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ABO blood groups has been associated with risk of several cancers; however, the results for an association with ovarian cancer are inconsistent and little is known about the expression of histo-blood group (ABH) antigens and ABO gene in ovarian tumor tissues.To assess the impact of genotype-derived ABO blood types on the risk of EOC, we conducted a case-control study in 1,870 EOC and 4,829 controls. Expression of A and B antigen in 70 pairs of ovarian tumor tissues and adjacent normal tissues were detected by immunohistochemistry. Gene expression and DNA methylation profiling was conducted in ovarian tumor tissues.We identified that blood group A was associated with increased risk for EOC compared to blood group O (OR = 1.18, 95% CI = 1.03-1.36, p = 0.019). Increased frequency of aberrant expression of histo-blood group antigens was observed in patients with blood group A (76.5%) compared to patients with blood group O (21.1%) and B (5.0%) by immunohistochemistry (p 0.001). ABO gene expression was down-regulated in ovarian tumor tissues compared with paired adjacent normal tissues (p = 0.027). In addition, ABO gene expression was positively correlated with NFYB (r = 0.38, p 0.001) and inversely correlated with DNA methylation level of four CpG sites on ABO gene (cg11879188, r = - 0.3, p = 0.002; cg22535403, r = - 0.30, p = 0.002; cg13506600, r = - 0.22, p = 0.025; cg07241568, r = - 0.21, p = 0.049) in ovarian tumor tissues.We identified blood group A was associated with increased EOC risk in Chinese women and provided the clues of the possible molecular mechanisms of blood group A related to ovarian cancer risk.

Background The association between tea consumption and ovarian cancer (OC) risk has been reported in several epidemiology studies. However, the results were inconsistent and the causal relationship remains unclear. To explore the causal relationship between tea consumption and OC risk, we performed a two-sample Mendelian randomization (MR) analysis. Methods MR analysis was conducted using two published genome wide association studies (GWASs) (25,509 cases and 40,941 controls of European population and 3,238 cases and 4,083 controls of East Asian population) and in house GWAS (2,147 OC cases and 3,179 controls of Chinese population) by inverse variance-weighted, weighted median, and MR-Egger methods. Genetic instruments of 233 single nucleotide polymorphisms (SNPs) for European population, 382 SNPs for East Asian population, and 172 SNPs for Chinese population were created. Results We identified that tea consumption has protective effect against overall OC in European population (OR = 0.95, 95%CI: 0.90–0.99, P = 2.65E-02) and Chinese population (OR = 0.96, 95%CI: 0.92-1.00, P = 3.63E-02). When stratified by histological subtype, we found that tea consumption was significantly associated with the risk of Serous OC in European (OR = 0.92, 95%CI: 0.88–0.98, P = 4.86E-03), East Asian (OR = 0.96, 95%CI: 0.92–0.99, P = 9.87E-03), and Chinese (OR = 0.94, 95%CI: 0.90–0.99, P = 1.69E-02) population. In European population, there was a reduced risk of ovarian tumors of low malignant potential (OR = 0.90, 95%CI: 0.81-1.00, P = 4.59E-02), but an increased risk of Endometrioid OC (OR = 1.14, 95%CI: 1.03–1.27, P = 1.12E-02). Conclusion Our study suggested that there might be a causal relationship between tea consumption and OC risk in both European and East Asian populations and also may provide the evidence for cancer prevention and control.

Objective: To develop and evaluate the screening performance of a low-cost high-risk screening strategy for breast cancer in low resource areas. Methods: Based on the Multi-modality Independent Screening Trial, 6 questionnaire-based risk factors of breast cancer (age at menarche, age at menopause, age at first live birth, oral contraceptive, obesity, family history of breast cancer) were used to determine the women with high risk of breast cancer. The screening performance of clinical breast examination (CBE), breast ultrasonography (BUS), and mammography (MAM) were calculated and compared to determine the optimal screening method for these high risk women. Results: A total of 94 breast cancers were detected among 31,720 asymptomatic Chinese women aged 45–65 years. Due to significantly higher detection rates (DRs) and suitable coverage of the population, high risk women were defined as those with any of 6 risk factors. Among high risk women, the DR for BUS [3.09/1,000 (33/10,694)] was similar to that for MAM [3.18/1,000 (34/10,696)], while it was significantly higher than that for the CBE [1.73/1,000 (19/10,959), P = 0.002]. Compared with MAM, BUS showed significantly higher specificity [98.64% (10,501/10,646) vs. 98.06% (10,443/10,650), P = 0.001], but no significant differences in sensitivity [68.75% (33/48) vs. 73.91% (34/46)], positive prediction values [18.54% (33/178) vs. 14.11% (34/241)], and negative prediction values [99.86% (10,501/10,516) vs. 99.89% (10,443/10,455)]. Further analyses showed no significant difference in the percentages of early stage breast cancer [53.57% (15/28) vs. 50.00% (15/30)], lymph node involvement [22.73% (5/22) vs. 28.00% (7/25)], and tumor size ≥ 2 cm [37.04% (10/27) vs. 29.03% (9/31)] between BUS and MAM. Subgroup analyses stratified by breast densities or age at enrollment showed similar results. Conclusions: The low-cost high-risk screening strategy based on 6 questionnaire-based risk factors was an easy-to-use method to identify women with high risk of breast cancer. Moreover, BUS and MAM had comparable screening performances among high risk women.

