Influence of nutritional supplements on antibody levels in pregnant women vaccinated with inactivated SARS-CoV-2 vaccines.

BACKGROUND: Because of the significantly higher demand for nutrients during pregnancy, pregnant women are more likely to have nutrient deficiencies, which may adversely affect maternal and fetal health. The influence of nutritional supplements on the immune effects of inactivated SARS-CoV-2 vaccines during pregnancy is not clear. METHODS: In a multicenter cross-sectional study, we enrolled 873 pregnant women aged 18-45 y in Guangdong, China. The general demographic characteristics of pregnant women and their use of nutritional supplements were investigated, and the serum antibody levels induced by inactivated SARS-CoV-2 vaccines were measured. A logistic regression model was used to analyze the association between nutritional supplements and SARS-CoV-2 antibody levels. RESULTS: Of the 873 pregnant women enrolled, 825 (94.5%) took folic acid during pregnancy, 165 (18.9%) took iron supplements, and 197 (22.6%) took DHA. All pregnant women received at least one dose of inactivated SARS-CoV-2 vaccine, and the positive rates of serum SARS-CoV-2 neutralizing antibodies (NAbs) and immunoglobulin G (IgG) antibodies were 44.7% and 46.4%, respectively. After adjustment for confounding factors, whether pregnant women took folic acid, iron supplements, or DHA did not influence NAb positivity or IgG positivity (P > 0.05). Compared with pregnant women who did not take folic acid, the odds ratios (ORs) for the presence of SARS-CoV-2 NAb and IgG antibody in pregnant women who took folic acid were 0.67 (P = 0.255; 95% CI, 0.34-1.32) and 1.24 (P = 0.547; 95% CI, 0.60-2.55), respectively. Compared with pregnant women who did not take iron supplements, the ORs for the presence of NAb and IgG antibody in pregnant women who took iron supplements were 1.16(P = 0.465; 95% CI, 0.77-1.76) and 0.98 (P = 0.931; 95% CI, 0.64-1.49), respectively. Similarly, the ORs for NAb and IgG antibody were 0.71 (P = 0.085; 95% CI, 0.49-1.04) and 0.95 (P = 0.801; 95% CI, 0.65-1.38) in pregnant women who took DHA compared with those who did not. CONCLUSIONS: Nutritional supplementation with folic acid, iron, or DHA during pregnancy was not associated with antibody levels in pregnant women who received inactivated SARS-CoV-2 vaccines.

Immune response and safety of inactivated SARS-CoV-2 vaccines during pregnancy: a real-world observational study.

BACKGROUND: As pregnant women are excluded from clinical trials of inactivated SARS-CoV-2 vaccines, it is important to assess the immune response in women receiving the vaccination while unknowingly pregnant. METHODS: In a multicenter cross-sectional study, we enrolled 873 pregnant women aged 18-45 years. Serum antibody levels induced by inactivated vaccines were determined. Adverse events were collected by self-reported survey after vaccination. Logistic regression model and restricted cubic spline model were used to investigate the association of factors with antibody positivity. RESULTS: As the doses of the vaccine increase, neutralizing antibody (NAb) positivity was 98.3%, 39.5%, and 9.5% in pregnant women, respectively. The dose of vaccine and duration since vaccination were associated with NAb positivity. The OR of two and three doses of vaccines were 7.20 and 458.33 (P < 0.05). NAb levels and duration since vaccination showed a linear relationship in pregnant women vaccinated two doses, with a decrease to a near seropositivity threshold at 22 weeks. Adverse events were mainly mild or moderate after vaccinated during pregnancy, with no increase in incidence compared with whom vaccinated during pre-pregnancy. CONCLUSIONS: The use of inactivated vaccines during pregnancy induced favorable immune persistence, and the incidence of adverse events did not increase.

Variations of bile bacterial community alongside gallstone disease progression and key taxa involved in poor outcomes after endoscopic surgery.

