Publications by authors named "Jiajun Shi"

75 Publications

Endogenous sex hormones, aromatase activity and lung cancer risk in postmenopausal never-smoking women.

Int J Cancer 2022 Mar 26. Epub 2022 Mar 26.

Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.

Although reproductive factors have been repeatedly associated with lung cancer risk, no study to date has directly evaluated the relationship with endogenous sex hormones nor with aromatase activity in postmenopausal never-smoking women. A case-control study of 397 incident lung cancer cases and their individually matched controls, nested within the Shanghai Women's Health Study, was conducted among postmenopausal women who were lifetime never smokers. Prediagnostic concentrations of sex hormones was quantitated using LC-MS/MS assays in plasma. The product-substrate molar ratio of estrone to androstenedione was used as an index of aromatase activity (IAA). Multivariable conditional logistic regression models were used to calculate odds ratios (ORs) for lung cancer. Baseline concentrations of estradiol, free testosterone and IAA were inversely associated with subsequent risk of lung cancer in multivariable-adjusted models. When further adjusted for body mass index, the inverse association with estradiol was attenuated and no longer statistically significant, but the association with free testosterone and IAA remained. In analyses confined to participants having never used menopausal hormone therapy in 376 case-control pairs, the inverse association with free testosterone and IAA was slightly strengthened. OR for the highest vs the lowest quartile of free testosterone was 0.55 (95% CI = 0.34-0.90; P  = .03), and the corresponding OR for IAA was 0.57 (95% CI = 0.34-0.96; P  = .04). Our study, for the first time, suggests that higher levels of circulating free testosterone and estimated aromatase activity may be associated with lower lung cancer risk in postmenopausal never-smoking women.
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http://dx.doi.org/10.1002/ijc.34005DOI Listing
March 2022

Assessment of Skeletal Maturation in Male Children With Unilateral Cleft Lip and Palate.

J Craniofac Surg 2022 Mar 14. Epub 2022 Mar 14.

Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, China Faculty of Dentistry, National University of Singapore, Singapore.

Objectives: To assess the skeletal maturation in male children with unilateral cleft lip and palate (UCLP) in comparison to that of noncleft peers using the cervical vertebral maturation (CVM) method.

Methods: A sample of 149 male UCLP patients aged from 8- to 16-year-old and 447 age-matched orthodontic individuals without clefts was retrospectively compiled. Cervical vertebral maturation was assessed based on the cephalometric radiographs.

Results: The proportion of children in CVMSI and CVMSII was higher in the UCLP group compared to that in the noncleft group, but there was no significant difference in the CVM stage of the cleft patients compared to their noncleft peers. In the 12- to 14-year-old group, children with UCLP showed significantly delayed skeletal maturity in comparison with their noncleft peers. No significant difference was found in the other 3 age groups. There was a statistically significant correlation between the skeletal age and chronological age in both the UCLP group and the noncleft group. There was no significant difference in the mean age at CVMII and CVMIII between the cleft patients and noncleft peers.

Conclusions: Males with UCLP aged 12- to 14-year-old have a statistically significant increased risk of delayed skeletal maturity in comparison with their noncleft peers. The chronological age is not an accurate indicator to assess the degree of skeletal maturation.
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http://dx.doi.org/10.1097/SCS.0000000000008646DOI Listing
March 2022

Association Between Long-Term Regular Exercise and Gut Microbiota Among Middle-Aged and Older Urban Chinese.

Int J Sport Nutr Exerc Metab 2022 05 25;32(3):144-152. Epub 2022 Jan 25.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN,USA.

Increasing evidence has suggested that physical activity may modulate gut microbiome composition. We investigated associations of long-term regular exercise with gut microbiota among middle-aged and older urban Chinese individuals. Gut microbiota was assessed using 16S ribosomal ribonucleic acid gene sequencing of stool samples from 2,151 participants from the Shanghai Women's Health Study and Shanghai Men's Health Study. Participants were free of cancer, diabetes, and cardiovascular diseases at the time of stool sample collection. Physical activity was assessed in repeat surveys between 1996 and 2015 using validated questionnaires. Regular exercise was defined as any type of leisure-time physical activity with a standard metabolic equivalent score >3.0. Stool samples were collected using the 95% ethanol method between 2015 and 2018 with an average of 3.0 years (SD = 0.9) after the latest exposure assessment. General linear regression and permutational multivariate analysis of variance were carried out to evaluate associations of microbial α- and β-diversity with regular exercise participation. Logistic regression and linear regression models were used to evaluate the prevalence and relative abundance of individual taxa in association with regular exercise. Regular exercise was significantly associated with β-diversity (Bray-Curtis and Jaccard dissimilarities, both false discovery rates = 0.03%, 0.12% and 0.09% variance explained, respectively) but not with α-diversity. Relative abundance of genus Ruminococcus was significantly lower among regular exercisers compared with nonexercisers (median relative abundance: 0.64% vs. 0.81%, false discovery rate <0.10). Further studies are needed to validate the findings from this study and evaluate health benefits of regular exercise on gut microbiota.
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http://dx.doi.org/10.1123/ijsnem.2021-0065DOI Listing
May 2022

Vasodilatory Effect of Guanxinning Tablet on Rabbit Thoracic Aorta is Modulated by Both Endothelium-Dependent and -Independent Mechanism.

Front Pharmacol 2021 1;12:754527. Epub 2021 Dec 1.

Animal Experimental Research Center, Academy of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou, China.

