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1.  Cost-effectiveness analysis of colon cancer treatments from MOSIAC and No. 16968 trials 
World Journal of Gastroenterology : WJG  2014;20(47):17976-17984.
AIM: To compare XELOX and FOLFOX4 as colon cancer adjuvant chemotherapy based on MOSAIC and No. 16968 trails from Chinese cost-effectiveness perspective.
METHODS: A decision-analytic Markov model was developed to compare the FOLFOX4 and XELOX regimens based MOSAIC and No. 16968 trial. Five states were included in our Markov model: well (state 1), minor toxicity (state 2), major toxicity (state 3), quitting adjuvant chemotherapy (state 4), and death due to adjuvant chemotherapy (state 5). Transitions among the 5 states were assumed to be Markovian. Costs were calculated from the perspective of the Chinese health-care payer. The utility data were taken from published studies. Sensitivity analyses were used to explore the impact of uncertainty factors in this cost-effectiveness analysis.
RESULTS: Total direct costs of FOLFOX4 and XELOX per patient were $19884.96 ± 4280.30 and $18113.25 ± 3122.20, respectively. The total fees related to adverse events per patient during the entire treatment were $204.75 ± 16.80 for the XELOX group, and $873.72 ± 27.60 for the FOLFOX4 group, and the costs for travel and absenteeism per patient were $18495.00 for the XELOX group and $21,352.68 for the FOLFOX4 group. The base-case analysis showed that FOLFOX4 was estimated to produce an additional 0.06 in quality adjusted life years (QALYs) at an additional cost of $3950.47 when compared to the XELOX regimen over the model time horizon. The cost per QALY gained was $8047.30 in the XELOX group, which was $900.98 less than in the FOLFOX4 group ($8948.28). The one way sensitivity analysis demonstrated that the utility for the well state and minor toxicity state greatly influenced the incremental cost-effectiveness ratio of FOLFOX4.
CONCLUSION: In term of cost-comparison, XELOX is expected to dominate FOLFOX4 regimes; Therefore, XELOX provides a more cost-effective adjuvant chemotherapy for colon cancer patients in China.
doi:10.3748/wjg.v20.i47.17976
PMCID: PMC4273149  PMID: 25548497
Cost-effectiveness; Adjuvant chemotherapy; Colon cancer; FOLFOX; XELOX
2.  Inhibition of Survivin Reduces HIF-1α, TGF-β1 and TFE3 in Salivary Adenoid Cystic Carcinoma 
PLoS ONE  2014;9(12):e114051.
In the present study, we explored the expression and correlation of survivin with HIF-1α, TGF-β1 and TFE3 in adenoid cystic carcinoma (AdCC). The expression of survivin, HIF-1α, TGF-β1 and TFE3 was assessed by immunohistochemical staining of a tissue microarray containing tissue samples of normal salivary gland (NSG), pleomorphic adenoma (PA) and AdCC. Correlation analysis of these proteins revealed that increased survivin expression was associated with the overexpression of HIF-1α (P<0.001, r = 0.5599), TGF-β1 (P<0.001, r = 0.6616) and TFE3 (P<0.001, r = 0.7747). The expression of survivin, HIF-1α, TGF-β1 and TFE3 was not correlated with the pathological type of human AdCC (P>0.05). Selective inhibition of survivin by YM155 and siRNA significantly reduced human SACC-83 cell proliferation, with the corresponding decrease in expression of HIF-1α, TGF-β1 and TFE3. The data indicate that the overexpression of survivin in AdCC is related to HIF-1α, TGF-β1 and TFE3. We hypothesize from these findings that the inhibition of survivin may be a novel strategy for neoadjuvant chemotherapeutic and radiosensitive treatment of AdCC.
doi:10.1371/journal.pone.0114051
PMCID: PMC4259474  PMID: 25485635
3.  Association of rs6982567 near GDF6 with neovascular age-related macular degeneration and polypoidal choroidal vasculopathy in a Han Chinese cohort 
BMC Ophthalmology  2014;14(1):140.
Background
Growth differentiation factor 6 (GDF6) has been reported to be a novel disease gene for age-related macular degeneration (AMD) in Caucasians. This study aimed to investigate whether rs6982567 was associated with neovascular AMD (nAMD) or polypoidal choroidal vasculopathy (PCV) in a Han Chinese cohort.
Methods
A total of 612 participants (251 PCV patients, 157 nAMD patients and 204 controls) were included in this study. The SNaPshot system was used to genotype the rs6982567. PLINK software was used to evaluate the genotypes and allele frequencies of patients and controls.
Results
The allele frequencies of rs6982567 were not significantly associated with nAMD, PCV or PCV and nAMD combined. Subjects with the TT genotype had a 2.42-fold greater risk of PCV (95% confidence interval, 1.07-5.43, p = 0.0290) than subjects with CC genotype. A recessive model of rs6982567 was statistically significantly associated with PCV (odds ratio, 2.29; 95% confidence interval, 1.04-5.05; p = 0.0351). However, the association did not withstand stringent Bonferroni correction. There were no significant differences in genotype distributions or models in nAMD.
