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Special protective clothing should have a certain thermal insulation and protective effect in the production in front of the blast furnace. In order to study the design of special protective clothing for blast furnace foreman, its temperature distribution and internal thickness structure are deeply analyzed. First, based on the existing experimental data, combined with heat transfer and the Fourier law theory, a one-dimensional unsteady heat conduction equation is established. Using the explicit finite difference solution algorithm, the distribution law of the temperature of each fabric layer with time is obtained and the error analysis is performed. The error result is 0.42877%, which shows that the numerical solution is stable and convergent. Then, through the intelligent optimization model of a simulated annealing ant colony (SA-ACO), compared with the single ant colony algorithm (ACO) and a simulated annealing algorithm (SA), it avoids falling into the local optimal solution, reversely solves the optimal thickness of two layers of protective clothing in front of the blast furnace, improves the convergence speed of optimization, and verifies the reliability of the model with a sensitivity test. Finally, this paper actually solves the problem of the protective clothing design and mathematical intelligent model in front of the blast furnace and combines it with numerical simulation software to realize the numerical simulation of temperature distribution and thickness optimization of special protective clothing in front of the blast furnace, so as to provide theoretical guidance for enterprise blast furnace production and development of special protective clothing. [ABSTRACT FROM AUTHOR]

To study the combustion process of fuel in the microwave plasma torch, we designed a butane microwave plasma device exploiting a tungsten rod as an electrode. Through analysis of the image record by high-speed camera, we found that the discharge of butane microwave plasma torch is a cyclic process at atmospheric pressure at a frequency of around 100 Hz. During the discharge, the active particles continuously diffuse from the electrode to the outside like the bloom of the flower. Then, the variation of plasma torch of jet height and temperature with microwave power is obtained. In addition, we studied the effects of different butane flow rates on the plasma torch. The results illustrate that excessive butane will lead to carbon deposition on the electrode. All in all, this work provides a new understanding of the combustion of the microwave plasma torch, which is conducive to the further development of microwave plasma in the fields of waste gas treatment, fuel combustion, and plasma engine. [ABSTRACT FROM AUTHOR]

Sparse principal component analysis (SPCA) produces principal components with sparse loadings, which is very important for handling data with many irrelevant features and also critical to interpret the results. To deal with orthogonal constraints, most previous approaches address SPCA with several components using techniques such as deflation technique and convex relaxations. However, the deflation technique usually suffers from suboptimal solutions due to poor approximations. On the other hand, the convex relaxations are often computationally expensive. To address the above issues, in this paper, we propose to address SPCA over the Stiefel manifold directly, and develop a stabilized Alternating Direction Method of Multipliers (SADMM) to handle the nonconvex orthogonal constraints. Compared to traditional ADMM, the proposed SADMM method converges well with a wide range of parameters and obtains a better solution. We also theoretically study the convergence property of the proposed SADMM method. Furthermore, most existing methods ignore an inherent drawback of SPCA — the importance of different components is not considered when doing feature selection, which often makes the selected features nonoptimal. To address this, we further propose a two-stage method which considers the importance of different components to select the most important features. Empirical studies on both synthetic and real-world datasets show that the proposed algorithms achieve better performance compared to existing state-of-the-art methods. [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]

It has been demonstrated that there are abundant stable microRNAs (miRNAs) in plasma/serum, which can be detected and are potentially disease specific. However, the lack of suitable endogenous controls for serum miRNA detection is the restriction for the widely usage of this kind of biomarkers and for the between-laboratory comparison of the findings. We first systematically screened for endogenous control miRNAs (ECMs) by testing 10 pooling samples (using both Solexa sequencing and TaqMan low density array) and 50 individual samples (using quantitative reverse transcription–PCR) of different cancer traits and healthy controls. Then we assessed serum miRNAs used as potential biomarkers for breast cancer risk prediction based on a two-stage case–control analysis, including 48 breast cancer patients and 48 controls for the discovery stage and 76 breast cancer patients and 76 controls for validation. We identified two candidate ECMs (miRNA-191 and miRNA-484). Normalized by the two ECMs, we found four miRNAs (miR-16, miR-25, miR-222 and miR-324-3p) that were consistently differentially expressed between breast cancer cases and controls. The area under the receiver operating characteristic curve is 0.954 for the four-miRNA signature in the discovery stage (sensitivity = 0.917 and specificity = 0.896) and 0.928 in the validation stage (sensitivity = 0.921 and specificity = 0.934). In conclusion, the four-miRNA signature from serum may serve as a non-invasive prediction biomarker for breast cancer. Furthermore, we proposed the combination of miRNA-484 and miRNA-191 as endogenous control for serum miRNA detection, at least for most common cancers. [ABSTRACT FROM AUTHOR]

Pathogenic mutations in mitochondrial DNA cause severe and often lethal multi-system symptoms in primary mitochondrial defects. However, effective therapies for these defects are still lacking. Strategies such as employing mitochondrially targeted restriction enzymes or programmable nucleases to shift the ratio of heteroplasmic mutations and allotopic expression of mitochondrial protein-coding genes have limitations in treating mitochondrial homoplasmic mutations, especially in non-coding genes. Here, we conduct a proof of concept study applying a screened DdCBE pair to correct the homoplasmic m.A4300G mutation in induced pluripotent stem cells derived from a patient with hypertrophic cardiomyopathy. We achieve efficient G4300A correction with limited off-target editing, and successfully restore mitochondrial function in corrected induced pluripotent stem cell clones. Our study demonstrates the feasibility of using DdCBE to treat primary mitochondrial defects caused by homoplasmic pathogenic mitochondrial DNA mutations. A proof-of-concept study applying a screened RNA-free DddA-derived cytosine base editor (DdCBE) pair to correct the homoplasmic m.A4300G mutation in induced pluripotent stem cells demonstrates the potential of DdCBE-based therapy for treating primary mitochondrial defects. [ABSTRACT FROM AUTHOR]

Splicing quantitative trait loci (sQTLs) have been demonstrated to contribute to disease etiology by affecting alternative splicing. However, the role of sQTLs in the development of non-small-cell lung cancer (NSCLC) remains unknown. Thus, we performed a genome-wide sQTL study to identify genetic variants that affect alternative splicing in lung tissues from 116 individuals of Chinese ancestry, which resulted in the identification of 1,385 sQTL-harboring genes (sGenes) containing 378,210 significant variant-intron pairs. A comprehensive characterization of these sQTLs showed that they were enriched in actively transcribed regions, genetic regulatory elements, and splicing-factor-binding sites. Moreover, sQTLs were largely distinct from expression quantitative trait loci (eQTLs) and showed significant enrichment in potential risk loci of NSCLC. We also integrated sQTLs into NSCLC GWAS datasets (13,327 affected individuals and 13,328 control individuals) by using splice-transcriptome-wide association study (spTWAS) and identified alternative splicing events in 19 genes that were significantly associated with NSCLC risk. By using functional annotation and experiments, we confirmed an sQTL variant, rs35861926, that reduced the risk of lung adenocarcinoma (rs35861926-T, OR = 0.88, 95% confidence interval [CI]: 0.82–0.93, p = 1.87 × 10−5) by promoting FARP1 exon 20 skipping to downregulate the expression level of the long transcript FARP1 -011. Transcript FARP1 -011 promoted the migration and proliferation of lung adenocarcinoma cells. Overall, our study provided informative lung sQTL resources and insights into the molecular mechanisms linking sQTL variants to NSCLC risk. [Display omitted] This study provided a comprehensive catalog of splicing quantitative trait loci (sQTLs) in lung tissues. Integrative sQTL analysis revealed risk loci for non-small-cell lung cancer. Further experiments confirmed that rs35861926 could reduce lung adenocarcinoma risk by promoting FARP1 exon 20 skipping to downregulate the expression level of transcript FARP1 -011. [ABSTRACT FROM AUTHOR]

