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1.  Hydrogen Peroxide Induce Human Cytomegalovirus Replication through the Activation of p38-MAPK Signaling Pathway 
Viruses  2015;7(6):2816-2833.
Human cytomegalovirus (HCMV) is a major risk factor in transplantation and AIDS patients, which induces high morbidity and mortality. These patients infected with HCMV experience an imbalance of redox homeostasis that cause accumulation of reactive oxygen species (ROS) at the cellular level. H2O2, the most common reactive oxygen species, is the main byproduct of oxidative metabolism. However, the function of H2O2 on HCMV infection is not yet fully understood and the effect and mechanism of N-acetylcysteine (NAC) on H2O2-stimulated HCMV replication is unclear. We, therefore, examined the effect of NAC on H2O2-induced HCMV production in human foreskin fibroblast cells. In the present study, we found that H2O2 enhanced HCMV lytic replication through promoting major immediate early (MIE) promoter activity and immediate early (IE) gene transcription. Conversely, NAC inhibited H2O2-upregulated viral IE gene expression and viral replication. The suppressive effect of NAC on CMV in an acute CMV-infected mouse model also showed a relationship between antioxidants and viral lytic replication. Intriguingly, the enhancement of HCMV replication via supplementation with H2O2 was accompanied with the activation of the p38 mitogen-activated protein kinase pathway. Similar to NAC, the p38 inhibitor SB203580 inhibited H2O2-induced p38 phosphorylation and HCMV upregulation, while upregulation of inducible ROS was unaffected. These results directly relate HCMV replication to H2O2, suggesting that treatment with antioxidants may be an attractive preventive and therapeutic strategy for HCMV.
doi:10.3390/v7062748
PMCID: PMC4488715  PMID: 26053925
CMV; H2O2; IE1; viral replication; antioxidants; p38-MAPK
2.  miR-942 promotes cancer stem cell-like traits in esophageal squamous cell carcinoma through activation of Wnt/β-catenin signalling pathway 
Oncotarget  2015;6(13):10964-10977.
The Wnt/β-catenin signalling pathway is known to play a vital role in the maintenance of cancer stem cells (CSCs), which are reported to be the origine of malignant cancers, and result in poor prognosis of multiple kinds of cancer. Therefore, it is of great importance to illuminate the mechanism by which the Wnt/β-catenin pathway regulates the cancer stem cell-like traits in cancers. Here, we report that miR-942 is significantly upregulated in esophageal squamous cell carcinoma (ESCC), and miR-942 levels are associated with poor prognosis in ESCC patients. Overexpression of miR-942 promotes, whereas inhibition of miR-942 decreases, the tumor sphere formation, the CD90+ subpopulation cells and the expression of pluripotency associated markers. Moreover, in vivo assay shows that miR-942 overexpressing cells form larger tumors and display higher tumourigenesis. Furthermore, we demonstrate that miR-942 upregulates the Wnt/β-catenin signaling activity via directly targeting sFRP4, GSK3β and TLE1, which are multiple level negative regulators of the Wnt/β-catenin signaling cascade. In addition, our results indicate that c-myc directly binds to the miR-942 promoter and promotes its expression. Taken together, our findings establish an oncogenic role of miR-942 in ESCC and indicate that miR-942 might be an effective therapeutic target for ESCC.
PMCID: PMC4484432  PMID: 25844602
miR-942; cancer stem cells; Wnt/β-catenin signalling pathway; esophageal squamous cell carcinoma
3.  Urinary Metabonomics for Diagnosis of Depression in Hepatitis B Virus-Infected Patients 
Background:
Depression is concomitantly presented in Hepatitis B Virus (HBV)-infected patients and decreases these patients’ quality of life. However, there are no laboratory-based methods to objectively diagnose this disorder.
Objectives:
The aim of this study was to investigate the alteration of urinary metabolites in depressed HBV-infected patients.
Patients and Methods:
In this study, 81 depressed HBV-infected patients, 68 non-depressed HBV-infected patients and 64 Healthy Controls (HC) were recruited. A nuclear magnetic resonance (NMR)-based urinary metabonomic method was used to characterize the urinary metabolic profiling of depressed and non-depressed subjects.
Results:
Seventeen differential urinary metabolites responsible for discriminating depressed HBV-infected patients from non-depressed HBV-infected patients and HC were identified. Among these metabolites, pyruvate, isobutyrate, N-methylnicotinamide, α-hydroxybutyrate, acetoacetate and malonate were identified as potential biomarkers for diagnosing depression in HBV-infected patients. A combined panel of these potential biomarkers could effectively discriminate depressed HBV-infected patients from non-depressed HBV-infected patients and HC, with an average accuracy of 89.6% in the training set and a predictive accuracy of 86.4% in the test set.
Conclusions:
These findings suggest that NMR-based urinary metabonomics approach might be a useful tool for the clinical diagnosis of depression in HBV-infected patients and the six potential biomarkers could be helpful for developing an objective diagnostic method. Limited by the number of recruited subjects, future studies are required to validate our conclusions.
doi:10.5812/ircmj.17(4)2015.27359
PMCID: PMC4443390  PMID: 26023351
Depression; Hepatitis B; Metabonomic
4.  Chitosan/siRNA functionalized titanium surface via a layer-by-layer approach for in vitro sustained gene silencing and osteogenic promotion 
Titanium surface modification is crucial to improving its bioactivity, mainly its bone binding ability in bone implant materials. In order to functionalize titanium with small interfering RNA (siRNA) for sustained gene silencing in nearby cells, the layer-by-layer (LbL) approach was applied using sodium hyaluronate and chitosan/siRNA (CS/siRNA) nanoparticles as polyanion and polycation, respectively, to build up the multilayered film on smooth titanium surfaces. The CS/siRNA nanoparticle characterization was analyzed first. Dynamic contact angle, atomic force microscopy, and scanning electron microscopy were used to monitor the layer accumulation. siRNA loaded in the film was quantitated and the release profile of film in phosphate-buffered saline was studied. In vitro knockdown effect and cytotoxicity evaluation of the film were investigated using H1299 human lung carcinoma cells expressing green fluorescent protein (GFP). The transfection of human osteoblast-like cell MG63 and H1299 were performed and the osteogenic differentiation of MG63 on LbL film was analyzed. The CS/siRNA nanoparticles exhibited nice size distribution. During formation of the film, the surface wettability, topography, and roughness were alternately changed, indicating successful adsorption of the individual layers. The scanning electron microscope images clearly demonstrated the hybrid structure between CS/siRNA nanoparticles and sodium hyaluronate polymer. The cumulated load of siRNA increased linearly with the bilayer number and, more importantly, a gradual release of the film allowed the siRNA to be maintained on the titanium surface over approximately 1 week. In vitro transfection revealed that the LbL film-associated siRNA could consistently suppress GFP expression in H1299 without showing significant cytotoxicity. The LbL film loading with osteogenic siRNA could dramatically increase the osteogenic differentiation in MG63. In conclusion, LbL technology can potentially modify titanium surfaces with specific gene-regulatory siRNAs to enhance biofunction.
