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1.  Number of negative lymph nodes is associated with disease-free survival in patients with breast cancer 
BMC Cancer  2015;15:43.
The aim of this study was to evaluate the prognostic value of the number of negative lymph nodes (NLNs) in breast cancer patients after mastectomy.
2,455 breast cancer patients who received a mastectomy between January 1998 and December 2007 were retrospectively reviewed. The prognostic impact of the number of NLNs with respect to disease-free survival (DFS) was analyzed.
The median follow-up time was 62.0 months, and the 5-year and 10-year DFS was 87.1% and 74.3%, respectively. The DFS of patients with >10 NLNs was significantly higher than that of patents with ≤10 NLNs, and the 5-year DFS rates were 87.5% and 69.5%, respectively (P < 0.001). Univariate Cox analysis showed that the NLN count (continuous variable) was a prognostic factor of DFS (hazard ratio [HR] = 0.913, 95% confidence interval [CI]: 0.896-0.930, P < 0.001). In multivariate Cox analysis, patients with a higher number of NLNs had a better DFS (HR = 0.977, 95% CI: 0.958-0.997, P = 0.022). Subgroup analysis showed that the NLN count had a prognostic value in patients at different pT stages and pN positive patients (log-rank P < 0.001). However, it had no prognostic value in pN0 patients (log-rank P = 0.684).
The number of NLNs is an independent prognostic factor of DFS in breast cancer patients after mastectomy, and patients with a higher number of NLNs have a better DFS.
PMCID: PMC4324425
Breast cancer; Mastectomy; Negative lymph nodes; Prognosis; Disease-free survival
2.  Evolutionary analysis of rubella viruses in mainland China during 2010–2012: endemic circulation of genotype 1E and introductions of genotype 2B 
Scientific Reports  2015;5:7999.
Rubella remains a significant burden in mainland China. In this report, 667 viruses collected in 24 of 31 provinces of mainland China during 2010–2012 were sequenced and analyzed, significantly extending previous reports on limited numbers of viruses collected before 2010. Only viruses of genotypes 1E and 2B were found. Genotype 1E viruses were found in all 24 provinces. Genotype 1E viruses were likely introduced into mainland China around 1997 and endemic transmission of primarily one lineage became established. Viruses reported here from 2010–2012 are largely in a single cluster within this lineage. Genotype 2B viruses were rarely detected in China prior to 2010. This report documents a previously undetected 2B lineage, which likely became endemic in eastern provinces of China between 2010 and 2012. Bayesian analyses were performed to estimate the evolutionary rates and dates of appearance of the genotype 1E and 2B viral linages in China. A skyline plot of viral population diversity did not provide evidence of reduction of diversity as a result of vaccination, but should be useful as a baseline for such reductions as vaccination programs for rubella become widespread in mainland China.
PMCID: PMC4303870  PMID: 25613734
3.  Ovarian Ablation Using Goserelin Improves Survival of Premenopausal Patients with Stage II/III Hormone Receptor-Positive Breast Cancer without Chemotherapy-Induced Amenorrhea 
The purpose of this study was to assess the value of ovarian ablation using goserelin in premenopausal patients with stage II/III hormone receptor-positive breast cancer without chemotherapy-induced amenorrhea (CIA).
Materials and Methods
We retrospectively reviewed the data of breast patients treated between October 1999 and November 2007 without CIA. The Kaplan-Meier method was used for calculation of the survival rate. Log rank method and Cox regression analysis were used for univariate and multivariate prognostic analysis.
The median follow-up period was 61 months. Initially, 353 patients remained without CIA after chemotherapy and 98 among those who received goserelin and tamoxifen (TAM). In univariate analysis, goserelin improved locoregional recurrence-free survival (LRFS) (98.9% vs. 94.1%, p=0.041), distant metastasis-free survival (DMFS) (85.4% vs. 71.9%, p=0.006), disease-free survival (DFS) (85.4% vs. 71.6%, p=0.005), and overall survival (OS) (93.5% vs. 83.5%, p=0.010). In multivariate analysis, goserelin treatment was an independent factor influencing DMFS (hazard ratio [HR], 1.603; 95% confidence interval [CI], 1.228 to 2.092; p=0.001), DFS (HR, 1.606; 95% CI, 1.231 to 2.096; p=0.001), and OS (HR, 3.311; 95% CI, 1.416 to 7.742; p=0.006). In addition, treatment with goserelin resulted in significantly improved LRFS (p=0.039), DMFS (p=0.043), DFS (p=0.036), and OS (p=0.010) in patients aged < 40 years. In patients aged ≥ 40 years, goserelin only improved DMFS (p=0.028) and DFS (p=0.027).
Ovarian ablation with goserelin plus TAM resulted in significantly improved therapeutic efficacy in premenopausal patients with stage II/III hormone receptor-positive breast cancer without CIA.
PMCID: PMC4296851  PMID: 25187267
Breast neoplasms; Goserelin; Ovarian ablation; Therapy-induced amenorrhea; Premenopause
4.  Number of Negative Lymph Nodes Can Predict Survival after Postmastectomy Radiotherapy According to Different Breast Cancer Subtypes 
Journal of Cancer  2015;6(3):261-269.