Gallstone disease is a prevalent biliary disease worldwide, and bacteria play vital roles in the disease development and progression, as well as the prognosis after endoscopic surgery. However, there have been limited studies to explore the key taxa involved. In this study, bile samples from healthy controls (HCs, liver donors without hepatobiliary disease) and three diseased groups, namely patients with gallbladder stones (GBS), patients with common bile duct stones (CBDS), and patients with stricture in the common bile duct (SCBD), were collected and analyzed. Bacterial community characterization based on 16S rRNA amplicon sequencing showed that bacterial diversities did not change significantly alongside gallstone disease development and progression. The predominant phyla in each group were Proteobacteria, Firmicutes, Bacteroidota, and Fusobacteriota, representing over 80% in abundance of the biliary bacteria community. Specifically, the abundance of Proteobacteria decreased greatly while that of Firmicutes and Bacteroidota increased greatly in the diseased groups when compared to that in HCs. Moreover, linear discriminant analysis identified several genera highly represented in the diseased groups. Among them, Klebsiella, Prevotella, Pseudomonas and Veillonella are persistent in both the HCs group and the diseased groups, indicating an enrichment of local bile bacteria in the diseased bile; while Lachnoanerobaculum, Atopobium, Oribacterium, and Stomatobaculum, those aligned to oral cavity taxa, are persistent in the diseased groups but are transient in the HCs group, and their abundances sequentially increased with the disease development and progression (HCs→GBS→CBDS→SCBD), implying a translocation and colonization of the oral cavity bacteria in the diseased bile. Moreover, co-occurrence network analysis revealed that bacterial infection (e.g., Photobacterium and Plesiomonas) from the intestine was developed during endoscopic surgery with reduced bile bacteria diversity. The results of this study revealed that the bile bacterial community is relatively stable and dominated by a few persistent taxa. Moreover, we hypothesized that translocation and colonization of specific bacteria from the oral cavity happens alongside gallstone disease development and progression, and bacterial infection from the intestinal tract results in poor outcomes after endoscopic surgery.

Novel prognostic nomograms in cervical cancer based on analysis of 1075 patients.

OBJECTIVE: To explore the factors affecting the prognosis of cervical cancer (CC), and to construct and evaluate predictive nomograms to guide individualized clinical treatment. METHODS: The clinicopathological and follow-up data of CC patients from June 2013 to December 2019 in Sun Yat-sen Memorial Hospital of Sun Yat-sen University were retrospectively analyzed. Log-rank test was used for univariate survival analysis, and Cox multivariate regression was used to identify independent prognostic factors, based on which nomogram models were established and evaluated in multiple aspects. RESULTS: Patients were randomly assigned into the training (n = 746) and validation sets (n = 329). Survival analysis of the training set identified cervical myometrial invasion, parametrial involvement, and malignant tumor history as prognosticators of postoperative DFS and pathological type, cervical myometrial invasion, and history of STD for OS. C-index was 0.799 and 0.839 for the nomograms for DFS and OS, respectively. Calibration curves and Brier scores also indicated high performance. Importantly, decision curve analysis suggested great clinical applicability of these nomograms. CONCLUSIONS: In this study, we analyzed a cohort of 1075 CC patients and identified DFS- or OS-associated clinicohistologic characteristics. Two nomograms were subsequently constructed for DFS and OS prognostication, respectively, and showed high performance in terms of discrimination, calibration, and clinical applicability. These models may facilitate individualized treatment and patient selection for clinical trials. Future investigations with larger cohorts and prospective designs are warranted for validating these prognostic models.

Drought Assessment Based on Data Fusion and Deep Learning.

Drought is a major factor affecting the sustainable development of society and the economy. Research on drought assessment is of great significance for formulating drought emergency policies and drought risk early warning and enhancing the ability to withstand drought risks. Taking the Yellow River Basin as the object, this paper utilizes data fusion, copula function, entropy theory, and deep learning, fuses the features of meteorological drought and hydrological drought into a drought assessment index, and establishes a long short-term memory (LSTM) network for drought assessment, based on deep learning theory. The results show that (1) after extracting the features of meteorological drought and hydrological drought, the drought convergence index (DCI) built on the fused features by copula function can accurately reflect the start and duration of the drought; (2) the drought assessment indices were effectively screened by judging the causality of the drought system, using the transfer entropy; (3) drawing on the idea of deep learning, LSTM for drought assessment, which was established on DCI and the drought assessment factors, can accurately assess the drought risks of the Yellow River Basin.

