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1.  Chinese Smokers’ Cigarette Purchase Behaviors, Cigarette Prices and Consumption: Findings from the ITC China Survey 
Tobacco control  2013;23(0 1):i67-i72.
While cigarette purchasing behavior has been shown to be linked with certain tobacco use outcomes such as quit intentions and quit attempts, there have been very few studies examining cigarette purchasing behaviors and their impact on cigarette price and consumption in China, the world’s largest cigarette consumer.
The goal of this study is to examine the extent and determinants of cost/price-related purchase behaviors, and estimate the impact of these behaviors on cigarette prices paid by Chinese smokers. It also assesses the socio-economic differences in compensatory purchase behaviors, and examines how they influence the relationship between purchase behaviors, cigarette prices, and cigarette consumption.
Multivariate analyses using the general estimating equations (GEE) method were conducted using data from the International Tobacco Control China Survey (the ITC China Survey), a longitudinal survey of adult smokers in seven cities in China: Beijing, Changsha, Guangzhou, Kunming, Shanghai, Shenyang, and Yinchuan. In each city, about 800 smokers were surveyed in each wave. The first three waves - Wave 1 (conducted between March to December 2006), Wave 2 (November 2007 to March 2008) and Wave 3 (May to October 2009 and February to March 2010) - of the ITC China Survey data were used in this analysis. Various aspects of smokers’ self-reported price/cost-related cigarette purchasing behaviors were analyzed.
Nearly three-quarters (72%) of smokers surveyed indicated that a major reason they chose their most-used cigarette brand was its low cost/price. Almost half (50.6%) of smokers reported buying in cartons in their most recent cigarette purchase. Smokers with lower income and/or low levels of education were more likely to choose a brand because of its low cost/price. However, those with higher income and/or high levels of education were more likely to buy cartons. Gender and age were also related to type of purchase behaviors. Those behaviors led to reductions in purchase prices. The price savings ranged from 0.54 Yuan to 1.01 Yuan per pack of cigarettes, depending on the behavior examined, representing a price reduction of 8% - 15%.
A significant portion of Chinese urban adult smokers engaged in cost/price-reducing purchase behaviors. Such behaviors reduce cigarette purchase prices and are associated with increased cigarette consumption. Smokers of different SES engaged in different purchase behaviors to mitigate the impact of higher cigarette prices. Reducing tobacco use through raising tobacco taxes/prices in China needs to take into account these cost/price-reducing behaviors.
PMCID: PMC4254716  PMID: 24048580
China; Cigarette Purchase Behavior; Smoking; Cigarette Price
2.  Activation of the Wnt pathway through use of AR79, a glycogen synthase kinase 3β inhibitor, promotes prostate cancer growth in soft tissue and bone 
Molecular cancer research : MCR  2013;11(12):10.1158/1541-7786.MCR-13-0332-T.
Due to its bone anabolic activity, methods to increase Wnt activity, such as inhibitors of dickkopf-1 and sclerostin, are being clinically explored. Glycogen synthase kinase (GSK3β) inhibits Wnt signaling through inducing β-catenin degradation. Therefore, AR79, an inhibitor of GSK3β, is being evaluated as a bone anabolic agent. However, Wnt activation has potential to promote tumor growth. The goal of this study was to determine if AR79 impacted progression of prostate cancer (PCa). PCa tumors were established in subcutaneous and bone sites of mice followed by AR79 administration. Tumor growth, β-catenin activation, proliferation (Ki67 expression) and apoptosis (caspase 3 activity) were measured. Additionally, PCa and osteoblast cell lines were treated with AR79 and β-catenin status, proliferation (with β-catenin knocked down in some cases) and proportion of the ALDH+CD133+ stem-like cells was determined. AR79 promoted PCa growth, decreased phospho-β-catenin expression and increased total and nuclear β-catenin expression in tumors and increased tumor-induced bone remodeling. Additionally, it decreased caspase 3 and increased Ki67 expression. In addition, AR79 increased bone formation in normal mouse tibiae. AR79 inhibited β-catenin phosphorylation, increased nuclear β-catenin accumulation in PCa and osteoblast cell lines and increased proliferation of PCa cells in vitro through β-catenin. Furthermore, AR79 increased the ALDH+CD133+ cancer stem cell-like proportion of the PCa cell lines. We conclude that AR79, while being bone anabolic, promotes PCa cell growth through Wnt pathway activation.
PMCID: PMC3869871  PMID: 24088787
Wnt; glycogen synthase kinase 3β; prostate cancer; bone metastases; cancer stem cell
3.  Radial Growth of Two Dominant Montane Conifer Tree Species in Response to Climate Change in North-Central China 
PLoS ONE  2014;9(11):e112537.
North-Central China is a region in which the air temperature has clearly increased for several decades. Picea meyeri and Larix principis-rupprechtii are the most dominant co-occurring tree species within the cold coniferous forest belt ranging vertically from 1800 m to 2800 m a.s.l. in this region. Based on a tree-ring analysis of 292 increment cores sampled from 146 trees at different elevations, this study aimed to examine if the radial growth of the two species in response to climate is similar, whether the responses are consistent along altitudinal gradients and which species might be favored in the future driven by the changing climate. The results indicated the following: (1) The two species grew in different rhythms at low and high elevation respectively; (2) Both species displayed inconsistent relationships between radial growth and climate data along altitudinal gradients. The correlation between radial growth and the monthly mean temperature in the spring or summer changed from negative at low elevation into positive at high elevation, whereas those between the radial growth and the total monthly precipitation displayed a change from positive into negative along the elevation gradient. These indicate the different influences of the horizontal climate and vertical mountainous climate on the radial growth of the two species; (3) The species-dependent different response to climate in radial growth appeared mainly in autumn of the previous year. The radial growth of L. principis-rupprechtii displayed negative responses both to temperature and to precipitation in the previous September, October or November, which was not observed in the radial growth of P. meyeri. (4) The radial growth of both species will tend to be increased at high elevation and limited at low elevation, and L. principis-rupprechtii might be more favored in the future, if the temperature keeps rising.
