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1.  Conventional NK cells can produce IL-22 and promote host defense in K. pneumoniae pneumonia1 
It has been reported that host defense against pulmonary K. pneumoniae infection requires IL-22, which has been proposed to be of T cell origin. Supporting a role for IL-22, we found that Il22−/− mice had decreased survival as compared with wild type mice after intratracheal infection with K. pneumoniae. Surprisingly, however, Rag2−/− mice did not differ from wild type mice in survival or levels of IL-22 in the lungs after infection with K. pneumoniae. By contrast, K. pneumoniae-infected Rag2−/−Il2rg−/− mice failed to produce IL-22. These data suggested a possible role for NK cells or other innate lymphoid cells (ILC) in host defense and production of IL-22. Unlike NK cell-like ILCs that produce IL-22 and display a surface phenotype of NK1.1−NKp46+CCR6+, lung NK cells showed the conventional phenotype, NK1.1+NKp46+CCR6−. Mice depleted of NK cells using anti-asialo GM1 showed decreased survival and higher lung bacterial counts as well as increased dissemination of K. pneumoniae to blood and liver as compared with control-treated mice. NK cell depletion also led to decreased production of IL-22 in the lung. Within one day after infection, although there was no increase in the number of lung NK cells, a subset of lung NK cells became competent to produce IL-22, and such cells were found in both wild type and Rag2−/− mice. Our data suggest that during pulmonary infection of mice with K. pneumoniae, conventional NK cells are required for optimal host defense, which includes the production of IL-22.
PMCID: PMC3995347  PMID: 24442439
2.  Central obesity and nonalcoholic fatty liver disease risk after adjusting for body mass index 
AIM: To investigate whether central obesity is associated with nonalcoholic fatty liver disease (NAFLD) formation after adjusting for general obesity.
METHODS: The online databases PubMed, EMBASE, and ISI Web of Science were searched for studies estimating the influence of central obesity on NAFLD occurrence published through April 2014. Studies that did not adjust for body mass index (BMI) were excluded. In addition, the independent effect of BMI was also assessed with the included studies. The pooled effect sizes and 95% confidence intervals (CIs) were calculated using random- or fixed-effects models based on the degree of heterogeneity. Furthermore, subgroup analyses, meta-regression, sensitivity analyses, and publication bias were performed.
RESULTS: Twenty eligible studies were identified. The summary odds ratio (OR) values per-unit increase in waist circumference (WC) and BMI for NAFLD formation were 1.07 (95%CI: 1.03-1.10, I2 = 73.9%, n = 11 studies) and 1.25 (95%CI: 1.13-1.38, I2 = 88.7%, n = 11 studies), respectively. When the indices were expressed as binary variables (with the non-obesity group as reference), the pooled OR in WC, waist-to-hip ratio, and BMI were 2.34 (95%CI: 1.83-3.00, I2 = 41.8%, n = 7 studies), 4.06 (95%CI: 1.53-10.79, I2 = 65.7%, n = 3 studies), and 2.85 (95%CI: 1.60-5.08, I2 = 57.8%, n = 5 studies), respectively. Using the same studies as the latter (n = 5), pooled OR in WC was 3.14 (95%CI: 2.07-4.77), which is greater than that in BMI.
CONCLUSION: Central obesity may pose a greater threat to national health than general obesity, although both are independently associated with increased risk of NAFLD.
PMCID: PMC4316109  PMID: 25663786
Central obesity; General obesity; Nonalcoholic fatty liver disease; Body mass index; Waist circumference
3.  Prognostic implications of estrogen receptor 1 and vascular endothelial growth factor A expression in primary gallbladder carcinoma 
AIM: To investigate the prognostic significance of estrogen receptor 1 (ER1) and vascular endothelial growth factor A (VEGF-A) expression in primary gallbladder carcinoma (GBC) to identify new prognostic markers for this malignancy.
METHODS: Using immunohistochemistry, we investigated ER1 and VEGF-A expression in 78 GBC and 78 cholelithiasis (CS) tissues. The results were correlated with clinicopathological features. Univariate and multivariate analyses were performed to evaluate the relationship between ER1 and VEGF-A expression and patients’ prognosis. Further Kaplan-Meier survival analysis was also performed.
RESULTS: ER1 and VEGF-A expression was significantly higher in GBC compared with CS (47/78 vs 28/78, P < 0.05; 51/78 vs 33/78, P < 0.05). ER1 expression was correlated with gender (P < 0.05) and VEGF-A expression was correlated with tumor differentiation in GBC patients (P < 0.05). In univariate analysis, age and tumor node metastasis (TNM) stage were factors associated with GBC prognosis (P < 0.05). Although there was no statistical difference between the expression of ER1 or VEGF-A and overall survival, the high expression of ER1 combined with VEGF-A predicted a poor prognosis for GBC patients (16.30 ± 1.87 vs 24.97 ± 2.09, log-rank P < 0.05). In multivariate analysis, combined expression of ER1 and VEGF-A and TNM stage were independent prognostic factors for GBC patients (P < 0.05).