Background：The association of ABO blood groups with epithelial ovarian cancer (EOC) risk has been reported. However, the results are inconsistent and little is known about the alterations of histo-blood group antigens expression and ABO gene expression in ovarian tumor tissues. Methods：We used two single nucleotide polymorphisms in ABO gene (rs8176719 and rs8176746) to determine ABO blood group of 1,870 EOC cases and 4,829 controls. Expression of A and B antigen in 70 ovarian tumor tissues and adjacent normal tissues were detected by immunohistochemistry. Gene expression and DNA methylation profiling was detected in ovarian tumor tissues.Results：In this case-control study, blood group A was associated with increased risk for EOC compared with blood group O (OR = 1.18, 95 % CI = 1.03 – 1.36, P = 0.019), this association remained significant after multivariate adjustment (adjusted OR = 1.48, 95% CI= 1.11 – 1.96, P = 0.007). Patients with blood group A had higher rate of aberrant histo-blood group antigen expression compared to patients with blood group O and B (76.5% vs. 21.1%, 5.0%, PABO gene expression was down-regulated in ovarian tumor tissues compared with paired adjacent normal tissues (P = 0.027). NFYB was positively correlated with ABO gene expression (r = 0.38, PABO gene expression (cg11879188, r = - 0.3, P = 0.002; cg22535403, r = - 0.30, P = 0.002; cg13506600, r = - 0.22, P = 0.025; cg07241568, r = - 0.21, P = 0.049). Conclusions：We identified blood group A was associated with increased EOC risk in Chinese women and provided the clues of the possible molecular mechanisms of blood group A related to ovarian cancer risk. Functional studies are warrant to clarify the role of A antigen and ABO gene in ovarian cancer carcinogenesis.

Background: Risk prediction models integrating classical risk factors (CRF), mammographic density (MD), and polygenic risk score (PRS) are increasingly developed to identify high-risk groups of breast cancer. Few studies investigate the screening performance in high-risk groups by these models.Methods: Based on a median follow-up of 11.7 years of 7794 women from the Multi-modality Independent Screening Trial (MIST), four risk prediction models with CRF (ModelCRF), CRF and MD (ModelCRF+MD), CRF and PRS (ModelCRF+PRS), and all three components (ModelFULL) were developed to identify high-risk groups of breast cancer. The hazard ratio (HR) and 95% confidential interval (CI) of breast-cancer mortality for high-risk groups compared to low-risk groups was calculated to determine potential benefit of risk-reducing interventions. The detection rate (DR), accuracy and cancer-stage for clinical breast examination (CBE), breast ultrasonography (BUS), and mammography (MAM) were compared to determine the optimal screening method for high-risk groups.Results: The areas under the curve of risk prediction model increased from 0.573 (95%CI: 0.532-0.614) for ModelCRF, to 0.587 (95%CI: 0.544-0.630) for ModelCRF+MD, 0.670 (95%CI: 0.622-0.717) for ModelCRF+PRS and 0.674 (95%CI: 0.623-0.725) for ModelFULL. The HRs of breast cancer mortality for high-risk groups compared to low-risk groups increased from 1.81 (95%CI: 1.17-2.81) for ModelCRF, to 2.22 (95%CI: 1.35-3.67) for ModelCRF+MD, 2.48 (95%CI: 1.43-4.29) for ModelCRF+PRS, and 3.68(95%CI: 1.94-6.99) for ModelFULL. Among high-risk groups by ModelCRF, the DR of BUS was similar to that of MAM (3.926/1,000 vs. 2.399/1,000, P=0.193), but significantly higher than that of CBE (1.091/1,000, P=0.024). Compared with MAM, BUS showed significantly lower sensitivity (50.0% vs. 81.8%, P=0.026), but comparable specificity (99.2% vs. 99.3%), positive prediction values (22.9% vs. 34.6%), and negative prediction values (99.8% vs. 99.9%). Further analyses showed no significant difference in the proportions of early-stage breast cancer detected between BUS and MAM (50.00% vs. 61.54%, P=0.673). Similar results were observed in high-risk groups by other models.Conclusions: Accurate risk assessment integrating CRF, MD and PRS is needed to identify high-risk groups of breast cancer. The higher the risk, the greater the benefit of the intervention. BUS was comparable to MAM for screening breast cancer in high-risk groups.

