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1.  Quantitative Hepatitis B Core Antibody Level Is a New Predictor for Treatment Response In HBeAg-positive Chronic Hepatitis B Patients Receiving Peginterferon 
Theranostics  2015;5(3):218-226.
A recent study revealed that quantitative hepatitis B core antibody (qAnti-HBc) level could serve as a novel marker for predicting treatment response. In the present study, we further investigated the predictive value of qAnti-HBc level in HBeAg-positive patients undergoing PEG-IFN therapy. A total of 140 HBeAg-positive patients who underwent PEG-IFN therapy for 48 weeks and follow-up for 24 weeks were enrolled in this study. Serum samples were taken every 12 weeks post-treatment. The predictive value of the baseline qAnti-HBc level for treatment response was evaluated. Patients were further divided into 2 groups according to the baseline qAnti-HBc level, and the response rate was compared. Additionally, the kinetics of the virological and biochemical parameters were analyzed. Patients who achieved response had a significantly higher baseline qAnti-HBc level (serological response [SR], 4.52±0.36 vs. 4.19±0.58, p=0.001; virological response [VR], 4.53±0.35 vs. 4.22±0.57, p=0.005; combined response [CR], 4.50±0.36 vs. 4.22±0.58, p=0.009)). Baseline qAnti-HBc was the only parameter that was independently correlated with SR (p=0.008), VR (p=0.010) and CR(p=0.019). Patients with baseline qAnti-HBc levels ≥30,000 IU/mL had significantly higher response rates, more HBV DNA suppression, and better hepatitis control in PEG-IFN treatment. In conclusion, qAnti-HBc level may be a novel biomarker for predicting treatment response in HBeAg-positive patients receiving PEG-IFN therapy.
PMCID: PMC4279186  PMID: 25553110
quantitative anti-HBc;  chronic hepatitis B; PEG-IFN treatment; treatment response prediction; pretreatment biomarker.
2.  Rapid identification of apolipoprotein E genotypes by high-resolution melting analysis in Chinese Han and African Fang populations 
Apolipoprotein E (APOE) gene polymorphism can affect APOE gene transcription, serum lipid levels and repair of tissue damage, which could place individuals at serious risk of cardiovascular disease or certain infectious diseases. Recently, high-resolution melting (HRM) analysis was reported to be a simple, inexpensive, accurate and sensitive method for the genotyping or/and scanning of rare mutations. For this reason, an HRM analysis was used in the present study for APOE genotyping in the Southern Chinese Han and African Fang populations. A total of 100 healthy Southern Chinese Han and 175 healthy African Fang individuals attended the study. Polymerase chain reaction-DNA sequencing was used as a reference method for the genotyping of these samples. The six APOE genotypes could all be rapidly and efficiently identified by HRM analysis, and 100% concordance was found between the HRM analysis and the reference method. The allele frequencies of APOE in the Southern Chinese Han population were 7.0, 87.5 and 5.5% for ɛ2, ɛ3 and ɛ4, respectively. In the African Fang population, the allele frequencies of APOE were 24.3, 65.7 and 10.0% for ɛ2, ɛ3 and ɛ4, respectively. A statistically significant difference was found between the allele frequencies between the populations (P<0.05). In conclusion, the present study revealed the molecular characterization of APOE gene polymorphism in the Han population from the Chaozhou region of Southern China and the Fang population from Equatorial Guinea. The findings of the study indicated that HRM analysis could be used as an accurate and sensitive method for the rapid screening and identification of APOE genotypes in prospective clinical and population genetic analyses.
PMCID: PMC4280925  PMID: 25574218
apolipoprotein E; genotype; high-resolution melting; Chinese Han; African Fang
3.  Turion morphological responses to water nutrient concentrations and plant density in the submerged macrophyte Potamogeton crispus 
Scientific Reports  2014;4:7079.
Asexual propagules are the dominant means of propagation in most submerged macrophytes. To improve the understanding of how water nutrient concentrations and population density influence the turion production of Potamogeton crispus L., the turions were planted in mesocosms with three water nutrient conditions (ambient lake water, high P and high N) and two plant density levels (4 and 15 turions m−2). After a 9-month experiment, the +P in the water column significantly increased the total turion number per plant under both of the plant density treatments. However, the +N in the water column did not affect the turion number per plant under low plant density. The +P in the water and high plant density significantly reduced the turion individual biomass. An examination of 3210 turion individuals from all treatments revealed that the increased water nutrient concentrations and plant density impacted the turion size by producing different stem diameters of individual turions. Most of the scale leaf morphological traits of the turions were significantly increased under higher water nutrients, but these traits were similar between the different plant density treatments. These results demonstrate that the water P concentration interacts with plant density, affecting both the production and traits of turions.