Purpose: To assess the prognostic value of the number of negative lymph nodes (NLNs) in breast cancer patients with positive axillary lymph nodes after mastectomy and its predictive value for radiotherapy efficacy of different breast cancer subtypes (BCS).
Methods: The records of 1,260 breast cancer patients with positive axillary lymph nodes who received mastectomy between January 1998 and December 2007 were reviewed. The prognostic impact and predictive value of the number of NLNs with respect to locoregional recurrence-free survival (LRFS), disease-free survival (DFS), and overall survival (OS) were analyzed.
Results: The median follow-up time was 58 months, and 444 patients (35.2%) received postmastectomy radiotherapy (PMRT). Univariate and multivariate Cox survival analysis indicated the number of NLNs was an independent prognostic factor of LRFS, DFS, and OS. Patients with a higher number of NLNs had better survival. PMRT improved the LRFS of patients with ≤ 8 NLNs ( p < 0.001), while failing to improve the LRFS of patients with > 8 NLNs (p = 0.075). In patients with luminal A subtype, PMRT improved the LRFS, DFS, and OS of patients with ≤ 8 NLNs, but in patients with > 8 NLNs only the LRFS was improved. For patients with luminal B subtype, PMRT only improved the LRFS of patients with ≤ 8 NLNs. The number of NLNs had no predictive value for the efficacy with PMRT in Her2+ and triple-negative subtypes.
Conclusions: The number of NLNs is a prognostic indicator in patients with node-positive breast cancer, and it can predict the efficacy of PMRT according to different BCS.
PMCID: PMC4317762  PMID: 25663944
Breast cancer; mastectomy; radiotherapy; negative lymph nodes; prognosis
5.  Number of negative lymph nodes can predict survival of breast cancer patients with four or more positive lymph nodes after postmastectomy radiotherapy 
This study was conducted to assess the prognostic value of the number of negative lymph nodes (NLNs) in breast cancer patients with four or more positive lymph nodes after postmastectomy radiotherapy (PMRT).
This retrospective study examined 605 breast cancer patients with four or more positive lymph nodes who underwent mastectomy. A total of 371 patients underwent PMRT. The prognostic value of the NLN count in patients with and without PMRT was analyzed. The log-rank test was used to compare survival curves, and Cox regression analysis was performed to identify prognostic factors.
The median follow-up was 54 months, and the overall 8-year locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) were 79.8%, 50.0%, 46.8%, and 57.9%, respectively. The optimal cut-off points for NLN count was 12. Univariate analysis showed that the number of NLNs, lymph node ratio (LNR) and pN stage predicted the LRFS of non-PMRT patients (p < 0.05 for all). Multivariate analysis showed that the number of NLNs was an independent prognostic factor affecting the LRFS, patients with a higher number of NLNs had a better LRFS (hazard ratio = 0.132, 95% confidence interval = 0.032-0.547, p =0.005). LNR and pN stage had no effect on LRFS. PMRT improved the LRFS (p < 0.001), DMFS (p = 0.018), DFS (p = 0.001), and OS (p = 0.008) of patients with 12 or fewer NLNs, but it did not any effect on survival of patients with more than 12 NLNs. PMRT improved the regional lymph node recurrence-free survival (p < 0.001) but not the chest wall recurrence-free survival (p = 0.221) in patients with 12 or fewer NLNs.
The number of NLNs can predict the survival of breast cancer patients with four or more positive lymph nodes after PMRT.
Electronic supplementary material
The online version of this article (doi:10.1186/s13014-014-0284-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4278342  PMID: 25511525
Breast cancer; Mastectomy; Negative lymph nodes; Radiotherapy
6.  Dosimetric analysis of the brachial plexus among patients with breast cancer treated with post-mastectomy radiotherapy to the ipsilateral supraclavicular area: report of 3 cases of radiation-induced brachial plexus neuropathy 
The purpose of this study was to evaluate the brachial plexus (BP) dose of postmastectomy radiotherapy (PMRT) to the ipsilateral supraclavicular (ISCL) area, and report the characteristics of radiation-induced brachial plexus neuropathy (RIBPN).
The BP dose of 31 patients who received adjuvant PMRT to the ISCL area and chest wall using three-dimensional conformal radiotherapy (3DCRT) and the records of 3 patients with RIBPN were retrospectively analyzed based on the standardized Radiation Therapy Oncology Group-endorsed guidelines. The total dose to the ISCL area and chest wall was 50 Gy in 25 fractions.
Patients with a higher number of removed lymph nodes (RLNs) had a higher risk of RIBPN (hazard ratio [HR]: 1.189, 95% confidence interval [CI]: 1.005-1.406, p = 0.044). In 31 patients treated with 3DCRT, the mean dose to the BP without irradiation to the ISCL area was significantly less than that with irradiation to the ISCL area (0.97 ± 0.20 vs. 44.39 ± 4.13 Gy, t = 136.75, p <0.001). In the 3DCRT plans with irradiation to the ISCL area and chest wall, the maximum dose to the BP was negatively correlated with age (r = −0.40, p = 0.026), body mass index (BMI) (r = −0.44, p = 0.014), and body weight (r = −0.45, p = 0.011). Symptoms of the 3 patients with RIBPN occurred 37–65 months after radiotherapy, and included progressive upper extremity numbness, pain, and motor disturbance. After treatment, 1 patient was stable, and the other 2 patients’ symptoms worsened.