Background and Objectives: The dismal outcome of malignant peripheral nerve sheath tumor (MPNST) highlights the necessity of identifying new biomarkers and pathogenesis for this aggressive sarcoma. Therefore, it is necessary to detect the aberrations of the TBX2-CHK2-p53 pathway and investigate its biological role in MPNST. Methods: Genetic aberrations of TBX2, CHK2 and p53 were detected by next generation sequencing (NGS) in 10 MPNST samples. Protein expression of TBX2, CHK2, p53, Ki-67 and cyclin D1 were assessed by immunohistochemistry (IHC) in 63 MPNST samples. Results: Our present data demonstrated that there were gene mutations of TBX2, CHK2 and p53 in MPNST samples. TBX2 expression was correlated with American Joint Committee on Cancer (AJCC) stage, recurrence and metastasis. Correlation analysis found that TBX2 was positively correlated with CHK2 (p=0.045) and CHK2 was positively correlated with p53 (p=0.006). Furthermore, both CHK2 and p53 were positively correlated with Ki-67 (p

The burden of breast cancer has grown rapidly in China during recent decades. However, the association between tumor markers (CA15-3, CA125, and CEA) and breast cancer survival among certain molecular subtypes is unclear; we described this association in a large, population-based study. We conducted a cohort study including 10,836 women according to the Tianjin Breast Cancer Cases Cohort. Demographic and epidemiologic data were collected by a structured face-to-face questionnaire. Clinico-pathological parameters were abstracted from medical records, and follow-up information was obtained once a year by telephone. The primary endpoints were breast cancer-specific survival (BCSS) and disease-free survival (DFS). We utilized the Cox proportional hazard model to calculate hazard ratios (HRs) and 95% confidence intervals (CI). Among all patients, elevated CA15-3 and CEA exhibited consistently and statistically significant reduced BCSS compared with normal ones (CA15-3: HR 1.54, 95% CI 1.01–2.34; CEA: HR 2.45, 95% CI 1.40–4.30). Similar patterns of association were observed for DFS (CA15-3: HR 2.09, 95% CI 1.44–3.02; CEA: HR 2.71, 95% CI 1.71–4.27). Moreover, in luminal A subtype, high CA15-3 and CEA levels were associated with decreased BCSS (CA15-3: HR 4.47, 95% CI 2.04–9.81; CEA: HR 3.79, 95% CI 1.68–8.55) and DFS (CA15-3: HR 4.06, 95% CI 2.29–7.18, CEA: HR 3.41, 95% CI 1.75–6.64). In basal-like subtype, elevated CEA conferred reduction for BCSS (HR 5.13, 95% CI 1.65–15.9). However, no association was observed between CA125 and breast cancer outcome. Preoperative CA15-3 and CEA levels differ in breast cancer molecular subtypes and yield strong prognostic information in Chinese women with breast cancer. Measuring CA15-3 and CEA levels before surgery may have the potential in predicting breast cancer survival and offering patients’ personalized treatment strategy among luminal A and basal-like subtypes.

Chemotherapy resistance remains a blockade for successful treatment and longer overall survival of patients with epithelial ovarian cancer (EOC). CTNNBIP1 is an inhibitor of β-catenin that is a chemotherapeutic target for EOC treatment. In the present study, we investigated associations between single nucleotide polymorphisms (SNPs) of CTNNBIP1 and platinum treatment response of Han Chinese EOC patients and subsequently performed functional prediction and validation of the resultant SNPs. We found that CTNNBIP1 rs935072 AT/TT variant genotypes were associated with platinum treatment response in the multivariate logistic regression analysis of EOC patients. Specifically, the CTNNBIP1 rs935072 AT/TT genotypes were associated with a decreased risk of developing chemoresistance ([adjusted odds ratio (OR)] = 0.89, 95% confidence interval (CI) = 0.82-0.97 and P=0.010), compared with the AA genotype. Further experiments showed that the underlying mechanism for the CTNNBIP1 rs935072 A>T change in chemotherapy treatment response resulted from a lower binding affinity of miR-27a-3p, thereby leading to up-regulation of the CTNNBIP1 expression. We further found that overexpression of CTNNBIP1 sensitized ovarian cancer cells to platinum treatment. Thus, the present study provides evidence that functional variants of CTNNBIP1 may regulate the expression of CTNNBIP1, a possible mechanism affecting platinum treatment response of EOC patients.

