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1.  The Antitumor Agent PBT-1 Directly Targets HSP90 and hnRNP A2/B1 and Inhibits Lung Adenocarcinoma Growth and Metastasis 
Journal of Medicinal Chemistry  2014;57(3):677-685.
Natural products are the major sources of currently available anticancer drugs. We recently reported that phenanthrene-based tylophorine derivative-1 (PBT-1) may be a potential antitumor agent for lung adenocarcinoma. We therefore examined the direct targets of PBT-1 and their effects in inhibiting lung adenocarcinoma. We found that PBT-1 reduced the level of Slug and inhibits the migration, invasion, and filopodia formation of lung adenocarcinoma CL1-5 cells in vitro. In addition, PBT-1 displayed in vivo antitumor and antimetastasis activities against subcutaneous and orthotopic xenografts of CL1-5 cells in nude mice. Chemical proteomics showed that heat shock protein 90 (HSP90) and heterogeneous nuclear ribonucleoproteins A2/B1 (hnRNP A2/B1) bound PBT-1 in CL1-5 cells. Inhibition of HSP90 and hnRNP A2/B1 reduced the activation of AKT and Slug expression. Taken together, these findings suggest that PBT-1 binds to HSP90 and/or hnRNP A2/B1 and initiates antitumor activities by affecting Slug- and AKT-mediated metastasis and tumorigenesis.
doi:10.1021/jm401686b
PMCID: PMC3983378  PMID: 24428777
2.  Effect of Grafting BMP2 Derived Peptide to Nanoparticles on Osteogenic and Vasculogenic Expression of Stromal Cells 
Bone morphogenetic protein-2 (BMP2) plays a major role in initiating the cascade of osteogenesis. However, high doses of exogenous BMP2 coupled with diffusion away from the intended site cause adverse side effects. An alternative is to use biodegradable polymeric nanoparticles (NPs) grafted with peptides of the active domains of BMP2. NPs present a multivalent form of the peptide for stronger interaction with cell surface receptors, leading to a stronger activation of osteogenic signaling pathways. The objective of this work was to compare osteogenic activity of the BMP2 peptide (BMP2Pe), corresponding to residues 73–92 of BMP2 protein (BMP2Pr), grafted to biodegradable NPs with that of BMP2 protein (BMP2Pr). BMP2Pe was functionalized with a cysteine residue and grafted to poly(lactide fumarate) and poly(lactide-co-ethylene oxide fumarate) (PLAF/PLEOF) NPs via a thioether link. The calcium content of bone marrow stromal (BMS) cells cultured in osteogenic media supplemented with BMP2 peptide/protein grafted NPs (BMP2Pe-gNP and BMP2Pr-gNP) was slightly higher than other BMP2 treated groups, but all osteogenic groups showed similar levels of mineralization after 21 days. The expression pattern of master transcription factors Dlx5 and Runx2 indicated that BMP2 protein induced a faster osteogenic signaling than the BMP peptide. The expression level of Osteopontin, Osteocalcin, and PECAM-1 in the NP grafted BMP2 groups was significantly higher than those of ungrafted BMP2Pr and BMP2Pe groups, which may be due to a more effective presentation of the peptide/protein to cell surface receptors, thus leading to a stronger interaction of the peptide/protein with clustered cell surface receptors.
doi:10.1002/term.1487
PMCID: PMC4076642  PMID: 22764116
nanoparticles; grafting; bone morphogenetic peptide; osteogenesis; marrow stromal cells; gene expression
3.  Case-control study of the PERIOD3 clock gene length polymorphism and colorectal adenoma formation 
Oncology Reports  2014;33(2):935-941.
Clock genes are expressed in a self-perpetuating, circadian pattern in virtually every tissue including the human gastrointestinal tract. They coordinate cellular processes critical for tumor development, including cell proliferation, DNA damage response and apoptosis. Circadian rhythm disturbances have been associated with an increased risk for colon cancer and other cancers. This mechanism has not been elucidated, yet may involve dysregulation of the ‘period’ (PER) clock genes, which have tumor suppressor properties. A variable number tandem repeat (VNTR) in the PERIOD3 (PER3) gene has been associated with sleep disorders, differences in diurnal hormone secretion, and increased premenopausal breast cancer risk. Susceptibility related to PER3 has not been examined in conjunction with adenomatous polyps. This exploratory case-control study was the first to test the hypothesis that the 5-repeat PER3 VNTR sequence is associated with increased odds of adenoma formation. Information on demographics, medical history, occupation and lifestyle was collected prior to colonoscopy. Cases (n=49) were individuals with at least one histopathologically confirmed adenoma. Controls (n=97) included patients with normal findings or hyperplastic polyps not requiring enhanced surveillance. Unconditional multiple logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs), after adjusting for potential confounding. Adenomas were detected in 34% of participants. Cases were more likely to possess the 5-repeat PER3 genotype relative to controls (4/5 OR, 2.1; 95% CI, 0.9–4.8; 5/5 OR, 5.1; 95% CI, 1.4–18.1; 4/5+5/5 OR, 2.5; 95% CI, 1.7–5.4). Examination of the Oncomine microarray database indicated lower PERIOD gene expression in adenomas relative to adjacent normal tissue. Results suggest a need for follow-up in a larger sample.
doi:10.3892/or.2014.3667
PMCID: PMC4306271  PMID: 25501848
adenoma; clock gene; circadian rhythm; colorectal cancer; variable number tandem repeat
4.  Diffusion-Weighted MRI Monitoring of Pancreatic Cancer Response to Radiofrequency Heat-Enhanced Intratumor Chemotherapy 
NMR in biomedicine  2013;26(12):10.1002/nbm.3014.