Background Growing evidence indicates the adverse effect of ultra-processed food (UPF) consumption. However, it remains unknown whether UPF consumption influences the risk of colorectal cancer (CRC) precursors, namely conventional adenomas and serrated lesions. Methods We drew data from the Nurses' Health Study, Nurses' Health Study II, and Health Professionals Follow-up Study, comprising 142 052 participants who had undergone at least 1 lower gastrointestinal endoscopy during follow-up. To handle multiple records per participants, we used multivariable logistic regression for clustered data to calculate odds ratios (OR) and 95% confidence intervals (CIs) of colorectal polyps in relation to cumulative average consumption of UPFs. All statistical tests were 2-sided. Results We documented 11 644 patients with conventional adenomas and 10 478 with serrated lesions during 18-20 years of follow-up. Compared with participants in the lowest quintile of UPF consumption, those in the highest quintile had an increased risk of conventional adenomas (OR = 1.18, 95% CI = 1.11 to 1.26) and serrated lesions (OR = 1.20, 95% CI = 1.13 to 1.28). Similar results were found for high-risk polyps (ie, advanced adenomas and ≥10 mm serrated lesions; OR = 1.17, 95% CI = 1.07 to 1.28). These associations were slightly attenuated but remained statistically significant after further adjusting for body mass index, Western dietary pattern score, or individual dietary factors (fiber, folate, calcium, and vitamin D). The results remained essentially unchanged after excluding processed meat from total UPF intake. Conclusions Higher consumption of UPFs is associated with an increased risk of CRC precursors. UPFs might be a modifiable target for early prevention of CRC. [ABSTRACT FROM AUTHOR]

Congenital heart disease (CHD) is the most common birth defect worldwide and a main cause of perinatal and infant mortality. Our previous genome-wide association study identified 53 SNPs that associated with CHD in the Han Chinese population. Here, we performed functional screening of 27 orthologous genes in zebrafish using injection of antisense morpholino oligos. From this screen, 5 genes were identified as essential for heart development, including iqgap2, ptprt, ptpn22, tbck and maml3. Presumptive roles of the novel CHD-related genes include heart chamber formation (iqgap2 and ptprt) and atrioventricular canal formation (ptpn22 and tbck). While deficiency of maml3 led to defective cardiac trabeculation and consequent heart failure in zebrafish embryos. Furthermore, we found that maml3 mutants showed decreased cardiomyocyte proliferation which caused a reduction in cardiac trabeculae due to inhibition of Notch signaling. Together, our study identifies 5 novel CHD-related genes that are essential for heart development in zebrafish and first demonstrates that maml3 is required for Notch signaling in vivo. [ABSTRACT FROM AUTHOR]

Background: Body mass index (BMI) has been found to be associated with a decreased risk of non-small cell lung cancer (NSCLC); however, the effect of BMI trajectories and potential interactions with genetic variants on NSCLC risk remain unknown.Methods: Cox proportional hazards regression model was applied to assess the association between BMI trajectory and NSCLC risk in a cohort of 138,110 participants from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. One-sample Mendelian randomization (MR) analysis was further used to access the causality between BMI trajectories and NSCLC risk. Additionally, polygenic risk score (PRS) and genome-wide interaction analysis (GWIA) were used to evaluate the multiplicative interaction between BMI trajectories and genetic variants in NSCLC risk.Results: Compared with individuals maintaining a stable normal BMI (n = 47,982, 34.74%), BMI trajectories from normal to overweight (n = 64,498, 46.70%), from normal to obese (n = 21,259, 15.39%), and from overweight to obese (n = 4,371, 3.16%) were associated with a decreased risk of NSCLC (hazard ratio [HR] for trend = 0.78, P < 2×10-16). An MR study using BMI trajectory associated with genetic variants revealed no significant association between BMI trajectories and NSCLC risk. Further analysis of PRS showed that a higher GWAS-identified PRS (PRSGWAS) was associated with an increased risk of NSCLC, while the interaction between BMI trajectories and PRSGWAS with the NSCLC risk was not significant (PsPRS= 0.863 and PwPRS= 0.704). In GWIA analysis, four independent susceptibility loci (P < 1×10-6) were found to be associated with BMI trajectories on NSCLC risk, including rs79297227 (12q14.1, located in SLC16A7, Pinteraction = 1.01×10-7), rs2336652 (3p22.3, near CLASP2, Pinteraction = 3.92×10-7), rs16018 (19p13.2, in CACNA1A, Pinteraction = 3.92×10-7), and rs4726760 (7q34, near BRAF, Pinteraction = 9.19×10-7). Functional annotation demonstrated that these loci may be involved in the development of NSCLC by regulating cell growth, differentiation, and inflammation.Conclusions: Our study has shown an association between BMI trajectories, genetic factors, and NSCLC risk. Interestingly, four novel genetic loci were identified to interact with BMI trajectories on NSCLC risk, providing more support for the aetiology research of NSCLC.Trial Registration: http://www.Clinicaltrials: gov , NCT01696968 . [ABSTRACT FROM AUTHOR]

Translational control is a fundamental mechanism regulating animal germ cell development. Gonadal somatic cells provide support and microenvironment for germ cell development to ensure fertility, yet the roles of translational control in gonadal somatic compartment remain largely undefined. We found that mouse homolog of conserved fly germline stem cell factor Pumilio, PUM1, is absent in oocytes of all growing follicles after the primordial follicle stage, instead, it is highly expressed in somatic compartments of ovaries. Global loss of Pum1, not oocyte-specific loss of Pum1, led to a significant reduction in follicular number and size as well as fertility. Whole-genome identification of PUM1 targets in ovarian somatic cells revealed an enrichment of cell proliferation pathway, including 48 key regulators of cell phase transition. Consistently granulosa cells proliferation is reduced and the protein expression of the PUM-bound Cell Cycle Regulators (PCCR) were altered accordingly in mutant ovaries, and specifically in granulosa cells. Increase in negative regulator expression and decrease in positive regulators in the mutant ovaries support a coordinated translational control of somatic cell cycle program via PUM proteins. Furthermore, postnatal knockdown, but not postnatal oocyte-specific loss, of Pum1 in Pum2 knockout mice reduced follicular growth and led to similar expression alteration of PCCR genes, supporting a critical role of PUM-mediated translational control in ovarian somatic cells for mammalian female fertility. Finally, expression of human PUM protein and its regulated cell cycle targets exhibited significant correlation with ovarian cancer and prognosis for cancer survival. Hence, PUMILIO-mediated cell cycle regulation represents an important mechanism in mammalian female reproduction and human cancer biology. [ABSTRACT FROM AUTHOR]

Background: Little prospective evidence exists about whether a combination of healthy lifestyle factors is related to a considerable reduction of liver cancer risk.Methods: Based on the prospective China Kadoorie Biobank (CKB) cohort with a total of 492,640 Chinese adults, we examined the associations of five lifestyle factors with risk of liver cancer. Low-risk lifestyle factors were defined as non-smoking, non-drinking, median or higher level of physical activity, a healthy diet, and waist-to-hip ratio (WHR) < 0.90 for men and <0.85 for women.Results: During a median of 10.12 years of follow-up, 2529 liver cancer events were observed. There was a significant decrease in liver cancer risk with the increasing of the healthy lifestyle index scores (P < 0.001). Participants with a favourable lifestyle (4 or 5 healthy lifestyle factors) had a 43% reduced liver cancer risk compared with those with an unfavourable lifestyle (0 or 1 healthy lifestyle factor) (HR, 0.57 [95% CI, 0.47-0.68]). The cumulative protective effect of a healthy lifestyle on liver cancer appeared to be more dramatic for patients with hepatitis B surface antigen (HBsAg) positive, the individuals at high risk of liver cancer.Conclusions: Individuals adhering to a favourable lifestyle was associated with a considerable absolute risk reduction of liver cancer. [ABSTRACT FROM AUTHOR]