Conclusions
There was a possible weak association between the rs6982567 near GDF6 and PCV in this replication study with an independent Han Chinese cohort. A complete survey of the GDF6 locus with a larger sample size is needed in future studies.
doi:10.1186/1471-2415-14-140
PMCID: PMC4251681  PMID: 25416513
Han Chinese population; Neovascular age-related macular degeneration; Polypoidal choroidal vasculopathy; Polymorphisms; Growth differentiation factor 6
4.  Inhibition of mTOR reduce Stat3 and PAI related angiogenesis in salivary gland adenoid cystic carcinoma 
Angiogenesis is a complex biological process, which is involved in tumorigenesis and progression. However, the molecular mechanism of underlying angiogenesis remains largely unknown. In this study, we accessed the expression of proteins related angiogenesis by immunohistochemical staining of human tissue microarray which contains 72 adenoid cystic carcinoma (AdCC), 12 pleomorphic adenoma (PMA) and 18 normal salivary gland (NSG) using digital pathological scanner and scoring system. We found that the expression of p-S6S235/236 (a downstream molecule of mTOR), p-Stat3T705, PAI, EGFR, and HIF-1α was significantly increased in AdCC as compared with PMA and (or) NSG (p < 0.05). While, the expression of these proteins was not associated with pathological type of human AdCC (p > 0.05). Correlation analysis of these proteins revealed that p-S6S235/236 up-regulates the expression of EGFR/p-Stat3T705 (p < 0.05) and HIF-1α/PAI (p < 0.05). Moreover, the activation of p-S6S235/236, EGFR/p-Stat3T705 and HIF-1α/PAI associated with angiogenesis (CD34) and proliferation (Ki-67). In vitro, Rapamycin suppressed the expression of p-S6S235/236, EGFR, p-Stat3T705, HIF-1α and PAI. Further more, target inhibition of mTOR by rapamycin effectively reduced tumor growth of SACC-83 cells line nude mice xenograft and decreased the expression of p-S6S235/236, EGFR/p-Stat3T705 and HIF-1α/PAI. Taken together, these data revealed that mTOR signaling pathway regulates tumor angiogenesis by EGFR/p-Stat3T705 and HIF-1α/PAI. Inhibition of mTOR by rapamycin could effectively reduced tumor growth. It is likely that mTOR inhibitors may be a potential candidate for treatment of AdCC.
PMCID: PMC4266710  PMID: 25520866
Adenoid cystic carcinoma; angiogenesis; mTOR; Stat3; PAI; rapamycin
5.  Modulating Human Mesenchymal Stem Cell Plasticity Using Micropatterning Technique 
PLoS ONE  2014;9(11):e113043.
In our previous work, we have reported that enforced elongation of human mesenchymal stem cells (hMSCs) through micropatterning promoted their myocardial lineage commitment. However, whether this approach is robust enough to retain the commitment when subsequently subjected to different conditions remains unsolved. This de-differentiation, if any, would have significant implication on the application of these myocardial-like hMSCs either as tissue engineered product or in stem cell therapy. Herein, we investigated the robustness of micropatterning induced differentiation by evaluating the retention of myocardial differentiation in patterned hMSCs when challenged with non-myocardial differentiation cues. Altogether, we designed four groups of experiments; 1) Patterned hMSCs cultured in normal growth medium serving as a positive control; 2) Patterned hMSCs cultured in normal growth medium for 14 days followed by osteogenic and adipogenic media for next 7 days (to study the robustness of the effect of micropatterning); 3) Patterned hMSCs (initially grown in normal growth medium for 14 days) trypsinized and recultured in different induction media for next 7 days (to study the robustness of the effect of micropatterning without any shape constrain) and 4) Patterned hMSCs cultured in osteogenic and adipogenic media for 14 days (to study the effects of biochemical cues versus biophysical cues). It was found that hMSCs that were primed to commit to myocardial lineage (Groups 2 and 3) were able to maintain myocardial lineage commitment despite subsequent culturing in osteogenic and adipogenic media. However, for hMSCs that were not primed (Group 4), the biochemical cues seem to dominate over the biophysical cue in modulating hMSCs differentiation. It demonstrates that cell shape modulation is not only capable of inducing stem cell differentiation but also ensuring the permanent lineage commitment.
doi:10.1371/journal.pone.0113043
PMCID: PMC4234627  PMID: 25401734
6.  Bio-Conjugated Polycaprolactone Membranes: A Novel Wound Dressing 
Archives of Plastic Surgery  2014;41(6):638-646.
Background
The combination of polycaprolactone and hyaluronic acid creates an ideal environment for wound healing. Hyaluronic acid maintains a moist wound environment and accelerates the in-growth of granulation tissue. Polycaprolactone has excellent mechanical strength, limits inflammation and is biocompatible. This study evaluates the safety and efficacy of bio-conjugated polycaprolactone membranes (BPM) as a wound dressing.
Methods
16 New Zealand white rabbits were sedated and local anaesthesia was administered. Two 3.0×3.0 cm full-thickness wounds were created on the dorsum of each rabbit, between the lowest rib and the pelvic bone. The wounds were dressed with either BPM (n=12) or Mepitel (n=12) (control), a polyamide-silicon wound dressing. These were evaluated macroscopically on the 7th, 14th, 21st, and 28th postoperative days for granulation, re-epithelialization, infection, and wound size, and histologically for epidermal and dermal regeneration.