The incidence of RIBPN was higher in patients with a higher number of RLNs after PMRT. The dose to the BP is primarily from irradiation of the ISCL area, and is higher in slim and young patients. Prevention should be the main focus of managing RIBPN, and the BP should be considered an organ-at-risk when designing a radiotherapy plan for the ISCL area.
PMCID: PMC4271326  PMID: 25499205
Breast cancer; Radiation therapy; Brachial plexus; Radiation-induced brachial plexus neuropathy
7.  Applications of Data Mining Methods in the Integrative Medical Studies of Coronary Heart Disease: Progress and Prospect 
A large amount of studies show that real-world study has strong external validity than the traditional randomized controlled trials and can evaluate the effect of interventions in a real clinical setting, which open up a new path for researches of integrative medicine in coronary heart disease. However, clinical data of integrative medicine in coronary heart disease are large in amount and complex in data types, making exploring the appropriate methodology a hot topic. Data mining techniques are to analyze and dig out useful information and knowledge from the mass data to guide people's practices. The present review provides insights for the main features of data mining and their applications of integrative medical studies in coronary heart disease, aiming to analyze the progress and prospect in this field.
PMCID: PMC4269208  PMID: 25544853
8.  Complement Factor B is the Downstream Effector of Toll-Like Receptors and Plays an Important Role in a Mouse Model of Severe Sepsis¶ 
Severe sepsis involves massive activation of the innate immune system and leads to high mortality. Previous studies have demonstrated that various types of Toll-like receptors (TLRs) mediate a systemic inflammatory response and contribute to organ injury and mortality in animal models of severe sepsis. However, the downstream mechanisms responsible for TLR-mediated septic injury are poorly understood. Here, we show that activation of TLR2, TLR3 and TLR4 markedly enhanced complement factor B (cfB) synthesis and release by macrophages and cardiac cells. Polymicrobial sepsis, created by cecal ligation and puncture (CLP) in a mouse model, augmented cfB levels in the serum, peritoneal cavity and major organs including the kidney and heart. CLP also led to the alternative pathway (AP) activation, C3 fragment deposition in the kidney and heart, and cfB-dependent C3dg elevation. Bacteria isolated from septic mice activated the serum AP via a factor D-dependent manner. MyD88 deletion attenuated cfB/C3 up-regulation as well as cleavage induced by polymicrobial infection. Importantly, during sepsis, absence of cfB conferred a protective effect with improved survival and cardiac function, and markedly attenuated acute kidney injury. cfB deletion also led to increased neutrophil migratory function during the early phase of sepsis, decreased local and systemic bacterial load, attenuated cytokine production and reduced neutrophil reactive oxygen species production. Together, our data indicate that cfB acts as a downstream effector of TLR signaling and plays a critical role in the pathogenesis of severe bacterial sepsis.
PMCID: PMC3906719  PMID: 24154627
9.  Effects of baicalin in CD4 + CD29 + T cell subsets of ulcerative colitis patients 
World Journal of Gastroenterology : WJG  2014;20(41):15299-15309.
AIM: To evaluate the role of baicalin in ulcerative colitis (UC) with regard to the CD4+CD29+ T helper cell, its surface markers and serum inflammatory cytokines.
METHODS: Flow cytometry was used to detect the percentage of CD4+CD29+ cells in patients with UC. Real time polymerase chain reaction was used to detect expression of GATA-3, forkhead box P3, T-box expressed in T cells (T-bet), and retinoic acid-related orphan nuclear hormone receptor C (RORC). Western blotting was used to analyze expression of nuclear factor-κB (NF-κB) p65, phosphorylation of NF-κB (p-NF-κB) p65, STAT4, p-STAT4, STAT6 and p-STAT6. The concentrations of interferon-γ (IFN-γ), interleukin (IL)-4, IL-5, IL-6, IL-10 and TGF-β in serum were determined by ELISA assay.
RESULTS: The percentages of CD4+CD29+ T cells were lower in treatment with 40 and 20 μmol/L baicalin than in the treatment of no baicalin. Treatment with 40 or 20 μmol/L baicalin significantly upregulated expression of IL-4, TGF-β1 and IL-10, increased p-STAT6/STAT6 ratio, but downregulated expression of IFN-γ, IL-5, IL-6, RORC, Foxp3 and T-bet, and decreased ratios of T-bet/GATA-3, p-STAT4/STAT4 and p-NF-κB/NF-κB compared to the treatment of no baicalin.
CONCLUSION: The results indicate that baicalin regulates immune balance and relieves the ulcerative colitis-induced inflammation reaction by promoting proliferation of CD4+CD29+ cells and modulating immunosuppressive pathways.
PMCID: PMC4223263  PMID: 25386078
Ulcerative colitis; Baicalin; CD4+CD29+; Cytokines; Nuclear factor-κB
10.  Obesity-associated gene FTO rs9939609 polymorphism in relation to the risk of tuberculosis 
BMC Infectious Diseases  2014;14(1):592.
