS) data.Setting: Medical university.Patient(s): Nine hundred and eighty-one men with NOA and 1,657 normal fertile male controls.Intervention(s): None.Main Outcome Measure(s): The MHC region imputation assessed with SNP2HLA software, taking the specific Han-MHC database as a reference panel; statistical significance of the MHC variants calculated using logistic regression models; functional annotation based on online public databases; and phenotypic variances explained by specific groups of genetic variants estimated using the fixed effects model from individual associations.Result(s): Two independent risk loci, rs7194 (odds ratio [OR] 1.37) at MHC class II molecules and rs4997052 (OR 1.30) at MHC class I molecules, were identified. Functional annotation showed rs7194 may tag the effect of multiple amino acid residues and the expression of HLA-DQB1 and HLA-DRB1; while rs4997052 showed the effect of amino acid changes of HLA-B at position 116 as well as the expression of HLA-B and CCHCR1, which coexpressed with genes enriched in pathways of spermatogenesis and male gamete generation. The novel variant rs4997052 identified in our study can explain another approximately 0.66% of the phenotypic variances of NOA.Conclusion(s): We fine-mapped the MHC region and identified two loci that independently drove NOA susceptibility. These results provide a deeper understanding of the association mechanisms of MHC and NOA risk. [ABSTRACT FROM AUTHOR]

Abstract Chromosome 4q12 and 17q12 have been identified as two regions associated with susceptibility to cervical cancer in a genome-wide association study. To identify potential causal variants within these two regions, we conducted a case-control study including 1486 patients with cervical cancer and 1536 age-matched (±5 years) healthy controls. Based on RegulomeDB database, 12 potentially functional variants were selected and then genotyped by using Sequenom MassARRAY. Univariate and multivariate logistic regression models were used to evaluate the associations. We found that the G allele of rs8076131 and the A allele of rs12150079 in 17q12 region were significantly associated with increased risk of cervical cancer (adjusted OR = 1.15, 95% CI = 1.02–1.30, P = 0.02 for rs8076131; adjusted OR = 1.19, 95% CI = 1.03–1.36, P = 0.02 for rs12150079). Individuals with 3–4 risk alleles of these two variants had 24% higher odds of cervical cancer than those without the risk alleles (OR = 1.24, 95% CI = 1.07–1.44, P < 0.01). The stratified analysis showed that the associations of rs8076131 and rs12150079 with cervical cancer risk were statistically significant in subgroups of older menarche age (>16 years), more parities (≥2), nonsmokers, and having no family cancer history, but the test results for subgroup heterogeneity were not significant. The current study provides the evidence that rs8076131 and rs12150079 in 17q12 region may contribute to cervical cancer susceptibility in the Han Chinese population. Highlights • A case-control study was conducted to identify potential causal variants within GWAS-identified regions for cervical cancer. • Based on RegulomeDB, twelve putative variants were selected and genotyped. • Rs8076131 and rs12150079 within 17q12 may contribute to cervical cancer susceptibility. [ABSTRACT FROM AUTHOR]