Long-term corneal recovery by simultaneous delivery of hPSC-derived corneal endothelial precursors and nicotinamide.

Human pluripotent stem cells (hPSCs) hold great promise for the treatment of various human diseases. However, their therapeutic benefits and mechanisms for treating corneal endothelial dysfunction remain undefined. Here, we developed a therapeutic regimen consisting of the combination of hPSC-derived corneal endothelial precursors (CEPs) with nicotinamide (NAM) for effective treatment of corneal endothelial dysfunction. In rabbit and nonhuman primate models, intracameral injection of CEPs and NAM achieved long-term recovery of corneal clarity and thickness, similar with the therapeutic outcome of cultured human corneal endothelial cells (CECs). The transplanted human CEPs exhibited structural and functional integration with host resident CECs. However, the long-term recovery relied on the stimulation of endogenous endothelial regeneration in rabbits, but predominantly on the replacing function of transplanted cells during the 3-year follow-up in nonhuman primates, which resemble human corneal endothelium with limited regenerative capacity. Mechanistically, NAM ensured in vivo proper maturation of transplanted CEPs into functional CECs by preventing premature senescence and endothelial-mesenchymal transition within the TGF-ß-enriched aqueous humor. Together, we provide compelling experimental evidence and mechanistic insights of simultaneous delivery of CEPs and NAM as a potential approach for treating corneal endothelial dysfunction.

Poly(ADP-ribose) polymerase inhibitor PJ34 protects against UVA-induced oxidative damage in corneal endothelium.

Fuchs endothelial corneal dystrophy (FECD) is one of the main causes for corneal endothelial blindness, which is characterized by the progressive decline of corneal endothelial cells. Poly (ADP-ribose) polymerase (PARP) was reported to be involved in cell death and apoptosis of several diseases. However, the role of PARP1 in the progression of FECD remains elusive. In the present study, we reported that UVA irradiation caused the corneal endothelial damage and corneal edema in mice, which was accompanied with the elevated activity of PARP1 and PAR. The PARP1 inhibitor PJ34 resolved the corneal edema and protected corneal endothelium from UVA-induced oxidative damage, mitochondrial dysfunction, and cell apoptosis. Mechanistically, PARP1 inhibition exerted its anti-apoptotic effects through downregulation of the phosphorylation levels of JNK1/2 and p38 MAPK and subsequently the increase of MKP-1. Our results suggest that PARP1 inhibition protects corneal endothelium from UVA-induced oxidative damage, which provides a potential alternative strategy for the therapy of FECD.

Transplantation of human induced pluripotent stem cell-derived neural crest cells for corneal endothelial regeneration.