Results
Both groups showed a comparable extent of granulation and re-epithelialization. No signs of infection were observed. There was no significant difference (P>0.05) in wound size between the two groups. BPM (n=6): 8.33 cm2, 4.90 cm2, 3.12 cm2, 1.84 cm2; Mepitel (n=6): 10.29 cm2, 5.53 cm2, 3.63 cm2, 2.02 cm2; at the 7th, 14th, 21st, and 28th postoperative days. The extents of epidermal and dermal regeneration were comparable between the two groups.
Conclusions
BPM is comparable to Mepitel as a safe and efficacious wound dressing.
doi:10.5999/aps.2014.41.6.638
PMCID: PMC4228204  PMID: 25396174
Skin; Wounds; Hyaluronic acid; Polycaprolactone; Rabbit
7.  Surgical Outcomes and Prognostic Factors of T4 Gastric Cancer Patients without Distant Metastasis 
PLoS ONE  2014;9(9):e107061.
Objective
To evaluate surgical outcomes and prognostic factors for T4 gastric cancer treated with curative resection.
Methods
Between January 1994 and December 2008, 94 patients diagnosed with histological T4 gastric carcinoma and treated with curative resection were recruited. Patient characteristics, surgical complications, survival, and prognostic factors were analyzed.
Results
Postoperative morbidity and mortality were 18.1% and 2.1%, respectively. Multivariate analysis indicated lymph node metastasis (hazard ratio, 2.496; 95% confidence interval, 1.218–5.115; p = 0.012) was independent prognostic factor.
Conclusions
For patients with T4 gastric cancer, lymph node metastasis was associated with poorer survival. Neoadjuvant chemotherapy or aggressive adjuvant chemotherapy after radical resection was strongly recommended for these patients.
doi:10.1371/journal.pone.0107061
PMCID: PMC4161379  PMID: 25211331
8.  Protective efficacy of a high-growth reassortant swine H3N2 inactivated vaccine constructed by reverse genetic manipulation 
Journal of Veterinary Science  2014;15(3):381-388.
Novel reassortant H3N2 swine influenza viruses (SwIV) with the matrix gene from the 2009 H1N1 pandemic virus have been isolated in many countries as well as during outbreaks in multiple states in the United States, indicating that H3N2 SwIV might be a potential threat to public health. Since southern China is the world's largest producer of pigs, efficient vaccines should be developed to prevent pigs from acquiring H3N2 subtype SwIV infections, and thus limit the possibility of SwIV infection at agricultural fairs. In this study, a high-growth reassortant virus (GD/PR8) was generated by plasmid-based reverse genetics and tested as a candidate inactivated vaccine. The protective efficacy of this vaccine was evaluated in mice by challenging them with another H3N2 SwIV isolate [A/Swine/Heilongjiang/1/05 (H3N2) (HLJ/05)]. Prime and booster inoculation with GD/PR8 vaccine yielded high-titer serum hemagglutination inhibiting antibodies and IgG antibodies. Complete protection of mice against H3N2 SwIV was observed, with significantly reduced lung lesion and viral loads in vaccine-inoculated mice relative to mock-vaccinated controls. These results suggest that the GD/PR8 vaccine may serve as a promising candidate for rapid intervention of H3N2 SwIV outbreaks in China.
doi:10.4142/jvs.2014.15.3.381
PMCID: PMC4178139  PMID: 24675833
H3N2 subtype; protective efficacy; reverse genetics; swine influenza virus
9.  The association between B vitamins supplementation and adverse cardiovascular events: a meta-analysis 
This study is to explore the association of adverse cardiovascular events with B vitamins supplementation. Rev.Man 5.1 and Stata 11.0 software were applied for the meta-analysis. The number of cardiovascular events was collected and calculated using indicates of odds ratio and 95% confidence intervals in a fixed-effects or a random-effects model when appropriate. The study includes 15 studies which consists of 37,358 study objects (experimental group: 19,601; control group: 17,757). This study showed that the pooled ORs was 1.01 (95% CI = 0.96~1.06, P > 0.05) for objects with Experimental group (B vitamins supplementation) vs. Control group (placebo or regular treatment), which suggests no significant differences were found in the overall effect of the number of cardiovascular events between the two groups. Further stratification of subgroup analysis indicates no significant differences were found between the two groups as well. There were also no publication bias existing by the Egger’s linear regression test (P > 0.05). Our result indicates that the number of cardiovascular events in experimental group using B vitamins supplementation during the treatment is equal to placebo or regular treatment group thus further studies is necessary.
