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1.  Functional Polymorphisms in FAS/FASL System Increase the Risk of Neuroblastoma in Chinese Population 
PLoS ONE  2013;8(8):e71656.
The FAS and FASL system plays a substantial role in apoptosis and immune escape of cells. Three polymorphisms located in the promoter regions of FAS (-1377G/A and -670A/G) and FASL (-844T/C) have been shown to alter the transcriptional activity of the genes, respectively. This study was conducted to evaluate the effects of these polymorphisms on the susceptibility of neuroblastoma in the Chinese population. A total of 203 patients with neuroblastoma and 411 controls were recruited in this case-control study. Polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) was applied for genotyping. Unconditional logistic regression was used to estimate cancer risk by calculating odds ratios (ORs) and their 95% confidence intervals (95% CIs). It was observed that significantly increased risks of neuroblastoma associated with FAS -1377G/A and FASL -844T/C polymorphisms, with ORs equal to 1.55 (95% CI, 1.10–2.20) for FAS -1377 A allele and 2.90 (95% CI, 2.04–4.12) for FASL -844CC genotype carriers compared with non-carriers, respectively. However, no association was found between the polymorphisms of FAS -670A/G and risk of neuroblastoma. In addition, the cumulative effect of FAS and FASL polymorphisms on risk of neuroblastoma was observed (P for trend = 2.502×10−10), with OR for the carriers of both FAS -1377A allele and FASL -844CC genotypes equaled to 3.95 (95% CI, 2.40–6.51). This work reveals that polymorphisms of FAS -1377G/A and FASL -844T/C but not FAS -670A/G are associated with risk of neuroblastoma in Chinese. These findings support the hypothesis that genetic polymorphism in FAS/FASL death system may influence individual susceptibility to neuroblastoma.
PMCID: PMC3741122  PMID: 23951214
2.  2-(3-Oxocyclo­hex-1-enylamino)acetic acid 
The six-membered ring of the title compound, C8H11NO3, adopts an envelope shape with the C atom in the meta position of the carbonyl representing the flap. This atom is disordered over two positions in an 0.865 (6): 0.135 (6) ratio. In the crystal, a two-dimensional supra­molecular network parallel to the ac plane is built up from O—H⋯O and N—H⋯O hydrogen bonds.
PMCID: PMC2971405  PMID: 21578369
3.  Soil Biochemical Responses to Nitrogen Addition in a Bamboo Forest 
PLoS ONE  2014;9(7):e102315.
Many vital ecosystem processes take place in the soils and are greatly affected by the increasing active nitrogen (N) deposition observed globally. Nitrogen deposition generally affects ecosystem processes through the changes in soil biochemical properties such as soil nutrient availability, microbial properties and enzyme activities. In order to evaluate the soil biochemical responses to elevated atmospheric N deposition in bamboo forest ecosystems, a two-year field N addition experiment in a hybrid bamboo (Bambusa pervariabilis × Dendrocalamopsis daii) plantation was conducted. Four levels of N treatment were applied: (1) control (CK, without N added), (2) low-nitrogen (LN, 50 kg N ha−1 year−1), (3) medium-nitrogen (MN, 150 kg N ha−1 year−1), and (4) high-nitrogen (HN, 300 kg N ha−1 year−1). Results indicated that N addition significantly increased the concentrations of NH4+, NO3−, microbial biomass carbon, microbial biomass N, the rates of nitrification and denitrification; significantly decreased soil pH and the concentration of available phosphorus, and had no effect on the total organic carbon and total N concentration in the 0–20 cm soil depth. Nitrogen addition significantly stimulated activities of hydrolytic enzyme that acquiring N (urease) and phosphorus (acid phosphatase) and depressed the oxidative enzymes (phenol oxidase, peroxidase and catalase) activities. Results suggest that (1) this bamboo forest ecosystem is moving towards being limited by P or co-limited by P under elevated N deposition, (2) the expected progressive increases in N deposition may have a potential important effect on forest litter decomposition due to the interaction of inorganic N and oxidative enzyme activities, in such bamboo forests under high levels of ambient N deposition.
