Publications by authors named "Hongbing Shen"

508 Publications

Global COVID-19 pandemic waves: Limited lessons learned worldwide over the past year.

Engineering (Beijing) 2021 Sep 14. Epub 2021 Sep 14.

Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China.

The occurrence of coronavirus disease 2019 (COVID-19) was followed by a small burst of cases around the world; afterward, due to a series of emergency non-pharmaceutical interventions (NPIs), the increasing number of confirmed cases slowed down in many countries. However, the subsequent gradual easing of governance led to a sudden increase in cases in late July 2020, arousing deep concern across the globe. This study evaluates the situation of the COVID-19 pandemic in countries and territories worldwide from January 2020 to February 2021. According to the time-varying reproduction number (()) of each country or territory, the results show that almost half of the countries and territories in the world have never controlled the epidemic. Among the countries and territories that had once contained the occurrence, nearly half failed to maintain their prevention and control, causing the COVID-19 pandemic to rebound across the world-resulting in even higher waves in half of the rebounding countries or territories. This work also proposes and uses a time-varying country-level transmission risk score (CTRS), which takes into account both () and daily new cases, to demonstrate country-level or territory-level transmission potential and trends. Time-varying hierarchical clustering of time-varying CTRS values was used to successfully reveal the countries and territories that contributed to the recent aggravation of the global pandemic in the last quarter of 2020 and the beginning of 2021, and to identify countries and territories with an increasing risk of COVID-19 transmission in the near future. Furthermore, a regression analysis indicated that the introduction and relaxation of NPIs, including workplace closure policies and stay-at-home requirements, appear to be associated with recent global transmission changes. In conclusion, a systematic evaluation of the global COVID-19 pandemic over the past year indicates that the world is now in an unexpected situation, with limited lessons learned. Summarizing the lessons learned could help in designing effective public responses for constraining future waves of COVID-19 worldwide.
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http://dx.doi.org/10.1016/j.eng.2021.07.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438800PMC
September 2021

Circulating C-reactive protein increases lung cancer risk: Results from a prospective cohort of UK Biobank.

Int J Cancer 2021 Aug 27. Epub 2021 Aug 27.

Department of Epidemiology, School of Public Health, Southeast University, Nanjing, China.

Chronic inflammation has been associated with the development of lung cancer. In this study, we examined the association between C-reactive protein (CRP) and lung cancer in a prospective cohort study and used Mendelian randomization (MR) to clarify the causality. We included 420 977 participants from the UK Biobank (UKB) in the analyses; 1892 thereof were diagnosed with lung cancer during the follow-up. Hazards ratios (HRs) of CRP concentrations were estimated by Cox proportional hazard models and two approaches of MR analysis were performed. Besides, we added CRP concentrations to epidemiological model of lung cancer to evaluate its prediagnostic role through time-dependent receiver operating characteristic curve analysis. Elevated CRP levels were associated with a 22% increased lung cancer risk per 1 SD increase (HR = 1.22, 95% confidence interval [CI] = 1.18-1.26). Positive associations were observed in small cell lung cancer (HR = 1.21, 95% CI = 1.10-1.33), lung adenocarcinoma (HR = 1.17, 95% CI = 1.11-1.23) and lung squamous cell carcinoma (HR = 1.22, 95% CI = 1.14-1.31). No genetical association of circulating CRP levels and lung cancer risk was observed in MR analysis. When added to a risk model of lung cancer, CRP improved the performance of model as long as 8 years among current smokers (basic model: C-statistic = 0.78 [95% CI = 0.75-0.80]; CRP model: C-statistic = 0.79 [95% CI = 0.76-0.81]; P  = .003, P  = .014). Our results did not support the causal association of circulating CRP with lung cancer risk. However, circulating CRP could be a prediagnostic marker of lung cancer as long as 8 years in advance for current smokers.
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http://dx.doi.org/10.1002/ijc.33780DOI Listing
August 2021

Comprehensive estimation for the length and dispersion of COVID-19 incubation period: a systematic review and meta-analysis.

Infection 2021 Aug 18. Epub 2021 Aug 18.

Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, China.

Purpose: To estimate the central tendency and dispersion for incubation period of COVID-19 and, in turn, assess the effect of a certain length of quarantine for close contacts in active monitoring.

Methods: Literature related to SARS-CoV-2 and COVID-19 was searched through April 26, 2020. Quality was assessed according to Agency for Healthcare Research and Quality guidelines. Log-normal distribution for the incubation period was assumed to estimate the parameters for each study. Incubation period median and dispersion were estimated, and distribution was simulated.

Results: Fifty-six studies encompassing 4095 cases were included in this meta-analysis. The estimated median incubation period for general transmissions was 5.8 days [95% confidence interval (95% CI): 5.3, 6.2]. Incubation period was significantly longer for asymptomatic transmissions (median: 7.7 days; 95% CI 6.3, 9.4) than for general transmissions (P = 0.0408). Median and dispersion were higher for SARS-CoV-2 incubation compared to other viral respiratory infections. Furthermore, about 12 in 10,000 contacts in active monitoring would develop symptoms after 14 days, or below 1 in 10,000 for asymptomatic transmissions. Meta-regression suggested that each 10-year increase in age resulted in an average 16% increment in length of median incubation (incubation period ratio, 1.16, 95% CI 1.01, 1.32; P = 0.0250).

Conclusion: This study estimated the median and dispersion of the SARS-CoV-2 incubation period more precisely. A 14-day quarantine period is sufficient to trace and identify symptomatic infections.
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http://dx.doi.org/10.1007/s15010-021-01682-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372687PMC
August 2021

Association of maternal diabetes during pregnancy with high refractive error in offspring: a nationwide population-based cohort study.

Diabetologia 2021 Aug 17. Epub 2021 Aug 17.

Department of Biostatistics, School of Public Health, Fudan University, Shanghai, China.

Aims/hypothesis: We aimed to investigate the associations between maternal diabetes before or during pregnancy and the risk of high refractive error (RE) in offspring until the age of 25 years.

Methods: This nationwide register-based cohort study comprised 2,470,580 individuals born in 1977-2016. The exposure was maternal diabetes during or before pregnancy (type 1 diabetes, type 2 diabetes and gestational diabetes). Cox regression was used to examine the association between maternal diabetes and the risk of high RE in offspring from birth until the age of 25 years, adjusting for multiple potential confounders.