PMCID: PMC4233331  PMID: 25399866
4.  Iron Metabolism Regulates p53 Signaling through Direct Heme-p53 Interaction and Modulation of p53 Localization, Stability, and Function 
Cell reports  2014;7(1):180-193.
Iron excess is closely associated with tumorigenesis in multiple types of human cancers, with underlying mechanisms yet unclear. Recently, iron deprivation has emerged as a major strategy for chemotherapy, but it exerts tumor suppression only on select human malignancies. Here, we report that the tumor suppressor protein p53 is downregulated during iron excess. Strikingly, the iron polyporphyrin heme binds to p53 protein, interferes with p53-DNA interactions, and triggers both nuclear export and cytosolic degradation of p53. Moreover, in a tumorigenicity assay, iron deprivation suppressed wild-type p53-dependent tumor growth, suggesting that upregulation of wild-type p53 signaling underlies the selective efficacy of iron deprivation. Our findings thus identify a direct link between iron/heme homeostasis and the regulation of p53 signaling, which not only provides mechanistic insights into iron-excess-associated tumorigenesis but may also help predict and improve outcomes in iron-deprivation-based chemotherapy.
PMCID: PMC4219651  PMID: 24685134
5.  Pulmonary resection in the treatment of 43 patients with well-localized, cavitary pulmonary multidrug-resistant tuberculosis in Shanghai 
Multidrug-resistant tuberculosis (MDR-TB), defined as tuberculosis resistant to at least isoniazid and rifampicin in vitro, poses a significant challenge to the control of TB worldwide. Despite global efforts to control tuberculosis, it remains the leading cause of death from an infectious agent. Although modern tuberculosis treatment relies on chemotherapy, surgery is accepted as adjuvant treatment for multidrug-resistant tuberculosis.
In a retrospective cohort study, 43 MDR-TB patients (28 males and 15 females: mean age 45.3 years) who underwent pulmonary resection between January 1993 and December 2011 were reviewed. Every patient with well-localized, cavitary lesions showed sputum-positive preoperatively. Individually tailored treatment regimens were selected at a once-weekly staff conference following review of the patient's case history and drug susceptibility results. The variables that affected treatment outcomes were identified through multivariate regression analysis.
There was no surgical mortality. Forty (93.0%) patients demonstrated sputum conversion and/or remained negative after surgery. Each patient had completed treatment, and during a mean of 81 follow-up months (range 18–214 months), 1 patient relapsed. This patient was cured after another course of treatment. Operative procedures included 30 (69.8%) lobectomies, 2 (4.7%) bilobectomies, 8 (18.6%) pneumonectomies and 3 (6.98%) lobectomies plus segmentectomy. There were no operation-related deaths, and there were five major postoperative complications (11.6%). Overall, 40 of 43 (93.0%) MDR-TB patients remained free of TB following surgery. The duration of chemotherapy before surgery had correlation with postoperative outcome (P = 0.001).
The proper selection of the patients and early decision for surgical intervention can achieve a high success rate of pulmonary MDR-TB with well-localized pulmonary cavities.
PMCID: PMC3745155  PMID: 23748869
Surgery; Tuberculosis; Multidrug resistant; Pulmonary cavity
6.  Oxytocin decreases colonic motility of cold water stressed rats via oxytocin receptors 
World Journal of Gastroenterology : WJG  2014;20(31):10886-10894.
AIM: To investigate whether cold water intake into the stomach affects colonic motility and the involvement of the oxytocin-oxytocin receptor pathway in rats.
METHODS: Female Sprague Dawley rats were used and some of them were ovariectomized. The rats were subjected to gastric instillation with cold (0-4 °C, cold group) or room temperature (20-25 °C, control group) saline for 14 consecutive days. Colon transit was determined with a bead inserted into the colon. Colonic longitudinal muscle strips were prepared to investigate the response to oxytocin in vitro. Plasma concentration of oxytocin was detected by ELISA. Oxytocin receptor expression was investigated by Western blot analysis. Immunohistochemistry was used to locate oxytocin receptors.
