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1.  Synthesis and evaluation of cyclic cationic polymers for nucleic acid delivery 
ACS macro letters  2013;2(12):10.1021/mz400560y.
doi:10.1021/mz400560y
PMCID: PMC3881557  PMID: 24409400
2.  Curcumin suppresses invasiveness and vasculogenic mimicry of squamous cell carcinoma of the larynx through the inhibition of JAK-2/STAT-3 signaling pathway 
To determine the role of JAK-2/STAT-3 signaling pathway in invasion and vasculogenic mimicry of laryngeal squamous cell carcinoma. HEp-2 cells were treated with 1 or 10 μmol/L curcumin and AG490 (the inhibitor of JAK-2) for 48 h, the invasion and vasculogenic mimicry of tumor cells were tested with Transwell chamber test and tube formation experiment. RT-PCR was used to measure the expression of MMP-2 and VEGF. Western blot assay was employed to determine the expression of JAK-2, STAT3, p-STAT3, MMP-2 and VEGF. Compared to control group,there were less tumor cells permeating membrane and less formed tubes after curcumin or AG490 treatment, RT-PCR showed that the expression of MMP-2 and VEGF at mRNA level were decreased (P < 0.01). Western blotting indicated that the expression of JAK-2, p-STAT3, MMP-2 and VEGF at protein levels were decreased (P < 0.01), while that of STAT-3 protein had no difference among each group (P > 0.05). Immunofluorescence staining demonstrated that the expression of eNOS was down-regulated (P < 0.01). Curcumin and AG490 significantly inhibits invasion and vasculogenic mimicry of laryngeal squamous cell carcinoma in vitro, and JAK-2/STAT-3 signaling pathway promotes above processes.
PMCID: PMC4300723  PMID: 25628937
Laryngeal squamous cell carcinoma; curcumin; JAK-2/STAT-3 signaling pathway; vasculogenic mimicry
3.  P2X7 Mediates ATP-Driven Invasiveness in Prostate Cancer Cells 
PLoS ONE  2014;9(12):e114371.
The ATP-gated P2X7 has been shown to play an important role in invasiveness and metastasis of some tumors. However, the possible links and underlying mechanisms between P2X7 and prostate cancer have not been elucidated. Here, we demonstrated that P2X7 was highly expressed in some prostate cancer cells. Down-regulation of P2X7 by siRNA significantly attenuated ATP- or BzATP-driven migration and invasion of prostate cancer cells in vitro, and inhibited tumor invasiveness and metastases in nude mice. In addition, silencing of P2X7 remarkably attenuated ATP- or BzATP- driven expression changes of EMT/invasion-related genes Snail, E-cadherin, Claudin-1, IL-8 and MMP-3, and weakened the phosphorylation of PI3K/AKT and ERK1/2 in vitro. Similar effects were observed in nude mice. These data indicate that P2X7 stimulates cell invasion and metastasis in prostate cancer cells via some EMT/invasion-related genes, as well as PI3K/AKT and ERK1/2 signaling pathways. P2X7 could be a promising therapeutic target for prostate cancer.
doi:10.1371/journal.pone.0114371
PMCID: PMC4259308  PMID: 25486274
4.  Large-scale genetic study in East Asians identifies six new loci associated with colorectal cancer risk 
Nature genetics  2014;46(6):533-542.
Known genetic loci explain only a small proportion of the familial relative risk of colorectal cancer (CRC). We conducted the largest genome-wide association study in East Asians with 14,963 CRC cases and 31,945 controls and identified six new loci associated with CRC risk (P = 3.42 × 10−8 to 9.22 × 10−21) at 10q22.3, 10q25.2, 11q12.2, 12p13.31, 17p13.3 and 19q13.2. Two of these loci map to genes (TCF7L2 and TGFB1) with established roles in colorectal tumorigenesis. Four other loci are located in or near genes involved in transcription regulation (ZMIZ1), genome maintenance (FEN1), fatty acid metabolism (FADS1 and FADS2), cancer cell motility and metastasis (CD9) and cell growth and differentiation (NXN). We also found suggestive evidence for three additional loci associated with CRC risk near genome-wide significance at 8q24.11, 10q21.1 and 10q24.2. Furthermore, we replicated 22 previously reported CRC loci. Our study provides insights into the genetic basis of CRC and suggests new biological pathways.
doi:10.1038/ng.2985
PMCID: PMC4068797  PMID: 24836286
5.  Aaptamine Derivatives with Antifungal and Anti-HIV-1 Activities from the South China Sea Sponge Aaptos aaptos 
Marine Drugs  2014;12(12):6003-6013.