PMCID: PMC4161532  PMID: 25232372
B vitamins supplementation; folic acid; cardiovascular events; meta-analysis
10.  Beclin 1 Expression is Closely Linked to Colorectal Carcinogenesis and Distant Metastasis of Colorectal Carcinoma 
Beclin 1 participates in development, autophagy, differentiation, anti- apoptosis, neurodegeneration, tumorigenesis and cancer progression. The roles of Beclin 1 in colorectal carcinogenesis and its subsequent progression are still unclear. Here, the mRNA and protein expression of Beclin 1 were determined in colorectal carcinoma and matched mucosa by Reverse transcriptase-polymerase chain reaction and Western blot. Immunohistochemistry and in situ hybridization (ISH) were performed on tissue microarryer with colorectal carcinoma, adenoma and mucosa. The expression of Beclin 1 mRNA and protein was found to be higher in colorectal carcinoma than matched mucosa by real-time PCR and Western blot (p < 0.05). According to the ISH data, Beclin 1 expression was lower in colorectal non-neoplastic mucosa (NNM) than adenoma and carcinoma (p < 0.05). Immunohistochemically, primary carcinoma showed stronger Beclin 1 expression than NNM and metastatic carcinoma in the liver (p < 0.05). Beclin 1 protein expression was negatively related to liver and distant metastasis (p < 0.05), but not correlated with age, sex, depth of invasion, lymphatic or venous invasion, lymph node metastasis, tumor-node-metastasis (TNM) staging, differentiation or serum carcinoembryonic antigen (CEA) concentration (p > 0.05). Survival analysis indicated that Beclin 1 expression was not linked to favorable prognosis of the patients with colorectal carcinoma (p > 0.05). Cox’s model indicated that depth of invasion and distant metastasis were independent prognostic factors for colorectal carcinomas (p < 0.05). It was suggested that Beclin 1 expression is closely linked to colorectal carcinogenesis and distant metastasis of colorectal carcinoma.
doi:10.3390/ijms150814372
PMCID: PMC4159856  PMID: 25196438
colorectal carcinoma; Beclin 1; tumorigenesis; pathogenesis; prognosis
11.  A novel rice C2H2-type zinc finger protein, ZFP36, is a key player involved in abscisic acid-induced antioxidant defence and oxidative stress tolerance in rice 
Journal of Experimental Botany  2014;65(20):5795-5809.
Summary
In this study it was found that ZFP36 is required for ABA-induced antioxidant defence and for the regulation of the cross-talk between NADPH oxidase, H2O2, and MAPK in ABA signalling.
C2H2-type zinc finger proteins (ZFPs) have been shown to play important roles in the responses of plants to oxidative and abiotic stresses, and different members of this family might have different roles during stresses. Here a novel abscisic acid (ABA)- and hydrogen peroxide (H2O2)-responsive C2H2-type ZFP gene, ZFP36, is identified in rice. The analyses of ZFP36-overexpressing and silenced transgenic rice plants showed that ZFP36 is involved in ABA-induced up-regulation of the expression and the activities of superoxide dismutase (SOD) and ascorbate peroxidase (APX). Overexpression of ZFP36 in rice plants was found to elevate the activities of antioxidant enzymes and to enhance the tolerance of rice plants to water stress and oxidative stress. In contrast, an RNA interference (RNAi) mutant of ZFP36 had lower activities of antioxidant enzymes and was more sensitive to water stress and oxidative stress. ABA-induced H2O2 production and ABA-activated mitogen-activated protein kinases (MAPKs) were shown to regulate the expression of ZFP36 in ABA signalling. On the other hand, ZFP36 also regulated the expression of NADPH oxidase genes, the production of H2O2, and the expression of OsMPK genes in ABA signalling. These results indicate that ZFP36 is required for ABA-induced antioxidant defence, for the tolerance of rice plants to water stress and oxidative stress, and for the regulation of the cross-talk between NADPH oxidase, H2O2, and MAPK in ABA signalling.
doi:10.1093/jxb/eru313
PMCID: PMC4203119  PMID: 25071223
Abscisic acid (ABA); antioxidant defence; C2H2-type zinc finger protein; oxidative stress; rice; water stress.
12.  5-Lipoxygenase Activating Protein (FLAP) Dependent Leukotriene Biosynthesis Inhibition (MK591) Attenuates Lipid A Endotoxin-Induced Inflammation 
PLoS ONE  2014;9(7):e102622.
The Lipid A moiety of endotoxin potently activates TLR-4 dependent host innate immune responses. We demonstrate that Lipid-A mediated leukotriene biosynthesis regulates pathogen-associated molecular patterns (PAMP)-dependent macrophage activation. Stimulation of murine macrophages (RAW264.7) with E. coli 0111:B4 endotoxin (LPS) or Kdo2-lipid A (Lipid A) induced inflammation and Lipid A was sufficient to induce TLR-4 mediated macrophage inflammation and rapid ERK activation. The contribution of leukotriene biosynthesis was evaluated with a 5-lipoxygenase activating protein (FLAP) inhibitor, MK591. MK591 pre-treatment not only enhanced but also sustained ERK activation for up to 4 hours after LPS and Lipid A stimulation while inhibiting cell proliferation and enhancing cellular apoptosis. Leukotriene biosynthesis inhibition attenuated inflammation induced by either whole LPS or the Lipid A fraction. These responses were regulated by inhibition of the key biosynthesis enzymes for the proinflammatory eicosanoids, 5-lipoxygenase (5-LO), and cyclooxygenase-2 (COX-2) quantified by immunoblotting. Inhibition of leukotriene biosynthesis differentially regulated TLR-2 and TLR-4 cell surface expression assessed by flow cytometry, suggesting a close mechanistic association between TLR expression and 5-LO associated eicosanoid activity in activated macrophages. Furthermore, MK591 pre-treatment enhanced ERK activation and inhibited cell proliferation after LPS or Lipid A stimulation. These effects were regulated in part by increased apoptosis and modulation of cell surface TLR expression. Together, these data clarify the mechanistic association between 5-lipoxygenase activating protein-mediated leukotriene biosynthesis and 5-LO dependent eicosanoid metabolites in mediating the TLR-dependent inflammatory response after endotoxin exposure typical of bacterial sepsis.
doi:10.1371/journal.pone.0102622
PMCID: PMC4099325  PMID: 25025775
13.  The role of RhoC in epithelial-to-mesenchymal transition of ovarian carcinoma cells 
BMC Cancer  2014;14:477.