Highlights: [•] OH radicals functioned as the main ROSs for the degradation of thiamethoxam. [•] Oxidative ions promote the degradation rate, while reductive anions inhibit it. [•] The thiophene ring is the most active site which reacts with ROSs. [•] 7 Photocatalytic intermediates were separated and identified by HPLC and HPLC/MS/MS. [•] Cleavage of oxadiazinane and hydroxylation of thiophene were led to degradation. [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]

Background: Comitant strabismus (CS) is a heterogeneous disorder that is a major contributing factor to unilateral childhood-onset visual impairment. Studies have confirmed that genetic factors play an important role in the development of CS. The aim of this study was to identify the genetic cause of non-syndromic familial CS.Methods: Fourteen unrelated CS families were recruited for the study. Twelve affected and 2 unaffected individuals from a large four-generation family (CS08) were selected to perform whole genome-wide linkage analysis. Parallel whole-exome sequencing (WES) was conducted in the same family (9 patients and 1 unaffected member) and 31 additional CS cases from 13 other unrelated families. Sanger sequencing was used to determine whether any of the remaining variants co-segregated with the disease phenotype in the corresponding family.Results: Based on linkage analysis, CS in family CS08 mapped to a novel region of 34.17 centimorgan (cM) on chromosome 2q22.3-2q32.1 between markers D2S151 and D2S364, with a maximum log odds (LOD) score of 3.54 (theta = 0) at D2S142. Parallel WES identified a heterozygous variant, LRP2 c.335 A > G (p.Q112R), located in such a linkage interval that completely co-segregated with the disease in the family. Furthermore, another novel heterozygous variant (c.7274A > G, p.D2425G) in LRP2 that co-segregated was detected in 2 additional affected individuals from another unrelated family by WES. Both variants are predicted to be damaging by PolyPhen-2, SIFT and MutationTaster, and were absent in 100 ethnically matched normal controls.Conclusion: LRP2 is a novel candidate genetic cause of non-syndromic familial CS. [ABSTRACT FROM AUTHOR]

Genetic variants may influence miRNA–mRNA interaction through modulate binding affinity, creating or destroying miRNA-binding sites. Twenty-four single nucleotide polymorphisms (SNPs) that were predicted to affect the binding affinity of breast cancer-related miRNAs to 3′-untranslated regions (UTR) of known genes were genotyped in 878 breast cancer cases and 900 controls in Chinese women. Three promising SNPs (rs10494836, rs10857748 and rs7963551) were further validated in additional 914 breast cancer cases and 967 controls. The variant allele (C) of rs7963551 at 3′-UTR of RAD52 showed a consistently reduced breast cancer risk in two stages with a combined odds ratio (OR) of 0.84 [95% confidence interval (CI) = 0.75–0.95], which was more prominent among women with early age at first live birth (OR = 0.71, 95% CI = 0.58–0.87). A significant interaction was observed between rs7963551 and age at first live birth on breast cancer risk (P for interaction = 0.04). Luciferase activity assay showed a higher expression level for rs7963551 C allele as compared with A allele (P = 5.19×10–3 for MCF-7 cell lines), which might be due to a reduced inhibition from a weakened binding capacity of miRNA to 3′-UTR of RAD52 harboring C allele. These findings indicate that rs7963551 located at hsa-let-7 binding site may alter expression of RAD52 through modulating miRNA–mRNA interaction and contribute to the development of breast cancer in Chinese women. [ABSTRACT FROM AUTHOR]

Background: Accumulative evidence suggests that low folate intake is associated with increased risk of breast cancer. Polymorphisms in genes involved in folate metabolism may influence DNA methylation, nucleotide synthesis, and thus individual susceptibility to cancer. Thymidylate synthase (TYMS) is a key enzyme that participates in folate metabolism and catalyzes the conversion of dUMP to dTMP in the process of DNA synthesis. Two potentially functional polymorphisms [a 28-bp tandem repeat in the TYMS 5'-untranslated enhanced region (TSER) and a 6-bp deletion/insertion in the TYMS 3'-untranslated region (TS 3'-UTR)] were suggested to be correlated with alteration of thymidylate synthase expression and associated with cancer risk. Methods: To test the hypothesis that polymorphisms of the TYMS gene are associated with risk of breast cancer, we genotyped these two polymorphisms in a case-control study of 432 incident cases with invasive breast cancer and 473 cancer-free controls in a Chinese population. Results: We found that the distribution of TS3'-UTR (1494del6) genotype frequencies were significantly different between the cases and controls (P = 0.026). Compared with the TS3'-UTR del6/del6 wild-type genotype, a significantly reduced risk was associated with the ins6/ins6 homozygous variant genotype (adjusted OR = 0.58, 95% CI = 0.35-0.97) but not the del6/ins6 genotype (OR = 1.09, 95% CI = 0.82-1.46). Furthermore, breast cancer risks associated with the TS3'-UTR del6/del6 genotype were more evident in older women, postmenopausal subjects, individuals with a younger age at first-live birth and individuals with an older age at menarche. However, there was no evidence for an association between the TSER polymorphism and breast cancer risks. Conclusion: These findings suggest that the TS3'-UTR del6 polymorphism may play a role in the etiology of breast cancer. Further larger population-based studies as well as functional evaluation of the variants are warranted to confirm our findings. [ABSTRACT FROM AUTHOR]

Gene–smoking interactions play important roles in the development of non-small cell lung cancer (NSCLC). To identify single-nucleotide polymorphisms (SNPs) that modify the association of smoking behavior with NSCLC risk, we conducted a genome-wide gene–smoking interaction study in Chinese populations. The genome-wide interaction analysis between SNPs and smoking status (ever- versus never-smokers) was carried out using genome-wide association studies of NSCLC, which included 13 327 cases and 13 328 controls. Stratified analysis by histological subtypes was also conducted. We used a genome-wide significance threshold of 5 × 10−8 for identifying significant gene–smoking interactions and 1 × 10–6 for identifying suggestive results. Functional annotation was performed to identify potential functional SNPs and target genes. We identified three novel loci with significant or suggestive gene–smoking interaction. For NSCLC, the interaction between rs2746087 (20q11.23) and smoking status reached genome-wide significance threshold [odds ratio (OR) = 0.63, 95% confidence interval (CI): 0.54–0.74, P = 3.31 × 10–8], and the interaction between rs11912498 (22q12.1) and smoking status reached suggestive significance threshold (OR = 0.72, 95% CI: 0.63–0.82, P = 8.10 × 10–7). Stratified analysis by histological subtypes identified suggestive interactions between rs459724 (5q11.2) and smoking status (OR = 0.61, 95% CI: 0.51–0.73, P = 7.55 × 10–8) in the risk of lung squamous cell carcinoma. Functional annotation indicated that both classic and novel biological processes, including nicotine addiction and airway clearance, may modulate the susceptibility to NSCLC. These novel loci provide new insights into the biological mechanisms underlying NSCLC risk. Independent replication in large-scale studies is needed and experimental studies are warranted to functionally validate these associations. [ABSTRACT FROM AUTHOR]

