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1.  Cancer stem cell markers correlate with early recurrence and survival in hepatocellular carcinoma 
AIM: To investigate whether expression of cancer stem cell (CSC) markers is associated with recurrence and survival in hepatocellular carcinoma (HCC) patients.
METHODS: A consecutive series of 90 HCC patients who underwent curative hepatectomy between April 2007 and April 2009 were analyzed. Of the 90 patients, 38 (42%) experienced recurrence within two years of surgery. To adjust for baseline differences between this early recurrence group and the other patients, propensity-score matching was used to generate 25 pairs of patients. Immunohistochemistry was used to compare expression of CD133, CD90, and epithelial cell adhesion molecule (EpCAM) in liver tissues from propensity score-matched patients and from 10 healthy adults. Associations of the three markers with HCC, clinicopathological characteristics, early recurrence, and survival time were explored.
RESULTS: The expression of all three CSC markers was significantly higher in HCC tissue than in healthy liver tissue (P < 0.001 for all). Among the HCC clinicopathology characteristics examined, the absence of tumor capsule was associated with CD133 expression (P = 0.005); higher histopathology grade and larger tumor size were associated with CD90 expression (P = 0.010 and 0.034, respectively); and elevated serum alpha-fetoprotein levels were associated with EpCAM expression (P = 0.021). Expression of CD90 and EpCAM was significantly higher in the early recurrence group than in other patients (P = 0.001 and 0.045, respectively), whereas CD133 expression was not significantly different between the two groups (P = 0.440). Multivariate analysis identified only CD90 expression as significantly associated with early recurrence. Log-rank analysis identified expression of both CD90 and EpCAM as significantly associated with survival time of HCC patients. Cox regression identified EpCAM expression as an independent predictor of survival time.
CONCLUSION: Expression of CD133, CD90, and EpCAM CSC markers may be linked to HCC tumor onset and/or progression. In addition, EpCAM expression is associated with shorter survival time, while CD90 expression is associated with early HCC recurrence.
PMCID: PMC3934481  PMID: 24616575
Hepatocellular carcinoma; Cancer stem cells; CD133; CD90; Epithelial cell adhesion molecule
2.  An Exceptionally Simple Strategy for DNA-Functionalized Up-conversion Nanoparticles as Biocompatible Agents for Nano-Assembly, DNA Delivery and Imaging 
Lanthanide-doped upconversion nanoparticles (UCNPs) have shown promise in biomedical applications. However, as the UCNPs are normally capped with hydrophobic ligands, it remains challenging to prepare biocompatible UCNPs with specific molecular recognition capabilities. We herein report an exceptionally simple strategy to prepare uniform DNA-modified upconversion nanoparticles (DNA-UCNPs) as versatile bioprobes. The approach can directly convert as-prepared hydrophobic UCNPs into water-soluble DNA-UCNPs without any chemical modification of UCNPs or oligonucleotides. Furthermore, DNA molecules on the DNA-UCNPs retain their biorecognition ability, allowing programmable assembly of hybrid nanostructures. More importantly, we show that these DNA-UCNPs are capable of crossing cell membranes without the need of transfection agents, and their use as agents for bioimaging and DNA delivery are also demonstrated. Finally, DNA aptamer-conjugated UCNPs can be readily used for targeted imaging of cancer cells.
PMCID: PMC3608408  PMID: 23356394
3.  Earlier-Season Vegetation Has Greater Temperature Sensitivity of Spring Phenology in Northern Hemisphere 
PLoS ONE  2014;9(2):e88178.
In recent decades, satellite-derived start of vegetation growing season (SOS) has advanced in many northern temperate and boreal regions. Both the magnitude of temperature increase and the sensitivity of the greenness phenology to temperature–the phenological change per unit temperature–can contribute the advancement. To determine the temperature-sensitivity, we examined the satellite-derived SOS and the potentially effective pre-season temperature (Teff) from 1982 to 2008 for vegetated land between 30°N and 80°N. Earlier season vegetation types, i.e., the vegetation types with earlier SOSmean (mean SOS for 1982–2008), showed greater advancement of SOS during 1982–2008. The advancing rate of SOS against year was also greater in the vegetation with earlier SOSmean even the Teff increase was the same. These results suggest that the spring phenology of vegetation may have high temperature sensitivity in a warmer area. Therefore it is important to consider temperature-sensitivity in assessing broad-scale phenological responses to climatic warming. Further studies are needed to explore the mechanisms and ecological consequences of the temperature-sensitivity of start of growing season in a warming climate.
PMCID: PMC3914920  PMID: 24505418
4.  Dynamics and Sources of Soil Organic C Following Afforestation of Croplands with Poplar in a Semi-Arid Region in Northeast China 
PLoS ONE  2014;9(1):e86640.