Prenatal environmental factors may affect the development of the offspring and can bring long lasting consequences to the offspring's health. To date, only few studies have reported inconclusive association between prenatal single trace element exposure and visual acuity, and no studies have investigated the association between prenatal exposure to trace elements mixture and visual acuity in infants. In the prospective cohort study, grating acuity in infants (12 ± 1 months) was measured by Teller Acuity Cards II. Concentrations of 20 trace elements in maternal urine samples collected in early-trimester were measured by Inductively Coupled Plasma Mass Spectrometry. Elastic net regression (ENET) was applied to select important trace elements. Nonlinear associations of the trace elements levels with abnormal grating were explored using the restricted cubic spline (RCS) method. The associations between selected individual elements and abnormal grating acuity were further appraised using the logistic regression model. Then Bayesian Kernel Machine Regression (BKMR) was used to estimate the joint effects of mixture and interactions between trace elements combining with NLinteraction. Of 932 mother-infant pairs, 70 infants had abnormal grating acuity. The ENET model produced 8 trace elements with non-zero coefficients, including cadmium, manganese, molybdenum, nickel, rubidium, antimony, tin and titanium. RCS analyses identified no nonlinear associations of the 8 elements with abnormal grating acuity. The single-exposure analyses using logistic regression revealed that prenatal molybdenum exposure possessed a significantly positive association with abnormal grating acuity (odds ratio [OR]: 1.44 per IQR increase, 95% confidence interval [CI]: 1.05, 1.96; P = 0.023), while prenatal nickel exposure presented with a significantly inverse association with abnormal grating acuity (OR: 0.64 per IQR increase, 95% CI: 0.45, 0.89; P = 0.009). Similar effects were also observed in BKMR models. Moreover, the BKMR models and NLinteraction method identified potential interaction between molybdenum and nickel. We established that prenatal exposure to high concentration of molybdenum and low concentration of nickel was associated with the increased risk of abnormal visual acuity. Potential interaction may exist between molybdenum and nickel on abnormal visual acuity. [Display omitted] • Prenatal molybdenum exposure may increase infants' risk of abnormal grating acuity. • Prenatal nickel exposure may decrease infants' risk of abnormal grating acuity. • Interaction exists between prenatal molybdenum and nickel exposure. [ABSTRACT FROM AUTHOR]

CpG-SNPs in gene promoter regions are proposed to be associated with multiple diseases. To date, few studies have focused on the associations between CpG-SNPs in miRNA promoters and the risk of breast cancer. In this study, 138 miRNAs differentially expressed between breast cancer and non-cancer tissues (fold change >2, P  < 0.05) were identified using The Cancer Genome Atlas (TCGA) Research database. In total, 13 SNPs were selected in the promoters of the miRNAs and were evaluated in a case-control study of Chinese women including 1486 cases and 1519 controls. After multivariate logistic regression analysis, we found that three CpG-SNPs: rs1190983, rs155247, and rs62382272, were significantly associated with breast-cancer susceptibility in the population (Additive model: rs1190983: adjusted OR = 0.88, 95% CI: 0.79–0.99, P  = 0.034; rs155247: adjusted OR = 0.83, 95% CI: 0.74–0.93, P  = 0.002; rs62382272: adjusted OR = 1.24, 95% CI: 1.04–1.47, P  = 0.016). eQTL analysis showed that these three SNPs were correlated with the expression of the related miRNAs in TCGA breast cancer tissues ( P  = 0.006,0.009,0.001 for rs1190983, rs155247, and rs62382272). Furthermore, rs1190983 was found to be associated with CpG site (cg20488673) methylation (meQTL) ( P  = 0.004), which was in turn correlated with miR-342 expression ( P  = 0.016). These findings indicated that the three CpG-SNPs in the promoters of miRNAs were likely to possess important biological functions to breast cancer in the Han Chinese population. [ABSTRACT FROM AUTHOR]

Autophagy associated genes (ATGs) played an important role in the repair process of DNA damage and decreased autophagy may weaken the repair process and aggravate DNA damage. Based on this, we hypothesized that DNA damage levels might be modified by genetic variants in autophagy associated genes. In order to validate our hypothesis, 307 subjects were recruited from three different cities (Zhuhai, Wuhan and Tianjin) in China. Demographic data, individual 24-h PM 2.5 exposure and peripheral blood DNA damage levels were also detected. Seven potentially functional polymorphisms in four essential autophagy associated genes ( ATG5 , ATG7 , ATG8 and ATG13 ) were screened to evaluate the relationship between the polymorphisms of autophagy associated genes and DNA damage levels. This association was assessed by using multivariable linear regression model, age, sex, smoke and PM 2.5 exposure levels were adjusted in each city. We found that rs12599322 in ATG8 (A > G, β = 0.263, 95% CI: 0.108–0.419, P = 8.98 × 10 − 4 ) and rs7484002 in ATG13 (A > G, β = 0.396, 95% CI: 0.085–0.708, P = 0.013) were significantly associated with higher DNA damage levels. Furthermore, functional annotations showed that both rs12599322 and rs7484002 located at transcription factor binding sites (TFBS), indicating that they could regulate the expression of related genes through TF regulation. Following allelic trend analysis revealed that the DNA damage levels were significantly aggravated with the increasing number of risk variants in autophagy associated genes ( P for trend: 8.09 × 10 − 5 ). Our findings suggested that the polymorphisms in ATGs may influence DNA damage levels in one of the Chinese population. [ABSTRACT FROM AUTHOR]