PMCID: PMC4100878  PMID: 25029346
4.  Generation and characterization of a new mammalian cell line continuously expressing virus-like particles of Japanese encephalitis virus for a subunit vaccine candidate 
BMC Biotechnology  2014;14:62.
Japanese encephalitis virus (JEV) is the most important cause of epidemic encephalitis in most Asian regions. There is no specific treatment available for Japanese encephalitis, and vaccination is the only effective way to prevent JEV infection in humans and domestic animals. The purpose of this study is to establish a new mammalian cell line stably and efficiently expressing virus-like particle of JEV for potential use of JEV subunit vaccine.
We generated a new cell clone (BJ-ME cells) that stably produces a secreted form of Japanese encephalitis virus (JEV) virus-like particle (VLP). The BJ-ME cells were engineered by transfecting BHK-21 cells with a code-optimized cDNA encoding JEV prM and E protein expression plasmid. Cell line BJ-ME can stably produces a secreted form of Japanese encephalitis virus virus-like particle (JEV-VLP) which contains the JEV envelope glycoprotein (E) and membrane protein (M). The amount of JEV-VLP antigen released into the culture fluid of BJ-ME cells was as high as 15–20 μg/ml. JEV-VLP production was stable after multiple cell passages and 100% cell expression was maintained without detectable cell fusion or apoptosis. Cell culture fluid containing the JEV-VLP antigen could be harvested five to seven times continuously at intervals of 4–6 days while maintaining the culture. Mice immunized with the JEV-VLP antigen with or without adjuvant developed high titers of neutralizing antibodies and 100% protection against lethal JEV challenge.
These results suggest that the recombinant JEV-VLP antigen produced by the BJ-ME cell line is an effective, safe and affordable subunit Japanese encephalitis vaccine candidate, especially for domestic animals such as pig and horse.
PMCID: PMC4094896  PMID: 25011456
Japanese encephalitis virus; Mammalian cell line; Virus-like particle; Subunit vaccine
5.  Does participation in a weight control program also improve clinical and functional outcomes for Chinese patients with schizophrenia treated with olanzapine? 
This study examined whether participation in a weight control program (WCP) by patients with schizophrenia treated with olanzapine was also associated with improvements in clinical and functional outcomes.
A post-hoc analysis was conducted using data from the Chinese subgroup (n=330) of a multi-country, 6-month, prospective, observational study of outpatients with schizophrenia who initiated or switched to oral olanzapine. At study entry and monthly visits, participants were assessed with the Clinical Global Impression of Severity, and measures of patient insight, social activities, and work impairment. The primary comparison was between the 153 patients who participated in a WCP at study entry (n=93) or during the study (n=60) and the 177 patients who did not participate in a weight control program (non-WCP). Mixed Models for Repeated Measures with baseline covariates were used to compare outcomes over time. Kaplan–Meier survival analysis was used to assess time to response.
Participants had a mean age of 29.0 years and 29.3 years, and 51.0% and 57.6% were female for WCP and non-WCP groups, respectively. Average initiated daily dose for olanzapine was 9.5±5.4 mg. WCP participants gained less weight than non-participants (3.9 kg vs 4.9 kg, P=0.03) and showed statistically significant better clinical and functional outcomes: greater improvement in illness severity (−2.8 vs −2.1, P<0.001), higher treatment response rates (94.1% vs 80.9%, P<0.001), shorter time to response (P<0.001), and greater improvement in patients’ insight (P<0.001). Patients who enrolled in a WCP during the study had greater initial weight gain than those who enrolled at baseline (P<0.05), but similar total weight gain.
Participation in a WCP may not only lower the risk of clinically significant weight gain in olanzapine-treated patients, but may also be associated with additional clinical and functional benefits.