Afforestation of former croplands has been proposed as a promising way to mitigate rising atmospheric CO2 concentration in view of the commitment to the Kyoto Protocol. Central to this C sequestration is the dynamics of soil organic C (SOC) storage and stability with the development of afforested plantations. Our previous study showed that SOC storage was not changed after afforestation except for the 0–10 cm layer in a semi-arid region of Keerqin Sandy Lands, northeast China. In this study, soil organic C was further separated into light and heavy fractions using the density fractionation method, and their organic C concentration and 13C signature were analyzed to investigate the turnover of old vs. new SOC in the afforested soils. Surface layer (0–10 cm) soil samples were collected from 14 paired plots of poplar (Populus × xiaozhuanica W. Y. Hsu & Liang) plantations with different stand basal areas (the sum of the cross-sectional area of all live trees in a stand), ranging from 0.2 to 32.6 m2 ha−1, and reference maize (Zea mays L.) croplands at the same sites as our previous study. Soil ΔC stocks (ΔC refers to the difference in SOC content between a poplar plantation and the paired cropland) in bulk soil and light fraction were positively correlated with stand basal area (R2 = 0.48, p<0.01 and R2 = 0.40, p = 0.02, respectively), but not for the heavy fraction. SOCcrop (SOC derived from crops) contents in the light and heavy fractions in poplar plantations were significantly lower as compared with SOC contents in croplands, but tree-derived C in bulk soil, light and heavy fraction pools increased gradually with increasing stand basal area after afforestation. Our study indicated that cropland afforestation could sequester new C derived from trees into surface mineral soil, but did not enhance the stability of SOC due to a fast turnover of SOC in this semi-arid region.
PMCID: PMC3900571  PMID: 24466183
5.  Correction: Comparison of Long-Term Survival of Patients with BCLC Stage B Hepatocellular Carcinoma after Liver Resection or Transarterial Chemoembolization 
PLoS ONE  2014;9(1):10.1371/annotation/32a8c7e3-5efc-478b-b374-c8cbfd1d3968.
PMCID: PMC3897329
6.  Distribution and location of Daxx in cervical epithelial cells with high risk human papillomavirus positive 
To provide the basis for further exploring the effect and its mechanism of Death domain associated protein (Daxx) on the progress of cervical carcinoma induced by human papillomavirus (HPV), the distribution and location of Daxx in cervical carcinoma with high risk HPV(HR-HPV) positive was analyzed.
The samples of normal cervical epithelial cells, cervical intraepithelial neoplasia grade I (CINI), CINII CINIII and cervical cancers were collected. Immunohistochemistry assay was used to analyze the distributions and locations of Daxx in the cervical tissue. Indirect immunoinfluorescence test was utilized to observe the locations of Daxx in Caski cells with HPV16 positive.
Under the light microscopy, the brown signals of Daxx distributed in the nuclei of normal cervical epithelial cells; Daxx mainly distributed in nuclear membrane and there were a small amount of Daxx in the nuclei in CINI. Daxx intensively distributed in the cytoplasm and cell membrane in CINII, CINIII and cervical cancer. Under fluorescent microscopy, the distribution and location of Daxx in Caski cells was similarly to that in cervical cells of CINII, CINIII and cervical cancer.
In the progress of the cervical cancer, Daxx gradually translocates from nucleus into nuclear membrane, cytoplasm and cell membrane. Daxx locates in the cytoplasm and cell membrane in CINII, CINIII and cervical cancer.
Virtual slides
The virtual slide(s) for this article can be found here:
PMCID: PMC3933295  PMID: 24398161
Human papillomavirus; Daxx; Cervical cancer; Intraepithelial neoplasia grade
7.  Genome-Wide and Differential Proteomic Analysis of Hepatitis B Virus and Aflatoxin B1 Related Hepatocellular Carcinoma in Guangxi, China 
PLoS ONE  2013;8(12):e83465.
Both hepatitis B virus (HBV) and aflatoxin B1 (AFB1) exposure can cause liver damage as well as increase the probability of hepatocellular carcinoma (HCC). To investigate the underlying genetic changes that may influence development of HCC associated with HBV infection and AFB1 exposure, HCC patients were subdivided into 4 groups depending upon HBV and AFB1 exposure status: (HBV(+)/AFB1(+), HBV(+)/AFB1(-), HBV(-)/AFB1(+), HBV(-)/AFB1(-)). Genetic abnormalities and protein expression profiles were analyzed by array-based comparative genomic hybridization and isobaric tagging for quantitation. A total of 573 chromosomal aberrations (CNAs) including 184 increased and 389 decreased were detected in our study population. Twenty-five recurrently altered regions (RARs; chromosomal alterations observed in ≥10 patients) in chromosomes were identified. Loss of 4q13.3-q35.2, 13q12.1-q21.2 and gain of 7q11.2-q35 were observed with a higher frequency in the HBV(+)/AFB1(+), HBV(+)/AFB1(-) and HBV(-)/AFB1(+) groups compared to the HBV(-)/AFB(-) group. Loss of 8p12-p23.2 was associated with high TNM stage tumors (P = 0.038) and was an unfavorable prognostic factor for tumor-free survival (P =0.045). A total of 133 differentially expressed proteins were identified in iTRAQ proteomics analysis, 69 (51.8%) of which mapped within identified RARs. The most common biological processes affected by HBV and AFB1 status in HCC tumorigenesis were detoxification and drug metabolism pathways, antigen processing and anti-apoptosis pathways. Expression of AKR1B10 was increased significantly in the HBV(+)/AFB1(+) and HBV(-)/AFB1(+) groups. A significant correlation between the expression of AKR1B10 mRNA and protein levels as well as AKR1B10 copy number was observered, which suggest that AKR1B10 may play a role in AFB1-related hepatocarcinogenesis. In summary, a number of genetic and gene expression alterations were found to be associated with HBV and AFB1- related HCC. The possible synergistic effects of HBV and AFB1 in hepatocarcinogenesis warrant further investigations.