Objectives Although both age at menarche and age at menopause may independently affect the risk of cardiovascular diseases and all-cause mortality, their joint association with mortality is less clear. The objectives of this study were to address the relationship between ages at menarche and at menopause with mortality among postmenopausal women. Study design The study included 75,359 U.S. postmenopausal women aged 50–78 years from the Prostate, Lung, Colorectal, and Ovarian (PLCO) cohort. Information on ages at menarche and menopause was self-reported and collected at baseline, by questionnaire. Main outcome measures All-cause, cardiovascular and cancer mortality. Results After a median follow-up of 13 years, we identified 7826 deaths among 75,359 women in the PLCO cohort. Compared with women with an age at menarche of 12–13 years and an age at menopause of 45–54 years, the adjusted hazard ratios (95% confidence interval) for all-cause mortality for women with early menarche (≤11 years) and menopause (≤44 years) and those with late menarche (≥14 years) and menopause (≥55 years) were 1.20 (1.09, 1.32) and 0.82 (0.71, 0.96), respectively. This association remained significant in a sensitivity analysis that excluded women who did not undergo natural menopause. The indexes for the additive effect of the combined association showed no excess risk due to an interaction. Conclusions Early menarche and early menopause seemed to have an exactly additive effect on all-cause mortality. The findings suggest that it is important to evaluate ages at both menarche and menopause rather than to consider either variable on its own in assessing the risk of mortality.

Aims. Although, the association between depression and cancer has already been very well studied, but studies about depressive symptoms and cancer development are scarce and inconclusive among Chinese adults. We aimed to investigate whether the severity of depressive symptoms is associated with total and site-specific cancer risk in a nationally representative sample of middle-aged and older Chinese adults. Methods. This study was based on the China Health and Retirement Longitudinal Study (CHARLS), which was initiated in 2011 and followed up to 2018. We included 11,974 individuals aged 45 years or older with complete information about depressive symptoms and no history of cancer at baseline. Depressive symptoms were assessed using the validated 10-item of Center for Epidemiologic Studies Depression Scale (CES-D). Incident cancer cases were documented in the biennial self-reported questionnaires. The multivariable Cox proportional hazards model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). Results. Of 11,794 individuals included in the analysis, 51.72% were women. After a median follow-up of 7.0 years, 265 incident cancer cases were identified. Overall, there was a significant positive association between CES-D score and cancer risk (HR 1.02, 95%CI 1.00-1.05, P=0.03). Severe depressive symptoms were associated with a 75% increased cancer risk (HR 1.75, 95%CI 1.10-2.78). Such associations were evident among women rather than men. In the cancer-specific analysis, the association of severe depressive symptoms and cancer risk was more pronounced for female hormone-related cancers (HR 5.58; 95% CI 2.70-11.54). Conclusions. The findings imply that individuals with severe depressive symptoms could be considered as high-risk population in cancer screening programs.

Despite robust evidence for the role of m6A in cancer development and progression, its association with immune infiltration and survival outcomes in melanoma remains obscure. Here, we aimed to develop an m6A-related risk signature to improve prognostic and immunotherapy responder prediction performance in the context of melanoma. We comprehensively analyzed the m6A cluster and immune infiltration phenotypes of public datasets. The TCGA (n = 457) and eleven independent melanoma cohorts (n = 758) were used as the training and validation datasets, respectively. We identified two m6A clusters (m6A-clusterA and m6A-clusterB) based on the expression pattern of m6A regulators via unsupervised consensus clustering. IGF2BP1 (7.49%), KIAA1429 (7.06%), and YTHDC1 (4.28%) were the three most frequently mutated genes. There was a correlation between driver genes mutation statuses and the expression of m6A regulators. A significant difference in tumor-associated immune infiltration between two m6A clusters was detected. Compared with m6A-clusterA, the m6A-clusterB was characterized by a lower immune score and immune cell infiltration but higher mRNA expression-based stemness index (mRNAsi). An m6A-related risk signature consisting of 12 genes was determined via Cox regression analysis and divided the patients into low- and high-risk groups (IL6ST, MBNL1, NXT2, EIF2A, CSGALNACT1, C11orf58, CD14, SPI1, NCCRP1, BOK, CD74, PAEP). A nomogram was developed for the prediction of the survival rate. Compared with the high-risk group, the low-risk group was characterized by high expression of immune checkpoints and immunophenoscore (IPS), activation of immune-related pathways, and more enriched in immune cell infiltrations. The low-risk group had a favorable prognosis and contained the potential beneficiaries of the immune checkpoint blockade therapy and verified by the IMvigor210 cohort (n = 298). The m6A-related signature we have determined in melanoma highlights the relationships between m6A regulators and immune cell infiltration. The established risk signature was identified as a promising clinical biomarker of melanoma.

