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1.  Interaction between Polymorphisms in Pre-MiRNA Genes and Cooking Oil Fume Exposure on the Risk of Lung Cancer in Chinese Non-Smoking Female Population 
PLoS ONE  2015;10(6):e0128572.
Both genetic polymorphisms and environmental risk factors play important roles in the development of human chronic diseases including lung cancer. This is the first case-control study of interaction between polymorphisms in pre-miRNA genes and cooking oil fume exposure on the risk of lung cancer.
A hospital-based case-control study of 258 cases and 310 controls was conducted. Six polymorphisms in miRNAs were determined by Taqman allelic discrimination method. The gene-environment interactions were assessed on both additive and multiplicative scale. The statistical analyses were performed mostly with SPSS.
The combination of the risk genotypes of five miRNA SNPs (miR-146a rs2910164, miR-196a2 rs11614913, miR-608 rs4919510, miR-27a rs895819 and miR-423 rs6505162) with risk factor (cooking oil fume exposure) contributed to a significantly higher risk of lung cancer, and the corresponding ORs (95% confidence intervals) were 1.91(1.04-3.52), 1.94 (1.16-3.25), 2.06 (1.22-3.49), 1.76 (1.03-2.98) and 2.13 (1.29-3.51). The individuals with both risk genotypes of miRNA SNPs and exposure to risk factor (cooking oil fumes) were in a higher risk of lung cancer than persons with only one of the two risk factors (ORs were 1.91, 1.05 and 1.41 for miR-146a rs2910164, ORs were 1.94, 1.23 and 1.34 for miR-196a2 rs11614913, ORs were 2.06, 1.41 and 1.68 for miR-608 rs4919510, ORs were 1.76, 0.82 and 1.07 for miR-27a rs895819, and ORs were 2.13, 1.15 and 1.02 for miR-423 rs6505162, respectively). All the measures of biological interaction indicate that there were not indeed biological interactions between the six SNPs of miRNAs and exposure to cooking oil fumes on an additive scale. Logistic models suggested that the gene-environment interactions were not statistically significant on a multiplicative scale.
The interactions between miRNA SNPs and cooking oil fume exposure suggested by ORs of different combination were not statistically significant.
PMCID: PMC4471348  PMID: 26083623
2.  TGFβ-1 and TGFBR2 polymorphisms, cooking oil fume exposure and risk of lung adenocarcinoma in Chinese nonsmoking females: a case control study 
BMC Medical Genetics  2015;16:22.
Transforming growth factor-β (TGF-β) plays an important role in regulating cellular functions, and many studies have demonstrated important roles for TGF-β in various cancers. Single nucleotide polymorphisms (SNPs) of TGF-β may influence lung carcinogenesis. The aim of this study was to test whether TGF-β1 C509T and TGF-β receptor II (TGFBR2) G-875A polymorphisms were associated with lung adenocarcinoma in nonsmoking females.
A hospital-based case–control study was performed in Chinese nonsmoking females. Genotyping was performed using TaqMan SNP genotyping assay, and demographic data and environmental exposure were collected by trained interviewers after informed consents were obtained.
A total of 272 (95.4%) cases and 313 (99.4%) controls were successfully genotyped, and the results showed that the polymorphic allele frequencies of C509T and G875A were similar among lung adenocarcinoma patients and controls (P=0.589 and 0.643, respectively). However, when the data were stratified for cooking oil fume exposure, the TT genotype of the TGFB1 C509T polymorphism showed a significantly decreased risk for lung adenocarcinoma compared with the CC genotype (adjusted OR=0.362, 95% CI=0.149–0.878, P=0.025).
TGF-β1 gene C509T polymorphism might be associated with decreased risk of lung adenocarcinoma in Chinese females exposed to cooking oil fumes, but no association was observed TGFBR2 gene G875A polymorphism.
PMCID: PMC4432980  PMID: 25928368
Transforming growth factor-β; Lung adenocarcinoma; Polymorphisms; Nonsmoking females
3.  Effect of Single Nucleotide Polymorphism Rs189037 in ATM Gene on Risk of Lung Cancer in Chinese: A Case-Control Study 
PLoS ONE  2014;9(12):e115845.
Accumulated evidence has indicated that ataxia-telangiectasia mutated (ATM) gene polymorphisms are closely related to lung cancer. We aimed to explore the prognostic value of rs189037 (G>A), one of ATM single nucleotide polymorphisms (SNPs), and detect whether it involves in the risk of lung cancer in Chinese Han people.
In this hospital-based matched case-control study, 852 lung cancer patients and 852 healthy controls have been put into comparison to analyze the association between rs189037 and lung cancer risk in Chinese. The single nucleotide polymorphisms were determined by TaqMan real-time PCR and we used SPSS software to perform the statistical analyses.
Individuals carrying variant AA genotype of rs189037 had higher lung cancer risk (adjusted OR: 1.56) than those carrying GG genotype. After analyzing data respectively from different groups divided by genders and smoking status, we observed that the risk effect of AA genotype on the lung cancer was significant in females, non-smokers and female non-smokers, as well as the risk effect of GA genotype in male smokers. Compared with non-smokers carrying GG genotype, smokers carrying at least one A allele had higher risk of developing lung cancer than those with GG genotype (adjusted OR: 3.52 vs. adjusted OR: 2.53).
This study suggested that rs189037 (G>A) polymorphism is associated with lung cancer risk in Chinese Han population. AA genotype and A allele may be dangerous lung cancer signals in Chinese and make contribution to diagnostic and treatment value.
PMCID: PMC4277362  PMID: 25541996
4.  Prognostic Role of Common MicroRNA Polymorphisms in Cancers: Evidence from a Meta-Analysis 
PLoS ONE  2014;9(10):e106799.