doi:10.2147/IJN.S76513
PMCID: PMC4378287  PMID: 25848254
sustained gene silencing; osteogenic differentiation; chitosan; small interfering RNA; titanium
5.  Linking carbon and nitrogen metabolism to depth distribution of submersed macrophytes using high ammonium dosing tests and a lake survey 
Freshwater Biology  2013;58(12):2532-2540.
Strategies of carbon (C) and nitrogen (N) utilisation are among the factors determining plant distribution. It has been argued that submersed macrophytes adapted to lower light environments are more efficient in maintaining C metabolic homeostasis due to their conservative C strategy and ability to balance C shortage. We studied how depth distributions of 12 submersed macrophytes in Lake Erhai, China, were linked to their C-N metabolic strategies when facing acute dosing. dosing changed C-N metabolism significantly by decreasing the soluble carbohydrate (SC) content and increasing the -N and free amino acid (FAA) content of plant tissues.The proportional changes in SC contents in the leaves and FAA contents in the stems induced by dosing were closely correlated (positive for SC and negative for FAA) with the colonising water depths of the plants in Lake Erhai, the plants adapted to lower light regimes being more efficient in maintaining SC and FAA homeostasis.These results indicate that conservative carbohydrate metabolism of submersed macrophytes allowed the plants to colonise greater water depths in eutrophic lakes, where low light availability in the water column diminishes carbohydrate production by the plants.
doi:10.1111/fwb.12230
PMCID: PMC4368047  PMID: 25810562
eutrophication; free amino acid; dosing; soluble carbohydrate; submersed macrophytes
6.  Alpha-enolase promotes cell glycolysis, growth, migration, and invasion in non-small cell lung cancer through FAK-mediated PI3K/AKT pathway 
Background
During tumor formation and expansion, increasing glucose metabolism is necessary for unrestricted growth of tumor cells. Expression of key glycolytic enzyme alpha-enolase (ENO1) is controversial and its modulatory mechanisms are still unclear in non-small cell lung cancer (NSCLC).
Methods
The expression of ENO1 was examined in NSCLC and non-cancerous lung tissues, NSCLC cell lines, and immortalized human bronchial epithelial cell (HBE) by quantitative real-time reverse transcription PCR (qRT-PCR), immunohistochemistry, and Western blot, respectively. The effects and modulatory mechanisms of ENO1 on cell glycolysis, growth, migration, invasion, and in vivo tumorigenesis and metastasis in nude mice were also analyzed.
Results
ENO1 expression was increased in NSCLC tissues in comparison to non-cancerous lung tissues. Similarly, NSCLC cell lines A549 and SPCA-1 also express higher ENO1 than HBE cell line in both mRNA and protein levels. Overexpressed ENO1 significantly elevated NSCLC cell glycolysis, proliferation, clone formation, migration, and invasion in vitro, as well as tumorigenesis and metastasis in vivo by regulating the expression of glycolysis, cell cycle, and epithelial-mesenchymal transition (EMT)-associated genes. Conversely, ENO1 knockdown reversed these effects. More importantly, our further study revealed that stably upregulated ENO1 activated FAK/PI3K/AKT and its downstream signals to regulate the glycolysis, cell cycle, and EMT-associated genes.
Conclusion
This study showed that ENO1 is responsible for NSCLC proliferation and metastasis; thus, ENO1 might serve as a potential molecular therapeutic target for NSCLC treatment.
Electronic supplementary material
The online version of this article (doi:10.1186/s13045-015-0117-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s13045-015-0117-5
PMCID: PMC4359783  PMID: 25887760
ENO1; NSCLC; Glycolysis; Cell proliferation; FAK/PI3K/AKT; EMT
7.  Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations 
Wu, Chen | Wang, Zhaoming | Song, Xin | Feng, Xiao-Shan | Abnet, Christian C. | He, Jie | Hu, Nan | Zuo, Xian-Bo | Tan, Wen | Zhan, Qimin | Hu, Zhibin | He, Zhonghu | Jia, Weihua | Zhou, Yifeng | Yu, Kai | Shu, Xiao-Ou | Yuan, Jian-Min | Zheng, Wei | Zhao, Xue-Ke | Gao, She-Gan | Yuan, Zhi-Qing | Zhou, Fu-You | Fan, Zong-Min | Cui, Ji-Li | Lin, Hong-Li | Han, Xue-Na | Li, Bei | Chen, Xi | Dawsey, Sanford M. | Liao, Linda | Lee, Maxwell P. | Ding, Ti | Qiao, You-Lin | Liu, Zhihua | Liu, Yu | Yu, Dianke | Chang, Jiang | Wei, Lixuan | Gao, Yu-Tang | Koh, Woon-Puay | Xiang, Yong-Bing | Tang, Ze-Zhong | Fan, Jin-Hu | Han, Jing-Jing | Zhou, Sheng-Li | Zhang, Peng | Zhang, Dong-Yun | Yuan, Yuan | Huang, Ying | Liu, Chunling | Zhai, Kan | Qiao, Yan | Jin, Guangfu | Guo, Chuanhai | Fu, Jianhua | Miao, Xiaoping | Lu, Changdong | Yang, Haijun | Wang, Chaoyu | Wheeler, William A. | Gail, Mitchell | Yeager, Meredith | Yuenger, Jeff | Guo, Er-Tao | Li, Ai-Li | Zhang, Wei | Li, Xue-Min | Sun, Liang-Dan | Ma, Bao-Gen | Li, Yan | Tang, Sa | Peng, Xiu-Qing | Liu, Jing | Hutchinson, Amy | Jacobs, Kevin | Giffen, Carol | Burdette, Laurie | Fraumeni, Joseph F. | Shen, Hongbing | Ke, Yang | Zeng, Yixin | Wu, Tangchun | Kraft, Peter | Chung, Charles C. | Tucker, Margaret A. | Hou, Zhi-Chao | Liu, Ya-Li | Hu, Yan-Long | Liu, Yu | Wang, Li | Yuan, Guo | Chen, Li-Sha | Liu, Xiao | Ma, Teng | Meng, Hui | Sun, Li | Li, Xin-Min | Li, Xiu-Min | Ku, Jian-Wei | Zhou, Ying-Fa | Yang, Liu-Qin | Wang, Zhou | Li, Yin | Qige, Qirenwang | Yang, Wen-Jun | Lei, Guang-Yan | Chen, Long-Qi | Li, En-Min | Yuan, Ling | Yue, Wen-Bin | Wang, Ran | Wang, Lu-Wen | Fan, Xue-Ping | Zhu, Fang-Heng | Zhao, Wei-Xing | Mao, Yi-Min | Zhang, Mei | Xing, Guo-Lan | Li, Ji-Lin | Han, Min | Ren, Jing-Li | Liu, Bin | Ren, Shu-Wei | Kong, Qing-Peng | Li, Feng | Sheyhidin, Ilyar | Wei, Wu | Zhang, Yan-Rui | Feng, Chang-Wei | Wang, Jin | Yang, Yu-Hua | Hao, Hong-Zhang | Bao, Qi-De | Liu, Bao-Chi | Wu, Ai-Qun | Xie, Dong | Yang, Wan-Cai | Wang, Liang | Zhao, Xiao-Hang | Chen, Shu-Qing | Hong, Jun-Yan | Zhang, Xue-Jun | Freedman, Neal D | Goldstein, Alisa M. | Lin, Dongxin | Taylor, Philip R. | Wang, Li-Dong | Chanock, Stephen J.
Nature genetics  2014;46(9):1001-1006.
We conducted a joint (pooled) analysis of three genome-wide association studies (GWAS) 1-3 of esophageal squamous cell carcinoma (ESCC) in ethnic Chinese (5,337 ESCC cases and 5,787 controls) with 9,654 ESCC cases and 10,058 controls for follow-up. In a logistic regression model adjusted for age, sex, study, and two eigenvectors, two new loci achieved genome-wide significance, marked by rs7447927 at 5q31.2 (per-allele odds ratio (OR) = 0.85, 95% CI 0.82-0.88; P=7.72x10−20) and rs1642764 at 17p13.1 (per-allele OR= 0.88, 95% CI 0.85-0.91; P=3.10x10−13). rs7447927 is a synonymous single nucleotide polymorphism (SNP) in TMEM173 and rs1642764 is an intronic SNP in ATP1B2, near TP53. Furthermore, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at highest risk for ESSC (OR=1.33, 95% CI 1.22-1.46; P=1.99x10−10). Our joint analysis identified new ESCC susceptibility loci overall as well as a new locus unique to the ESCC high risk Taihang Mountain region.
doi:10.1038/ng.3064
PMCID: PMC4212832  PMID: 25129146
8.  A Sequence Variant in the Phospholipase C Epsilon C2 Domain Is Associated With Esophageal Carcinoma and Esophagitis 
Molecular carcinogenesis  2013;52(0 1):E80-E86.
A single-nucleotide polymorphism (rs2274223: A5780G:His1927Arg) in the phospholipase C epsilon gene (PLCε) was recently identified as a susceptibility locus for esophageal cancer in Chinese subjects. To determine the underlying mechanisms of PLCε and this SNP in esophageal carcinogenesis, we analyzed PLCε genotypes, expression, and their correlation in esophageal cancer cell lines, non-transformed esophageal cells, 58 esophageal squamous cell carcinomas and 10,614 non-cancer subjects from China. We found that the G allele (AG or GG) was associated with increased PLCε mRNA and protein expression in esophageal cancer tissues and in esophageal cancer cell lines. G allele was also associated with higher enzyme activity, which might be associated with increased protein expression. Quantitative analysis of the C2 domain sequences revealed that A:G allelic imbalance was strongly linked to esophageal malignancy. Moreover, the analysis of 10,614 non-cancer subjects demonstrated that the G allele was strongly associated with moderate to severe esophagitis in the subjects from the high-incidence areas of China (OR 6.03, 95% CI 1.59–22.9 in high-incidence area vs. OR 0.74, 95% CI 0.33–1.64 in low-incidence area; P = 0.008). In conclusion, the PLCε gene, particularly the 5780G allele, might play a pivotal role in esophageal carcinogenesis via upregulating PLCε mRNA, protein, and enzyme activity, and augmenting inflammatory process in esophageal epithelium. Thus, 5780G allele may constitute a promising biomarker for esophageal squamous cell carcinoma risk stratification, early detection, and progression prediction.
doi:10.1002/mc.22016
PMCID: PMC3931523  PMID: 23390063
phospholipase C epsilon; esophageal cancer; esophagitis
9.  Obesity attenuates gender differences in cardiovascular mortality 
Background
To estimate cardiovascular disease (CVD) mortality in relation to obesity and gender.
Methods
Data from 11 prospective cohorts from four European countries including 23 629 men and 21 965 women, aged 24 to 99 years, with a median follow-up of 7.9 years were analyzed. Hazards ratios (HR) for CVD mortality in relation to baseline body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) were estimated using Cox proportional hazards models with age as the timescale.
Results
Men had higher CVD mortality than women in all four BMI categories (<25.0, 25.0-29.9, 30.0-34.9 and ≥35.0 kg/m2). Compared with the lowest BMI category in women, multivariable adjusted HRs (95% confidence intervals) for higher BMI categories are 1.0 (0.8-1.4), 1.6 (1.1-2.1) and 2.8 (2.0-3.8) in women and 2.8 (2.2-3.6), 3.1 (2.5-3.9), 3.8 (2.9-4.9) and 5.4 (3.8-7.7) in men, respectively. Similar findings were observed for abdominal obesity defined by WC, WHR or WHtR. The gender difference was slightly smaller in obese than in non-obese individuals; but the interaction was statistically significant only between gender and WC (p = 0.02), and WHtR (p = 0.01). None of the interaction terms was significant among non-diabetic individuals.