Five new alkaloids of aaptamine family, compounds (1–5) and three known derivatives (6–8), have been isolated from the South China Sea sponge Aaptos aaptos. The structures of all compounds were unambiguously elucidated by spectroscopic analyses, as well as by comparison with the literature data. Compounds 1–2 are characterized with triazapyrene lactam skeleton, whereas compounds 4–5 share an imidazole-fused aaptamine moiety. These compounds were evaluated in antifungal and anti-HIV-1 assays. Compounds 3, 7, and 8 showed antifungal activity against six fungi, with MIC values in the range of 4 to 64 μg/mL. Compounds 7–8 exhibited anti-HIV-1 activity, with inhibitory rates of 88.0% and 72.3%, respectively, at a concentration of 10 μM.
doi:10.3390/md12126003
PMCID: PMC4278215  PMID: 25532563
Aaptos aaptos; aaptamine; antifungal; anti-HIV-1 activity
6.  Searching the Cytochrome P450 Enzymes for the Metabolism of Meranzin Hydrate: A Prospective Antidepressant Originating from Chaihu-Shugan-San 
PLoS ONE  2014;9(11):e113819.
Meranzin hydrate (MH), an absorbed bioactive compound from the Traditional Chinese Medicine (TCM) Chaihu-Shugan-San (CSS), was first isolated in our laboratory and was found to possess anti-depression activity. However, the role of cytochrome P450s (CYPs) in the metabolism of MH was unclear. In this study, we screened the CYPs for the metabolism of MH in vitro by human liver microsomes (HLMs) or human recombinant CYPs. MH inhibited the enzyme activities of CYP1A2 and CYP2C19 in a concentration-dependent manner in the HLMs. The Km and Vmax values of MH were 10.3±1.3 µM and 99.1±3.3 nmol/mg protein/min, respectively, for the HLMs; 8.0±1.6 µM and 112.4±5.7 nmol/nmol P450/min, respectively, for CYP1A2; and 25.9±6.6 µM and 134.3±12.4 nmol/nmol P450/min, respectively, for CYP2C19. Other human CYP isoforms including CYP2A6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4 showed minimal or no effect on MH metabolism. The results suggested that MH was simultaneously a substrate and an inhibitor of CYP1A2 and CYP2C9, and MH had the potential to perpetrate drug-drug interactions with other CYP1A2 and CYP2C19 substrates.
doi:10.1371/journal.pone.0113819
PMCID: PMC4245237  PMID: 25427198
7.  DCE-MRI assessment of the effect of Epstein-Barr virus-encoded latent membrane protein-1 targeted DNAzyme on tumor vasculature in patients with nasopharyngeal carcinomas 
BMC Cancer  2014;14(1):835.
Background
EBV-encoded latent membrane protein 1 (EBV-LMP1) is an important oncogenic protein for nasopharyngeal carcinoma (NPC) and has been shown to engage a plethora of signaling pathways. Correspondingly, an LMP1-targeted DNAzyme was found to inhibit the growth of NPC cells both in vivo and in vitro by suppressing cell proliferation and inducing apoptosis. However, it remains unknown whether an LMP1-targeted DNAzyme would affect the vasculature of NPC. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been applied in the clinical trials of anti-angiogenic drugs for more than ten years, and Ktrans has been recommended as a primary endpoint. Therefore, the objective of the current study was to use DCE-MRI to longitudinally study the effect of an EBV-LMP1-targeted DNAzyme on the vasculature of patients with NPC.
Methods
Twenty-four patients were randomly divided into two groups: a combined treatment group (radiotherapy + LMP1-targeted DNAzyme) and a radiotherapy alone group (radiotherapy + normal saline). DCE-MRI scans were conducted 1 ~ 2 days before radiotherapy (Pre-RT), during radiotherapy (RT 50 Gy), upon completion of radiotherapy (RT 70 Gy), and three months after radiotherapy (3 months post-RT). Parameters of vascular permeability and intra- and extravascular volumes were subsequently obtained (e.g., Ktrans, kep, ve) using nordicICE software.
Results
Both Ktrans and kep values for NPC tumor tissues decreased for both groups after treatment. Moreover, a statistically significant difference in Ktrans values at the pre-therapy and post-therapy timepoints emerged earlier for the combined treatment group (RT 50 Gy, P =0.045) compared to the radiotherapy alone group (3 months post-RT, P = 0.032). For the kep values, the downward trend observed for both the combined treatment group and the radiotherapy alone group were similar. In contrast, ve values for all of the tumor tissues increased following therapy.
Conclusions
The EBV-LMP1-targeted DNAzyme that was tested was found to accelerate the decline of Ktrans values for patients with NPC. Correspondingly, the LMP1-targeted DNAzyme treatments were found to affect the angiogenesis and microvascular permeability of NPC.
Trial registration
ClinicalTrials.gov: NCT01449942. Registered 6 October 2011.
doi:10.1186/1471-2407-14-835
PMCID: PMC4246516  PMID: 25407966
Nasopharyngeal neoplasm; Epstein-Barr virus encoded latent membrane protein-1; Magnetic resonance imaging; Dynamic contrast-enhanced magnetic resonance imaging; Molecular therapy; DNAzyme
8.  An integrated approach for genome annotation of the eukaryotic thermophile Chaetomium thermophilum 
Nucleic Acids Research  2014;42(22):13525-13533.