PMCID: PMC4231039  PMID: 25393738
4.  Awareness, Trial, and Current Use of Electronic Cigarettes in 10 Countries: Findings from the ITC Project 
Background: In recent years, electronic cigarettes (e-cigarettes) have generated considerable interest and debate on the implications for tobacco control and public health. Although the rapid growth of e-cigarettes is global, at present, little is known about awareness and use. This paper presents self-reported awareness, trial and current use of e-cigarettes in 10 countries surveyed between 2009 and 2013; for six of these countries, we present the first data on e-cigarettes from probability samples of adult smokers. Methods: A cross-sectional analysis of probability samples of adult (≥ 18 years) current and former smokers participating in the International Tobacco Control (ITC) surveys from 10 countries. Surveys were administered either via phone, face-to-face interviews, or the web. Survey questions included sociodemographic and smoking-related variables, and questions about e-cigarette awareness, trial and current use. Results: There was considerable cross-country variation by year of data collection and for awareness of e-cigarettes (Netherlands (2013: 88%), Republic of Korea (2010: 79%), United States (2010: 73%), Australia (2013: 66%), Malaysia (2011: 62%), United Kingdom (2010: 54%), Canada (2010: 40%), Brazil (2013: 35%), Mexico (2012: 34%), and China (2009: 31%)), in self-reports of ever having tried e-cigarettes (Australia, (20%), Malaysia (19%), Netherlands (18%), United States (15%), Republic of Korea (11%), United Kingdom (10%), Mexico (4%), Canada (4%), Brazil (3%), and China (2%)), and in current use (Malaysia (14%), Republic of Korea (7%), Australia (7%), United States (6%), United Kingdom (4%), Netherlands (3%), Canada (1%), and China (0.05%)). Conclusions: The cross-country variability in awareness, trial, and current use of e-cigarettes is likely due to a confluence of country-specific market factors, tobacco control policies and regulations (e.g., the legal status of e-cigarettes and nicotine), and the survey timing along the trajectory of e-cigarette awareness and trial/use in each country. These ITC results constitute an important snapshot of an early stage of what appears to be a rapid progression of global e-cigarette use.
PMCID: PMC4245638  PMID: 25421063
e-cigarette; electronic cigarette; nicotine; smoking; international
5.  Urothelial Dysfunction and Increased Suburothelial Inflammation of Urinary Bladder Are Involved in Patients with Upper Urinary Tract Urolithiasis – Clinical and Immunohistochemistry Study 
PLoS ONE  2014;9(10):e110754.
To investigate the urothelial dysfunction and inflammation of urinary bladder in patients with upper urinary tract (UUT) urolithiasis through the results of cystoscopic hydrodistension and immunohistochemistry study.
Ninety-one patients with UUT urolithiasis underwent cystoscopic hydrodistension before the stone surgery. Immunofluorescence staining of E-cadherin, zonula occludens-1 (ZO-1), tryptase (mast cell activation), and TUNEL (urothelial apoptosis) were performed in 42 patients with glomerulations after hydrodistension, 10 without glomerulations, and 10 controls.
Of the 91 patients, 62 (68.2%) developed glomerulations after hydrodistension. Lower urinary tract symptoms (LUTS) were present in 53.8% patients, in whom significantly smaller maximal anesthetic bladder capacity (MBC) was noted. Patients with middle or lower 1/3 ureteral stones had a significantly higher glomerulation rate (88.6% vs. 55.4%, p<0.01) and lower MBC (618.4±167.6 vs. 701.2±158.4 ml, p = 0.027) than those with upper 1/3 ureteral or renal stones. Patients with UUT urolithiasis had significantly lower expression of E-cadherin (26.2±14.8 vs. 42.4±16.7) and ZO-1 (5.16±4.02 vs. 11.02±5.66); and higher suburothelial mast cell (13.3±6.8 vs. 1.3±1.2) and apoptotic cell (2.6±2.5 vs. 0.1±0.3) numbers than in controls (all p<0.01).
Urothelial dysfunction and increased suburothelial inflammation and apoptosis are highly prevalent in the bladders of UUT urolithiasis patients, indicating inflammation cross-talk between UUT and urinary bladder. Patients with UUT urolithiaisis concomitant with LUTS had a smaller MBC, which may explain the presence of irritative bladder symptoms.
PMCID: PMC4203847  PMID: 25329457
6.  Increase in Nontuberculous Mycobacteria Isolated in Shanghai, China: Results from a Population-Based Study 
PLoS ONE  2014;9(10):e109736.
In China, the prevalence of nontuberculous mycobacteria (NTM) in isolates from mycobacterial culture-positive patients with pulmonary tuberculosis (TB) is largely unknown.
We used conventional biochemical and 16S rRNA gene sequencing to identify species of mycobacteria in specimens from patients suspected of having TB. Drug-susceptibility testing was performed on NTM isolates using the proportion method. We also determined the independent risk factors associated with infection with NTM compared with infection with Mycobacterium tuberculosis.