Previous animal studies provided the evidence that prenatal titanium exposure can cause neurotoxicity in their offspring, while human data is vacant. Our aim was to identify the associations of prenatal titanium exposure with the child neurodevelopment. Participants in present study were recruited during early pregnancy between 2014 and 2017. Urinary concentrations of titanium at first trimester were determined. We assessed child neurodevelopment using the Chinese version of Gesell Developmental Schedules at first year follow-up. The multivariable linear regressions and the robust modified Poisson regressions were used to estimate the associations of specific gravity corrected urinary titanium concentrations with the child neurodevelopment. In adjusted models, children's developmental quotient scores in the language domain were 2.03 points (95% CI: −3.66, −0.40) lower in the highest tertile of prenatal urinary titanium than in the lowest tertile. Also, children with prenatal urinary titanium in the highest tertile had 1.42 times (95% CI: 1.17, 1.72) increased risk of language development delay compared to those in the lowest tertile. No statistically significant associations were observed between titanium exposure and child development delay in motor, adaptive and social areas. The findings indicated that prenatal higher titanium exposure was associated with impaired language development, suggesting that titanium might act as developmental neurotoxicants. [Display omitted] • We accessed the associations of prenatal titanium exposure with child neurodevelopment. • The higher titanium levels in the first trimester were associated with child language development delay at 1 year of age. • No significant association was observed between prenatal titanium exposure and child adaptive, motor or social development. [ABSTRACT FROM AUTHOR]

• 9 pairs of cervical cancer and paracancerous tissues were used. • We identified a new circZNF208 related ceRNA network through bioinformatic analysis. • circZNF208 can promote fibroblast proliferation. • circZNF208 interfering with hsa-miR-324-3p regulate downstream gene LPHN3. • Our results might be valuable for diagnosis and treatment of cervical cancer. Cervical cancer is one of the major cancers that threaten the health of women. CircRNA is an important factor in the regulation of cancer development and progression. The role of circRNA in cervical cancer is less well studied. The aim of this study was to explore the mechanism of circRNA effects on cervical cancer using circRNA-seq technology to study the expression profile data of 9 pairs of primary cervical cancer and paracancerous tissues. DESeq2 was used to analyse differentially expressed circRNA and mRNA in cervical cancer and paracancerous tissues. MiRanda and TargetScan are used to predict miRNAs that interact with circRNAs and mRNAs and to construct circRNA-miRNA-mRNA regulatory networks. KEGG and GO are used for functional annotation of differentially expressed genes. TIDE, TIMER2.0 was used to assess the status of the tumour immune microenvironment in cervical cancer. GEPIA2 was used to validate the results of differential expression analysis. We eventually obtained 22 differentially expressed circRNAs (7 up-regulated and 15 down-regulated) and 1834 differentially expressed genes (613 up-regulated and 1221 down-regulated). The results of the KEGG analysis showed that the differentially expressed genes were mainly enriched in cell cycle and cancer-related signalling pathways. The new circRNA: circZNF208 was identified to promote fibroblast proliferation by interfering with its downstream hsa-miR-324-3p regulating four downstream genes LPHN3. The level of fibroblast infiltration is implicated in the poor prognosis of cervical cancer. We have identified a novel circRNA: circZNF208 that can interfere with fibroblast proliferation in cervical cancer through a ceRNA regulatory network, thereby promoting fibroblast proliferation in cervical cancer and affecting the prognosis of cancer patients. [ABSTRACT FROM AUTHOR]