PMCID: PMC3877066  PMID: 24391771
8.  Neuroprotective Effect of Ginkgolide B on Bupivacaine-Induced Apoptosis in SH-SY5Y Cells 
Local anesthetics are used routinely and effectively. However, many are also known to activate neurotoxic pathways. We tested the neuroprotective efficacy of ginkgolide B (GB), an active component of Ginkgo biloba, against ROS-mediated neurotoxicity caused by the local anesthetic bupivacaine. SH-SY5Y cells were treated with different concentrations of bupivacaine alone or following preincubation with GB. Pretreatment with GB increased SH-SY5Y cell viability and attenuated intracellular ROS accumulation, apoptosis, mitochondrial dysfunction, and ER stress. GB suppressed bupivacaine-induced mitochondrial depolarization and mitochondria complex I and III inhibition and increased cleaved caspase-3 and Htra2 expression, which was strongly indicative of activation of mitochondria-dependent apoptosis with concomitantly enhanced expressions of Grp78, caspase-12 mRNA, protein, and ER stress. GB also improved ultrastructural changes indicative of mitochondrial and ER damage induced by bupivacaine. These results implicate bupivacaine-induced ROS-dependent mitochondria, ER dysfunction, and apoptosis, which can be attenuated by GB through its antioxidant property.
PMCID: PMC3818975  PMID: 24228138
9.  Direct Detection of Adenosine in Undiluted Serum Using a Luminescent Aptamer Sensor Attached to a Terbium Complex 
Analytical chemistry  2012;84(18):7852-7856.
Aptamers, single-stranded nucleic acids that can selectively bind to various target molecules, have been widely used for constructing biosensors. A major challenge in this field, however, is direct sensing of analytes in complex biological media such as undiluted serum. While progress has been made in developing inhomogeneous assay by using a pre-separation step to wash away the interferences within serum, a facile strategy for direct detection of targets in homogenous unprocessed serum is highly desired. We herein report a turn-on luminescent aptamer biosensor for the direct detection of adenosine in undiluted and unprocessed serum, by taking advantage of a terbium chelate complex with long luminescence lifetime to achieve time-resolved detection. The sensor exhibits a detection limit of 60 µM adenosine while marinating excellent selectivity that is comparable to those in buffer. The approach demonstrated here can be applied for direct detection and quantification of a broad range of analytes in biological media by using other aptamers.
PMCID: PMC3461325  PMID: 22894546
Aptamer; sensor; serum; luminescence; terbium complex
10.  Methylenetetrahydrofolate Reductase Gene Polymorphism and Risk of Type 2 Diabetes Mellitus 
PLoS ONE  2013;8(9):e74521.
This review aimed to comprehensively assess the literature examining a possible link between the rs1801133 polymorphism (677C→T) in the gene encoding the methylenetetrahydrofolate reductase (MTHFR) gene and risk of type 2 diabetes mellitus (DM).
Research Design and Methods
Several research databases were systematically searched for studies examining the genotype at the rs1801133 polymorphism in healthy control individuals and individuals with type 2 DM. Genotype frequency data were examined across all studies and across subsets of studies according to ethnicity and presence of serious DM-related complications. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated.
A total of 4855 individuals with type 2 DM and 5242 healthy controls from 15 countries comprising Asian, Caucasian and African ethnicities were found to satisfy the inclusion criteria and included in the review. Genotype at the rs1801133 polymorphism was not consistently associated with either increased or reduced risk of type 2 DM; the OR across all studies was 0.91 (95%CI 0.82 to 1.00) for the C- vs. T-allele, 0.88 (0.75 to 1.03) for CC vs. CT+TT, 0.82 (0.71 to 0.95) for CC vs. TT, and 1.15 (1.03 to 1.29) for TT vs. CC+CT. Similar results were found when the meta-analysis was repeated separately for each ethnic subgroup, and for subgroups with or without serious DM-related complications.