The overall rate of NTM isolated from mycobacterial culture-positive patients was 5.9% in this population, with a significantly increasing trend from 3.0% in 2008 to 8.5% in 2012 (P for trend <0.001). The organism most frequently identified was M. kansasii (45.0%), followed by M. intracellulare (20.8%) and M. chelonae/abscessus (14.9%). The overall proportion of isolates resistant to the four first-line anti-TB agents were 64.6% for isoniazid, 77.6% for streptomycin, 63.3% for rifampicin and 75.1% for ethambutol. The risk factors most often associated with NTM infection were older age (P for trend <0.001), being a resident of Shanghai (adjusted odds ratio [aOR], 1.48; 95% CI, 1.10–2.00), having been treated for tuberculosis (aOR, 1.64; 95% CI, 1.18–2.29), having a cavity on chest X-ray (aOR, 1.51; 95% CI, 1.16–1.96), and being sputum smear–negative (aOR, 1.59; 95% CI, 1.16–2.18).
The prevalence of NTM isolated in Shanghai increased between 2008 and 2012, thus clinicians should consider NTM as a possible cause of TB-like disease. Accurate species identification is imperative so that proper treatment can be administered for diseases caused by the diversity of NTM species.
PMCID: PMC4199589  PMID: 25330201
7.  Persistent Long-Term Facilitation at an Identified Synapse Becomes Labile with Activation of Short-Term Heterosynaptic Plasticity 
The Journal of Neuroscience  2014;34(14):4776-4785.
Short-term and long-term synaptic plasticity are cellular correlates of learning and memory of different durations. Little is known, however, how these two forms of plasticity interact at the same synaptic connection. We examined the reciprocal impact of short-term heterosynaptic or homosynaptic plasticity at sensorimotor synapses of Aplysia in cell culture when expressing persistent long-term facilitation (P-LTF) evoked by serotonin [5-hydroxytryptamine (5-HT)]. Short-term heterosynaptic plasticity induced by 5-HT (facilitation) or the neuropeptide FMRFa (depression) and short-term homosynaptic plasticity induced by tetanus [post-tetanic potentiation (PTP)] or low-frequency stimulation [homosynaptic depression (HSD)] of the sensory neuron were expressed in both control synapses and synapses expressing P-LTF in the absence or presence of protein synthesis inhibitors. All forms of short-term plasticity failed to significantly affect ongoing P-LTF in the absence of protein synthesis inhibitors. However, P-LTF reversed to control levels when either 5-HT or FMRFa was applied in the presence of rapamycin. In contrast, P-LTF was unaffected when either PTP or HSD was evoked in the presence of either rapamycin or anisomycin. These results indicate that synapses expressing persistent plasticity acquire a “new” baseline and functionally express short-term changes as naive synapses, but the new baseline becomes labile following selective activations—heterosynaptic stimuli that evoke opposite forms of plasticity—such that when presented in the presence of protein synthesis inhibitors produce a rapid reversal of the persistent plasticity. Activity-selective induction of a labile state at synapses expressing persistent plasticity may facilitate the development of therapies for reversing inappropriate memories.
PMCID: PMC3972711  PMID: 24695698
8.  Comparing the Experience of Regret and Its Predictors Among Smokers in Four Asian Countries: Findings From the ITC Surveys in Thailand, South Korea, Malaysia, and China 
Nicotine & Tobacco Research  2013;15(10):1663-1672.
Nearly all smokers in high-income Western countries report that they regret smoking (Fong, G. T., Hammond, D., Laux, F. L., Zanna, M. P., Cummings, M. K., Borland, R., & Ross, H. [2004]. The near-universal experience of regret among smokers in four countries: Findings from the International Tobacco Control Policy Evaluation Survey. Nicotine and Tobacco Research, 6, S341–S351. doi:10.1080/14622200412331320743), but no research to date has examined the prevalence of regret among smokers in non-Western, low- and middle-income countries.
Data were from the International Tobacco Control (ITC) Surveys of smokers in 4 Asian countries (China, Malaysia, South Korea, and Thailand); N = 9,738. Regret was measured with the statement: “If you had to do it over again, you would not have started smoking.”
Prevalence of regret in 3 countries (South Korea = 87%, Malaysia = 77%, and China = 74%) was lower than that found by Fong et al. in the United States, Australia, Canada, and the United Kingdom (89%–90%); but was higher in Thailand (93%). These significant country differences in regret corresponded with differences in tobacco control and norms regarding smoking. The predictors of regret in the Asian countries were very similar to those in the 4 Western countries: Regret was more likely to be experienced by smokers who smoked fewer cigarettes per day, perceived greater benefits of quitting and higher financial costs of smoking, had more prior quit attempts, worried that smoking would damage their health, and felt that their loved ones and society disapproved of smoking. Regret was also positively associated with intentions to quit (r = 0.23, p < .001).
Across the Asian countries and high-income Western countries, the prevalence of regret varies, but the factors predicting regret are quite consistent. Regret may be an important indicator of tobacco control and is related to factors associated with future quitting.