CONCLUSION: Combined expression of ER1 and VEGF-A is a potential prognostic marker for GBC patients. Clinical detection of ER1 and VEGF-A in surgically resected GBC tissues would provide an important reference for decision-making of postoperative treatment programs.
PMCID: PMC4306169  PMID: 25632198
Gallbladder carcinoma; Estrogen receptor 1; Vascular endothelial growth factor A
4.  Associations of psychological capital, demographic and occupational factors with cigarette smoking among Chinese underground coal miners 
BMC Public Health  2015;15:20.
As a specific male occupational group, underground coal miners have been commonly found to have a high prevalence of cigarette smoking. It is of urgent need to explore some factors that could be intervened to reduce smoking from personal or internal perspective. The purpose of the present study was to examine the associations of psychological capital (PsyCap), demographic and occupational factors with smoking among Chinese underground coal miners.
A cross-sectional survey was conducted in a coal-mining population in northeast China. Twenty-five hundreds of male underground miners were sampled from six coal mines. Self-administered questionnaires involving current smoking status, specific scales to measure the levels of PsyCap, effort-reward imbalance (ERI) and perceived physical environment (PPE), and some demographic and occupational factors were completed anonymously after a day shift. Complete responses were obtained from 1,956 participants (response rate: 78.2%). Multivariate logistic regression analysis was used to estimate the factors in relation to current smoking.
The overall smoking prevalence was 52.4%. After controlling for demographic and occupational variables, PsyCap was not associated with smoking. Compared with the miners in the lowest tertile of resilience, the odds ratios (ORs) of smoking for the miners in the intermediate tertile and highest tertile were 1.30 (95% confidence intervals (CI): 0.99–1.70) and 1.58 (95% CI: 1.13–2.20), respectively. Compared with the miners in the lowest tertile of optimism, the ORs of smoking for the miners in the intermediate tertile and highest tertile were 0.79 (95% CI: 0.61–1.03) and 0.69 (95% CI: 0.51–0.92), respectively. Low education and high PPE were the risk factors of smoking, whereas ERI had no association with smoking.
More than half of the underground coal miners were current smokers, which indicated that cigarette smoking might be a common health risk behavior in this occupational population. High resilience and PPE, together with low education were the risk factors of smoking, whereas high optimism was a protective factor. Consequently, PsyCap had mixed effects on cigarette smoking. Investment in resilience and optimism should be given more attention for the purposes of the prevention and reduction of smoking among occupational populations.
Electronic supplementary material
The online version of this article (doi:10.1186/s12889-015-1349-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4311445  PMID: 25604331
Smoking; Psychological capital; Effort-reward imbalance; Perceived physical environment; Underground coal miners
5.  Effects of TGF-β1 on OPG/RANKL Expression of Cementoblasts and Osteoblasts Are Similar without Stress but Different with Mechanical Compressive Stress 
The Scientific World Journal  2015;2015:718180.
Introduction. This study aimed to explore the effects of TGF-β1 on regulating activities of cementoblasts and osteoblasts with or without stress. Material and Methods. Human recombinant TGF-β1 was added with different doses. Immunohistochemical test of osteoprotegerin (OPG)/receptor activator of nuclear factor-kappaB ligand (RANKL) and Alizarin Red-S staining were conducted. Mechanical compressive stress was obtained by increasing the pressure of gaseous phase. OPG/RANKL expression was detected in both cells through quantitative real-time PCR. Results. Similar significant differences (P < 0.05) existed in OPG/RANKL change with increasing concentration of TGF-β1 without mechanical stress for cementoblasts and osteoblasts. However, under 3 h stress, OPG increased and RANKL decreased significantly (P < 0.01) but with similar OPG/RANKL change. Moreover, under 24 h stress, OPG change exhibited no difference (P > 0.05), but RANKL decreased significantly (P < 0.01) at 10 and 100 ng/mL TGF-β1 in cementoblasts. In osteoblasts, OPG increased significantly (P < 0.01) at 10 and 100 ng/mL, whereas RANKL decreased with statistical difference (P < 0.05) at 1 and 10 ng/mL. Conclusions. The effects of TGF-β1 on OPG/RANKL expression of cementoblasts and osteoblasts are similar even without mechanical stress. However, these effects are different under mechanical compressive stress.
PMCID: PMC4312653
6.  Efficacy of Combined Vancomycin and Fosfomycin against Methicillin-Resistant Staphylococcus aureus in Biofilms In Vivo 
PLoS ONE  2014;9(12):e113133.