Observational studies suggested inconsistent associations between lipid-lowering drugs, such as statins, and renal cell carcinoma (RCC) risk. In a two-sample Mendelian randomization (MR) framework, we assessed the causal influence of lipid-lowering agents and circulating lipid traits on overall and sex-specific RCC risk. Genetic variants of six drug-target genes were selected to proxy the effects of low-density lipoprotein cholesterol (LDL-C) lowering therapies. Instrumental variables for circulating lipid traits were constructed from two large genome-wide association studies. We used endpoints for RCC from summary statistics of two studies [International Agency for Research on Cancer [IARC], N = 13,230; National Cancer Institute [NCI], N = 4,735]. The robustness of results was assessed through conventional MR sensitivity analyses. Overall, there was no significant association between genetically proxied HMG-CoA reductase (HMGCR) inhibition and RCC risk [Odds ratio [OR] = 1.42, 95% CI, 0.29–6.99]. In the sex-stratified analysis, we observed a positive association for genetically proxied drug targets with RCC risk. Specifically, genetically proxied proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition was associated with a higher risk of RCC in men [OR = 2.20 [95% CI, 1.24–3.89]], and the difference by sex was moderate. This study suggested genetically proxied inhibition of HMGCR was not associated with RCC risk, while genetically proxied PCSK9 inhibition might be associated with a higher risk of RCC in male.

Purpose We aim to construct a nomogram to predict breast cancer survival and guide postoperative adjuvant chemotherapy in China. Patients and methods A total of 5,504 breast cancer patients from the Tianjin Breast Cancer Cases Cohort were included. Multivariable Cox regression was used to investigate the factors associated with overall survival (OS) and a nomogram was constructed based on these prognostic factors. The nomogram was internal and external validated and the performance was evaluated by area under the curve (AUC) and calibration curve. The partial score was also constructed and stratified them into low, moderate and high-risk subgroups for death according to the tripartite grouping method. Multivariate Cox regression analysis and the propensity score matching method were respectively used to test the association between adjuvant chemotherapy and OS in different risk subgroups. Results Age, diameter, histological differentiation, lymph node metastasis, estrogen, and progesterone receptor were incorporated into the nomogram and validation results showed this nomogram was well-calibrated to predict the 3-year [AUC =74.1%; 95% confidence interval (CI): 70.1-78.0%] and 5-year overall survival [AUC =72.3%; 95% CI: 69.6-75.1%]. Adjuvant chemotherapy was negatively associated with death in high risk subgroup [Hazard Ratio (HR) = 0.54; 95% CI: 0.37-0.77; P

Age at menarche (AAM) was found to be associated with ovarian cancer risk in previous observational studies. However, the causality of this association remains unclear. Here, after systematic meta‐analyses, we performed two‐sample Mendelian randomization (MR) analyses to evaluate the causal effect of AAM in epithelial ovarian cancer (EOC) etiology. We performed meta‐analyses including 11 410 cases and 1 163 117 noncases to quantitatively evaluate the association between AAM and ovarian cancer risk. In MR analyses, we used 25 single nucleotide polymorphisms (SNPs) associated with AAM for Chinese and 390 SNPs for Europeans as instrumental variables. MR estimates were calculated using inverse‐variance weighted methods from 1044 cases and 1172 controls in a Chinese genome‐wide association study and validated by the Ovarian Cancer Association Consortium and Consortium of Investigators of Modifiers of BRCA1/2 studies with 29 396 cases and 68 502 controls of European ancestry. In meta‐analyses, we observed an inverse association (odds ratio [OR] = 0.96, 95% confidence interval [CI] = 0.93 to 1.00, P = 0.036) between per year older AAM and ovarian cancer risk in case–control studies, but no association was observed in cohort studies. In MR analyses, the OR of EOC risk per year increase in AAM was 0.81 (95% CI = 0.67 to 0.97, P = 0.026) in Chinese and 0.94 (95% CI = 0.90 to 0.98, P = 0.003) in Europeans, respectively. Our study supports a causal association between AAM and EOC risk.