PMCID: PMC3768330  PMID: 23509091
9.  In Vitro and In Vivo Activities of Pterostilbene against Candida albicans Biofilms 
Pterostilbene (PTE) is a stilbene-derived phytoalexin that originates from several natural plant sources. In this study, we evaluated the activity of PTE against Candida albicans biofilms and explored the underlying mechanisms. In 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) reduction assays, biofilm biomass measurement, confocal laser scanning microscopy, and scanning electron microscopy, we found that ≤16 μg/ml PTE had a significant effect against C. albicans biofilms in vitro, while it had no fungicidal effect on planktonic C. albicans cells, which suggested a unique antibiofilm effect of PTE. Then we found that PTE could inhibit biofilm formation and destroy the maintenance of mature biofilms. At 4 μg/ml, PTE decreased cellular surface hydrophobicity (CSH) and suppressed hyphal formation. Gene expression microarrays and real-time reverse transcription-PCR showed that exposure of C. albicans to 16 μg/ml PTE altered the expression of genes that function in morphological transition, ergosterol biosynthesis, oxidoreductase activity, and cell surface and protein unfolding processes (heat shock proteins). Filamentation-related genes, especially those regulated by the Ras/cyclic AMP (cAMP) pathway, including ECE1, ALS3, HWP1, HGC1, and RAS1 itself, were downregulated upon PTE treatment, indicating that the antibiofilm effect of PTE was related to the Ras/cAMP pathway. Then, we found that the addition of exogenous cAMP reverted the PTE-induced filamentous growth defect. Finally, with a rat central venous catheter infection model, we confirmed the in vivo activity of PTE against C. albicans biofilms. Collectively, PTE had strong activities against C. albicans biofilms both in vitro and in vivo, and these activities were associated with the Ras/cAMP pathway.
PMCID: PMC4023736  PMID: 24514088
10.  Ste18p Is a Positive Control Element in the Mating Process of Candida albicans 
Eukaryotic Cell  2014;13(4):461-469.
Heterotrimeric G proteins are an important class of eukaryotic signaling molecules that have been identified as central elements in the pheromone response pathways of many fungi. In the fungal pathogen Candida albicans, the STE18 gene (ORF19.6551.1) encodes a potential γ subunit of a heterotrimeric G protein; this protein contains the C-terminal CAAX box characteristic of γ subunits and has sequence similarity to γ subunits implicated in the mating pathways of a variety of fungi. Disruption of this gene was shown to cause sterility of MTLa mating cells and to block pheromone-induced gene expression and shmoo formation; deletion of just the CAAX box residues is sufficient to inactivate Ste18 function in the mating process. Intriguingly, ectopic expression behind the strong ACT1 promoter of either the Gα or the Gβ subunit of the heterotrimeric G protein is able to suppress the mating defect caused by deletion of the Gγ subunit and restore both pheromone-induced gene expression and morphology changes.
PMCID: PMC4000101  PMID: 24489040
11.  Utility of the Asia-Pacific colorectal screening scoring system and the presence of metabolic syndrome components in screening for sporadic colorectal cancer 
World Journal of Gastroenterology : WJG  2014;20(32):11394-11399.
AIM: To determine the utility of the Asia-Pacific colorectal screening (APCS) scoring system and metabolic syndrome components in individual screening for sporadic colorectal cancer.
METHODS: The subjects were patients admitted to the Peking University People’s Hospital for colonoscopy between October 2012 and July 2013. Clinical information, including patient willingness to undergo colonoscopy, medical history, endoscopic findings, histology, and other information, was collected, and the patients were grouped according to APCS scores and the presence of metabolic syndrome components. Colorectal tumor detection rates were compared between the groups.
RESULTS: A total of 219 patients were included in the study, 108 were male and 111 were female, resulting in a male-to-female ratio of 1:1.03. The average age of the patients was 56.8 ± 13.7 years. According to APCS scores, 88 (40.2%) patients were included in the average-risk (AR) group, 113 (51.6%) patients were included in the moderate-risk (MR) group, and 18 (8.2%) patients were included in the high-risk (HR) group. Colorectal tumors were detected in 69 (31.5%) subjects, and the detection rates in the AR, MR, and HR groups were 15.9%, 36.3%, and 77.8%, respectively. The difference in the detection rates between the three groups was statistically significant (P < 0.01). The combined detection rate of colorectal tumors in the APCS MR and HR groups was 42.0%. However, patients in the MR and HR groups who presented with metabolic syndrome components, in particular obesity, exhibited a significantly higher colorectal tumor detection rate (59.5%) than did those without these components (19.2%, P < 0.01) and those who underwent colonoscopy because of doctor’s recommendation (36.5%, P < 0.01).
CONCLUSION: The APCS scoring system can be used in individual screening for sporadic colorectal cancer. The combined use of APCS scores and the metabolic syndrome components, in particular obesity, will significantly improve the efficacy of individual colorectal cancer screening.
PMCID: PMC4145781  PMID: 25170227
Asia-Pacific colorectal screening scoring system; Metabolic syndrome; Obesity; Colorectal cancer; Individual screening
12.  Efficacy and Safety of Intravesical OnabotulinumtoxinA Injection on Elderly Patients with Chronic Central Nervous System Lesions and Overactive Bladder 
PLoS ONE  2014;9(8):e105989.
Intravesical injection of onabotulinumtoxinA is an effective treatment for overactive bladder (OAB). Nonetheless, the treatment outcome is unclear in OAB patients with central nervous system (CNS) lesions. This study evaluated the efficacy and safety of intravesical onabotulinumtoxinA treatment in elderly patients with chronic cerebrovascular accidents (CVAs), Parkinson’s disease (PD) and dementia.
Materials and Methods
Patients with CVA, PD, dementia, and OAB refractory to antimuscarinic therapy were consecutively enrolled in the study group. Age-matched OAB patients without CNS lesions were selected to serve as a control group. OnabotulinumtoxinA (100 U) was injected into the bladder suburothelium at 20 sites. The clinical effects, adverse events, and urodynamic parameters were assessed at baseline and 3 months post-treatment. The Kaplan-Meier method was used to compare long-term success rates between groups.