Background
RhoC is a small G protein/GTPase and involved in tumor mobility, invasion and metastasis. Previously, up-regulated RhoC expression is found to play an important role in ovarian carcinogenesis and subsequent progression by modulating proliferation, apoptosis, migration and invasion.
Methods
We transfected RhoC-expressing plasmid and RhoC siRNA into CAOV3 and OVCAR3 cells respectively. These cells and transfectants were exposed to vascular epithelial growth factor (VEGF), transforming growth factor (TGF)-β1 or their receptor inhibitors with the phenotypes and their related-molecules examined.
Results
TGF-β1R or VEGFR inhibitor suppressed the proliferation, migration, invasion and lamellipodia formation, the expression of N-cadherin, α-SMA, snail and Notch1 mRNA or protein, and enhanced E-cadherin mRNA and protein expression in CAOV3 and its RhoC-overexpressing transfectants, whereas both growth factors had the opposite effects in OVCAR3 cells and their RhoC-hypoexpressing transfectants. Ectopic RhoC expression enhanced migration, invasion, lamellipodia formation and the alteration in epithelial to mesenchymal transition (EMT) markers of CAOV3 cells regardless of the treatment of VEGFR or TGF-β1R inhibitor, whereas RhoC knockdown resulted in the converse in OVCAR3 cells even with the exposure to VEGF or TGF-β1.
Conclusion
RhoC expression might be involved in EMT of ovarian epithelial carcinoma cells, stimulated by TGF-β1 and VEGF.
doi:10.1186/1471-2407-14-477
PMCID: PMC4226981  PMID: 24986540
Ovarian carcinoma; RhoC; Epithelial-to-mesenchymal transition
14.  Circulating Endothelial-Derived Activated Microparticle: A Useful Biomarker for Predicting One-Year Mortality in Patients with Advanced Non-Small Cell Lung Cancer 
BioMed Research International  2014;2014:173401.
Background. This study tested the hypothesis that circulating microparticles (MPs) are useful biomarkers for predicting one-year mortality in patients with end-stage non-small cell lung cancer (ES-NSCLC). Methods and Results. One hundred seven patients were prospectively enrolled into the study between April 2011 and February 2012, and each patient received regular follow-up after enrollment. Levels of four MPs in circulation, (1) platelet-derived activated MPs (PDAc-MPs), (2) platelet-derived apoptotic MPs (PDAp-MPs), (3) endothelial-derived activated MPs (EDAc-MPs), and (4) endothelial-derived apoptotic MPs (EDAp-MPs), were measured just after the patient was enrolled into the study using flow cytometry. Patients who survived for more than one year were categorized into group 1 (n = 56) (one-year survivors) and patients who survived less than one year were categorized into group 2 (n = 51) (one-year nonsurvivors). Male gender, incidence of liver metastasis, progression of disease after first-line treatment, poor performance status, and the Charlson comorbidity index were significantly higher in group 2 than in group 1 (all P < 0.05). Additionally, as measured by flow cytometry, only the circulating level of EDAc-MPs was found to be significantly higher in group 2 than in group 1 (P = 0.006). Multivariate analysis demonstrated that circulating level of EDAc-MPs along with brain metastasis and male gender significantly and independently predictive of one-year mortality (all P < 0.035). Conclusion. Circulating EDAc-MPs may be a useful biomarker predictive of one-year morality in ES-NSCLC patients.
doi:10.1155/2014/173401
PMCID: PMC4100353  PMID: 25061601
15.  Anacardic Acid Enhances the Proliferation of Human Ovarian Cancer Cells 
PLoS ONE  2014;9(6):e99361.
Background
Anacardic acid (AA) is a mixture of 2-hydroxy-6-alkylbenzoic acid homologs. Certain antitumor activities of AA have been reported in a variety of cancers. However, the function of AA in ovarian cancer, to date, has remained unknown.
Methods
Ovarian cancer cell lines were exposed to AA, after which cell proliferation, apoptosis, invasion and migration assays were performed. Phalloidin staining was used to observe lamellipodia formation. Reverse transcription polymerase chain reaction (RT-PCR) and western blotting were used to assess the mRNA and protein expression levels of Phosphatidylinositol 3-kinase (PI3K), vascular endothelial growth factor (VEGF) and caspase 3.
Results
Our results showed that AA promotes ovarian cancer cell proliferation, inhibits late apoptosis, and induces cell migration and invasion, as well as lamellipodia formation. AA exposure significantly up-regulated PI3K and VEGF mRNA and protein expression, while, in contrast, it down-regulated caspase 3 mRNA and protein expression in comparison to untreated control cells.