BACKGROUND: The corneal endothelium maintains corneal hydration through the barrier and pump function, while its dysfunction may cause corneal edema and vision reduction. Considering its development from neural crest cells (NCCs), here we investigated the efficacy of the human induced pluripotent stem cell (hiPSC)-derived NCCs for corneal endothelial regeneration in rabbits. METHODS: Directed differentiation of hiPSC-derived NCCs was achieved using the chemically defined medium containing GSK-3 inhibitor and TGF-ß inhibitor. The differentiated cells were characterized by immunofluorescence staining, FACS analysis, and in vitro multi-lineage differentiation capacity. For in vivo functional evaluation, 1.0 × 106 hiPSC-derived NCCs or NIH-3 T3 fibroblasts (as control) combined with 100 µM Y-27632 were intracamerally injected into the anterior chamber of rabbits following removal of corneal endothelium. Rabbit corneal thickness and phenotype changes of the transplanted cells were examined at 7 and 14 days with handy pachymeter, dual-immunofluorescence staining, and quantitative RT-PCR. RESULTS: The hiPSC-derived NCCs were differentiated homogenously through 7 days of induction and exhibited multi-lineage differentiation capacity into peripheral neurons, mesenchymal stem cells, and corneal keratocytes. After 7 days of intracameral injection in rabbit, the hiPSC-derived NCCs led to a gradual recovery of normal corneal thickness and clarity, when comparing to control rabbit with fibroblasts injection. However, the recovery efficacy after 14 days deteriorated and caused the reappearance of corneal edema. Mechanistically, the transplanted cells exhibited the impaired maturation, cellular senescence, and endothelial-mesenchymal transition (EnMT) after the early stage of the in vivo directional differentiation. CONCLUSIONS: Transplantation of the hiPSC-derived NCCs rapidly restored rabbit corneal thickness and clarity. However, the long-term recovery efficacy was impaired by the improper maturation, senescence, and EnMT of the transplanted cells.

Multiple roles of FGF10 in the regulation of corneal endothelial wound healing.

Corneal endothelial dysfunction usually induces corneal haze and oedema, which seriously affect visual function. The main therapeutic strategy for this condition is corneal transplantation, but the use of this strategy is limited by the shortage of healthy donor corneas. Compared with corneal transplantation, drug intervention is less invasive and more accessible; thus, finding an effective pharmaceutical alternative for cornea transplantation is critical for the treatment of corneal endothelial dysfunction. In this study, we established a rabbit scratch model to investigate the effect of fibroblast growth factor 10 (FGF10) on corneal endothelial wound healing. Results showed that FGF10 injection accelerated the recovery of corneal transparency and increased the protein expression levels of ZO1, Na+/K+-ATPase and AQP-1. Moreover, FGF10 significantly inhibited the expression levels of endothelial-to-mesenchymal transition proteins and reduced the expression levels of the proinflammatory factors IL-1ß and TNF-α in the anterior chamber aqueous humour. FGF10 also enhanced the Na+/K+-ATPase activity by enhancing mitochondrial function as a result of its direct interaction with its conjugate receptor. Thus, FGF10 could be a new pharmaceutical preparation as treatment for corneal endothelial dysfunction.

LncRNA TINCR favors tumorigenesis via STAT3-TINCR-EGFR-feedback loop by recruiting DNMT1 and acting as a competing endogenous RNA in human breast cancer.

The long noncoding RNA (lncRNA) TINCR has recently been found to be associated with the progression of human malignancies, but the molecular mechanism of TINCR action remains elusive, particularly in breast cancer. The oncogenic role of TINCR was examined in vitro and in vivo in breast cancer. Next, the interaction between TINCR, DNMT1, and miR-503-5p methylation was explored. Moreover, the mechanism by which TINCR enhances EGFR expression and downstream signaling via an RNA-RNA interaction was comprehensively investigated. Furthermore, upstream transcriptional regulation of TINCR expression by STAT3 was examined by performing chromatin immunoprecipitation. Finally, feedback signaling in the STAT3-TINCR-EGFR downstream cascade was also investigated. TINCR is upregulated in human breast cancer tissues, and TINCR knockdown suppresses tumorigenesis in vitro and in vivo. Mechanistically, TINCR recruits DNMT1 to the miR-503-5p locus promoter, which increases the methylation and suppresses the transcriptional expression of miR-503-5p. Furthermore, TINCR also functions as a competing endogenous RNA to upregulate EGFR expression by sponging miR-503-5p. In addition, TINCR stimulates JAK2-STAT3 signaling downstream from EGFR, and STAT3 reciprocally enhances the transcriptional expression of TINCR. Our findings broaden the current understanding of the diverse manners in which TINCR functions in cancer biology. The newly identified STAT3-TINCR-EGFR-feedback loop could serve as a potential therapeutic target for human cancer.

ABTB2 Regulatory Variant as Predictor of Epirubicin-Based Neoadjuvant Chemotherapy in Luminal A Breast Cancer.