Infection by methicillin-resistant Staphylococcus aureus (MRSA) is a life-threatening condition, and formation of biofilms can lead to treatment failure in a clinical setting. The aim of this study was to demonstrate the in vivo bactericidal effects of a combination of vancomycin (VAN) and fosfomycin (FOS) against MRSA in a rat carboxymethyl cellulose-pouch biofilm model. The results of the time-kill assay showed that the combination therapy was capable of killing at low minimal inhibitory concentrations (MIC) (½× MIC VAN +1× MIC FOS and 1× MIC VAN + 1× MIC FOS). In the in vivo study, a synergistically bactericidal effect was observed when using the combination therapy on MRSA embedded in the mature biofilm model. In comparison with the untreated control group and the groups receiving either VAN or FOS alone, the rats treated with combination therapy had lower MRSA colony counts in exudates from the pouch, lower white blood cell and neutrophil counts, and C-reactive protein (CRP) in peripheral blood. Furthermore, histological analysis of the pouch wall indicated combination therapy resulted in disappearance of biofilm-like structures, marked decrease in necrosis, and formation of granular tissue. In conclusion, the combination of VAN with FOS had a synergistic bactericidal effect on chronic MRSA infection embedded in biofilm, providing an alternative approach to treating this condition.
PMCID: PMC4281042  PMID: 25551618
7.  Relative Food Prices and Obesity in U.S. Metropolitan Areas: 1976-2001 
PLoS ONE  2014;9(12):e114707.
This study investigates the impact of food price on obesity, by exploring the co-occurrence of obesity growth with relative food price reduction between 1976 and 2001. Analyses control for female labor participation and metropolitan outlet densities that might affect body weight. Both the first-difference and fixed effects approaches provide consistent evidence suggesting that relative food prices have substantial impacts on obesity and such impacts were more pronounced among the low-educated. These findings imply that relative food price reductions during the time period could plausibly explain about 18% of the increase in obesity among the U.S. adults in metropolitan areas.
PMCID: PMC4264774  PMID: 25502888
8.  Identification of Genomic Alterations in Pancreatic Cancer Using Array-Based Comparative Genomic Hybridization 
PLoS ONE  2014;9(12):e114616.
Genomic aberration is a common feature of human cancers and also is one of the basic mechanisms that lead to overexpression of oncogenes and underexpression of tumor suppressor genes. Our study aims to identify frequent genomic changes in pancreatic cancer.
Materials and Methods
We used array comparative genomic hybridization (array CGH) to identify recurrent genomic alterations and validated the protein expression of selected genes by immunohistochemistry.
Sixteen gains and thirty-two losses occurred in more than 30% and 60% of the tumors, respectively. High-level amplifications at 7q21.3–q22.1 and 19q13.2 and homozygous deletions at 1p33–p32.3, 1p22.1, 1q22, 3q27.2, 6p22.3, 6p21.31, 12q13.2, 17p13.2, 17q21.31 and 22q13.1 were identified. Especially, amplification of AKT2 was detected in two carcinomas and homozygous deletion of CDKN2C in other two cases. In 15 independent validation samples, we found that AKT2 (19q13.2) and MCM7 (7q22.1) were amplified in 6 and 9 cases, and CAMTA2 (17p13.2) and PFN1 (17p13.2) were homozygously deleted in 3 and 1 cases. AKT2 and MCM7 were overexpressed, and CAMTA2 and PFN1 were underexpressed in pancreatic cancer tissues than in morphologically normal operative margin tissues. Both GISTIC and Genomic Workbench software identified 22q13.1 containing APOBEC3A and APOBEC3B as the only homozygous deletion region. And the expression levels of APOBEC3A and APOBEC3B were significantly lower in tumor tissues than in morphologically normal operative margin tissues. Further validation showed that overexpression of PSCA was significantly associated with lymph node metastasis, and overexpression of HMGA2 was significantly associated with invasive depth of pancreatic cancer.
These recurrent genomic changes may be useful for revealing the mechanism of pancreatic carcinogenesis and providing candidate biomarkers.
PMCID: PMC4263743  PMID: 25502777
9.  Copy number variation analysis based on AluScan sequences 
AluScan combines inter-Alu PCR using multiple Alu-based primers with opposite orientations and next-generation sequencing to capture a huge number of Alu-proximal genomic sequences for investigation. Its requirement of only sub-microgram quantities of DNA facilitates the examination of large numbers of samples. However, the special features of AluScan data rendered difficult the calling of copy number variation (CNV) directly using the calling algorithms designed for whole genome sequencing (WGS) or exome sequencing.
In this study, an AluScanCNV package has been assembled for efficient CNV calling from AluScan sequencing data employing a Geary-Hinkley transformation (GHT) of read-depth ratios between either paired test-control samples, or between test samples and a reference template constructed from reference samples, to call the localized CNVs, followed by use of a GISTIC-like algorithm to identify recurrent CNVs and circular binary segmentation (CBS) to reveal large extended CNVs. To evaluate the utility of CNVs called from AluScan data, the AluScans from 23 non-cancer and 38 cancer genomes were analyzed in this study. The glioma samples analyzed yielded the familiar extended copy-number losses on chromosomes 1p and 9. Also, the recurrent somatic CNVs identified from liver cancer samples were similar to those reported for liver cancer WGS with respect to a striking enrichment of copy-number gains in chromosomes 1q and 8q. When localized or recurrent CNV-features capable of distinguishing between liver and non-liver cancer samples were selected by correlation-based machine learning, a highly accurate separation of the liver and non-liver cancer classes was attained.