The morbidity and mortality of cancer increase remarkably every year. It's a heavy burden for family and society. The detection of prognostic biomarkers can help to improve the theraputic effect and prolong the lifetime of patients. microRNAs have an influential role in cancer prognosis. The results of articles discussing the relationship between microRNA polymorphisms and cancer prognosis are inconsistent.
We conduct a meta-analysis of 19 publications concerning the association of four common polymorphisms, mir-146a rs2910164, mir-149 rs2292832, mir-196a2 rs11614913 and mir-499 rs3746444, with cancer prognosis. Pooled Hazard Ratios with 95% Confidence Intervals for the relationship between four genetic polymorphisms and Overall Survival, Recurrence-free Survival, Disease-free survival, recurrence are calculated. Subgroup analysis by population and type of tumor are conducted.
GG genotype of mir-146a may be the protective factor for overall survival, especially in Caucasian population. C-containing genotypes of mir-196a2 act as a risk role for overall survival. The same result exists in Asian population, in Non-Small Cell Lung Cancer and digestive cancer. The patients with C allele of mir-149 have a better overall survival, especially in Non-Small Cell Lung Cancer. No significant results are obtained for mir-499 polymorphisms.
Genetic polymorphisms in mir-146a, mir-196a2 and mir-149 may be associated with overall survival. This effect varies with different types of cancer. Genetic polymorphism in mir-499 may have nothing to do with cancer prognosis.
PMCID: PMC4206268  PMID: 25337946
5.  4-Hydroxychalcone Attenuates Hyperaldosteronism, Inflammation, and Renal Injury in Cryptochrome-Null Mice 
BioMed Research International  2014;2014:603415.
In the present study, we aimed to investigate the preventive effects of 4-hydroxychalcone (4HCH) on resistant hypertension. We used cryptochrome-null mice, which characteristically show high plasma aldosterone levels, inflammation, and renal injury. The cryptochrome-null mice received high-salt treatment and were treated orally with 4HCH 10 mg/kg, 4HCH 20 mg/kg, and 4HCH 40 mg/kg, respectively. The salt administration in cryptochrome-null mice is able to induce an increase in systolic pressure which is associated with hyperaldosteronism, inflammation, and kidney injury. Treatment with 40 mg/kg 4HCH reduced systolic hypertension, serum IL-1β, and TNF-α levels and suppressed the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and renal injury. The impact of 4HCH on the hyperaldosteronism, inflammation, and kidney injury provides new insights for future development of therapeutic strategies in resistant hypertension.
PMCID: PMC4070534  PMID: 25003119
6.  An eight-miRNA signature as a potential biomarker for predicting survival in lung adenocarcinoma 
Lung adenocarcinoma is a heterogernous disease that creates challenges for classification and management. The purpose of this study is to identify specific miRNA markers closely associated with the survival of LUAD patients from a large dataset of significantly altered miRNAs, and to assess the prognostic value of this miRNA expression profile for OS in patients with LUAD.
We obtained miRNA expression profiles and corresponding clinical information for 372 LUAD patients from The Cancer Genome Atlas (TCGA), and identified the most significantly altered miRNAs between tumor and normal samples. Using survival analysis and supervised principal components method, we identified an eight-miRNA signature for the prediction of overall survival (OS) of LUAD patients. The relationship between OS and the identified miRNA signature was self-validated in the TCGA cohort (randomly classified into two subgroups: n = 186 for the training set and n = 186 for the testing set). Survival receiver operating characteristic (ROC) analysis was used to assess the performance of survival prediction. The biological relevance of putative miRNA targets was also analyzed using bioinformatics.
Sixteen of the 111 most significantly altered miRNAs were associated with OS across different clinical subclasses of the TCGA-derived LUAD cohort. A linear prognostic model of eight miRNAs (miR-31, miR-196b, miR-766, miR-519a-1, miR-375, miR-187, miR-331 and miR-101-1) was constructed and weighted by the importance scores from the supervised principal component method to divide patients into high- and low-risk groups. Patients assigned to the high-risk group exhibited poor OS compared with patients in the low-risk group (hazard ratio [HR] = 1.99, P <0.001). The eight-miRNA signature is an independent prognostic marker of OS of LUAD patients and demonstrates good performance for predicting 5-year OS (Area Under the respective ROC Curves [AUC] = 0.626, P = 0.003), especially for non-smokers (AUC = 0.686, P = 0.023).
We identified an eight-miRNA signature that is prognostic of LUAD. The miRNA signature, if validated in other prospective studies, may have important implications in clinical practice, in particular identifying a subgroup of patients with LUAD who are at high risk of mortality.
PMCID: PMC4062505  PMID: 24893932
Lung adenocarcinoma; MicroRNA; Prognostic markers; Overall survival
7.  Valsartan ameliorates ageing-induced aorta degeneration via angiotensin II type 1 receptor-mediated ERK activity 
Angiotensin II (Ang II) plays important roles in ageing-related disorders through its type 1 receptor (AT1R). However, the role and underlying mechanisms of AT1R in ageing-related vascular degeneration are not well understood. In this study, 40 ageing rats were randomly divided into two groups: ageing group which received no treatment (ageing control), and valsartan group which took valsartan (selective AT1R blocker) daily for 6 months. 20 young rats were used as adult control. The aorta structure were analysed by histological staining and electron microscopy. Bcl-2/Bax expression in aorta was analysed by immunohistochemical staining, RT-PCR and Western blotting. The expressions of AT1R, AT2R and mitogen-activated protein kinases (MAPKs) were detected. Significant structural degeneration of aorta in the ageing rats was observed, and the degeneration was remarkably ameliorated by long-term administration of valsartan. With ageing, the expression of AT1R was elevated, the ratio of Bcl-2/Bax was decreased and meanwhile, an important subgroup of MAPKs, extracellular signal-regulated kinase (ERK) activity was elevated. However, these changes in ageing rats could be reversed to some extent by valsartan. In vitro experiments observed consistent results as in vivo study. Furthermore, ERK inhibitor could also acquire partial effects as valsartan without affecting AT1R expression. The results indicated that AT1R involved in the ageing-related degeneration of aorta and AT1R-mediated ERK activity was an important mechanism underlying the process.