There does not appear to be compelling evidence of an association between the genotype at the rs1801133 polymorphism of the MTHFR gene and risk of type 2 DM.
PMCID: PMC3762795  PMID: 24023947
11.  Antiviral therapy for hepatitis B virus-related hepatocellular carcinoma after radical hepatectomy 
Cancer Biology & Medicine  2013;10(3):158-164.
To assess the effect of antiviral therapy for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after radical hepatectomy.
A total of 478 HBV-related HCC patients treated by radical hepatectomy were retrospectively collected. Patients in the treatment group (n=141) received postoperative lamivudine treatment (100 mg/d), whereas patients in the control group (n=337) did not. Recurrence-free survival (RFS) rates, overall survival (OS) rates, treatments for recurrent HCC and cause of death were compared between the two groups. Propensity score matching (PSM) analysis was also conducted to reduce confounding bias between the two groups.
The 1-, 3-, and 5-year RFS rates didn't significantly differ between the two groups (P=0.778); however, the 1-, 3-, and 5-year OS rates in the treatment group were significantly higher than those in the control group (P=0.002). Similar results were observed in the matched data. Subgroup analysis showed that antiviral treatment conferred a significant survival benefit for Barcelona Clinical Liver Cancer stage A/B patients. Following HCC recurrence, more people in the treatment group were able to choose curative treatments than those in the control group (P=0.031). For cause of death, fewer people in the treatment group died of liver failure than those in the control group (P=0.041).
Postoperative antiviral therapy increases chances of receiving curative treatments for recurrent HCC and prevents death because of liver failure, thereby significantly prolonging OS, especially in early- or intermedian-stage tumors.
PMCID: PMC3860342  PMID: 24379991
Antiviral therapy; hepatocellular carcinoma; propensity score matching; recurrence-free survival rate
12.  Mitochondrial DNA haplogroup associated with sperm motility in the Han population 
Asian Journal of Andrology  2013;15(5):630-633.
In this study, we aimed to determine whether the main mitochondrial DNA (mtDNA) haplogroups of the Han people have an impact on spermatozoa motility. We recruited 312 men who were consecutively admitted to two affiliated hospitals of College of Medicine, Zhejiang University from May 2011 to April 2012 as part of fertility investigations. Semen and whole blood samples were collected from the men. We determined the mtDNA haplogroups by analysing the sequences of mtDNA hypervariable segment I and testing diagnostic polymorphisms in the mtDNA coding region with DNA probes. No significant differences were found in the clinical characteristics of the mtDNA haplogroup R and non-R (P>0.05). Our results suggest that mtDNA haplogroup R is a strong independent predictor of sperm motility in the Han population, conferring a 2.97-fold (95% confidence interval: 1.74–4.48, P<0.001) decreased chance of asthenozoospermia compared with those without haplogroup R.
PMCID: PMC3881638  PMID: 23912313
asthenozoospermia; haplogroup; mitochondrial DNA (mtDNA)
13.  Comparison of Long-Term Survival of Patients with BCLC Stage B Hepatocellular Carcinoma after Liver Resection or Transarterial Chemoembolization 
PLoS ONE  2013;8(7):e68193.
Background and Aims
Treatment of patients with Barcelona Clinic Liver Cancer Stage B hepatocellular carcinoma (BCLC-B HCC) is controversial. This study compared the long-term survival of patients with BCLC-B HCC who received liver resection (LR) or transarterial chemoembolization (TACE).
A total of 257 and 135 BCLC-B HCC patients undergoing LR and TACE, respectively, were retrospectively evaluated. Kaplan–Meier method was used for long-term survival analysis. Independent prognostic predictors were determined by the Cox proportional hazards model.
The hospital mortality rate was similar between groups (3.1% vs. 3.7%; P = 0.76). However, the LR group showed a significantly higher postoperative complication rate than the TACE group (28 vs. 18.5%; P = 0.04). At the same time, the LR group showed significantly higher overall survival rates (1 year, 84 vs. 69%; 3 years, 59 vs. 29%; 5 years, 37 vs. 14%; P<0.001). Moreover, similar results were observed in the propensity score model. Three independent prognostic factors were associated with worse overall survival: serum AFP level (≥400 ng/ml), serum ALT level, and TACE.
LR appears to be as safe as TACE for patients with BCLC-B HCC, and it provides better long-term overall survival. However, prospective studies are needed to disclose if LR may be regarded as the preferred treatment for these patients as long as liver function is preserved.
PMCID: PMC3706592  PMID: 23874536
14.  Biomimetic Surface Engineering of Lanthanide-Doped Upconversion Nanoparticles as Versatile Bioprobes 
A general and versatile biomimetic approach to synthesize water dispersible and functionalizable upconverting nanoparticles (UCNPs) for selective imaging of live cancer cells is reported. The approach involves coating the surface of UCNPs with a monolayer of phospholipids containing different functional groups, allowing for conjugation of many molecules for a wide range of applications in fields such as bioinspired nanoassembly, biosensing, and bio-medicine.