PMCID: PMC4096454  PMID: 25031537
body weight; olanzapine; schizophrenia; epidemiologic studies; prospective studies
6.  Elevated Soluble VEGF Receptor sFlt-1 Correlates with Endothelial Injury in IgA Nephropathy 
PLoS ONE  2014;9(7):e101779.
Endothelial injury, which may present clinically as hypertension, proteinuria and increased von Willebrand Factor (vWF) level, is a common manifestation in IgA nephropathy (IgAN). However, causal factors for endothelial injury in IgAN are not completely understood. An imbalance of vascular endothelial growth factor/Soluble fms-like tyrosine kinase-1 (VEGF/sFlt-1) has been observed in many diseases with endothelial dysfunction, including pre-eclampsia and diabetic retinopathy, but whether it contributes to endothelial injury in IgAN requires further exploration.
Initially, 96 IgAN patients and 22 healthy volunteers were enrolled as a discovery cohort. VEGF/sFlt-1, sFlt-1 and VEGF levels were compared between patients with IgAN and healthy volunteers to explore the underlying factors that contribute to endothelial injury in IgAN. The identified contributor (sFlt-1) was further confirmed in a replication cohort, which included 109 IgAN patients and 30 healthy volunteers. Correlations of sFlt-1 with hypertension, proteinuria, Oxford-E score and plasma vWF were further evaluated in the combined 205 patients with IgAN.
VEGF/sFlt-1 levels were significantly lower in IgAN patients than healthy volunteers (0.33±0.27 vs. 0.43±0.22, p = 0.02) in the discovery cohort. Within the ratio, plasma sFlt-1 levels were significantly elevated (101.18±25.19 vs. 79.73±18.85 pg/ml, p<0.001), but plasma VEGF levels showed no significant differences. Elevated sFlt-1 levels in the replication cohort were confirmed in IgAN patients (93.40±39.78 vs. 71.92±15.78 pg/ml, p<0.001). Plasma sFlt-1 levels in IgAN patients correlated with proteinuria (severe (>3.5 g/d) vs. moderate (1–3.5 g/d) vs. mild (<1 g/d) proteinuria: 115.95±39.09 vs. 99.89±28.55 vs. 83.24±33.92 pg/ml; severe vs. mild: p<0.001, moderate vs. mild p = 0.001, severe vs. moderate: p = 0.014), hypertension (with vs. without hypertension: 107.87±31.94 vs. 87.32±32.76 pg/ml, p = 0.015) and vWF levels (r = 0.161, p = 0.021).
The present study found elevated sFlt-1 in IgAN patients and further identified its correlation with proteinuria, hypertension and vWF levels. These results suggested that elevated sFlt-1 contributes to endothelial injury in IgAN.
PMCID: PMC4090210  PMID: 25007257
7.  The High Diagnostic Accuracy of Combined Test of Thyroid Transcription Factor 1 and Napsin A to Distinguish between Lung Adenocarcinoma and Squamous Cell Carcinoma: A Meta-Analysis 
PLoS ONE  2014;9(7):e100837.
Accurate classification of non-small cell lung cancer (NSCLC) using morphological features has several limitations. However, the use of thyroid transcription factor 1 (TTF-1) and Napsin A as markers for the identification of various subtypes of NSCLC has shown promise. This meta-analysis was designed to evaluate the diagnostic value of combined TTF-1 and Napsin A test to distinguish lung adenocarcinoma from squamous cell carcinoma.
The Medline, EMBASE and Web of Science databases were searched, along with the reference lists of relevant articles (up to May 4, 2014). Ten studies containing 1,446 subjects were identified. The sensitivity, specificity, diagnostic odds ratio (DOR) and area under the summary receiver operating characteristics curve (AUC) were calculated to estimate the combined diagnostic value of TTF-1 and Napsin A.