RESULTS: Colon transit was slower in the cold group than in the control group (P < 0.05). Colonic smooth muscle contractile response to oxytocin decreased, and the inhibitory effect of oxytocin on muscle contractility was enhanced by cold water intake (0.69 ± 0.08 vs 0.88 ± 0.16, P < 0.05). Atosiban and tetrodotoxin inhibited the effect of oxytocin on colonic motility. Oxytocin receptors were located in the myenteric plexus, and their expression was up-regulated in the cold group (P < 0.05). Cold water intake increased blood concentration of oxytocin, but this effect was attenuated in ovariectomized rats (286.99 ± 83.72 pg/mL vs 100.56 ± 92.71 pg/mL, P < 0.05). However, in ovariectomized rats, estradiol treatment increased blood oxytocin, and the response of colonic muscle strips to oxytocin was attenuated.
CONCLUSION: Cold water intake inhibits colonic motility partially through oxytocin-oxytocin receptor signaling in the myenteric nervous system pathway, which is estrogen dependent.
PMCID: PMC4138467  PMID: 25152590
Intragastric cold water stress; Colonic motility; Estradiol; Oxytocin; Oxytocin receptor; Irritable bowel syndrome
7.  Preparation of bufalin-loaded pluronic polyetherimide nanoparticles, cellular uptake, distribution, and effect on colorectal cancer 
A large number of studies have shown that bufalin can have a significant antitumor effect in a variety of tumors. However, because of toxicity, insolubility in water, fast metabolism, short half-life, and other shortcomings, its application is limited in cancer therapy. In this study, we explored the anti-metastatic role of bufalin-loaded pluronic polyetherimide nanoparticles on HCT116 colon cancer-bearing mice. Nanoparticle size, shape, drug loading, encapsulation efficiency, and in vitro drug release were studied. Also, cellular uptake of nanoparticles, in vivo tumor targeting, and tumor metastasis were studied. The nanoparticles had a particle size of about 60 nm and an encapsulation efficiency of 75.71%, by weight. The in vitro release data showed that free bufalin was released faster than bufalin-loaded pluronic polyetherimide nanoparticles, and almost 80% of free bufalin was released after 32 hours. Nanoparticles had an even size distribution, were stable, and had a slow release and a tumor-targeting effect. Bufalin-loaded pluronic polyetherimide nanoparticles can significantly inhibit the growth and metastasis of colorectal cancer.
PMCID: PMC4149445  PMID: 25187707
colon cancer; nanoparticles; tumor target; bufalin
8.  An Invasive Clonal Plant Benefits from Clonal Integration More than a Co-Occurring Native Plant in Nutrient-Patchy and Competitive Environments 
PLoS ONE  2014;9(5):e97246.
Many notorious invasive plants are clonal, however, little is known about the different roles of clonal integration effects between invasive and native plants. Here, we hypothesize that clonal integration affect growth, photosynthetic performance, biomass allocation and thus competitive ability of invasive and native clonal plants, and invasive clonal plants benefit from clonal integration more than co-occurring native plants in heterogeneous habitats. To test these hypotheses, two stoloniferous clonal plants, Alternanthera philoxeroides (invasive), Jussiaea repens (native) were studied in China. The apical parts of both species were grown either with or without neighboring vegetation and the basal parts without competitors were in nutrient- rich or -poor habitats, with stolon connections were either severed or kept intact. Competition significantly reduced growth and photosynthetic performance of the apical ramets in both species, but not the biomass of neighboring vegetation. Without competition, clonal integration greatly improved the growth and photosynthetic performance of both species, especially when the basal parts were in nutrient-rich habitats. When grown with neighboring vegetation, growth of J. repens and photosynthetic performance of both species were significantly enhanced by clonal integration with the basal parts in both nutrient-rich and -poor habitats, while growth and relative neighbor effect (RNE) of A. philoxeroides were greatly improved by clonal integration only when the basal parts were in nutrient-rich habitats. Moreover, clonal integration increased A. philoxeroides's biomass allocation to roots without competition, but decreased it with competition, especially when the basal ramets were in nutrient-rich sections. Effects of clonal integration on biomass allocation of J. repens was similar to that of A. philoxeroides but with less significance. These results supported our hypothesis that invasive clonal plants A. philoxeroides benefits from clonal integration more than co-occurring native J. repens, suggesting that the invasiveness of A. philoxeroides may be closely related to clonal integration in heterogeneous environments.
PMCID: PMC4016286  PMID: 24816849
9.  BEAST 2: A Software Platform for Bayesian Evolutionary Analysis 
PLoS Computational Biology  2014;10(4):e1003537.