Obesity is known to affect cell-mediated immune responses. Recent studies have revealed that genetic polymorphisms in the fat mass and obesity associated (FTO) gene are related to human obesity. We hypothesize that this gene may also play a role in the risk of immune-related infectious diseases such as tuberculosis.
This case–control study included 1625 pulmonary tuberculosis cases and 1570 unaffected controls recruited from the Jiangsu province in China. Single nucleotide polymorphisms (SNPs), rs9939609 and rs8050136, in the FTO gene were genotyped using TaqMan allelic discrimination assays. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using the unconditional logistic regression model.
We observed a significant association between the genetic polymorphism rs9939609 and tuberculosis risk. Compared with the common genotype TT, individuals carrying AA had a significantly increased risk, with an OR of 3.77 (95% CI: 2.26-6.28). After adjusting for potential confounders, the relationship remains significant. An additive model showed that carriers of an allele A had a 26% increased risk of tuberculosis compared with the T allele (OR: 1.26, 95% CI: 1.08-1.48). Compared with the common haplotype rs9939609T-rs8050136C, the haplotype rs9939609A-rs8050136C was related to an increased risk of tuberculosis (OR = 6.09, 95% CI: 3.27-12.34).
The FTO polymorphism rs9939609 is associated with a risk of pulmonary tuberculosis in the Chinese population.
PMCID: PMC4226896  PMID: 25377722
11.  Helicobacter pylori infection does not promote hepatocellular cancer in a transgenic mouse model of hepatitis C virus pathogenesis 
Gut Microbes  2013;4(6):577-590.
Helicobacter pylori (H. pylori) and hepatitis C virus (HCV) infect millions of people and can induce cancer. We investigated if H. pylori infection promoted HCV-associated liver cancer. Helicobacter-free C3B6F1 wild-type (WT) and C3B6F1-Tg(Alb1-HCVN)35Sml (HT) male and female mice were orally inoculated with H. pylori SS1 or sterile media. Mice were euthanized at ~12 mo postinoculation and samples were collected for analyses. There were no significant differences in hepatocellular tumor promotion between WT and HT mice; however, HT female mice developed significantly larger livers with more hepatic steatosis than WT female mice. H. pylori did not colonize the liver nor promote hepatocellular tumors in WT or HT mice. In the stomach, H. pylori induced more corpus lesions in WT and HT female mice than in WT and HT male mice, respectively. The increased corpus pathology in WT and HT female mice was associated with decreased gastric H. pylori colonization, increased gastric and hepatic interferon gamma expression, and increased serum Th1 immune responses against H. pylori. HT male mice appeared to be protected from H. pylori-induced corpus lesions. Furthermore, during gastric H. pylori infection, HT male mice were protected from gastric antral lesions and hepatic steatosis relative to WT male mice and these effects were associated with increased serum TNF-α. Our findings indicate that H. pylori is a gastric pathogen that does not promote hepatocellular cancer and suggest that the HCV transgene is associated with amelioration of specific liver and gastric lesions observed during concurrent H. pylori infection in mice.
PMCID: PMC3928167  PMID: 23929035
Hepatitis; helicobacter; cancer; infection; virus; bacteria; mice; transgenic
12.  Paradoxical role of CBX8 in proliferation and metastasis of colorectal cancer 
Oncotarget  2014;5(21):10778-10790.
The effect of polycomb chromobox (Cbx) proteins in cancer is context-dependent. The Chromobox homolog 8 (CBX8) was originally characterized as a transcriptional repressor, which inhibits cell proliferation in Ink4a-Arf-dependent and -independent manner. However, the role of CBX8 in colorectal cancer remains unknown. Here, we found that high CBX8 expression was associated with a low rate of distant metastasis and good prognosis in CRC patients, even though CBX8 was up-regulated in CRC cell lines and clinical samples. Knockdown of CBX8 inhibited CRC proliferation in vitro and in vivo, mostly by increasing p53 and its downstream effectors. However, knockdown of CBX8 enhanced CRC migration, invasion and metastasis in vitro and in vivo, in part through direct up-regulation of integrin β4 (ITGB4) that in turn decreased RhoA activity. Collectively, the knockdown of CBX8 inhibited CRC proliferation, while promoting its metastasis, thus exerting paradoxical effects in CRC progression.
PMCID: PMC4279409  PMID: 25360999
CBX8; Polycomb Group protein; colorectal cancer; metastasis; proliferation; p53; integrin
13.  Loss of the Endothelial Glucocorticoid Receptor Prevents the Therapeutic Protection Afforded by Dexamethasone after LPS 
PLoS ONE  2014;9(10):e108126.
Glucocorticoids are normally regarded as anti-inflammatory therapy for a wide variety of conditions and have been used with some success in treating sepsis and sepsis-like syndromes. We previously demonstrated that mice lacking the glucocorticoid receptor in the endothelium (GR EC KO mice) are extremely sensitive to low-dose LPS and demonstrate prolonged activation and up regulation of NF-κB. In this study we pre-treated these GR EC KO mice with dexamethasone and assessed their response to an identical dose of LPS. Surprisingly, the GR EC KO mice fared even worse than when given LPS alone demonstrating increased mortality, increased levels of the inflammatory cytokines TNF-α and IL-6 and increased nitric oxide release after the dexamethasone pre-treatment. As expected, control animals pre-treated with dexamethasone showed improvement in all parameters assayed. Mechanistically we demonstrate that GR EC KO mice show increased iNOS production and NF-κB activation despite treatment with dexamethasone.