The pooled sensitivity and specificity were 0.76 (95% CI: 0.69–0.83) and 1.00 (95% CI: 0.92–1.00), respectively. The positive and negative likelihood ratios were 877.60 (95% CI: 8.40–91533.40) and 0.24 (95% CI: 0.18–0.32). The DOR was 3719 (95% CI: 33–414884). The AUC was 0.92 (95%CI: 0.89–0.94). The patient's location was a source of heterogeneity for sensitivity. The patient's location, the study's sample size and the threshold used to determine positive staining were consistently found to be sources of heterogeneity for specificity in subgroup analyses and meta-regression.
The combined test of TTF-1 and Napsin A presents a promising alternative method, useful to distinguish between lung adenocarcinoma and squamous cell carcinoma.
PMCID: PMC4086931  PMID: 25003505
8.  Colorectal cancer mortality in Inner Mongolia between 2008 and 2012 
AIM: To determine the extent of colorectal cancer (CRC) mortality and the association between demographic characteristics and CRC mortality in Inner Mongolia.
METHODS: Data were collected from the Death Registry System, maintained by the Inner Mongolia Centers for Disease Control and Prevention, from 2008 to 2012. Deaths were classified according to the International Classification of Disease, 10th Revision. Years of life lost, average years of life lost (AYLL), and mortality were calculated over the five years between 2008 and 2012. A conditional logistic regression model was used to analyze the association between marital status, occupational status, education level, area of residence, and the risk of CRC.
RESULTS: The AYLL of CRC was 17.39 years. The average mortality of CRC was 5.6/100000. People living in urban areas and having a higher education level had a significantly higher risk of CRC (OR = 1.74 and 95%CI: 1.29-2.35, P < 0.001 and OR = 2.39, 95%CI: 1.76-3.25, P < 0.001, respectively). People who were employed had a lower risk of CRC (OR = 0.64, 95%CI: 0.48-0.86, P = 0.003). The mortality of CRC was positively correlated with the education level (P < 0.001). No statistically significant association was observed between marital status and CRC risk (P = 0.259).
CONCLUSION: Living in urban areas, higher education level and unemployment are associated with CRC mortality in Inner Mongolia.
PMCID: PMC4081694  PMID: 25009394
Colorectal cancer; Average years of life lost; Mortality; Education level
9.  Clinical features and outcome of acute hepatitis B in pregnancy 
BMC Infectious Diseases  2014;14:368.
The impact of pregnancy on the clinical course of acute hepatitis B (AHB) is still largely unclear, mainly because most studies have not included matched controls. This study was conducted to investigate the clinical features and outcome of AHB in pregnancy using matched controls.
Consecutive AHB inpatients who were admitted to Jinan Infectious Disease Hospital, Jinan, between January 2006 and December 2010 were evaluated and followed. Demographic data, clinical manifestations, and results of laboratory tests were compared between pregnant patients and age and sex matched non-pregnant patients at admission, discharge, and final follow-up.
A total of 618 AHB inpatients were identified during the study period. 22 pregnant patients and 87 age and sex matched non-pregnant patients were enrolled in this study. Prodromal fever was less common (0% vs. 20.7%, P = 0.02), serum alanine aminotransferase levels were significantly lower, and HBsAg > 250 IU/mL rate and serum bilirubin levels were significantly higher in pregnant patients than in non-pregnant patients. After a mean (range) of 7(5.2-8.3) months follow-up, 18.2% pregnant patients and 4.6% non-pregnant patients were still HBsAg positive (P = 0.03). For pregnant patients, the relative risk (95% confidence interval) of HBsAg positive at the end of follow-up was 4.6 (1.1-20.2). The median (95% confidence interval) days of HBsAg seroclearance form disease onset in pregnant and non-pregnant patients were 145.0 (110.5-179.5) and 80.0 (62.6-97.4), respectively.
The HBsAg loss and seroconversion were delayed and lower in pregnant patients. Pregnancy might be a possible risk of chronicity following acute HBV infection.