PURPOSE
To evaluate the feasibility of using diffusion-weighted MRI to monitor the early response of pancreatic cancers to radiofrequency heat (RFH)-enhanced chemotherapy.
MATERIALS AND METHODS
Human pancreatic carcinoma cells (PANC-1) in different groups and twenty four mice with pancreatic cancer xenografts in four groups were treated by phosphate buffered saline (PBS) as a control, RFH at 42 °C, gemcitabine and gemcitabine plus RFH at 42°C. One day before and 1, 7, and 14 days after the treatment, diffusion-weighted MR imaging and T2 weighted imaging were applied to monitor the apparent diffusion coefficients (ADCs) of tumors and tumors growth. MRI findings were correlated with results of tumors apoptosis analysis.
RESULTS
Of the in vitro experiments, quantitative viability assay showed lower relative cell viabilities treated by gemcitabine plus RFH at 42°C, compared to those by RFH only and gemcitabine only (37% ± 5% vs 65% ± 4% and 58% ± 8%, p < 0.05). Of the in vivo experiments, the combination therapy resulted in smaller relative tumor volume than RFH-only and chemotherapy-only (0.82 ± 0.17 vs 2.23 ± 0.90 and 1.64 ± 0.44, p = 0.003). In vivo 14T MRI demonstrated a remarkable decrease of ADCs at day 1 and increased ADCs at days 7 and 14 in the combination therapy group. The apoptosis index in the combination therapy group was significantly higher than those in the groups of chemotherapy-only, RFH-only and PBS treatments (37% ± 6% vs 20% ± 5%, 8% ± 2%, and 3% ± 1%, p < 0.05).
CONCLUSION
This study confirms that it is feasible to use MRI to monitor RFH-enhanced chemotherapy on pancreatic cancers, which may present new options for efficient treatment of pancreatic malignancies using MR/RF-integrated local chemotherapy.
doi:10.1002/nbm.3014
PMCID: PMC3838434  PMID: 24038282
5.  ABRO1 suppresses tumourigenesis and regulates the DNA damage response by stabilizing p53 
Nature Communications  2014;5:5059.
Abraxas brother 1 (ABRO1) has been reported to be a component of the BRISC complex, a multiprotein complex that specifically cleaves ‘Lys-63’-linked ubiquitin. However, current knowledge of the functions of ABRO1 is limited. Here we report that ABRO1 is frequently downregulated in human liver, kidney, breast and thyroid gland tumour tissues. Depletion of ABRO1 in cancer cells reduces p53 levels and enhances clone formation and cellular transformation. Conversely, overexpression of ABRO1 suppresses cell proliferation and tumour formation in a p53-dependent manner. We further show that ABRO1 stabilizes p53 by facilitating the interaction of p53 with USP7. DNA-damage induced accumulation of endogenous ABRO1 as well as translocation of ABRO1 to the nucleus, and the induction of p53 by DNA damage is almost completely attenuated by ABRO1 depletion. Our study shows that ABRO1 is a novel p53 regulator that plays an important role in tumour suppression and the DNA damage response.
The scaffold protein Abraxas brother 1 (ABRO1) accumulates in the nucleus after oxidative stress but its role in cellular responses to DNA damage has not been elucidated. Here the authors show that ABRO1 exerts its tumour suppressor activity by regulating p53 stability via USP7 deubiquitinase.
doi:10.1038/ncomms6059
PMCID: PMC4205886  PMID: 25283148
6.  Period 2 Mutation Accelerates ApcMin/+ Tumorigenesis 
Molecular cancer research : MCR  2008;6(11):1786-1793.
Colorectal cancer risk is increased in shift workers with presumed circadian disruption. Intestinal epithelial cell proliferation is gated throughout each day by the circadian clock. Period 2 (Per2) is a key circadian clock gene. Per2 mutant (Per2m/m) mice show an increase in lymphomas and deregulated expression of cyclin D and c-Myc genes that are key to proliferation control. We asked whether Per2 clock gene inactivation would accelerate intestinal and colonic tumorigenesis. The effects of PER2 on cell proliferation and β-catenin were studied in colon cancer cell lines by its down-regulation following RNA interference. The effects of Per2 inactivation in vivo on β-catenin and on intestinal and colonic polyp formation were studied in mice with Per2 mutation alone and in combination with an Apc mutation using polyp-prone ApcMin/+ mice. Down-regulation of PER2 in colon cell lines (HCT116 and SW480) increases β-catenin, cyclin D, and cell proliferation. Down-regulation of β-catenin along with Per2 blocks the increase in cyclin D and cell proliferation. Per2m/m mice develop colonic polyps and show an increase in small intestinal mucosa β-catenin and cyclin D protein levels compared with wild-type mice. ApcMin/+Per2m/m mice develop twice the number of small intestinal and colonic polyps, with more severe anemia and splenomegaly, compared with ApcMin/+ mice. These data suggest that Per2 gene product suppresses tumorigenesis in the small intestine and colon by down-regulation of β-catenin and β-catenin target genes, and this circadian core clock gene may represent a novel target for colorectal cancer prevention and control.