PMCID: PMC4508146  PMID: 24548645
vascular ageing; angiotensin II; valsartan; Bcl-2; Bax; mitogen-activated protein kinase
8.  Single Nucleotide Polymorphism in ATM Gene, Cooking Oil Fumes and Lung Adenocarcinoma Susceptibility in Chinese Female Non-Smokers: A Case-Control Study 
PLoS ONE  2014;9(5):e96911.
The ataxia-telangiectasia mutated (ATM) gene plays an important role in the DNA double-strand breaks repair pathway. Single nucleotide polymorphisms (SNPs) of DNA repair genes are suspected to influence the risk of lung cancer. This study aimed to investigate the association between the ATM -111G>A (rs189037) polymorphism, environmental risk factors and the risk of lung adenocarcinoma in Chinese female non-smokers.
A hospital-based case-control study of 487 lung cancer patients and 516 matched cancer-free controls was conducted. Information concerning demographic and environmental risk factors was obtained for each case and control by a trained interviewer. After informed consent was obtained, 10 ml venous blood was collected from each subject for biomarker testing. Single nucleotide polymorphism was determined by using TaqMan method.
This study showed that the individuals with ATM rs189037 AA genotype were at an increased risk for lung adenocarcinoma compared with those carrying the GA or GG genotype (adjusted odds ratios (OR) 1.44, 95% confidence interval (CI) 1.02–2.02, P = 0.039). The stratified analysis suggested that increased risk associated with ATM rs189037 AA genotype in individuals who never or seldom were exposed to cooking oil fumes (adjusted OR 1.89, 95%CI 1.03–3.49, P = 0.040).
ATM rs189037 might be associated with the risk of lung adenocarcinoma in Chinese non-smoking females. Furthermore, ATM rs189037 AA genotype might be a risk factor of lung adenocarcinoma among female non-smokers without cooking oil fume exposure.
PMCID: PMC4018408  PMID: 24819391
9.  Hypoxia Promotes Migration and Induces CXCR4 Expression via HIF-1α Activation in Human Osteosarcoma 
PLoS ONE  2014;9(3):e90518.
Cellular adaptation to a hypoxic microenvironment is essential for tumor progression and is largely mediated by HIF-1α through coordinated regulation of hypoxia-responsive genes. The chemokine SDF-1α and its unique receptor CXCR4 have been implicated in organ-specific metastases of many cancers. In this study, we investigated the response of osteosarcoma cells to hypoxia and the expression of CXCR4 and HIF-1α in human osteosarcoma specimens and explored the roles of CXCR4 and HIF-1α in the cell migration process.
Methodology/Principal Findings
We performed immunohistochemistry, immunocytochemistry, quantitative real-time PCR, Western blots and fluorescent reporter assays to evaluate the correlation between CXCR4 and HIF-1α expression in human osteosarcoma specimens or SOSP-9607 cells under normoxic and hypoxic conditions. Transwell assays were used to assess cell migration under different conditions. Exposure of SOSP-9607 cells to hypoxic conditions resulted in significantly increased migration. When SOSP-9607 cells were subjected to hypoxic conditions, the mRNA and protein levels of CXCR4 were significantly increased in a time-dependent manner. Moreover, siHIF-1α significantly decreased the mRNA and protein levels of CXCR4 under hypoxia, whereas pcDNA-HIF-1α significantly increased the mRNA and protein levels of CXCR4 under normoxia. A luciferase reporter gene study showed that siHIF-1α reduced pGL3-CXCR4 luciferase activity. Furthermore, coexpression of HIF-1α and CXCR4 was significantly higher in patients with distant metastasis compared with those without metastasis.
The hypoxia-HIF-1α-CXCR4 pathway plays a crucial role during the migration of human osteosarcoma cells, and targeting this pathway might represent a novel therapeutic strategy for patients suffering from osteosarcoma.
PMCID: PMC3949690  PMID: 24618817
10.  Association of X-Ray Repair Cross-Complementing Group 1 Arg194Trp, Arg399Gln and Arg280His Polymorphisms with Head and Neck Cancer Susceptibility: A Meta-Analysis 
PLoS ONE  2014;9(1):e86798.
Previous studies on the association of X-ray repair cross-complementing group 1 (XRCC1) Arg194Trp, Arg399Gln, and Arg280His polymorphisms with head and neck cancer (HNC) have produced inconsistent results. The aim of the present study was to evaluate the effects of these three polymorphic variants on HNC risk.
The PubMed and EMBASE databases were searched for genetic association studies on the XRCC1 Arg194Trp, Arg399Gln, and Arg280His polymorphisms and HNC risk. (The most recent search was conducted on 20 August, 2013.) Twenty-six studies were identified and meta-analysis was performed to evaluate the association between the polymorphism and HNC by calculating combined odds ratios and 95% confidence intervals.
No significant association was found under the allelic, homozygous, heterozygote, and dominant genetic models in the overall comparison. Further, no significant association between the XRCC1 Arg399Gln and Arg280His polymorphisms and HNC risk was detected under the four genetic models in subgroup analyses based on ethnicity, cancer site, and whether or not the studies had been adjusted for cigarette smoking and alcohol. However, in stratified analyses based on cancer site, a significant association was found between the XRCC1 Arg194Trp polymorphism and oral cancer under the allelic, heterozygote, and dominant models. The XRCC1 Arg194Trp polymorphism was significantly associated with HNC risk in studies that were adjusted for smoking and alcohol under the homozygous and heterozygote models.