To date, the 5-year overall survival of epithelial ovarian cancer (EOC) remains poor. Because studies suggest that RUVBL1 may be a chemotherapeutic target for the treatment of cancer, in this study, therefore, we investigated the role of potentially functional single nucleotide polymorphisms (SNPs) of RUVBL1 in the survival of Chinese patients with EOC, and we subsequently performed functional prediction and validation of the identified significant SNPs. We found that RUVBL1 rs1057156 A>G and RUVBL1 rs149652370 A>G were associated with survival of EOC patients in the multivariate Cox proportional hazards regression analysis. Specifically, the RUVBL1 rs149652370 AG genotype was associated with a shorter progression-free survival ([adjusted hazards ratio (HR)] = 3.32, 95% confidence interval (CI) = 1.76–6.25 and P = 2.01E–04), compared with the AA genotype. The RUVBL1 rs1057156 AG (only nine had GG) genotype was also associated with a poor overall survival (adjusted HR = 1.73, 95% CI = 1.19–2.52, P = 0.004), compared with the AA genotype. Further experiments showed that the RUVBL1 rs1057156 A>G change lowered its binding affinity to microRNA-4294 and led to upregulation of the RUVBL1 expression. We further found that overexpression of RUVBL1 promoted cell proliferation and metastatic potential. Overall, RUVBL1 enhanced EOC cell proliferation, invasion and migration presumably by stimulating the process of glycolysis. Thus, this study provides evidence that functional variants of RUVBL1 may regulate its gene expression, a possible mechanism affecting survival of EOC patients and that RUVBL1 may be a potential chemotherapeutic target for the treatment of EOC patients.

Background Diabetes mellitus and thyroid disease are two areas of broad interest in the field of endocrinology and metabolism. Variation of thyroid hormone concentration, even within the normal range, may portend the onset of type 2 diabetes mellitus (T2DM), especially among those with prediabetes. However, current evidence is mixed. Methods Prospective studies which assessed diabetes incidence were identified using a database search of MEDLINE and Embase through May 1, 2021. The Sidik-Jonkman random-effects model and cubic spline model were used to evaluate the associations and dose-response relationships between thyroid function/hormone levels and risk of T2DM and cardiovascular disease (CVD) risk among T2DM patients. Results A total of 12 prospective studies were included. We found that high baseline TSH levels were related to a 17% higher risk of T2DM (RR 1.17, 95% CI 1.01, 1.36; I2=78%, PI2=59%, P=0.03) and low FT4 (RR 1.33, 95% CI 1.04, 1.71; I2=62%, P=0.02) levels were significantly associated with risk of T2DM. The cubic spline model indicated a J-shaped relationship with TSH, but inverted-J-shaped relationships with FT3 and FT4. CVD events and all-cause deaths were prospectively evaluated in four studies, but were not associated with abnormal thyroid function. Conclusions Our meta-analysis determined that abnormal thyroid hormone level is associated with an increased risk of T2DM, showing a J-shaped relationship with TSH and inverted-J-shaped relationships with FT3 and FT4. Trial registration Registered number in PROSPERO: CRD42021225695.

Identifying causal regulatory variants and their target genes from the majority of non-coding disease-associated genetic loci is the main challenge in post-Genome-Wide Association Studies (GWAS) functional studies. Although chromosome conformation capture (3C) and its derivative technologies have been successfully applied to nominate putative causal genes for non-coding variants, many GWAS target genes have not been identified yet. This study generated a high-resolution contact map from epithelial ovarian cancer (EOC) cells with two H3K27ac-HiChIP libraries and analyzed the underlying gene networks for 15 risk loci identified from the largest EOC GWAS. By combinatory analysis of 4,021 fine-mapped credible variants of EOC GWAS and high-resolution contact map, we obtained 162 target genes that mainly enriched in cancer related pathways. Compared with GTEx eQTL genes in ovarian tissue and annotated proximal genes, 132 HiChIP targets were first identified for EOC causal variants. More than half of the credible variants (CVs) involved interactions that were over 185 kb in distance, indicating that long-range transcriptional regulation is an important mechanism for the function of GWAS variants in EOC. We also found that many HiChIP gene targets showed significantly differential expressions between normal ovarian and EOC tumor samples. We validated one of these targets by manipulating the rs9303542 located region with CRISPR-Cas9 deletion and dCas9-VP64 activation experiments and found altered expression of HOXB7 and HOXB8 at 17q21.32. This study presents a systematic analysis to identify putative target genes for causal variants of EOC, providing an in-depth investigation of the mechanisms of non-coding regulatory variants in the etiology and pathogenesis of ovarian cancer.