Idiopathic achalasia (IA) is a severe motility disorder characterized by neuronal degeneration in the myenteric plexus, but the etiology remains largely unknown. We performed whole-exome sequencing (WES) in 100 IA-affected individuals and 313 non-IA control subjects and validated the results in 230 IA-affected individuals and 1,760 non-IA control subjects. Common missense variants rs1705003 (CUTA , GenBank: NC_000006.11:g.33385953A>G) and rs1126511 (HLA-DPB1 , GenBank: NC_000006.11:g.33048466G>T) at 6p21.32 were reproducibly associated with increased risk of IA (rs1126511: OR = 1.83, p = 2.34 × 10−9; rs1705003: OR = 2.37, p = 3.21 × 10−7), meeting exome-wide significance. Both variants can affect the expression of their target genes at the transcript level. An array-based association analysis in 280 affected individuals and 1,121 control subjects determined the same signal at 6p21.32. Further conditional analyses supported that the two missense variants identified in WES-based association study were potential causal variants of IA. For rare variants, the top genes identified by gene-based analysis were significantly enriched in nerve and muscle phenotypic genes in the mouse. Moreover, the functional rare variants in these genes tended to cooccur in IA-affected individuals. In an independent cohort, we successfully validated three rare variants (CREB5 , GenBank: NC_000007.13:g.28848865G>T; ESYT3 , GenBank: NC_000003.11:g.138183253C>T; and LPIN1 , GenBank: NC_000002.11:g.11925128A>G) which heightens the risk of developing IA. Our study identified and validated two common variants and three rare variants associated with IA in immunologic and neurological genes, providing new insight into the etiology of IA. [ABSTRACT FROM AUTHOR]

The assembly of primordial follicles in mammals represents one of the most critical processes in ovarian biology. It directly affects the number of oocytes available to a female throughout her reproductive life. Premature depletion of primordial follicles contributes to the ovarian pathology primary ovarian insufficiency (POI). To delineate the developmental trajectory and regulatory mechanisms of oocytes during the process, we performed RNA‐seq on single germ cells from newborn (P0.5) ovaries. Three cell clusters were classified which corresponded to three cell states (germ cell cyst, cyst breakdown, and follicle) in the newborn ovary. By Monocle analysis, a uniform trajectory of oocyte development was built with a series of genes showed dynamic changes along the pseudo‐timeline. Gene Ontology term enrichment revealed a significant decrease in meiosis‐related genes and a dramatic increase in oocyte‐specific genes which marked the transition from a germ cell to a functional oocyte. We then established a network of regulons by using single‐cell regulatory network inference and clustering (SCENIC) algorithm and identified possible candidate transcription factors that may maintain transcription programs during follicle formation. Following functional studies further revealed the differential regulation of the identified regulon Id2 and its family member Id1, on the establishment of primordial follicle pool by using siRNA knockdown and genetic modified mouse models. In summary, our study systematically reconstructed molecular cascades in oocytes and identified a series of genes and molecular pathways in follicle formation and development. [ABSTRACT FROM AUTHOR]

Background: In recent years, births to older mothers and multiparous mothers have increased rapidly with the change of birth policy in China. And mothers of advanced age are more likely to have maternal complications and poor birth outcomes. We aimed to estimate the recent trends and underlying risk factors of maternal mortality.Methods: In this systematic assessment, we used data from the National Maternal and Child Health Routine Reporting System (2013-2018), Jiangsu Provincial Maternal Mortality Surveillance System (2017-2018), the Integrated National Mortality Surveillance System (2018), City Statistical Yearbooks (2018), City Health Statistical Yearbooks (2018). The factors associated with maternal mortality ratio (MMR) were explored using the stepwise regression analysis and cluster analysis.Results: The MMR maintained at low levels between 2013 and 2016 and there was a slight increase in maternal mortality after 2016 in Jiangsu province. With the implementation of the China's universal two child policies, the percentage of multiparous mothers ascended from 34.2% (95% confidence interval (CI) = 34.1-34.3%) in 2013 to 51.4% (95% CI = 51.3-51.6%) in 2018 (beta = 3.88, P < 0.001). Consistently, the percentage of advanced maternal age (≥ 35) increased from 8.4% (95% CI = 8.4-8.5%) in 2013 to 10.4% (95% CI = 10.3-10.4%) in 2018 (beta = 0.50, P = 0.012). And we found that the percentage of multiparous mothers and advanced maternal age among maternal deaths were higher than all pregnant women (P < 0.001). In the stepwise regression analysis, four risk factors were significantly associated with maternal mortality ratio (primary industry of gross domestic product (GDP), rate of delivery in maternal and child health hospital, rate of cesarean section and rate of low birth weight). As the results derived from cluster analysis, the relatively developed regions had lower preventable maternal mortality ratio (43.5% (95% CI = 31.2-56.7%) vs. 62.6% (95% CI = 52.3-72.0%), P = 0.027).Conclusions: Since the universal two child policy has been associated with changes in health related birth characteristics: women giving birth have been more likely to be multiparous, and more likely to be aged 35 and over. This somewhat magnifies the impact of differences in economic development and obstetric services on MMR. The findings based on prefecture level data suggest that interventions must target economic development, the health system and maternal risk factors in synergy. These approaches will be of great benefit to control or diminish environmental factors associated with preventable deaths and will effectively reduce MMR and narrow the gap among the different regions. [ABSTRACT FROM AUTHOR]

N6-Methyladenosine (m6A) is an RNA modification that interacts with numerous coding and non-coding RNAs and plays important roles in the development of cancers. Nonetheless, the clinical impacts of m6A interactive genes on these cancers largely remain unclear since most studies focus only on a single cancer type. We comprehensively evaluated m6A modification patterns, including 23 m6A regulators and 83 interactive coding and non-coding RNAs among 9,804 pan-cancer samples. We used clustering analysis to identify m6A subtypes and constructed the m6A signature based on an unsupervised approach. We used the signatures to identify potential m6A modification targets across the genome. The prognostic value of one target was further validated in 3,444 samples from six external datasets. We developed three distinct m6A modification subtypes with different tumor microenvironment cell infiltration degrees: immunological, intermediate, and tumor proliferative. They were significantly associated with overall survival in 24 of 27 cancer types. Our constructed individual-level m6A signature was associated with survival, tumor mutation burden, and classical pathways. With the signature, we identified 114 novel genes as potential m6A targets. The gene shared most commonly between cancer types, BCL9L, is an oncogene and interacts with m6A patterns in the Wnt signaling pathway. In conclusion, m6A regulators and their interactive genes impact the outcome of various cancers. Evaluating the m6A subtype and the signature of individual tumors may inform the design of adjuvant treatments. [ABSTRACT FROM AUTHOR]

Background: Sex hormones have been suggested to play a role in colorectal cancer (CRC), but their influence on early initiation of CRC remains unknown.Methods: We retrospectively examined the associations with risk of CRC precursors, including conventional adenomas and serrated polyps, for plasma estrone, estradiol, free estradiol, testosterone, free testosterone, sex hormone-binding globulin (SHBG), and the ratio of estradiol to testosterone among 5404 postmenopausal women from the Nurses' Health Study I and II. Multivariable logistic regression was used to calculate the odds ratio (OR) and 95% confidence intervals (CI). Given multiple testing, P < 0.005 was considered statistically significant.Results: During 20 years of follow-up, we documented 535 conventional adenoma cases and 402 serrated polyp cases. Higher concentrations of SHBG were associated with lower risk of conventional adenomas, particularly advanced adenomas (multivariable OR comparing the highest to the lowest quartile, 0.40, 95% CI 0.24-0.67, P for trend < 0.0001). A nominally significant association was found for SHBG with lower risk of large serrated polyps (≥ 10 mm) (OR, 0.47, 95% CI 0.17-1.35, P for trend = 0.02) as well as free estradiol and free testosterone with higher risk of conventional adenomas (OR, 1.54, 95% CI 1.02-2.31, P for trend = 0.03 and OR, 1.33, 95% CI 0.99-1.78, P for trend = 0.03, respectively).Conclusions: The findings suggest a potential role of sex hormones, particularly SHBG, in early colorectal carcinogenesis. [ABSTRACT FROM AUTHOR]