doi:10.1158/1541-7786.MCR-08-0196
PMCID: PMC4136553  PMID: 19010825
7.  Drug Release Kinetics, Cell Uptake, and Tumor Toxicity of Hybrid VVVVVVKK Peptide-Assembled Polylactide Nanoparticles 
An exciting approach to tumor delivery is encapsulation of the drug in self-assembled polymer-peptide nanoparticles. The objective of this work was to synthesize a conjugate of low molecular weight polylactide (LMW PLA) and V6K2 peptide, and investigate self-assembly, drug release kinetics, cell uptake and toxicity, drug pharmacokinetics, and tumor cell invasion with Doxorubicin (DOX) or paclitaxel (PTX). The results for PLA-V6K2 self-assembled NPs were compared with those of polyethylene glycol stabilized PLA (PLA-EG) NPs. The size of PLA-V6K2 and PLA-EG NPs were 100±20 and 130±50 nm, respectively, with polydispersity index of 1.04 and 1.14. The encapsulation efficiency of DOX in PLA-V6K2 and PLA-EG NPs was 44±9% and 55±5%, respectively, and that of PTX was >90 for both NP types. The release of DOX and PTX from PLA-V6K2 was slower than that of PLA-EG and the release rate was relatively constant with time. Based on molecular dynamic simulation, the less hydrophobic DOX was distributed in the lactide core as well as the peptide shell while the hydrophobic PTX was localized mainly to the lactide core. PLA-V6K2 NPs had significantly higher cell uptake by 4T1 mouse breast carcinoma cells compared to PLA-EG NPs, which was attributed to the electrostatic interactions between the peptide and negatively charged moieties on the cell membrane. PLA-V6K2 NPs showed no toxicity to marrow stromal cells. DOX loaded PLA-V6K2 NPs showed higher toxicity to 4T1 cells and the DNA damage response and apoptosis was delayed compared to the free DOX. DOX or PTX encapsulated in PLA-V6K2 NPs significantly reduced invasion of 4T1 cells compared to those cells treated with the drug in PLA-EG NPs. Invasion of 4T1 cells treated with DOX in PLA-V6K2 and PLA-EG NPs was 5±1% and 30±5%, respectively, and that of PTX was 11±2% and 40±7%. The AUC of DOX in PLA-V6K2 NPs was 67% and 21% higher than those of free DOX and PLA-EG NPs, respectively. DOX loaded PLA-V6K2 NPs injected in C3HeB/FeJ mice inoculated with MTCL syngeneic breast cancer cells displayed higher tumor toxicity than PLA-EG NPs and lower host toxicity than the free DOX. Cationic PLA-V6K2 NPs with higher tumor toxicity than the PLA-EG NPs are potentially useful in chemotherapy.
doi:10.1016/j.ejpb.2012.12.012
PMCID: PMC3626769  PMID: 23275111
Self-assembling peptide; polymer conjugation; hybrid nanoparticle; cell uptake; drug pharmacokinetics; tumor toxicity
8.  Three-Dimensional-Engineered Matrix to Study Cancer Stem Cells and Tumorsphere Formation: Effect of Matrix Modulus 
Tissue Engineering. Part A  2012;19(5-6):669-684.
Maintenance of cancer stem cells (CSCs) is regulated by the tumor microenvironment. Synthetic hydrogels provide the flexibility to design three-dimensional (3D) matrices to isolate and study individual factors in the tumor microenvironment. The objective of this work was to investigate the effect of matrix modulus on tumorsphere formation by breast cancer cells and maintenance of CSCs in an inert microenvironment without the interference of other factors. In that regard, 4T1 mouse breast cancer cells were encapsulated in inert polyethylene glycol diacrylate hydrogels and the effect of matrix modulus on tumorsphere formation and expression of CSC markers was investigated. The gel modulus had a strong effect on tumorsphere formation and the effect was bimodal. Tumorsphere formation and expression of CSC markers peaked after 8 days of culture. At day 8, as the matrix modulus was increased from 2.5 kPa to 5.3, 26.1, and 47.1 kPa, the average tumorsphere size changed from 37±6 μm to 57±6, 20±4, and 12±2 μm, respectively; cell number density in the gel changed from 0.8±0.1×105 cells/mL to 1.7±0.2×105, 0.4±0.1×105, and 0.2±0.1×105 cells/mL after initial encapsulation of 0.14×105 cells/mL; and the expression of CD44 breast CSC marker changed from 17±4-fold to 38±9-, 3±1-, and 2±1-fold increase compared with the initial level. Similar results were obtained with MCF7 human breast carcinoma cells. Mouse 4T1 and human MCF7 cells encapsulated in the gel with 5.3 kPa modulus formed the largest tumorspheres and highest density of tumorspheres, and had highest expression of breast CSC markers CD44 and ABCG2. The inert polyethylene glycol hydrogel can be used as a model-engineered 3D matrix to study the role of individual factors in the tumor microenvironment on tumorigenesis and maintenance of CSCs without the interference of other factors.
doi:10.1089/ten.tea.2012.0333
PMCID: PMC3566656  PMID: 23013450
9.  Radiofrequency Heat-Enhanced Chemotherapy for Breast Cancer: Towards Interventional Molecular Image-Guided Chemotherapy 
Theranostics  2014;4(11):1145-1152.
Breast cancer is the most common malignancy in women worldwide. Recent developments in minimally invasive interventional radiology techniques have significantly improved breast cancer treatment. This study aimed to develop a novel technique for the local management of breast cancers using radiofrequency heat (RFH). We performed both in vitro experiments using human breast cancer cells and in vivo validation in xenograft animal models with magnetic resonance imaging (MRI) and pathological correlation to investigate the feasibility of our approach. Four treatment groups, including (1) no treatment (control), (2) RFH-only, (3) chemo (doxorubicin)-only, and (4) combination therapy with both doxorubicin and RFH, were conducted in each experiment. In vitro combination therapy significantly decreased breast cancer cell proliferation while increased their apoptosis index compared to the other three groups. MRI demonstrated a significant tumor size reduction in animals treated with combination therapy compared to those receiving other treatments in vivo. Such result was further confirmed by pathological examination. In conclusion, our findings suggests that RFH can enhance the therapeutic efficiency of doxorubicin on breast cancers, thus establishing the basis for future development of interventional molecular image-guided local chemotherapy for breast malignancies.
doi:10.7150/thno.10006
PMCID: PMC4165778  PMID: 25250095
breast cancer; radiofrequency; doxorubicin; MRI; hyperthermia.
