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1.  Association between Polymorphism of the Interleukin-13 Gene and Susceptibility to Hepatocellular Carcinoma in the Chinese Population 
PLoS ONE  2015;10(2):e0116682.
Objective
Interleukin-13 (IL-13) is a potent pleiotropic cytokine that is produced by activated CD4 T cells. This study was undertaken to determine the relationship between two IL-13 gene single nucleotide polymorphisms (SNP rs1800925 and SNP rs20541) and the incidence of hepatitis B virus-related (HBV) hepatocellular carcinoma (HCC).
Method
Three hundred and ninety-eight HBV-positive individuals (192 HCC and 206 patients with chronic hepatitis) and one hundred and ninety-two healthy participants from the First Affiliated Hospital of Guangxi Medical University were enrolled in this study.
Results
The results showed no significant differences between the genotype and allele frequencies of the IL-13 gene rs1800925 and rs20541 polymorphisms and chronic hepatitis B risk after adjusting for age, sex, tobacco use, and alcohol intake using binary logistic regression analyses. Regarding the rs20541 SNP, the GA genotype was significantly related to a decreased risk of HCC after adjusting for age, sex, tobacco use, and alcohol intake using binary logistic regression analyses (The odds ratio (OR) = 0.54, 95% confidence intervals (CI) 0.34–0.87). The adjusted OR for the GA and AA genotypes combined was 0.68 (95% CI 0.39–0.90).
Conclusion
This study indicates that the functional IL-13 rs20541 polymorphism may contribute to the risk of HCC and that the rs20541 polymorphism is a protective factor for HCC.
doi:10.1371/journal.pone.0116682
PMCID: PMC4319784  PMID: 25658755
2.  Microbiota That Affect Risk for Shigellosis in Children in Low-Income Countries 
Emerging Infectious Diseases  2015;21(2):242-250.
Co-infection with Shigella spp. and other microbes modifies diarrhea risk.
Pathogens in the gastrointestinal tract exist within a vast population of microbes. We examined associations between pathogens and composition of gut microbiota as they relate to Shigella spp./enteroinvasive Escherichia coli infection. We analyzed 3,035 stool specimens (1,735 nondiarrheal and 1,300 moderate-to-severe diarrheal) from the Global Enteric Multicenter Study for 9 enteropathogens. Diarrheal specimens had a higher number of enteropathogens (diarrheal mean 1.4, nondiarrheal mean 0.95; p<0.0001). Rotavirus showed a negative association with Shigella spp. in cases of diarrhea (odds ratio 0.31, 95% CI 0.17–0.55) and had a large combined effect on moderate-to-severe diarrhea (odds ratio 29, 95% CI 3.8–220). In 4 Lactobacillus taxa identified by 16S rRNA gene sequencing, the association between pathogen and disease was decreased, which is consistent with the possibility that Lactobacillus spp. are protective against Shigella spp.–induced diarrhea. Bacterial diversity of gut microbiota was associated with diarrhea status, not high levels of the Shigella spp. ipaH gene.
doi:10.3201/eid2101.140795
PMCID: PMC4313639  PMID: 25625766
shigellosis; Shigella; bacteria; polymicrobial infection; Escherichia coli; enteroinvasive E. coli; EIEC; Lactobacillus; rotavirus; viruses; co-occurring pathogens; enteropathogens; microbiota; ipaH gene; diarrhea; children; low-income countries
3.  Association of Single Nucleotide Polymorphisms in VDR and DBP Genes with HBV-Related Hepatocellular Carcinoma Risk in a Chinese Population 
PLoS ONE  2014;9(12):e116026.
Background
Polymorphisms of genes encoding components of the vitamin D pathway including vitamin D receptor (VDR) and vitamin D binding protein (DBP) have been widely investigated because of the complex role played by vitamin D in cancer tumorogenesis. In this study, we investigated the association between VDR and DBP gene polymorphisms and HBV-related HCC risk in a Chinese population.
Methods
Study subjects were divided into three groups: 184 HBV patients with HCC, 296 HBV patients without HCC, and 180 healthy controls. The VDR rs2228570, and rs3782905 and the DBP rs7041 polymorphisms were genotyped using PCR-RFLP and the VDR rs11568820 polymorphism was genotyped by PCR-SSP, respectively. DNA sequencing was performed to validate the genotype results.
Results
We found that there were significant differences in the genotype and allele frequencies of the VDR rs2228570 and DBP rs7041 polymorphisms between HBV patients with HCC and healthy controls. The rs2228570 T allele was associated with a significant increased HBV-related HCC risk as compared with the C allele. The rs2228570 TT and TT/TC genotypes were correlated with a significant increased HBV-related HCC risk when compared with the wild-type CC homozygote. Similarly, the rs7041 G allele was associated with a significant increased HBV-related HCC risk as compared with the T allele. The rs7041 GG and GG/TG genotypes were correlated with a significant increased HBV-related HCC risk when compared with the wild-type TT homozygote. However, we did not observe any significant effect of VDR rs11568820, and rs3782905 polymorphisms on HBV-related HCC risk in this population. In haplotype analysis, we also did not find any significant differences in haplotype frequencies of the VDR gene between HBV patients with HCC and the healthy controls.