Vasodilatory therapy plays an important role in the treatment of cardiovascular diseases, especially hypertension and coronary heart disease. Previous research found that Guanxinning tablet (GXNT), a traditional Chinese compound preparation composed of (Danshen) and (Chuanxiong), increase blood flow in the arteries, but whether vasodilation plays a role in this effect remains unclear. Here, we found that GXNT significantly alleviated the vasoconstriction of isolated rabbit thoracic aorta induced by phenylephrine (PE), norepinephrine (NE), and KCl in a dose-dependent manner with or without endothelial cells (ECs). Changes in calcium ion levels in vascular smooth muscle cells (VSMCs) showed that both intracellular calcium release and extracellular calcium influx through receptor-dependent calcium channel (ROC) declined with GXNT treatment. Experiments to examine potassium channels suggested that endothelium-denuded vessels were also regulated by calcium-activated potassium channels (K) and ATP-related potassium channels (K) but not voltage-gated potassium channels (k) and inward rectifying potassium channels (K). For endothelium-intact vessels, the nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) contents in vascular tissue obviously increased after GXNT treatment, and pretreatment with the NO synthase inhibitor Nw-nitro-L-arginine methyl ester (L-NAME) or guanylyl cyclase inhibitor methylthionine chloride (MB) significantly inhibited vasodilation. An assessment of NO-related pathway protein expression revealed that GXNT enhanced the expression of phosphorylated endothelial NO synthase (eNOS) in a dose-dependent manner but had no effect on total eNOS, p-Akt, Akt, or PI3K levels in human umbilical vein ECs (HUVECs). In addition to PI3K/AKT signaling, Ca/calmodulin (CaM)-Ca/CaM-dependent protein kinase II (CaMKII) signaling is a major signal transduction pathway involved in eNOS activation in ECs. Further results showed that free calcium ion levels were decreased in HUVECs with GXNT treatment, accompanied by an increase in p-CaMKII expression, implying an increase in the Ca/CaM-Ca/CaMKII cascade. Taken together, these findings suggest that the GXNT may have exerted their vasodilative effect by activating the endothelial CaMKII/eNOS signaling pathway in endothelium-intact rings and calcium-related ion channels in endothelium-denuded vessels.
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http://dx.doi.org/10.3389/fphar.2021.754527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8672209PMC
December 2021

Tumor stemness and immune infiltration synergistically predict response of radiotherapy or immunotherapy and relapse in lung adenocarcinoma.

Cancer Med 2021 12 5;10(24):8944-8960. Epub 2021 Nov 5.

Department of Thoracic and Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.

Cancer stem cells (CSCs) have been shown to accelerate tumor recurrence, radiotherapy, and chemotherapy resistance. Immunotherapy is a powerful anticancer treatment that can significantly prolong the overall survival of patients with lung adenocarcinoma (LUAD). However, little is known about the function of genes related to tumor stemness and immune infiltration in LUAD. After integrating the tumor stemness index based on mRNA expression (mRNAsi), immune score, mRNA expression, and clinical information from the TCGA database, we screened 380 tumor stemness and immune (TSI)-related genes and constructed a five TSI-specific-gene (CPS1, CCR2, NT5E, ANLN, and ABCC2) signature (TSISig) using a machine learning method. Survival analysis indicated that TSISig could stably predict the prognosis of patients with LUAD. Comparison of mRNAsi and immune score between high- and low-TSISig groups suggested that TSISig characterized tumor stemness and immune infiltration. In addition, enrichment of immune subpopulations showed that the low-TSISig group held more immune subpopulations. GSEA revealed that TSISig had a strong association with the cell cycle and human immune response. Further analysis revealed that TSISig not only had a good predictive ability for prognosis but could also serve as an excellent predictor of tumor recurrence and response to radiotherapy and immunotherapy in LUAD patients. TSISig might regulate the development of LUAD by coordinating tumor stemness and immune infiltration. Finally, a connectivity map (CMap) analysis demonstrated that the HDAC inhibitor could target TSISig.
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http://dx.doi.org/10.1002/cam4.4377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8683560PMC
December 2021

Switch-associated protein 70 protects against nonalcoholic fatty liver disease through suppression of TAK1.

Hepatology 2022 Jun 25;75(6):1507-1522. Epub 2022 Apr 25.

Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.

Background And Aims: NAFLD is a progressive disease without known effective drug treatments. Switch-associated protein 70 (SWAP70) is a guanine nucleotide exchange factor that participates in the regulation of many cellular processes. However, the role of SWAP70 in NAFLD remains unclear. This study aimed to identify the function and mechanism of SWAP70 in NAFLD.

Approach And Results: The results showed that the expression of SWAP70 was significantly increased in mice and hepatocytes after metabolic stimulation. Overexpression of SWAP70 in hepatocytes suppressed lipid deposition and inflammation, and SWAP70 knockdown created the inverse effect. Using hepatocyte-specific Swap70 knockout and overexpression mice fed a high-fat, high-cholesterol diet, we demonstrated that SWAP70 suppressed the progression of nonalcoholic steatohepatitis by inhibiting lipid accumulation, inflammatory response, and fibrosis. Mechanically, RNA sequencing analysis and immunoprecipitation assays revealed that SWAP70 inhibited the interaction between transforming growth factor β-activated kinase 1 (TAK1) binding protein 1 and TAK1 and sequentially suppressed the phosphorylation of TAK1 and subsequent c-Jun N-terminal kinase/P38 signaling. Inhibition of TAK1 activation blocked hepatocyte lipid deposition and inflammation caused by SWAP70 knockdown.

Conclusions: SWAP70 is a protective molecule that can suppress the progression of NAFLD by inhibiting hepatic steatosis and inflammation. SWAP70 may be important for mitigating the progression of NAFLD.
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http://dx.doi.org/10.1002/hep.32213DOI Listing
June 2022

Sex-Specific Associations between Gut Microbiome and Non-Alcoholic Fatty Liver Disease among Urban Chinese Adults.

Microorganisms 2021 Oct 8;9(10). Epub 2021 Oct 8.

Department of Medicine, Division of Epidemiology, Vanderbilt University Medical Center, Suite 600, Nashville, TN 37232, USA.

Non-alcoholic fatty liver disease (NAFLD) has been linked to altered gut microbiome; however, evidence from large population-based studies is limited. We compared gut microbiome profiles of 188 male and 233 female NAFLD cases with 571 male and 567 female controls from two longitudinal studies of urban Chinese adults. History of NAFLD was assessed during surveys administered in 2004-2017. Microbiota were assessed using 16S rRNA sequencing of stool samples collected in 2015-2018. Associations of NAFLD with microbiome diversity and composition were evaluated by generalized linear or logistic regression models. Compared with controls, male cases had lower microbial α-diversity, higher abundance of genera and and species, lower abundance of genus , and lower prevalence of taxa including order (all < 0.05). In contrast, female cases had higher α-diversity, higher abundance of genus and a family of order , lower abundance of and species, and higher prevalence of . Significant NAFLD-sex interactions were found for α-diversity and above taxa (all false discovery rate < 0.1). In conclusion, we observed sex-specific gut microbiome features related to history of NAFLD. Further studies are needed to validate our findings and evaluate the health effects of NAFLD-related gut microbiota.
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http://dx.doi.org/10.3390/microorganisms9102118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537656PMC
October 2021

First Report of Causing Calyx and Receptacle Blight on Strawberry in China.