10.  MiR-133b Is Down-Regulated in Human Osteosarcoma and Inhibits Osteosarcoma Cells Proliferation, Migration and Invasion, and Promotes Apoptosis 
PLoS ONE  2013;8(12):e83571.
MicroRNAs (miRNAs) decrease the expression of specific target oncogenes or tumor suppressor genes and thereby play crucial roles in tumorigenesis and tumor growth. To date, the potential miRNAs regulating osteosarcoma growth and progression are not fully identified yet. In this study, the miRNA microarray assay and hierarchical clustering analysis were performed in human osteosarcoma samples. In comparison with normal human skeletal muscle, 43 miRNAs were significantly differentially expressed in human osteosarcomas (fold change ≥2 and p≤0.05). Among these miRNAs, miR-133a and miR-133b expression was decreased by 135 folds and 47 folds respectively and the decreased expression was confirmed in both frozen and paraffin-embedded osteosarcoma samples. The miR-133b precursor expression vector was then transfected into osteosarcoma cell lines U2-OS and MG-63, and the stable transfectants were selected by puromycin. We found that stable over-expression of miR-133b in osteosarcoma cell lines U2-OS and MG-63 inhibited cell proliferation, invasion and migration, and induced apoptosis. Further, over-expression of miR-133b decreased the expression of predicted target genes BCL2L2, MCL-1, IGF1R and MET, as well as the expression of phospho-Akt and FAK. This study provides a new insight into miRNAs dysregulation in osteosarcoma, and indicates that miR-133b may play as a tumor suppressor gene in osteosarcoma.
doi:10.1371/journal.pone.0083571
PMCID: PMC3877051  PMID: 24391788
11.  Computed tomography fluoroscopy-guided percutaneous 125I seed implantation for safe, effective and real-time monitoring radiotherapy of inoperable stage T1-3N0M0 non-small-cell lung cancer 
Molecular and Clinical Oncology  2013;1(6):1019-1024.
The management of inoperable lung cancer remains a challenge. It has been proven that computed tomography (CT)-guided iodine-125 (125I) seed implantation is a safe and efficient method for treating lung cancer. Computed tomographic fluoroscopy (CTF) is superior to traditional CT for percutaneous management of lung lesions, due to the real-time guidance and accurate localization of the lesions. The aim of the present prospective study was to evaluate the feasibility, safety and efficacy of CTF-guided percutaneous permanent implantation of 125I seeds for the treatment of selected patients with inoperable stage T1-3N0M0 non-small-cell lung cancer (NSCLC). A total of 24 patients with resectable but inoperable stage T1-3N0 NSCLC, with a total of 28 lesions, underwent CTF-guided percutaneous implantation of radioactive 125I seeds. A prescription dose of 100–120 Gy was delivered to each lesion. The complications and local tumor control rates were documented. Survival was estimated using the Kaplan-Meier method. All the patients successfully completed the procedure, with a mean procedure duration of 45.7 min (range, 30–75 min). No severe complications occurred. Small asymptomatic pneumothorax with lung volume compression of <10% and minor hemorrhage along the needle track without hemoptysis occurred immediately after the procedure in 3 (12.5%) and 4 (16.7%) of the 24 patients, respectively. At a median follow-up of 31.5 months (range, 8–46 months), the local control rate (LCR) of the lesions was 78.6% (22/28). The 1-, 2- and 3-year overall survival rate was 95.8, 78 and 55%, respectively. In conclusion, CTF is the favourable imaging guidance method for the percutaneous implantation of 125I seeds. CTF-guided brachytherapy with implantation of 125I seeds is a safe, feasible and effective modality for the treatment of inoperable early-stage NSCLC and may be considered an alternative option in selected patients with medically inoperable NSCLC.
doi:10.3892/mco.2013.171
PMCID: PMC3915541  PMID: 24649287
non-small-cell lung cancer; iodine-125 seed; brachytherapy; computed tomography fluoroscopy; image guidance
12.  Antitumor Agents 295. E-ring Hydroxylated Antofine and Cryptopleurine Analogs as Antiproliferative Agents: Design, Synthesis, and Mechanistic Studies 
Journal of medicinal chemistry  2012;55(15):6751-6761.
Various E-ring hydroxylated antofine and cryptopleurine analogs were designed, synthesized, and tested against five human cancer cell lines. Interesting structure-activity relationship (SAR) correlations were found among these new compounds. The most potent compound 13b was further tested against a series of non-small cell lung cancer (NSCLC) cell lines, in which it showed impressive antiproliferative activity. Mechanistic studies revealed that 13b is able to down-regulate HSP90 and β-catenin in A549 lung adenocarcinoma cells in a dose-dependent manner, suggesting a potential use for treating Hedgehog pathway-driven tumorigenesis.