A total of 40 patients with OAB due to CVA (23), PD (9), dementia (8) and 160 control patients were included in this retrospetive analysis. Improvement of urgency severity scale, increased bladder capacity and increased post-void residual volume were comparable between the groups at 3 months. Patients with CNS lesions did not experience increased risks of acute urinary retention and urinary tract infection; nonetheless, patients with CVA experienced a higher rate of straining to void. Long-term success rates did not differ between the patients with and without CNS lesions.
Intravesical injection of 100 U of onabotulinumtoxinA effectively decreased urgency symptoms in elderly OAB patients with CNS lesions. The adverse events were acceptable, and long-term effects were comparable to OAB patients in general. Nonetheless, the possibility of longstanding urinary retention and chronic catheterization need careful evaluation for this very vulnerable population before choosing intravesical onabotulinumtoxinA treatment.
PMCID: PMC4141863  PMID: 25148378
13.  Design, synthesis, and anticancer activity of novel berberine derivatives prepared via CuAAC “click” chemistry as potential anticancer agents 
A series of novel derivatives of phenyl-substituted berberine triazolyls has been designed and synthesized via copper-catalyzed azide-alkyne cycloaddition click chemistry in an attempt to develop antitumor agents. All of the compounds were evaluated for anticancer activity against a panel of three human cancer cell lines, including MCF-7 (breast), SW-1990 (pancreatic), and SMMC-7721 (liver) and the noncancerous human umbilical vein endothelial cell (HUVEC) cell lines. The results indicated that most of the compounds displayed notable anticancer activities against the MCF-7 cells compared with berberine. Among these derivatives, compound 16 showed the most potent inhibitory activity against the SW-1990 and SMMC-7721 cell lines, with half-maximal inhibitory concentration (IC50) values of 8.54±1.97 μM and 11.87±1.83 μM, respectively. Compound 36 exhibited the most potent inhibitory activity against the MCF-7 cell line, with an IC50 value of 12.57±1.96 μM. Compound 16 and compound 36 exhibited low cytotoxicity in the HUVEC cell line, with IC50 values of 25.49±3.24 μM and 30.47±3.47 μM. Furthermore, compounds 14, 15, 16, 17, 18, 32, and 36 exhibited much better selectivity than berberine toward the normal cell line HUVEC.
PMCID: PMC4128789  PMID: 25120353
berberine; anticancer; click chemistry; structure–activity relationship
14.  RASAL2 down-regulation in ovarian cancer promotes epithelial-mesenchymal transition and metastasis 
Oncotarget  2014;5(16):6734-6745.
Ovarian cancer is the most lethal gynecologic malignancy, and transcoelomic metastasis is responsible for the greatest disease mortality. Although intensive efforts have been made, the mechanism behind this process remains unclear. RASAL2 is a GTPase activating proteins (GAPs) which was recently reported as a tumor suppressor in breast cancer. In this study, we identified RASAL2 as a regulator of epithelial-mesenchymal transition (EMT) and metastasis in ovarian cancer. RASAL2 was down-regulated in ovarian cancer samples compared with normal tissue samples, especially in advanced stages and grades. RASAL2 knockdown in ovarian cancer cell lines promoted in vitro anchorage-independent growth, cell migration and invasion and in vivo tumor formation. Moreover, we observed EMT in RASAL2-depleted cells. E-cadherin-mediated cell-cell adhesion was attenuated, and mesenchymal markers were up-regulated. Further investigation revealed that the oncogenic role of RASAL2 down-regulation was mediated by the Ras-ERK pathway. RASAL2 knockdown activated the Ras-ERK pathway, and inhibition of the pathway reversed the functional effects of RASAL2 depletion. Together, our results implicate RASAL2 as an EMT regulator and tumor suppressor in ovarian cancer, and down-regulation of RASAL2 promotes ovarian cancer progression.
PMCID: PMC4196159  PMID: 25216515
ovarian cancer; RASAL2; EMT; MAPK; metastasis
15.  Synergistic Antifungal Effect of Glabridin and Fluconazole 
PLoS ONE  2014;9(7):e103442.
The incidence of invasive fungal infections is increasing in recent years. The present study mainly investigated glabridin (Gla) alone and especially in combination with fluconazole (FLC) against Cryptococcus neoformans and Candida species (Candida albicans, Candida tropicalis, Candida krusei, Candida parapsilosis and Candida Glabratas) by different methods. The minimal inhibitory concentration (MIC) and the minimal fungicidal concentration (MFC) indicated that Gla possessed a broad-spectrum antifungal activity at relatively high concentrations. After combining with FLC, Gla exerted a potent synergistic effect against drug-resistant C. albicans and C. tropicalis at lower concentrations when interpreted by fractional inhibitory concentration index (FICI). Disk diffusion test and time-killing test confirming the synergistic fungicidal effect. Cell growth tests suggested that the synergistic effect of the two drugs depended more on the concentration of Gla. The cell envelop damage including a significant decrease of cell size and membrane permeability increasing were found after Gla treatment. Together, our results suggested that Gla possessed a synergistic effect with FLC and the cell envelope damage maybe contributed to the synergistic effect, which providing new information for developing novel antifungal agents.
PMCID: PMC4110026  PMID: 25058485
16.  Ascophyllan Purified from Ascophyllum nodosum Induces Th1 and Tc1 Immune Responses by Promoting Dendritic Cell Maturation 
Marine Drugs  2014;12(7):4148-4164.