Conclusions
Men had higher CVD mortality than women across categories of anthropometric measures of obesity. The gender difference was attenuated in obese individuals, which warrants further investigation.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-014-0144-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12933-014-0144-5
PMCID: PMC4212094  PMID: 25928355
Obesity; Gender; Cardiovascular disease mortality
10.  Candidate tumour suppressor CCDC19 regulates miR-184 direct targeting of C-Myc thereby suppressing cell growth in non-small cell lung cancers 
We previously reported and revised the nasopharyngeal epithelium specific protein CCDC19 and identified it as a potential tumour suppressor in nasopharyngeal carcinoma. The purpose of this study was to investigate the involvement of CCDC19 in the pathogenesis of human non-small cell lung cancers (NSCLC). Down-regulated CCDC19 expression was observed in NSCLC tissues and cells compared to normal tissues. However, reduced protein expression did not correlate with the status of NSCLC progression. Instead, we observed that patients with lower CCDC19 expression had a shorter overall survival than did patients with higher CCDC19 expression. Lentiviral-mediated CCDC19 overexpression significantly suppressed cell proliferation and cell cycle transition from G1 to S and G2 phases in NSCLC cells. Knocking down CCDC19 expression significantly restored the ability of cell growth in CCDC19 overexpressing NSCLC cells. Mechanistically CCDC19 functions as a potential tumour suppressor by stimulating miR-184 suppression of C-Myc thus blocking cell growth mediated by the PI3K/AKT/C-Jun pathway. Our studies are the first to demonstrate that reduced expression of CCDC19 is an unfavourable factor in NSCLC.
doi:10.1111/jcmm.12317
PMCID: PMC4190912  PMID: 24976536
CCDC19; tumour suppressor; lung cancer; PI3K/AKT; miR-184
11.  Micro-ribonucleic acid expression profiling and bioinformatic target gene analyses in laryngeal carcinoma 
OncoTargets and therapy  2014;7:525-533.
Abnormal expression of micro-ribonucleic acid (miRNA) might be clinically valuable as a biomarker or treatment target in the early diagnosis, treatment, and prognosis of tumors. However, little is known concerning abnormal miRNA expression of laryngeal carcinoma, one of the most commonly encountered head and neck tumors. Microarray analysis was used to obtain miRNA-expression profiles of ten pairs of freshly frozen laryngeal carcinoma tissue and surrounding normal tissue specimens. Characteristic miRNAs that were significantly related to laryngeal carcinoma were identified. Verification was performed using an additional 32 pairs of samples. The expression of two miRNAs (miR-21-3p and miR-106b-3p) was upregulated in both microarray and quantitative real-time polymerase chain-reaction analyses, whereas the expression of six miRNAs (let-7f-5p, miR-10a-5p, miR-125a-5p, miR-144-3p, miR-195-5p, and miR-203) was downregulated. The decreased expression of let-7f-5p and miR-195-5p is a novel finding in head and neck cancer. The target genes of these miRNAs were also predicted through multiple software programs. The differential expression of miRNAs might be related to the early onset and development of laryngeal carcinoma, and may be exploited as new biomarkers and therapeutic targets in the treatment of laryngeal carcinoma.
doi:10.2147/OTT.S59871
PMCID: PMC3983076  PMID: 24741319
microRNA; laryngeal carcinoma; expression profiling; bioinformatics; target prediction
12.  Variations in the MHC Region Confer Risk to Esophageal Squamous Cell Carcinoma on the Subjects from High-Incidence Area in Northern China 
PLoS ONE  2014;9(3):e90438.
Background
The human major histocompatibility complex (MHC) is the most important region in vertebrate genome, and is crucial in innate immunity. Recent studies have demonstrated the possible role of polymorphisms in the MHC region to high risk for esophageal squamous cell carcinoma (ESCC). Our previous genome-wide association study (GWAS) has indicated that the MHC region may confer important risk loci for ESCC, but without further fine mapping. The aim of this study is to further identify the risk loci in the MHC region for ESCC in Chinese population.
Methods
Conditional logistic regression analysis (CLRA) was performed on 24 single nucleotide polymorphisms (SNPs) within the MHC region, which were obtained from the genetically matched 937 cases and 692 controls of Chinese Han population. The identified promising SNPs were further correlated with clinical and clinicopathology characteristics. Immunohistochemistry was performed to explore the protein expression pattern of the related genes in ESCC and neighboring normal tissues.
Results
Of the 24 promising SNPs analyzed, we identified three independent SNPs in the MHC region associated with ESCC: rs35399661 (P = 6.07E-06, OR = 1.71, 95%CI = 1.36–2.17), rs3763338 (P = 1.62E-05, OR = 0.63, 95%CI = 0.50–0.78) and rs2844695 (P = 7.60E-05, OR = 0.74, 95%CI = 0.64–0.86). These three SNPs were located at the genes of HLA-DQA1, TRIM27, and DPCR1, respectively. Further analyses showed that rs2844695 was preferentially associated with younger ESCC cases (P = 0.009). The positive immunostaining rates both for HLA-DQA1 and TRIM27 were much higher in ESCC tissues than in neighboring normal tissues (69.4% vs. 26.8% for HLA-DQA1 and 77.6% vs. 47.8% for TRIM27, P<0.001). Furthermore, the overexpression of HLA-DQA1 is correlated significantly with age (P = 0.001) and family history (P<0.001).