We present a new open source, extensible and flexible software platform for Bayesian evolutionary analysis called BEAST 2. This software platform is a re-design of the popular BEAST 1 platform to correct structural deficiencies that became evident as the BEAST 1 software evolved. Key among those deficiencies was the lack of post-deployment extensibility. BEAST 2 now has a fully developed package management system that allows third party developers to write additional functionality that can be directly installed to the BEAST 2 analysis platform via a package manager without requiring a new software release of the platform. This package architecture is showcased with a number of recently published new models encompassing birth-death-sampling tree priors, phylodynamics and model averaging for substitution models and site partitioning. A second major improvement is the ability to read/write the entire state of the MCMC chain to/from disk allowing it to be easily shared between multiple instances of the BEAST software. This facilitates checkpointing and better support for multi-processor and high-end computing extensions. Finally, the functionality in new packages can be easily added to the user interface (BEAUti 2) by a simple XML template-based mechanism because BEAST 2 has been re-designed to provide greater integration between the analysis engine and the user interface so that, for example BEAST and BEAUti use exactly the same XML file format.
PMCID: PMC3985171  PMID: 24722319
10.  Processing Uncertain RFID Data in Traceability Supply Chains 
The Scientific World Journal  2014;2014:535690.
Radio Frequency Identification (RFID) is widely used to track and trace objects in traceability supply chains. However, massive uncertain data produced by RFID readers are not effective and efficient to be used in RFID application systems. Following the analysis of key features of RFID objects, this paper proposes a new framework for effectively and efficiently processing uncertain RFID data, and supporting a variety of queries for tracking and tracing RFID objects. We adjust different smoothing windows according to different rates of uncertain data, employ different strategies to process uncertain readings, and distinguish ghost, missing, and incomplete data according to their apparent positions. We propose a comprehensive data model which is suitable for different application scenarios. In addition, a path coding scheme is proposed to significantly compress massive data by aggregating the path sequence, the position, and the time intervals. The scheme is suitable for cyclic or long paths. Moreover, we further propose a processing algorithm for group and independent objects. Experimental evaluations show that our approach is effective and efficient in terms of the compression and traceability queries.
PMCID: PMC3967727  PMID: 24737978
11.  TGF-β-miR-34a-CCL22 Signaling-Induced Treg Cell Recruitment Promotes Venous Metastases of HBV-Positive Hepatocellular Carcinoma 
Cancer cell  2012;22(3):291-303.
Portal vein tumor thrombus (PVTT) is strongly correlated to a poor prognosis for patients with hepatocellular carcinoma (HCC). In this study, we uncovered a causative link between hepatitis B virus (HBV) infection and development of PVTT. Mechanistically, elevated TGF-β activity, associated with the persistent presence of HBV in the liver tissue, suppresses the expression of microRNA-34a, leading to enhanced production of chemokine CCL22, which recruits regulatory T (Treg) cells to facilitate immune escape. These findings strongly suggest that HBV infection and activity of the TGF-β-miR-34a-CCL22 axis serve as potent etiological factors to predispose HCC patients for the development of PVTT, possibly through the creation of an immune-subversive microenvironment to favor colonization of disseminated HCC cells in the portal venous system.
PMCID: PMC3443566  PMID: 22975373
12.  Critical Roles of p53 in Epithelial-Mesenchymal Transition and Metastasis of Hepatocellular Carcinoma Cells 
PLoS ONE  2013;8(9):e72846.
Hepatocellular carcinoma (HCC) is one of the most malignant tumors and the biggest obstacle in curing HCC is its high metastasis potential. Alteration of p53 is the most frequent genetic change found in HCC. Although the biological function of p53 in tumor initiation and progression has been well characterized, whether or not p53 is implicated in metastasis of HCC is largely unknown. In this study, we analyzed the potential functions of p53 in epithelial-mesenchymal transition (EMT) and metastasis of HCC cells. Both insulin- and TGF-β1-induced changes of critical EMT markers were greatly enhanced by p53 knockdown in HCC cells. The insulin- and TGF-β1-stimulated migration of HCC cells were enhanced by p53 knockdown. Furthermore, in vivo metastasis of HCC cells using different mouse models was robustly enhanced by p53 knockdown. In addition, we found that p53 regulation on EMT and metastasis involves β-catenin signaling. The nuclear accumulation and transcriptional activity of β-catenin was modulated by p53. The enhanced EMT phenotype, cell migration and tumor metastasis of HCC cells by p53 knockdown were abrogated by inhibiting β-catenin signal pathway. In conclusion, this study reveals that p53 plays a pivotal role in EMT and metastasis of HCC cells via its regulation on β-catenin signaling.