Background: The World Health Organization (WHO) in 2015 stated that every effort should be made to provide cesarean delivery (CD) for women in need. In China, the two-child policy largely prompts the number of advanced age childbirth, which raises the possibility of an increasing number of women who need a c-section. The aim of this study was to assess the trends in the overall and medical indication-classified CD rates in the era of the two-child policy in Jiangsu, China.Methods: A retrospective cross-sectional study of 291,448 women who delivered in 11 hospitals in Jiangsu province between 2012 and 2019 was conducted. Medical cesarean indication for each woman was ascertained by manually reviewing the medical records. The 291,448 women were divided into two subgroups according to the presence of the indications: the indicated group (7.80%) and the non-indicated group (92.20%). We then fitted joinpoint regression and log-binomial regression models to estimate trends in the CD rates across the study period.Results: The overall CD rate was observed with a declining trend from 52.51% in 2012-2015 to 49.76% in 2016-2019 (adjusted RR, 0.92; 95% CI, 0.91-0.93; P < 0.001), along with an annual percentage change (APC) to be - 1.0 (95% CI, - 2.1 to 0.0) across the period. The participants were then divided into two subgroups according to the presence of medical CD indications: the indicated group (7.80%) and the non-indicated group (92.20%).We found the declining trend was most pronounced in the non-indicated group, with the CD rates decreased from 50.02% in 2012-2015 to 46.27% in 2016-2019 (adjusted RR, 0.90; 95% CI, 0.89-0.90; P < 0.001). By contrast, we observed a steady trend in the CD rate of the indicated group, which maintained from 87.47% in 2012-2015 to 86.57% in 2016-2019 (P = 0.448). In the indicated group, a higher risk of adverse pregnancy outcomes was revealed for those women who delivered vaginally as compared with those who received c-section. We further investigated that women with following specific indications had a higher proportion of vaginal delivery, i.e., pregnancy complications, fetal macrosomia, and pregnancy complicated with tumor (34.70%, 10.84%, and 16.34%, respectively). Women with the above 3 indications were observed with a higher risk of adverse pregnancy outcomes if delivered vaginally. The incidence rates of the medical indications among the general population increased considerably over the 8-year period (P < 0.001).Conclusions: Although the overall CD rate apparently decreased in the recent years, along with the decline of the unnecessary CD rate, a considerable proportion of indicated women were not provided with CD service in Jiangsu, China. Instead of targeting the overall CD rate, we need to take actions to reduce unnecessary CD rate and provide adequate c-section service for women with indications, particularly for those with underlying diseases and suspected fetal macrosomia. [ABSTRACT FROM AUTHOR]

Objective: Coffee may protect against multiple chronic diseases, particularly type 2 diabetes, but the mechanisms remain unclear.Research Design and Methods: Leveraging dietary and metabolomic data in two large cohorts of women (the Nurses' Health Study [NHS] and NHSII), we identified and validated plasma metabolites associated with coffee intake in 1,595 women. We then evaluated the prospective association of coffee-related metabolites with diabetes risk and the added predictivity of these metabolites for diabetes in two nested case-control studies (n = 457 case and 1,371 control subjects).Results: Of 461 metabolites, 34 were identified and validated to be associated with total coffee intake, including 13 positive associations (primarily trigonelline, polyphenol metabolites, and caffeine metabolites) and 21 inverse associations (primarily triacylglycerols [TAGs] and diacylglycerols [DAGs]). These associations were generally consistent for caffeinated and decaffeinated coffee, except for caffeine and its metabolites that were only associated with caffeinated coffee intake. The three cholesteryl esters positively associated with coffee intake showed inverse associations with diabetes risk, whereas the 12 metabolites negatively associated with coffee (5 DAGs and 7 TAGs) showed positive associations with diabetes. Adding the 15 diabetes-associated metabolites to a classical risk factor-based prediction model increased the C-statistic from 0.79 (95% CI 0.76, 0.83) to 0.83 (95% CI 0.80, 0.86) (P < 0.001). Similar improvement was observed in the validation set.Conclusions: Coffee consumption is associated with widespread metabolic changes, among which lipid metabolites may be critical for the antidiabetes benefit of coffee. Coffee-related metabolites might help improve prediction of diabetes, but further validation studies are needed. [ABSTRACT FROM AUTHOR]

BRCA1 and BRCA2 as important DNA repair genes have been thoroughly investigated in abundant studies. The potential relationships of BRCA1/2 pathogenic variants between multicancers have been verified in Caucasians but few in Chinese. In this study, we performed a two-stage study to screen BRCA1/2 pathogenic variants or variants of uncertain significance (VUS) with 7580 cancer cases and 4874 cancer-free controls, consisting of a discovery stage with 70 familial breast cancer cases and a subsequent validation stage with 7510 cases (3217 breast cancer, 1133 cervical cancer, 2044 hepatocellular carcinoma, and 1116 colorectal cancer). 48 variants were obtained from 70 familial breast cancer cases after BRCA1/2 exon detection, and finally, 20 pathogenic variants or VUS were selected for subsequent validation. Four recurrent variants in sporadic cases (BRCA1 c.4801A>T, BRCA1 c.3257del, BRCA1 c.440del, and BRCA2 c.7409dup) were identified and three of them were labeled Class 5 by ENIGMA. Two variants (BRCA1 c.3257del and c.440del) were specific in breast cancer cases, while BRCA2 c.7409dup and c.4307T>C were detected in two hepatocellular carcinoma patients and the BRCA1 c.4801A>T variant in one cervical cancer patient, respectively. Moreover, BRCA1 c.3257del was the most frequent variant observed in Chinese sporadic breast cancer and showed increased proliferation of BRCA1c.3257del-overexpressing triple-negative breast cancer cell lines (MDA-MB-231) in vitro. In addition to the known founder deleterious mutations, our findings highlight that the recurrently pathogenic variants in breast cancer cases could be taken as candidate genetic screening loci for a more efficient genetic screening of the Chinese population. [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]