Conclusions
We conclude that the VDR rs2228570 and DBP rs7041 polymorphisms may contribute to increased susceptibility to HBV-related HCC in the Chinese population. Due to the marginal significance, further large and well-designed studies in diverse ethnic populations are needed to confirm our results.
doi:10.1371/journal.pone.0116026
PMCID: PMC4277456  PMID: 25541958
4.  TGF-β signaling and the development of osteoarthritis 
Bone research  2014;2:14002.
Osteoarthritis (OA) is a common joint degenerative disease affecting the whole joint structure, including articular cartilage, subchondral bone and synovial tissue. Although extensive work has been done in recent years to explore the molecular mechanism underlying this disease, the pathogenesis of OA is still poorly understood and currently, there is no effective disease-modifying treatment for OA. Recently, both in vitro and in vivo studies suggest that confirmed (TGF-β)/SMAD pathway plays a critical role during OA development. This short review will focus on the function and signaling mechanisms of TGF-β/SMAD pathway in articular chondrocytes, mesenchymal progenitor cells of subchondral bone and synovial lining cells during OA development.
doi:10.1038/boneres.2014.2
PMCID: PMC4274935  PMID: 25541594
5.  Randomized trial of leuprolide versus continuous oral contraceptives in the treatment of endometriosis-associated pelvic pain 
Fertility and sterility  2011;95(5):1568-1573.
Objective
To compare the efficacy of leuprolide and continuous oral contraceptives in the treatment of endometriosis-associated pain.
Design
Prospective, randomized, double-blind controlled trial.
Setting
Academic medical centers in Rochester, New York, and Boston, Massachusetts.
Patient(s)
Forty-seven women with endometriosis-associated pelvic pain.
Intervention(s)
Forty-eight weeks of either depot leuprolide, 11.25 mg IM every 12 weeks with hormonal add-back using norethindrone acetate 5 mg orally, daily; or a generic monophasic oral contraceptive (1 mg norethindrone + 35 mg ethinyl estradiol) given daily.
Main Outcome Measure(s)
Biberoglu and Behrman (B&B) pain scores, numerical rating scores (NRS), Beck Depression Inventory (BDI), and Index of Sexual Satisfaction (ISS).
Result(s)
Based on enrollment of 47 women randomized to continuous oral contraceptives and to leuprolide, there were statistically significant declines in B&B, NRS, and BDI scores from baseline in both groups. There were no significant differences, however, in the extent of reduction in these measures between the groups.
Conclusion(s)
Leuprolide and continuous oral contraceptives appear to be equally effective in the treatment of endometriosis-associated pelvic pain. (Fertil Steril 2011;95:1568–73. 2011 by American Society for Reproductive Medicine.)
doi:10.1016/j.fertnstert.2011.01.027
PMCID: PMC4271794  PMID: 21300339
Endometriosis; pelvic pain; GnRH agonists; gonadotropin-releasing hormone agonist; oral contraceptives; randomized controlled trial
6.  Time trends and age-period-cohort analyses on incidence rates of thyroid cancer in Shanghai and Hong Kong 
BMC Cancer  2014;14(1):975.
Background
Increasing incidence rates of thyroid cancer have been noted worldwide, while the underlying reasons remain unclear.
Methods
Using data from population-based cancer registries, we examined the time trends of thyroid cancer incidence in two largest cities in China, Shanghai and Hong Kong, during the periods 1973–2009 and 1983–2011, respectively. We further performed age-period-cohort analyses to address the possible underlying reasons for the observed temporal trends.
Results
We observed continuous increases in the incidence rates of thyroid cancer in Shanghai and Hong Kong, since the 1980s, in addition to higher incidence rates in the 1970s in both sexes in Shanghai. The age-standardized incidence rate of thyroid cancer increased by 3.1% [95% confidence interval (CI): 1.0%, 5.1%] and 3.8% (95% CI: 1.9%, 5.7%) per year on average, respectively, in Shanghai men and women during the period 1973–2009, while it increased by 2.2% (95% CI: 1.5%, 2.8%) and 2.7% (1.6%, 3.8%) per year on average, respectively, in Hong Kong men and women during the period 1983–2011. We observed global changes in trends across all age groups in similar ways, in addition to varied trends across different generations (birth cohorts).
Conclusions
The increased incidence rates of thyroid cancer in these two Chinese populations during recent decades may be contributable to a combination of the introduction of more sensitive diagnostic techniques and the increasing prevalence of environmental exposures in the populations.