PMCID: PMC3759437  PMID: 24023784
13.  miR-126 and miR-126* repress recruitment of mesenchymal stem cells and inflammatory monocytes to inhibit breast cancer metastasis 
Nature cell biology  2013;15(3):284-294.
The tumour stroma is an active participant during cancer progression. Stromal cells promote tumour progression and metastasis through multiple mechanisms including enhancing tumour invasiveness and angiogenesis, and suppressing immune surveillance. We report here that miR-126/miR-126*, a microRNA pair derived from a single precursor, independently suppress the sequential recruitment of mesenchymal stem cells and inflammatory monocytes into the tumour stroma to inhibit lung metastasis by breast tumour cells in a mouse xenograft model. miR-126/miR-126* directly inhibit stromal cell-derived factor-1 alpha (Sdf-1α) expression, and indirectly suppress the expression of chemokine (C–C motif) ligand 2 (Ccl2) by cancer cells in an Sdf-1α-dependent manner. miR-126/miR-126* expression is downregulated in cancer cells by promoter methylation of their host gene Egfl7. These findings determine how this microRNA pair alters the composition of the primary tumour microenvironment to favour breast cancer metastasis, and demonstrate a correlation between miR-126/126* downregulation and poor metastasis-free survival of breast cancer patients.
PMCID: PMC3672398  PMID: 23396050
14.  Identification of a small molecule 1,4-bis-[4-(3-phenoxy-propoxy)-but-2-ynyl]-piperazine as a novel inhibitor of the transcription factor p53 
Acta Pharmacologica Sinica  2013;34(6):805-810.
To identify novel small compound inhibitor of p53 protein.
Mouse embryonic fibroblasts (MEF) and mouse embryonic stem (ES) cells were tested. Cell proliferation rate was determined using a Cell Proliferation Kit. The mRNA and protein levels of p53-related genes were measured using real-time PCR and Western blotting, respectively. Global response in the p53 signaling network was analyzed using Illumina whole-genome expression BeadChips.
Treatment of MEF cells with a small molecule 1,4-bis-[4-(3-phenoxy-propoxy)-but-2-ynyl]-piperazine (G5) at 10 μmol/L for 24 h markedly reduced the mRNA and protein levels of the p53 downstream genes MDM2 and p21. In G5-treated ES cells, a total of 372 differentially expressed genes were identified, and 18 among them were direct downstream genes of p53; 6 out of 9 p53-repressed genes were upregulated, and 5 out of 9 p53-activated genes were downregulated. In both MEF cells and ES cells, treatment of with G5 (10 μmol/L) up to 48 h neither affected the proliferation rate nor caused morphological alterations.
G5 inhibits p53 activity and simultaneously preserves the normal growth and proliferation of cells, therefore is a new compound for studies of p53-mediated cell manipulation.
PMCID: PMC3674519  PMID: 23736005
1,4-bis-[4-(3-phenoxy-propoxy)-but-2-ynyl]-piperazine; tumor suppressor protein; p53; p53 inhibitor; embryonic fibroblast; embryonic stem cell; proliferation
15.  Identification of 5-Iodotubercidin as a Genotoxic Drug with Anti-Cancer Potential 
PLoS ONE  2013;8(5):e62527.
Tumor suppressor p53, which is activated by various stress and oncogene activation, is a target for anti-cancer drug development. In this study, by screening panels of protein kinase inhibitors and protein phosphatase inhibitors, we identified 5-Iodotubercidin as a strong p53 activator. 5-Iodotubercidin is purine derivative and is used as an inhibitor for various kinases including adenosine kinase. We found that 5-Iodotubercidin could cause DNA damage, verified by induction of DNA breaks and nuclear foci positive for γH2AX and TopBP1, activation of Atm and Chk2, and S15 phosphorylation and up-regulation of p53. As such, 5-Iodotubercidin induces G2 cell cycle arrest in a p53-dependent manner. Itu also induces cell death in p53-dependent and -independent manners. DNA breaks were likely generated by incorporation of 5-Iodotubercidin metabolite into DNA. Moreover, 5-Iodotubercidin showed anti-tumor activity as it could reduce the tumor size in carcinoma xenograft mouse models in p53-dependent and -independent manners. These findings reveal 5-Iodotubercidin as a novel genotoxic drug that has chemotherapeutic potential.
PMCID: PMC3646850  PMID: 23667485
16.  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.
PMCID: PMC3315211  PMID: 22323360
17.  Higher Blood 25(OH)D Level May Reduce the Breast Cancer Risk: Evidence from a Chinese Population Based Case-Control Study and Meta-Analysis of the Observational Studies 
PLoS ONE  2013;8(1):e49312.