Chromatin remodeling complexes utilize the energy of ATP hydrolysis to remodel nucleosomes and have essential roles in transcriptional modulation. Increasing evidences indicate that these complexes directly interact with numerous proteins and regulate the formation of cancer. However, few studies reported the association of polymorphisms in chromatin remodeling genes and lung cancer. We hypothesized that variants in critical genes of chromatin remodeling pathway might contribute to the susceptibility of lung cancer. To validate this hypothesis, we systematically screened 40 polymorphisms in six key chromatin remodeling genes ( SMARCA5 , SMARCC2 , SMARCD2 , ARID1A , NR3C1 and SATB1 ) and evaluated them with a case-control study including 1341 cases and 1982 controls. Logistic regression revealed that four variants in NR3C1 and SATB1 were significantly associated with lung cancer risk after false discovery rate (FDR) correction [For NR3C1 , rs9324921: odds ratio (OR) = 1.23, P for FDR = 0.029; rs12521436: OR = 0.85, P for FDR = 0.040; rs4912913: OR = 1.17, P for FDR = 0.040; For SATB1 , rs6808523: OR = 1.33, P for FDR = 0.040]. Combing analysis presented a significant allele-dosage tendency for the number of risk alleles and lung cancer risk ( P trend < 0.001). Moreover, expression quantitative trait loci (eQTL) analysis revealed that these two genes were differently expressed between lung tumor and adjacent normal tissues in the database of The Cancer Genome Atlas (TCGA) ( P = 0.009 for rs6808523). These findings suggested that genetic variants in key chromatin remodeling genes may contribute to lung cancer risk in Chinese population. Further large and well-designed studies are warranted to validate our results. [ABSTRACT FROM AUTHOR]

• Co-exposure to trace elements impacts children's early neurodevelopment. • Lithium, aluminum and iron contributed most to an increase in cognitive composite score. • Zinc, silver, and antimony mainly contributed to motor composite score. • An inverted U-shaped relationship between Sb and motor function was identified. • We found antagonistic interaction effect between Ba and Sb on motor function. Prenatal exposures to neurotoxic metals and trace elements are associated with early childhood neurodevelopmental outcomes. However, consequences of simultaneous exposure to mixtures of elements remain unclear. To examine individual and joint effects of prenatal trace element exposure on early childhood neurodevelopment. Using a well-established Bangladesh prospective birth cohort (2008–2011), we measured concentrations of 52 trace elements in umbilical cord serum of 569 mother–infant pairs using inductively coupled plasma mass spectrometry. Neurodevelopment was evaluated at 20–40 months of age using Bayley Scales of Infant and Toddler Development, Third Edition. Stability elastic net (ENET) was used to screen elements individually associated with the outcome; candidate exposures were combined by weighted linear combination to form a risk score representing their mixture effect on early childhood neurodevelopment. Stability ENET identified 15 trace elements associated with cognitive composite score and 14 associated with motor composite score, which were linearly combined to form the element risk score (ERS). Children with higher ERS cognitive had lower probability of cognitive developmental delay (OR highest vs lowest : 0.21; 95 %CI: 0.10, 0.40; P < 0.001; P trend < 0.001). Children with ERS motor in the top quintile had a significantly lower risk of motor developmental delay (OR: 0.16; 95 %CI: 0.09, 0.31; P < 0.001; P trend < 0.001) versus the lowest quintile. In Bayesian kernel machine regression analyses, lithium [conditional posterior inclusion probability (cPIP) = 0.68], aluminum (cPIP = 0.83) and iron (cPIP = 1.00) contributed most to the lower cognitive composite score; zinc (cPIP = 1.00), silver (cPIP = 0.81), and antimony (cPIP = 0.65) mainly contributed to the change of motor composite score. Co-exposure to lithium/aluminum/iron or zinc/silver/antimony appears to impact children's neurodevelopment. ERS score reflecting maternal exposure could indicate children's risk of neurodevelopmental delay, warranting further studies to explore the underlying mechanism. [ABSTRACT FROM AUTHOR]