Conclusion
Taken together, our results demonstrate for the first time that AA may potentiate the proliferation, invasion, metastasis and lamellipodia formation in ovarian cancer cell lines via PI3K, VEGF and caspase 3 pathways.
doi:10.1371/journal.pone.0099361
PMCID: PMC4055655  PMID: 24921663
16.  CD163+ Tumor-Associated Macrophages Correlated with Poor Prognosis and Cancer Stem Cells in Oral Squamous Cell Carcinoma 
BioMed Research International  2014;2014:838632.
Tumor-associated macrophages (TAMs) play an important role in the progression and prognostication of numerous cancers. However, the role and clinical significance of TAM markers in oral squamous cell carcinoma (OSCC) has not been elucidated. The present study was designed to investigate the correlation between the expression of TAM markers and pathological features in OSCC by tissue microarray. Tissue microarrays containing 16 normal oral mucosa, 6 oral epithelial dysplasia, and 43 OSCC specimens were studied by immunohistochemistry. We observed that the protein expression of the TAM markers CD68 and CD163 as well as the cancer stem cell (CSC) markers ALDH1, CD44, and SOX2 increased successively from the normal oral mucosa to OSCC. The expressions of CD68 and CD163 were significantly associated with lymph node status, and SOX2 was significantly correlated with pathological grade and lymph node status, whereas ALDH1 was correlated with tumor stage. Furthermore, CD68 was significantly correlated with CD163, SOX2, and ALDH1 (P < 0.05). Kaplan-Meier analysis revealed that OSCC patients overexpressing CD163 had significantly worse overall survival (P < 0.05). TAM markers are associated with cancer stem cell marker and OSCC overall survival, suggesting their potential prognostic value in OSCC.
doi:10.1155/2014/838632
PMCID: PMC4032721  PMID: 24883329
17.  Comparison of Leaf Proteomes of Cassava (Manihot esculenta Crantz) Cultivar NZ199 Diploid and Autotetraploid Genotypes 
PLoS ONE  2014;9(4):e85991.
Cassava polyploid breeding has drastically improved our knowledge on increasing root yield and its significant tolerance to stresses. In polyploid cassava plants, increases in DNA content highly affect cell volumes and anatomical structures. However, the mechanism of this effect is poorly understood. The purpose of the present study was to compare and validate the changes between cassava cultivar NZ199 diploid and autotetraploid at proteomic levels. The results showed that leaf proteome of cassava cultivar NZ199 diploid was clearly differentiated from its autotetraploid genotype using 2-DE combined MS technique. Sixty-five differential protein spots were seen in 2-DE image of autotetraploid genotype in comparison with that of diploid. Fifty-two proteins were identified by MALDI-TOF-MS/MS, of which 47 were up-regulated and 5 were down-regulated in autotetraploid genotype compared with diploid genotype. The classified functions of 32 up-regulated proteins were associated with photosynthesis, defense system, hydrocyanic acid (HCN) metabolism, protein biosynthesis, chaperones, amino acid metabolism and signal transduction. The remarkable variation in photosynthetic activity, HCN content and resistance to salt stress between diploid and autotetraploid genotypes is closely linked with expression levels of proteomic profiles. The analysis of protein interaction networks indicated there are direct interactions between the 15 up-regulation proteins involved in the pathways described above. This work provides an insight into understanding the protein regulation mechanism of cassava polyploid genotype, and gives a clue to improve cassava polyploidy breeding in increasing photosynthesis and resistance efficiencies.
doi:10.1371/journal.pone.0085991
PMCID: PMC3984080  PMID: 24727655
18.  WISP-1 Contributes to Fractionated Irradiation-Induced Radioresistance in Esophageal Carcinoma Cell Lines and Mice 
PLoS ONE  2014;9(4):e94751.
Cancer cells that survive fractionated irradiation can be radioresistant and cause tumor recurrence. However, the molecular mechanisms underlying the development of radioresistance in cancer cells remain elusive. The aim of this study was to investigate the role of WISP-1 in the development of radioresistance in esophageal carcinoma during fractionated irradiation. Radioresistant esophageal cancer cells were generated from normal esophageal cancer cells via fractionated irradiation, and expression levels of related proteins were determined by Western blot. Radiosensitivity of cells was established by clonogenic cell survival assays, and cell cycle distribution was evaluated by flow cytometry. Protein distributions were determined by immunofluorescence, and cell toxicity was evaluated by cell counting kit-8 assays. In vivo validations were performed in a xenograft transplantation mouse model. Our data indicate that WISP-1 plays an important role in the development of radioresistance in esophageal cancer cells during fractionated irradiation. The overexression of WISP-1 in esophageal cancer cells was associated with radioresistance. Depletion of extracellular WISP-1 by antibody neutralizing reversed radioresistance and directly induced mitotic catastrophe resulting in cell death. WISP-1 may be a candidate therapeutic target in the treatment of recurrent esophageal carcinoma after radiotherapy.
doi:10.1371/journal.pone.0094751
PMCID: PMC3984255  PMID: 24728101
19.  Use of Targeted Exome Sequencing in Genetic Diagnosis of Chinese Familial Hypercholesterolemia 
PLoS ONE  2014;9(4):e94697.