The thermophilic fungus Chaetomium thermophilum holds great promise for structural biology. To increase the efficiency of its biochemical and structural characterization and to explore its thermophilic properties beyond those of individual proteins, we obtained transcriptomics and proteomics data, and integrated them with computational annotation methods and a multitude of biochemical experiments conducted by the structural biology community. We considerably improved the genome annotation of Chaetomium thermophilum and characterized the transcripts and expression of thousands of genes. We furthermore show that the composition and structure of the expressed proteome of Chaetomium thermophilum is similar to its mesophilic relatives. Data were deposited in a publicly available repository and provide a rich source to the structural biology community.
doi:10.1093/nar/gku1147
PMCID: PMC4267624  PMID: 25398899
9.  Development of 107 SSR markers from whole genome shotgun sequences of Chinese bayberry (Myrica rubra) and their application in seedling identification* #  
Chinese bayberry (Myrica rubra Sieb. et Zucc.) is one of the important subtropical fruit crops native to the South of China and Asian countries. In this study, 107 novel simple sequence repeat (SSR) molecular markers, a powerful tool for genetic diversity studies, cultivar identification, and linkage map construction, were developed and characterized from whole genome shotgun sequences. M13 tailing for forward primers was applied as a simple method in different situations. In total, 828 alleles across 45 accessions were detected, with an average of 8 alleles per locus. The number of effective alleles ranged from 1.22 to 10.41 with an average of 4.08. The polymorphic information content (PIC) varied from 0.13 to 0.89, with an average of 0.63. Moreover, these markers could also be amplified in their related species Myrica cerifera (syn. Morella cerifera) and Myrica adenophora. Seventy-eight SSR markers can be used to produce a genetic map of a cross between ‘Biqi’ and ‘Dongkui’. A neighbor-joining (NJ) tree was constructed to assess the genetic relationships among accessions, and the elite accessions ‘Y2010-70’, ‘Y2012-140’, and ‘Y2012-145’, were characterized as potential new genotypes for cultivation.
doi:10.1631/jzus.B1400051
PMCID: PMC4228512  PMID: 25367792
Chinese bayberry; Simple sequence repeat (SSR); Genetic diversity
10.  Association of BRCA2 N372H polymorphism with cancer susceptibility: A comprehensive review and meta-analysis 
Scientific Reports  2014;4:6791.
BRCA2 gene plays an important role in homologous recombination. Polymorphic variants in this gene has been suggested to confer cancer susceptibility. Numerous studies have investigated association between BRCA2 N372H polymorphism and risk of several cancers, especially breast cancer. However, the results were inconsistent. We performed a comprehensive meta-analysis to provide a more precise assessment of the association between N372H and cancer risk, following the latest meta-analysis guidelines (PRISMA). Forty six studies involving 36299 cases and 48483 controls were included in our meta-analysis. The crude ORs and the 95% CIs were used to evaluate the strength of the association. The results indicated that the BRCA2 N372H variant was significantly associated with an increased risk of overall cancer (dominant model: OR = 1.07, 95% CI = 1.01–1.13; recessive model: OR = 1.12, 95% CI = 1.02–1.23). Moreover, stratified analyses by the cancer type and source of control observed significantly increased risk associated with BRCA2 N372H in subgroups with ovarian cancer, non-Hodgkin lymphoma and population-based controls, but not breast cancer or hospital-based controls. We also found such association among Africans. Overall, the meta-analysis suggested that BRCA2 N372H may be a cancer susceptibility polymorphism. Well-designed and large-scale studies are needed to substantiate the association between BRCA2 N372H polymorphism and cancer risk.
doi:10.1038/srep06791
PMCID: PMC4210867  PMID: 25348552
11.  iBrick: A New Standard for Iterative Assembly of Biological Parts with Homing Endonucleases 
PLoS ONE  2014;9(10):e110852.
The BioBricks standard has made the construction of DNA modules easier, quicker and cheaper. So far, over 100 BioBricks assembly schemes have been developed and many of them, including the original standard of BBF RFC 10, are now widely used. However, because the restriction endonucleases employed by these standards usually recognize short DNA sequences that are widely spread among natural DNA sequences, and these recognition sites must be removed before the parts construction, there is much inconvenience in dealing with large-size DNA parts (e.g., more than couple kilobases in length) with the present standards. Here, we introduce a new standard, namely iBrick, which uses two homing endonucleases of I-SceI and PI-PspI. Because both enzymes recognize long DNA sequences (>18 bps), their sites are extremely rare in natural DNA sources, thus providing additional convenience, especially in handling large pieces of DNA fragments. Using the iBrick standard, the carotenoid biosynthetic cluster (>4 kb) was successfully assembled and the actinorhodin biosynthetic cluster (>20 kb) was easily cloned and heterologously expressed. In addition, a corresponding nomenclature system has been established for the iBrick standard.