Background: Epirubicin combined with docetaxel is the cornerstone of neoadjuvant chemotherapy (NAC) for breast cancer. The efficacy of NAC for luminal A breast cancer patients is very limited, and single nucleotide polymorphism is one of the most important factors that influences the efficacy. Our study is aimed to explore genetic markers for the efficacy of epirubicin combined with docetaxel for NAC in patients with luminal A breast cancer. Methods: A total of 421 patients with two stages of luminal A breast cancer were enrolled in this study from 2 centers. Among them 231 patients were included in the discovery cohort and 190 patients are in the replication cohort. All patients received epirubicin 75 mg/m2 and docetaxel 75 mg/m2 on day 1, in a 21-day cycle, a cycle for 2-6 cycles. Before treatment, 2 ml of peripheral blood was collected from each patient to isolate genomic DNA. Fourteen functional variants potentially regulating epirubicin/docetaxel response genes were prioritized by CellMiner and bioinformatics approaches. Moreover, biological assays were performed to determine the effect of genetic variations on response to chemotherapy. Results: The patients carrying rs6484711 variant A allele suffered a poor response to epirubicin and docetaxel for NAC (OR = 0.37, 95% CI: 0.18-0.74, P = 0.005) in combined stage. Moreover, expression quantitative trait loci (eQTL) analyses and luciferase reporter assays revealed that rs6484711 A allele significantly increased the expression of ABTB2. Subsequent biological assays illustrated that upregulation of ABTB2 significantly reduced the apoptosis rate of breast cancer cells and enhanced the chemo-resistance to epirubicin. Conclusions: Our study demonstrated rs6484711 polymorphism regulating ABTB2 expression might predict efficacy to epirubicin based NAC in luminal A breast cancer patients. These results provided valuable information about potential role of genetic variations in individualized chemotherapy.

Nonreceptor protein tyrosine phosphatases (NRPTPs) gene family associates with the risk of hepatocellular carcinoma in a Chinese hepatitis B virus-related subjects.

Nonreceptor protein tyrosine phosphatases (NRPTPs) are reported to be associated with several human cancers, but their roles in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remain unclear. Here, we integrated bioinformatics tools, population association analyses, and biological assays to systematically screen for potentially functional single nucleotide polymorphisms (SNPs) within the 17 NRPTPs genes and evaluate the effects of candidate SNPs on the risk of HCC or persistent HBV infection. A total of 790 HBV-related HCC cases and 1454 cancer-free controls were enrolled. Controls included 711 HBV persistent carriers and 743 spontaneously recovered subjects. Results demonstrated that PTPN4 rs9308777 (odds ratio [OR] = 1.25, 95% confidence interval [CI] = 1.06-1.49, P = .009) and PTPN12 rs350050 (OR = 1.26, 95% CI = 1.10-1.45, P = .001), were significantly associated with HCC risk, but not with persistent HBV infection risk. The cumulative risk effect of these two SNPs was more significantly increased the susceptibility to HCC (OR = 1.27, 95% CI = 1.14-1.41, P = 2.40 × 10-5 ). Subsequent biological assays further revealed the potential pathogenesis that PTPN4 rs9308777 might decrease the gene expression, and PTPN12 rs3750050 might promote cell proliferation by attenuating PTPN12's inhibitory activity on EGFR/ERK pathway. In summary, our integrative study highlights that PTPN4 and PTPN12 are significantly associated with HBV-related HCC risk, but do not influence persistent HBV infection. These findings shed light on the importance of the synergistic effects of regulatory and missense variants on the risk for HCC, and provide data to support personalized cancer medicine in the future.

Laminin 511 Precoating Promotes the Functional Recovery of Transplanted Corneal Endothelial Cells.