Results: During up to 25 years of follow-up, 553 offspring of mothers with diabetes and 19,695 offspring of mothers without diabetes were diagnosed with high RE. Prenatal exposure to maternal diabetes was associated with a 39% increased risk of high RE: HR 1.39 (95% CI 1.28, 1.51), p < 0.001; standardised cumulative incidence in unexposed offspring at 25 years of age 1.18% (95% CI 1.16%, 1.19%); cumulative incidence difference 0.72% (95% CI 0.51%, 0.94%). The elevated risks were observed for hypermetropia (HR 1.37 [95% CI 1.24, 1.51], p < 0.001), myopia (HR 1.34 [95% CI 1.08, 1.66], p = 0.007) and astigmatism (HR 1.58 [95% CI 1.29, 1.92], p < 0.001). The increased risks were more pronounced among offspring of mothers with diabetic complications (HR 2.05 [95% CI 1.60, 2.64], p < 0.001), compared with those of mothers with diabetes but no diabetic complications (HR 1.18 [95% CI 1.02, 1.37], p = 0.030).

Conclusions/interpretation: Our findings suggest that maternal diabetes during pregnancy is associated with an increased risk of high RE in offspring, in particular among those of mothers with diabetic complications. Early ophthalmological screening should be recommended in offspring of mothers with diabetes diagnosed before or during pregnancy.
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http://dx.doi.org/10.1007/s00125-021-05526-zDOI Listing
August 2021

Assisted reproductive technology and birth defects in a Chinese birth cohort study.

Lancet Reg Health West Pac 2021 Feb 22;7:100090. Epub 2021 Jan 22.

State Key Laboratory of Reproductive Medicine, Centre for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.

Background: It has been consistently shown in several meta-analyses that infants born after ART have an excess of birth defects compared with those after spontaneous conception, however, the prevalence of birth defects among ART offspring in China is incompletely studied. Moreover, it is unclear to what extent the risk of birth defects is associated with parental infertility characteristics, specific ART procedures and twinning.

Methods: In the prospective cohort study, we included women who participated in the cohort, and had pregnancies of at least 20 gestational weeks between August 2016 and May 2019, and followed them until their children reached 1 year of age. Exposures of interest were ART, as well as infertility-related characteristics, certain ART procedures and specific medication usage. The primary outcome was birth defects including both major and minor defects, which we analysed with logistic generalized estimating equations to investigate the association with ART and certain ART characteristics.

Findings: A total of 1,825 women with ART-pregnancy and 3,483 women with spontaneous-pregnancy were included in the analysis. The prevalence of any defects was significantly higher among ART-births than their non-ART counterparts at each follow-up, specifically at prenatal screening (2•2% vs. 1•2%), at delivery (4•9% vs. 2•9%), at 6 months (10•4% vs. 5•3%) and 1 year of age (13•9% vs. 7•0%), and the associations between ART and increased risk of birth defects at each follow-up were similarly robust. Among ART-births, GnRH antagonist regimen for ovulation induction in women was associated with an increased risk of birth defects in their offspring after taking into account potential influencing factors (Multivariable model: adjusted risk ratio [aRR] 1•47, 1•04-2•07). Additionally, mediation through twinning accounted for 31•1% of the risk of ART-associated birth defects.

Interpretation: The results suggest that ART confers an increased risk for birth defects in offspring. The risk is partly attributable to infertility characteristics, certain ovulation induction regimen, and to some extent mediated by twinning. Our findings highlight the importance of long-term follow-up of children conceived via ART for health conditions.

Funding: National Key Research and Development Program of China, National Natural Science Foundation of China and Natural Science Foundation of Jiangsu Province.
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http://dx.doi.org/10.1016/j.lanwpc.2020.100090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315325PMC
February 2021

Genetic Risk for Overall Cancer and the Benefit of Adherence to a Healthy Lifestyle.

Cancer Res 2021 Sep 28;81(17):4618-4627. Epub 2021 Jul 28.

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

Cancer site-specific polygenic risk scores (PRS) effectively identify individuals at high risk of individual cancers, but the effectiveness of PRS on overall cancer risk assessment and the extent to which a high genetic risk of overall cancer can be offset by a healthy lifestyle remain unclear. Here, we constructed an incidence-weighted overall cancer polygenic risk score (CPRS) based on 20 cancer site-specific PRSs. Lifestyle was determined according to smoking, alcohol consumption, physical activity, body mass index, and diet. Cox regression by sex was used to analyze associations of genetic and lifestyle factors with cancer incidence using UK Biobank data ( = 442,501). Compared with participants at low genetic risk (bottom quintile of CPRS), those at intermediate (quintiles 2 to 4) or high (top quintile) genetic risk had HRs of 1.27 (95% confidence interval, 1.21-1.34) or 1.91 (1.81-2.02) for overall cancer, respectively, for men, and 1.21 (1.16-1.27) or 1.62 (1.54-1.71), respectively, for women. A joint effect of genetic and lifestyle factors on overall cancer risk was observed, with HRs reaching 2.99 (2.45-3.64) for men and 2.38 (2.05-2.76) for women with high genetic risk and unfavorable lifestyle compared with those with low genetic risk and favorable lifestyle. Among participants at high genetic risk, the standardized 5-year cancer incidence was significantly reduced from 7.23% to 5.51% for men and from 5.77% to 3.69% for women having a favorable lifestyle. In summary, individuals at high genetic risk of overall cancer can be identified by CPRS, and risk can be attenuated by adopting a healthy lifestyle. SIGNIFICANCE: A new indicator of cancer polygenic risk score measures genetic risk for overall cancer, which could identify individuals with high cancer risk to facilitate decision-making about lifestyle modifications for personalized prevention.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-0836DOI Listing
September 2021

Comparative Characterization and Risk Stratification of Asymptomatic and Presymptomatic Patients With COVID-19.

Front Immunol 2021 9;12:700449. Epub 2021 Jul 9.