Plant Dis 2022 04 22;106(4):1307. Epub 2022 Mar 22.

College of Plant Protection, Shenyang Agricultural University, Shenyang 110866, P.R. China.

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http://dx.doi.org/10.1094/PDIS-07-21-1376-PDNDOI Listing
April 2022

Association of oral microbiota with lung cancer risk in a low-income population in the Southeastern USA.

Cancer Causes Control 2021 Dec 25;32(12):1423-1432. Epub 2021 Aug 25.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, 1161 21st Avenue South, Nashville, TN, USA.

Purpose: Oral microbiome plays an important role in oral health and systemic diseases, including cancer. We aimed to prospectively investigate the association of oral microbiome with lung cancer risk.

Methods: We analyzed 156 incident lung cancer cases (73 European Americans and 83 African Americans) and 156 individually matched controls nested within the Southern Community Cohort Study. Oral microbiota were assessed using 16S rRNA gene sequencing in pre-diagnostic mouth rinse samples. Paired t test and the permutational multivariate analysis of variance test were used to evaluate lung cancer risk association with alpha diversity or beta diversity, respectively. Conditional logistic regression models were used to evaluate the association of individual bacterial abundance or prevalence with lung cancer risk.

Results: No significant differences were observed for alpha or beta diversity between lung cancer cases and controls. Abundance of families Lachnospiraceae_[XIV], Peptostreptococcaceae_[XI], and Erysipelotrichaceae and species Parvimonas micra was associated with decreased lung cancer risk, with odds ratios (ORs) and 95% confidence intervals (CIs) of 0.76 (0.59-0.98), 0.80 (0.66-0.97), 0.81 (0.67-0.99), and 0.83 (0.71-0.98), respectively (all p < 0.05). Prevalence of five pre-defined oral pathogens were not significantly associated with overall lung cancer risk. Prevalence of genus Bacteroidetes_[G-5] and species Alloprevotella sp._oral_taxon_912, Capnocytophaga sputigena, Lactococcus lactis, Peptoniphilaceae_[G-1] sp._oral_taxon_113, Leptotrichia sp._oral_taxon_225, and Fretibacterium fastidiosum was associated with decreased lung cancer risk, with ORs and 95% CIs of 0.55 (0.30-1.00), 0.36 (0.17-0.73), 0.53 (0.31-0.92), 0.43 (0.21-0.88), 0.43 (0.19-0.94), 0.57 (0.34-0.99), and 0.54 (0.31-0.94), respectively (all p < 0.05). Species L. sp._oral_taxon_225 was significantly associated with decreased lung cancer risk in African Americans (OR [95% CIs] 0.28 [0.12-0.66]; p = 0.00012).

Conclusion: Results from this study suggest that oral microbiota may play a role in the development of lung cancer.
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http://dx.doi.org/10.1007/s10552-021-01490-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8541916PMC
December 2021

Retrospective study of gene signatures and prognostic value of m6A regulatory factor in non-small cell lung cancer using TCGA database and the verification of FTO.

Aging (Albany NY) 2020 Sep 9;12(17):17022-17037. Epub 2020 Sep 9.

Department of Thoracic and Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.

N6-methyladenosine (m6A) is the most common internal modification in eukaryotic mRNA. However, little is known about its role in non-small cell lung cancer (NSCLC). In this study, a total of 1017 NSCLC patients from the cancer genome atlas (TCGA) database with copy number variation (CNV) data were included. Log-rank tests and Cox regression model were used for survival analysis. The relationship between m6A regulators and clinicopathological features was evaluated using the chi-square test. The alteration of m6A regulators were related to T stage. Patients with any CNVs of regulators genes had worse overall survival (OS) than those with diploid genes. The deletion of m6A writer genes was an independent risk factor for poor OS, and the effect synergized with that of copy number gain of eraser genes. High expression of Fat mass-and obesity-associated gene (FTO) was associated with KRAS signaling up. Knockdown of FTO increased m6A content and inhibit proliferation of A549 lung cancer cell. Thus, we identified the genetic changes of m6A regulatory factors in NSCLC for the first time and found a significant relationship between these changes and poor clinical characteristics. FTO might play an important role in promoting NSCLC by decreasing m6A level and activating KRAS signaling.
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http://dx.doi.org/10.18632/aging.103622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521517PMC
September 2020

MdHAL3, a 4'-phosphopantothenoylcysteine decarboxylase, is involved in the salt tolerance of autotetraploid apple.

Plant Cell Rep 2020 Nov 5;39(11):1479-1491. Epub 2020 Aug 5.

College of Horticulture, Shenyang Agricultural University, Shenyang, 110866, People's Republic of China.

Key Message: MdHAL3 has PPCDC activity and is involved in the salt tolerance of autotetraploid apple. Apple (Malus × domestica) is the most widely planted fruit tree species worldwide. However, the growth and development of apple have been increasingly affected by abiotic stress, such as high salinity. In our previous study, RNA sequencing (RNA-seq) analysis revealed that the expression level of the MdHAL3 gene was significantly upregulated in the autotetraploid apple cultivar Hanfu. In the present study, we first isolated HAL3, whose product was shown to exert 4'-phosphopantothenoylcysteine decarboxylase (PPCDC) activity, from apple. MdHAL3 was expressed in all organs of apple, and its expression was rapidly induced by salt stress. The MdHAL3 protein was localized to the cytomembrane and cytoplasm. Five MdHAL3 overexpression (OE) lines and five MdHAL3-RNAi apple lines were obtained. We found that MdHAL3 enhanced the salt stress tolerance of apple and that the OE plants rooted more easily than the wild-type (WT) plants. The coenzyme A (CoA) content in the leaves of the OE plants was greater than that in the leaves of the WT plants, and the CoA content in the MdHAL3-RNAi plants was lower than that in the WT plants. Taken together, our findings indicate that MdHAL3 plays an essential role in the response to salt stress in apple.
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http://dx.doi.org/10.1007/s00299-020-02576-2DOI Listing
November 2020

Resveratrol Attenuates Aortic Dissection by Increasing Endothelial Barrier Function Through the SIRT1 Pathway.