doi:10.1021/jm3001218
PMCID: PMC3422873  PMID: 22823514
13.  Alcohol consumption in 0.5 million people from 10 diverse regions of China: prevalence, patterns and socio-demographic and health-related correlates 
Millwood, Iona Y | Li, Liming | Smith, Margaret | Guo, Yu | Yang, Ling | Bian, Zheng | Lewington, Sarah | Whitlock, Gary | Sherliker, Paul | Collins, Rory | Chen, Junshi | Peto, Richard | Wang, Hongmei | Xu, Jiujiu | He, Jian | Yu, Min | Liu, Huilin | Chen, Zhengming | Li, Liming | Chen, Zhengming | Chen, Junshi | Collins, Rory | Wu, Fan | Peto, Richard | Chen, Zhengming | Lancaster, Garry | Yang, Xiaoming | Williams, Alex | Smith, Margaret | Yang, Ling | Chang, Yumei | Millwood, Iona | Chen, Yiping | Zhang, Qiuli | Lewington, Sarah | Whitlock, Gary | Guo, Yu | Zhao, Guoqing | Bian, Zheng | Wu, Lixue | Hou, Can | Pang, Zengchang | Wang, Shaojie | Zhang, Yun | Zhang, Kui | Liu, Silu | Zhao, Zhonghou | Liu, Shumei | Pang, Zhigang | Feng, Weijia | Wu, Shuling | Yang, Liqiu | Han, Huili | He, Hui | Pan, Xianhai | Wang, Shanqing | Wang, Hongmei | Hao, Xinhua | Chen, Chunxing | Lin, Shuxiong | Hu, Xiaoshu | Zhou, Minghao | Wu, Ming | Wang, Yeyuan | Hu, Yihe | Ma, Liangcai | Zhou, Renxian | Xu, Guanqun | Dong, Baiqing | Chen, Naying | Huang, Ying | Li, Mingqiang | Meng, Jinhuai | Gan, Zhigao | Xu, Jiujiu | Liu, Yun | Wu, Xianping | Gao, Yali | Zhang, Ningmei | Luo, Guojin | Que, Xiangsan | Chen, Xiaofang | Ge, Pengfei | He, Jian | Ren, Xiaolan | Zhang, Hui | Mao, Enke | Li, Guanzhong | Li, Zhongxiao | He, Jun | Liu, Guohua | Zhu, Baoyu | Zhou, Gang | Feng, Shixian | Gao, Yulian | He, Tianyou | Jiang, Li | Qin, Jianhua | Sun, Huarong | Liu, Liqun | Yu, Min | Chen, Yaping | Hu, Zhixiang | Hu, Jianjin | Qian, Yijian | Wu, Zhiying | Chen, Lingli | Liu, Wen | Li, Guangchun | Liu, Huilin | Long, Xiangquan | Xiong, Youping | Tan, Zhongwen | Xie, Xuqiu | Peng, Yunfang
Background Drinking alcohol has a long tradition in Chinese culture. However, data on the prevalence and patterns of alcohol consumption in China, and its main correlates, are limited.
Methods During 2004–08 the China Kadoorie Biobank recruited 512 891 men and women aged 30–79 years from 10 urban and rural areas of China. Detailed information on alcohol consumption was collected using a standardized questionnaire, and related to socio-demographic, physical and behavioural characteristics in men and women separately.
Results Overall, 76% of men and 36% of women reported drinking some alcohol during the past 12 months, with 33% of men and 2% of women drinking at least weekly; the prevalence of weekly drinking in men varied from 7% to 51% across the 10 study areas. Mean consumption was 286 g/week and was higher in those with less education. Most weekly drinkers habitually drank spirits, although this varied by area, and beer consumption was highest among younger drinkers; 37% of male weekly drinkers (12% of all men) reported weekly heavy drinking episodes, with the prevalence highest in younger men. Drinking alcohol was positively correlated with regular smoking, blood pressure and heart rate. Among male weekly drinkers, each 20 g/day alcohol consumed was associated with 2 mmHg higher systolic blood pressure. Potential indicators of problem drinking were reported by 24% of male weekly drinkers.
Conclusion The prevalence and patterns of drinking in China differ greatly by age, sex and geographical region. Alcohol consumption is associated with a number of unfavourable health behaviours and characteristics.
doi:10.1093/ije/dyt078
PMCID: PMC3733702  PMID: 23918852
Alcohol; drinking; cohort study; descriptive analysis; China
14.  Hydroxysteroid Sulfotransferase SULT2B1b Promotes Hepatocellular Carcinoma Cells Proliferation In Vitro and In Vivo 
PLoS ONE  2013;8(4):e60853.
Hydroxysteroid sulfotransferase 2B1b (SULT2B1b) is highly selective for the addition of sulfate groups to 3β-hydroxysteroids. Although previous reports have suggested that SULT2B1b is correlated with cell proliferation of hepatocytes, the relationship between SULT2B1b and the malignant phenotype of hepatocarcinoma cells was not clear. In the present study, we found that SULT2B1 was comparatively higher in the human hepatocarcinoma tumorous tissues than their adjacent tissues. Besides, SULT2B1b overexpression promoted the growth of the mouse hepatocarcinoma cell line Hepa1-6, while Lentivirus-mediated SULT2B1b interference inhibited growth as assessed by the CCK-8 assay. Likewise, inhibition of SULT2B1b expression induced cell-cycle arrest and apoptosis in Hepa1-6 cells by upregulating the expression of FAS, downregulating the expression of cyclinB1, BCL2 and MYC in vitro and in vivo at both the transcript and protein levels. Knock-down of SULT2B1b expression significantly suppressed tumor growth in nude mouse xenografts. Moreover, proliferation rates and SULT2B1b expression were highly correlated in the human hepatocarcinoma cell lines Huh-7, Hep3B, SMMC-7721 and BEL-7402 cells. Knock-down of SULT2B1b inhibited cell growth and cyclinB1 levels in human hepatocarcinoma cells and suppressed xenograft growth in vivo. In conclusion, SULT2B1b expression promotes proliferation of hepatocellular carcinoma cells in vitro and in vivo, which may contribute to the progression of HCC.
doi:10.1371/journal.pone.0060853
PMCID: PMC3623875  PMID: 23593328
15.  Effect of CD44 Binding Peptide Conjugated to an Engineered Inert Matrix on Maintenance of Breast Cancer Stem Cells and Tumorsphere Formation 
PLoS ONE  2013;8(3):e59147.