PMCID: PMC4191990  PMID: 25299055
14.  Corn Peptides Protect Against Thioacetamide-Induced Hepatic Fibrosis in Rats 
Journal of Medicinal Food  2013;16(10):912-919.
Certain bioactive peptides are reported to be able to alleviate hepatic fibrosis. Our previous work has confirmed the hepatoprotective effect of corn peptides (CPs) that are prepared from a high protein by-product, corn gluten meal, on acute liver injury in an animal model. However, the antifibrotic activity of CPs remained to be elucidated. In this study, the hepatoprotective effect of CPs on thioacetamide (TAA)-induced liver fibrosis was tested. Results showed that CPs (100 mg/kg body weight) significantly decreased the levels of alanine transaminase/aspartate transaminase, laminin, type IV collagen, and type III collagen in serum and increased the serum albumin levels and total antioxidant capacity. Additionally, with CP treatment (100 mg/kg body weight), a significant decrease was observed in the levels of malondialdehyde, nitric oxide, hydroxyproline, transforming growth factor β1, and lactate dehydrogenase activity as well as the liver index, while the activity of superoxidedismutase was significantly increased in livers. The histological and morphological analysis showed that the hepatocyte structure in CP-treated rats was superior to that of TAA-injured rats, and inflammation and fibrosis were also ameliorated. Therefore, CPs can be used as an option for prevention and adjuvant therapy of liver fibrosis.
PMCID: PMC3806372  PMID: 24063407
antioxidative activity; corn peptides (CPs); hepatic fibrosis; hepatoprotective effect; thioacetamide (TAA)
15.  Characterization of the PH1704 Protease from Pyrococcus horikoshii OT3 and the Critical Functions of Tyr120 
PLoS ONE  2014;9(9):e103902.
The PH1704 protease from hyperthermophilic archaean Pyrococcus horikoshii OT3 is a member of DJ-1/ThiJ/PfpI superfamily with diverse functional subclasses. The recombinant PH1704 was efficiently purified and was systematically characterized by a combination of substrate specificity analysis, steady-state kinetics study and molecular docking research. The homogeneous protease was obtained as a presumed dodecamer with molecular weight of ∼240 kDa. Iodoacetamide strongly inhibited the peptidase activity, confirming that Cys100 is a nucleophilic residue. The recombinant protein was identified as both an aminopeptidase and an endopeptidase. Experimental data showed that L-R-amc was the best substrate of PH1704. Structural interaction fingerprint analysis (SIFt) indicated the binding pose of PH1704 and showed that Tyr120 is important in substrate binding. Kinetic parameters Kcat and Kcat/Km of the Y120P mutant with L-R-amc was about 7 and 7.8 times higher than that of the wild type (WT). For the endopeptidase Y120P with AAFR-amc, Kcat and Kcat/Km is 10- and 21- fold higher than that of WT. Experimental data indicate the important functions of Tyr120: involvement in enzyme activity to form a hydrogen bond with Cys100 and as an entrance gate of the substrate with Lys43. The results of this study can be used to investigate the DJ-1/ThiJ/PfpI superfamily.
PMCID: PMC4156298  PMID: 25192005
16.  Enhancing the Electrocatalytic Property of Hollow Structured Platinum Nanoparticles for Methanol Oxidation Through A Hybrid Construction 
Scientific Reports  2014;4:6204.
The integration of different components into a hybrid nanosystem for the utilization of the synergistic effects is an effective way to design the electrocatalysts. Herein, we demonstrate a hybrid strategy to enhance the electrocatalytic property of hollow structured Pt nanoparticles for methanol oxidation reaction. This strategy begins with the preparation of bimetallic Ag-Pt nanoparticles with a core-shell construction. Element sulfur is then added to transform the core-shell Ag-Pt nanostructures into hybrid nanodimers consisting of Ag2S nanocrystals and remaining Pt domains with intact hollow interiors (Ag2S-hPt). Finally, Au is deposited at the surface of the Ag2S domain in each hetero-dimer, resulting in the formation of ternary Ag2S-Au-hPt nanocomposites with solid-state interfaces. The ternary nanocomposites exhibit enhanced electrocatalytic property toward methanol oxidation due to the strong electronic coupling between Pt and other domains in the hybrid particles. The concept might be used toward the design and synthesis of other hetero-nanostructures with technological importance.
PMCID: PMC4145286  PMID: 25160947
17.  Expression of DNA topoisomerase II-α: Clinical significance in laryngeal carcinoma 
Oncology Letters  2014;8(4):1575-1580.