J Cardiovasc Pharmacol 2020 07;76(1):86-93

Department of Thoracic and Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.

Aortic dissection (AD) is a serious condition and a health issue on a global scale. β-Aminopropionitrile-induced AD in mice is similar to the pathogenesis of AD in humans. Resveratrol (RSV) is a natural polyphenolic substance that provides anti-inflammatory and cardiovascular effects, but the role of RSV in AD is unclear. In this study, we investigated the effects and mechanisms of RSV on β-aminopropionitrile-induced AD in mice. Our results indicate that RSV can prevent the occurrence of AD. More meaningfully, we found that the protective effect comprises an increase in sirtuin 1 (SIRT1) expression in endothelial cells for the reconstruction of their structure, reducing the recruitment of inflammatory cells by endothelial cells and inhibiting the inflammation response, thereby suppressing the occurrence of AD.
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http://dx.doi.org/10.1097/FJC.0000000000000837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340227PMC
July 2020

Evaluation of pathogenetic mutations in breast cancer predisposition genes in population-based studies conducted among Chinese women.

Breast Cancer Res Treat 2020 Jun 21;181(2):465-473. Epub 2020 Apr 21.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.

Purpose: Limited studies have been conducted to evaluate pathogenetic mutations in breast cancer predisposition genes among Chinese women. To fully characterize germline mutations of these genes in this population, we used the whole-exome sequencing data in a population-based case-control study conducted in Shanghai, China.

Methods: We evaluated exonic, splicing, and copy number variants in 11 established and 14 candidate breast cancer predisposition genes in 831 invasive breast cancer cases and 839 controls. We identified 55 pathogenic variants, including 15 newly identified in this study.

Results: Approximately 8% of the cases and 0.6% of the cancer-free controls carried these pathogenetic variants (P = 3.05 × 10). Among cases, 3.7% had a BRCA2 pathogenic variant and 1.6% had a BRCA1 pathogenic variant, while 2.5% had a pathogenic variant in other genes including ATM, CHEK2, NBN, NF1, CDH1, PALB2, PTEN, TP53 as well as BARD1, BRIP, and RAD51D. Patients with BRCA1/2 pathogenic variants were more likely to have a family history of breast cancer and hormone receptor negative tumors compared with patients without pathogenic variants.

Conclusions: This study highlighted the importance of hereditary breast cancer genes in the breast cancer etiology in this understudied population. Together with previous studies in East Asian women, this study suggested a relatively more prominent role of BRCA2 compared to BRCA1. This study also provides additional evidence to design cost-efficient genetic testing among Chinese women for risk assessment and early detection of breast cancer.
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http://dx.doi.org/10.1007/s10549-020-05643-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188717PMC
June 2020

Identification of novel breast cancer susceptibility loci in meta-analyses conducted among Asian and European descendants.

Nat Commun 2020 03 5;11(1):1217. Epub 2020 Mar 5.

Departments of Health Research and Policy, School of Medicine, Stanford University, California, CA, USA.

Known risk variants explain only a small proportion of breast cancer heritability, particularly in Asian women. To search for additional genetic susceptibility loci for breast cancer, here we perform a meta-analysis of data from genome-wide association studies (GWAS) conducted in Asians (24,206 cases and 24,775 controls) and European descendants (122,977 cases and 105,974 controls). We identified 31 potential novel loci with the lead variant showing an association with breast cancer risk at P < 5 × 10. The associations for 10 of these loci were replicated in an independent sample of 16,787 cases and 16,680 controls of Asian women (P < 0.05). In addition, we replicated the associations for 78 of the 166 known risk variants at P < 0.05 in Asians. These findings improve our understanding of breast cancer genetics and etiology and extend previous findings from studies of European descendants to Asian women.
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http://dx.doi.org/10.1038/s41467-020-15046-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057957PMC
March 2020

Galangin Protects against Symptoms of Dextran Sodium Sulfate-induced Acute Colitis by Activating Autophagy and Modulating the Gut Microbiota.

Nutrients 2020 Jan 29;12(2). Epub 2020 Jan 29.

State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, 2 Yuanmingyuan West Road, Beijing 100193, China.

Galangin is a natural flavonoid that has been reported to provide substantial health benefits. Nevertheless, little is known about the potential effects of galangin against inflammatory bowel diseases. Here, an in vivo study was performed to investigate the preventive effects of galangin against dextran sulphate sodium (DSS)-induced acute murine colitis, which mimics the symptoms of human ulcerative colitis (UC). Pre-treatment with galangin (15 mg/kg, ) resulted in a significant decreased in the macroscopic signs of DSS-induced colitic symptoms, including a decreased disease activity index, prevention of the colon length shortening, and alleviation of the pathological changes occurring in the colon. Colonic pro-inflammatory mediators, including tumor necrosis factor-alpha, interleukin (IL)-1 beta, and IL-6, as well as myeloperoxidase activities were decreased following galangin pre-treatment when compared with the DSS control group. Moreover, galangin pre-treatment significantly increased the expressions of autophagy-related proteins and promoted the formation of autophagosome in the colon. Galangin pre-treatment increased the diversity of the gut microbiota, and this was accompanied by increased levels of short-chain fatty acids. These observed changes could involve the modulating effects conferred by galangin in relation to some specific bacteria populations, including the recovery of spp., and increased spp. Overall, these results support the use of galangin in the prevention of UC.
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http://dx.doi.org/10.3390/nu12020347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071155PMC
January 2020

Identification of Novel Loci and New Risk Variant in Known Loci for Colorectal Cancer Risk in East Asians.