The meta-analysis results suggest that the XRCC1 Arg399Gln and Arg280His polymorphisms are probably not associated with the risk of HNC, but the XRCC1 Arg194Trp polymorphism was associated with increased risk of HNC in the subgroup analysis of studies adjusted for smoking and alcohol and with increased risk of oral cancer in the stratified analyses based on cancer site. Further studies with larger samples are needed to confirm these findings.
PMCID: PMC3907446  PMID: 24497981
11.  Genetic variant in TP63 on locus 3q28 is associated with risk of lung adenocarcinoma among never-smoking females in Asia 
Hosgood, H. Dean | Wang, Wen-Chang | Hong, Yun-Chul | Wang, Jiu-Cun | Chen, Kexin | Chang, I-Shou | Chen, Chien-Jen | Lu, Daru | Yin, Zhihua | Wu, Chen | Zheng, Wei | Qian, Biyun | Park, Jae Yong | Kim, Yeul Hong | Chatterjee, Nilanjan | Chen, Ying | Chang, Gee-Chen | Hsiao, Chin-Fu | Yeager, Meredith | Tsai, Ying-Huang | Wei, Hu | Kim, Young Tae | Wu, Wei | Zhao, Zhenhong | Chow, Wong-Ho | Zhu, Xiaoling | Lo, Yen-Li | Sung, Sook Whan | Chen, Kuan-Yu | Yuenger, Jeff | Kim, Joo Hyun | Huang, Liming | Chen, Ying-Hsiang | Gao, Yu-Tang | Kim, Jin Hee | Huang, Ming-Shyan | Jung, Tae Hoon | Caporaso, Neil | Zhao, Xueying | Huan, Zhang | Yu, Dianke | Kim, Chang Ho | Su, Wu-Chou | Shu, Xiao-Ou | Kim, In-San | Bassig, Bryan | Chen, Yuh-Min | Cha, Sung Ick | Tan, Wen | Chen, Hongyan | Yang, Tsung-Ying | Sung, Jae Sook | Wang, Chih-Liang | Li, Xuelian | Park, Kyong Hwa | Yu, Chong-Jen | Ryu, Jeong-Seon | Xiang, Yongbing | Hutchinson, Amy | Kim, Jun Suk | Cai, Qiuyin | Landi, Maria Teresa | Lee, Kyoung-Mu | Hung, Jen-Yu | Park, Ju-Yeon | Tucker, Margaret | Lin, Chien-Chung | Ren, Yangwu | Perng, Reury-Perng | Chen, Chih-Yi | Jin, Li | Chen, Kun-Chieh | Li, Yao-Jen | Chiu, Yu-Fang | Tsai, Fang-Yu | Yang, Pan-Chyr | Fraumeni, Joseph F. | Seow, Adeline | Lin, Dongxin | Zhou, Baosen | Chanock, Stephen | Hsiung, Chao Agnes | Rothman, Nathaniel | Lan, Qing
Human genetics  2012;131(7):10.1007/s00439-012-1144-8.
A recent genome-wide association study (GWAS) of subjects from Japan and South Korea reported a novel association between the TP63 locus on chromosome 3q28 and risk of lung adenocarcinoma (p = 7.3 × 10−12); however, this association did not achieve genome-wide significance (p < 10−7) among never-smoking males or females. To determine if this association with lung cancer risk is independent of tobacco use, we genotyped the TP63 SNPs reported by the previous GWAS (rs10937405 and rs4488809) in 3,467 never-smoking female lung cancer cases and 3,787 never-smoking female controls from 10 studies conducted in Taiwan, Mainland China, South Korea, and Singapore. Genetic variation in rs10937405 was associated with risk of lung adenocarcinoma [n = 2,529 cases; p = 7.1 × 10−8; allelic risk = 0.80, 95% confidence interval (CI) = 0.74–0.87]. There was also evidence of association with squamous cell carcinoma of the lung (n = 302 cases; p = 0.037; allelic risk = 0.82, 95% CI = 0.67–0.99). Our findings provide strong evidence that genetic variation in TP63 is associated with the risk of lung adenocarcinoma among Asian females in the absence of tobacco smoking.
PMCID: PMC3875137  PMID: 22367405
12.  Abnormal fecal microbiota community and functions in patients with hepatitis B liver cirrhosis as revealed by a metagenomic approach 
BMC Gastroenterology  2013;13:175.
Assessment and characterization of human colon microbiota is now a major research area in human diseases, including in patients with hepatitis B liver cirrhosis (HBLC).
We recruited 120 patients with HBLC and 120 healthy controls. The fecal microbial community and functions in the two groups were analyzed using high-throughput Solexa sequencing of the complete metagenomic DNA and bioinformatics methods.
Community and metabolism-wide changes of the fecal microbiota in 20 HBLC patients and 20 healthy controls were observed and compared. A negative correlation was observed between the Child-Turcotte-Pugh scores and Bacteroidetes (P < 0.01), whereas a positive correlation was observed between the scores and Enterobacteriaceae and Veillonella (P < 0.01). Analysis of the additional 200 fecal microbiota samples demonstrated that these intestinal microbial markers might be useful for distinguishing liver cirrhosis microbiota samples from normal ones. The functional diversity was significantly reduced in the fecal microbiota of cirrhotic patients compared with in the controls. At the module or pathway levels, the fecal microbiota of the HBLC patients showed enrichment in the metabolism of glutathione, gluconeogenesis, branched-chain amino acid, nitrogen, and lipid (P < 0.05), whereas there was a decrease in the level of aromatic amino acid, bile acid and cell cycle related metabolism (P < 0.05).
Extensive differences in the microbiota community and metabolic potential were detected in the fecal microbiota of cirrhotic patients. The intestinal microbial community may act as an independent organ to regulate the body’s metabolic balance, which may affect the prognosis for HBLC patients.