Background Both coronavirus disease 2019 (COVID-19) and severe acute respiratory syndrome (SARS) are caused by coronaviruses and have infected people in China and worldwide. We aimed to investigate whether COVID-19 and SARS exhibited similar spatial and temporal features at provincial level in mainland China. Methods The number of people infected by COVID-19 and SARS were extracted from daily briefings on newly confirmed cases during the epidemics, as of Mar. 4, 2020 and Aug. 3, 2003, respectively. We depicted spatiotemporal patterns of the COVID-19 and SARS epidemics using spatial statistics such as Moran’s I and the local indicators of spatial association (LISA). Results Compared to SARS, COVID-19 had a higher overall incidence. We identified 3 clusters (predominantly located in south-central China; the highest RR = 135.08, 95% CI: 128.36–142.08) for COVID-19 and 4 clusters (mainly in Northern China; the highest RR = 423.51, 95% CI: 240.96–722.32) for SARS. Fewer secondary clusters were identified after the “Wuhan lockdown”. The LISA cluster map detected a significantly high-low (Hubei) and low-high spatial clustering (Anhui, Hunan, and Jiangxi, in Central China) for COVID-19. Two significant high-high (Beijing and Tianjin) and low-high (Hebei) clusters were detected for SARS. Conclusions COVID-19 and SARS outbreaks exhibited distinct spatiotemporal clustering patterns at the provincial levels in mainland China, which may be attributable to changes in social and demographic factors, local government containment strategies or differences in transmission mechanisms.

Chemotherapy resistance remains a blockade for successful treatment and longer overall survival of patients with epithelial ovarian cancer (EOC). CTNNBIP1 is an inhibitor of β-catenin that is a chemotherapeutic target for EOC treatment. In the present study, we investigated associations between single nucleotide polymorphisms (SNPs) of CTNNBIP1 and platinum treatment response of Han Chinese EOC patients and subsequently performed functional prediction and validation of the resultant SNPs. We found that CTNNBIP1 rs935072 AT/TT variant genotypes were associated with platinum treatment response in the multivariate logistic regression analysis of EOC patients. Specifically, the CTNNBIP1 rs935072 AT/TT genotypes were associated with a decreased risk of developing chemoresistance ([adjusted odds ratio (OR)] = 0.89, 95% confidence interval (CI) = 0.82-0.97 and P=0.010), compared with the AA genotype. Further experiments showed that the underlying mechanism for the CTNNBIP1 rs935072 A>T change in chemotherapy treatment response resulted from a lower binding affinity of miR-27a-3p, thereby leading to up-regulation of the CTNNBIP1 expression. We further found that overexpression of CTNNBIP1 sensitized ovarian cancer cells to platinum treatment. Thus, the present study provides evidence that functional variants of CTNNBIP1 may regulate the expression of CTNNBIP1, a possible mechanism affecting platinum treatment response of EOC patients.

BackgroundBoth coronavirus disease 2019 (COVID-19) and severe acute respiratory syndrome (SARS) are caused by coronaviruses and have infected people in China and worldwide. We aimed to investigate whether COVID-19 and SARS exhibited similar spatial and temporal features at the provincial level in mainland China.MethodsThe number of people infected by COVID-19 and SARS were extracted from daily briefings on newly confirmed cases during the epidemics, as of Mar. 4, 2020 and Aug. 3, 2003, respectively. We depicted the spatiotemporal patterns of the COVID-19 and SARS epidemics using spatial statistics such as Moran’s I and the local indicators of spatial association (LISA).ResultsCompared to SARS, COVID-19 had a higher incidence. We identified 3 clusters (predominantly located in south-central China, highest RR=135.08) for COVID-19 and 4 clusters (mainly in Northern China, highest RR=423.51) for SARS. Fewer secondary clusters were identified after the “Wuhan lockdown”. The LISA cluster map detected a significantly high-low (Hubei) and low-high spatial clustering (Anhui, Hunan, and Jiangxi, in Central China) for COVID-19. Two significant high-high (Beijing and Tianjin) and low-high (Hebei) clusters were detected for SARS, although the global Moran’s I value was not significant.ConclusionsThe different spatiotemporal clustering patterns between COVID-19 and SARS could point to changes in social and demographic factors, local government containment strategies or differences in transmission mechanisms between these coronaviruses.