Corneal endothelial dysfunction is a major cause of corneal blindness and is mainly treated by corneal transplantation. However, the global shortage of donor cornea hampers its application. Intracameral injection of cultured primary corneal endothelial cells (CECs) was recently confirmed in clinical trials. However, abnormal adhesion of the grafted CECs affects the application of this strategy. In this study, we explored if laminin 511 (LN511) improves the therapeutic function of the intracameral CEC injection for corneal endothelial dysfunction. To mimic the late stage of corneal endothelial diseases, intense scraping was developed to remove CECs and extracellular matrix of the posterior Descemet's membrane (DM) without DM removal in rabbits. Then, Dulbecco's phosphate-buffered saline (DPBS) and LN511 were intracamerally injected as the control and intervention groups, respectively. We found that the injected LN511 could settle and form a coating on the posterior surface of DM. After CEC transplantation, corneal clarity of rabbits in the LN511 group was rapidly recovered within 7 days, whereas the corneal recovery took 14 days in the DPBS group. Corneal thickness of LN511 group decreased to 413.3 ± 20.8 µm 7 days after operation, which was significantly lower than 1086.3 ± 78.6 µm of DPBS group (p < 0.01). Moreover, for the grafted CECs, LN511 promoted the rapid adhesion, tight junction formation, and expression of Na+/K+-ATPase and ZO-1. In vitro analysis revealed that the functions of LN511 on the cultured human CECs mechanistically depended on the cell density and the nuclear-cytoplasmic translocation of the Yes-associated protein. Our study demonstrated that LN511 precoating promoted the adhesion of the transplanted CECs and enhanced the functional regeneration of the corneal endothelium. Thus, our data suggested that the strategy of LN511 precoating and CECs' intracameral injection could be a potential method for the therapy of corneal endothelial dysfunction. Impact statement Intracameral injection of cultured corneal endothelial cells (CECs) is a potential alternative therapy for corneal endothelial dysfunction and has been proven to be effective in clinical trials. However, abnormal adhesion of the grafted CECs affects its application. In this study, intense scraping was developed to remove CECs and extracellular matrix of the posterior Descemet's membrane (DM) without DM removal for the therapy of late stage of corneal endothelial diseases. Laminin 511 was intracamerally injected to form a coating, improve the posterior DM, enhance the adhesion of the grafted CECs, and promote the functional regeneration of CEC transplantation through Yes-associated protein signaling.

Incidence of and risk factors for surgical site infection after colorectal surgery: A multiple-center prospective study of 3,663 consecutive patients in China.

BACKGROUND: Surgical site infection (SSI) after colorectal surgery (CRS) remains a significant problem for its negative clinical outcomes. However, it is poorly understood in China. This study aims to investigate the incidence, risk factors and microbiology of SSI after CRS. METHODS: A nationwide prospective multicenter design was applied. Patients in 19 Chinese hospitals from 2015 to 2018 were prospectively monitored for SSI after CRS. Demographic data, hospital characteristics, and potential perioperative risk factors were collected and analyzed, using univariate and multivariate logistic regression models. RESULTS: Among 3,663 study participants, 134(3.66%) episodes of SSI were identified. The incidence rate of SSI decreased from 5.9 infections per 100 procedures in 2015 to 3.1 infections per 100 procedures in 2018 (incidence rate ratio, 0.52; 95% CI, 0.28-0.94). The SSI rates were 1.88, 4.15, 6.27 and 11.58 per 100 operations for the National Nosocomial Infections Surveillance system (NNIS) risk index categories of 0, 1, and 2 or 3, respectively. Escherichia coli (54/134, 40.3%) and Klebsiella pneumoniae (10/134, 7.5%) were the most frequently isolated microorganisms. A high prevalence of antibiotic resistance were observed in our study, with rates of extended spectrum beta-lactamase-producing or carbapenem-resistant Escherichia coli and Klebsiella pneumonia of 50.0%(27/54) and 30.0%(3/10) respectively. Preoperative hospital stay ≥ 48h (OR=2.28, 95% CI: 1.03-5.02, P=0.042) and contaminated or dirty wound (OR=3.38, 95% CI: 1.88-6.06, P=4.50×10-5) were significantly associated with increasing risk of SSI after CRS. CONCLUSION: A statistically significant but modest decrease in the incidence rate of CRS SSI over the 4-year study period was observed in this study. Noticeably, the relatively high rates of multidrug-resistant pathogens causing SSI after CRS should be alert, while more studies with large population are needed due to the small number of isolates identified in our survey.