The results obtained from non-cancer and cancerous tissues indicated that the AluScanCNV package can be employed to call localized, recurrent and extended CNVs from AluScan sequences. Moreover, both the localized and recurrent CNVs identified by this method could be subjected to machine-learning selection to yield distinguishing CNV-features that were capable of separating between liver cancers and other types of cancers. Since the method is applicable to any human DNA sample with or without the availability of a paired control, it can also be employed to analyze the constitutional CNVs of individuals.
Electronic supplementary material
The online version of this article (doi:10.1186/s13336-014-0015-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4273479  PMID: 25558350
AluScan sequencing; CNV calling; Cancer classification; Machine learning
10.  Single Cell Spectroscopy: Noninvasive Measures of Small-Scale Structure and Function 
Methods (San Diego, Calif.)  2013;64(2):10.1016/j.ymeth.2013.07.025.
The advancement of spectroscopy methods attained through increases in sensitivity, and often with the coupling of complementary techniques, has enabled real-time structure and function measurements of single cells. The purpose of this review is to illustrate, in light of advances, the strengths and the weaknesses of these methods. Included also is an assessment of the impact of the experimental setup and conditions of each method on cellular function and integrity. A particular emphasis is placed on noninvasive and nondestructive techniques for achieving single cell detection, including nuclear magnetic resonance, in addition to physical, optical, and vibrational methods.
PMCID: PMC3833896  PMID: 23886910
Spectroscopy; Single Cells; Nuclear Magnetic Resonance; Fluorescence Microscopy; Atomic Force Microscopy
11.  Distinct functions of Ulk1 and Ulk2 in the regulation of lipid metabolism in adipocytes 
Autophagy  2013;9(12):2103-2114.
ULK1 (unc-51 like kinase 1) is a serine/threonine protein kinase that plays a key role in regulating the induction of autophagy. Recent studies using autophagy-defective mouse models, such as atg5- or atg7-deficient mice, revealed an important function of autophagy in adipocyte differentiation. Suppression of adipogenesis in autophagy-defective conditions has made it difficult to study the roles of autophagy in metabolism of differentiated adipocytes. In this study, we established autophagy defective-differentiated 3T3-L1 adipocytes, and investigated the roles of Ulk1 and its close homolog Ulk2 in lipid and glucose metabolism using the established adipocytes. Through knockdown approaches, we determined that Ulk1 and Ulk2 are important for basal and MTORC1 inhibition-induced autophagy, basal lipolysis, and mitochondrial respiration. However, unlike other autophagy genes (Atg5, Atg13, Rb1cc1/Fip200, and Becn1) Ulk1 was dispensable for adipogenesis without affecting the expression of CCAAT/enhancer binding protein α (CEBPA) and peroxisome proliferation-activated receptor gamma (PPARG). Ulk1 knockdown reduced fatty acid oxidation and enhanced fatty acid uptake, the metabolic changes that could contribute to adipogenesis, whereas Ulk2 knockdown had opposing effects. We also found that the expression levels of insulin receptor (INSR), insulin receptor substrate 1 (IRS1), and glucose transporter 4 (SLC2A4/GLUT4) were increased in Ulk1-silenced adipocytes, which was accompanied by upregulation of insulin-stimulated glucose uptake. These results suggest that ULK1, albeit its important autophagic role, regulates lipid metabolism and glucose uptake in adipocytes distinctly from other autophagy proteins.
PMCID: PMC4028344  PMID: 24135897
ULK1; ULK2; mTORC1; adipogenesis; adipocytes; lipid metabolism
12.  Distribution and Determinants of Plasma Homocysteine Levels in Rural Chinese Twins across the Lifespan 
Nutrients  2014;6(12):5900-5914.
Plasma homocysteine (Hcy) is a modifiable, independent risk factor for cardiovascular disease (CVD) and is affected by both environmental and genetic factors. This study aimed to describe the gender- and age-specific distribution of Hcy concentration for 1117 subjects aged 10–66 years, a subset of a community-based rural Chinese twin cohort. In addition, we examined environmental and genetic contributions to variances in Hcy concentration by gender and age groups. We found that the distribution pattern for Hcy varied by both age and gender. Males had higher Hcy than females across all ages. Elevated Hcy was found in 43% of male adults and 13% of female adults. Moreover, nearly one fifth of children had elevated Hcy. Genetic factors could explain 52%, 36% and 69% of the variation in Hcy concentration among children, male adults and female adults, respectively. The MTHFR C677T variant was significantly associated with Hcy concentrations. Smokers with the TT genotype had the highest Hcy levels. Overall, our results indicate that elevated Hcy is prevalent in the children and adults in this rural Chinese population. The early identification of elevated Hcy will offer a window of opportunity for the primary prevention of CVD and metabolic syndrome.