MicroRNAs (miRNAs) of the miR-30 family are closely linked with tumor metastasis and play key roles in the complex malignant phenotypes of cancers by targeting many tumor-related genes. Deregulated expression of miR-30 family members has been commonly observed in breast cancer. However, associations between the genetic variants in the regulatory region of miR-30 family and the risk of breast cancer are still limited, especially in the Chinese Han population. In the present study, we conducted a case-control analysis wherein 1064 breast cancer patients and 1073 healthy controls underwent genotyping of 10 SNPs in the regulatory region of miR-30 family members. Multivariate logistic regression analyses illustrated that the rs763354 variant in the miR-30a regulatory region was linked with a significant decrease in breast cancer risk in an additive model (adjusted OR = 0.86 , 95% CI: 0.75-0.98, P = 0.022). Further, eQTL analyses also indicated that this SNP was associated with miR-30a expression levels in breast cancer samples compiled in the TCGA database (P = 0.020). The Kaplan-Meier plotter showed that breast cancer patients with higher miR-30a expression have significantly better outcomes than do patients expressing low levels of this miRNA (HR = 0.75 , 95% CI: 0.61-0.91, P = 0.0041). Together, these findings suggest that the miR-30a rs763354 SNP is an important regulator of breast cancer risk, thus making it a potentially viable prognostic biomarker and one that can be used to guide therapeutic treatment in affected patients. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence suggests that conventional adenomas (CAs) and serrated polyps (SPs) represent two distinct groups of precursor lesions for colorectal cancer (CRC). The influence of common genetic variants on risk of CAs and SPs remain largely unknown.Methods: Among 27 426 participants within three prospective cohort studies, we created a weighted genetic risk score (GRS) based on 40 CRC-related single nucleotide polymorphisms (SNPs) identified in previous genome-wide association studies; and we examined the association of GRS (per one standard deviation increment) with risk of CAs, SPs and synchronous CAs and SPs, by multivariable logistic regression. We also analysed individual variants in the secondary analysis.Results: During 18-20 years of follow-up, we documented 2952 CAs, 1585 SPs and 794 synchronous CAs and SPs. Higher GRS was associated with increased risk of CAs [odds ratio (OR) = 1.17, 95% confidence interval (CI): 1.12-1.21] and SPs (OR = 1.09, 95% CI: 1.03-1.14), with a stronger association for CAs than SPs (Pheterogeneity=0.01). An even stronger association was found for patients with synchronous CAs and SPs (OR = 1.32), advanced CAs (OR = 1.22) and multiple CAs (OR = 1.25). Different sets of variants were associated with CAs and SPs, with a Spearman correlation coefficient of 0.02 between the ORs associating the 40 SNPs with the two lesions. After correcting for multiple testing, three variants were associated with CAs (rs3802842, rs6983267 and rs7136702) and two with SPs (rs16892766 and rs4779584).Conclusions: Common genetic variants play a potential role in the conventional and serrated pathways of CRC. Different sets of variants are identified for the two pathways, further supporting the aetiological heterogeneity of CRC. [ABSTRACT FROM AUTHOR]

Background: Nasopharyngeal carcinoma (NPC) is one of the most frequent head and neck malignant tumors. Long noncoding RNAs play critical roles in tumorigenesis. Methods: Real‐time quantitative PCR arrays were used to evaluate the expression levels of cytoskeleton regulator RNA (CYTOR) in NPC tissues and cells. Cell counting kit‐8 and colony formation analyses were used to test the NPC cell viability, while wound healing and transwell assays were employed to detect cell invasion and migration ability. Luciferase reporter assay and Western blot analyses were employed to explore the relationships among CYTOR, miR‐613, and ANXA2. Results: We found that CYTOR expression was elevated both in NPC tissues and cells. Functional assays revealed that CYTOR promoted the invasion and migration of NPC cells. The established spontaneous lymph node metastasis model also confirmed that CYTOR promoted NPC cell metastasis in vivo. Mechanically, we found that the subcellular localization of CYTOR mostly occurred in the cell cytoplasm. Luciferase reporter and RIP assays confirmed that CYTOR functioned as the molecular sponge of miR‐613. Subsequent experiments confirmed that ANXA2 was directly targeted by miR‐613. Gain‐ and loss‐of‐function studies further confirmed that CYTOR induced the upregulation of ANXA2 by competitively binding to miR‐613, thus leading to NPC metastasis. Conclusion: Our results highlight the importance of CYTOR in NPC development and provide new insights into potential therapeutic targets for NPC. [ABSTRACT FROM AUTHOR]

Associations between telomere length and cancer risk have been investigated in many epidemiological studies, but the results are controversial. These associations may be biased by reverse causation or confounded by environmental exposures. To avoid potential biases, we used Mendelian randomization method to evaluate whether TL is the causal risk factor for lung cancer. We conducted Mendelian randomization analysis in two published East Asian GWAS studies (7127 cases and 6818 controls). We used both weighted genetic risk score and inverse‐variance weighting method to estimate the relationship between TL and lung cancer risk. Nonlinear test also used to detect potential association trends. We observed that increased weight GRS was associated with increased risk of lung cancer (OR = 2.25, 95%CI: 1.81‐2.78, P = 1.18 × 10−13). In different subtypes, weight GRS was significantly associated with lung adenocarcinoma risk (OR = 2.69, 95% CI: 2.11‐3.42, P = 7.20 × 10−16); while lung squamous cell carcinoma showed a marginal association (OR = 1.45, 95% CI = 1.01‐2.10, P = .047). Nonlinear analysis suggested a log‐linear dose‐response relationship between increased weight GRS and lung cancer risk. Our results indicated that longer TL increases lung cancer risk. Those biological mechanisms changes caused by long TL may play an important role in lung carcinogenesis. [ABSTRACT FROM AUTHOR]

Purpose: The overexpression and knockdown of PLK4 were both reported to generate aneuploidy. Thus, we aimed to investigate whether genetic variants in PLK4 contribute to the development of hepatocellular carcinoma (HCC). Methods: We evaluated associations of common variants in PLK4 and its promoter for the risk of HCC in our association study (1300 cases and 1344 controls). The genotype‐tissue expression (GTEx) and The cancer genome atlas (TCGA) databases were used to quantify the expression of PLK4. Cell proliferation and migration affected by PLK4 in HCC were assessed in vitro. Drug susceptibility testing (DST) model was used to assess the sensibility of PLK4‐activated HCC to CFI‐400945, a small molecule inhibitor of PLK4. Results: Herein, we found a significant association between rs3811741, located in the PLK4 intron, and liver cancer risk (OR = 1.26, P = 9.81 × 10−5). Although PLK4 expressed at lower levels in somatic tissues compared to the testis, the risk allele A of rs3811741 was associated with increased PLK4 expression in liver cancer tissues. Additionally, PLK4 high expression was remarkably associated with shortened survival of HCC (HR = 1.97, P = .001). Furthermore, overexpression of PLK4 promoted, while knockdown of PLK4 suppressed cancer cell proliferation, migration, and invasion. DST model demonstrated that CFI‐400945 can effectively suppress rampant proliferation of HCC with highly expressed PLK4. Conclusion: Taken together, our study demonstrated that PLK4 is a susceptibility gene and plays an oncogenic role in HCC. Furthermore, we identified that PLK4 sensitives HCC to CFI‐400945, which may be an ideal therapy target for HCC. [ABSTRACT FROM AUTHOR]

Background: Although high‐risk human papillomavirus (HR‐HPV) infection is recognized as the main cause of cervical cancer, only a minority of HPV‐infected women develop this malignancy. Increasing evidence suggests that alterations of telomere length might be implicated in carcinogenesis. However, the association between cervical cancer and telomere length remains unknown. Methods: This case‐control study included 591 cervical cancer patients and 373 cancer‐free controls, all of whom were infected with HR‐HPV. Relative telomere length (RTL) in cervical cancer exfoliated cells was measured by quantitative PCR. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression analysis. Results: HPV16, 18, 52, and 58 were common in both case and control groups. The proportion of HPV16 infection tended to increase across the quartiles of RTL (Ptrend < 0.001). There was no statistically significant association of RTL with tumor differentiation, histological type, and FIGO stage. After adjustment for age and HPV types, the lowest quartile of RTL presented a 49% lower risk (OR = 0.51, 95% CI: 0.35, 0.76; P < 0.001) than those with the highest quartile of RTL. There was also a dose‐response relationship of shorter RTL on lower risk of cervical cancer (Ptrend < 0.001). Conclusion: Shortened telomere length in cervical exfoliated cells was related to the lower risk of cervical cancer among HR‐HPV‐positive women, which might help to improve cervical cancer screening and surveillance. Further prospective studies with large sample should be designed to validate our preliminary findings, and evaluate the potential efficacy of telomere length for cervical cancer screening. New triage biomarkers for human papillomavirus‐positive women are necessary to improve the identification of individuals at high risk of cervical cancer progression. Shorter telomere length in cervical exfoliated cells was associated with the lower risk of cervical cancer. Shortened telomere length may act as a protective factor in cervical carcinogenesis and represent a potential biomarker for this malignancy. [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]