doi:10.1186/1471-2407-14-975
PMCID: PMC4301456  PMID: 25519305
Thyroid cancer; Incidence; Time trend; Age–period–cohort analysis; Etiology
7.  Biological mechanism analysis of acute renal allograft rejection: integrated of mRNA and microRNA expression profiles 
Objectives: Renal transplantation is the preferred method for most patients with end-stage renal disease, however, acute renal allograft rejection is still a major risk factor for recipients leading to renal injury. To improve the early diagnosis and treatment of acute rejection, study on the molecular mechanism of it is urgent. Methods: MicroRNA (miRNA) expression profile and mRNA expression profile of acute renal allograft rejection and well-functioning allograft downloaded from ArrayExpress database were applied to identify differentially expressed (DE) miRNAs and DE mRNAs. DE miRNAs targets were predicted by combining five algorithm. By overlapping the DE mRNAs and DE miRNAs targets, common genes were obtained. Differentially co-expressed genes (DCGs) were identified by differential co-expression profile (DCp) and differential co-expression enrichment (DCe) methods in Differentially Co-expressed Genes and Links (DCGL) package. Then, co-expression network of DCGs and the cluster analysis were performed. Functional enrichment analysis for DCGs was undergone. Results: A total of 1270 miRNA targets were predicted and 698 DE mRNAs were obtained. While overlapping miRNA targets and DE mRNAs, 59 common genes were gained. We obtained 103 DCGs and 5 transcription factors (TFs) based on regulatory impact factors (RIF), then built the regulation network of miRNA targets and DE mRNAs. By clustering the co-expression network, 5 modules were obtained. Thereinto, module 1 had the highest degree and module 2 showed the most number of DCGs and common genes. TF CEBPB and several common genes, such as RXRA, BASP1 and AKAP10, were mapped on the co-expression network. C1R showed the highest degree in the network. These genes might be associated with human acute renal allograft rejection. Conclusions: We conducted biological analysis on integration of DE mRNA and DE miRNA in acute renal allograft rejection, displayed gene expression patterns and screened out genes and TFs that may be related to acute renal allograft rejection.
PMCID: PMC4307466  PMID: 25664019
Renal transplantation; acute rejection; microRNA; mRNA; transcription factor
8.  A recessive variant of XRCC4 predisposes to non-BRCA1/2 breast cancer in chinese women and impairs the DNA damage response via dysregulated nuclear localization 
Oncotarget  2014;5(23):12218-12232.
XRCC4 plays a crucial role in the non-homologous end joining pathway that maintains genome stability. In this two-stage case-control study with 1,764 non-BRCA1/2 breast cancer patients and 1,623 cancer-free controls, we investigated the contribution of genetic variants of XRCC4 to breast cancer susceptibility in Chinese women. We identified a recessive missense variant, rs3734091 (c.739G>T, p.Ala247Ser), of XRCC4 that was significantly associated with an increased risk of breast cancer (odds ratio [OR] = 3.92, P = 0.007), particularly with the risk of developing triple-negative breast cancer (OR = 18.65, P < 0.0001). This p.Ala247Ser variant disturbed the nuclear localization of XRCC4 in cells homozygous for the rs3734091-T allele but not in heterozygous cells at both the cellular and tissue levels. In heterozygous cells, wild-type XRCC4 facilitated the nuclear localization of the XRCC4A247S mutant, thus compensating for the impaired localization of XRCC4A247S. This provided a biological mechanism by which rs3734091 conferred an increased susceptibility to non-BRCA1/2 breast cancer exclusively under a recessive model. Further functional analyses revealed that p.Ala247Ser impaired the DNA damage repair capacity and ultimately perturbed genomic stability. Taken together, our findings document the role of XRCC4 in non-BRCA1/2 breast cancer predisposition and reveal its underlying biological mechanism of action.
PMCID: PMC4322983  PMID: 25360583
XRCC4; homozygous variant; nuclear localization; susceptibility; breast cancer
9.  Glutathione S-transferase gene GSTM1, gene-gene interaction, and gastric cancer susceptibility: evidence from an updated meta-analysis 
Cancer Cell International  2014;14(1):127.
Background
The null genotype of GSTM1 have been implicated in gastric cancer risk, but numerous individual studies showed mixed, or even conflicting results. Thus, a meta-analysis was performed.
Results
We identified 54 individual studies involving 9,322 cases and 15,118 controls through computer-based searches of PubMed, Embase, and Cochrane Library. It was found that the null genotype of GSTM1 was associated with an increased gastric cancer risk (OR = 1.207, 95% CI: 1.106-1.317, P < 0.001), under the random-effects model (I2 : 49.9%, PQ <0.001). From stratification analyses for ethnicity, alcohol drinking, Helicobacter pylori infection, an effect modification of gastric cancer risk was found in the subgroups of ethnicity, smoking status, Helicobacter pylori infection, whereas null result was found in the subgroups of alcohol drinking. We also undertook gene-gene interaction analysis between GSTM1 and GSTT1 genes for gastric cancer risk, and the results indicated that the dual null genotypes of GSTM1 and GSTT1 might elevate the risk of gastric cancer (OR = 1.505, 95% CI: 1.165-1.944, P = 002).
Conclusions
This meta-analysis suggests that the null genotype of GSTM1 may be a important genetic risk factor for gastric cancer development.
doi:10.1186/s12935-014-0127-3
PMCID: PMC4255933  PMID: 25477765
Gastric cancer; Genetic polymorphism; Glutathione S-transferase M1; Gene-gene interaction; Meta-analysis
10.  Diffuse alveolar hemorrhage after erlotinib combined with concurrent chemoradiotherapy in a patient with esophageal carcinoma 
Diffuse alveolar hemorrhage (DAH) is a life-threatening clinical pathologic syndrome caused by a variety of diseases. We report a case of DAH related to combination therapy of chemoradiotherapy and erlotinib. As to know, DAH following chemoradiotherapy was only reported among hematopoietic stem cell transplant recipients with hematologic malignancies till now. DAH associated with chemoradiotherapy for oesophageal carcinoma has not been reported. This is the first DAH report on erlotinib-combined chemoradiotherapy for esophageal cancer. The authors believe epidermal growth factor receptor tyrosine kinase inhibitor erlotinib increased the lung injury. Molecular targeted drugs are gradually applied to be combined with chemoradiation, whether this combination will cause the increase of serious adverse reactions need further study. This case can provide certain reference for erlotinib in the treatment. Meanwhile, after long term hormone therapy for DAH, the patient was diagnosed with pneumocystis carinii pneumonia. It reminds us to attach importance to the immunosuppressive diseases after long-term hormone treatment.