doi:10.1371/journal.pone.0110852
PMCID: PMC4203835  PMID: 25329380
12.  Effect of atorvastatin on the expression of gamma-glutamyl transferase in aortic atherosclerotic plaques of apolipoprotein E–knockout mice 
Background
Gamma-glutamyl transpeptidase (GGT) is now considered to be one of the risk factors for cardiovascular disease. However, whether statins can alter GGT levels in arterial atheromatous plaque has not yet been studied. Therefore, the aim of this study is to determine whether statins can effectively decrease the expression of GGT in arterial atheromatous plaques.
Methods
We randomly divided 45 apolipoprotein E–knockout (ApoE KO) male mice into three groups: normal diet (ND) group,high-cholesterol diet (HCD) group and high-cholesterol diet and atorvastatin (HCD + Ato) group. We fed high-cholesterol food to the HCD and HCD + Ato group. After eight weeks, atorvastatin 5 mg•kg−1•d−1 was given to HCD + Ato group mice. The serum GGT-1, intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell-adhesion molecule-1 (VCAM-1) levels were measured at end of 16 weeks by using ELISA methods. The expressions of GGT-1, ICAM-1 and VCAM-1 in aorta were measured by RT-PCR and Western Blot.
Results
The ApoE KO mice with HCD were associated with a marked increase in plasma lipid, inflammatory factors, GGT-1, ICAM-1 and VCAM-1. The expressions of GGT-1, ICAM-1 and VCAM-1 in HCD aortic tissue were increased. At the HCD + Ato group were treated with atorvastatin, the levels of lipid, GGT-1, ICAM-1 and VCAM-1were suppressed. Meanwhile, the expressions of GGT-1, ICAM-1 and VCAM-1 were significantly decreased in the whole aorta plaques.
Conclusions
The effect of statins on the expression of GGT in aorta plaque was firstly observed in animal model. The research shows that statins can significantly decrease the expression of GGT in aortic atherosclerotic plaques.
doi:10.1186/1471-2261-14-145
PMCID: PMC4210575  PMID: 25326709
Statins; Atherosclerosis; Gamma-glutamyltransferase; Inflammation
13.  Comparison of Long-Term Survival and Toxicity of Cisplatin Delivered Weekly versus Every Three Weeks Concurrently with Intensity-Modulated Radiotherapy in Nasopharyngeal Carcinoma 
PLoS ONE  2014;9(10):e110765.
Background
We aimed to compare the long-term survival outcomes and acute toxicity of cisplatin administered weekly versus every three weeks concurrently with intensity-modulated radiotherapy (IMRT) in patients with nasopharyngeal carcinoma (NPC).
Methods
This was a retrospective review of 154 patients with histologically proven, non-disseminated NPC who were treated using IMRT between January 2003 and December 2007. Seventy-three patients (47.4%) received 5–7 weeks of 30–40 mg/m2 cisplatin weekly; 81 patients (52.6%) received two or three cycles of 80 mg/m2 cisplatin every three weeks. IMRT was delivered at 68 Gy/30 fractions to the nasopharyngeal gross target volume and 60–66 Gy to the involved neck area.
Results
The clinical characteristics and treatment factors of the two groups were well-balanced. The median follow-up was 74 months (range, 6–123 months), and the 5-year overall survival, disease-free survival, locoregional relapse-free survival, and distant metastasis–free survival rates were 85.2% vs. 78.9% (P = 0.318), 71.6% vs. 71.0% (P = 0.847), 93.5% vs. 92.6% (P = 0.904), and 80.9% vs. 80.1% (P = 0.925) for the group treated every three weeks and weekly, respectively. Subgroup analyses indicated no significant differences in the survival rates of the two groups among patients with early- or advanced-stage disease. The incidence of acute toxicities was similar between groups.
Conclusion
IMRT with concurrent cisplatin administered weekly or every three weeks leads to similar long-term survival outcomes and acute toxicity in NPC regardless of whether patients have early- or advanced-stage disease.
doi:10.1371/journal.pone.0110765
PMCID: PMC4199726  PMID: 25329593
14.  Successful treatment of refractory gastric antral vascular ectasia by distal gastrectomy: A case report 
World Journal of Gastroenterology : WJG  2014;20(38):14073-14075.