Cancer Epidemiol Biomarkers Prev 2020 02 11;29(2):477-486. Epub 2019 Dec 11.

Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.

Background: Risk variants identified so far for colorectal cancer explain only a small proportion of familial risk of this cancer, particularly in Asians.

Methods: We performed a genome-wide association study (GWAS) of colorectal cancer in East Asians, including 23,572 colorectal cancer cases and 48,700 controls. To identify novel risk loci, we selected 60 promising risk variants for replication using data from 58,131 colorectal cancer cases and 67,347 controls of European descent. To identify additional risk variants in known colorectal cancer loci, we performed conditional analyses in East Asians.

Results: An indel variant, rs67052019 at 1p13.3, was found to be associated with colorectal cancer risk at × 10 in Asians ( per allele deletion = 1.13, 95% confidence interval = 1.08-1.18). This association was replicated in European descendants using a variant (rs2938616) in complete linkage disequilibrium with rs67052019 ( = 7.7 × 10). Of the remaining 59 variants, 12 showed an association at < 0.05 in the European-ancestry study, including rs11108175 and rs9634162 at < 5 × 10 and two variants with an association near the genome-wide significance level (rs60911071, = 5.8 × 10; rs62558833, = 7.5 × 10) in the combined analyses of Asian- and European-ancestry data. In addition, using data from East Asians, we identified 13 new risk variants at 11 loci reported from previous GWAS.

Conclusions: In this large GWAS, we identified three novel risk loci and two highly suggestive loci for colorectal cancer risk and provided evidence for potential roles of multiple genes and pathways in the etiology of colorectal cancer. In addition, we showed that additional risk variants exist in many colorectal cancer risk loci identified previously.

Impact: Our study provides novel data to improve the understanding of the genetic basis for colorectal cancer risk.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571256PMC
February 2020

Exosomal miR-196a-1 promotes gastric cancer cell invasion and metastasis by targeting SFRP1.

Nanomedicine (Lond) 2019 10 14;14(19):2579-2593. Epub 2019 Oct 14.

Department of Gastroenterology, Nanjing Drum Tower Hospital affiliated to Medical School of Nanjing University, Nanjing 210008, PR China.

To investigate the role of exosomal miRNAs on gastric cancer (GC) metastasis. miRNA expression profiles of exosomes with distinct invasion potentials were analyzed using miRNA microarray and validated by quantitative real-time PCR. and experiments assessed the role of exosomal miR-196a-1 in GC's metastasis. High expression level of exosomal miR-196a-1 expression was significantly associated with poor survival in GC. Exosomes that contained miR-196a-1 were secreted from high-invasive GC cells. Ectopic miR-196a-1 expression promoted invasion of low-invasive GC cells by targeting SFRP1. miR-196a-1 was delivered from high-invasive GC into low-invasive GC cells via exosomes and promoted metastasis to the liver and .
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http://dx.doi.org/10.2217/nnm-2019-0053DOI Listing
October 2019

Exosomal miRNA-139 in cancer-associated fibroblasts inhibits gastric cancer progression by repressing MMP11 expression.

Int J Biol Sci 2019 22;15(11):2320-2329. Epub 2019 Aug 22.

Department of General surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China.

Solid tumors consist of various types of stromal cells in addition to cancer cells. Cancer-associated fibroblasts (CAFs) are a major component of the tumor stroma and play an essential role in tumor progression and metastasis in a variety of malignancies, including gastric cancer. However, the effects of CAFs on gastric cancer cells' progression and metastasis are not well studied. Here we show that matrix metalloproteinase 11 (MMP11) in exosomes secreted from CAFs can be delivered into gastric cancer cells. Gastric CAFs promote gastric cancer cell migration partially through exosomal MMP11. Moreover, MMP11 is overexpressed in exosomes purified from plasma of gastric cancer patients and tumor tissues and associated with overall survival of gastric patients. We also find that MMP11 is negatively regulated by exosomal miR-139 in the CAFs of gastric cancer. Exosomal miR-139 inhibits tumor growth and metastasis of gastric cancer cells by decreasing the expression of MMP11 and . Thus, we propose that exosomal miR-139 derived from gastric CAFs could inhibit the progression and metastasis of gastric cancer by decreasing MMP11 in tumor microenvironment.
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http://dx.doi.org/10.7150/ijbs.33750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775321PMC
May 2020

Large-Scale Genome-Wide Association Study of East Asians Identifies Loci Associated With Risk for Colorectal Cancer.

Gastroenterology 2019 Apr 6;156(5):1455-1466. Epub 2018 Dec 6.

Clalit Health Services National Israeli Cancer Control Center, Haifa, Israel; Department of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel; Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

Background & Aims: Genome-wide association studies (GWASs) have associated approximately 50 loci with risk of colorectal cancer (CRC)-nearly one third of these loci were initially associated with CRC in studies conducted in East Asian populations. We conducted a GWAS of East Asians to identify CRC risk loci and evaluate the generalizability of findings from GWASs of European populations to Asian populations.

Methods: We analyzed genetic data from 22,775 patients with CRC (cases) and 47,731 individuals without cancer (controls) from 14 studies in the Asia Colorectal Cancer Consortium. First, we performed a meta-analysis of 7 GWASs (10,625 cases and 34,595 controls) and identified 46,554 promising risk variants for replication by adding them to the Multi-Ethnic Global Array (MEGA) for genotype analysis in 6445 cases and 7175 controls. These data were analyzed, along with data from an additional 5705 cases and 5961 controls genotyped using the OncoArray. We also obtained data from 57,976 cases and 67,242 controls of European descent. Variants at identified risk loci were functionally annotated and evaluated in correlation with gene expression levels.