CDC25B is associated with the risk of hepatocellular carcinoma, but not related to persistent infection of hepatitis B virus in a Chinese population.

The cell division cycle 25 (CDC25) gene members, including CDC25A, CDC25B and CDC25C, are reported to be associated with several human cancers. Here, we aim to investigate the association of functional polymorphisms of CDC25 gene family with the risk of hepatocellular carcinoma (HCC) and persistent infection of Hepatitis B virus (HBV) in a Chinese HBV-related population. First, we used bioinformatics tools to systematically screen functional polymorphisms within CDC25 gene family. Second, we evaluated the effects of candidate polymorphisms by recruiting 790 HCC cases, 709 persistent HBV carriers (PHC), and 741 subjects with HBV natural clearance (SHNC). MassARRAY platform was used for genotyping. At last, we conducted functional prediction and assay to further explore the pathogenic mechanism of the identified polymorphism. Our results demonstrated that CDC25B rs2295348 played a protective role in HCC risk in a HBV-related Chinese population (adjusted odds ratio [OR] = 0.77, 95% confidence interval [CI] 0.65-0.93, P = 0.006). It showed a more significantly reduced HCC risk in the SHNC population (adjusted OR = 0.73, 95% CI 0.59-0.89, P = 0.002). However, we did not observe the association between CDC25B rs2295348 and the risk of persistent HBV infection. Further functional prediction and assay demonstrated that the mutant A allele of CDC25B rs2295348 might significantly decrease gene expression to modify the HCC risk. Our results suggest that CDC25B rs2295348 may confer a protective effect on HCC risk in a HBV-related Chinese population, but do not influence the susceptibility to persistent HBV infection.

PNPLA3 rs738409 is not associated with the risk of hepatocellular carcinoma and persistent infection of hepatitis B virus (HBV) in HBV-related subjects: A case-control study and meta-analysis on Asians.

The association between rs738409 (C>G, I148M) with patatin-like phospholipase domain-containing 3 (PNPLA3) gene and the risk of hepatocellular carcinoma (HCC) was controversial in different ethnic populations. Our study aimed to explore the effect of PNPLA3 rs738409 on the risk of HCC and persistent infection of Hepatitis B virus (HBV) in a Chinese HBV-related population, and further evaluate its role in HCC risk among Asians. First, we performed a case-control study by recruiting 786 HBV-related HCC cases, 695 HBV persistent carriers and 719 HBV natural clearance subjects. PNPLA3 rs738409 was genotyped by MassARRAY platform. Second, we conducted a systematic review and meta-analysis on Asians to further validate our results. Our case-control study demonstrated that PNPLA3 rs738409 was not associated with HCC risk or persistent HBV infection (All P > 0.05). The subsequent meta-analysis included 13 Asian studies with 9,802 subjects. Results showed that PNPLA3 rs738409 might increase HCC risk among healthy subjects (pooled odds ratio [OR] = 1.47, 95% confidence interval [CI] = 1.11-1.95), but it had no influence on the development of HCC among HBV-related subjects (pooled OR = 1.07, 95%CI = 0.89-1.30). Our case-control study highlights that PNPLA3 rs738409 is probably not associated with the risk of HCC or persistent HBV infection in a Chinese HBV-related population. Besides, our systematic review and meta-analysis on Asians further suggest that PNPLA3 rs738409 may confer an increased risk of HCC among healthy people, but contribute little to the development of HCC among HBV-related subjects. Future studies are required to confirm these results.

A functional variant in TNXB promoter associates with the risk of esophageal squamous-cell carcinoma.