Introduction
As cancer cells are affected by many factors in their microenvironment, a major challenge is to isolate the effect of a specific factor on cancer stem cells (CSCs) while keeping other factors unchanged. We have developed a synthetic inert 3D polyethylene glycol diacrylate (PEGDA) gel culture system as a unique tool to study the effect of microenvironmental factors on CSCs response. We have reported that CSCs formed in the inert PEGDA gel by encapsulation of breast cancer cells maintain their stemness within a certain range of gel stiffness. The objective was to investigate the effect of CD44 binding peptide (CD44BP) conjugated to the gel on the maintenance of breast CSCs.
Methods
4T1 or MCF7 breast cancer cells were encapsulated in PEGDA gel with CD44BP conjugation. Control groups included dissolved CD44BP and the gel with mutant CD44BP conjugation. Tumorsphere size and density, and expression of CSC markers were determined after 9 days. For in vivo, cell encapsulated gels were inoculated in syngeneic Balb/C mice and tumor formation was determined after 4 weeks. Effect of CD44BP conjugation on breast CSC maintenance was compared with integrin binding RGD peptide (IBP) and fibronectin-derived heparin binding peptide (FHBP).
Results
Conjugation of CD44BP to the gel inhibited breast tumorsphere formation in vitro and in vivo. The ability of the encapsulated cells to form tumorspheres in the peptide-conjugated gels correlated with the expression of CSC markers. Tumorsphere formation in vitro was enhanced by FHBP while it was abolished by IBP.
Conclusion
CD44BP and IBP conjugated to the gel abolished tumorsphere formation by encapsulated 4T1 cells while FHBP enhanced tumorsphere formation compared to cells in the gel without peptide. The PEGDA hydrogel culture system provides a novel tool to investigate the individual effect of factors in the microenvironment on CSC maintenance without interference of other factors.
doi:10.1371/journal.pone.0059147
PMCID: PMC3601067  PMID: 23527117
16.  MRI-Monitored Intra-Shunt Local Agent Delivery of Motexafin Gadolinium: Towards Improving Long-Term Patency of TIPS 
PLoS ONE  2013;8(2):e57419.
Background
Transjugular intrahepatic portosystemic shunt (TIPS) has become an important and effective interventional procedure in treatment of the complications related to portal hypertension. Although the primary patency of TIPS has been greatly improved due to the clinical application of cover stent-grafts, the long-term patency is still suboptimal. This study was to investigate the feasibility of using magnetic resonance imaging (MRI)-monitored intra-shunt local agent delivery of motexafin gadolinium (MGd) into shunt-vein walls of TIPS. This new technique aimed to ultimately inhibit shuntstenosis of TIPS.
Methodology
Human umbilical vein smooth muscle cells (SMCs) were incubated with various concentrations of MGd, and then examed by confocal microscopy and T1-map MRI. In addition, the proliferation of MGd-treated cells was evaluated. For in vivo validation, seventeen pigs underwent TIPS. Before placement of the stent, an MGd/trypan-blue mixture was locally delivered, via a microporous balloon, into eleven shunt-hepatic vein walls under dynamic MRI monitoring, while trypan-blue only was locally delivered into six shunt-hepatic vein walls as serve as controls. T1-weighted MRI of the shunt-vein walls was achieved before- and at different time points after agent injections. Contrast-to-noise ratio (CNR) of the shunt-vein wall at each time-point was measured. Shunts were harvested for subsequent histology confirmation.
Principal Findings
In vitro studies confirmed the capability of SMCs in uptaking MGds in a concentration-dependent fashion, and demonstrated the suppression of cell proliferation by MGds as well. Dynamic MRI displayed MGd/blue penetration into the shunt-vein walls, showing significantly higher CNR of shunt-vein walls on post-delivery images than on pre-delivery images (49.5±9.4 vs 11.2±1.6, P<0.01), which was confirmed by histology.
Conclusion
Results of this study indicate that MRI-monitored intra-shunt local MGd delivery is feasible and MGd functions as a potential therapeutic agent to inhibit the proliferation of SMCs, which may open alternative avenues to improve the long-term patency of TIPS.
doi:10.1371/journal.pone.0057419
PMCID: PMC3585394  PMID: 23468986
17.  Identification of Novel Protein-Protein Interactions of Yersinia pestis Type III Secretion System by Yeast Two Hybrid System 
PLoS ONE  2013;8(1):e54121.
Type III secretion system (T3SS) of the plague bacterium Y. pestis encodes a syringe-like structure consisting of more than 20 proteins, which can inject virulence effectors into host cells to modulate the cellular functions. Here in this report, interactions among the possible components in T3SS of Yersinia pestis were identified using yeast mating technique. A total of 57 genes, including all the pCD1-encoded genes except those involved in plasmid replication and partition, pseudogenes, and the putative transposase genes, were subjected to yeast mating analysis. 21 pairs of interaction proteins were identified, among which 9 pairs had been previously reported and 12 novel pairs were identified in this study. Six of them were tested by GST pull down assay, and interaction pairs of YscG-SycD, YscG-TyeA, YscI-YscF, and YopN-YpCD1.09c were successfully validated, suggesting that these interactions might play potential roles in function of Yersinia T3SS. Several potential new interactions among T3SS components could help to understand the assembly and regulation of Yersinia T3SS.
doi:10.1371/journal.pone.0054121
PMCID: PMC3551969  PMID: 23349800
18.  Cryptopleurine Analogs with Modification of E Ring Exhibit Different Mechanism to Rac-Cryptopleurine and Tylophorine 
PLoS ONE  2012;7(12):e51138.