Results: A meta-analyses of all samples from people of Asian descent identified 13 loci and 1 new variant at a known locus (10q24.2) associated with risk of CRC at the genome-wide significance level of P < 5 × 10. We did not perform experiments to replicate these associations in additional individuals of Asian ancestry. However, the lead risk variant in 6 of these loci was also significantly associated with risk of CRC in European descendants. A strong association (44%-75% increase in risk per allele) was found for 2 low-frequency variants: rs201395236 at 1q44 (minor allele frequency, 1.34%) and rs77969132 at 12p11.21 (minor allele frequency, 1.53%). For 8 of the 13 associated loci, the variants with the highest levels of significant association were located inside or near the protein-coding genes L1TD1, EFCAB2, PPP1R21, SLCO2A1, HLA-G, NOTCH4, DENND5B, and GNAS. For other intergenic loci, we provided evidence for the possible involvement of the genes ALDH7A1, PRICKLE1, KLF5, WWOX, and GLP2R. We replicated findings for 41 of 52 previously reported risk loci.

Conclusions: We showed that most of the risk loci previously associated with CRC risk in individuals of European descent were also associated with CRC risk in East Asians. Furthermore, we identified 13 loci significantly associated with risk for CRC in Asians. Many of these loci contained genes that regulate the immune response, Wnt signaling to β-catenin, prostaglandin E2 catabolism, and cell pluripotency and proliferation. Further analyses of these genes and their variants is warranted, particularly for the 8 loci for which the lead CRC risk variants were not replicated in persons of European descent.
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http://dx.doi.org/10.1053/j.gastro.2018.11.066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441622PMC
April 2019

Colorectal cancer susceptibility loci and influence on survival.

Genes Chromosomes Cancer 2018 12 22;57(12):630-637. Epub 2018 Oct 22.

Center for Colorectal Cancer, National Cancer Center, Goyang, South Korea.

Genome-wide association studies (GWAS) have identified multiple single-nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. To evaluate the potential influence of colorectal cancer susceptibility SNPs on disease prognosis, we investigated whether GWAS-identified colorectal cancer risk SNPs and polygenic risk scores (PRSs) might be associated with survival among colorectal cancer patients. A total of 1374 colorectal cancer patients were recruited from the Korean National Cancer Center. For genotyping, 30 colorectal cancer-susceptibility SNPs previously identified by GWAS were selected. The Cox proportional hazard model was used to evaluate associations of these risk SNPs and PRSs with disease-free survival (DFS) and overall survival (OS). The prognostic values were compared between genetic and nongenetic models using Harrell's c index. During the follow-up period (median: 88, 91 months for DFS and OS), 570 DFS (41.5%) and 487 OS (35.4%) events were observed. We found that 5 SNPs were significantly associated with DFS or OS among colorectal cancer patients at P < .05: rs10936599 at 3q26.2 (MYNN), rs704017 at 10q22.3 (ZMIZ1-AS1), rs11196172 at 10q25.2 (TCF7L2), rs3802842 at 11q23.1 (COLCA1-2), and rs9929218 at 16q22.1 (CDH1). The PRSs constructed using these 5 SNPs were associated with worse survival (DFS: P  = .02 unweighted PRS, P  = .01 weighted PRS, OS: P  = 3.7 × 10 unweighted, P  = .02 weighted PRS). Our results suggest that several colorectal cancer susceptibility SNPs might also be related to survival by influencing disease progression.
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http://dx.doi.org/10.1002/gcc.22674DOI Listing
December 2018

Optimal Computational Power Allocation in Multi-Access Mobile Edge Computing for Blockchain.

Sensors (Basel) 2018 Oct 15;18(10). Epub 2018 Oct 15.

Department of Electrical and Computer Engineering, University of Nebraska-Lincoln, Omaha, NE 68182-0572, USA.

Blockchain has emerged as a decentralized and trustable ledger for recording and storing digital transactions. The mining process of Blockchain, however, incurs a heavy computational workload for miners to solve the proof-of-work puzzle (i.e., a series of the hashing computation), which is prohibitive from the perspective of the mobile terminals (MTs). The advanced multi-access mobile edge computing (MEC), which enables the MTs to offload part of the computational workloads (for solving the proof-of-work) to the nearby edge-servers (ESs), provides a promising approach to address this issue. By offloading the computational workloads via multi-access MEC, the MTs can effectively increase their successful probabilities when participating in the mining game and gain the consequent reward (i.e., winning the bitcoin). However, as a compensation to the ESs which provide the computational resources to the MTs, the MTs need to pay the ESs for the corresponding resource-acquisition costs. Thus, to investigate the trade-off between obtaining the computational resources from the ESs (for solving the proof-of-work) and paying for the consequent cost, we formulate an optimization problem in which the MTs determine their acquired computational resources from different ESs, with the objective of maximizing the MTs' social net-reward in the mining process while keeping the fairness among the MTs. In spite of the non-convexity of the formulated problem, we exploit its layered structure and propose efficient distributed algorithms for the MTs to individually determine their optimal computational resources acquired from different ESs. Numerical results are provided to validate the effectiveness of our proposed algorithms and the performance of our proposed multi-access MEC for Blockchain.
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http://dx.doi.org/10.3390/s18103472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211055PMC
October 2018

Three-Year Follow-Up of a Patient With Unilateral Cleft Lip and Palate Treated With Maxillary Protraction and Alveolar Bone Grafting: An Approach Exploring the Potential Power of Growth.

J Craniofac Surg 2018 Nov;29(8):e818-e824

Department of Orthodontics, Shanghai Ninth People's Hospital, School of Stomatology, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University, Shanghai, China.

Clinically, patients with operated unilateral cleft lip and palate always present with a concave profile, depressed midface, maxillary hypoplasia, narrow upper dental arch, and class III malocclusion. In this clinical report, the authors describe the successful orthodontic treatment of a patient with unilateral cleft lip and palate. A boy, 7 years 11 months of age, with a history of unilateral cleft lip and cleft palate presented with a Class I malocclusion on Skeletal Class III base. A satisfactory occlusion and a favorable lateral profile were achieved after maxillary protraction (face mask) combined with fixed appliance treatment, including alveolar bone grafting surgery. An acceptable occlusion and facial proportion were maintained after a 3-year retention period. These results suggest orthodontic treatment with growth interference is an effective option for a patient with cleft lip and palate.
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http://dx.doi.org/10.1097/SCS.0000000000004865DOI Listing
November 2018

Transcriptome-Wide Association Study Identifies Susceptibility Loci and Genes for Age at Natural Menopause.