PMCID: PMC3516999  PMID: 22566291
Upconverting nanoparticles; surface engineering; functionalizable; bioapplication
15.  mEH Tyr113His polymorphism and the risk of ovarian cancer development 
The causes of ovarian cancer are complex and may be influenced by many factors, including polymorphism in the microsomal epoxide hydrolase (mEH) gene. Previous work suggests an association between the Tyr113His mEH polymorphism rs1051740 and susceptibility to ovarian cancer, but the results have been inconsistent.
PubMed, EMBASE, Google Scholar, and Chinese National Knowledge Infrastructure databases were systematically searched to identify relevant studies. A meta-analysis was performed to examine the association between Tyr113His mEH polymorphism and susceptibility to ovarian cancer. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated.
Five studies involving 2,566 cases and 2,839 controls were included. Although the polymorphism did not affect ovarian cancer risk in the allelic contrast model (OR = 0.99, 95% CI = 0.83-1.17, P = 0.86), the mutant CC genotype was significantly associated with increased risk in the homozygote comparison (OR = 1.20, 95% CI = 1.01-1.43, P = 0.04) and recessive genetic models (OR = 1.20, 95% CI = 1.01-1.41, P = 0.03). The wild-type TT genotype was not associated with higher or lower ovarian cancer risk in the dominant genetic model (OR = 1.04, 95% CI = 0.83-1.29, P = 0.74). These results were robust to sensitivity analysis.
The CC genotype of Tyr113His mEH may confer increased risk of ovarian cancer. These conclusions should be verified in large and well-designed studies.
PMCID: PMC3681615  PMID: 23742121
Meta-analysis; Microsomal epoxide hydrolase; Polymorphism; Ovarian cancer
16.  Persistence and intergenerational transmission of differentially expressed genes in the testes of intracytoplasmic sperm injection conceived mice*  
Intracytoplasmic sperm injection (ICSI) is commonly used to solve male infertility problems. Previous studies showed that early environmental exposure of an embryo may influence postnatal development. To detect whether ICSI operations affect the reproductive health of a male or his offspring, we established assisted reproductive technologies (ART) conceived mouse models, and analyzed gene expression profiles in the testes of both ICSI and naturally conceived (NC) newborn F1 mice using micro-array analysis. Among the differentially expressed genes, we focused on the expression of eight male reproduction-related genes. Quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) was used to analyze the expression of these genes in the testes of both adult and old F1 generation mice and adult F2 generation mice. Our results showed that down-regulated and somatic cell-expressed genes in newborn mice retained their differential expression patterns in adult and old F1 generation individuals, implying the persistence and fetal origin of the alteration in the expression of these genes. The intergenerational transmission of differential gene expression was observed, but most changes tended to be reduced in adult F2 generations. Controlled ovarian hyperstimulation (COH) and in vitro fertilization (IVF) mice models were added to explore the precise factors contributing to the differences in ICSI offspring. The data demonstrated that superovulation, in vitro culture, and mechanical stimulation involved in ICSI had a cumulative effect on the differential expression of these male reproductive genes.
PMCID: PMC3650451  PMID: 23645174
Intracytoplasmic sperm injection; Testis; Intergenerational transmission
17.  Single Nucleotide Polymorphism 8q24 rs13281615 and Risk of Breast Cancer: Meta-Analysis of More than 100,000 Cases 
PLoS ONE  2013;8(4):e60108.
The onset and progression of breast cancer (BC) is influenced by many factors, including the single nucleotide polymorphism (SNP) rs13281615 at 8q24. However, studies of the potential association between rs13281615 at 8q24 and risk of BC have given inconsistent results. We performed a meta-analysis to address this controversy.
PubMed, EMBASE and the Chinese National Knowledge Infrastructure databases were systematically searched to identify relevant studies. Two curators independently extracted data, and odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated to assess the strength of the association between rs13281615 at 8q24 and risk of BC.
Fourteen studies are included in the meta-analysis, involving 44,283 cases (5,170 Chinese and 39,113 mixed) and 55,756 controls (5,589 Chinese and 50,167 mixed). The GG and G-allele genotypes of rs13281615 at 8q24 are significantly associated with increased risk of BC (GG vs. AG+AA, OR 1.13, 95% CI 1.08–1.19, P<0.001; G-allele vs. A-allele, OR 1.10, 95% CI 1.06–1.14, P<0.001; GG vs. AA, OR 1.20, 95% CI 1.12–1.29, P<0.001). Conversely, the AA genotype is significantly associated with decreased risk of BC (AA vs. AG+GG, OR 0.89, 95% CI 0.84–0.93, P<0.001).