DNA topoisomerase II-α (Topo II-α) is essential for numerous cell processes, including DNA replication, transcription, recombination, and chromosome separation and condensation. Altered Topo II-α expression may lead to carcinogenesis and cancer progression. The aim of the present study was to investigate the association between Topo II-α expression levels and clinicopathological data from laryngeal cancer patients. Immunohistochemistry was used to analyze Topo II-α expression in laryngeal squamous cell carcinoma and distant healthy tissues obtained from 70 patients. In addition, fluorescence in situ hybridization was used to detect Topo II-α amplification and chromosome 17 ploidy using a laryngeal cancer tissue microarray. The expression of Topo II-α protein was detected in 71.43% (50/70) of laryngeal carcinoma tissues, in contrast to 9% of healthy tissues (2/22). Furthermore, the expression of Topo II-α protein was found to be associated with tumor de-differentiation and advanced tumor T stage. However, the expression of Topo II-α protein was not identified to be associated with Topo II-α amplification in laryngeal carcinoma, although was found to positively correlate with chromosome 17 aneuploidy (P<0.05). A higher aneuploidy rate contributed to increased expression levels of Topo II-α protein. Aberrant Topo II-α expression and chromosome 17 aneuploidy contributed to the development and progression of laryngeal cancer, indicating that targeting Topo II-α may provide a treatment strategy for patients with laryngeal cancer.
PMCID: PMC4156233  PMID: 25202370
DNA topoisomerase II-α; immunohistochemistry; chromosome 17 aneuploidy; laryngeal squamous cell carcinoma; fluorescence in situ hybridization
18.  Promoter methylation of Raf kinase inhibitory protein: A significant prognostic indicator for patients with gastric adenocarcinoma 
DNA methylation has an important role in the development of carcinomas. As a metastasis suppressor gene, Raf kinase inhibitory protein (RKIP) suppresses tumor cell invasion and metastasis. In the present study, the associations between RKIP protein expression and promoter methylation with clinicopathological parameters, prognosis and survival rates in gastric adenocarcinoma were investigated. RKIP protein expression and promoter methylation were measured in 135 cases of surgically resected gastric adenocarcinoma specimens and corresponding normal tissues using immunohistochemistry and methylation-specific polymerase chain reaction, respectively. Kaplan-Meier analyses were performed to analyze the patient survival rate. Prognostic factors were determined using multivariate Cox analysis. RKIP promoter methylation was detected in 48.9% of gastric carcinoma tissues and 5.17% of adjacent tissues (P<0.05). RKIP protein expression was detected in 43.0% of gastric carcinoma tissues and 91.1% of adjacent tissues (P<0.05). The protein expression levels and promoter methylation of RKIP were shown to correlate with pathological staging, Union for International Cancer Control-stage, tumor differentiation and lymph node metastasis (P<0.05). In addition, the protein expression of RKIP in gastric carcinomas was demonstrated to be associated with promoter methylation of RKIP. Survival analysis of gastric carcinoma patients revealed that promoter methylation in RKIP-positive tumors correlated with a significantly shorter survival time when compared with RKIP-negative tumors (P=0.0002, using the log-rank test). Using multivariate Cox analysis, promoter methylation of RKIP was shown to be an independent prognostic factor (P=0.033). These results indicated that abnormal promoter methylation of RKIP may be one cause of downregulated RKIP expression. Downregulation of RKIP expression was shown to correlate with the incidence and development of gastric carcinomas. Thus, abnormal promoter methylation of RKIP may be a valuable biomarker for estimating gastric carcinoma prognosis.
PMCID: PMC4113522  PMID: 25120612
Raf kinase inhibitory protein; methylation; gastric adenocarcinoma; prognosis
19.  Long-term exposure to decabrominated diphenyl ether impairs CD8 T-cell function in adult mice 
Cellular and Molecular Immunology  2014;11(4):367-376.
Polybrominated diphenyl ethers (PBDEs) are ubiquitous environmental pollutants that accumulate to high levels in human populations that are subject to occupational or regional industry exposure. PBDEs have been shown to affect human neuronal, endocrine and reproductive systems, but their effect on the immune system is not well understood. In this study, experimental adult mice were intragastrically administered 2,2′,3,3′,4,4′,5,5′,6,6′-decabromodiphenyl ether (BDE-209) at doses of 8, 80 or 800 mg/kg of body weight (bw) at 2-day intervals. Our results showed that continuous exposure to BDE-209 resulted in high levels of BDE-209 in the plasma that approached the levels found in people who work in professions with high risks of PDBE exposure. Reduced leukocytes, decreased cytokine (IFN-γ, IL-2 and TNF-α) production and lower CD8 T-cell proliferation were observed in the mice exposed to BDE-209. Additionally, mice with long-term BDE-209 exposure had lower numbers of antigen-specific CD8 T cells after immunization with recombinant Listeria monocytogenes expressing ovalbumin (rLm-OVA) and the OVA-specific CD8 T cells had reduced functionality. Taken together, our study demonstrates that continuous BDE-209 exposure causes adverse effects on the number and functionality of immune cells in adult mice.
PMCID: PMC4085518  PMID: 24705197
BDE-209; CD8 T cells; continuous exposure; immunotoxicity; T-cell functions
20.  Neuroprotective effects of Asiaticoside 
Neural Regeneration Research  2014;9(13):1275-1282.