Reprod Sci 2019 04 30;26(4):496-502. Epub 2018 May 30.

1 Department of Medicine, Vanderbilt Epidemiology Center and Division of Epidemiology, Vanderbilt University School of Medicine, Nashville, TN, USA.

Objective: To identify novel susceptibility genes for age at natural menopause (ANM).

Methods: Using transcription data generated in tissues from normal hypothalami (n = 73) and ovaries (n = 68) and high-density genotyping data provided by the Genotype-Tissue Expression (GTEx) database, we built 16 164 genetic models to predict gene expression across the transcriptome in these tissues. We used these models and summary statistics data from genome-wide association studies (GWAS) of ANM generated in 69 360 women of European ancestry to identify genes with their predicted expression related to ANM.

Results: We found the predicted expression of 34 genes to be significantly associated with ANM at a Bonferroni-corrected threshold of P < 3.09 ×10. These include 4 genes located more than 1 Mb away from any previously GWAS-identified ANM-associated variants, 24 genes that reside in known GWAS-identified loci but have not been previously implicated, and 6 genes previously implicated as ANM-associated genes.

Conclusion: Results from this transcriptome-wide association study, which integrated Expression quantitative trait loci (eQTL) data with summary statistics of GWAS of ANM, improves our understanding of the genetics and biology of female reproductive aging.
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http://dx.doi.org/10.1177/1933719118776788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421625PMC
April 2019

A Comprehensive cis-eQTL Analysis Revealed Target Genes in Breast Cancer Susceptibility Loci Identified in Genome-wide Association Studies.

Am J Hum Genet 2018 05;102(5):890-903

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA.

Genome-wide association studies (GWASs) have identified more than 150 common genetic loci for breast cancer risk. However, the target genes and underlying mechanisms remain largely unknown. We conducted a cis-expression quantitative trait loci (cis-eQTL) analysis using normal or tumor breast transcriptome data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), The Cancer Genome Atlas (TCGA), and the Genotype-Tissue Expression (GTEx) project. We identified a total of 101 genes for 51 lead variants after combing the results of a meta-analysis of METABRIC and TCGA, and the results from GTEx at a Benjamini-Hochberg (BH)-adjusted p < 0.05. Using luciferase reporter assays in both estrogen-receptor positive (ER) and negative (ER) cell lines, we showed that alternative alleles of potential functional single-nucleotide polymorphisms (SNPs), rs11552449 (DCLRE1B), rs7257932 (SSBP4), rs3747479 (MRPS30), rs2236007 (PAX9), and rs73134739 (ATG10), could significantly change promoter activities of their target genes compared to reference alleles. Furthermore, we performed in vitro assays in breast cancer cell lines, and our results indicated that DCLRE1B, MRPS30, and ATG10 played a vital role in breast tumorigenesis via certain disruption of cell behaviors. Our findings revealed potential target genes for associations of genetic susceptibility risk loci and provided underlying mechanisms for a better understanding of the pathogenesis of breast cancer.
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http://dx.doi.org/10.1016/j.ajhg.2018.03.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986971PMC
May 2018

Correction to: Age at menarche and age at natural menopause in East Asian women: a genome-wide association study.

Geroscience 2018 02;40(1):71-72

Department of Medicine, Vanderbilt Epidemiology Center and Division of Epidemiology, Vanderbilt University School of Medicine, 2525 West End Avenue, Suite 600, IMPH, Nashville, TN, 37203, USA.

The original version of this article unfortunately contained a mistake.
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http://dx.doi.org/10.1007/s11357-018-0007-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832656PMC
February 2018

Use of deep whole-genome sequencing data to identify structure risk variants in breast cancer susceptibility genes.

Hum Mol Genet 2018 03;27(5):853-859

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, and Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37203, USA.

Functional disruptions of susceptibility genes by large genomic structure variant (SV) deletions in germlines are known to be associated with cancer risk. However, few studies have been conducted to systematically search for SV deletions in breast cancer susceptibility genes. We analysed deep (> 30x) whole-genome sequencing (WGS) data generated in blood samples from 128 breast cancer patients of Asian and European descent with either a strong family history of breast cancer or early cancer onset disease. To identify SV deletions in known or suspected breast cancer susceptibility genes, we used multiple SV calling tools including Genome STRiP, Delly, Manta, BreakDancer and Pindel. SV deletions were detected by at least three of these bioinformatics tools in five genes. Specifically, we identified heterozygous deletions covering a fraction of the coding regions of BRCA1 (with approximately 80kb in two patients), and TP53 genes (with ∼1.6 kb in two patients), and of intronic regions (∼1 kb) of the PALB2 (one patient), PTEN (three patients) and RAD51C genes (one patient). We confirmed the presence of these deletions using real-time quantitative PCR (qPCR). Our study identified novel SV deletions in breast cancer susceptibility genes and the identification of such SV deletions may improve clinical testing.
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http://dx.doi.org/10.1093/hmg/ddy005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454518PMC
March 2018

Genetic Evidence for the Association between Schizophrenia and Breast Cancer.

J Psychiatr Brain Sci 2018 8;3(4). Epub 2018 Aug 8.

Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA.

Objective: To estimate the potential effect of schizophrenia on breast cancer risk in women, we performed a two-sample Mendelian randomization (MR) study.

Methods: The instrumental variables comprised 170 uncorrelated and non-pleiotropic single nucleotide polymorphisms (SNPs) that are significantly associated with schizophrenia risk in genome-wide association studies in 105,000 European descent individuals of the Psychiatric Genomics Consortium (http://www.med.unc.edu/pgc/) and the United Kingdom Clozapine Clinic. The association between these SNPs determined schizophrenia and breast cancer risk was estimated in approximately 229,000 European descent females from the Breast Cancer Association Consortium using the inverse-variance weighted and the weighted median MR methods.

Results: We found that the genetically-predicted risk of schizophrenia was associated with increased breast cancer risk (under a random-effects model: odds ratio per 1 unit increase in log odds of schizophrenia = 1.04, 95% confidence interval: 1.02-1.06, = 5.6 × 10). Similar significant associations were observed in analyses using a weighted median model and sensitivity analysis excluding six SNPs with genotype imputation score of less than 0.8, as well as analyses stratified by estrogen receptor status of breast cancer.