PMCID: PMC4276233  PMID: 25550975
Diffuse alveolar hemorrhage; chemoradiotherapy; erlotinib; esophageal carcinoma
11.  Prognostic Value of Myeloid Differentiation Primary Response 88 and Toll-Like Receptor 4 in Breast Cancer Patients 
PLoS ONE  2014;9(10):e111639.
Purpose
Breast cancer remains a major cause of death in women worldwide, and tumor metastasis is the leading cause of death in breast cancer patients after conventional treatment. Chronic inflammation is often related to the occurrence and growth of various malignancies. This study evaluated the prognosis of breast cancer patients based on contributors to the innate immune response: myeloid differentiation primary response 88 (MyD88) and Toll-like receptor 4 (TLR4).
Methods
We analyzed data from 205 breast invasive ductal carcinoma (IDC) patients who were treated at the Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, from 2002 to 2006. Overall survival (OS) and disease-free survival (DFS) were compared.
Results
In total, 152 patients (74.15%) were disease-free without relapse or metastasis, whereas 53 (25.85%) patients developed recurrence or metastasis. A significant positive correlation was observed between MyD88 and TLR4 expression (p<0.001). Patients with high expression were more likely to experience death and recurrence/metastasis events (p<0.05). Patients with low MyD88 or TLR4 expression levels had better DFS and OS than patients with high expression levels (log-rank test: p<0.001). Patients with low MyD88 and TLR4 expression levels had better DFS and OS than patients with high expression levels of either (log-rank test: p<0.001). In a multivariate analysis, high MyD88 expression was an independent predictive factor for decreased DFS (adjusted HR, 3.324; 95% CI, 1.663–6.641; p = 0.001) and OS (adjusted HR, 4.500; 95% CI, 1.546–13.098; p = 0.006).
Conclusions
TLR4-MyD88 signaling pathway activation or MyD88 activation alone may be a risk factor for poor prognosis in breast cancer. Therefore, TLR4-MyD88 signaling pathway activation in tumor biology provides a novel potential target for breast cancer therapy.
doi:10.1371/journal.pone.0111639
PMCID: PMC4216121  PMID: 25360699
12.  Utility of Clostridium difficile Toxin B for Inducing Anti-Tumor Immunity 
PLoS ONE  2014;9(10):e110826.
Clostridium difficile toxin B (TcdB) is a key virulence factor of bacterium and induces intestinal inflammatory disease. Because of its potent cytotoxic and proinflammatory activities, we investigated the utility of TcdB in developing anti-tumor immunity. TcdB induced cell death in mouse colorectal cancer CT26 cells, and the intoxicated cells stimulated the activation of mouse bone marrow-derived dendritic cells and subsequent T cell activation in vitro. Immunization of BALB/c mice with toxin-treated CT26 cells elicited potent anti-tumor immunity that protected mice from a lethal challenge of the same tumor cells and rejected pre-injected tumors. The anti-tumor immunity generated was cell-mediated, long-term, and tumor-specific. Further experiments demonstrated that the intact cell bodies were important for the immunogenicity since lysing the toxin-treated tumor cells reduced their ability to induce antitumor immunity. Finally, we showed that TcdB is able to induce potent anti-tumor immunity in B16-F10 melanoma model. Taken together, these data demonstrate the utility of C. difficile toxin B for developing anti-tumor immunity.
doi:10.1371/journal.pone.0110826
PMCID: PMC4207755  PMID: 25340750
13.  Role of IL-4 Gene Polymorphisms in HBV-Related Hepatocellular Carcinoma in a Chinese Population 
PLoS ONE  2014;9(10):e110061.
Background
Interleukin-4 (IL-4) is best known as an important mediator and modulator of immune and inflammatory responses. Hepatocellular carcinoma (HCC) is a typical inflammation-related cancer, and genetic variations in the IL-4 gene may be associated with the risk of hepatitis B virus (HBV)-related HCC. However, few studies have been conducted on their association.
Objectives
To clarify the effects of IL-4 gene polymorphisms on the risk of HBV-related HCC, two common variants, −590C/T (rs2243250) and −33C/T (rs2070874), and their relationship with HBV-related disease risk were investigated in a Chinese population.
Methods
IL-4 −590C/T and −33C/T polymorphisms were examined in 154 patients with HBV-related HCC, 62 patients with HBV-induced liver cirrhosis (LC), 129 patients with chronic hepatitis B (CHB), and 94 healthy controls, using the polymerase chain reaction-restriction fragment length polymorphism method and DNA sequencing.
Results
Overall, no significant differences were observed regarding the IL-4 −590C/T and −33C/T polymorphism genotypes, alleles, or haplotypes between the patient groups and the healthy controls. However, the CC genotypes of IL-4 −590C/T and −33C/T polymorphisms were observed to be significantly associated with CHB in subgroup analysis in males [CC versus TT (OR: 4.193, 95% CI: 1.094–16.071, P = 0.037; and OR: 3.438, 95% CI: 1.032–11.458, P = 0.044) and CC versus TT+CT (OR: 4.09, 95% CI: 1.08–15.49, P = 0.038; and OR: 3.43, 95% CI: 1.04–11.28, P = 0.042)].