Experimental data suggest a protective effect of vitamin D on breast cancer; however, epidemiologic results remain inclusive. With a Chinese population-based case-control study and meta-analysis of the observational studies, we here systematically evaluated the association of blood 25(OH)D level and breast cancer risk. With 593 breast cancer cases and 580 cancer-free controls from Shanghai, China, we found that 80% of the normal women had severe vitamin D deficiency (less than 20 ng/mL) and 15.2% had mild deficiency (20 to 30 ng/mL) and only 4.8% of women had sufficient vitamin D level (>30 ng/mL) while the proportion was 96.1%, 3.2% and 0.7% respectively for the breast cancer patients. Compared to those with the lowest quartile of plasma 25(OH)D level, women with highest quartile 25(OH)D level showed a significant decreased breast cancer risk (Q4 vs.Q1: OR = 0.10, 95% CI = 0.06–0.15) and every 1 ng/ml increment of plasma 25(OH)D level led to a 16% lower odds of breast cancer (OR = 0.84, 95% CI = 0.81–0.87; P<0.001). From the meta-analysis of the observational studies, we found that women with highest quantile of blood 25(OH)D level was associated with a significantly reduced breast cancer risk compared to those with lowest quantile of blood 25(OH)D level for the 11 nested case-control and retrospective studies (pooled OR = 0.86, 95% CI = 0.75–1.00) and 10 case-control studies (7 population based, OR = 0.35, 95% CI = 0.24–0.52; 3 hospital based, OR = 0.08, 95% CI = 0.02–0.33). These results suggest that vitamin D may have a chemo-preventive effect against breast cancer.
PMCID: PMC3559701  PMID: 23382798
18.  Bilateral bullectomy through uniportal video-assisted thoracoscopic surgery combined with contralateral access to the anterior mediastinum*,**  
Video-assisted thoracoscopic surgery (VATS) has been a surgical intervention of choice for the treatment of spontaneous pneumothorax (SP) with lung bulla. Our objective was to introduce a uniportal VATS approach for simultaneous bilateral bullectomy and to evaluate its therapeutic efficacy.
Between May of 2011 and January of 2012, five patients underwent bilateral bullectomy conducted using this approach. All of the patients presented with bilateral SP. Preoperative HRCT revealed that all of the patients had bilateral apical bullae. We reviewed the surgical indications, surgical procedures, and outcomes.
All of the patients were successfully submitted to this approach for bilateral bullectomy, and there were no intraoperative complications. The median time to chest tube removal was 4.2 days, and the median length of the postoperative hospital stay was 5.2 days. The median postoperative follow-up period was 11.2 months. One patient experienced recurrence of left SP three weeks after the surgery and underwent pleural abrasion.
Bilateral bullectomy through uniportal VATS combined with contralateral access to the anterior mediastinum is technically reliable and provides favorable surgical outcomes for patients with bilateral SP who develop bilateral apical bullae. However, among other requirements, this surgical procedure demands that surgeons be experienced in VATS and that the appropriate thoracoscopic instruments are available.
PMCID: PMC4075809  PMID: 23503483
Pneumothorax; Thoracic surgery; video-assisted; Pleural cavity; Mediastinum
19.  Estimation of Leaf Area Index and Plant Area Index of a Submerged Macrophyte Canopy Using Digital Photography 
PLoS ONE  2012;7(12):e51034.
Non-destructive estimation using digital cameras is a common approach for estimating leaf area index (LAI) of terrestrial vegetation. However, no attempt has been made so far to develop non-destructive approaches to LAI estimation for aquatic vegetation. Using the submerged plant species Potamogeton malainus, the objective of this study was to determine whether the gap fraction derived from vertical photographs could be used to estimate LAI of aquatic vegetation. Our results suggested that upward-oriented photographs taken from beneath the water surface were more suitable for distinguishing vegetation from other objects than were downward-oriented photographs taken from above the water surface. Exposure settings had a substantial influence on the identification of vegetation in upward-oriented photographs. Automatic exposure performed nearly as well as the optimal trial exposure, making it a good choice for operational convenience. Similar to terrestrial vegetation, our results suggested that photographs taken for the purpose of distinguishing gap fraction in aquatic vegetation should be taken under diffuse light conditions. Significant logarithmic relationships were observed between the vertical gap fraction derived from upward-oriented photographs and plant area index (PAI) and LAI derived from destructive harvesting. The model we developed to depict the relationship between PAI and gap fraction was similar to the modified theoretical Poisson model, with coefficients of 1.82 and 1.90 for our model and the theoretical model, respectively. This suggests that vertical upward-oriented photographs taken from below the water surface are a feasible alternative to destructive harvesting for estimating PAI and LAI for the submerged aquatic plant Potamogeton malainus.