Conclusion
This study for the first time provides evidence that multiple genetic factors within the MHC region confer risk to ESCC on the subjects from high-risk area in northern China.
doi:10.1371/journal.pone.0090438
PMCID: PMC3942432  PMID: 24595008
13.  Evaluation of secondary surgery to enlarge the peeling of the internal limiting membrane following the failed surgery of idiopathic macular holes 
The aim of the present study was to evaluate the clinical results of pars plana vitrectomy (PPV) combined with the surgical enlargement of internal limiting membrane (ILM) peeling in patients who had previously undergone failed idiopathic macular hole (IMH) surgery. In the study, 134 eyes from 130 IMH patients who had received PPV combined with ILM peeling surgery (2 disk diameters) were analyzed. Within this cohort, 14 eyes had IMHs that were not closed, of which 13 eyes underwent a second surgery involving enlargement of the ILM peeling. The extent of the ILM peeling was increased to the vascular arcades of the posterior fundus in the secondary surgery. Of the 13 eyes that underwent secondary surgery, five were in stage III and nine were in stage IV. The second surgery successfully achieved IMH closure in 61.5% (8/13) of the eyes. The IMH was completely closed following surgery and the logMAR vision increased from 0.98 to 0.84 (P=0.013) in the 8 successfully treated cases. The surgical enlargement of ILM peeling closed the IMHs and improved vision in the majority of patients. In addition, the procedures were safe. Therefore, the results of the present study indicate that enlargement of ILM peeling may be an effective therapy for patients who have previously undergone the failed surgical correction of an IMH.
doi:10.3892/etm.2014.1477
PMCID: PMC3919896  PMID: 24520279
idiopathic macular holes; internal limiting membrane peeling enlargement surgery; pars plana vitrectomy
14.  Correction: Retrospective Analysis of Prognostic Factors in 205 Patients with Laryngeal Squamous Cell Carcinoma Who Underwent Surgical Treatment 
PLoS ONE  2013;8(12):10.1371/annotation/9c5dbeb2-9990-464e-a05d-72d329f11647.
doi:10.1371/annotation/9c5dbeb2-9990-464e-a05d-72d329f11647
PMCID: PMC3865305
15.  Genome-Wide Copy Number Variations Inferred from SNP Genotyping Arrays Using a Large White and Minzhu Intercross Population 
PLoS ONE  2013;8(10):e74879.
Copy number variations (CNVs) are one of the main contributors to genetic diversity in animals and are broadly distributed in the genomes of swine. Investigating the performance and evolutionary impacts of pig CNVs requires comprehensive knowledge of their structure and function within and between breeds. In the current study, 4 different programs (i.e., GADA, PennCNV, QuantiSNP, and cnvPartition) were used to analyze Porcine SNP60 genotyping data of 585 pigs from one Large White × Minzhu intercross population to detect copy number variant regions (CNVRs). Overlapping CNVRs recalled by at least 2 programs were used to construct a powerful and comprehensive CNVR map, which contained249 CNVRs (i.e., 70 gains, 43 losses, and 136 gains/losses) and covered 26.22% of the regions in the swine genome. Ten CNVRs, representing different predicted statuses, were selected for validation via quantitative real-time PCR (QPCR); 9/10 CNVRs (i.e., 90%) were validated. When being traced back to the F0 generation, 58 events were identified in only Minzhu F0 parents and 2 events were identified in only Large White F0 parents. A series of CNVR function analyses were performed. Some of the CNVRs functions were predicted, and several interesting CNVRs for meat quality traits and hematological parameters were obtained. A comprehensive and lower false rate genome-wide CNV map was constructed for Large White and Minzhu pig genomes in this study. Our results may provide an important basis for determining the relationship between CNVRs and important qualitative and quantitative traits. In addition, it can help to further understand genetic processes in pigs.
doi:10.1371/journal.pone.0074879
PMCID: PMC3787955  PMID: 24098353
16.  Polymorphism of A133S and promoter hypermethylation in Ras association domain family 1A gene (RASSF1A) is associated with risk of esophageal and gastric cardia cancers in Chinese population from high incidence area in northern China 
BMC Cancer  2013;13:259.
Background
The role of tumor suppressor gene RASSF1A in the esophageal and gastric cardia carcinogenesis is still inconclusive. In this study, the polymorphism, promoter methylation and gene expression of RASSF1A were characterized in esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA).
Methods
We firstly analyzed the prevalence of RASSF1A A133S in a total of 228 cancer patients with ESCC (n=112) and GCA (n=116) and 235 normal controls by polymerase chain reaction (PCR) and restriction enzyme-digestion assay. Then, the promoter methylation status of the RASSF1A in ESCC (n=143), GCA (n=92) and corresponding adjacent normal tissues were further investigated using methylation-specific PCR (MSP) approach. Finally, the RASSF1A protein expression were determined in ESCC (n=27), GCA (n=24) and the matched adjacent normal tissues by immunohistochemical method.
Results
The frequency of 133Ala/Se and Ser/Ser genotype was significantly higher in GCA patients than in normal controls (19.0% vs. 10.2%, P=0.02). Compared with Ala/Ala genotype, Ala/Se and Ser/Ser genotype significantly increased susceptibility to GCA (OR=2.06, 95% CI=1.09–3.97). However, this polymorphism had no association with ESCC (P=0.69). The promoter methylation of RASSF1A gene was significantly increased the risk to both ESCC (OR=5.90, 95% CI=2.78–12.52) and GCA (OR=7.50, 95% CI= 2.78–20.23). Promoter methylation of RASSF1A gene in ESCC was also associated with age and cancer cell differentiation (for age: OR=3.11, 95% CI=1.10–8.73; for differentiation: OR=0.29, 95% CI=0.12–0.69). RASSF1A positive expression was significantly decreased the risk of GCA (OR=0.16, 95% CI=0.03–0.83). In contrast, there was no statistical significance between RASSF1A positive expression and ESCC. The expression of RASSF1A protein trend to be positively related with older GCA patients (OR=16.20, 95% CI=1.57–167.74).