PMCID: PMC4096733  PMID: 24993389
Acute hepatitis B; Pregnancy; Clinical features; Outcome; Hepatitis B surface antigen; Chronicity
10.  The Impact of Social Factors on Human Immunodeficiency Virus and Hepatitis C Virus Co-Infection in a Minority Region of Si-Chuan, the People's Republic of China: A Population-Based Survey and Testing Study 
PLoS ONE  2014;9(7):e101241.
While many human immunodeficiency virus (HIV) studies have been performed in Liangshan, most were focused only on HIV infection and based on a sampling survey. In order to fully understand HIV and hepatitis C virus (HCV) prevalence and related risk factors in this region, this study implemented in 2009, included a survey, physical examination, HIV and HCV test in two towns.
All residents in two towns of the Butuo county were provided a physical examination and blood tests for HIV and HCV, and then followed by an interview for questionnaire.
In total, 10,104 residents (92.4%) were enrolled and 9,179 blood samples were collected for HIV and HCV testing, 6,072 were from individuals >14 years old. The rates of HIV, HCV, and HIV/HCV co-infection were 11.4%, 14.0%, and 7.7%, respectively for >14-year-old residents. The 25–34 yr age group had the highest prevalence of HIV, HCV, and HIV/HCV co-infections, reaching 24.4%, 26.2% and 16.0%, respectively. Overall, males had a much higher prevalence of all infections than females (HIV: 16.3% vs. 6.8%, HCV: 24.6% vs. 3.9%, HIV/HCV co-infected: 14.7% vs. 1.1%, respectively; P = 0.000). Approximately half of intravenous drug users tested positive for HIV (48.7%) and 68.4% tested positive for HCV. Logistic regression analysis showed that five factors were significantly associated with HIV and HCV infection: gender (odds ratio [OR]  = 5.8), education (OR = 2.29); occupation (student as reference; farmer: OR = 5.02, migrant worker: OR = 6.12); drug abuse (OR = 18.0); and multiple sexual partners (OR = 2.92). Knowledge of HIV was not associated with infection.
HIV and HCV prevalence in the Liangshan region is very serious and drug use, multiple sexual partners, and low education levels were the three main risk factors. The government should focus on improving education and personal health awareness while enhancing drug control programs.
PMCID: PMC4079678  PMID: 24988219
11.  Novel S-Gal® analogs as 1H MRI reporters for in vivo detection of β-galactosidase 
Magnetic resonance imaging  2013;31(6):1006-1011.
The quantitative assessment of gene expression and related enzyme activity in vivo could be important for the characterization of gene altering diseases and therapy. The development of imaging techniques, based on specific reporter molecules may enable routine non-invasive assessment of enzyme activity and gene expression in vivo. We recently reported the use of commercially available S-Gal® as a β-galactosidase reporter for 1HMRI, and the synthesis of several S-Gal® analogs with enhanced response to β-galactosidase activity. We have now compared these analogs in vitro and have identified the optimal analog, C3-GD, based on strong T1 and T2 response to enzyme presence (ΔR1 and ΔR2 ∼ 1.8 times S-Gal®). Moreover, application is demonstrated in vivo in human breast tumor xenografts. MRI studies in MCF7-lacZ tumors implanted subcutaneously in athymic nude mice (n = 6), showed significant reduction in T1 and T2 values (each ∼ 13%) 2 h after intratumoral injection of C3-GD, whereas the MCF7 (wild type) tumors showed slight increase. Thus, C3-GD successfully detects β-galactosidase activity in vivo and shows promise as a lacZ gene 1HMR reporter molecule.
PMCID: PMC3800276  PMID: 23602729
β-galactosidase; 1H MRI; T1; T2; Signal enhancement; Fe-chelation; lacZ; Gene reporters
12.  Soot superaggregates from flaming wildfires and their direct radiative forcing 
Scientific Reports  2014;4:5508.