PMCID: PMC3878425  PMID: 24369878
Metagenome; Cirrhosis; Microbiota; Metabolism
13.  The relationship between thyroiditis and polycystic ovary syndrome: a meta-analysis 
Background: The link between AIT and PCOS has been reported on several studies, but it’s true pathogenesis is far from being elucidated. In an attempt to provide evidence of the relationship between PCOS and AIT, relevant literature of AIT markers in women with PCOS was reviewed and analyzed. Methods: PubMed, Embase, Medline, Web of Knowledge and the Cochrane trial register were searched with English language restriction for only human beings. Data were collected and analyzed by Revman. Results: A total of 6 studies, involving 726 PCOS patients and 879 controls, were eligible for our meta-analysis. Conculsion: The prevalence of AIT, serum TSH, anti-TPO and anti-Tg positive rate in PCOS patients are all significantly higher than those in control groups, which suggests PCOS may be a kind of autoimmune disease and has close association with AIT. So, It will be helpful to assess thyroid function routinely in patients with PCOS and offer thyroid hormone replacement therapy if necessary.
PMCID: PMC3832324  PMID: 24260593
Polycystic ovary syndrome; thyroiditis; atuoimmune diseases; meta-analysis
14.  Investigating ligand-receptor interactions at bilayer surface using electronic absorption spectroscopy and Fluorescence Resonance Energy Transfer 
We investigate interactions between receptors and ligands at bilayer surface of polydiacetylene (PDA) liposomal nanoparticles using changes in electronic absorption spectroscopy and Fluorescence Resonance Energy Transfer (FRET). We study the effect of mode of linkage (covalent versus non-covalent) between the receptor and liposome bilayer. We also examine the effect of size dependent interactions between liposome and analyte through electronic absorption and FRET responses. Glucose (receptor) molecules were either covalently or non-covalently attached at the bilayer of nanoparticles, and they provided selectivity for molecular interactions between glucose and glycoprotein ligands of E. coli. The receptor-ligand interactions between glucose and ligand on E. Coli surface induced stress on conjugated PDA chain which resulted in changes (blue to red) in the absorption spectrum of PDA. The changes in electronic absorbance also led to changes in FRET efficiency between conjugated PDA chains (acceptor) and fluorophores (Sulphorhodamine-101) (donor) attached to the bilayer surface. Interestingly, we did not find significant differences in UV-Vis and FRET responses for covalently- and non-covalently-bound glucose to liposomes following their interactions with E. Coli. We attributed these results to close proximity of glucose receptor molecules to the liposome bilayer surface such that induced stress were similar in both the cases. We also found that PDA emission from direct excitation mechanism was ~ 2 - 10 times larger than that of FRET based response. These differences in emission signals were attributed to three major reasons: non-specific interactions between E. Coli and liposomes; size differences between analyte and liposomes; and a much higher PDA concentration with respect to sulpho-rhodamine (SR-101). We have proposed a model to explain our experimental observations. Our fundamental studies reported here will help in enhancing our knowledge regarding interactions involved between soft particles at molecular levels.
PMCID: PMC3439585  PMID: 22734511
15.  Downregulation of miR-151-5p Contributes to Increased Susceptibility to Arrhythmogenesis during Myocardial Infarction with Estrogen Deprivation 
PLoS ONE  2013;8(9):e72985.
Estrogen deficiency is associated with increased incidence of cardiovascular diseases. But merely estrogen supplementary treatment can induce many severe complications such as breast cancer. The present study was designed to elucidate molecular mechanisms underlying increased susceptibility of arrhythmogenesis during myocardial infarction with estrogen deprivation, which provides us a new target to cure cardiac disease accompanied with estrogen deprivation. We successfully established a rat model of myocardial ischemia (MI) accompanied with estrogen deprivation by coronary artery ligation and ovariectomy (OVX). Vulnerability and mortality of ventricular arrhythmias increased in estrogen deficiency rats compared to non estrogen deficiency rats when suffered MI, which was associated with down-regulation of microRNA-151-5p (miR-151-5p). Luciferase Reporter Assay demonstrated that miR-151-5p can bind to the 3′-UTR of FXYD1 (coding gene of phospholemman, PLM) and inhibit its expression. We found that the expression of PLM was increased in (OVX+MI) group compared with MI group. More changes such as down-regulation of Kir2.1/IK1, calcium overload had emerged in (OVX+MI) group compared to MI group merely. Transfection of miR-151-5p into primary cultured myocytes decreased PLM levels and [Ca2+]i, however, increased Kir2.1 levels. These effects were abolished by the antisense oligonucleotides against miR-151-5p. Co-immunoprecipitation and immunofluorescent experiments confirmed the co-localization between Kir2.1 and PLM in rat ventricular tissue. We conclude that the increased ventricular arrhythmias vulnerability in response to acute myocardial ischemia in rat is critically dependent upon down-regulation of miR-151-5p. These findings support the proposal that miR-151-5p could be a potential therapeutic target for the prevention of ischemic arrhythmias in the subjects with estrogen deficiency.
PMCID: PMC3767733  PMID: 24039836
16.  The Joint Effect of hOGG1, APE1, and ADPRT Polymorphisms and Cooking Oil Fumes on the Risk of Lung Adenocarcinoma in Chinese Non-Smoking Females 
PLoS ONE  2013;8(8):e71157.
The human 8-oxoguanine DNA glycosylase 1 (hOGG1), apurinic/apyrimidinic endonuclease 1 (APE1), and adenosine diphosphate ribosyl transferase (ADPRT) genes play an important role in the DNA base excision repair pathway. Single nucleotide polymorphisms (SNPs) in critical genes are suspected to be associated with the risk of lung cancer. This study aimed to identify the association between the polymorphisms of hOGG1 Ser326Cys, APE1 Asp148Glu, and ADPRT Val762Ala, and the risk of lung adenocarcinoma in the non-smoking female population, and investigated the interaction between genetic polymorphisms and environmental exposure in lung adenocarcinoma.