Background Left ventricular noncompaction (LVNC) is a genetic cardiomyopathy results from the failure of myocardial development during embryogenesis. Previous reports show that defects in TAZ , SCN5A , TPM1 , YWHAE , MYH7 , ACTC1 and TNNT2 are associated with LVNC. Sequencing of individuals using family-based design is a powerful approach for hereditary disease. In this study, we used whole-exome sequencing to screen potentially novel causal mutations in a Chinese Han family with LVNC. Methods DNA from 3 individuals belonging to the same family was extracted and sequenced based on standard whole-exome sequencing protocol. The exome sequence data was analyzed using BWA, PICARD and Genome Analysis Toolkit (GATK v2.8). Non-silent single nucleotide variants (SNVs) were further selected if they exist in both LVNC patients and not in the health control. A web-based software Snv Prioritization via the INtegration of Genomic data (SPRING), was used to prioritize the causal SNV by calculating a q-value which indicates the statistical significance that a variant is causative for a query disease. Results From the LVNC family in which the mother and son were affected, a novel single nucleotide variant c.C1492G in exon 15 of MYH7 was identified probably to be the causal SNV of the family with P -value of 3.45E− 05 and q-value of 4.65E− 03 by SPRING. The SNV was predicted as deleterious in SIFT, PolyPhe2 and MutatioTaster database. Another 12 SNVs were also identified with P -value less than 0.05 by SPRING. Conclusions A novel genetic variant in the coding regions of MYH7 gene was identified in a Chinese LVNC-family. The results support the previous evidence that MYH7 is a pathogenic gene for LVNC. [ABSTRACT FROM AUTHOR]

Abstract: MicroRNAs (miRNAs) can act as oncogenes or tumor-suppressor genes in human cancers including HCC. Previous studies have identified miR-34 family as an important component of the tumor suppressor network during carcinogenesis. In this study, we investigated the methylation status of miR-34 family in HCC tumor and adjacent non-tumor tissues using methylation-specific PCR (MSP). The methylation frequencies of miR-34a and miR-34b/c were 72.1% (31/43) and 79.1% (34/43) in HCC tissues, which were significantly higher than that in the adjacent non-tumor tissues (P <0.05), respectively. The results were validated by bisulfite sequencing PCR (BSP). Quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis showed that the expression of miR-34a and miR-34b was significantly down-regulated in HCC tissues compared with adjacent non-tumor tissues (P <0.05). Moreover, the expression of miR-34b was inversely correlated to CpG island methylation in tumor tissues, but not for miR-34a. In summary, our results suggest that DNA methylation may be involved in the inactivation of miR-34b in HCC. [Copyright &y& Elsevier]

• CT gene LIN28B could be activated by promoter hypomethylation in gastric cancer cells. • CRISPR/dCas9 technique was introduced to accurately mediate promoter hypomethylation and verify its roles in LIN28B expression. • LIN28B promotes cell proliferation and metastasis in gastric cancer. Previous studies have revealed the significance of several cancer/testis (CT) genes in gastric cancer (GC). Here, we identified candidate CT oncogenes in GC, which were activated by the promoter (p) hypomethylation. Transcriptome profiling and DNA methylation data of stomach adenocarcinoma (STAD) were downloaded from The Cancer Genome Atlas (TCGA) database. We applied multiple Cox regression analysis to identify survival-related CT genes. CpG sites associated with hypomethylated activation were defined by Spearman's rank correlation analysis. We used the CRISPR/dCas9 technique to accurately mediate p hypomethylation in a GC cell line (HGC27) and verify the effect of targeted CpG sites on gene expression. Finally, we verified the function via gain- and loss-of-function assays in vitro. We recognized LIN28B as a highly activated CT gene in GC, whose high expression was associated with poor prognosis of GC patients [hazard ratio (HR) = 1.90, 95 %CI:1.26–2.87, P = 2.14 × 10−3]. Bioinformatics analysis found that hypomethylation of four CpG sites at LIN28B p were negatively correlated with its elevated expression, and we verified that p hypomethylation could activate LIN28B expression via accurately mediated p methylation. Moreover, knockout of LIN28B markedly repressed proliferation, metastasis, and invasion of GC cells in vitro. In contrast, LIN28B over-expression could promote metastasis and invasion of GC cells. In summary, we found that CT gene LIN28B could be activated by p hypomethylation in GC, which suggested that hypomethylation of specific CpG sites could be a potential molecular marker for prognosis prediction and individualized treatment among GC patients. [ABSTRACT FROM AUTHOR]