Central Lab of Biomedical Research Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

The identification of asymptomatic, non-severe presymptomatic, and severe presymptomatic coronavirus disease 2019 (COVID-19) in patients may help optimize risk-stratified clinical management and improve prognosis. This single-center case series from Wuhan Huoshenshan Hospital, China, included 2,980 patients with COVID-19 who were hospitalized between February 4, 2020 and April 10, 2020. Patients were diagnosed as asymptomatic (n = 39), presymptomatic (n = 34), and symptomatic (n = 2,907) upon admission. This study provided an overview of asymptomatic, presymptomatic, and symptomatic COVID-19 patients, including detection, demographics, clinical characteristics, and outcomes. Upon admission, there was no significant difference in clinical symptoms and CT image between asymptomatic and presymptomatic patients for diagnosis reference. The mean area under the receiver operating characteristic curve (AUC) of the differential diagnosis model to discriminate presymptomatic patients from asymptomatic patients was 0.89 (95% CI, 0.81-0.98). Importantly, the severe and non-severe presymptomatic patients can be further stratified (AUC = 0.82). In conclusion, the two-step risk-stratification model based on 10 laboratory indicators can distinguish among asymptomatic, severe presymptomatic, and non-severe presymptomatic COVID-19 patients on admission. Moreover, single-cell data analyses revealed that the CD8+T cell exhaustion correlated to the progression of COVID-19.
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http://dx.doi.org/10.3389/fimmu.2021.700449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301218PMC
August 2021

Genome-wide gene-smoking interaction study identified novel susceptibility loci for non-small cell lung cancer in Chinese populations.

Carcinogenesis 2021 Jul 23. Epub 2021 Jul 23.

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

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 (GWAS) 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 (OR = 0.63, 95%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.
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http://dx.doi.org/10.1093/carcin/bgab064DOI Listing
July 2021

Air Pollution, Genetic Factors and the Risk of Lung Cancer: A Prospective Study in the UK Biobank.

Am J Respir Crit Care Med 2021 Jul 12. Epub 2021 Jul 12.

Nanjing Medical University School of Public Health, 572407, Department of Epidemiology, Center for Global Health, Nanjing, China.

Both genetic and environmental factors contribute to lung cancer, but the degree to which air pollution modifies the impact of genetic susceptibility on lung cancer remains unknown. To investigate whether air pollution and genetic factors jointly contribute to incident lung cancer. We analyzed data from 455,974 participants (53% women) without previous cancer at baseline in the UK Biobank. The concentrations of particulate matter (PM, PM and PM), nitrogen dioxide (NO), and nitrogen oxides (NO) were estimated by land-use regression models, and the association between air pollutants and incident lung cancer was investigated using a Cox proportional hazard model. Furthermore, we constructed a polygenic risk score and evaluated whether air pollutants modified the effect of genetic susceptibility on the development of lung cancer. The results showed significant associations between the risk of lung cancer and PM (hazard ratio [HR]: 1.63, 95% confidence interval [CI]: 1.33-2.01; per 5 μg/m), PM (1.53, 1.20-1.96; per 10 μg/m), NO (1.10, 1.05-1.15; per 10 μg/m), and NO (1.13, 1.07-1.18; per 20 μg/m). There were additive interactions between air pollutants and the genetic risk. Compared with participants with low genetic risk and low air pollution, those with high air pollution and high genetic risk had the highest risk of lung cancer (PM: HR: 1.71, 95% CI:1.45-2.02; PM: 1.77, 1.50-2.10; NO: 1.77, 1.42-2.22; NO: 1.67, 1.43-1.95). Long-term exposure to air pollution may increase the risk of lung cancer, especially in those with high genetic risk.
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http://dx.doi.org/10.1164/rccm.202011-4063OCDOI Listing
July 2021

Sex Hormone and Colorectal Cancer: The Knowns and Unknowns.

Cancer Epidemiol Biomarkers Prev 2021 Jul;30(7):1302-1304

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, P.R. China.

Sex hormones have been suggested as a contributor to gender disparity in incidence and mortality of colorectal cancer, but previous observational studies on endogenous sex hormones and colorectal cancer risk have led to contradictory results. Leveraging the large-scale UK biobank resource, Dimou and colleagues performed both observational and Mendelian randomization (MR) analyses to investigate the association of serum testosterone and sex hormone binding globulin concentrations with the risk of colorectal cancer. Although the findings provide little evidence for independent roles of the hormones in colorectal cancer, further interrogation of possible mediating effects of sex hormones on the causal pathways of colorectal cancer could deepen our understanding of colorectal cancer etiology and improve tailored prevention. While MR analysis is useful for inferring causality in observational studies, the current null results should be interpreted with caution because of insufficient statistical power and predefined assumptions of linearity. Moreover, given the widespread use of testosterone supplementation in older men to restore age-related decline of endogenous concentrations, large and long-term randomized controlled trials are required to clarify the effect of testosterone on colorectal cancer risk, which would provide critical evidence for health decision making..
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0472DOI Listing
July 2021

An Improved Detection of Circulating Tumor DNA in Extracellular Vesicles-Depleted Plasma.

Front Oncol 2021 11;11:691798. Epub 2021 Jun 11.

Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, United States.

Circulating tumor DNA (ctDNA) in plasma has been used as a biomarker for cancer detection and outcome prediction. In this study, we collected the five precipitates (fractions 1-5) and leftover supernatant plasma component (fraction 6) by a sequential centrifugation in plasma samples from nine small cell lung cancer (SCLC) patients. The fractions 3, 5 and 6 were large vesicles, exosomes and extracellular vesicles (EVs)-depleted plasma, respectively. Fragment size analysis using DNAs from these fractions showed dramatical differences from a peak of 7-10 kb in fraction 1 to 140-160 bp in fraction 6. To determine ctDNA content, we performed whole genome sequencing and applied copy number-based algorithm to calculate ctDNA percentage. This analysis showed the highest ctDNA content in EV-depleted plasma (average = 27.22%), followed by exosomes (average = 22.09%) and large vesicles (average = 19.70%). Comparatively, whole plasma, which has been used in most ctDNA studies, showed an average of 23.84% ctDNA content in the same group of patients. To further demonstrate higher ctDNA content in fraction 6, we performed mutational analysis in the plasma samples from 22 non-small cell lung cancer (NSCLC) patients with known EGFR mutations. This analysis confirmed higher mutation detection rates in fraction 6 (14/22) than whole plasma (10/22). This study provides a new insight into potential application of using fractionated plasma for an improved ctDNA detection.
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http://dx.doi.org/10.3389/fonc.2021.691798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226168PMC
June 2021

Association of assisted reproductive technology, germline de novo mutations and congenital heart defects in a prospective birth cohort study.