In the central nervous system, Asiaticoside has been shown to attenuate in vitro neuronal damage caused by exposure to β-amyloid. In vivo studies demonstrated that Asiaticoside could attenuate neurobehavioral, neurochemical and histological changes in transient focal middle cerebral artery occlusion animals. In addition, Asiaticoside showed anxiolytic effects in acute and chronic stress animals. However, its potential neuroprotective properties in glutamate-induced excitotoxicity have not been fully studied. We investigated the neuroprotective effects of Asiaticoside in primary cultured mouse cortical neurons exposed to glutamate-induced excitotoxicity invoked by N-methyl-D-aspartate. Pretreatment with Asiaticoside decreased neuronal cell loss in a concentration-dependent manner and restored changes in expression of apoptotic-related proteins Bcl-2 and Bax. Asiaticoside pretreatment also attenuated the upregulation of NR2B expression, a subunit of N-methyl-D-aspartate receptors, but did not affect expression of NR2A subunits. Additionally, in cultured neurons, Asiaticoside significantly inhibited Ca2+ influx induced by N-methyl-D-aspartate. These experimental findings provide preliminary evidence that during excitotoxicity induced by N-methyl-D-aspartate exposure in cultured cortical neurons, the neuroprotective effects of Asiaticoside are mediated through inhibition of calcium influx. Aside from its anti-oxidant activity, down-regulation of NR2B-containing N-methyl-D-aspartate receptors may be one of the underlying mechanisms in Asiaticoside neuroprotection.
PMCID: PMC4160853  PMID: 25221579
nerve regeneration; brain injury; Asiaticoside; apoptosis; N-methyl-D-aspartate; glutamate; neurotransmitter; neurotoxicity; calcium imaging; Bcl-2; Bax; NSFC grant; neural regeneration
21.  Targeting the Neddylation Pathway to Suppress the Growth of Prostate Cancer Cells: Therapeutic Implication for the Men's Cancer 
BioMed Research International  2014;2014:974309.
The neddylation pathway has been recognized as an attractive anticancer target in several malignancies, and its selective inhibitor, MLN4924, has recently advanced to clinical development. However, the anticancer effect of this compound against prostate cancer has not been well investigated. In this study, we demonstrated that the neddylation pathway was functional and targetable in prostate cancer cells. Specific inhibition of this pathway with MLN4924 suppressed the proliferation and clonogenic survival of prostate cancer cells. Mechanistically, MLN4924 treatment inhibited cullin neddylation, inactivated Cullin-RING E3 ligases (CRLs), and led to accumulation of tumor-suppressive CRLs substrates, including cell cycle inhibitors (p21, p27, and WEE1), NF-κB signaling inhibitor IκBα, and DNA replication licensing proteins (CDT1 and ORC1). As a result, MLN4924 triggered DNA damage, G2 phase cell cycle arrest, and apoptosis. Taken together, our results demonstrate the effectiveness of targeting the neddylation pathway with MLN4924 in suppressing the growth of prostate cancer cells, implicating a potentially new therapeutic approach for the men's cancer.
PMCID: PMC4100379  PMID: 25093192
22.  Gastric colonisation with a restricted commensal microbiota replicates the promotion of neoplastic lesions by diverse intestinal microbiota in the Helicobacter pylori INS-GAS mouse model of gastric carcinogenesis 
Gut  2013;63(1):54-63.
Gastric colonisation with intestinal flora (IF) has been shown to promote Helicobacter pylori (Hp)-associated gastric cancer. However, it is unknown if the mechanism involves colonisation with specific or diverse microbiota secondary to gastric atrophy.
Gastric colonisation with Altered Schaedler’s flora (ASF) and Hp were correlated with pathology, immune responses and mRNA expression for proinflammatory and cancer-related genes in germ-free (GF), Hp monoassociated (mHp), restricted ASF (rASF; 3 species), and specific pathogen-free (complex IF), hypergastrinemic INS-GAS mice 7 months postinfection.
Male mice cocolonised with rASFHp or IFHp developed the most severe pathology. IFHp males had the highest inflammatory responses, and 40% developed invasive gastrointestinal intraepithelial neoplasia (GIN). Notably, rASFHp colonisation was highest in males and 23% developed invasive GIN with elevated expression of inflammatory biomarkers. Lesions were less severe in females and none developed GIN. Gastritis in male rASFHp mice was accompanied by decreased Clostridum species ASF356 and Bacteroides species ASF519 colonisation and an overgrowth of Lactobacillus murinus ASF361, supporting that inflammation-driven atrophy alters the gastric niche for GI commensals. Hp colonisation also elevated expression of IL-11 and cancer-related genes, Ptger4 and Tgf-β, further supporting that Hp infection accelerates gastric cancer development in INS-GAS mice.
rASFHp colonisation was sufficient for GIN development in males, and lower GIN incidence in females was associated with lower inflammatory responses and gastric commensal and Hp colonisation. Colonisation efficiency of commensals appears more important than microbial diversity and lessens the probability that specific gastrointestinal pathogens are contributing to cancer risk.