Conclusions
These findings suggest that genetic variants in IL-4 −590C/T and −33C/T polymorphisms may be a risk factor for CHB in Chinese males but not for HBV-related LC or HCC.
doi:10.1371/journal.pone.0110061
PMCID: PMC4190355  PMID: 25295591
14.  Risk of Primary Liver Cancer Associated with Gallstones and Cholecystectomy: A Meta-Analysis 
PLoS ONE  2014;9(10):e109733.
Background
Recent epidemiological evidence points to an association between gallstones or cholecystectomy and the incidence risk of liver cancer, but the results are inconsistent. We present a meta-analysis of observational studies to explore this association.
Methods
We identified studies by a literature search of PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and relevant conference proceedings up to March 2014. A random-effects model was used to generate pooled multivariable adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Between-study heterogeneity was assessed using Cochran’s Q statistic and the I2.
Results
Fifteen studies (five case-control and 10 cohort studies) were included in this analysis. There were 4,487,662 subjects in total, 17,945 diagnoses of liver cancer, 328,420 exposed to gallstones, and 884,507 exposed to cholecystectomy. Pooled results indicated a significant increased risk of liver cancer in patients with a history of gallstones (OR = 2.54; 95% CI, 1.71–3.79; n = 11 studies), as well as cholecystectomy (OR = 1.62; 95% CI, 1.29–2.02; n = 12 studies), but there was considerable heterogeneity among these studies. The effects estimates did not vary markedly when stratified by gender, study design, study region, and study quality. The multivariate meta-regression analysis suggested that study region and study quality appeared to explain the heterogeneity observed in the cholecystectomy analysis.
Conclusions
Our results suggest that individuals with a history of gallstones and cholecystectomy may have an increased risk of liver cancer.
doi:10.1371/journal.pone.0109733
PMCID: PMC4188756  PMID: 25290940
15.  Biogenesis of C-Glycosyl Flavones and Profiling of Flavonoid Glycosides in Lotus (Nelumbo nucifera) 
PLoS ONE  2014;9(10):e108860.
Flavonoids in nine tissues of Nelumbo nucifera Gaertner were identified and quantified by high-performance liquid chromatography with diode array detector (HPLC-DAD) and HPLC-electrospray ionization-mass spectrometry (HPLC-ESI-MSn). Thirty-eight flavonoids were identified; eleven C-glycosides and five O-glycosides were discovered for the first time in N. nucifera. Most importantly, the C-glycosyl apigenin or luteolin detected in lotus plumules proved valuable for deep elucidation of flavonoid composition in lotus tissues and for further utilization as functional tea and medicine materials. Lotus leaves possessed the significantly highest amount of flavonoids (2.06E3±0.08 mg 100 g−1 FW) and separating and purifying the bioactive compound, quercetin 3-O-glucuronide, from leaves showed great potential. In contrast, flavonoids in flower stalks, seed coats and kernels were extremely low. Simultaneously, the optimal picking time was confirmed by comparing the compound contents in five developmental phases. Finally, we proposed the putative flavonoid biosynthesis pathway in N. nucifera.
doi:10.1371/journal.pone.0108860
PMCID: PMC4184820  PMID: 25279809
16.  SIRT1-mediated epigenetic downregulation of plasminogen activator inhibitor-1 prevents vascular endothelial replicative senescence 
Aging Cell  2014;13(5):890-899.
The inactivation of plasminogen activator inhibitor-1 (PAI-1) has been shown to exert beneficial effects in age-related vascular diseases. Limited information is available on the molecular mechanisms regarding the negatively regulated expression of PAI-1 in the vascular system. In this study, we observed an inverse correlation between SIRT1, a class III histone deacetylase, and PAI-1 expression in human atherosclerotic plaques and the aortas of old mice, suggesting that internal negative regulation exists between SIRT1 and PAI-1. SIRT1 overexpression reversed the increased PAI-1 expression in senescent human umbilical vein endothelial cells (HUVECs) and aortas of old mice, accompanied by decreased SA-β-gal activity in vitro and improved endothelial function and reduced arterial stiffness in vivo. Moreover, the SIRT1-mediated inhibition of PAI-1 expression exerted an antisenescence effect in HUVECs. Furthermore, we demonstrated that SIRT1 is able to bind to the PAI-1 promoter, resulting in a decrease in the acetylation of histone H4 lysine 16 (H4K16) on the PAI-1 promoter region. Thus, our findings suggest that the SIRT1-mediated epigenetic inhibition of PAI-1 expression exerts a protective effect in vascular endothelial senescence.
doi:10.1111/acel.12247
PMCID: PMC4331759  PMID: 25040736
atherosclerosis; endothelial replicative senescence; epigenetic; PAI-1; H4K16 acetylation; SIRT1
17.  A Novel Method Applied in Determination and Assessment of Trace Amount of Lead and Cadmium in Rice from Four Provinces, China 
PLoS ONE  2014;9(9):e107733.