We performed a hospital-based case-control study, including 410 lung adenocarcinoma patients and 410 cancer-free hospital control subjects who were matched for age. Each case and control was interviewed to collect information by well-trained interviewers. A total of 10 ml of venous blood was collected for genotype testing. Three polymorphisms were analyzed by the polymerase chain reaction-restriction fragment length polymorphism technique.
We found that individuals who were homozygous for the variant hOGG1 326Cys/Cys showed a significantly increased risk of lung adenocarcinoma (OR = 1.54; 95% CI: 1.01–2.36; P = 0.045). When the combined effect of variant alleles was analyzed, we found an increased OR of 1.89 (95% CI: 1.24–2.88, P = 0.003) for lung adenocarcinoma individuals with more than one homozygous variant allele. In stratified analyses, we found that the OR for the gene-environment interaction between Ser/Cys and Cys/Cys genotypes of hOGG1 codon 326 and cooking oil fumes for the risk of lung adenocarcinoma was 1.37 (95% CI: 0.77–2.44; P = 0.279) and 2.79 (95% CI: 1.50–5.18; P = 0.001), respectively.
The hOGG1 Ser326Cys polymorphism might be associated with the risk of lung adenocarcinoma in Chinese non-smoking females. Furthermore, there is a significant gene-environment association between cooking oil fumes and hOGG1 326 Cys/Cys genotype in lung adenocarcinoma among female non-smokers.
PMCID: PMC3741325  PMID: 23951099
17.  Association of methylenetetrahydrofolate reductase C677T and A1298C polymorphisms with colorectal cancer risk: A meta-analysis 
Biomedical Reports  2013;1(5):781-791.
Colorectal cancer (CRC) is one of the most common types of cancer worldwide and a leading cause of cancer-related mortality. This meta-analysis was conducted to determine the effect of methylenetetrahydrofolate reductase (MTHFR) mutants on the risk of CRC. A literature search was conducted on PubMed, Medline and the China National Knowledge Infrastructure (CNKI) databases. Eligible studies were collected based on rigorous criteria of inclusion. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by the fixed- or random-effects model. After all the studies were pooled, the OR of CRC for individuals carrying the MTHFR 677TT genotype, compared to the CC genotype, was 0.89 (95% CI: 0.82–0.97). When analyzed by ethnicity, Asians with the MTHFR 1298CC genotype exhibited a decreased risk of CRC (OR=0.69; 95% CI: 0.54–0.89). In a mixed population, a significantly reduced risk of CRC was observed among carriers of the 677TT (OR=0.86; 95% CI: 0.76–0.96) and the 1298CC (OR=0.82; 95% CI: 0.69–0.98) genotypes, compared to the wild-type homozygous genotype. In the subgroup of colon cancer, the OR of 677TT vs. CC+CT was 0.83 (95% CI: 0.72–0.96) and the OR of 1298CC vs. AA+AC was 0.81 (95% CI: 0.69–0.96). In the rectal cancer subgroup, the OR of 677TT vs. CC+CT was 0.86 (95% CI: 0.77–0.97). Therefore, this meta-analysis suggested that the MTHFR 677T and 1298C alleles were associated with a low risk of CRC.
PMCID: PMC3917732  PMID: 24649029
methylenetetrahydrofolate reductase; polymorphism; colorectal cancer; meta-analysis
18.  Genetic Variations in TERT-CLPTM1L Genes and Risk of Lung Cancer in Chinese Women Nonsmokers 
PLoS ONE  2013;8(5):e64988.
The TERT gene is the reverse transcriptase component of telomerase and is essential for the maintenance of telomere DNA length, chromosomal stability and cellular immortality. CLPTM1L gene encodes a protein linked to cisplatin resistance, and it is well conserved and express in various normal or malignant tissues, including lung.
To test this hypothesis, we genotyped for two significant SNPs TERT-rs2736098 and CLPTM1L-rs4016981 in a case-control study with 501 cancer cases and 576 cancer-free controls in Chinese nonsmoking population. Information concerning demographic and risk factors was obtained for each case and control by a trained interviewer. Gene polymorphisms were determined by TaqMan methodology.
We found that the homozygous variant genetic model of TERT gene was associated with a significantly increased risk of lung cancer with adjusted OR of 1.72(95%CI = 1.19–2.51, P = 0.004 for heterogeneity). The joint effect of TERT and CLPTM1L increased risk for lung cancer with adjusted OR is 1.31(95%CI = 1.00–1.74, P = 0.052 for heterogeneity).
Genetic variants in TERT and CLPTM1L may affect the susceptibility of lung cancer, especially adenocarcinoma in Chinese women nonsmokers.
PMCID: PMC3667812  PMID: 23738012
19.  Overexpression of microRNA-1 Causes Atrioventricular Block in Rodents 
The present study was designed to investigate whether microRNAs (miRNAs) are involved in atrioventricular block (AVB) in the setting of myocardial ischemia (MI). A cardiac-specific miR-1 transgenic (Tg) mouse model was successfully established for the first time in this study using microinjection. miR-1 level was measured by real-time qRT-PCR. Whole-cell patch clamp was employed to record L-type calcium current (ICa,L) and inward rectifier K+ current (IK1). Expression of connexin 43 (Cx43) protein was determined by western blot analysis. Alternations of [Ca2+]i was detected by laser scanning confocal microscopy in ventricular myocytes. The incidence of AVB was higher in miR-1 Tg mice than that in wild-type (WT) mice. The normalized peak current amplitude of ICa,L was lower in ventricular myocytes from miR-1 Tg mice as compared with WT mice. Similarly, the current density of IK1 was decreased in miR-1 Tg mice than that in WT mice. Compared with WT mice, miR-1 Tg mice exhibited a significant decrease of the systolic [Ca2+]i in ventricular myocytes but a prominent increase of the resting [Ca2+]i. Moreover, Cx43 protein was downregulated in miR-1 Tg mice compared to that in WT mice. Administration of LNA-modified antimiR-1 reversed all the above changes. miR-1 overexpression may contribute to the increased susceptibility of the heart to AVB, which provides us novel insights into the molecular mechanisms underlying ischemic cardiac arrhythmias.