Our previous study identified a tag single-nucleotide polymorphism (SNP) rs204900 in TNXB associated with risk of esophageal squamous-cell carcinoma (ESCC) in the Chinese population. However, the functional role of TNXB and causal variants had not been interrogated in that study. In the present study, we explored the effects of TNXB expression in the development of ESCC and searched for functional variants in this gene. We found TNXB was downregulated in ESCC tumors. Using small interfering RNAs and CRISPR-Cas9 methods, we identified that both knockdown and knockout of TNXB significantly promoted ESCC cell growth in vitro, suggesting a tumor suppressor role of this gene in ESCC. Through further fine-mapping analysis, we identified that a noncoding variant in the promoter of TNXB, rs411337, predisposed to ESCC risk (odds ratio = 1.36, 95% confidence interval: 1.22-1.51, P = 9.10 × 10-9 ). These findings revealed the functional mechanism of TNXB in the development of ESCC and may contribute to the prevention and treatment of this disease in the future.

Genetic variants in m6A modification genes are associated with esophageal squamous-cell carcinoma in the Chinese population.

N 6-methyladenosine (m6A) is an abundant modification in RNAs that affects RNA metabolism, and it is reported to be closely related to cancer occurrence and metastasis. In this study, we focused on evaluating the associations between genetic variants in m6A modification genes and the risk of esophageal squamous-cell carcinoma (ESCC). By integrating data of our previous genome-wide association studies and the predictions of several annotation tools, we identified a single nucleotide polymorphism, rs2416282 in the promoter of YTHDC2, that was significantly associated with the susceptibility of ESCC (odds ratio = 0.84, 95% CI: 0.77-0.92, P = 2.81 × 10-4). Through further functional experiments in vitro, we demonstrated that rs2416282 regulated YTHDC2 expression. Knockdown of YTHDC2 substantially promoted the proliferation rate of ESCC cells by affecting several cancer-related signaling pathways. Our results suggested that rs2416282 contributed to ESCC risk by regulating YTHDC2 expression. This study provided us a valuable insight into the roles of genetic variants in m6A modification genes for ESCC susceptibility and may contribute to the prevention of this disease in the future.

Genetic Predisposition to Colon and Rectal Adenocarcinoma Is Mediated by a Super-enhancer Polymorphism Coactivating CD9 and PLEKHG6.

BACKGROUND: Genome-wide association studies (GWAS) have identified dozens of loci associated with colon and rectal adenocarcinoma risk. As tissue-specific super-enhancers (SE) play important roles in tumorigenesis, we systematically investigate SEs and inner variants in established GWAS loci to decipher the underlying biological mechanisms. METHODS: Through a comprehensive bioinformatics analysis on multi-omics data, we screen potential single-nucleotide polymorphisms (SNP) in cancer-specific SEs, and then subject them to a two-stage case-control study containing 4,929 cases and 7,083 controls from the Chinese population. A series of functional assays, including reporter gene assays, electrophoretic mobility shift assays (EMSA), CRISPR-Cas9 genome editing, chromosome conformation capture (3C) assays, and cell proliferation experiments, are performed to characterize the variant's molecular consequence and target genes. RESULTS: The SNP rs11064124 in 12p13.31 is found significantly associated with the risk of colon and rectal adenocarcinoma with an odds ratio (OR) of 0.87 [95% confidence interval (CI), 0.82-0.92, P = 8.67E-06]. The protective rs11064124-G weakens the binding affinity with vitamin D receptor (VDR) and increases the enhancer's activity and interactions with two target genes' promoters, thus coactivating the transcription of CD9 and PLEKHG6, which are both putative tumor suppressor genes for colon and rectal adenocarcinoma. CONCLUSIONS: Our integrative study highlights an SE polymorphism rs11064124 and two susceptibility genes CD9 and PLEKHG6 in 12p13.31 for colon and rectal adenocarcinoma. IMPACT: These findings suggest a novel insight for genetic pathogenesis of colon and rectal adenocarcinoma, involving transcriptional coactivation of diverse susceptibility genes via the SE element as a gene regulation hub.