Conclusions
The present findings suggest that alterations of RASSF1A may play an important role in gastric cardia carcinogenesis in terms of polymorphism, promoter hypermethylation and protein expression. Whereas, RASSF1A hypermethylation may probably also be involved in esophageal squamous cell carcinogenesis.
doi:10.1186/1471-2407-13-259
PMCID: PMC3668992  PMID: 23705663
Esophageal squamous cell carcinoma; Gastric cardia adenocarcinoma; A133S in RASSF1A; Polymorphism; Methylation; Protein expression
17.  Genotypic variants at 2q33 and risk of esophageal squamous cell carcinoma in China: a meta-analysis of genome-wide association studies 
Abnet, Christian C. | Wang, Zhaoming | Song, Xin | Hu, Nan | Zhou, Fu-You | Freedman, Neal D. | Li, Xue-Min | Yu, Kai | Shu, Xiao-Ou | Yuan, Jian-Min | Zheng, Wei | Dawsey, Sanford M. | Liao, Linda M. | Lee, Maxwell P. | Ding, Ti | Qiao, You-Lin | Gao, Yu-Tang | Koh, Woon-Puay | Xiang, Yong-Bing | Tang, Ze-Zhong | Fan, Jin-Hu | Chung, Charles C. | Wang, Chaoyu | Wheeler, William | Yeager, Meredith | Yuenger, Jeff | Hutchinson, Amy | Jacobs, Kevin B. | Giffen, Carol A. | Burdett, Laurie | Fraumeni, Joseph F. | Tucker, Margaret A. | Chow, Wong-Ho | Zhao, Xue-Ke | Li, Jiang-Man | Li, Ai-Li | Sun, Liang-Dan | Wei, Wu | Li, Ji-Lin | Zhang, Peng | Li, Hong-Lei | Cui, Wen-Yan | Wang, Wei-Peng | Liu, Zhi-Cai | Yang, Xia | Fu, Wen-Jing | Cui, Ji-Li | Lin, Hong-Li | Zhu, Wen-Liang | Liu, Min | Chen, Xi | Chen, Jie | Guo, Li | Han, Jing-Jing | Zhou, Sheng-Li | Huang, Jia | Wu, Yue | Yuan, Chao | Huang, Jing | Ji, Ai-Fang | Kul, Jian-Wei | Fan, Zhong-Min | Wang, Jian-Po | Zhang, Dong-Yun | Zhang, Lian-Qun | Zhang, Wei | Chen, Yuan-Fang | Ren, Jing-Li | Li, Xiu-Min | Dong, Jin-Cheng | Xing, Guo-Lan | Guo, Zhi-Gang | Yang, Jian-Xue | Mao, Yi-Ming | Yuan, Yuan | Guo, Er-Tao | Zhang, Wei | Hou, Zhi-Chao | Liu, Jing | Li, Yan | Tang, Sa | Chang, Jia | Peng, Xiu-Qin | Han, Min | Yin, Wan-Li | Liu, Ya-Li | Hu, Yan-Long | Liu, Yu | Yang, Liu-Qin | Zhu, Fu-Guo | Yang, Xiu-Feng | Feng, Xiao-Shan | Wang, Zhou | Li, Yin | Gao, She-Gan | Liu, Hai-Lin | Yuan, Ling | Jin, Yan | Zhang, Yan-Rui | Sheyhidin, Ilyar | Li, Feng | Chen, Bao-Ping | Ren, Shu-Wei | Liu, Bin | Li, Dan | Zhang, Gao-Fu | Yue, Wen-Bin | Feng, Chang-Wei | Qige, Qirenwang | Zhao, Jian-Ting | Yang, Wen-Jun | Lei, Guang-Yan | Chen, Long-Qi | Li, En-Min | Xu, Li-Yan | Wu, Zhi-Yong | Bao, Zhi-Qin | Chen, Ji-Li | Li, Xian-Chang | Zhuang, Xiang | Zhou, Ying-Fa | Zuo, Xian-Bo | Dong, Zi-Ming | Wang, Lu-Wen | Fan, Xue-Pin | Wang, Jin | Zhou, Qi | Ma, Guo-Shun | Zhang, Qin-Xian | Liu, Hai | Jian, Xin-Ying | Lian, Sin-Yong | Wang, Jin-Sheng | Chang, Fu-Bao | Lu, Chang-Dong | Miao, Jian-Jun | Chen, Zhi-Guo | Wang, Ran | Guo, Ming | Fan, Zeng-Lin | Tao, Ping | Liu, Tai-Jing | Wei, Jin-Chang | Kong, Qing-Peng | Fan, Lei | Wang, Xian-Zeng | Gao, Fu-Sheng | Wang, Tian-Yun | Xie, Dong | Wang, Li | Chen, Shu-Qing | Yang, Wan-Cai | Hong, Jun-Yan | Wang, Liang | Qiu, Song-Liang | Goldstein, Alisa M. | Yuan, Zhi-Qing | Chanock, Stephen J. | Zhang, Xue-Jun | Taylor, Philip R. | Wang, Li-Dong
Human Molecular Genetics  2012;21(9):2132-2141.
Genome-wide association studies have identified susceptibility loci for esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis of all single-nucleotide polymorphisms (SNPs) that showed nominally significant P-values in two previously published genome-wide scans that included a total of 2961 ESCC cases and 3400 controls. The meta-analysis revealed five SNPs at 2q33 with P< 5 × 10−8, and the strongest signal was rs13016963, with a combined odds ratio (95% confidence interval) of 1.29 (1.19–1.40) and P= 7.63 × 10−10. An imputation analysis of 4304 SNPs at 2q33 suggested a single association signal, and the strongest imputed SNP associations were similar to those from the genotyped SNPs. We conducted an ancestral recombination graph analysis with 53 SNPs to identify one or more haplotypes that harbor the variants directly responsible for the detected association signal. This showed that the five SNPs exist in a single haplotype along with 45 imputed SNPs in strong linkage disequilibrium, and the strongest candidate was rs10201587, one of the genotyped SNPs. Our meta-analysis found genome-wide significant SNPs at 2q33 that map to the CASP8/ALS2CR12/TRAK2 gene region. Variants in CASP8 have been extensively studied across a spectrum of cancers with mixed results. The locus we identified appears to be distinct from the widely studied rs3834129 and rs1045485 SNPs in CASP8. Future studies of esophageal and other cancers should focus on comprehensive sequencing of this 2q33 locus and functional analysis of rs13016963 and rs10201587 and other strongly correlated variants.
doi:10.1093/hmg/dds029
PMCID: PMC3315211  PMID: 22323360
18.  Retrospective Analysis of Prognostic Factors in 205 Patients with Laryngeal Squamous Cell Carcinoma Who Underwent Surgical Treatment 
PLoS ONE  2013;8(4):e60157.
Objectives
To investigate the most important factors affecting the prognosis of the patients with squamous cell carcinoma (SCC) of the larynx.