Familial hypercholesterolemia is an autosomal dominant inherited disease characterized by elevated plasma low-density lipoprotein cholesterol (LDL-C). It is mainly caused by mutations of the low-density lipoprotein receptor (LDLR) gene. Currently, the methods of whole genome sequencing or whole exome sequencing for screening mutations in familial hypercholesterolemia are not applicable in China due to high cost. We performed targeted exome sequencing of 167 genes implicated in the homozygous phenotype of a proband pedigree to identify candidate mutations, validated them in the family of the proband, studied the functions of the mutant protein, and followed up serum lipid levels after treatment. We discovered that exon 9 c.1268 T>C and exon 8 c.1129 T>G compound heterozygous mutations in the LDLR gene in the proband derived from the mother and father, respectively, in which the mutation of c.1129 T>G has not been reported previously. The mutant LDL-R protein had 57% and 52% binding and internalization functions, respectively, compared with that of the wild type. After 6 months of therapy, the LDL-C level of the proband decreased by more than 50% and the LDL-C of the other family members with heterozygous mutation also reduced to normal. Targeted exome sequencing is an effective method for screening mutation genes in familial hypercholesterolemia. The exon 8 and 9 mutations of the LDLR gene were pedigree mutations. The functions of the mutant LDL-R protein were decreased significantly compared with that of the wild type. Simvastatin plus ezetimibe was proven safe and effective in this preschool-age child.
doi:10.1371/journal.pone.0094697
PMCID: PMC3983231  PMID: 24722143
20.  Downregulated inhibitor of growth 3 (ING3) expression during colorectal carcinogenesis 
Background & objectives:
ING3 (inhibitor of growth protein 3) overexpression decreased S-phase cell population and colony-forming efficiency, and induced apoptosis at a p53-mediated manner. The aim of this study was to investigate the clinicopathological and prognostic significance of ING3 expression in colorectal carcinogenesis and subsequent progression.
Methods:
ING3 expression was examined by immunohistochemistry on tissue microarray containing colorectal non-neoplastic mucosa (NNM), adenoma and adenocarcinoma. Colorectal carcinoma tissue and cell lines were studied for ING3 expression by Western blot or RT-PCR.
Results:
ING3 mRNA was differentially expressed in Colo201, Colo205, DLD-1, HCT-15, HCT-116, HT-29, KM-12, SW480, SW620 and WiDr cells. Carcinomas showed significantly lower ING3 expression than matched NNM at mRNA level (P< 0.05), but not at protein level. Immunohistochemically, ING3 expression was significantly decreased from NNM, adenoma to adenocarcinoma (P< 0.05). ING3 expression was not correlated with age, sex, tumour size, depth of invasion, lymphatic or venous invasion, lymph node metastasis, tumour- node- metastasis staging or differentiation. Kaplan-Meier analysis indicated that ING3 protein expression was not associated the prognosis of the patients with colorectal carcinoma (P< 0.05).
Interpretation & conclusions:
Our study showed that downregulated ING3 expression might play an important role in colorectal adenoma-adenocarcinoma sequence. Further studies are required to understand the mechanism.
PMCID: PMC4078494  PMID: 24927342
Carcinogenesis; colorectal carcinoma; ING3; prognosis; progression
21.  Apolipoprotein E gene polymorphism and Alzheimer's disease in Chinese population: a meta-analysis 
Scientific Reports  2014;4:4383.
The relationship between Apolipoprotein E (ApoE) genotype and the risk of Alzheimer's disease (AD) is relatively well established in Caucasians, but less established in other ethnicities. To examine the association between ApoE polymorphism and the onset of AD in Chinese population, we searched the commonly used electronic databases between January 2000 and November 2013 for relevant studies. Total 20 studies, including 1576 cases and 1741 controls, were retrieved. The results showed statistically significant positive association between risk factor ε4 allele carriers and AD in Chinese population (OR = 3.93, 95% CI = 3.37–4.58, P < 0.00001). Genotype ApoE ε4/ε4 and ε4/ε3 have statistically significant association with AD as well (ε4/ε4: OR = 11.76, 95% CI = 6.38–21.47, P < 0.00001; ε4/ε3: OR = 3.08, 95% CI = 2.57–3.69, P < 0.00001). Furthermore, the frequency of the ApoE ε3 is lower in AD than that in the health controls, and the difference of ε3 allele is also statistically significant (OR = 0.42, 95% CI = 0.37–0.47, P < 0.00001). No significant heterogeneity was observed among all studies. This meta-analysis suggests that the subject with at least one ApoE ε4 allele has higher risk suffering from AD than controls in Chinese population. The results also provide a support for the protection effect of ApoE ε3 allele in developing AD.
doi:10.1038/srep04383
PMCID: PMC3955907  PMID: 24632849
22.  Impact of Serum Biomarkers and Clinical Factors on Intensive Care Unit Mortality and 6-Month Outcome in Relatively Healthy Patients with Severe Pneumonia and Acute Respiratory Distress Syndrome 
Disease Markers  2014;2014:804654.