Marine-derived sulfated polysaccharides have been shown to possess certain anti-virus, anti-tumor, anti-inflammatory and anti-coagulant activities. However, the in vivo immunomodulatory effects of marine-derived pure compounds have been less well characterized. In this study, we investigated the effect of ascophyllan, a sulfated polysaccharide purified from Ascophyllum nodosum, on the maturation of mouse dendritic cells (DCs) in vitro and in vivo. Ascophyllan induced up-regulation of co-stimulatory molecules and production of pro-inflammatory cytokines in bone marrow-derived DCs (BMDCs). Moreover, in vivo administration of ascophyllan promotes up-regulation of CD40, CD80, CD86, MHC class I and MHC class II and production of IL-6, IL-12 and TNF-α in spleen cDCs. Interestingly, ascophyllan induced a higher degree of co-stimulatory molecule up-regulation and pro-inflammatory cytokine production than fucoidan, a marine-derived polysaccharide with well-defined effect for promoting DC maturation. Ascophyllan also promoted the generation of IFN-γ-producing Th1 and Tc1 cells in the presence of DCs in an IL-12-dependent manner. Finally, myeloid differentiation primary response 88 (MyD88) signaling pathway was essential for DC maturation induced by ascophyllan. Taken together, these results demonstrate that ascophyllan induces DC maturation, and consequently enhances Th1 and Tc1 responses in vivo. This knowledge could facilitate the development of novel therapeutic strategies to combat infectious diseases and cancer.
PMCID: PMC4113820  PMID: 25026264
ascophyllan; dendritic cells; DC maturation; Th1 cells; Tc1 cells
17.  Family-based association test using normal approximation to gene dropping null distribution 
BMC Proceedings  2014;8(Suppl 1):S18.
We derive the analytical mean and variance of the score test statistic in gene-dropping simulations and approximate the null distribution of the test statistic by a normal distribution. We provide insights into the gene-dropping test by decomposing the test statistic into two components: the first component provides information about linkage, and the second component provides information about fine mapping under the linkage peak. We demonstrate our theoretical findings by applying the gene-dropping test to the simulated data set from Genetic Analysis Workshop 18 and comparing its performance with existing population and family-based association tests.
PMCID: PMC4143692  PMID: 25519313
18.  Fucoidan Can Function as an Adjuvant In Vivo to Enhance Dendritic Cell Maturation and Function and Promote Antigen-Specific T Cell Immune Responses 
PLoS ONE  2014;9(6):e99396.
Fucoidan, a sulfated polysaccharide purified from brown algae, has a variety of immune-modulation effects, including promoting antigen uptake and enhancing anti-viral and anti-tumor effects. However, the effect of fucoidan in vivo, especially its adjuvant effect on in vivo anti-tumor immune responses, was not fully investigated. In this study, we investigated the effect of fucoidan on the function of spleen dendritic cells (DCs) and its adjuvant effect in vivo. Systemic administration of fucoidan induced up-regulation of CD40, CD80 and CD86 expression and production of IL-6, IL-12 and TNF-α in spleen cDCs. Fucoidan also promoted the generation of IFN-γ-producing Th1 and Tc1 cells in an IL-12-dependent manner. When used as an adjuvant in vivo with ovalbumin (OVA) antigen, fucoidan promoted OVA-specific antibody production and primed IFN-γ production in OVA-specific T cells. Moreover, fucoidan enhanced OVA-induced up-regulation of MHC class I and II on spleen cDCs and strongly prompted the proliferation of OVA-specific CD4 and CD8 T cells. Finally, OVA immunization with fucoidan as adjuvant protected mice from the challenge with B16-OVA tumor cells. Taken together, these results suggest that fucoidan can function as an adjuvant to induce Th1 immune response and CTL activation, which may be useful in tumor vaccine development.
PMCID: PMC4049775  PMID: 24911024
19.  First Insight into the Genotypic Diversity of Clinical Mycobacterium tuberculosis Isolates from Gansu Province, China 
PLoS ONE  2014;9(6):e99357.
Investigations of Mycobacterium tuberculosis genetic diversity in China have indicated a significant regional distribution. The aim of this study was to characterize the genotypes of clinical M. tuberculosis isolates obtained from Gansu, which has a special geographic location in China.
Methodology/Principal Findings
A total of 467 clinical M. tuberculosis strains isolated in Gansu Province were genotyped by 15-locus mycobacterial interspersed repetitive units–variable number tandem repeats (MIRU-VNTR) and spoligotyping. The results showed that 445 isolates belonged to six known spoligotype lineages, whereas 22 isolates were unknown. The Beijing genotype was the most prevalent (87.58%, n = 409), while the shared type 1 was the dominant genotype (80.94%, n = 378). The second most common lineage was the T lineage, with 25 isolates (5.35%), followed by the H lineage with 5 isolates (1.07%), the MANU family (0.64%, 3 isolates), the U family (0.43%, 2 isolates) and the CAS lineage with 1 isolate (0.21%). By using the VNTR15China method, we observed 15 groups and 228 genotypes among the 467 isolates. We found no association between the five larger groups (including the Beijing genotype) and sex, age, or treatment status, and there was no noticeable difference in the group analysis in different areas. In the present study, seven of the 15 MIRU-VNTR loci were highly or moderately discriminative according to their Hunter-Gaston discriminatory index.