PMCID: PMC4277006  PMID: 25529062
homocysteine; Chinese twins; heritability; gender difference; smoking
13.  Territrem and Butyrolactone Derivatives from a Marine-Derived Fungus Aspergillus Terreus 
Marine Drugs  2014;12(12):6113-6124.
Seventeen lactones including eight territrem derivatives (1–8) and nine butyrolactone derivatives (9–17) were isolated from a marine-derived fungus Aspergillus terreus SCSGAF0162 under solid-state fermentation of rice. Compounds 1–3 and 9–10 were new, and their structures were elucidated by spectroscopic analysis. The acetylcholinesterase inhibitory activity and antiviral activity of compounds 1–17 were evaluated. Among them, compounds 1 and 2 showed strong inhibitory activity against acetylcholinesterase with IC50 values of 4.2 ± 0.6, 4.5 ± 0.6 nM, respectively. This is the first time it has been reported that 3, 6, 10, 12 had evident antiviral activity towards HSV-1 with IC50 values of 16.4 ± 0.6, 6.34 ± 0.4, 21.8 ± 0.8 and 28.9 ± 0.8 μg·mL−1, respectively. Antifouling bioassay tests showed that compounds 1, 11, 12, 15 had potent antifouling activity with EC50 values of 12.9 ± 0.5, 22.1 ± 0.8, 7.4 ± 0.6, 16.1 ± 0.6 μg·mL−1 toward barnacle Balanus amphitrite larvae, respectively.
PMCID: PMC4278221  PMID: 25522319
Aspergillusterreus; anti-acetylcholinesterase; anti-HSV-1; antifouling; butyrolactone derivative; territrem derivative
14.  Interactions between an anti-sigma protein and two sigma factors that regulate the pyoverdine signaling pathway in Pseudomonas aeruginosa 
BMC Microbiology  2014;14(1):287.
Synthesis and uptake of pyoverdine, the primary siderophore of the opportunistic pathogen Pseudomonas aeruginosa, is dependent on two extra-cytoplasmic function (ECF) sigma factors, FpvI and PvdS. FpvI and PvdS are required for expression of the ferri-pyoverdine receptor gene fpvA and of pyoverdine synthesis genes respectively. In the absence of pyoverdine the anti-sigma factor FpvR that spans the cytoplasmic membrane inhibits the activities of both FpvI and PvdS, despite the two sigma factors having low sequence identity.
To investigate the interactions of FpvR with FpvI and PvdS, we first used a tandem affinity purification system to demonstrate binding of PvdS by the cytoplasmic region of FpvR in P. aeruginosa at physiological levels. The cytoplasmic region of FpvR bound to and inhibited both FpvI and PvdS when the proteins were co-expressed in Escherichia coli. Each sigma factor was then subjected to error prone PCR and site-directed mutagenesis to identify mutations that increased sigma factor activity in the presence of FpvR. In FpvI, the amino acid changes clustered around conserved region four of the protein and are likely to disrupt interactions with FpvR. Deletion of five amino acids from the C-terminal end of FpvI also disrupted interactions with FpvR. Mutations in PvdS were present in conserved regions two and four. Most of these mutations as well as deletion of thirteen amino acids from the C-terminal end of PvdS increased sigma factor activity independent of whether FpvR was present, suggesting that they increase either the stability of PvdS or its affinity for core RNA polymerase.
These data show that FpvR binds to PvdS in both P. aeruginosa and E. coli, inhibiting its activity. FpvR also binds to and inhibits FpvI and binding of FpvI is likely to involve conserved region four of the sigma factor protein.
Electronic supplementary material
The online version of this article (doi:10.1186/s12866-014-0287-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4256889  PMID: 25433393
Siderophore; Gene expression; ECF sigma factor; Anti-sigma factor; Pyoverdine; Pseudomonas; Cell surface signaling; TonB-dependent signaling; Tandem affinity purification
15.  Effect of supersaturation on hillock of directional Growth of KDP crystals 
Scientific Reports  2014;4:6886.
KDP single crystals were grown in aqueous solution by using “point seeds” with a defined crystallographic direction of 59° to the Z axis. When hillock slopes on the (100) face of KDP crystals were measured within the supersaturation (σ) range of 0 < σ ≤ 0.06, the slope of hillocks with hollow cores depended nonlinearly on supersaturation. Below σ = 0.02, the hillock slope depended on supersaturation, but when σ was ≥ 0.02, the hillock slope increased more gradually and was less dependent on supersaturation. Hollow funnel-shaped growth dislocation on the (100) face of KDP crystals was observed at σ = 0.04, characterized by large holes with micro-steps and step bunching inside, the formation of which were analyzed. The result verified that the reversed growth appears to occur within hollow channels found on growth hillocks.
PMCID: PMC4217111  PMID: 25363505
16.  Genomic and molecular characterization of esophageal squamous cell carcinoma 
Nature genetics  2014;46(5):467-473.