Gastric antral vascular ectasia (GAVE) is an uncommon and often neglected cause of gastric hemorrhage. The treatments for GAVE include surgery, endoscopy and medical therapies. Here, we report an unusual case of GAVE. A 72-year-old man with a three-month history of recurrent melena was diagnosed with GAVE. Endoscopy revealed the classical “watermelon stomach” appearance of GAVE and complete pyloric involvement. Melena reoccurred three days after argon plasma coagulation treatment, and the level of hemoglobin dropped to 47 g/L. The patient was then successfully treated with distal gastrectomy with Billroth II anastomosis. We propose that surgery should be considered as an effective option for GAVE patients with extensive and severe lesions upon deterioration of general conditions and hemodynamic instability.
doi:10.3748/wjg.v20.i38.14073
PMCID: PMC4194595  PMID: 25320549
Gastric antral vascular ectasia; Melena; Distal gastrectomy; Argon plasma coagulation; Endoscopic band ligation
15.  miR-21 and miR-375 microRNAs as candidate diagnostic biomarkers in squamous cell carcinoma of the larynx: association with patient survival 
The dismal outcome of laryngeal squamous cell carcinoma (SCC) patients highlights the need for novel prognostic biomarkers. The involvement of microRNAs in cancer and their potential as biomarkers of diagnosis and prognosis are becoming increasingly appreciated. We sought to identify microRNAs that exhibit altered expression in laryngeal SCC and to determine whether microRNA (miRNA) expression is predictive of disease progression and/or patient survival. The expression of two miRNAs, miR-21 and miR-375, was evaluated using total RNA isolated from freshly-frozen primary tumors and non-cancerous laryngeal squamous epithelial tissues and quantitative real-time polymerase chain reaction (qRT-PCR) analysis. We further analyzed the association between the expression of miRNAs and the clinicopathological features. A marked difference in the microRNA expression pattern was observed between tumors and non-cancerous tissue. MiR-21 and miR-375 were expressed at higher and lower levels, respectively, in the laryngeal SCC samples, compared to the normal samples (p < 0.01 and p < 0.001, respectively). There was no correlation between characteristics such as age, sex, clinical stage, and alcohol use, and the expression level of mir-21. The relative expression of mir-375 in laryngeal SCC was shown to be associated with localization of the tumor in these patients (p = 0.037) and with alcohol use (p < 0.05). Patients with high miR-21 or low miR-375 expression in tumor tissues had poorer prognoses compared to patients with lower miR-21 or higher miR-375 expression. Furthermore, the miR-21/miR-375 expression ratio was highly sensitive (0.94) and specific (0.94) for disease prediction. These data suggest that the pattern of microRNA expression in primary laryngeal SCC tissues is reflective of the disease status and that miR-21 and miR-375 expression levels, in particular, may serve as potential biomarkers with applications in the clinical setting.
PMCID: PMC4212934  PMID: 25360224
Laryngeal squamous cell carcinoma; microRNA; biomarker; prognosis
16.  Up-regulation of hexokinase1 in the right ventricle of monocrotaline induced pulmonary hypertension 
Respiratory Research  2014;15(1):119.
Background
Pulmonary arterial hypertension (PAH) is a proliferative arteriopathy associated with a glycolytic shift during heart metabolism. An increase in glycolytic metabolism can be detected in the right ventricle during PAH. Expression levels of glycolysis genes in the right ventricle during glycolysis that occur in monocrotaline (MCT)-induced pulmonary hypertension (PH) remain unknown.
Methods
PH was induced by a single subcutaneous injection of MCT (50 mg/kg) into rats, eventually causing right heart failure. Concurrently, a control group was injected with normal saline. The MCT-PH rats were randomly divided into three groups according to MCT treatment: MCT-2 week, 3 week, and 4 week groups (MCT-2w, 3w, 4w). At the end of the study, hemodynamics and right ventricular hypertrophy were compared among experimental groups. Expression of key glycolytic candidate genes was screened in the right ventricle.
Results
We observed an increase in mean pulmonary arterial pressure, right ventricular systolic pressure and right ventricular hypertrophy index three weeks following MCT injection. Alterations in the morphology and structure of right ventricular myocardial cells, as well as the pulmonary vasculature were observed. Expression of hexokinase 1 (HK1) mRNA began to increase in the right ventricle of the MCT-3w group and MCT-4w group, while the expression of lactate dehydrogenase A (LDHA) was elevated in the right ventricle of the MCT-4w group. Hexokinase 2(HK2), pyruvate dehydrogenase complex α1 (PDHα1), and LDHA mRNA expression showed no changes in the right ventricle. HK1 mRNA expression was further confirmed by HK1 protein expression and immunohistochemical analyses. All findings underlie the glycolytic phenotype in the right ventricle.
Conclusions
There was an increase in the protein and mRNA expression of hexokinase-1 (HK1) three and four weeks after the injection of monocrotaline in the right ventricle, intervention of HK1 may be amenable to therapeutic intervention.
doi:10.1186/s12931-014-0119-9
PMCID: PMC4198683  PMID: 25287584
Pulmonary hypertension; Right heart failure; Glycolysis; Hexokinase 1
17.  Selective ligands of estrogen receptor β discovered using pharmacophore mapping and structure-based virtual screening 
Acta Pharmacologica Sinica  2014;35(10):1333-1341.