G-allele genotypes of rs13281615 at 8q24 polymorphism are a risk factor for developing BC, while the AA genotype is a protective factor. Further large and well-designed studies are required to confirm this conclusion.
PMCID: PMC3614948  PMID: 23565189
18.  Postoperative Use of the Chemopreventive Vitamin K2 Analog in Patients with Hepatocellular Carcinoma 
PLoS ONE  2013;8(3):e58082.
To evaluate the chemopreventive efficacy of vitamin K2 (VK2) analog in patients with hepatocellular carcinoma (HCC) after curative hepatic resection or local ablation, since a recent randomized control trial (RCT) and systematic review have given contradictory results.
MEDLINE, EMBASE and Cochrane library databases were systematically searched through the end of May 2012. Meta-analysis of RCTs and cohort studies was performed to estimate the effects of the VK2 analog on tumor recurrence rate and overall survival (OS). Risk ratios (RRs) and 95% confidence intervals (95% CIs) were calculated.
Six RCTs and one cohort study involving a total of 930 patients were included. VK2 analog therapy did not reduce the 1-year recurrence rate, with a pooled RR of 0.67 (95% CI 0.39–1.13, p = 0.13). However, VK2 analog therapy was associated with a significant reduction in the 2- and 3-year tumor recurrence rates, with respective pooled RRs of 0.65 (95% CI 0.51–0.83, p<0.001) and 0.70 (95% CI = 0.58–0.85, p<0.001). The therapy was also associated with a significant improvement in 1-, 2-, and 3-year OS, with respective pooled RRs of 1.03 (95% CI 1.01–1.05, p = 0.02), 1.11 (95% CI 1.03–1.19, p = 0.005) and 1.14 (95% CI 1.02–1.28, p = 0.02). None of the studies reported adverse effects attributable to VK2 analog therapy.
The VK2 analog may reduce recurrence rate after 1 year and improve OS in HCC patients as early as 1 year. However, these findings should be considered preliminary since the majority of patients came from an RCT with survival data out to only 1 year. More extensive studies with larger sample sizes and longer follow-up are needed.
PMCID: PMC3591458  PMID: 23505456
19.  Meta-Analysis of Microsomal Epoxide Hydrolase Gene Polymorphism and Risk of Hepatocellular Carcinoma 
PLoS ONE  2013;8(2):e57064.
Hepatocarcinogenesis is a complex process that may be influenced by many factors, including polymorphism in microsomal epoxide hydrolase (mEH). Previous work suggests an association between the Tyr113His and His139Arg mEH polymorphisms and susceptibility to hepatocellular carcinoma (HCC), but the results have been inconsistent.
PubMed, EMBASE, Google Scholar and the Chinese National Knowledge Infrastructure databases were systematically searched to identify relevant studies. A meta-analysis was performed to examine the association between Tyr113His and His139Arg mEH polymorphism and susceptibility to HCC. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.
Eleven studies were included in the meta-analysis, involving 1,696 HCC cases and 3,600 controls. The 113His- mEH allele was significantly associated with increased risk of HCC based on allelic contrast (OR = 1.35, 95% CI = 1.04–1.75, p = 0.02), homozygote comparison (OR = 1.65, 95% CI = 1.07–2.54, p = 0.02) and a recessive genetic model (OR = 1.54, 95% CI = 1.21–1.96, p<0.001), while individuals carrying the Arg139Arg mEH genotype had no association with increased or decreased risk of HCC.
The 113His- allele polymorphism in mEH may be a risk factor for hepatocarcinogenesis, while the mEH 139Arg- allele may not be a risk or protective factor. There is substantial evidence that mEH polymorphisms interact synergistically with other genes and the environment to modulate risk of HCC. Further large and well-designed studies are needed to confirm these conclusions.
PMCID: PMC3581564  PMID: 23451147
20.  The Glutathione S-Transferase P1 341C>T Polymorphism and Cancer Risk: A Meta-Analysis of 28 Case-Control Studies 
PLoS ONE  2013;8(2):e56722.
GSTP1, which is one major group of the glutathione S-transferase family, plays an important role in the metabolism of carcinogens and toxins, reducing damage of DNA as a suppressor of carcinogenesis. The 341C>T polymorphism of the GSTP1 has been implicated in cancer risk through cutting down its metabolic detoxification activities. However, results from previous studies remain conflicting rather than conclusive. To clarify the correlation and provide more statistical evidence for detecting the significance of 341C>T, a meta-analysis was conducted.