PMCID: PMC3654494  PMID: 23678295
atrioventricular block (AVB); miR-1; L-type calcium current ICa,L; inward rectifier K+ current IK1; connexin 43.
20.  Sensitive and Rapid Detection of the New Delhi Metallo-Beta-Lactamase Gene by Loop-Mediated Isothermal Amplification 
Journal of Clinical Microbiology  2012;50(5):1580-1585.
New Delhi metallo-β-lactamase 1 (NDM-1), which is associated with resistance to carbapenem, was first reported in 2008. A sensitive and rapid molecular assay to detect the plasmid blaNDM-1 in clinical isolates is needed to control its spread. We describe a loop-mediated isothermal amplification (LAMP) assay for the rapid detection of blaNDM-1 from pure culture and sputum, urine, and fecal samples. Eight sets of primers were designed to recognize six or eight distinct sequences on target blaNDM-1, and one set was selected as the most appropriate set of primers for its rapid detection. The specificity and sensitivity of the primers in the LAMP reactions for blaNDM-1 detection were determined. The sensitivity of the LAMP assay for blaNDM-1 detection in sputum, urine, and fecal samples was also tested. Two methods, namely, monitoring of turbidity and addition of calcein to the reaction tube, were used to determine negative and positive results. The results showed that target DNA was amplified and visualized by the two detection methods within 70 min at an isothermal temperature of 65°C. The sensitivity of LAMP, with a detection limit of 10.70 pg/μl DNA, was 100-fold greater than that of PCR. Thirteen infection bacterial strains without blaNDM-1 were selected for testing of specificity, and the results of the amplification were negative, which showed that the primers had good levels of specificity. The LAMP method reported here is demonstrated to be a potentially valuable means for the detection of blaNDM-1 and rapid clinical diagnosis, being fast, simple, and low in cost.
PMCID: PMC3347096  PMID: 22357496
21.  Beta-adrenoceptor regulates miRNA expression in rat heart 
MicroRNAs (miRNAs) are noncoding RNAs of 18–25 nucleotides that post-transcriptionally regulate gene expression and are involved in a wide range of physiological and pathological conditions. The β-adrenergic signaling pathway plays a fundamental role in regulation of heart function. The present study was designed to investigate the expression profile of miRNAs and functional implications under conditions of β-adrenoceptor activation or inhibition in rat heart.
Hemodynamic parameters were measured to assess heart function in Wistar rats treated with isoproterenol (ISO) or propranolol (PRO). miRNA expression was analyzed by miRNA Microarray and confirmed by real-time quantitative reverse transcription PCR (real-time qRT-PCR).
Isoproterenol (ISO, a β-adrenoceptor activator) and propranolol (PRO, a β-adrenoceptor inhibitor) induced differential miRNA expression profiles. Out of 349 miRNAs measured, 43 were upregulated and nine downregulated in the ISO group, while five miRNAs were upregulated and 28 downregulated in PRO group. Among these altered miRNAs in both PRO and ISO groups, 11 were cardiac abundant and 11 showed opposite profiles between the PRO and ISO groups. The recognized anti-hypertrophic miRNAs miR-1, miR-21 and miR-27b, and the pro-hypertrophic miRNAs miR-22, miR-24, miR-199a, miR-212 and miR-214, were upregulated in the ISO group. In the PRO group, pro-hypertrophic miRNA miR-30c was upregulated, whereas miR-212 was downregulated.
β-adrenoceptor intervention alters miRNA expression profile, and miRNAs may be involved in the β-adrenoceptor signaling pathway. Cardiomyocyte hypertrophy is a balanced process between pro-hypertrophic and anti-hypertrophic regulation and involves, at the very least, miRNA participation.
PMCID: PMC3560703  PMID: 22847192
β-adrenoceptor; miRNAs; antagonistic effect; hypertrophy
22.  Meta-analysis of human lung cancer microRNA expression profiling studies comparing cancer tissues with normal tissues 
Lung cancer is the major cause of cancer death globally, it is often diagnosed at an advanced stage and has one of the lowest survival rates of any type of cancer. The common interest in the field of lung cancer research is the identification of biomarkers for early diagnosis and accurate prognosis. There is increasing evidence to suggest that microRNAs play important and complex roles in lung cancer.
A meta-analysis was conducted to review the published microRNA expression profiling studies that compared the microRNAs expression profiles in lung cancer tissues with those in normal lung tissues. A vote-counting strategy that considers the total number of studies reporting its differential expression, the total number of tissue samples used in the studies and the average fold change was employed.
A total of 184 differentially expressed microRNAs were reported in the fourteen microRNA expression profiling studies that compared lung cancer tissues with normal tissues, with 61 microRNAs were reported in at least two studies. In the panel of consistently reported up-regulated microRNAs, miR-210 was reported in nine studies and miR-21 was reported in seven studies. In the consistently reported down-regulated microRNAs, miR-126 was reported in ten studies and miR-30a was reported in eight studies. Four up-regulated microRNAs (miR-210, miR-21, miR-31 and miR-182) and two down-regulated mcroiRNAs (miR-126 and miR-145) were consistently reported both in squamous carcinoma and adenocarcinoma-based subgroup analysis, with the other 14 microRNAs solely reported in one or the other subset.