Conclusion: Our findings implicate a modest increased risk for breast cancer in genetically determined schizophrenic females.
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http://dx.doi.org/10.20900/jpbs.20180007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402491PMC
August 2018

EGFR with TKI-sensitive mutations in exon 19 is highly expressed and frequently detected in Chinese patients with lung squamous carcinoma.

Onco Targets Ther 2017 18;10:4607-4613. Epub 2017 Sep 18.

State Key Laboratory of Microbial Metabolism, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University.

Recently, tyrosine kinase inhibitors (TKIs) have been recommended as a first-line treatment for advanced non-small cell lung cancer (NSCLC), significantly improving the treatment outcomes of lung adenocarcinoma patients with the EGFR mutation. However, the application of TKIs for lung squamous cell carcinoma (SCC), the second largest pathological subtype of NSCLC, remains controversial because available data for the EGFR mutation profile and frequency in SCC patients are limited. In this study, 89 bronchoscopic-biopsy specimens from Chinese SCC male patients were assayed for EGFR exon 19 mutation, using improved polymerase chain reaction-denature gel gradient electrophoresis. EGFR exon 19 mutations were detected in 77 of 89 (86.5%) patients, and included six kinds of point mutations (11.6%) and two deletions (Del_747-751 [64.9%] and Del_746-751 [23.3%]). We found that the proportion of mutated EGFR varied from 0.98% to 100% in positive specimens and increased with the development of the disease. The difference of proportion between Stage IV patients and Stage II patients or Stage III patients was significant (<0.001). These results provided valuable clues to explain the reason why patients harboring the same mutation responded distinctly to TKI treatment. Del_747-751 and Del_746-751 were the dominant mutations in the assayed SCC patients (76.4%), and both belong to the EGFR-TKI-sensitive mutation. Recently research demonstrated that Del_746-751 patients have better response to EGFR-TKI than Del_L747-751 patients. However, our study indicated that majority of SCC patients (55.5%) carried Del_ L747-751. We suggest that the unique clinic features of SCC should be further studied to reveal the mechanism of poorer treatment outcome of EGFR-TKI therapy, and that a better treatment plan and more specific, potent targeted drugs for lung SCC need to be developed.
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http://dx.doi.org/10.2147/OTT.S130051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609803PMC
September 2017

Age at menarche and age at natural menopause in East Asian women: a genome-wide association study.

Age (Dordr) 2016 Dec 14;38(5-6):513-523. Epub 2016 Sep 14.

Department of Medicine, Vanderbilt Epidemiology Center and Division of Epidemiology, Vanderbilt University School of Medicine, 2525 West End Avenue, Suite 600, IMPH, Nashville, Tennessee, 37203, USA.

Age at menarche (AM) and age at natural menopause (ANM) are complex traits with a high heritability. Abnormal timing of menarche or menopause is associated with a reduced span of fertility and risk for several age-related diseases including breast, endometrial and ovarian cancer, cardiovascular disease, and osteoporosis. To identify novel genetic loci for AM or ANM in East Asian women and to replicate previously identified loci primarily in women of European ancestry by genome-wide association studies (GWASs), we conducted a two-stage GWAS. Stage I aimed to discover promising novel AM and ANM loci using GWAS data of 8073 women from Shanghai, China. The Stage II replication study used the data from another Chinese GWAS (n = 1230 for AM and n = 1458 for ANM), a Korean GWAS (n = 4215 for AM and n = 1739 for ANM), and de novo genotyping of 2877 additional Chinese women. Previous GWAS-identified loci for AM and ANM were also evaluated. We identified two suggestive menarcheal age loci tagged by rs79195475 at 10q21.3 (beta = -0.118 years, P = 3.4 × 10) and rs1023935 at 4p15.1 (beta = -0.145 years, P = 4.9 × 10) and one menopausal age locus tagged by rs3818134 at 22q12.2 (beta = -0.276 years, P = 8.8 × 10). These suggestive loci warrant a further validation in independent populations. Although limited by low statistical power, we replicated 19 of the 98 menarche loci and 5 of the 20 menopause loci previously identified in women of European ancestry in East Asian women, suggesting a shared genetic architecture for these two traits across populations.
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http://dx.doi.org/10.1007/s11357-016-9939-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5266214PMC
December 2016

Genome-wide association study in East Asians identifies two novel breast cancer susceptibility loci.

Hum Mol Genet 2016 08 27;25(15):3361-3371. Epub 2016 Jun 27.

Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, South Korea.

Breast cancer is one of the most common malignancies among women worldwide. Genetic factors have been shown to play an important role in breast cancer aetiology. We conducted a two-stage genome-wide association study (GWAS) including 14 224 cases and 14 829 controls of East Asian women to search for novel genetic susceptibility loci for breast cancer. Single nucleotide polymorphisms (SNPs) in two loci were found to be associated with breast cancer risk at the genome-wide significance level. The first locus, represented by rs12118297 at 1p22.3 (near the LMO4 gene), was associated with breast cancer risk with odds ratio (OR) and (95% confidence interval (CI)) of 0.91 (0.88-0.94) and a P-value of 4.48 × 10  This association was replicated in another study, DRIVE GAME-ON Consortium, including 16 003 cases and 41 335 controls of European ancestry (OR = 0.95, 95% CI = 0.91-0.99, P-value = 0.019). The second locus, rs16992204 at 21q22.12 (near the LINC00160 gene), was associated with breast cancer risk with OR (95% CI) of 1.13 (1.07-1.18) and a P-value of 4.63 × 10   The risk allele frequency for this SNP is zero in European-ancestry populations in 1000 Genomes Project and thus its association with breast cancer risk cannot be assessed in DRIVE GAME-ON Consortium. Functional annotation using the ENCODE data indicates that rs12118297 might be located in a repressed element and locus 21q22.12 may affect breast cancer risk through regulating LINC00160 expressions and interaction with oestrogen receptor signalling. Our findings provide additional insights into the genetics of breast cancer.
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http://dx.doi.org/10.1093/hmg/ddw164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5179918PMC
August 2016
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