Tylophorine analogs exhibit a broad range of pharmacological activities, including anti-cancer, anti-inflammatory, anti-autoimmune, and anti-virus effects. Structure-activity relationship study of different structure tylophorine analogs can provide further understanding of their biological activity. Modifications on the E ring of the quinolizidine moiety of cryptopleurine analogs changed the potency and the selective inhibitory effect on NF-κB, AP-1, and CRE signaling pathways. Functional cryptopleurine analogs showed potent inhibition of NF-κB signaling pathway in both HepG2 and HEK-293 cell lines. The E ring structure analogs also differed in suppression of protein translation, and expression of cyclin D1. Our results showed that DCB-3503 or Rac-cryptopleurine could be a scaffold for modification to yield compounds with different mechanisms of action.
doi:10.1371/journal.pone.0051138
PMCID: PMC3519526  PMID: 23251437
19.  Ultrasound-Guided Creation of a Small Animal Model of Aortic Injury 
Purpose
To develop a small animal model of controlled aortic intimal injury with ultrasound imaging guidance.
Materials and Methods
Via carotid artery cut down, we advanced a custom-made micro-catheter/angled-metal-device system to damage the intima of the ascending aortas of 20 Sprague Dawley (SD) rats and 10 JCR atherosclerotic rats. This minimally invasive endovascular procedure was monitored by a clinical ultrasound imaging system. Injured aortas were harvested for histologic confirmations using a grading system: Grade I with intima injury, Grade II with injury to media, and Grade III with injury through the entire aortic wall. Neointimal reactions at the injury site were compared by calculating the ratio of intimal to medial thickness among different animal groups at various survival times (week 1, weeks 2–3 and weeks 4–7).
Results
Clear visualization of the architectures of the heart, great vessels and the exact location of the angled-metal-device by ultrasound imaging ensured consistent intimal damage of the aorta. Histopathology confirmed that most of the aortic injures were classified as Grade I. There was no significant difference between the two rat groups. Analysis on pathophysiological reactions at the injury sites revealed increased thickening of neointimal hyperplasia as animal survival times extended from week 1 to weeks 4–7 after the aortic interventions.
Conclusions
This study demonstrates the feasibility of using clinical ultrasound imaging to precisely guide the creation of controlled aortic intimal injury in rats, which may become a useful tool to facilitate research involving the prevention and treatment of atherosclerotic cardiovascular disease.
doi:10.1016/j.jvir.2011.02.032
PMCID: PMC3148304  PMID: 21570869
atherosclerotic cardiovascular disease; rat model; ultrasound; vascular injury
20.  Insight into Bacterial Virulence Mechanisms against Host Immune Response via the Yersinia pestis-Human Protein-Protein Interaction Network ▿ †  
Infection and Immunity  2011;79(11):4413-4424.
A Yersinia pestis-human protein interaction network is reported here to improve our understanding of its pathogenesis. Up to 204 interactions between 66 Y. pestis bait proteins and 109 human proteins were identified by yeast two-hybrid assay and then combined with 23 previously published interactions to construct a protein-protein interaction network. Topological analysis of the interaction network revealed that human proteins targeted by Y. pestis were significantly enriched in the proteins that are central in the human protein-protein interaction network. Analysis of this network showed that signaling pathways important for host immune responses were preferentially targeted by Y. pestis, including the pathways involved in focal adhesion, regulation of cytoskeleton, leukocyte transendoepithelial migration, and Toll-like receptor (TLR) and mitogen-activated protein kinase (MAPK) signaling. Cellular pathways targeted by Y. pestis are highly relevant to its pathogenesis. Interactions with host proteins involved in focal adhesion and cytoskeketon regulation pathways could account for resistance of Y. pestis to phagocytosis. Interference with TLR and MAPK signaling pathways by Y. pestis reflects common characteristics of pathogen-host interaction that bacterial pathogens have evolved to evade host innate immune response by interacting with proteins in those signaling pathways. Interestingly, a large portion of human proteins interacting with Y. pestis (16/109) also interacted with viral proteins (Epstein-Barr virus [EBV] and hepatitis C virus [HCV]), suggesting that viral and bacterial pathogens attack common cellular functions to facilitate infections. In addition, we identified vasodilator-stimulated phosphoprotein (VASP) as a novel interaction partner of YpkA and showed that YpkA could inhibit in vitro actin assembly mediated by VASP.
doi:10.1128/IAI.05622-11
PMCID: PMC3257920  PMID: 21911467
21.  Recent progress of research on medicinal mushrooms, foods, and other herbal products used in traditional Chinese medicine 
This article will review selected herbal products used in traditional Chinese medicine, including medicinal mushrooms (巴西蘑菇 bā xī mó gū; Agaricus blazei, 雲芝 yún zhī; Coriolus versicolor, 靈芝 líng zhī; Ganoderma lucidum, 香蕈 xiāng xùn; shiitake, Lentinus edodes, 牛樟芝 niú zhāng zhī; Taiwanofungus camphoratus), Cordyceps (冬蟲夏草 dōng chóng xià cǎo), pomegranate (石榴 shí liú; Granati Fructus), green tea (綠茶 lǜ chá; Theae Folium Non Fermentatum), garlic (大蒜 dà suàn; Allii Sativi Bulbus), turmeric (薑黃 jiāng huáng; Curcumae Longae Rhizoma), and Artemisiae Annuae Herba (青蒿 qīng hāo; sweet wormwood). Many of the discussed herbal products have gained popularity in their uses as dietary supplements for health benefits. The review will focus on the active constituents of the herbs and their bioactivities, with emphasis on the most recent progress in research for the period of 2003 to 2011.
PMCID: PMC3942920  PMID: 24716120
Herbal Products; Medicinal Mushrooms; Dietary Supplements; Traditional Chinese Medicine (TCM)
22.  Development of Nanoparticle-Based Magnetic Resonance Colonography 
Magnetic Resonance in Medicine  2010;65(3):673-679.