Objectives. This study aimed to identify the independent biomarkers and clinical factors that could predict ICU mortality and 6-month outcomes in relatively healthy patients with severe pneumonia and acute respiratory distress syndrome (ARDS). Patients and Methods. We prospectively enrolled patients with severe pneumonia-related ARDS that required mechanical ventilation. Patients were excluded if they were unable to take care of themselves. Several biomarkers and clinical factors were evaluated prospectively on day 1 and day 3 after ICU admission. All biomarkers and clinical factors were collected for analysis. Results. 56 patients were enrolled in this study. We determined that the initial appropriate antibiotics use was an independent clinical factor and day 1 high-mobility group protein B1 (HMGB1) concentration was an independent biomarker for ICU mortality. Interestingly, we also found that a low day 1 albumin level was an independent biomarker for predicting patient life dependence 6 months after a pneumonia event. Conclusion. Patients with severe pneumonia and ARDS requiring mechanical ventilation experience high rates of ICU mortality or disability, even if they were quite healthy before. Initial appropriate antibiotics use and day 1 level of HMGB1 were independent factors for predicting ICU mortality. Day 1 albumin level was predictive of 6-month patient life dependence.
doi:10.1155/2014/804654
PMCID: PMC3958786  PMID: 24723739
23.  Regional Homogeneity Changes in Hemodialysis Patients with End Stage Renal Disease: In Vivo Resting-State Functional MRI Study 
PLoS ONE  2014;9(2):e87114.
Objective
To prospectively investigate and detect early cerebral regional homogeneity (ReHo) changes in neurologically asymptomatic patients with end stage renal disease (ESRD) using in vivo resting-state functional MR imaging (Rs-fMRI).
Methods
We enrolled 20 patients (15 men, 5 women; meanage, 37.1 years; range, 19–49 years) with ESRD and 20 healthy controls (15 men, 5 women; mean age, 38.3 years; range, 28–49 years). The mean duration of hemodialysis for the patient group was 10.7±6.4 monthes. There was no significant sex or age difference between the ESRD and control groups. Rs-fMRI was performed using a gradient-echo echo-planar imaging sequence. ReHo was calculated using software (DPARSF). Voxel-based analysis of the ReHo maps between ESRD and control groups was performed with a two-samples t test. Statistical maps were set at P value less than 0.05 and were corrected for multiple comparisons. The Mini-Mental State Examination (MMSE) was administered to all participants at imaging.
Results
ReHo values were increased in the bilateral superior temporal gyrus and left medial frontal gyrus in the ERSD group compared with controls, but a significantly decreased ReHo value was found in the right middle temporal gyrus. There was no significant correlation between ReHo values and the duration of hemodialysis in the ESRD group. Both the patients and control subjects had normal MMSE scores (≥28).
Conclusions
Our finding revealed that abnormal brain activity was distributed mainly in the memory and cognition related cotices in patients with ESRD. The abnormal spontaneous neuronal activity in those areas provide information on the neural mechanisms underlying cognitive impairment in patients with ESRD, and demonstrate that Rs-fMRI with ReHo analysis is a useful non-invasive imaging tool for the detection of early cerebral ReHo changes in hemodialysis patients with ESRD.
doi:10.1371/journal.pone.0087114
PMCID: PMC3916321  PMID: 24516545
24.  The impact of both platinum-based chemotherapy and EGFR-TKIs on overall survival of patients with advanced non-small cell lung cancer 
Chinese Journal of Cancer  2014;33(2):105-114.
Both platinum-based doublet chemotherapy (PBC) and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) prolong the survival of patients with advanced non-small cell lung cancer (NSCLC). In early studies, most patients underwent PBC as first-line treatment, but not all patients could afford EGFR-TKIs as second-line treatment. To understand the impact of PBC and EGFR-TKIs on NSCLC prognosis, we evaluated the association between the receipt of both regimens and overall survival (OS). Using MEDLINE and EMBASE, we identified prospective, randomized, controlled phase III clinical trials in advanced NSCLC that met the inclusion criteria: in general population with advanced NSCLC, the percentage of patients treated with both PBC and EGFR-TKIs was available in the trial and OS was reported. After collecting data from the selected trials, we correlated the percentage of patients treated with both PBC and EGFR-TKIs with the reported OS, using a weighted analysis. Fifteen phase III clinical trials—involving 11,456 adult patients in 32 arms—were included in the analysis, including 6 trials in Asian populations and 9 in non-Asian (predominantly Caucasian) populations. The OS was positively correlated with the percentage of patients treated with both PBC and EGFR-TKIs (r = 0.797, P < 0.001). The correlation was obvious in the trials in Asian populations (r = 0.936, P < 0.001) but was not statistically significant in the trials in predominantly Caucasian populations (r = 0.116, P = 0.588). These results suggest that treatment with PBC and EGFR-TKIs may provide a survival benefit to patients with advanced NSCLC, highlighting the importance of having both modalities available for therapy.
doi:10.5732/cjc.012.10274
PMCID: PMC3935012  PMID: 23816558
NSCLC; platinum-based doublet chemotherapy; correlation; EGFR-TKIs; overall survival
25.  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.
doi:10.1371/annotation/32a8c7e3-5efc-478b-b374-c8cbfd1d3968
PMCID: PMC3897329

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