Cell Res 2021 Aug 9;31(8):919-928. Epub 2021 Jun 9.

State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.

Emerging evidence suggests that children conceived through assisted reproductive technology (ART) have a higher risk of congenital heart defects (CHDs) even when there is no family history. De novo mutation (DNM) is a well-known cause of sporadic congenital diseases; however, whether ART procedures increase the number of germline DNM (gDNM) has not yet been well studied. Here, we performed whole-genome sequencing of 1137 individuals from 160 families conceived through ART and 205 families conceived spontaneously. Children conceived via ART carried 4.59 more gDNMs than children conceived spontaneously, including 3.32 paternal and 1.26 maternal DNMs, after correcting for parental age at conception, cigarette smoking, alcohol drinking, and exercise behaviors. Paternal DNMs in offspring conceived via ART are characterized by C>T substitutions at CpG sites, which potentially affect protein-coding genes and are significantly associated with the increased risk of CHD. In addition, the accumulation of non-coding functional mutations was independently associated with CHD and 87.9% of the mutations were originated from the father. Among ART offspring, infertility of the father was associated with elevated paternal DNMs; usage of both recombinant and urinary follicle-stimulating hormone and high-dosage human chorionic gonadotropin trigger was associated with an increase of maternal DNMs. In sum, the increased gDNMs in offspring conceived by ART were primarily originated from fathers, indicating that ART itself may not be a major reason for the accumulation of gDNMs. Our findings emphasize the importance of evaluating the germline status of the fathers in families with the use of ART.
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http://dx.doi.org/10.1038/s41422-021-00521-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324888PMC
August 2021

Genetic variants associated with expression of contribute to the risk of head and neck cancer in Chinese population.

J Med Genet 2021 Mar 5. Epub 2021 Mar 5.

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China

Background: Squamous cell carcinoma of the head and neck (SCCHN) is one of the most common cancers worldwide and includes cancers arising from the oral cavity, pharynx and larynx. Genome-wide association studies have found several genetic variants related to the risk of SCCHN; however, they could only explain a small fraction of the heritability. Thus, more susceptibility loci associated with SCCHN need to be identified.

Methods: An association study was conducted by genotyping 555 patients with SCCHN and 1367 controls in a Chinese population. Single-variant association analysis was conducted on 63 373 SNPs, and the promising variants were then confirmed by a two-stage validation with 1875 SCCHN cases and 4637 controls. Bioinformatics analysis and functional assays were applied to uncover the potential pathogenic mechanism of the promising variants and genes associated with SCCHN.

Results: We first identified three novel genetic variants significantly associated with the risk of SCCHN (p=7.45×10 for rs2517611 at 6p22.1, p=1.76×10 for rs2524182 at 6p21.33 and p=2.17×10 for rs3131018 at 6p21.33). Further analysis and biochemical assays showed that rs3094187, which was in a region in high linkage disequilibrium with rs3131018, could modify expression by regulating the binding affinity of the transcription factor to the promoter of . In addition, experiments revealed that the inhibition of may affect several important pathways involved in tumourigenesis and attenuate the cell proliferation and migration of SCCHN.

Conclusion: These findings offer important evidence that functional genetic variants could contribute to development of SCCHN and that may function as a putative susceptibility gene for SCCHN.
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http://dx.doi.org/10.1136/jmedgenet-2020-107410DOI Listing
March 2021

Identification of A-to-I RNA editing profiles and their clinical relevance in lung adenocarcinoma.

Sci China Life Sci 2021 May 27. Epub 2021 May 27.

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.

Adenosine-to-inosine (A-to-I) RNA editing is a widespread posttranscriptional modification that has been shown to play an important role in tumorigenesis. Here, we evaluated a total of 19,316 RNA editing sites in the tissues of 80 lung adenocarcinoma (LUAD) patients from our Nanjing Lung Cancer Cohort (NJLCC) and 486 LUAD patients from the TCGA database. The global RNA editing level was significantly increased in tumor tissues and was highly heterogeneous across patients. The high RNA editing level in tumors was attributed to both RNA (ADAR1 expression) and DNA alterations (mutation load). Consensus clustering on RNA editing sites revealed a new molecular subtype (EC3) that was associated with the poorest prognosis of LUAD patients. Importantly, the new classification was independent of classic molecular subtypes based on gene expression or DNA methylation. We further proposed a simplified model including eight RNA editing sites to accurately distinguish the EC3 subtype in our patients. The model was further validated in the TCGA dataset and had an area under the curve (AUC) of the receiver operating characteristic curve of 0.93 (95%CI: 0.91-0.95). In addition, we found that LUAD cell lines with the EC3 subtype were sensitive to four chemotherapy drugs. These findings highlighted the importance of RNA editing events in the tumorigenesis of LUAD and provided insight into the application of RNA editing in the molecular subtyping and clinical treatment of cancer.
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http://dx.doi.org/10.1007/s11427-020-1928-0DOI Listing
May 2021

Development and Validation of a Polygenic Risk Score for Stroke in the Chinese Population.

Neurology 2021 08 24;97(6):e619-e628. Epub 2021 May 24.

From the Key Laboratory of Cardiovascular Epidemiology and Department of Epidemiology (Xiangfeng Lu, X.N., Fangchao Liu, Z.L., K.H., L.W., J.L., J.C., S.C., H.L., Xigui Wu, Y.L., J.H., D.G.), State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing; Department of Epidemiology and Biostatistics (C.S., Z.H., H.S.), Center for Global Health, School of Public Health, Nanjing Medical University; Department of Biostatistics and Epidemiology (D.H.), School of Public Health, Shenzhen University Health Science Center, Guangdong; Cardio-Cerebrovascular Control and Research Center (Y.Z., Fanghong Lu), Institute of Basic Medicine, Shandong First Medical University (Shandong Academy of Medical Sciences), Jinan; Tianjin Key Laboratory of Environment, Nutrition and Public Health (X.Y.), Department of Occupational and Environmental Health, School of Public Health, Tianjin Medical University, Tianjin; Division of Epidemiology (Xiaoqing Liu), Guangdong Provincial People's Hospital and Cardiovascular Institute, Guangzhou; Department of Neurology (W.T., Z.R.), Affiliated Yixing People's Hospital of Jiangsu University, People's Hospital of Yixing City, Yixing; Department of Cardiology (L.Y.), Fujian Provincial Hospital, Fuzhou; Center for Chronic and Noncommunicable Disease Control and Prevention (Xianping Wu), Sichuan Center for Disease Control and Prevention, Chengdu; Center for Genetic Epidemiology and Genomics (H.Z.), School of Public Health and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou; Research Unit of Prospective Cohort of Cardiovascular Diseases and Cancer (H.S.), Chinese Academy of Medical Sciences (2019RU038); and Department of Internal Medicine, Division of Cardiovascular Medicine (C.J.W.), and Department of Human Genetics (C.J.W.), University of Michigan, Ann Arbor.