In conclusion, the top two most consistently reported up-regulated microRNAs were miR-210 and miR-21. The results of this meta-analysis of human lung cancer microRNA expression profiling studies might provide some clues of the potential biomarkers in lung cancer. Further mechanistic and external validation studies are needed for their clinical significance and role in the development of lung cancer.
PMCID: PMC3502083  PMID: 22672859
MicroRNAs; Profiling; Lung cancer; Meta-analysis
23.  Prevalence and risk factors for depression and anxiety among outpatient migraineurs in mainland China 
The Journal of Headache and Pain  2012;13(4):303-310.
This study aimed to investigate the prevalence and risk factors for anxiety and depression symptoms in outpatient migraineurs in mainland China. In addition, we evaluated whether the Hospital Anxiety and Depression Scale (HADS) provided sufficient validity to screen depression and anxiety. A cross-sectional study was conducted consecutively at our headache clinic. Migraine was diagnosed according to International Classification of Headache Disorders, 2nd edition (ICHD-II). Demographic characteristics and clinical features were collected by headache questionnaire. Anxiety and depression symptoms about migraineurs were assessed using HADS. Several questionnaires were simultaneously used to evaluate patients with depressive disorder including the Hamilton Depression Rating Scale-17 (HAMD), Hamilton Anxiety Rating Scale (HAMA) and HADS. Pearson correlation analysis was applied to test the validity of HADS. 176 outpatients with migraine (81.8 % female) were included. Overall, 17.6 and 38.1 % participants had depression and anxiety, respectively. Possible risk factors for depression in migraineurs included headache intensity of first onset of migraine, migraine with presymptom, migraine with family history and migraine disability. The possible risk factors for anxiety included fixed attack time of headache in one day and poor sleeping, and age represented a protective factor for anxiety. The correlation coefficient of HADS-A and HADS-D with HAMA and HAMD was 0.666 and 0.508, respectively (P < 0.01). This study demonstrates that depression and anxiety comorbidity in our mainland Chinese migraineurs are also common, and several risk factors were identified that may provide predictive value. These findings can help clinicians to identify and treat anxiety and depression in order to improve migraine management.
PMCID: PMC3356469  PMID: 22466285
Anxiety; Cross-sectional study; Depression; Migraine; Risk factor
24.  Association between polymorphisms in XRCC1 gene and clinical outcomes of patients with lung cancer: a meta-analysis 
BMC Cancer  2012;12:71.
X-ray repair cross-complementing group 1 (XRCC1) protein plays an important role in the repair of DNA damage and adducts. Single nucleotide polymorphisms (SNPs) of XRCC1 are suspected to have some relationship with response to chemotherapy and overall survival of lung cancer. This meta-analysis aimed to summarize published data on the association between the commonest SNPs of XRCC1 (Arg194Trp, C > T, rs1799782 and Arg399Gln, G > A, rs25487) and clinical outcome of lung cancer patients.
We retrieved the relevant articles from PubMed, EMBASE and the China National Knowledge Infrastructure (CNKI) databases. Studies were selected using specific inclusion and exclusion criteria. Primary outcomes included objective response (i.e., complete response + partial response vs. progressive disease + stable disease) and overall survival (OS). Odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI) were estimated. All analyses were performed using the Stata software.
Twenty-two articles were included in the present analysis. XRCC1 Arg194Trp and Arg399Gln polymorphisms were significantly associated with response to treatment in lung cancer patients. Patients with C/T genotype, T/T genotype and minor variant T allele at Arg194Trp were more likely to respond to platinum-based chemotherapy compared with those with C/C genotype (C/T vs. C/C: OR, 2.54; 95%CI, 1.95-3.31; T/T vs. C/C: OR, 2.06; 95%CI, 1.39-3.06; C/T+T/T vs. C/C: OR, 2.42; 95% CI, 1.88-3.10). For XRCC1 Arg399Gln, G/A genotype, A/A genotype and minor variant A allele were associated with objective response in all patients (G/A vs. G/G: OR, 0.67; 95%CI, 0.50-0.90; A/A vs. G/G: OR, 0.43; 95%CI, 0.25-0.73; A/A+G/A vs. G/G: OR, 0.63; 95%CI, 0.49-0.83). Both G/A and A/A genotypes of XRCC1 Arg399Gln could influence overall survival of lung cancer patients (G/A vs. G/G: HR, 1.23; 95%CI, 1.06-1.44; A/A vs. G/G: HR, 2.03; 95%CI, 1.20-3.45). Interaction analysis suggested that compared with the patients carrying C/T+T/T genotype at XRCC1 194 and G/G genotype at XRCC1 399, the patients carrying 194 C/C and 399 G/A+A/A or 194 C/C and 399 G/G genotype showed much worse objective response.
Genetic polymorphisms in XRCC1 gene might be associated with overall survival and response to platinum-based chemotherapy in lung cancer patients.
PMCID: PMC3305620  PMID: 22339849
25.  Photo-Pens: A Simple and Versatile Tool for Maskless Photolithography 
We demonstrate conical pores etched in tracked glass chips for fabricating patterns at micron-scale. Highly fluorescent patterns based on photopolymerization of diacetylene films were formed by irradiating UV light through conical pores called “photo-pens”. The properties of photo-pens were investigated through experiments, Finite-difference-time-domain (FDTD) simulations and numerical calculations based on Fresnel equations. We show that the pattern dimensions are easily controlled by adjusting the exposure time. Thus, patterns with a range of dimensions can be fabricated without any need of changes in the pore diameter. Parallel patterning was also demonstrated by simultaneously exposing the films to photons through multiple pores in the chip. Our method provides an inexpensive, versatile, and efficient way for patterning without the use of sophisticated masks.
PMCID: PMC2978279  PMID: 20886901

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