Methodology/Principal Findings
The relevant studies were identified through searching of PubMed, Embase, ISI Web of Knowledge and China National Knowledge Infrastructure in August 2012, and selected based on the established inclusion criteria for publications, then a meta-analysis was performed to quantitatively summarize the association of GSTP1 341C>T polymorphism with cancer susceptibility. Stratified analyses were employed to identify the source of heterogeneity. Publication bias was evaluated as well as sensitivity analysis. Based on 28 case-control studies with 13249 cases and 16798 controls, the pooled results indicated that the variant genotypes significantly increased the risk of cancer in homozygote comparison (TT versus CC: P = 0.012, OR = 1.40, 95% CI: 1.08–1.81, Phet. = 0.575), and recessive model (TT versus CT/CC: P = 0.012, OR = 1.40, 95% CI: 1.08–1.81, Phet. = 0.562). This was confirmed when stratified analyses were conducted according to ethnicity, source of control, matched control, quality score and cancer types. Moreover, significantly increased risk of cancer was also found in lung cancer (heterozygote comparison and dominant model). The stability of these observations was confirmed by a sensitivity analysis. Begger's funnel plot and Egger's test did not reveal any publication bias.
This meta-analysis suggests that the GSTP1 341C>T polymorphism may contribute to genetic susceptibility to cancer, especially to lung cancer, and in Asian population. Nevertheless, additional well-designed studies focusing on different ethnicity and cancer types are needed to provide a more exact and comprehensive conclusion.
PMCID: PMC3578943  PMID: 23437223
21.  Haem oxygenase-1 is involved in salicylic acid-induced alleviation of oxidative stress due to cadmium stress in Medicago sativa  
Journal of Experimental Botany  2012;63(15):5521-5534.
This work examines the involvement of haem oxygenase-1 (HO-1) in salicylic acid (SA)-induced alleviation of oxidative stress as a result of cadmium (Cd) stress in alfalfa (Medicago sativa L.) seedling roots. CdCl2 exposure caused severe growth inhibition and Cd accumulation, which were potentiated by pre-treatment with zinc protoporphyrin (ZnPPIX), a potent HO-1 inhibitor. Pre-treatment of plants with the HO-1 inducer haemin or SA, both of which could induce MsHO1 gene expression, significantly reduced the inhibition of growth and Cd accumulation. The alleviation effects were also evidenced by a decreased content of thiobarbituric acid-reactive substances (TBARS). The antioxidant behaviour was confirmed by histochemical staining for the detection of lipid peroxidation and the loss of plasma membrane integrity. Furthermore, haemin and SA pre-treatment modulated the activities of ascorbate peroxidase (APX), superoxide dismutase (SOD), and guaiacol peroxidase (POD), or their corresponding transcripts. Significant enhancement of the ratios of reduced/oxidized homoglutathione (hGSH), ascorbic acid (ASA)/dehydroascorbate (DHA), and NAD(P)H/NAD(P)+, and expression of their metabolism genes was observed, consistent with a decreased reactive oxygen species (ROS) distribution in the root tips. These effects are specific for HO-1, since ZnPPIX blocked the above actions, and the aggravated effects triggered by SA plus ZnPPIX were differentially reversed when carbon monoxide (CO) or bilirubin (BR), two catalytic by-products of HO-1, was added. Together, the results suggest that HO-1 is involved in the SA-induced alleviation of Cd-triggered oxidative stress by re-establishing redox homeostasis.
PMCID: PMC3444266  PMID: 22915740
Cadmium; haem oxygenase-1; Medicago sativa; oxidative stress; redox state homeostasis; salicylic acid
22.  Insulin resistance, metabolic stress, and atherosclerosis 
Atherosclerosis, a pathological process that underlies the development of cardiovascular disease, is the primary cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). T2DM is characterized by hyperglycemia and insulin resistance (IR), in which target tissues fail to respond to insulin. Systemic IR is associated with impaired insulin signaling in the metabolic tissues and vasculature. Insulin receptor is highly expressed in the liver, muscle, pancreas, and adipose tissue. It is also expressed in vascular cells. It has been suggested that insulin signaling in vascular cells regulates cell proliferation and vascular function. In this review, we discuss the association between IR, metabolic stress, and atherosclerosis with focus on 1) tissue and cell distribution of insulin receptor and its differential signaling transduction and 2) potential mechanism of insulin signaling impairment and its role in the development of atherosclerosis and vascular function in metabolic disorders including hyperglycemia, hypertension, dyslipidemia, and hyperhomocysteinemia. We propose that insulin signaling impairment is the foremost biochemical mechanism underlying increased cardiovascular morbidity and mortality in atherosclerosis, T2DM, and metabolic syndrome.
PMCID: PMC3319745  PMID: 22202099
Insulin signaling; Atherosclerosis; Diabetes; Review
23.  Epidermal Growth Factor Gene Polymorphism and Risk of Hepatocellular Carcinoma: A Meta-Analysis 
PLoS ONE  2012;7(3):e32159.
Hepatocarcinogenesis is a complex process that may be influenced by many factors, including polymorphism in the epidermal growth factor (EGF) gene. Previous work suggests an association between the EGF 61*A/G polymorphism (rs4444903) and susceptibility to hepatocellular carcinoma (HCC), but the results have been inconsistent. Therefore, we performed a meta-analysis of several studies covering a large population to address this controversy.