Objective: To construct a polygenic risk score (PRS) for stroke and evaluate its utility in risk stratification and primary prevention for stroke.

Methods: Using a meta-analytic approach and large genome-wide association results for stroke and stroke-related traits in East Asians, we generated a combined PRS (metaPRS) by incorporating 534 genetic variants in a training set of 2,872 patients with stroke and 2,494 controls. We then validated its association with incident stroke using Cox regression models in large Chinese population-based prospective cohorts comprising 41,006 individuals.

Results: During a total of 367,750 person-years (mean follow-up 9.0 years), 1,227 participants developed stroke before age 80 years. Individuals with high polygenic risk had an about 2-fold higher risk of incident stroke compared with those with low polygenic risk (hazard ratio [HR] 1.99, 95% confidence interval [CI] 1.66-2.38), with the lifetime risk of stroke being 25.2% (95% CI 22.5%-27.7%) and 13.6% (95% CI 11.6%-15.5%), respectively. Individuals with both high polygenic risk and family history displayed lifetime risk as high as 41.1% (95% CI 31.4%-49.5%). Individuals with high polygenic risk achieved greater benefits in terms of absolute risk reductions from adherence to ideal fasting blood glucose and total cholesterol than those with low polygenic risk. Maintaining favorable cardiovascular health (CVH) profile could substantially mitigate the increased risk conferred by high polygenic risk to the level of low polygenic risk (from 34.6% to 13.2%).

Conclusions: Our metaPRS has great potential for risk stratification of stroke and identification of individuals who may benefit more from maintaining ideal CVH.

Classification Of Evidence: This study provides Class I evidence that metaPRS is predictive of stroke risk.
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http://dx.doi.org/10.1212/WNL.0000000000012263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424497PMC
August 2021

A multi-omics study links TNS3 and SEPT7 to long-term former smoking NSCLC survival.

NPJ Precis Oncol 2021 May 17;5(1):39. Epub 2021 May 17.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, 02115, USA.

The genetic architecture of non-small cell lung cancer (NSCLC) is relevant to smoking status. However, the genetic contribution of long-term smoking cessation to the prognosis of NSCLC patients remains largely unknown. We conducted a genome-wide association study primarily on the prognosis of 1299 NSCLC patients of long-term former smokers from independent discovery (n = 566) and validation (n = 733) sets, and used in-silico function prediction and multi-omics analysis to identify single nucleotide polymorphisms (SNPs) on prognostics with NSCLC. We further detected SNPs with at least moderate association strength on survival within each group of never, short-term former, long-term former, and current smokers, and compared their genetic similarity at the SNP, gene, expression quantitative trait loci (eQTL), enhancer, and pathway levels. We identified two SNPs, rs34211819 at 7p12.3 (P = 3.90 × 10) and rs1143149 at 7p14.2 (P = 9.75 × 10), were significantly associated with survival of NSCLC patients who were long-term former smokers. Both SNPs had significant interaction effects with years of smoking cessation (rs34211819: P = 8.0 × 10; rs1143149: P = 0.003). In addition, in silico function prediction and multi-omics analysis provided evidence that these QTLs were associated with survival. Moreover, comparison analysis found higher genetic similarity between long-term former smokers and never-smokers, compared to short-term former smokers or current smokers. Pathway enrichment analysis indicated a unique pattern among long-term former smokers that was related to immune pathways. This study provides important insights into the genetic architecture associated with long-term former smoking NSCLC.
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http://dx.doi.org/10.1038/s41698-021-00182-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128887PMC
May 2021

Potential functional variants of KIAA genes are associated with breast cancer risk in a case control study.

Ann Transl Med 2021 Apr;9(7):549

Department of Epidemiology, International Joint Research Center on Environment and Human Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

Background: KIAA genes identified in the Kazusa cDNA-sequencing project may play important roles in biological processes and are involved in carcinogenesis of many cancers. Genetic variants of KIAA genes are implicated in the abnormal expression of these genes and are linked to susceptibility of several human complex diseases.

Methods: The differentially expressed KIAA genes were screened and identified in The Cancer Genome Atlas (TCGA) database of breast cancer. A total of 48 variants located in the 28 KIAA genes were selected to investigate the associations between polymorphism and breast cancer in 1,032 cases and 1,063 cancer-free controls in a Chinese population.

Results: Two coding variants, which included a SNP rs2306369 in and a SNP rs1205434 in , were identified to be associated with the incidences of breast cancer. Logistic regression analysis showed that the SNP rs2306369 G allele was associated with a decreased risk of breast cancer (additive model: OR =0.81, 95% CI: 0.66-0.99, P=0.038), whereas the SNP rs1205434 A allele was involved with a higher risk of breast cancer (additive model: OR =1.19, 95% CI: 1.02-1.38, P= 0.025). Further stratified analysis revealed that the SNP rs1205434 showed a significant difference for age at menarche strata (heterogeneity test P=0.009). Multiplicative interaction analysis indicated that there was positive multiplicative interaction between the SNP rs1205434 and menarche age (OR =1.09, 95% CI: 1.01-1.17, P=0.036). Additionally, expression quantitative trait loci analysis revealed that the SNP rs1205434 A allele could decrease the expression in the Genotype-Tissue Expression (GTEx) database (P=0.002). The Kaplan-Meier plotter showed that breast cancer patients with high expression have significantly better outcomes than those with low levels of expression (HR =0.84, 95% CI: 0.72-0.99, P=0.033).

Conclusions: The results indicate that the genetic variants (rs2306369 and rs1205434) in the coding region of and respectively may affect Chinese females' breast cancer susceptibility and act as potential predictive biomarkers for breast cancer.
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http://dx.doi.org/10.21037/atm-20-6108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105804PMC
April 2021

A cross-tissue transcriptome-wide association study identifies novel susceptibility genes for lung cancer in Chinese populations.