The Beijing genotype is the predominant genotype in Gansu province. We confirm that VNTR15China is suitable for typing Beijing strains in China and that it has a better discriminatory power than spoligotyping. Therefore, the use of both methods is the most suitable for genotyping analysis of M. tuberculosis.
PMCID: PMC4049826  PMID: 24911588
20.  Fluconazole Assists Berberine To Kill Fluconazole-Resistant Candida albicans 
Antimicrobial Agents and Chemotherapy  2013;57(12):6016-6027.
It was found in our previous study that berberine (BBR) and fluconazole (FLC) used concomitantly exhibited a synergism against FLC-resistant Candida albicans in vitro. The aim of the present study was to clarify how BBR and FLC worked synergistically and the underlying mechanism. Antifungal time-kill curves indicated that the synergistic effect of the two drugs was BBR dose dependent rather than FLC dose dependent. In addition, we found that BBR accumulated in C. albicans cells, especially in the nucleus, and resulted in cell cycle arrest and significant change in the transcription of cell cycle-related genes. Besides BBR, other DNA intercalators, including methylene blue, sanguinarine, and acridine orange, were all found to synergize with FLC against FLC-resistant C. albicans. Detection of intracellular BBR accumulation by fluorescence measurement showed that FLC played a role in increasing intracellular BBR concentration, probably due to its effect in disrupting the fungal cell membrane. Similar to the case with FLC, other antifungal agents acting on the cell membrane were able to synergize with BBR. Interestingly, we found that the efflux of intracellular BBR was FLC independent but strongly glucose dependent and associated with the drug efflux pump Cdr2p. These results suggest that BBR plays a major antifungal role in the synergism of FLC and BBR, while FLC plays a role in increasing the intracellular BBR concentration.
PMCID: PMC3837902  PMID: 24060867
21.  The effect of cigarette prices on brand-switching in China: a longitudinal analysis of data from the ITC China Survey 
Tobacco control  2013;23(0 1):i54-i60.
Recent studies have found that Chinese smokers are relatively unresponsive to cigarette prices. As the Chinese government contemplates higher tobacco taxes, it is important to understand the reasons for this low response. One possible explanation is that smokers buffer themselves from rising cigarette prices by switching to cheaper cigarette brands.
This study examines how cigarette prices influence consumers’ choices of cigarette brands in China.
This study uses panel data from the first three waves of the International Tobacco Control China Survey, drawn from six large cities in China and collected between 2006 and 2009. The study sample includes 3477 smokers who are present in at least two waves (8552 person-years). Cigarette brands are sorted by price into four tiers, using excise tax categories to determine the cut-off for each tier. The analysis relies on a conditional logit model to identify the relationship between price and brand choice.
Overall, 38% of smokers switched price tiers from one wave to the next. A ¥1 change in the price of cigarettes alters the tier choice of 4–7% of smokers. Restricting the sample to those who chose each given tier at baseline, a ¥1 increase in price in a given tier would decrease the share choosing that tier by 4% for Tier 1 and 1–2% for Tiers 2 and 3.
China's large price spread across cigarette brands appears to alter the brand selection of some consumers, especially smokers of cheaper brands. Tobacco pricing and tax policy can influence consumers’ incentives to switch brands. In particular, whereas ad valorem taxes in a tiered pricing system like China's encourage trading down, specific excise taxes discourage the practice.
PMCID: PMC4035484  PMID: 23697645
22.  Identification, expression and interaction analyses of calcium-dependent protein kinase (CPK) genes in canola (Brassica napus L.) 
BMC Genomics  2014;15:211.
Canola (Brassica napus L.) is one of the most important oil-producing crops in China and worldwide. The yield and quality of canola is frequently threatened by environmental stresses including drought, cold and high salinity. Calcium is a well-known ubiquitous intracellular secondary messenger in plants. Calcium-dependent protein kinases (CPKs) are Ser/Thr protein kinases found only in plants and some protozoans. CPKs are Ca2+ sensors that have both Ca2+ sensing function and kinase activity within a single protein and play crucial roles in plant development and responses to various environmental stresses.
In this study, we mined the available expressed sequence tags (ESTs) of B. napus and identified a total of 25 CPK genes, among which cDNA sequences of 23 genes were successfully cloned from a double haploid cultivar of canola. Phylogenetic analysis demonstrated that they could be clustered into four subgroups. The subcellular localization of five selected BnaCPKs was determined using green fluorescence protein (GFP) as the reporter. Furthermore, the expression levels of 21 BnaCPK genes in response to salt, drought, cold, heat, abscisic acid (ABA), low potassium (LK) and oxidative stress were studied by quantitative RT-PCR and were found to respond to multiple stimuli, suggesting that canola CPKs may be convergence points of different signaling pathways. We also identified and cloned five and eight Clade A basic leucine zipper (bZIP) and protein phosphatase type 2C (PP2C) genes from canola and, using yeast two-hybrid and bimolecular fluorescence complementation (BiFC), determined the interaction between individual BnaCPKs and BnabZIPs or BnaPP2Cs (Clade A). We identified novel, interesting interaction partners for some of the BnaCPK proteins.
We present the sequences and characterization of CPK gene family members in canola for the first time. This work provides a foundation for further crop improvement and improved understanding of signal transduction in plants.
PMCID: PMC4000008  PMID: 24646378
Abiotic stress; Basic leucine zipper transcription factor; Brassica napus; Calcium-dependent protein kinase; Protein phosphatase 2C
23.  Decrease of Urinary Nerve Growth Factor but Not Brain-Derived Neurotrophic Factor in Patients with Interstitial Cystitis/Bladder Pain Syndrome Treated with Hyaluronic Acid 
PLoS ONE  2014;9(3):e91609.