PubMed, EMBASE, Google Scholar and the Chinese National Knowledge Infrastructure databases were systematically searched to identify relevant studies. Data were abstracted independently by two reviewers. A meta-analysis was performed to examine the association between EGF 61*A/G polymorphism and susceptibility to HCC. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.
Eight studies were chosen in this meta-analysis, involving 1,304 HCC cases (1135 Chinese, 44 Caucasian and 125 mixed) and 2,613 controls (1638 Chinese, 77 Caucasian and 898 mixed). The EGF 61*G allele was significantly associated with increased risk of HCC based on allelic contrast (OR = 1.29, 95% CI = 1.16–1.44, p<0.001), homozygote comparison (OR = 1.79, 95% CI = 1.39–2.29, p<0.001) and a recessive genetic model (OR = 1.34, 95% CI = 1.16–1.54, p<0.001), while patients carrying the EGF 61*A/A genotype had significantly lower risk of HCC than those with the G/A or G/G genotype (A/A vs. G/A+G/G, OR = 0.66, 95% CI = 0.53–0.83, p<0.001).
The 61*G polymorphism in EGF is a risk factor for hepatocarcinogenesis while the EGF 61*A allele is a protective factor. Further large and well-designed studies are needed to confirm this conclusion.
PMCID: PMC3293888  PMID: 22403631
24.  Video-assisted thoracoscopic surgery versus open lobectomy for stage I lung cancer: A meta-analysis of long-term outcomes 
The present study aimed to evaluate the evidence comparing video-assisted thoracoscopic surgery (VATS) and open lobectomy for the treatment of stage I lung cancer using meta-analytical techniques. A literature search was undertaken until July 2011 to identify comparative studies evaluating survival rates, recurrence rates and complications. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were calculated with either the fixed- or random-effects model. These studies included a total of 1,362 patients: 668 treated with VATS and 694 treated with open lobectomy. The overall survival was significantly higher in patients treated with VATS than with open thoracotomy (OR=2.01, 95% CI 1.44–2.78) at 5 years. However, there was no statistically significant difference in 1.3-year overall survival between the VATS and open lobectomy groups (OR=3.21, 95% CI 0.77–13.40; OR=0.91, 95% CI 0.49–1.70). The data did not demonstrate a significant difference in locoregional recurrence (OR=0.58, 95% CI 0.33–1.03) compared to the open lobectomy group, but suggested a reduced systemic recurrence rate (OR=0.52, 95% CI 0.23–0.82) and complications (OR=0.36, 95% CI 0.23–0.57) of VATS. VATS was superior to open lobectomy for the prognosis of stage I lung cancer. However, the findings have to be carefully interpreted due to the lower levels of evidence.
PMCID: PMC3438553  PMID: 22969988
lung cancer; meta-analysis; video-assisted thoracoscopic surgery; open lobectomy; prognosis
25.  Both FA- and mPEG-conjugated chitosan nanoparticles for targeted cellular uptake and enhanced tumor tissue distribution 
Nanoscale Research Letters  2011;6(1):563.
Both folic acid (FA)- and methoxypoly(ethylene glycol) (mPEG)-conjugated chitosan nanoparticles (NPs) had been designed for targeted and prolong anticancer drug delivery system. The chitosan NPs were prepared with combination of ionic gelation and chemical cross-linking method, followed by conjugation with both FA and mPEG, respectively. FA-mPEG-NPs were compared with either NPs or mPEG-/FA-NPs in terms of their size, targeting cellular efficiency and tumor tissue distribution. The specificity of the mPEG-FA-NPs targeting cancerous cells was demonstrated by comparative intracellular uptake of NPs and mPEG-/FA-NPs by human adenocarcinoma HeLa cells. Mitomycin C (MMC), as a model drug, was loaded to the mPEG-FA-NPs. Results show that the chitosan NPs presented a narrow-size distribution with an average diameter about 200 nm regardless of the type of functional group. In addition, MMC was easily loaded to the mPEG-FA-NPs with drug-loading content of 9.1%, and the drug releases were biphasic with an initial burst release, followed by a subsequent slower release. Laser confocal scanning imaging proved that both mPEG-FA-NPs and FA-NPs could greatly enhance uptake by HeLa cells. In vivo animal experiments, using a nude mice xenograft model, demonstrated that an increased amount of mPEG-FA-NPs or FA-NPs were accumulated in the tumor tissue relative to the mPEG-NPs or NPs alone. These results suggest that both FA- and mPEG-conjugated chitosan NPs are potentially prolonged drug delivery system for tumor cell-selective targeting treatments.
PMCID: PMC3306018  PMID: 22027239
chitosan; nanoparticles; drug delivery; mitomycin C

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