Aim:
To discover novel ligands of estrogen receptor (ER) β using pharmacophore mapping and structure-based screening.
Methods:
A computer-aided strategy combining pharmacophore mapping and structure-based screening was used to screen the Maybridge and Enamine databases. Yeast two-hybrid (Y2H) assay was used to detect the activity and selectivity of the chosen compounds. The transcriptional activities of the chosen compounds were demonstrated with luciferase reporter assays. The anti-proliferative effects of ER antagonists against MCF-7 and MDA-MB-231 breast cancer cells were examined using MTT assay, and the mechanisms of action were analyzed with flow cytometry analysis and Western blotting.
Results:
Through in silico screen, 95 compounds were chosen for testing in Y2H assay, which led to 20 potent ligands, including 10 agonists, 8 antagonists and 2 partial agonists with EC50 or IC50 values at μmol/L. Furthermore, 6 agonists exhibited absolute selectivity for ERβ, and 3 agonists showed higher selectivity for ERβ. The agonists 1g and 1h (10, 25, and 50 μmol/L) dose-dependently increased ER transcriptional activities, whereas the antagonists 2a and 2d (10, 25, and 50 μmol/L) caused dose-dependent inhibition on the activities. The antagonists and partial agonists at 100 μmol/L suppressed the proliferation of ERα positive MCF-7 cells and ERβ positive MDA-MB-231 cells, but were more effective against MDA-MB-231 cells. Treatment of MDA-MB-231 cells with antagonists 2a and 2d (25 and 50 μmol/L) dose-dependently increased the population of cells in the S phase. Both 2a and 2d treatment dose-dependently decreased the expression levels of cyclin A and CDK2. Meanwhile, the downregulation of cyclin E was only caused by 2d, while 2a treatment did not cause significant changes in the protein levels of cyclin E.
Conclusion:
The selective ligands discovered in this study are promising drug candidates to be used as molecular probes to explore the differences between ERα and ERβ.
doi:10.1038/aps.2014.69
PMCID: PMC4186986  PMID: 25176400
estrogen receptor; subtype-selective ligand; estradiol; tamoxifen; pharmacophore mapping; structure-based virtual screening; breast cancer; anti-proliferation; cell cycle arrest
18.  Clostridium difficile carriage in hospitalized cancer patients: a prospective investigation in eastern China 
BMC Infectious Diseases  2014;14(1):523.
Background
Clostridium difficile carriage has been considered as a potential source for the deadly infection, but its role in cancer patients is still unclear. We aimed to identify the clinical and immunological factors that are related to C. difficile carriage in Chinese cancer patients.
Methods
A total of 400 stool samples were collected from cancer patients who received chemotherapy in three hospitals of eastern China. Bacterial genomic DNA was extracted and two toxin genes (tcdA and tcdB) were detected. PCR ribotyping was performed using capillary gel electrophoresis. Concentrations of prostaglandin E2 (PGE2), transforming growth factor beta (TGF-β) and interleukin-10 (IL-10) were measured using enzyme-linked immunosorbent assay (ELISA) kits.
Results
Eighty-two (20.5%) samples were confirmed to be C. difficile-positive and positive for tpi, tcdA, and tcdB genes. The C. difficile-positive rates in patients with diarrhea and no diarrhea were 35% and 19.7%, respectively (p = 0.09). Patients who were younger than 50 years old and were hospitalized for at least 10 days had a C. difficile-positive rate as high as 35%. In contrast, patients who were older than 50 years old and were hospitalized for less than 10 days had a C. difficile-positive rate of only 12.7% (p = 0.0009). No association was found between C. difficile carriage and chemotherapy regimen, antibiotic drug use, or immunosuppressive mediators, such as prostaglandin E2 (PGE2), transforming growth factor beta (TGF-β), or interleukin-10 (IL-10). Twelve ribotypes of C. difficile were identified, but none of them belonged to ribotype 027.
Conclusions
We conclude that younger patients and those with longer hospitalization stays may be more prone to C. difficile carriage. Studies of larger populations are warranted to clarify the exact role of C. difficile carriage in hospitalized cancer patients in China.
doi:10.1186/1471-2334-14-523
PMCID: PMC4261591  PMID: 25267108
Clostridium difficile; Carriage; Age; Hospitalization days
19.  Modified technique of renal pedicle lymphatic disconnection for chyluria through the laparoscopic surgery 
Fifteen cases of chyluria were diagnosed by Sudan staining test and the sides of chylous reflux were determined by cystoscopy. All patients underwent the modified laparoscopic technique. The operations had been successfully without unexpected injury. The postoperative urine chyle tests were negative in all patients. Recurrence developed in 1 patient during the follow-up. The modified technique does not require complete disconnection of perirenal fat tissue and fasciectomy diminishing necessity of nephropexy and preventing renal torsion. It is a feasible and effective surgical procedure for chyluria with a short operation time, minimal invasion and few complications.