To investigate urinary nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) levels in interstitial cystitis/bladder pain syndrome (IC/BPS) patients after hyaluronic acid (HA) therapy.
Thirty-three patients with IC/BPS were prospectively studied; a group of 45 age-matched healthy subjects served as controls. All IC/BPS patients received nine intravesical HA instillations during the 6-month treatment regimen. Urine samples were collected for measuring urinary NGF and BDNF levels at baseline and 2 weeks after the last HA treatment. The clinical parameters including visual analog scale (VAS) of pain, daily frequency nocturia episodes, functional bladder capacity (FBC) and global response assessment (GRA) were recorded. Urinary NGF and BDNF levels were compared between IC/BPS patients and controls at baseline and after HA treatment.
Urinary NGF, NGF/Cr, BDNF, and BDNF/Cr levels were significantly higher in IC/BPS patients compared to controls. Both NGF and NGF/Cr levels significantly decreased after HA treatment. Urinary NGF and NGF/Cr levels significantly decreased in the responders with a VAS pain reduction by 2 (both p < 0.05) and the GRA improved by 2 (both p < 0.05), but not in non-responders. Urinary BDNF and BDNF/Cr did not decrease in responders or non-responders after HA therapy.
Urinary NGF, but not BDNF, levels decreased significantly after HA therapy; both of these factors remained higher than in controls even after HA treatment. HA had a beneficial effect on IC/BPS, but it was limited. The reduction of urinary NGF levels was significant in responders, with a reduction of pain and improved GRA.
PMCID: PMC3948883  PMID: 24614892
24.  Identification and functional analysis of mitogen-activated protein kinase kinase kinase (MAPKKK) genes in canola (Brassica napus L.) 
Journal of Experimental Botany  2014;65(8):2171-2188.
Twenty-eight BnaMAPKKK genes were cloned. Phylogenetic and expression profiling analyses indicated their relationship and roles in stress and hormone signalling. Two novel BnaMAPKKK genes were identified to mediate cell death independent of pathogens.
Mitogen-activated protein kinase (MAPK) signalling cascades, consisting of three types of reversibly phosphorylated kinases (MAPKKK, MAPKK, and MAPK), are involved in important processes including plant immunity and hormone responses. The MAPKKKs comprise the largest family in the MAPK cascades, yet only a few of these genes have been associated with physiological functions, even in the model plant Arabidopsis thaliana. Canola (Brassica napus L.) is one of the most important oilseed crops in China and worldwide. To explore MAPKKK functions in biotic and abiotic stress responses in canola, 66 MAPKKK genes were identified and 28 of them were cloned. Phylogenetic analysis of these canola MAPKKKs with homologous genes from representative species classified them into three groups (A–C), comprising four MAPKKKs, seven ZIKs, and 17 Raf genes. A further 15 interaction pairs between these MAPKKKs and the downstream BnaMKKs were identified through a yeast two-hybrid assay. The interactions were further validated through bimolecular fluorescence complementation (BiFC) analysis. In addition, by quantitative real-time reverse transcription–PCR, it was further observed that some of these BnaMAPKKK genes were regulated by different hormone stimuli, abiotic stresses, or fungal pathogen treatments. Interestingly, two novel BnaMAPKKK genes, BnaMAPKKK18 and BnaMAPKKK19, which could elicit hypersensitive response (HR)-like cell death when transiently expressed in Nicotiana benthamiana leaves, were successfully identified. Moreover, it was found that BnaMAPKKK19 probably mediated cell death through BnaMKK9. Overall, the present work has laid the foundation for further characterization of this important MAPKKK gene family in canola.
PMCID: PMC3991747  PMID: 24604738
Abiotic stress; Brassica napus; cell death; MAPKKK; MKK; Sclerotinia sclerotiorum.
25.  Who purchases cigarettes from cheaper sources in China? Findings from the ITC China Survey 
Tobacco control  2013;23(0 1):i97-i101.
The availability of cigarettes from cheaper sources constitutes a major challenge to public health throughout the world, including China, because it may counteract price-based tobacco control policies. The goal of this study was to identify factors associated with purchasing cigarettes from cheaper sources among adult smokers in China.
Data were analyzed from Waves 1–3 of the International Tobacco Control China Survey, conducted in 2006–2009 among adult smokers in six cities in China (N=7,980). One survey question asked, “In the last six months, have you purchased cheaper cigarettes than you can get from local stores for economic reasons?” We examined whether sociodemographic factors and smoking intensity were associated with purchasing cigarettes from cheaper sources using the general estimating equations (GEE) model. Sociodemographic factors considered were gender, age, marital status, monthly household income, education, employment status, and city of residence.
15.6% of smokers reported purchasing cigarettes from cheaper sources. After controlling for other covariates, the associations of the behavior of purchasing cigarettes from cheaper sources with age (AOR=1.49, 95% CI=1.17–3.92 for age 18–24 compared to age 55+) and with income (AOR=2.93, 95%CI=2.27–3.79 for low income compared to high income) were statistically significant, but there was no statistically significant relationship with smoking intensity.
Our findings indicate that young and low income smokers are more likely than older and high income smokers to purchase cigarettes from cheaper sources in China. Tobacco control policies that reduce the availability of cigarettes from cheaper sources could have an impact on reducing cigarette consumption among young and low income smokers in China.
PMCID: PMC3931911  PMID: 24078076
Cheaper sources; Smoking; China; Taxation; Income

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