Abstract: Autophagy is a cellular process directed at recycling of cellular proteins and removal of intracellular microorganisms, which is important for balancing sources of energy at critical times in development and in response to nutrient stress. It has been reported to be a critical process in cancer initiation and progression. We hypothesized that genetic variants in critical genes of autophagy may be involve in the development of breast cancer. Thus, we systematically screened 14 potentially functional polymorphisms in six autophagy-related genes (ATG3, ATG5, ATG7, ATG10, and ATG12 and LC3) that are core components in autophagosome formation. We conducted a case-control study including 1064 breast cancer cases and 1073 cancer-free controls to evaluate the associations of these variants with breast cancer risk. We found that rs1864182 and rs10514231 in ATG10 were significantly associated with a decreased risk of breast cancer [odds ratios (OR)=0.77, 95% confidence interval (CI): 0.61–0.96, P =0.023; and OR=0.75, 95% CI: 0.59–0.93, P =0.010, respectively]. Similar protective effects for both loci were observed between subgroups stratified by ages at diagnosis/recruitment, menarche and first live birth, and status of menopause, estrogen receptor (ER) and progesterone receptor (PR). These results suggest that genetic variants in ATG10 may implicate with breast cancer susceptibility in Chinese population. Further large and functional studies are needed to confirm our findings. [Copyright &y& Elsevier]

• Family-based WGS was performed to detect the genetic architecture of TOF. • A newly identified compound heterozygous pattern in TOF probands was establised. • Noncoding mutation in regulatory element was firstly involved in the pattern. • The noncoding mutation increased silencer activity to reduce NOTCH1 expression. • The compound heterozygous pattern in this study may increase the penetrance of TOF. Tetralogy of Fallot (TOF) is one of most serious cyanotic congenital heart disease (CHD) and the prevalence is estimated to be 1 in 3000 live births worldwide. Though multiple studies have found genetic variants as risk factors for TOF, they could only explain a small fraction of the pathogenesis. Here, we performed whole genome sequencing (WGS) for 6 individuals derived from 2 families to evaluate pathogenic mutations located in both coding and noncoding regions. We characterized the annotated deleterious coding mutations and impaired noncoding mutations in regulatory elements by various data analysis. Additionally, functional assays were conducted to validate function regulatory elements and noncoding mutations. Interestingly, a compound heterozygous pattern with pathogenic coding and noncoding mutations was identified in probands. In proband 1, biallelic mutations (g.139409115A > T, encoding p.Asn685Ile; g.139444949C > A) in NOTCH1 exon and its regulatory element were detected. In vitro experiments revealed that the regulatory element acted as a silencer and the noncoding mutation decreased the expression of NOTCH1. In proband 2, we also found compound heterozygous mutations (g. 216235029C > T, encoding p.Val2281Met; g. 216525154A > C) which potentially regulated the function of FN1 gene. In summary, our study firstly reported an instance of newly identified noncoding mutation in regulatory element within the compound heterozygous pattern in TOF. The results provided a deeper understanding of TOF genetic architectures. [ABSTRACT FROM AUTHOR]