Cancer‐testis (CT) genes are a group of genes restrictedly expressed in testis and multiple cancers and can serve as candidate driver genes participating in the development of cancers. Our previous study identified a number of CT genes in nongerm cell tumors, but their expression pattern in testicular germ cell tumor (TGCT), a cancer type characterized by less genomic alterations, remained largely unknown. In this study, we systematically investigated the expression pattern of CT genes in TGCT samples and evaluated the transcriptome difference between TGCT and normal testis tissues, using datasets from the UCSC Xena platform, The Cancer Genome Atlas (TCGA) and the Genotype‐Tissue Expression (GTEx) project. Pathway enrichment analysis and survival analysis were conducted to evaluate the biological function and prognostic effect of expressed CT genes. We identified that 1036 testis‐specific expressed protein‐coding genes and 863 testis‐specific expressed long noncoding RNAs (lncRNAs) were expressed in TGCT samples, including 883 CT protein‐coding genes and 710 CT lncRNAs defined previously. The number of expressed CT genes was significantly higher in seminomas (P = 3.48 × 10−13) which were characterized by frequent mutations in driver genes (KIT, KRAS and NRAS). In contrast, the number of expressed CT genes showed a moderate negative correlation with the fraction of copy number altered genomes (cor = −0.28, P = 1.20 × 10−3). Unlike other cancers, our analysis revealed that 96.16% of the CT genes were down‐regulated in TGCT samples, while CT genes in stem cell maintenance related pathways were up‐regulated. Further survival analysis provided evidence that CT genes could also predict the prognosis of TGCT patients with both disease‐free interval and progression‐free interval as clinical endpoints. Taken together, our study provided a global view of CT genes in TGCT and provided evidence that CT genes played important roles in the progression and maintenance of TGCT. [ABSTRACT FROM AUTHOR]

Background: Accompanied by HBV infection, HBV mutations gradually occur because HBV polymerase appears proofread deficiencies. In our previous study, we have identified that EnhII/BCP/PC mutations and genotype C of HBV DNA were associated with hepatocellular carcinoma (HCC) risk. In this study, we extend our research to explore HCC prognosis associated genotype and mutations in EnhII/BCP/PC regions. Methods: We designed a case‐cohort study of 331 HCC patients to evaluate the effects of the HBV genotypes and mutations on HCC survival. Log‐rank test and Cox proportional hazard models were used for the analyses. Results: Results showed that genotype C, which was more frequent in HBV‐related HCC (77.4%), presented a negative signal with HCC survival. Interestingly, we detected a significant association between EnhII/BCP/PC mutation nt1753 and HCC prognosis (Log‐rank P = 0.034). Subgroup analysis revealed that this risk effect was more pronounced in non‐B genotype (P = 0.090 for heterogeneity test). We also detected a borderline multiplicative interaction between genotypes of nt1753 and HBV genotype on HCC survival (P for interaction = 0.069). Conclusions: These findings indicated that, in Chinese population, nt1753 in EnhII/BCP/PC region might be a novel marker for HCC prognosis. [ABSTRACT FROM AUTHOR]

Our previous work demonstrated cancer‐testis (CT) genes as a new source of candidate driver of cancer. Recently, mounting evidence indicates that long noncoding RNAs (lncRNAs) with CT expression pattern could play a pivotal role in cancer biology. Here, we characterized a conserved CT long noncoding RNA (CT‐lncRNA), PCAT6, which is expressed exclusively in the testis and is reactivated in liver hepatocellular carcinoma (LIHC) tissues due to the highly frequent amplification. The expression in LIHC was correlated with clinical prognosis in TCGA data. Knockdown of PCAT6 could inhibit cell proliferation and migration in hepatocellular carcinoma (LIHC) cells. Gene set enrichment analysis (GSEA) based on coexpression network revealed that PCAT6 was involved in similar cilium‐related pathways in the testis and LIHC tissues. However, PCAT6 was mainly positively correlated with gametogenesis‐related pathways in the testis but was coexpressed with mitotic cell cycle genes in LIHC. Together, our data demonstrated that CT‐lncRNA PCAT6 represents the similarity and difference between tumorigenesis and gametogenesis. The CT expression pattern and important role in LIHC oncogenesis make PCAT6 an ideal target for LIHC diagnosis and therapy. [ABSTRACT FROM AUTHOR]

Background: The association of ABO blood groups with gastric cancer risk was proposed decades ago, but the results have been inconsistent.Methods: We used two single nucleotide polymorphisms to determine ABO genotype in 4932 gastric cancer cases and 6158 controls of Chinese descent, and evaluated the associations of ABO blood groups and genotypes with risk of gastric cancer using multivariable logistic regression models. We also systematically reviewed published literature and performed a meta-analysis of all relevant studies.Results: In the case-control study, compared with blood group O, both blood group A and AB were associated with increased gastric cancer risk (for group A, odds ratio (OR) = 1.13, 95% confidence interval (CI): 1.02-1.24; for group AB, OR = 1.18, 95% CI: 1.02-1.36, respectively). Analyses of ABO genotypes revealed associations of AO and AB with risk of gastric cancer compared with OO genotype. Consistent with the case-control study, meta-analysis of 40 studies including 33,613 cases and 2,431,327 controls demonstrated that blood group A (OR = 1.19, 95% CI: 1.13-1.25) and AB (OR = 1.09, 95% CI: 1.03-1.16) were associated with increased risk of gastric cancer.Conclusions: Our analyses validated the association of blood group A with risk of gastric cancer, and suggested that blood group AB was also associated with gastric cancer risk. Functional investigations are warranted to elucidate the exact mechanism of ABO blood groups in gastric carcinogenesis. [ABSTRACT FROM AUTHOR]

Circulating tumour cells (CTCs) draw significant attention as a promising biomarker for cancer prognosis, status monitoring, and metastasis diagnosis. However, the concentration of CTCs in peripheral blood is usually extremely low, thereby requiring enrichment followed by isolation of CTCs prior to detection. An immunomagnetic separation is a promising tool for CTCs enrichment. In this study, a cost‐effective magnetic separation method, based on streptavidin–biotin complexation, was developed and the effects of magnetic beads' size in CTCs capture were compared. Magnetic nanobeads which were 25 nm in diameter lead to highest capture efficiency (82.2%) compared with 150 nm magnetic beads and 1 µm microbeads. Based on the streptavidin–biotin system, 25 nm magnetic nanobeads could capture model CTCs over 80% efficiency even at concentrations as low as ∼25 cells/mL that may represent the actual level of CTCs in peripheral blood of cancer patients. Furthermore, the isolated cells remained robust and healthy showing insignificant changes in morphology and behaviour when cultured for 24 h immediately after capture and isolation. The magnetic nanobeads based on streptavidin–biotin complexation showed promise for the easy and efficient capture and isolation of healthy CTCs for further diagnosis and analysis. [ABSTRACT FROM AUTHOR]