Esophageal squamous cell carcinoma (ESCC) is a world-wide prevalent cancer, which is particularly common in certain regions of Asia. Here we report the whole-exome or targeted deep sequencing of 139 paired ESCC cases, and analysis of somatic copy number variations (SCNV) of over 180 ESCCs. We identified novel significantly mutated genes such as FAT1, FAT2, ZNF750 and KMT2D, in addition to previously discovered ones (TP53, PIK3CA and NOTCH1). Further SCNV evaluation, immunohistochemistry and biological analysis suggested their functional relevance in ESCC. Notably, RTK-MAPK-PI3K pathways, cell cycle and epigenetic regulation are frequently dysregulated by multiple molecular mechanisms in this cancer. Moreover, our approaches uncovered many novel druggable candidates, and XPO1 was further explored as a therapeutic target because of its mutation and protein overexpression. Together, our integrated study unmasks a number of novel genetic lesions in ESCC and provides an important molecular foundation for understanding esophageal tumors and developing therapeutic targets.
PMCID: PMC4070589  PMID: 24686850
17.  A Panel of Overexpressed Proteins for Prognosis in Esophageal Squamous Cell Carcinoma 
PLoS ONE  2014;9(10):e111045.
Esophageal squamous cell carcinoma (ESCC) is a common cancer with poor prognosis. In order to identify useful biomarkers for accurately classifying prognostic risks for ESCC patients, we examined the expression of six proteins by immunohistochemistry (IHC) in 590 paraffin-embedded ESCC samples. The candidate proteins include p53, EGFR, c-KIT, TIMP1 and PI3K-p110α reported to be altered in ESCC tissues as well as another important component of PI3K, PI3K-p85α. Of the six proteins tested, p53, EGFR, c-KIT, TIMP1 and PI3K-p85α were detected with high expression in 43.0%, 36.6%, 55.9%, 70.7% and 57.1% of tumors, respectively. Significant associations were found between high expression of PI3K-p85α, EGFR and p53 and poor prognosis (P = 0.00111; 0.00001; 0.00426). Applying these three proteins as an IHC panel could divide patients into different subgroups (P<0.000001). Multivariate cox regression analysis indicated that the three-protein panel was an independent prognostic factor with very high statistical significance (HR = 2.090, 95% CI: 1.621–2.696, P = 0.00000001). The data suggest that the three-protein panel of PI3K-p85α, EGFR and p53 is an important candidate biomarker for the prognosis of patients with ESCC.
PMCID: PMC4206450  PMID: 25337715
18.  Meta-analysis of nonsteroidal anti-inflammatory drug intake and prostate cancer risk 
Epidemiological studies of the association between nonsteroidal anti-inflammatory drug (NSAID) intake and the risk of prostate cancer still remain controversial. Therefore, we conducted a meta-analysis to evaluate the potential association between NSAID intake and prostate cancer risk.
Eligible studies were retrieved by both computerized searches and reviews of references. Subgroup analyses on country and design of study were also performed. Random or fixed-effect models were used to pool estimates of odds ratios (ORs) with 95% confidence intervals (CIs).
We observed that the intake of aspirin was associated with a marginally decreased risk of prostate cancer (OR =0.95, 95% CI =0.93 to 0.98). A similar result was found between nonaspirin NSAIDs and prostate cancer risk (OR =0.94, 95% CI =0.90 to 0.98). However, a positive relation between all-NSAID intake and prostate cancer risk was observed (OR =1.18, 95% CI =1.15 to 1.22).
We observed a marginally inverse correlation between the intake of aspirin and prostate cancer risk. On the contrary, a positive relationship between all-NSAID intake and prostate cancer was detected. Further research needs to be conducted to better clarify potential biological mechanisms.
PMCID: PMC4194408  PMID: 25282624
Etiology; Meta-analysis; NSAIDs; Prostate cancer
19.  TAK1 inhibitor 5Z-7-oxozeaenol sensitizes neuroblastoma to chemotherapy 
Treatment failure in high risk neuroblastoma is largely due to development of chemoresistance. NF-κB activation is one of the resistance mechanisms for cancer cells to escape from chemotherapy-induced cell-death. TAK1 is an essential component in genotoxic stresses-induced NF-κB activation; however, the role of TAK1 in the development of chemoresistance in neuroblastoma remains unknown. Using a panel of neuroblastoma cell lines, we found that TAK1 inhibitor 5Z-7-oxozeaenol significantly augmented the cytotoxic effects of doxorubicin (Dox) and etoposide (VP-16) on neuroblastoma cell lines. TAK1 inhibition also enhanced the inhibitory effect of Dox and VP-16 on anchorage-independent growth. Treatment of neuroblastoma cells with 5Z-7-oxozeaenol blocked Dox-and VP16-induced NF-κB activation and enhanced Dox-and VP16-induced apoptosis. Moreover, 5Z-7-oxozeaenol was able to overcome the established chemoresistance in LA-N-6 neuroblastoma cells. Using an orthotopic neuroblastoma mouse model, we found that 5Z-7-oxozeaenol significantly enhanced chemotherapeutic efficacy in vivo. Together, our results provide a proof-of-concept that TAK1 inhibition significantly increases the sensitivity of neuroblastoma cells to chemotherapy-induced cell-death and can serve as an effective adjunct to current chemotherapeutic regimens for high risk diseases.