Methods
Based on the clinical and follow-up data, 205 patients with SCC of the larynx receiving total laryngectomy, partial laryngectomy, or CO2 laser surgery in GuangDong General Hospital were retrospectively analyzed. A survival analysis was performed by the Kaplan-Meier method and a multivariable analysis of prognostic factors was carried out using the Cox proportional hazard model.
Results
Subtypes of carcinoma included 69.8% glottic and 30.2% supraglottic. Most patients were in N0 stage (77.6%), and 22.4% patients were in N1∼N3 stage. Over half of the patients were in T1∼T2 stage (55.1%), 20.0% in T3, and 24.9% in T4. Mean follow-up duration was 49.2 months. The survival rates 1, 2, and 3 years after the surgery were 99.0%, 91.7%, and 81.5%, respectively. The survival rate for those patients with clinical stage IV was significantly lower than for those with clinical stage I and II (p<0.001 and p = 0.013, respectively). The disease-free progression rates 1, 2, and 3 years after the surgery were 83.9%, 74.6%, and 71.2%, respectively. Futhermore, those patients with a Charlson score of 1 to 2 and ≥3 had higher risk of mortality than those with a Charlson score of 0 (hazard ratios of 1.8 and 2.41 p = 0.042 and p = 0.008). Multivariable analysis revealed that clinical stage, surgical margin, and comorbidity were significantly associated with both mortality and disease-free progression.
Conclusion
The surgical resection margin, clinical stage, and comorbidity were independent factors affecting the laryngeal cancer prognosis. The survival rates were lower for patients with advanced laryngeal cancer, positive surgical margins, or severe comorbidity, suggesting the importance of early diagnosis, early treatment, negative surgical margins, and conditions of comorbidity.
doi:10.1371/journal.pone.0060157
PMCID: PMC3617169  PMID: 23593169
19.  Role of Thermal Process on Self-Assembled Structures of 4′-([2,2′:6′,2″-Terpyridin]-4′-Yl)-[1,1′-Biphenyl]-4-Carboxylic Acid on Au(III) 
The role of dynamic processes on self-assembled structures of 4′-([2,2′:6′, 2″-terpyridin]-4′-yl)-[1,1′-biphenyl]-4-carboxylic acid (l) molecules on Au(III) has been studied by scanning tunneling microscopy. The as-deposited monolayer is closed-packed and periodic in a short-range due to dipole forces. A thermal annealing process at 110 degrees drives such disordered monolayer into ordered chain-like structures, determined by the combination of the dipole forces and hydrogen bonding. Further annealing at 130 degrees turns the whole monolayer into a bowknot-like structure in which hydrogen bonding plays the dominant role in the formation of assembled structures. Such dependence of an assembled structure on the process demonstrates that an assembled structure can be regulated and controlled not only by the molecular structure but also by the thermal process to form the assembled structure.
doi:10.3390/ijms14035686
PMCID: PMC3634450  PMID: 23478440
dynamic processes; self-assembled structure; hydrogen bond; dipole
20.  Potentiation of tumor radiotherapy by a radiation-inducible oncolytic and oncoapoptotic adenovirus in cervical cancer xenografts 
The p53 tumor suppressor pathway is impaired in more than 90% of cervical cancers and cancer-derived cell lines as a result of infection by human papillomavirus (HPV). The HPV E6 oncoprotein forms complexes with p53 and promotes its degradation via the ubiquitin-dependent mechanism. In this study, we attempted to improve the clinical outcomes of this combined therapy by modifying the p53-targeted adenovirus to become radiation-responsive. The anti-tumor adenovirus was constructed by inserting a radiation-responsive expression cassette composed of the promoter of early growth response-1 (Egr-1) and the pro-apoptotic protein TRAIL. We showed that the addition of adenovirus containing Egr-1/TRAIL significantly increased cell death and apoptosis caused by radiotherapy. In mice bearing xenograft tumors, intratumoral administration of the Egr-1/TRAIL adenovirus followed by radiation significantly reduced tumor growth and enhanced tumor survival. Our Egr-1/TRAIL adenoviral gene product may offer a novel “one-two punch” tumor therapy for cervical cancers not only by potentiating radiation treatment but also by preserving p53 defect-specific tumor killing of the oncolytic adenovirus.
doi:10.1002/ijc.26013
PMCID: PMC3118272  PMID: 21351100
Egr-1 promoter; TRAIL; gene therapy; radiotherapy; tumor; apoptosis; adenovirus
21.  Risk factors for adverse outcome in low rectal cancer 
AIM: To demonstrate the oncologic outcomes of low rectal cancer and to clarify the risk factors for survival, focusing particularly on the type of surgery performed.
METHODS: Data from patients with low rectal carcinomas who underwent surgery, either sphincter-preserving surgery (SPS) or abdominoperineal resection (APR), at The First Affiliated Hospital of Sun Yat-sen University in China from August 1994 to December 2005 were retrospectively analyzed.
RESULTS: Of 331 patients with low rectal cancer, 159 (48.0%) were treated with SPS. A higher incidence of positive resection margins and a higher 5-year cumulative local recurrence rate (14.7% vs 6.8%, P = 0.041) were observed in patients after APR compared to SPS. The five-year overall survival (OS) was 54.6% after APR and 66.8% after SPS (P = 0.018), and the 5-year disease-free survival (DFS) was 52.9% after APR and 65.5% after SPS (P = 0.013). In multivariate analysis, poor OS and DFS were significantly related to positive resection margins, pT3-4, and pTNM III-IV but not to the type of surgery.