Hum Mol Genet 2021 Aug;30(17):1666-1676

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.

Although dozens of susceptibility loci have been identified for lung cancer in genome-wide association studies (GWASs), the susceptibility genes and underlying mechanisms remain unclear. In this study, we conducted a cross-tissue transcriptome-wide association study (TWAS) with UTMOST based on summary statistics from 13 327 lung cancer cases and 13 328 controls and the genetic-expression matrix over 44 human tissues in the Genotype-Tissue Expression (GTEx) project. After further evaluating the associations in each tissue, we revealed 6 susceptibility genes in known loci and identified 12 novel ones. Among those, five novel genes, including DCAF16 (Pcross-tissue = 2.57 × 10-5, PLung = 2.89 × 10-5), CBL (Pcross-tissue = 5.08 × 10-7, PLung = 1.82 × 10-4), ATR (Pcross-tissue = 1.45 × 10-5, PLung = 9.68 × 10-5), GYPE (Pcross-tissue = 1.45 × 10-5, PLung = 2.17 × 10-3) and PARD3 (Pcross-tissue = 5.79 × 10-6, PLung = 4.05 × 10-3), were significantly associated with the risk of lung cancer in both cross-tissue and lung tissue models. Further colocalization analysis indicated that rs7667864 (C > A) and rs2298650 (G > T) drove the GWAS association signals at 4p15.31-32 (OR = 1.09, 95%CI: 1.04-1.12, PGWAS = 5.54 × 10-5) and 11q23.3 (OR = 1.08, 95%CI: 1.04-1.13, PGWAS = 5.55 × 10-5), as well as the expression of DCAF16 (βGTEx = 0.24, PGTEx = 9.81 × 10-15; βNJLCC = 0.29, PNJLCC = 3.84 × 10-8) and CBL (βGTEx = -0.17, PGTEx = 2.82 × 10-8; βNJLCC = -0.32, PNJLCC = 2.61 × 10-7) in lung tissue. Functional annotations and phenotype assays supported the carcinogenic effect of these novel susceptibility genes in lung carcinogenesis.
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http://dx.doi.org/10.1093/hmg/ddab119DOI Listing
August 2021

Comprehensive analyses of m6A regulators and interactive coding and non-coding RNAs across 32 cancer types.

Mol Cancer 2021 04 13;20(1):67. Epub 2021 Apr 13.

State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166, China.

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.
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http://dx.doi.org/10.1186/s12943-021-01362-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045265PMC
April 2021

Child marriage, maternal serum metal exposure, and risk of preterm birth in rural Bangladesh: evidence from mediation analysis.

J Expo Sci Environ Epidemiol 2021 05 6;31(3):571-580. Epub 2021 Apr 6.

State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.

Background: The prevalence of preterm birth in Bangladesh is estimated to be 19.1%, the highest in the world. Although prenatal exposure to several metals has been linked with preterm birth, fewer prospective studies have investigated the socioeconomic factors that affect metal exposure, leading to preterm birth risk.

Objective: We aim to identify novel metal biomarkers and their critical exposure windows, as well as the upstream socioeconomic risk factors for preterm birth in rural Bangladeshi, to shed light for future interventional strategies.

Methods: This study included data from 780 mother-offspring pairs, who were recruited to participate in a prospective birth cohort in Bangladesh (2008-2011). Serum concentrations of 19 metals were measured in the first and second trimesters using inductively coupled plasma mass spectrometry. Mediation analysis was performed to explore the upstream socioeconomic factors that affect the risk of preterm birth mediated via metal exposure concentrations.

Results: Early pregnancy exposure to serum zinc, arsenic, and strontium and mid-pregnancy exposure to barium were significantly associated with risk of preterm birth. Furthermore, younger marriage age was associated with an exponential increase in the risk of preterm birth, and women who married after 18 years old had a considerably lower risk of preterm birth. Mediation analysis indicated that these four elements mediated 30.2% of the effect of marriage age on preterm birth.

Conclusion: This study indicated that maternal serum metal exposure mediates the impact of child marriage on the increased risk of preterm birth via metal exposures. The findings shed light on the mechanisms underlying such association and provide insights into future interventional strategies.
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http://dx.doi.org/10.1038/s41370-021-00319-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134042PMC
May 2021

Relationships between sleep traits and lung cancer risk: a prospective cohort study in UK Biobank.

Sleep 2021 Sep;44(9)

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

Study Objectives: To prospectively investigate the association between sleep traits and lung cancer risk, accounting for the interactions with genetic predisposition of lung cancer.

Methods: We included 469 691 individuals free of lung cancer at recruitment from UK Biobank, measuring sleep behaviors with a standardized questionnaire and identifying incident lung cancer cases through linkage to national cancer and death registries. We estimated multivariable-adjusted hazard ratios (HRs) for lung cancer (2177 incident cases) across four sleep traits (sleep duration, chronotype, insomnia, and snoring) and examined the interaction and joint effects with a lung cancer polygenic risk score.

Results: A U-shaped association was observed for sleep duration and lung cancer risk, with an 18% higher risk (95% confidence interval [CI]: 1.07 to 1.30) for short sleepers and a 17% higher risk (95% CI: 1.02 to 1.34) for long sleepers compared with normal sleepers (7-8 h/day). Evening preference was associated with elevated lung cancer risk compared with morning preference (HR: 1.25; 95% CI: 1.07 to 1.46), but no association was found for insomnia or snoring. Compared with participants with favorable sleep traits and low genetic risk, those with both unfavorable sleep duration (<7 hours or >8 hours) or evening preference and high genetic risk showed the greatest lung cancer risk (HRsleep duration: 1.83; 95% CI: 1.47 to 2.27; HRchronotype: 1.85; 95% CI: 1.34 to 2.56).

Conclusions: Both unfavorable sleep duration and evening chronotype were associated with increased lung cancer incidence, especially for those with low to moderate genetic risk. These results indicate that sleep behaviors as modifiable risk factors may have potential implications for lung cancer risk.
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http://dx.doi.org/10.1093/sleep/zsab089DOI Listing
September 2021

Risk Assessment for Longitudinal Trajectories of Modifiable Lifestyle Factors on Chronic Kidney Disease Burden in China: A Population-based Study.