PMCID: PMC3778057  PMID: 23700229
Neuroblastoma; TAK1 inhibitor; 5Z-7-oxozeaenol; Chemotherapy
20.  Simvastatin prevents alveolar bone loss in an experimental rat model of periodontitis after ovariectomy 
Periodontitis is an inflammatory disease characterized by the loss of connective tissue and alveolar bone. There is an increasing evidence that periodontitis is associated with a number of chronic disease, including osteoporosis. Periodontitis and osteoporosis are both bone destructive diseases and of high prevalence in adult population. Osteoporosis could increase some inflammatory factors that also participate in the progression of periodontitis, so as to facilitate the alveolar bone resorption. Simvastatin, specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme reductase, is of pleiotropic effects including anti-catabolic and anabolic effect on bone metabolism. This study aimed to explore the local and systemic effect of simvastatin on maxillary in rats with both osteoporosis and periodontitis.
Thirty-six 4-month-old female Sprague Dawley rats were randomly assigned to six groups: sham group, ligature group, ovariectomized (OVX) + ligature group, local simvastatin administration to OVX + ligature rats (local simvastatin group), oral simvastatin administration to OVX + ligature rats (oral simvastatin group), local and oral simvastatin administration to OVX + ligature rats (L&O simvastatin group). One month after OVX, ligatures were placed on the maxillary first (M1) and second molars (M2) for 4 weeks on all rats except those in the sham group, followed by simvastatin treatment for 2 months. The maxillae, serum, and femurs were collected for further examination including micro-computed (micro-CT) tomography, hematoxylin and eosin (H&E) staining, tartrate-resistant acid phosphatase (TRAP) staining, enzyme-linked immunosorbent assays (ELISA), and the three-point bending test.
Local simvastatin administration increased alveolar crest height and prevented local alveolar bone loss without alteration of systemic bone loss. Oral administration prevented local and systemic bone loss with no effect on alveolar crest height.
Our results indicate that simvastatin has the potential of promoting bone formation and reducing alveolar bone loss in maxillary following ovariectomy (OVX) and ligature placement in rats.
PMCID: PMC4192445  PMID: 25269614
Simvastatin; Alveolar bone loss; Periodontitis; Osteoporosis; Maxillary
21.  Insights into Deep-Sea Sediment Fungal Communities from the East Indian Ocean Using Targeted Environmental Sequencing Combined with Traditional Cultivation 
PLoS ONE  2014;9(10):e109118.
The fungal diversity in deep-sea environments has recently gained an increasing amount attention. Our knowledge and understanding of the true fungal diversity and the role it plays in deep-sea environments, however, is still limited. We investigated the fungal community structure in five sediments from a depth of ∼4000 m in the East India Ocean using a combination of targeted environmental sequencing and traditional cultivation. This approach resulted in the recovery of a total of 45 fungal operational taxonomic units (OTUs) and 20 culturable fungal phylotypes. This finding indicates that there is a great amount of fungal diversity in the deep-sea sediments collected in the East Indian Ocean. Three fungal OTUs and one culturable phylotype demonstrated high divergence (89%–97%) from the existing sequences in the GenBank. Moreover, 44.4% fungal OTUs and 30% culturable fungal phylotypes are new reports for deep-sea sediments. These results suggest that the deep-sea sediments from the East India Ocean can serve as habitats for new fungal communities compared with other deep-sea environments. In addition, different fungal community could be detected when using targeted environmental sequencing compared with traditional cultivation in this study, which suggests that a combination of targeted environmental sequencing and traditional cultivation will generate a more diverse fungal community in deep-sea environments than using either targeted environmental sequencing or traditional cultivation alone. This study is the first to report new insights into the fungal communities in deep-sea sediments from the East Indian Ocean, which increases our knowledge and understanding of the fungal diversity in deep-sea environments.
PMCID: PMC4182876  PMID: 25272044
22.  Giant appendiceal neurofibroma in von Recklinghausen’s disease: A case report and literature review 
Oncology Letters  2014;8(5):1957-1960.
A 62-year-old female with neurofibromatosis type 1 (NF1; also von Recklinghausen’s disease) was diagnosed with a giant, thick-walled tubular mass, mainly located in the right abdominal area on computed tomography, following an examination for intermittent abdominal pain and increasing abdominal distension. According to the clinical manifestations and imaging features, the giant tubular mass was considered most likely to be a dilated fallopian tube associated with infection, while the possibility of obstructed bowel loops was excluded. However, the subsequent laparotomy revealed a giant appendix, caused by a large neurofibroma in the root region of the appendix, which occluded the lumen. Neurofibroma of the appendix is extremely rare, even in patients with NF1. To the best of our knowledge, only three such cases have previously been reported in the English literature to date.