Acquired platinum resistance impedes successful treatment of epithelial ovarian cancer (EOC), and this resistance may be associated with inherited DNA damage–repair response. In the present study, we performed a two-phase analysis to assess associations between 8191 single-nucleotide polymorphisms within 127 genes of nucleotide excision repair pathway from a genome-wide association study dataset and platinum treatment response in 803 Han Chinese EOC patients. As a result, we identified that platinum-based chemotherapeutic response was associated with two potentially functional variants MNAT1 rs2284704 T>C [TC + CC versus TT, adjusted odds ratio (OR) = 0.89, 95% confidence interval (CI) = 0.83–0.95 and P = 0.0005] and HUS1B rs61748571 A>G (AG + GG versus AA, OR = 1.10, 95% CI = 1.03–1.18 and P = 0.005). Compared with the prediction model for clinical factors only, models incorporating HUS1B rs61748571 [area under the curve (AUC) 0.652 versus 0.672, P = 0.026] and the number of unfavorable genotypes (AUC 0.652 versus 0.668, P = 0.040) demonstrated a significant increase in the AUC. Further expression quantitative trait loci analysis suggested that MNAT1 rs2284704 T>C significantly influenced mRNA expression levels of MNAT1 (P = 0.003). These results indicated that MNAT1 rs2284704 T>C and HUS1B rs61748571 A>G may serve as potential biomarkers for predicting platinum treatment response of Chinese EOC patients, once validated by further functional studies.

Additional file 1 Spatiotemporal clustering of COVID-19 incident cases in stage1 from January 20 to February 6, 2020 (a) and stage2 from February 7 to March 4, 2020 (b) (excluding Hubei province). We drew this figure using ArcGIS software v10.2.2.

Additional file 2 Spatiotemporal clustering of COVID-19 incident cases in stage1 from January 20 to February 6, 2020 (a) and stage2 from February 7 to March 4, 2020 (b) (excluding Hubei province). We drew this figure using ArcGIS software v10.2.2.

To identify genetic variants in Notch signalling pathway genes that may predict survival of Han Chinese patients with epithelial ovarian cancer (EOC), we analysed a total of 1273 single nucleotide polymorphisms (SNPs) within 75 Notch genes in 480 patients from a published EOC genomewide association study (GWAS). We found that PSEN1 rs165934 and MAML2 rs76032516 were associated with overall survival (OS) of patients by multivariate Cox proportional hazards regression analysis. Specifically, the PSEN1 rs165934 AA genotype was associated with a poorer survival (adjusted hazards ratio [adjHR] = 1.41, 95% CI = 1.07‐1.84, and P = .014), compared with the CC + CA genotype, while MAML2 rs76032516 AA + AC genotypes were associated with a poorer survival (adjHR = 1.58, 95% CI = 1.16‐2.14, P = .004), compared with the CC genotype. The combined analysis of these two SNPs revealed that the death risk increased as the number of unfavourable genotypes increased in a dose‐dependent manner (P trend < .001). Additionally, the expression quantitative trait loci analysis revealed that the SNP rs165932 in the rs165934 LD block (r 2 = .946) was associated with expression levels of PSEN1, which might be responsible for the observed association with SNP rs165934. The associations of PSEN1 rs165934 and MAML2 rs76032516 of the Notch signalling pathway genes with OS in Chinese EOC patients are novel findings, which need to be validated in other large and independent studies.

Until now, no studies have investigated whether women other than those with dense breasts are suitable for adjunctive ultrasonography after negative mammography, and investigated whether all women with negative mammography are suitable for adjunctive ultrasonography.Based on the Multi-modality Independent Screening Trial in China, a total of 31,918 women aged 45 to 65 years underwent both ultrasonography and mammography. Physicians performed ultrasonography and mammography separately and were blinded to each other's findings until their interpretations had been recorded. For both ultrasonography and mammography, suspicious results and those highly suggestive of a malignancy were confirmed by pathologic examination, whereas other results were confirmed by 1-year follow-up after initial screening.Based on Breast Imaging Reporting and Data System (BIRADS) assessments, 84 (84.8%) of 99 cancers were identified on mammography (detection rate, 2.6/1000), and 61 (61.6%) of 99 cancers were identified on ultrasonography (detection rate, 1.9/1000). Integrated mammography with ultrasonography identified 94 (95.0%) of 99 cancers, with an increment of 11.9% in cancer detection rate (from 2.6/1000 to 2.9/1000) (P .05). Moreover, among women with BIRADS 3, adjunctive ultrasonography detected no cancers. All 10 additional cancers detected by adjunctive ultrasonography were from women with BIRADS 0 to 2, at a cost of 207 women with false positives. Additionally, dense breasts and benign breast disease were significantly associated with positive ultrasonography after BIRADS 0 to 2 (all P values .05).After negative mammography, adjunctive ultrasonography should only be recommended for BIRADS 0 to 2 but not BIRADS 3, especially for women with dense breasts or benign breast disease.