PMCID: PMC4211809  PMID: 25356159
Chyluria; laparoscopy; renal lymphatic vessels disconnection
20.  Expression of annexin A7 and its clinical significance in differentiation and metastasis of gastric carcinoma 
Objective: To investigate the expression and clinical significance of annexin A7 in the differentiation and lymphatic metastasis of gastric cancer (GC). Methods: The clinical and pathological data were recorded for analysis. Immunohistochemical staining and Western blot were performed to analyze the expression of ANXA 7 in primary GC tissues. Logistic regression analyses were conducted to evaluate the associations between annexin A7 expression levels and differentiations of GC. Analyses of the ROC were conducted to determine the cut-off value of the ratio of pixel density of annexin A7 for predicting lymphatic metastasis of GC. Results: A total of 162 GC patients were enrolled in this study, and expression rate of annexin A7 was 65.4% in GC. The survival rate of patients with positive expression of annexin A7 was lower than that in patients with negative expression (P=0.000). The results of COX regression showed that the positive expression of annexin A7, submucosal confinement and pathological stage of GC were associated with poor clinical outcomes. The ratio of pixel density value of primary GC tissues with PN 1-3 lymphatic spread was significantly higher than those in tissues with PN 0 lymphatic spread (0.56±0.09 vs. 0.42±0.07, P < 0.05). ROC analysis showed a high area under the curve for the ratio of pixel density value of annexin A7 in primary GC tissues. At a cut-off level of > 0.505, the ratio of pixel density value of annexin A7 exhibited 76.7% sensitivity and 88.3% specificity for detecting lymphatic metastasis of GC. Conclusion: High annexin A7 expression is associated with poor differentiation in GC patients, and it may be a predictor for lymphatic metastasis of GC.
PMCID: PMC4230099  PMID: 25400735
Annexin A7; gastric cancer; cancer differentiation; lymphatic metastasis; predictor
21.  Hydrogen-Rich Saline Inhibits NLRP3 Inflammasome Activation and Attenuates Experimental Acute Pancreatitis in Mice 
Mediators of Inflammation  2014;2014:930894.
Increasing evidence has demonstrated that reactive oxygen species (ROS) induces oxidative stress and plays a crucial role in the pathogenesis of acute pancreatitis (AP). Hydrogen-rich saline (HRS), a well-known ROS scavenger, has been shown to possess therapeutic benefit on AP in many animal experiments. Recent findings have indicated that the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome, an intracellular multiprotein complex required for the maturation of interleukin- (IL-) 1β, may probably be a potential target of HRS in the treatment of AP. Therefore, in this study, we evaluated the activation of NLRP3 inflammasome and meanwhile assessed the degree of oxidative stress and inflammatory cascades, as well as the histological alterations in mice suffering from cerulein-induced AP after the treatment of HRS. The results showed that the activation of NLRP3 inflammasome in AP mice was substantially inhibited following the administration of HRS, which was paralleled with the decreased NF-κB activity and cytokines production, attenuated oxidative stress and the amelioration of pancreatic tissue damage. In conclusion, our study has, for the first time, revealed that inhibition of the activation of NLRP3 inflammasome probably contributed to the therapeutic potential of HRS in AP.
doi:10.1155/2014/930894
PMCID: PMC4158121  PMID: 25214720
22.  Identification of potential anticancer compounds from Oplopanax horridus 
Oplopanax horridus is a plant native to North America. Previous reports have demonstrated that this herb has antiproliferative effects on cancer cells but study mostly focused on its extract or fractions. Because there has been limited phytochemical study on this herb, its bioactive compounds are largely unknown. We recently isolated and identified 13 compounds, including six polyynes, three sesquiterpenes, two triterpenoids, and two phenolic acids, of which five are novel compounds. In this study, we systemically evaluated the anticancer effects of compounds isolated from O. horridus. Their antiproliferative effects on a panel of human colorectal and breast cancer cells were determined using the MTS assay. Cell cycle distribution and apoptotic effects were analyzed by flow cytometry. The in vivo antitumor effect was examined using a xenograft tumor model. Among the 13 compounds, strong antiproliferative effects were observed from falcarindiol and a novel compound oplopantriol A. Falcarindiol showed the most potent antiproliferative effects, significantly inducing pro-apoptosis and cell cycle arrest in the S and G2/M phases. The anticancer potential of falcarindiol was further verified in vivo, significantly inhibiting HCT-116 tumor growth in an athymic nude mouse model at 15 mg/kg. We also analyzed the relationship between polyyne structures and their pharmacological activities. We observed that both the terminal hydroxyl group and double bond obviously affected their anticancer potential. Results from this study supplied valuable information for future semi-synthesis of polyyne derivatives to develop novel cancer chemopreventive agents.