This study was to develop a novel method of nanoparticle-based MR colonography. Two types of solid lipid nanoparticles (SLNs) were synthesized with loading of (a) gadolinium-diethylenetriaminepenta-acetic-acid (Gd-DTPA) to construct Gd-SLNs as an MR T1 contrast agent; and (b) otcadecylamine-fluorescein-isothiocyanate (ODA-FITC) to construct Gd-FITC-SLNs for histologic confirmation of MR findings. Through an in vitro experiment, we first evaluated the size distribution and Gd-DTPA entrapment efficiency of these SLNs. The SLNs displayed a size distribution of 50–300 nm and a Gd-DTPA entrapment efficiency of 56%. For in vivo validation, thirty mice were divided into five groups, each of which was administered a transrectal enema using: (i) Gd-SLNs (n=6); (ii) Gd-FITC-SLNs (n=6); (iii) blank SLNs (n=6); (iv) Gd-DTPA (n=6); and (v) water (n=6). T1-weighted FLAIR MRI was then performed on mice after transrectal infusion of Gd-SLNs or Gd-FITC-SLNs, which demonstrated bright enhancement of the colonic walls, with decrease in T1 relaxation time. When Gd-FITC-SLNs were delivered, green fluorescent spots were visualized in both the extracellular space and the cytoplasm through colonic walls under confocal microscopy and fluorescence microscopy. This study establishes the “proof-of-principle” of a new imaging technique, called “nanoparticle-based MR colonography,” which may provide a useful imaging tool for the diagnosis of colorectal diseases.
doi:10.1002/mrm.22654
PMCID: PMC2997759  PMID: 21337401
Magnetic resonance (MR); Colonography; Solid lipid nanoparticles (SLNs); Gadolinium diethylenetriaminepenta acetic acid (Gd-DTPA)
23.  MRI of Auto-Transplantation of Bone Marrow-Derived Stem-Progenitor Cells for Potential Repair of Injured Arteries 
PLoS ONE  2012;7(2):e31137.
Background
This study was to validate the feasibility of using clinical 3.0T MRI to monitor the migration of autotransplanted bone marrow (BM)-derived stem-progenitor cells (SPC) to the injured arteries of near-human sized swine for potential cell-based arterial repair.
Methodology
The study was divided into two phases. For in vitro evaluation, BM cells were extracted from the iliac crests of 13 domestic pigs and then labeled with a T2 contrast agent, Feridex, and/or a fluorescent tissue marker, PKH26. The viability, the proliferation efficiency and the efficacies of Feridex and/or PKH26 labeling were determined. For in vivo validation, the 13 pigs underwent endovascular balloon-mediated intimal damages of the iliofemoral arteries. The labeled or un-labeled BM cells were autotransplanted back to the same pig from which the BM cells were extracted. Approximately three weeks post-cell transplantation, 3.0T T2-weighted MRI was performed to detect Feridex-created signal voids of the transplanted BM cells in the injured iliofemoral arteries, which was confirmed by subsequent histologic correlation.
Principal Findings
Of the in vitro study, the viability of dual-labeled BM cells was 95–98%. The proliferation efficiencies of dual-labeled BM cells were not significantly different compared to those of non-labeled cells. The efficacies of Feridex- and PKH26 labeling were 90% and 100%, respectively. Of the in vivo study, 3.0T MRI detected the auto-transplanted BM cells migrated to the injured arteries, which was confirmed by histologic examinations.
Conclusion
This study demonstrates the capability of using clinical 3.0T MRI to monitor the auto-transplantation of BM cells that migrate to the injured arteries of large animals, which may provide a useful MRI technique to monitor cell-based arterial repair.
doi:10.1371/journal.pone.0031137
PMCID: PMC3281926  PMID: 22363566
24.  Recent Progress of Research on Herbal Products Used in Traditional Chinese Medicine: the Herbs belonging to The Divine Husbandman's Herbal Foundation Canon (神農本草經 Shén Nóng Běn Cǎo Jīng) 
This article will review selected herbal products from Chinese Materia Medica that are used in Traditional Chinese Medicine. The herbs come from the upper, middle, and lower class medicines as listed in The Divine Husbandman's Herbal Foundation Canon (神農本草經 Shén Nóng Běn Cǎo Jīng). The review will focus on the active constituents of the herbs and their bioactivities, with emphasis on the most recent progress in research for the period of 2003 to 2011.
PMCID: PMC3943012  PMID: 24716110
Herbal products; Chinese Materia Medica (CMM) (中藥 zhōng yào); Traditional Chinese Medicine (TCM); Shén Nóng Běn Cǎo Jīng (神農本草經 The Divine Husbandman's Herbal Foundation Canon by Shen Nong)
25.  Toward an understanding of the protein interaction network of the human liver 
Toward an understanding of the protein interaction network of the human liver
An extensive interaction network of human liver-expressed proteins is described, composed of 3484 interactions among 2582 proteins. Proteins associated with liver disease tend to be central and highly connected in the network.
Proteome-scale protein interaction maps are available for many organisms, ranging from bacteria, yeast, worms and flies to humans. These maps provide substantial new insights into systems biology, disease research and drug discovery. However, only a small fraction of the total number of human protein–protein interactions has been identified. In this study, we map the interactions of an unbiased selection of 5026 human liver expression proteins by yeast two-hybrid technology and establish a human liver protein interaction network (HLPN) composed of 3484 interactions among 2582 proteins. The data set has a validation rate of over 72% as determined by three independent biochemical or cellular assays. The network includes metabolic enzymes and liver-specific, liver-phenotype and liver-disease proteins that are individually critical for the maintenance of liver functions. The liver enriched proteins had significantly different topological properties and increased our understanding of the functional relationships among proteins in a liver-specific manner. Our data represent the first comprehensive description of a HLPN, which could be a valuable tool for understanding the functioning of the protein interaction network of the human liver.
doi:10.1038/msb.2011.67
PMCID: PMC3261708  PMID: 21988832
human liver; network; protein–protein interaction; yeast two hybrid

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