PMCID: PMC4023484  PMID: 23812323
23.  Transdermal fentanyl for pain due to chemoradiotherapy-induced oral mucositis in nasopharyngeal cancer patients: evaluating efficacy, safety, and improvement in quality of life 
This study evaluated the efficacy, safety, and quality of life (QoL) measure of transdermal fentanyl (TDF) for moderate-to-severe pain due to oral mucositis caused by chemoradiotherapy in patients with advanced nasopharyngeal carcinoma (NPC). Patients with NPC who experienced moderate-to-severe oral mucosal pain during chemoradiotherapy (n=78) received TDF for pain relief. Pain relief and QoL were compared before and after treatment. The mean numeric rating scale score was reduced from 7.41±0.96 before treatment to 5.54±0.86, 3.27±0.73, 2.88±0.62, and 2.82±0.68 on days 1, 4, 7, and 10, respectively, after treatment (P<0.001). Karnofsky performance status and SPAASMS (Score for pain, Physical activity levels, Additional pain medication, Additional physician/emergency room visits, Sleep, Mood, and Side effects) scores showed significant improvement after treatment, indicating an improved QoL of patients (both P<0.001). The most common adverse reactions were nausea and vomiting (10.26%). No serious life-threatening adverse events and no symptoms of drug withdrawal were observed. TDF is effective, safe, and improves QoL in treating pain due to oral mucositis caused by chemoradiotherapy in NPC patients.
PMCID: PMC4026399  PMID: 24872680
nasopharyngeal cancer; transdermal fentanyl; noncancerous pain; quality of life; mucositis
24.  A Recombinant Hendra Virus G Glycoprotein Subunit Vaccine Protects Nonhuman Primates against Hendra Virus Challenge 
Journal of Virology  2014;88(9):4624-4631.
Hendra virus (HeV) is a zoonotic emerging virus belonging to the family Paramyxoviridae. HeV causes severe and often fatal respiratory and/or neurologic disease in both animals and humans. Currently, there are no licensed vaccines or antiviral drugs approved for human use. A number of animal models have been developed for studying HeV infection, with the African green monkey (AGM) appearing to most faithfully reproduce the human disease. Here, we assessed the utility of a newly developed recombinant subunit vaccine based on the HeV attachment (G) glycoprotein in the AGM model. Four AGMs were vaccinated with two doses of the HeV vaccine (sGHeV) containing Alhydrogel, four AGMs received the sGHeV with Alhydrogel and CpG, and four control animals did not receive the sGHeV vaccine. Animals were challenged with a high dose of infectious HeV 21 days after the boost vaccination. None of the eight specifically vaccinated animals showed any evidence of clinical illness and survived the challenge. All four controls became severely ill with symptoms consistent with HeV infection, and three of the four animals succumbed 8 days after exposure. Success of the recombinant subunit vaccine in AGMs provides pivotal data in supporting its further preclinical development for potential human use.
IMPORTANCE A Hendra virus attachment (G) glycoprotein subunit vaccine was tested in nonhuman primates to assess its ability to protect them from a lethal infection with Hendra virus. It was found that all vaccinated African green monkeys were completely protected against subsequent Hendra virus infection and disease. The success of this new subunit vaccine in nonhuman primates provides critical data in support of its further development for future human use.
PMCID: PMC3993805  PMID: 24522928
25.  Toll-like receptor 2 plays a critical role in cardiac dysfunction during polymicrobial sepsis 
Critical care medicine  2010;38(5):1335-1342.
To determine the role of toll-like receptor 2 in cardiac dysfunction during polymicrobial sepsis.
Controlled animal study.
University hospital research laboratory.
Male C57BL/6, wild-type, toll-like receptor 2−/−.
Polymicrobial peritonitis, a clinically relevant model of sepsis, was generated by cecum ligation and puncture. Wild-type and toll-like receptor 2−/− mice were divided into sham and cecum ligation and puncture groups. The sham animals underwent laparotomy but without cecum ligation and puncture. Twenty-four hours after surgeries, the cardiac function was assessed by serial echocardiography in vivo, a pressure transducer catheter was inserted into the left ventricles of isolated hearts (Langendorff model), and in vitro measurement of Ca2+ transients and sarcomere shortening in adult cardiomyocytes were isolated from the sham and septic animals. In addition, myocardial and serum cytokines, blood white blood cell counts, peritoneal neutrophil recruitment, chemokine receptor expression, and survival rates were examined.
Measurements and Results
Compared to septic wild-type mice, toll-like receptor 2−/− mice had markedly improved cardiac function during sepsis, as demonstrated by in vivo tissue Doppler imaging, better-preserved left ventricle function in isolated heart, and improved sarcomere shortening measured in single cardiomyocytes. There was also a significant survival benefit in toll-like receptor 2−/− mice compared to wild-type mice. These favorable outcomes in toll-like receptor 2−/− mice were associated with attenuated cardiodepressant cytokine levels in the myocardium and serum and enhanced neutrophil migratory function.
These studies suggest that toll-like receptor 2 signaling plays a critical role in mediating cardiomyopathy, deleterious myocardial and systemic inflammation, and high mortality during polymicrobial sepsis.
PMCID: PMC3997231  PMID: 20228680
Toll-like receptor 2; sepsis; cardiac dysfunction; inflammation; neutrophils

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