Heavy metal contamination of soils or water can lead to excessive lead (Pb) and cadmium (Cd) levels in rice. As cumulative poisons, consumption of Pb and Cd in contaminated rice may cause many toxic effects in humans. In the present study, Pb and Cd levels in rice samples from Hubei, Jiangxi, Heilongjiang, and Guangdong provinces in China were analyzed by cloud point extraction and graphite furnace atomic absorption spectrometry (GFAAS). The heavy metals in the rice samples were reacted with 8-quinolinol to form a complex at pH 9.0 and 40°C. Analytes were quantitatively extracted to a surfactant-rich phase (Triton X-45) after centrifugation and analyzed by GFAAS. The effects of experimental conditions, including pH, concentration of reagents, and equilibration time and temperature, on cloud point extraction were optimized efficiently using Plackett–Burman and Box–Behnken experimental designs. Under the optimum conditions, good linearity was observed in the concentration ranges of 0.5–5 µg/L for Pb and 0.05–0.50 µg/L for Cd. The limits of detection were 0.043 µg/L for Pb with a concentration factor of 24.2 in a 10 mL sample and 0.018 µg/L for Cd with a concentration factor of 18.4 in a 10 mL sample. Twenty rice samples from four provinces were analyzed successfully, and the mean levels of Pb and Cd in the rice were all below their maximum allowable concentrations in China. Comparing the tolerable daily intakes given by FAO/WHO with the mean estimated daily intakes; Pb and Cd mean daily intake through rice consumption were 0.84 µg/kg bw/day and 0.40 µg/kg bw/day, which were lower than the tolerable daily intakes.
doi:10.1371/journal.pone.0107733
PMCID: PMC4175464  PMID: 25251454
18.  Similar Source of Differential Blood mRNAs in Lung Cancer and Pulmonary Inflammatory Diseases: Calls for Improved Strategy for Identifying Cancer-Specific Biomarkers 
PLoS ONE  2014;9(9):e108104.
Background
Many studies try to identify cancer diagnostic biomarkers by comparing peripheral whole blood (PWB) of cancer samples and healthy controls, explicitly or implicitly assuming that such biomarkers are potential candidate biomarkers for distinguishing cancer from nonmalignant inflammation-associated diseases.
Methods
Multiple PWB gene expression profiles for lung cancer/inflammation-associated pulmonary diseases were used for differential mRNAs identification and comparison and for proportion estimation of PWB cell subtypes.
Results
The differentially expressed genes (DE genes) between lung cancer/inflammation-associated pulmonary patients and healthy controls were reproducibly identified in different datasets. For these DE genes observed in lung cancer/inflammation-associated pulmonary diseases, more than 90.2% were differentially expressed between myeloid cells and lymphoid cells, with at least 96.8% having consistent directions of regulation (up- or down-regulations) in myeloid cells compared to lymphoid cells, explainable by the shifted populations of PWB cell subtypes under the disease conditions. The comparison of DE genes for lung cancer and inflammation-associated pulmonary diseases showed that the overlapping genes were 100% consistent in the sense of direction of regulation.
Conclusions
The differential blood mRNAs observed in lung cancer and in inflammation-associated pulmonary diseases were similar, both mainly reflecting the difference between myeloid cells and lymphoid cells predominantly determined by PWB cell population shifts. Thus, the strategy of comparing cancer with healthy controls may provide little information of the ability of the identified candidate biomarkers in discriminating cancer from inflammation-associated pulmonary diseases.
doi:10.1371/journal.pone.0108104
PMCID: PMC4171535  PMID: 25243474
19.  ANKLE DORSIFLEXOR STRENGTH RELATES TO THE ABILITY TO RESTORE BALANCE DURING A BACKWARD SUPPORT SURFACE TRANSLATION 
Gait & posture  2013;38(4):812-817.
Functional base of support (FBOS), the effective area for center of pressure (COP) movement, decreases with aging, which would reduce one’s ability to restore balance during perturbed stance. We investigated the relationship between ankle muscle strength and FBOS as well as the threshold perturbation acceleration that required a heel-rise (HR) or step (STEP) to maintain balance. Standing posture of 16 young and 16 elderly adults was perturbed with a backward support surface translation with the speed ranging from 15 to 70cm/s. Dorsiflexor (DF) strength was found to significantly correlate with FBOS measures and threshold acceleration for HR. Significant correlations were also found between FBOS measures and threshold accelerations for HR and STEP, except for the backward FBOS and threshold acceleration for STEP. Elderly subjects demonstrated significantly smaller DF strength and FBOS measures than young subjects, but no significant group difference was detected in plantarflexor (PF) strength. Most elderly subjects took a step once they raised their heels, while most young subjects were able to restore balance after heel-rise. These findings, taken together, imply that weakness in ankle dorsiflexors could limit the ability of elderly adults to restore balance while standing on their toes. FBOS measures and ankle dorsiflexor strength could be sensitive measures to detect individuals with declined balance control.
doi:10.1016/j.gaitpost.2013.03.026
PMCID: PMC3735801  PMID: 23602447
Balance; Perturbation; Functional base of support; Ankle muscle strength
20.  Post-mastectomy radiotherapy benefits subgroups of breast cancer patients with T1–2 tumor and 1–3 axillary lymph node(s) metastasis 
Radiology and Oncology  2014;48(3):314-322.
Background
To determine the role of postmastectomy radiotherapy (PMRT) in breast cancer patients with T1–2 and N1 disease.
Patients and methods.