J Epidemiol 2021 Apr 3. Epub 2021 Apr 3.

National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine.

Background: Chronic kidney disease (CKD) is an important contributor to morbidity and mortality from noncommunicable diseases. We aimed to examine the longitudinal trajectories in risk factors, estimate their impact on CKD burden in China from 1991 to 2011, and project trends in the next 20 years.

Methods: We used data from a cohort of the China Health and Nutrition Survey and applied the comparative risk assessment method to estimate the number of CKD events attributable to all non-optimal levels of each risk factors.

Results: In 2011, current smoking was the leading individual attributable factor for CKD burden in China responsible for 7.9 (95% CI, 7.5-8.3) million CKD cases with a population-attributable fraction of 8.7% (95% CI, 6.0-11.6), while the rates of smoking have reduced and may have mitigated the increase in CKD. High triglyceride (TG) and high systolic blood pressure (SBP) were the leading metabolic risk factors responsible for 6.8 (95% CI, 6.4-7.1) million and 5.8 (95% CI, 5.5-6.1) million CKD-attributable cases, respectively. Additionally, the number of CKD cases associated with high body mass index (BMI), high diastolic blood pressure (DBP), high plasma glucose, and low high-density lipoprotein cholesterol (HDL-C) was 5.4 (95% CI, 5.1-5.6), 3.9 (95% CI, 3.7-4.1), 3.0 (95% CI, 2.8-3.1) and 2.6 (95% CI, 2.5-2.8) million, respectively.

Conclusions: Current smoking, high TG, and high SBP were the top three risk factors that contributed to CKD burden in China. Increased BMI, DBP, plasma glucose, and decreased HDL-C were also associated with the increase in CKD burden.
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http://dx.doi.org/10.2188/jea.JE20200497DOI Listing
April 2021

Editorial commentary on the special issue of CRISPR Trends in Biomedical Research.

Authors:
Hongbing Shen

J Biomed Res 2021 Mar;35(2):75

Editor-in-Chief, Journal of Biomedical Research.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038531PMC
March 2021

Sex-specific associations of circulating testosterone levels with all-cause and cause-specific mortality.

Eur J Endocrinol 2021 May;184(5):723-732

Department of Epidemiology and Biostatistics, International Joint Research Center on Environment and Human Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

Objective: Testosterone is a critical determinant of health in both genders. However, the relationship between circulating levels of testosterone and mortality remains undetermined.

Methods: We examined the associations of serum total testosterone (TT) and free testosterone (FT) with all-cause and cause-specific mortality in 154 965 men and 93 314 postmenopausal women from UK Biobank. Cox regression models were used to calculate the hazard ratios (HR) and 95% CIs. Given multiple testing, P < 0.005 was considered statistically significant.

Results: Over a median follow-up of 8.9 (inter-quartile range: 8.3-9.5) years, we documented 5754 deaths in men, including 1243 (21.6%) from CVD and 2987 (51.9%) from cancer. In postmenopausal women, 2435 deaths occurred, including 346 (14.2%) from CVD and 1583 (65.0%) from cancer. TT and FT concentrations were inversely associated with all-cause mortality in men, with the multivariable HR of 0.82 (95% CI: 0.75-0.91) and 0.80 (95% CI: 0.73-0.87) for the highest (Q5) vs the lowest quintile (Q1), respectively. In postmenopausal women, TT concentrations showed a positive association with all-cause mortality (HR for Q5 vs Q1 = 1.20, 95% CI: 1.06-1.37). Furthermore, higher TT and FT concentrations were associated with a lower risk of cancer mortality in men (both P for trend = 0.001), whereas TT concentrations were suggestively associated with a higher risk of cancer mortality in postmenopausal women (P for trend = 0.03).

Conclusions: Our findings suggest that high levels of circulating testosterone may be beneficial for all-cause and cancer mortality in men but detrimental in postmenopausal women.
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http://dx.doi.org/10.1530/EJE-20-1253DOI Listing
May 2021

The cancer-testis gene, sensitizes triple-negative breast cancer to PARP1 inhibitors by inducing homologous recombination deficiency.

Cancer Biol Med 2021 02;18(1):74-87

State Key Laboratory of Reproductive Medicine, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.

Objective: The newly defined cancer-testis (CT) gene, was previously found to play key roles in DNA double-strand break (DSB) repair. In this study, we aimed to investigate the effects and mechanisms of MEIOB in the carcinogenesis of triple-negative breast cancers (TNBCs).

Methods: The Cancer Genome Atlas database was used to quantify the expression of . Cox regression analysis was used to evaluate the association between expression and the prognosis of human TNBC. The effects of MEIOB on cell proliferation and migration in TNBCs were also assessed . Patient-derived xenograft (PDX) models were used to assess the sensitivity of breast cancers with active MEIOB to PARP1 inhibitors.

Results: We confirmed as a CT gene whose expression was restricted to the testes and breast tumors, especially TNBCs. Its activation was significantly associated with poor survival in breast cancer patients [overall, hazard ratio (HR) = 1.90 (1.16-2.06); TNBCs: HR = 7.05 (1.16-41.80)]. In addition, we found that was oncogenic and significantly promoted the proliferation of TNBC cells. Further analysis showed that participated in DSB repair in TNBCs. However, in contrast to its function in meiosis, it mediated homologous recombination deficiency (HRD) through the activation of polyADP-ribose polymerase (PARP)1 by interacting with YBX1. Furthermore, activated MEIOB was shown to confer sensitivity to PARP inhibitors, which was confirmed in PDX models.

Conclusions: played an oncogenic role in TNBC through its involvement in HRD. In addition, dysregulation of sensitized TNBC cells to PARP inhibitors, so may be a therapeutic target of PARP1 inhibitors in TNBC.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877187PMC
February 2021

Antibody seroprevalence in the epicenter Wuhan, Hubei, and six selected provinces after containment of the first epidemic wave of COVID-19 in China.

Lancet Reg Health West Pac 2021 Mar 5;8:100094. Epub 2021 Feb 5.

National Institute for Viral Disease Control and Prevention (China CDC), Beijing, China.

Background: China implemented containment measures to stop SARS-CoV-2 transmission in response to the COVID-19 epidemic. After the first epidemic wave, we conducted population-based serological surveys to determine extent of infection, risk factors for infection, and neutralization antibody levels to assess the real infections in the random sampled population.