PMCID: PMC3514177  PMID: 23226557
20.  Research Advances at the Institute for Nutritional Sciences at Shanghai, China12 
Advances in Nutrition  2011;2(5):428-439.
Nutrition-related health issues have emerged as a major threat to public health since the rebirth of the economy in China starting in the 1980s. To meet this challenge, the Chinese Academy of Sciences established the Institute for Nutritional Sciences (INS) at Shanghai, China ∼8 y ago. The mission of the INS is to apply modern technologies and concepts in nutritional research to understand the molecular mechanism and provide means of intervention in the combat against nutrition-related diseases, including type 2 diabetes, metabolic syndrome, obesity, cardiovascular diseases, and many types of cancers. Through diligent and orchestrated efforts by INS scientists, graduate students, and research staff in the past few years, the INS has become the leading institution in China in the areas of basic nutritional research and metabolic regulation. Scientists at the INS have made important progress in many areas, including the characterization of genetic and nutritional properties of the Chinese population, metabolic control associated with nutrient sensing, molecular mechanisms underlying glucose and lipid metabolism, regulation of metabolism by adipokines and inflammatory pathways, disease intervention using functional foods or extracts of Chinese herbs, and many biological studies related to carcinogenesis. The INS will continue its efforts in understanding the optimal nutritional needs for Chinese people and the molecular causes associated with metabolic diseases, thus paving the way for effective and individualized intervention in the future. This review highlights the major research endeavors undertaken by INS scientists in recent years.
PMCID: PMC3183593  PMID: 22332084
21.  HGF and Direct Mesenchymal Stem Cells Contact Synergize to Inhibit Hepatic Stellate Cells Activation through TLR4/NF-kB Pathway 
PLoS ONE  2012;7(8):e43408.
Bone marrow-derived mesenchymal stem cells (BMSCs) can reduce liver fibrosis. Apart from the paracrine mechanism by which the antifibrotic effects of BMSCs inhibit activated hepatic stellate cells (HSCs), the effects of direct interplay and juxtacrine signaling between the two cell types are poorly understood. The purpose of this study was to explore the underlying mechanisms by which BMSCs modulate the function of activated HSCs.
We used BMSCs directly and indirectly co-culture system with HSCs to evaluate the anti-fibrosis effect of BMSCs. Cell proliferation and activation were examined in the presence of BMSCs and HGF. c-met was knockdown in HSCs to evaluate the effect of HGF secreted by BMSCs. The TLR4 and Myeloid differentiation primary response gene 88(MyD88) mRNA levels and the NF-kB pathway activation were determined by real-time PCR and western blotting analyses. The effect of BMSCs on HSCs activation was investigated in vitro in either MyD88 silencing or overexpression in HSCs. Liver fibrosis in rats fed CCl4 with and without BMSCs supplementation was compared. Histopathological examinations and serum biochemical tests were compared between the two groups.
BMSCs remarkably inhibited the proliferation and activation of HSCs by interfering with LPS-TLR4 pathway through a cell–cell contact mode that was partially mediated by HGF secretion. The NF-kB pathway is involved in HSCs activation inhibition by BMSCs. MyD88 over expression reduced the BMSC inhibition of NF-kB luciferase activation. BMSCs protected liver fibrosis in vivo.
BMSCs modulate HSCs in vitro via TLR4/MyD88/NF-kB signaling pathway through cell–cell contact and secreting HGF. BMSCs have therapeutic effects on cirrhosis rats. Our results provide new insights into the treatment of hepatic fibrosis with BMSCs.
PMCID: PMC3426540  PMID: 22927965
22.  Upregulator of Cell Proliferation Predicts Poor Prognosis in Hepatocellular Carcinoma and Contributes to Hepatocarcinogenesis by Downregulating FOXO3a 
PLoS ONE  2012;7(7):e40607.
The goal of the present study was to investigate the potential correlation between the expression level of upregulator of cell proliferation (URGCP/URG4) and the prognosis of hepatocellular carcinoma (HCC), and to examine the biological function of URGCP/URG4 in the progression of HCC, to better understand its underlying molecular mechanism in hepatic tumorigenesis.