doi:10.1016/j.phymed.2013.04.013
PMCID: PMC3729876  PMID: 23746754
Oplopanax horridus; Phytochemistry; Polyynes; Oplopantriol A; Falcarindiol; Anticancer; Cell cycle; Apoptosis; Structure-activity relationship
23.  Embryonal rhabdomyosarcoma of the paranasal sinuses: a case report and review of literature 
Embryonal rhabdomyosarcoma (ERMS) is a rare malignancy with a poor outcome. In this article, we describe a case of ERMS in the paranasal sinuses from a 60-year-old male patient. ERMS derived from the paranasal sinuses is extremely rare. The diagnosis of ERMS must be based on histological findings and immunohistochemical findings. In this case, microscopic observation showed tumor cells were arranged in flocked sheets, cord-like and acinar-like by hyperplastic fibrous tissue. And ERMS tissues were immunopositive for myogenin, desmin, MSA, CD56, vimentin, CD99, Syn and Ki-67 (40%+), and immunonegative for CK, EMA, LCA, GFAP, NSE, S-100, HMB-45 and Melan-A. Here, the patient was treated with multimodal therapy including endoscopic surgery, chemotherapy and radiation, but the patient’s postoperative recovery is not too smooth.
PMCID: PMC4161599  PMID: 25232439
Embryonal rhabdomyosarcoma; paranasal sinuses; immunohistochemistry
24.  A four actin-binding protein signature model for poor prognosis of patients with esophageal squamous cell carcinoma 
The actin cytoskeleton is a dynamic structure with actin-binding proteins (ABPs) playing an essential role in the regulation of migration, differentiation and signal transduction in all eukaryotic cells. We examined the relationship between altered expression of four ABPs and clinical parameters in esophageal squamous cell carcinoma (ESCC). To this end, we analyzed 152 formalin-fixed and paraffin-embedded esophageal curative resection specimens by immunohistochemistry for tensin, profilin-1, villin-1 and talin. A molecular predictor model, based on the combined expression of the four proteins, was developed to correlate the expression pattern of the four ABPs with clinical factors and prognosis of ESCC. According to the results, weak significance was found for tensin in lymph node metastasis (P=0.033), and profilin-1 in pTNM stage (P=0.031). However, our four-protein model showed strong correlation with the 5-year overall survival rate (P=0.002). Similarly, Kendall’s tau-b test also showed the relationship between the collective expression pattern of the four ABPs with lymph node metastasis (P=0.005) and pTNM stage (P=0.001). Our results demonstrate that the collective protein expression pattern of four actin-binding proteins could be a biomarker to estimate the prognosis of ESCC patients.
PMCID: PMC4203210  PMID: 25337239
Actin-binding protein; a molecular prognostic model; prognosis; esophageal squamous cell carcinoma
25.  Human leukocyte antigen-DRB1*1501 and DQB1*0602 alleles are cervical cancer protective factors among Uighur and Han people in Xinjiang, China 
Human papillomavirus (HPV) infection is a major risk factor for cervical cancer. However, only some high risk human papillomavirus (HR-HPV)-infected women progress to cervical cancer, host immunogenetic factors human leukocyte antigen (HLA) may account for viral antigens presenting individually or together in the progression to cervical cancer. This study examined the association between the development of invasive cervical cancer (ICC) and the determinant factors including HLA-DRB1*1501 and DQB1*0602, HR-HPV infection among Chinese Uighur and Han populations. Blood samples, cervical swabs and biopsies were obtained from 287 patients with ICC (192 Uighurs and 95 Hans) and 312 healthy controls (218 Uighurs and 94 Hans). HPV DNA was detected by PCR and HLA-DRB1*1501 and DQB1*0602 alleles were performed using PCR-SSP method. HPV16 infection rates was significantly higher among Uighur and Han with ICC as compared to healthy controls (OR = 58.317; 95% CI: 39.663-85.744; OR = 33.778; 95% CI: 12.581-90.691; P < 0.05 for all). HLA-DRB1*1501 (OR = 0.305; 95% CI: 0.115-0.813; P < 0.05) and HLA-DRB1*1501-DQB1*0602 haplotype frequencies (OR = 0.274; 95% CI: 0.086-0.874; P < 0.05) were significantly reduced in Han ICC. The HLA-DQB1*0602 frequency significantly decreased among Uighur women with ICC (OR = 0.482; 95% CI: 0.325-0.716; P < 0.05). Similar tendencies were observed for DQB1*0602 with HPV16-positive ICC (OR = 0.550; 95% CI: 0.362-0.837; P < 0.05). This study suggests that HLA-DRB1*1501 and DQB1*0602 alleles may influence the immune response to HPV16 infection and decrease the risk of ICC among Uighurs and Hans in Xinjiang, China.
PMCID: PMC4203236  PMID: 25337265
HLA; invasive cervical cancer; HPV; susceptibility; Uighur

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