• An improved RF method was proposed to better identify key risk factors in GWAS data. • A total of 24 independent SNVs were identified to be associated with DNA damage levels. • The potential biological mechanism of 24 SNVs in influencing DNA damage levels was explored by mediation analysis and functional annotation analysis. Recent studies have found multiple single nucleotide variants (SNVs) associated with DNA damage. However, previous association analysis may ignore the potential interaction effects between SNVs. Therefore, we used an improved random forest (RF) analysis to identify the SNVs related to personal DNA damage in exon-focused genome-wide association study (GWAS). A total of 301 subjects from three independent centers (Zhuhai, Wuhan, and Tianjin) were retained for analysis. An improved RF procedure was used to systematically screen key SNVs associated with DNA damage. Furthermore, we used genetic risk score (GRS) and mediation analysis to investigate the integrative effect and potential mechanism of these genetic variants on DNA damage. Besides, gene set enrichment analysis was conducted to identify the pathways enriched by key SNVs using the Data-driven Expression Prioritized Integration for Complex Traits (DEPICT). Finally, a set of 24 SNVs with the lowest mean square errors (MSE) were identified by improved RF analysis. Both weighted and unweighted GRSs were associated with increased DNA damage levels (P weight < 0.001 and P unweight < 0.001). Gene set enrichment analysis indicated that these loci were significantly enriched in several biological features associated with DNA damage. These findings suggested the role of SNVs in modifying DNA damage levels. It may be convincing that this improved RF analysis can effectively identify SNVs associated with DNA damage levels. [ABSTRACT FROM AUTHOR]

Objective: To investigate the associations between genetically cis-regulated gene expression levels and nonobstructive azoospermia (NOA) susceptibility.Design: Transcriptome-wide association study (TWAS).Setting: Medical university.Interventions: None.Main Outcome Measure(s): The cis-hg2 values for each gene were estimated with GCTA software. The effect sizes of cis-single-nucleotide polymorphisms (SNPs) on gene expression were measured using GEMMA software. Gene expression levels were entered into our existing NOA GWAS cohort using GEMMA software. The TWAS P-values were calculated using logistic regression models.Result(s): Expression levels of 1,296 cis-heritable genes were entered into our existing NOA GWAS data. The TWAS results identified two novel genes as statistically significantly associated with NOA susceptibility: PILRA and ZNF676. In addition, 6p21.32, previously reported in NOA GWAS, was further validated to be a susceptible region to NOA risk.Conclusion(s): Analysis with TWAS provides fruitful targets for follow-up functional studies. [ABSTRACT FROM AUTHOR]

Objective: To conduct a meta-analysis of studies assessing the effect of IVF and intracytoplasmic sperm injection (ICSI) on birth defects. Design: Meta-analysis. Setting: Centers for reproductive care. Patient(s): Patients treated by IVF and/or ICSI. Intervention(s): We identified all studies published by September 2011 with data related to birth defects in children conceived by IVF and/or ICSI compared with spontaneously conceived children, or birth defects in the children conceived by IVF compared with those by ICSI. Risk ratios from individual studies were pooled with the fixed and random effect models. Main Outcome Measure(s): Risk of birth defects in children conceived by IVF and/or ICSI. Result(s): Of 925 studies reviewed for eligibility, 802 were excluded after screening titles and abstracts, 67 were excluded for duplicated data, data unavailable, or inappropriate control group, 56 were included in the final analysis. Among the 56 studies, 46 studies had data on birth defects in children conceived by IVF and/or ICSI (124,468) compared with spontaneously conceived children. These studies provided a pooled risk estimation of 1.37 (95% confidence interval [CI]: 1.26–1.48), which is also evident in subgroup analysis. In addition, 24 studies had data on birth defects in children conceived by IVF (46,890) compared with those by ICSI (27,754), which provided an overall no risk difference. Conclusion(s): Children conceived by IVF and/or ICSI are at significantly increased risk for birth defects, and there is no risk difference between children conceived by IVF and/or ICSI. [ABSTRACT FROM AUTHOR]