CONCLUSION: Despite a higher rate of positive resection margins after APR, the type of surgery was not identified as an independent risk factor for survival.
doi:10.3748/wjg.v18.i1.64
PMCID: PMC3251807  PMID: 22228972
Abdominoperineal resection; Prognosis; Rectal neoplasms; Sphincter-preserving surgery; Surgery
22.  Data Mining in Networks of Differentially Expressed Genes during Sow Pregnancy 
Small to moderate gains in Pig fertility can mean large returns in overall efficiency, and developing methods to improve it is highly desirable. High fertility rates depend on completion of successful pregnancies. To understand the molecular signals associated with pregnancy in sows, expression profiling experiments were conducted to identify differentially expressed genes in ovary and myometrium at different pregnancy periods using the Affymetrix Porcine GeneChipTM. A total of 974, 1800, 335 and 710 differentially expressed transcripts were identified in the myometrium during early pregnancy (EP) and late pregnancy (LP), and in the ovary during EP and LP, respectively. Self-Organizing Map (SOM) clusters indicated the differentially expressed genes belonged to 7 different functional groups. Based on BLASTX searches and Gene Ontology (GO) classifications, 129 unique genes closely related to pregnancy showed differential expression patterns. GO analysis also indicated that there were 21 different molecular function categories, 20 different biological process categories, and 8 different cellular component categories of genes differentially expressed during sow pregnancy. Gene regulatory network reconstruction provided us with an interaction model of known genes such as insulin-like growth factor 2 (IGF2) gene, estrogen receptor (ESR) gene, retinol-binding protein-4 (RBP4) gene, and several unknown candidate genes related to reproduction. Several pitch point genes were selected for association study with reproduction traits. For instance, DPPA5 g.363 T>C was found to associate with litter born weight at later parities in Beijing Black pigs significantly (p < 0.05). Overall, this study contributes to elucidating the mechanism underlying pregnancy processes, which maybe provide valuable information for pig reproduction improvement.
doi:10.7150/ijbs.4071
PMCID: PMC3334670  PMID: 22532788
gene network; microarray; myometrium; ovary; sow pregnancy
23.  Genome-Wide Association Analysis of Meat Quality Traits in a Porcine Large White × Minzhu Intercross Population 
Pork quality is an economically important trait and one of the main selection criteria for breeding in the swine industry. In this genome-wide association study (GWAS), 455 pigs from a porcine Large White × Minzhu intercross population were genotyped using the Illumina PorcineSNP60K Beadchip, and phenotyped for intramuscular fat content (IMF), marbling, moisture, color L*, color a*, color b* and color score in the longissimus muscle (LM). Association tests between each trait and the SNPs were performed via the Genome Wide Rapid Association using the Mixed Model and Regression-Genomic Control (GRAMMAR-GC) approach. From the Ensembl porcine database, SNP annotation was implemented using Sus scrofa Build 9. A total of 45 SNPs showed significant association with one or multiple meat quality traits. Of the 45 SNPs, 36 were located on SSC12. These significantly associated SNPs aligned to or were in close approximation to previously reported quantitative trait loci (QTL) and some were located within introns of previously reported candidate genes. Two haplotype blocks ASGA0100525-ASGA0055225-ALGA0067099-MARC0004712-DIAS0000861, and ASGA0085522-H3GA0056170 were detected in the significant region. The first block contained the genes MYH1, MYH2 and MYH4. A SNP (ASGA0094812) within an intron of the USP43 gene was significantly associated with five meat quality traits. The present results effectively narrowed down the associated regions compared to previous QTL studies and revealed haplotypes and candidate genes on SSC12 for meat quality traits in pigs.
doi:10.7150/ijbs.3614
PMCID: PMC3334672  PMID: 22532790
F2 design; genome-wide association study; meat quality trait; pig; SNP.
24.  Genome-wide Association Study of Porcine Hematological Parameters in a Large White × Minzhu F2 Resource Population 
Hematological traits, which are important indicators of immune function in animals, have been commonly examined as biomarkers of disease and disease severity in humans and animals. Genome-wide significant quantitative trait loci (QTLs) provide important information for use in breeding programs of animals such as pigs. QTLs for hematological parameters (hematological traits) have been detected in pig chromosomes, although these are often mapped by linkage analysis to large intervals making identification of the underlying mutation problematic. Single nucleotide polymorphisms (SNPs) are the common form of genetic variation among individuals and are thought to account for the majority of inherited traits. In this study, a genome-wide association study (GWAS) was performed to detect regions of association with hematological traits in a three-generation resource population produced by intercrossing Large White boars and Minzhu sows during the period from 2007 to 2011. Illumina PorcineSNP60 BeadChip technology was used to genotype each animal and seven hematological parameters were measured (hematocrit (HCT), hemoglobin (HGB), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), red blood cell count (RBC) and red blood cell volume distribution width (RDW)). Data were analyzed in a three step Genome-wide Rapid Association using the Mixed Model and Regression-Genomic Control (GRAMMAR-GC) method. A total of 62 genome-wide significant and three chromosome-wide significant SNPs associated with hematological parameters were detected in this GWAS. Seven and five SNPs were associated with HCT and HGB, respectively. These SNPs were all located within the region of 34.6-36.5 Mb on SSC7. Four SNPs within the region of 43.7-47.0 Mb and fifty-five SNPs within the region of 42.2-73.8 Mb on SSC8 showed significant association with MCH and MCV, respectively. At chromosome-wide significant level, one SNP at 29.2 Mb on SSC1 and two SNPs within the region of 26.0-26.2 Mb were found to be significantly associated with RBC and RDW, respectively. Many of the SNPs were located within previously reported QTL regions and appeared to narrow down the regions compared with previously described QTL intervals. In current research, a total of seven significant SNPs were found within six candidate genes SCUBE3, KDR, TDO, IGFBP7, ADAMTS3 and AFP. In addition, the KIT gene, which has been previously reported to relate to hematological parameters, was located within the region significantly associated with MCH and MCV and could be a candidate gene. These results of this study may lead to a better understanding of the molecular mechanisms of hematological parameters in pigs.
doi:10.7150/ijbs.4027
PMCID: PMC3385009  PMID: 22745577
genome-wide association study; porcine; hematological parameters
25.  Malignant Peripheral Nerve Sheath Tumors: Differentiation Patterns and Immunohistochemical Features - A Mini-Review and Our New Findings 
Journal of Cancer  2012;3:303-309.
Malignant peripheral nerve sheath tumors (MPNST) represent a group of highly heterogeneous human malignancies often with multiple histological origins, divergent differentiation patterns, and diverse immunohistochemical presentations. The differential diagnosis of MPNST from other spindle cell neoplasms poses great challenges for pathologists. This report provides a mini-review of these unique features associated with MPNST and also presents the first cases of MPNST with six differentiation patterns.
doi:10.7150/jca.4179
PMCID: PMC3390600  PMID: 22773934
Malignant peripheral nerve sheath tumor; Liposarcomatous; Glandular; Fibrohistiocytoid; Neuroendocrine differentiation; Cartilage; Triton tumor; Gangliocyte.

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