PMCID: PMC4186601  PMID: 25295078
neurofibromatosis type 1; von Recklinghausen’s disease; appendix; neurofibromatosis
23.  ER-α36: a novel biomarker and potential therapeutic target in breast cancer 
OncoTargets and therapy  2014;7:1525-1533.
Estrogen receptor-alpha36 (ER-α36) is a 36-kDa variant of estrogen receptor-alpha (ER-α) firstly identified and cloned by Wang et al in 2005. It lacks both transactivation domains (activation function 1 and activation function 2) and has different biological characteristics compared to traditional ER-α (ER-α66). ER-α36 primarily locates on plasma membrane and cytoplasm and functions as a mediator in the rapid membrane-initiated non-genomic signaling pathway. Additionally, it inhibits the traditional genomic signaling pathway mediated by ER-α66 in a dominant-negative pattern. Accumulating evidence has demonstrated that ER-α36 regulates the physiological function of various tissues. Thus, dysregulation of ER-α36 is closely associated with plenty of diseases including cancers. ER-α36 is recognized as a molecular abnormality which solidly correlates to carcinogenesis, aggressiveness, and therapeutic response of breast cancer. Additionally, special attention has been paid to the role of ER-α36 in endocrine therapy resistance. Therefore, ER-α36 provides a novel biomarker of great value for diagnosis, prognosis, and treatment of breast cancer. It may also be a potential therapeutic target for breast cancer patients, especially for those who are resistant to endocrine therapy. In this review, we will overview and update the biological characteristics, underlying mechanism, and function of ER-α36, focusing on its biological function in breast cancer and endocrine therapy resistance. We will evaluate its application value in clinical practice.
PMCID: PMC4155893  PMID: 25210466
ER; ER-α36; breast cancer; endocrine therapy resistance
24.  Retinal Vascular Fractals and Cognitive Impairment 
Retinal microvascular network changes have been found in patients with age-related brain diseases such as stroke and dementia including Alzheimer's disease. We examine whether retinal microvascular network changes are also present in preclinical stages of dementia.
This is a cross-sectional study of 300 Chinese participants (age: ≥60 years) from the ongoing Epidemiology of Dementia in Singapore study who underwent detailed clinical examinations including retinal photography, brain imaging and neuropsychological testing. Retinal vascular parameters were assessed from optic disc-centered photographs using a semiautomated program. A comprehensive neuropsychological battery was administered, and cognitive function was summarized as composite and domain-specific Z-scores. Cognitive impairment no dementia (CIND) and dementia were diagnosed according to standard diagnostic criteria.
Among 268 eligible nondemented participants, 78 subjects were categorized as CIND-mild and 69 as CIND-moderate. In multivariable adjusted models, reduced retinal arteriolar and venular fractal dimensions were associated with an increased risk of CIND-mild and CIND-moderate. Reduced fractal dimensions were associated with poorer cognitive performance globally and in the specific domains of verbal memory, visuoconstruction and visuomotor speed.
A sparser retinal microvascular network, represented by reduced arteriolar and venular fractal dimensions, was associated with cognitive impairment, suggesting that early microvascular damage may be present in preclinical stages of dementia.
PMCID: PMC4176466  PMID: 25298774
Cognitive impairment; Retina; Microvasculature; Fractal dimension; Cognition
25.  Model based on γ-glutamyltransferase and alkaline phosphatase for hepatocellular carcinoma prognosis 
World Journal of Gastroenterology : WJG  2014;20(31):10944-10952.
AIM: To determine the prognostic value of alkaline phosphatase (ALP) and γ-glutamyltransferase (GGT) for hepatocellular carcinoma (HCC) .
METHODS: We analyzed the outcome of 172 HCC patients who underwent liver resection. Receiver operating characteristic (ROC) curve analysis was performed to determine the cut-off value of ALP and GGT. Then, preoperative risk factors for survival were evaluated by multivariate analysis. Based on the significant factors, a prognostic score model was established.
RESULTS: By ROC curve analysis, ALP > 120 U/L and GGT > 115 U/L were considered elevated. Overall survival (OS) and tumor-free survival (TFS) for patients with elevated ALP and GGT were significantly worse than for patients with ALP and GGT within the normal range. Multivariate analysis showed that the elevated levels of ALP, GGT and tumor size were independent prognostic factors. Giving each positive factor as a score of 1, we established a preoperative prognostic score model. The 5-year OS for patients with a score of 0, 1, 2 and 3 were 84.0%, 45.9%, 44.1% and 0%, respectively, while the TFS was 80.6%, 40.0%, 38.8% and 0%, respectively. When combining patients with scores of 1 and 2 into the middle risk group, and patients with scores of 0 and 3 into the low-risk and high-risk groups, respectively, different outcomes would be significantly distinguished by the risk groups.
CONCLUSION: Elevated ALP and GGT levels were risk predictors in HCC patients. Our prognostic model might vary the outcomes of patients from different risk groups.
PMCID: PMC4138475  PMID: 25152598
Alkaline phosphatase; γ-Glutamyltransferase; Prognosis; Hepatocellular carcinoma

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