Methods: We used a multistage, stratified cluster random sampling strategy to conduct serological surveys in three areas - Wuhan, Hubei Province outside Wuhan, and six provinces selected on COVID-19 incidence and containment strategy. Participants were consenting individuals >1 year old who resided in the survey area >14 days during the epidemic. Provinces screened sera for SARS-CoV-2-specific IgM, IgG, and total antibody by two lateral flow immunoassays and one magnetic chemiluminescence enzyme immunoassay; positive samples were verified by micro-neutralization assay.

Findings: We enrolled 34,857 participants (overall response rate, 92%); 427 were positive by micro-neutralization assay. Wuhan had the highest weighted seroprevalence (4•43%, 95% confidence interval [95%CI]=3•48%-5•62%), followed by Hubei-ex-Wuhan (0•44%, 95%CI=0•26%-0•76%), and the other provinces (<0•1%). Living in Wuhan (adjusted odds ratio aOR=13•70, 95%CI= 7•91-23•75), contact with COVID-19 patients (aOR=7•35, 95%CI=5•05-10•69), and age over 40 (aOR=1•36, 95%CI=1•07-1•72) were significantly associated with SARS-CoV-2 infection. Among seropositives, 101 (24%) reported symptoms and had higher geometric mean neutralizing antibody titers than among the 326 (76%) without symptoms (30±2•4 vs 15±2•1, <0•001).

Interpretation: The low overall extent of infection and steep gradient of seropositivity from Wuhan to the outer provinces provide evidence supporting the success of containment of the first wave of COVID-19 in China. SARS-CoV-2 infection was largely asymptomatic, emphasizing the importance of active case finding and physical distancing. Virtually the entire population of China remains susceptible to SARS-CoV-2; vaccination will be needed for long-term protection.

Funding: This study was supported by the Ministry of Science and Technology (2020YFC0846900) and the National Natural Science Foundation of China (82041026, 82041027, 82041028, 82041029, 82041030, 82041032, 82041033).
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http://dx.doi.org/10.1016/j.lanwpc.2021.100094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864613PMC
March 2021

Association between dietary sodium, potassium intake and lung cancer risk: evidence from the prostate, lung, colorectal and ovarian cancer screening trial and the Women's Health Initiative.

Transl Lung Cancer Res 2021 Jan;10(1):45-56

Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.

Background: Epidemiological studies have reported that dietary mineral intake plays an important role on lung cancer risk, but the association of sodium, potassium intake is still unclear.

Methods: We determined the association between dietary sodium, potassium intake and lung cancer risk based on the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial and the Women's Health Initiative (WHI). Totally 165,409 participants who completed the baseline questionnaire (BQ) and diet history questionnaire (DHQ) were included into the analytical dataset, including 92,984 (44,959 men and 48,025 women) from the PLCO trial and 72,425 (women only) from the WHI cohort. Multivariable Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of incident lung cancer associated with dietary potassium and sodium intake. The dose-response relationship was also described using the spline smoothed curve after adjusting covariates.

Results: After the median follow-up of 8.55 and 18.56 years, 1,278 and 1,631 new cases of lung cancer were identified in the PLCO trial and WHI cohort, respectively. Intake of sodium was significantly associated with the incidence of lung cancer in the PLCO trial after multivariate adjustment for men (HR: 1.19, 95% CI: 1.05-1.35; P for linear trend =0.044). There was a suggestion that lung cancer risk had a quadratic curve correlation with the increase of potassium intake for women (third vs. lowest quintile: HR: 0.72, 95% CI: 0.54-0.96; P for quadratic trend =0.042). The similar results showing an inverse association between potassium intake and lung cancer risk were also observed in the WHI cohort for women (highest vs. lowest quintile: HR: 0.82, 95% CI: 0.70-0.97; P for linear trend =0.009).

Conclusions: Appropriate intake of potassium has a protective effect against lung cancer, while high consumption of sodium is associated with an increased risk of lung cancer.
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http://dx.doi.org/10.21037/tlcr-20-870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867772PMC
January 2021

Prediction and clinical utility of a liver cancer risk model in Chinese adults: A prospective cohort study of 0.5 million people.

Int J Cancer 2021 06 15;148(12):2924-2934. Epub 2021 Feb 15.

Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China.

China has made rapid progress in reducing the incidence of HBV infection in the past three decades, along with a rapidly changing lifestyle and aging population. We aimed to develop and validate an up-to-date liver cancer risk prediction model with routinely available predictors and evaluate its applicability for screening guidance. Using data from the China Kadoorie Biobank, we included 486 285 participants in this analysis. Fifteen risk factors were included in the model. Flexible parametric survival models were used to estimate the 10-year absolute risk of liver cancer. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility. A total of 2706 participants occurred liver cancer over the 4 814 320 person-years of follow-up. Excellent discrimination of the model was observed in both development and validation datasets, with c-statistics (95% CI) of 0.80 (0.79-0.81) and 0.80 (0.78-0.82) respectively, as well as excellent calibration of observed and predicted risks. Decision curve analysis revealed that use of the model in selecting participants for screening improved benefit at a threshold of 2% 10-year risk, compared to current guideline of screening all HBsAg carriers. Our model was more sensitive than current guideline for cancer screening (28.17% vs 25.96%). We developed and validated a CKB-PLR (Prediction for Liver cancer Risk Based on the China Kadoorie Biobank Study) model to predict the absolute risk of liver cancer for both HBsAg seropositive and seronegative populations. Application of the model is beneficial for precisely identifying the high-risk groups among the general population.
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http://dx.doi.org/10.1002/ijc.33487DOI Listing
June 2021

Plasma sex hormones and risk of conventional and serrated precursors of colorectal cancer in postmenopausal women.

BMC Med 2021 Jan 28;19(1):18. Epub 2021 Jan 28.

Department of Nutrition, Harvard T.H. Chan School of Public Health, 667 Huntington Avenue, Kresge 906A, Boston, MA, 02115, USA.

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.
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http://dx.doi.org/10.1186/s12916-020-01895-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841996PMC
January 2021

The rates and medical necessity of cesarean delivery in China, 2012-2019: an inspiration from Jiangsu.

BMC Med 2021 01 25;19(1):14. Epub 2021 Jan 25.

State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166, China.

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.
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http://dx.doi.org/10.1186/s12916-020-01890-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831243PMC
January 2021
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