Even though genome-wide association studies (GWASs) have identified dozens of single nucleotide polymorphisms (SNPs) affecting the susceptibility to lung cancer, only a tiny fraction of heritability can be explained. Regulating the expression of surrounding genes is one of the important mechanisms for SNPs to exert their effect. So it is necessary to systematically evaluate the associations between expression quantitative trait loci (eQTL) and lung cancer risk. In this study, a two-stage case–control design was used to evaluate the associations of eQTL SNPs (eSNPs) defined by GTEx in normal lung tissues with the risk of lung cancer based on two GWAS datasets, including 7127 cases and 6818 controls. Promising variants were replicated in an independent population with 1026 lung cancer cases and 1006 controls. Functional annotations of the identified eSNPs and related genes were performed based on multiple public databases. Finally, we identified two potential eSNPs associated with the risk of lung cancer in 3q28 [rs505974, OR = 0.90 (0.86 – 0.94), P = 6.51 × 10−6] and 21q22.3 [rs79589812, OR = 1.38 (1.21 – 1.58), P = 2.46 × 10−6]. Subgroup analysis showed rs505974 might interact with smoking behaviour. Gene-set enrichment and pathway analysis revealed that rs505974 may affect the susceptibility to lung cancer via regulating the expression of CLDN16, which may be involved in the chemical carcinogenesis pathway, whereas rs79589812 may regulate the expression of SPATC1L, which may be involved in the base excision repair pathway. These results provide an overview of the associations between eSNPs and lung cancer in Asian populations. [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]

Background. Interleukin 1 receptor associated kinases (IRAKs) play a central role in TLR signaling pathway. Scarce literature has investigated the association of potential functional genetic variants of IRAKs with Hepatitis B Virus- (HBV-) related hepatocellular carcinoma (HCC). Methods. A case-control study with 1,538 HBV-positive HCC patients and 1,465 chronic HBV carriers was conducted to evaluate the effects of common missense variants of IRAK family members on HCC. Proliferation assays and real-time polymerase chain reactions were carried out to evaluate the functions. Multivariable adjusted logistic regression was adopted to estimate effect size and identify risk factors. Results. Association analysis indicated that rs4251545 A allele of IRAK4 (p.Ala428Thr) was positively associated with HBV-related HCC risk (OR = 1.30, 95% CI: 1.09–1.54, P=0.003). Functional annotation indicated that rs4251545 reduced its own expression in liver (P=0.031). Further molecular functional analysis detected that rs4251545 increased the proliferation rate of L02 cells (P<0.05). Meanwhile, rs4251545 reduced mRNA expressions of IL-6, IL-8, CXCL-1, and CXCL-2 in L02 cells (P<0.01). Conclusion. rs4251545 of IRAK4 (p.Ala428Thr) modified the susceptibility to HBV-related HCC via increased proliferation rate and reduced production of inflammatory cytokines and chemokines. Further well-designed experiments are warranted to validate our findings. [ABSTRACT FROM AUTHOR]

Abstract: Emerging evidence indicates that circular RNAs (circRNAs) are implicated in cancer development. This study aimed to evaluate whether circulating circRNAs may serve as novel biomarkers for non‐small cell lung cancer (NSCLC). We used RNA sequencing (RNA‐seq) and quantitative real‐time PCR to explore cancer‐related circRNAs. Bioinformatics and functional analyses were performed to reveal biological effects of circRNAs on lung cancer cells. A total of 5471 distinct circRNAs were identified by total RNA‐seq, in which 185 were differentially expressed between cancerous and adjacent normal tissues. A circRNA derived from exon 5–7 of the FARSA gene, termed circFARSA, was observed to increase in cancerous tissues (P = 0.016), and was more abundant in patients’ plasma than controls (P < 0.001). Overexpression of circFARSA in A549 cell line significantly promoted cell migration and invasion. In silico analysis suggested that circFARSA might sponge miR‐330‐5p and miR‐326, thereby relieving their inhibitory effects on oncogene fatty acid synthase. Summarily, this study revealed circRNA profile of NSCLC for the first time and provided the evidence of plasma circFARSA as a potential noninvasive biomarker for this malignancy. [ABSTRACT FROM AUTHOR]

Abstract: Mitochondria show the special role in cellular bioenergy and many essential physiological activities. Previous researches have suggested that variations of mitochondrial DNA copy number contribute to development of different types of carcinomas. However, the relationship of mtDNA copy number in peripheral blood leukocytes (PBLs) with the risk of head and neck squamous cell carcinoma (HNSCC) is still inconclusive. We investigated the association of mtDNA with HNSCC risk through a case–control study including 570 HNSCC cases and 597 cancer‐free controls. mtDNA copy number in PBLs was measured by real‐time qPCR. Logistic regression was performed to estimate the association between the mtDNA copy number in PBLs and HNSCC risk. A U‐shaped relation between the mtDNA copy number and HNSCC risk was found. Compared with those in the second quartile group, the adjusted odds ratios (ORs) and 95% confidence interval (CI) for those in the first and the forth quartile groups were 1.95 (1.37–2.76) and 2.16 (1.53–3.04), respectively. Using restricted cubic spline analysis, we confirmed such a significant U‐shaped relation. Furthermore, the U‐shaped association remained significant in different subgroups stratified by age, gender, tobacco smoking, and alcohol consumption. Both extremely low and high mtDNA copy numbers had significant associations with the increased HNSCC risk. [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]

Recent studies have found that cancer-testis (CT) genes, which are expressed predominantly in germ and cancer cells, may be candidate cancer drivers. Because of their crucial roles, genetic variants in these genes may contribute to the development of cancer. Here, we systematically evaluated associations of common variants in CT genes and their promoters for the risk of lung cancer in our initial GWAS (2331 cases and 3077 controls), followed by in silico replication using additional 10,512 lung cancer cases and 9562 controls. We found a significant association between rs3747093 located in the CCDC116 promoter and lung cancer risk (OR = 0.91, P = 7.81 × 10). Although CCDC116 was expressed at lower levels in somatic tissues compared to the testis, the protective allele A of rs3747093 was associated with decreased CCDC116 expression in many normal tissues, including the lung ( P = 8.1 × 10). We subsequently genotyped this variant in another four commonly diagnosed cancers (gastric, esophageal, colorectal, and breast cancers), as we found expression quantitative trait locus (eQTL) signals for rs3747093 and CCDC116 in their corresponding normal tissues. Interestingly, we observed consistent associations between rs3747093 and multiple cancers (gastric cancer: OR = 0.85, P = 2.21 × 10; esophageal cancer: OR = 0.91, P = 2.57 × 10; colorectal cancer: OR = 0.80, P = 1.85 × 10; and breast cancer: OR = 0.87, P = 1.55 × 10). Taken together, the A allele of rs3747093 showed significant protective effects on cancer risk (OR = 0.88, P = 6.52 × 10) in an Asian population. Moreover, our findings suggest that low abundance expression of CT genes in normal tissues may also contribute to tumorigenesis, providing a new mechanism of CT genes in the development of cancer. [ABSTRACT FROM AUTHOR]

Variants in microRNA genes may affect their expression by interfering with the microRNA maturation process and may substantially contribute to the risk of breast cancer. Recent studies have identified miR-10b as an interesting candidate because of its close association with the metastatic behavior of breast cancer. However, the roles of miR-10b-related single nucleotide polymorphisms in breast cancer susceptibility remain unclear. This case-control study evaluated the associations between variants in the upstream transcription regulation region of miR-10b and the risk of breast cancer among Chinese women. Seven potentially functional SNPs were investigated using genotyping assays. The potential biological functions of the identified positive SNPs were further evaluated using in silico databases. We found that rs4078756, which was located at the promoter region of miR-10b, was significantly associated with breast cancer risk (rs4078756 AG/GG versus AA, adjusted odds ratio: 1.17, 95% confidence interval: 1.02–1.35). The other six single nucleotide polymorphisms exhibited negative associations. Based on the in silico prediction, rs4078756 potentially regulated miR-10b expression through promoter activation or repression. These findings indicate that a potentially functional SNP (rs4078756) in the promoter region of miR-10b may contribute to breast cancer susceptibility among Chinese women. [ABSTRACT FROM AUTHOR]