URGCP/URG4 expression was analyzed in 15 HCC cell lines, in 278 archived paraffin-embedded HCC sections, and in 10 pairs of fresh HCC tumor and para-tumor non-cancerous tissues using immunohistochemistry (IHC) and Western blotting analysis (WB). The effect of URGCP/URG4 on cell proliferation and tumorigenesis was examined in vitro and in vivo. WB and luciferase reporter analyses were performed to identify the effects of URGCP/URG4-overexpression or -knockdown on expression of cell cycle regulators and transcriptional activity of FOXO3a.
IHC results revealed an upregulation of URGCP/URG4 in all HCC cell lines and fresh HCC samples as compared with normal liver cells and para-tumor tissues, respectively. URGCP/URG4 was also expressed at a high level in 122 of the 278 (43.8%) archived HCC specimens. The expression level of URGCP/URG4 was significantly correlated with clinical staging and poor patient survival of HCC in the study cohort, and in various clinical subgroups. Strikingly, ectopic expression of URGCP/URG4 induced proliferation and anchorage-independent growth of HCC cells, while silencing of URGCP/URG4 had the opposite effect. Furthermore, URGCP/URG4 overexpression in HCC cells increased cellular entry into the G1/S transitional phase, associated with downregulation of p27Kip1 and p21Cip1 and upregulation of cyclin D1. These effects were accompanied by enhanced Akt activity and reduced FOXO3a transcriptional activity.
URGCP/URG4 plays an important role in promoting proliferation and tumorigenesis of HCC and may represent a novel prognostic biomarker and therapeutic target for this disease.
PMCID: PMC3398045  PMID: 22815774
23.  Filtering Gene Ontology semantic similarity for identifying protein complexes in large protein interaction networks 
Proteome Science  2012;10(Suppl 1):S18.
Many biological processes recognize in particular the importance of protein complexes, and various computational approaches have been developed to identify complexes from protein-protein interaction (PPI) networks. However, high false-positive rate of PPIs leads to challenging identification.
A protein semantic similarity measure is proposed in this study, based on the ontology structure of Gene Ontology (GO) terms and GO annotations to estimate the reliability of interactions in PPI networks. Interaction pairs with low GO semantic similarity are removed from the network as unreliable interactions. Then, a cluster-expanding algorithm is used to detect complexes with core-attachment structure on filtered network. Our method is applied to three different yeast PPI networks. The effectiveness of our method is examined on two benchmark complex datasets. Experimental results show that our method performed better than other state-of-the-art approaches in most evaluation metrics.
The method detects protein complexes from large scale PPI networks by filtering GO semantic similarity. Removing interactions with low GO similarity significantly improves the performance of complex identification. The expanding strategy is also effective to identify attachment proteins of complexes.
PMCID: PMC3380758  PMID: 22759576
24.  Factor Structure of a Multidimensional Gender Identity Scale in a Sample of Chinese Elementary School Children 
The Scientific World Journal  2012;2012:595813.
This study examined the factor structure of a scale based on the four-dimensional gender identity model (Egan and Perry, 2001) in 726 Chinese elementary school students. Exploratory factor analyses suggested a three-factor model, two of which corresponded to “Felt Pressure” and “Intergroup Bias” in the original model. The third factor “Gender Compatibility” appeared to be a combination of “Gender Typicality” and “Gender Contentment” in the original model. Follow-up confirmatory factor analysis (CFA) indicated that, relative to the initial four-factor structure, the three-factor model fits the current Chinese sample better. These results are discussed in light of cross-cultural similarities and differences in development of gender identity.
PMCID: PMC3373173  PMID: 22701363
25.  Bayesian Phylogenetics with BEAUti and the BEAST 1.7 
Molecular Biology and Evolution  2012;29(8):1969-1973.
Computational evolutionary biology, statistical phylogenetics and coalescent-based population genetics are becoming increasingly central to the analysis and understanding of molecular sequence data. We present the Bayesian Evolutionary Analysis by Sampling Trees (BEAST) software package version 1.7, which implements a family of Markov chain Monte Carlo (MCMC) algorithms for Bayesian phylogenetic inference, divergence time dating, coalescent analysis, phylogeography and related molecular evolutionary analyses. This package includes an enhanced graphical user interface program called Bayesian Evolutionary Analysis Utility (BEAUti) that enables access to advanced models for molecular sequence and phenotypic trait evolution that were previously available to developers only. The package also provides new tools for visualizing and summarizing multispecies coalescent and phylogeographic analyses. BEAUti and BEAST 1.7 are open source under the GNU lesser general public license and available at and
PMCID: PMC3408070  PMID: 22367748
Bayesian phylogenetics; evolution; phylogenetics; molecular evolution; coalescent theory

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