A total of 207 postmastectomy women were enrolled. The 5-year Kaplan-Meier estimates of locoregional recurrence rate (LRR), distant recurrence rate (DRR) and overall survival (OS) were analyzed by different tumor characteristics. Multivariate analyses were performed using Cox proportional hazards modeling.
Results
With median follow-up 59.5 months, the 5-year LRR, DRR and OS were 9.1%, 20.3% and 84.4%, respectively. On univariate analysis, age < 40 years old (p = 0.003) and Her-2/neu over-expression (p = 0.016) were associated with higher LRR, whereas presence of LVI significantly predicted higher DRR (p = 0.026). Negative estrogen status (p = 0.033), Her-2/neu overexpression (p = 0.001) and LVI (p = 0.01) were significantly correlated with worse OS. PMRT didn’t prove to reduce 5-year LRR (p = 0.107), as well as 5-year OS (p = 0.918). In subgroup analysis, PMRT showed significant benefits of improvement LRR and OS in patients with positive LVI.
Conclusions
For patients with T1–2 and N1 stage breast cancer, PMRT can decrease locoregional recurrence and increase overall survival only in patients with lymphovascular invasion.
doi:10.2478/raon-2013-0085
PMCID: PMC4110089  PMID: 25177247
breast cancer; postmastectomy radiotherapy; overall survival; locoregional recurrence; lymphovascular invasion
21.  Age-related changes in joint coordination during balance recovery 
Age  2012;35(4):1299-1309.
Falls represent a significant health risk in the elderly and often result in injuries that require medical attention. Reduced ability to control motion of the whole-body center of mass (COM) has been shown to identify elderly people at risk of falling. To explore effective preventive strategies and interventions, we studied adult age-related differences in multijoint coordination to control the COM during balance recovery. We used the uncontrolled manifold (UCM) analysis, which can decompose movement variability of joints into good movement variability (motor equivalent) and bad movement variability (nonmotor equivalent). The good variability does not affect the COM position, while the bad variability does. Twenty-nine subjects, including 16 healthy young (26.1 ± 4.5 year) and 13 older (74.6 ± 5.6 year) adults without systematic disease, neurological disease, or a severe degenerative condition stood on a flat platform, and received an unexpected backward translation. The older adults had similar amounts of joint movement as the young adults during balance recovery except for the thoracic–lumbar joint. However, the UCM analysis showed that the older adults changed their joint coordination pattern to control the COM and had a lower motor equivalent index with increased nonmotor equivalent variability (bad variability). We conclude that normal aging adults lose the compensatory strategy of flexibly controlling multiple joints when stabilizing the COM after receiving a balance perturbation.
doi:10.1007/s11357-012-9422-x
PMCID: PMC3705105  PMID: 22618298
Posture; Joint coordination; Variability; Standing; Aging; Uncontrolled manifold
22.  XPC Lys939Gln polymorphism contributes to colorectal cancer susceptibility: evidence from a meta-analysis 
Diagnostic Pathology  2014;9:120.
Abstract
Background
Published studies investigating the association between XPC Lys939Gln polymorphism and colorectal cancer (CRC) risk reported inconclusive results. We performed a meta-analysis to derive a precise estimation of the relationship.
Methods
A comprehensive literature search was done in databases PubMed, EMBASE, and Cochrane library up to December 2013. The association between XPC Lys939Gln polymorphism and CRC risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs).
Results
Eight studies with 3,301 cases and 4,177 controls were included in the meta-analysis. We observed that the XPC Lys939Gln polymorphism was correlated with an increased CRC risk when all studies were pooled into the meta-analysis (Gln/lys vs. Lys/Lys: OR = 1.293, 95% CI 1.169–1.430, P = 0.000; Gln/Gln + Gln/lys vs. Lys/Lys: OR = 1.260, 95% CI 1.145–1.388, P = 0.000). In stratified analyses by ethnicity, smoking, and study quality, significant increased CRC risk was found in Asians (Gln/lys vs. Lys/Lys: OR = 1.345, 95% CI 1.187–1.523, P = 0.000; Gln/Gln + Gln/lys vs. Lys/Lys: OR = 1.317, 95% CI 1.170–1.484, P = 0.000), nonsmokers (Gln/Gln + Gln/lys vs. Lys/Lys: OR = 1.286, 95% CI 1.020–1.622, P = 0.033), and high quality studies. In subgroup analysis by source of control, significant increased CRC risk was found in both hospital-based studies and population-based studies. However, in subgroup analysis according to cancer location, no any significant association was detected.
Conclusions
This meta-analysis suggests that the XPC is a candidate gene for CRC susceptibility. The XPC Lys939Gln polymorphism may play an important role in CRC development among Asians and nonsmokers. Further large and well-designed studies are needed to confirm this association.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1665902729125948
doi:10.1186/1746-1596-9-120
PMCID: PMC4098961  PMID: 24947936
Colorectal cancer; XPC; Polymorphism; Meta-analysis
23.  Genetic Variations Affecting Serum Carcinoembryonic Antigen Levels and Status of Regional Lymph Nodes in Patients with Sporadic Colorectal Cancer from Southern China 
PLoS ONE  2014;9(6):e97923.
Background
Serum carcinoembryonic antigen (sCEA) level might be an indicator of disease. Indeed, an elevated sCEA level is a prognostic factor in colorectal cancer (CRC) patients. However, the genetic determinants of sCEA level in healthy and CRC population remains unclear. Thus we investigated the genetic markers associated with elevated serum sCEA level in these two populations and its clinical implications.
Methods and Findings
Genome-wide association study (GWAS) was conducted in a cohort study with 4,346 healthy male adults using the Illumina Omni 1 M chip. Candidate SNPs associated with elevated sCEA levels were validated in 194 CRC patients on ABI Taqman platform. Eight candidate SNPs were validated in CRC patients. The rs1047781 (chr19- FUT2) (A/T) was associated with elevated sCEA levels, and rs8176746 (chr9- ABO) was associated with the regional lymph metastasis in the CRC patients. The preoperative sCEA level was a risk factor for tumor recurrence in 5 years after operation (OR = 1.427, 95% CI: 1.005∼1.843, P = 0.006). It was also one of the risk factors for regional lymph node metastasis (OR = 2.266, 95% CI: 1.196∼4.293, P = 0.012). The sCEA level in rs1047781-T carriers was higher than that in the A carriers in CRC patients without lymph node metastasis (P = 0.006). The regional lymph node metastasis in patients with homozygote AA of rs8176746 was more common than that in the heterozygote AG carriers (P = 0.022). In addition, rs1047781-AT and TT CRC patients exhibited a worse disease-free survival than AA genotype carriers (P = 0.023).
Conclusions
We found candidate SNPs associated with elevated sCEA levels in both healthy males and CRC population. Rs1047781 (chr19- FUT2) may be the susceptible locus for recurrence of CRC in a population from Southern China.
doi:10.1371/journal.pone.0097923
PMCID: PMC4062418  PMID: 24941225
24.  Peri-Transplant Psychosocial Factors and Neutrophil Recovery following Hematopoietic Stem Cell Transplantation 
PLoS ONE  2014;9(6):e99778.
Objective
Multiple psychosocial factors appear to affect cancer progression in various populations; however, research investigating the relationship between psychosocial factors and outcomes following hematopoietic stem cell transplantation (HCT) is scarce. Subject to adverse immunological and psychological conditions, HCT patients may be especially vulnerable to psychosomatic health sequelae; therefore, we studied whether optimism and anxiety influence the pertinent clinical outcome of days to neutrophil engraftment (DTE).
Method
54 adults undergoing either autologous or allogeneic HCT completed self-report questionnaires measuring optimism and anxiety. We assessed the association between these psychosocial variables and DTE.
Results
Greater optimism and less anxiety were associated with the favorable outcome of fewer DTE in autologous HCT recipients, though this relationship was no longer significant when reducing the sample size to only subjects who filled out their baseline survey by the time of engraftment.
Conclusion
Our findings are suggestive that optimism and anxiety may be associated with time to neutrophil recovery in autologous, but not allogeneic, adult HCT recipients. Further investigation in larger, more homogeneous subjects with consistent baseline sampling is warranted.
doi:10.1371/journal.pone.0099778
PMCID: PMC4051840  PMID: 24915544
25.  Association between OGG1 Ser326Cys and APEX1 Asp148Glu polymorphisms and breast cancer risk: a meta-analysis 
Diagnostic Pathology  2014;9:108.
Background
The base excision repair (BER) pathway removes DNA damage caused by ionizing radiation, reactive oxidative species and methylating agents. OGG1 and APE1 are two important genes in the BER pathway. Many epidemiological studies have evaluated the association between polymorphisms in the two BER genes (OGG1 Ser326Cys and APE1 Asp148Glu) and breast cancer risk. However, the results are inconsistent.
Methods
We searched the electronic databases including PubMed, Embase and Cochrane library for all eligible studies for the period up to February 2014. Data were extracted by two independent authors and pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to assess the strength of the association.
Results
A total of 17 studies including 9,040 cases and 10,042 controls were available for OGG1 Ser326Cys polymorphism and 7 studies containing 2,979 cases and 3,111 controls were included for APE1 Asp148Glu polymorphism. With respect to OGG1 Ser326Cys polymorphism, we did not find a significant association with breast cancer risk when all eligible studies were pooled into the meta-analysis. However, in subgroup analyses by ethnicity and menopausal status, statistical significant increased breast cancer risk was found in Asian populations (Cys/Cys vs. Ser/Ser: OR = 1.157, 95% CI 1.013–1.321, P = 0.011; Cys/Cys vs. Ser/Cys + Ser/Ser: OR = 1.113, 95% CI 1.009–1.227, P = 0.014) and postmenopausal patients (Cys/Cys vs. Ser/Cys + Ser/Ser: OR = 1.162, 95% CI 1.003–1.346, P = 0.024). In subgroup analysis according to quality score, source of control, and HWE in controls, no any significant association was detected. With respect to APE1 Asp148Glu polymorphism, no significant association with breast cancer risk was demonstrated in the overall and stratified analyses.
Conclusions
The present meta-analysis suggests that the OGG1 Ser326Cys polymorphism may be a risk factor for breast cancer in Asians and postmenopausal patients. Further large and well-designed studies are needed to confirm this association.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1156934297124915
doi:10.1186/1746-1596-9-108
PMCID: PMC4064811  PMID: 24893568
Breast cancer; OGG1; APE1; Polymorphism; Meta-analysis

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