Wildfires contribute significantly to global soot emissions, yet their aerosol formation mechanisms and resulting particle properties are poorly understood and parameterized in climate models. The conventional view holds that soot is formed via the cluster-dilute aggregation mechanism in wildfires and emitted as aggregates with fractal dimension Df ≈ 1.8 mobility diameter Dm ≤ 1 μm, and aerodynamic diameter Da ≤ 300 nm. Here we report the ubiquitous presence of soot superaggregates (SAs) in the outflow from a major wildfire in India. SAs are porous, low-density aggregates of cluster-dilute aggregates with characteristic Df ≈ 2.6, Dm > 1 μm, and Da ≤ 300 nm that form via the cluster-dense aggregation mechanism. We present additional observations of soot SAs in wildfire smoke-laden air masses over Northern California, New Mexico, and Mexico City. We estimate that SAs contribute, per unit optical depth, up to 35% less atmospheric warming than freshly-emitted (Df ≈ 1.8) aggregates, and ≈90% more warming than the volume-equivalent spherical soot particles simulated in climate models.
PMCID: PMC4076688  PMID: 24981204
13.  Anti-Retroviral Therapy Decreases but Does Not Normalize Indoleamine 2,3-Dioxygenase Activity in HIV-Infected Patients 
PLoS ONE  2014;9(7):e100446.
Indoleamine 2,3-dioxygenase (IDO), which is mainly expressed in activated dendritic cells, catabolizes tryptophan to kynurenine and other downstream catabolites. It is known to be an immune mediator in HIV pathogenesis. The impact of anti-retroviral therapy on its activity has not been well established.
We measured systemic IDO activity (the ratio of plasma kynurenine to tryptophan) in HIV-infected patients before and after highly active antiretroviral therapy (HAART) and its association with a microbial translocation marker, soluble CD14 (sCD14).
Among 76 participants, higher baseline IDO activity was associated with lower CD4+ T cell counts (P<0.05) and higher plasma sCD14 levels (P<0.001). After 1 year of HAART, IDO activity decreased significantly (P<0.01), but was still higher than in healthy controls (P<0.05). The baseline IDO activity did not predict CD4+ T cell recovery after 1 year of therapy. The percentages of myeloid and plasmacytoid dendritic cells were not correlated with IDO activity.
IDO activity is elevated in HIV-infected patients, which is partially associated with microbial translocation. HAART reduced, but did not normalize the activity of IDO.
PMCID: PMC4077698  PMID: 24983463
14.  Optimizing the synthesis of CdS/ZnS core/shell semiconductor nanocrystals for bioimaging applications 
In this study, we report on CdS/ZnS nanocrystals as a luminescence probe for bioimaging applications. CdS nanocrystals capped with a ZnS shell had enhanced luminescence intensity, stronger stability and exhibited a longer lifetime compared to uncapped CdS. The CdS/ZnS nanocrystals were stabilized in Pluronic F127 block copolymer micelles, offering an optically and colloidally stable contrast agents for in vitro and in vivo imaging. Photostability test exhibited that the ZnS protective shell not only enhances the brightness of the QDs but also improves their stability in a biological environment. An in-vivo imaging study showed that F127-CdS/ZnS micelles had strong luminescence. These results suggest that these nanoparticles have significant advantages for bioimaging applications and may offer a new direction for the early detection of cancer in humans.
PMCID: PMC4077458  PMID: 24991530
bioimaging; CdS/ZnS quantum dots; Pluronic F127
15.  KCNQ1, KCNE2, and Na+-Coupled Solute Transporters Form Reciprocally Regulating Complexes that Affect Neuronal Excitability 
Science signaling  2014;7(315):ra22.
Na+-coupled solute transport is crucial for the uptake of nutrients and metabolic precursors, such as myo-inositol, an important osmolyte and precursor for various cell signaling molecules. Here, we found that various solute transporters and potassium channel subunits formed complexes and reciprocally regulated each other in vitro and in vivo. Global metabolite profiling revealed that mice lacking KCNE2, a K+ channel β subunit, showed a reduction in the myo-inositol concentration in cerebrospinal fluid (CSF) but not in serum. Increased behavorial responsiveness to stress and seizure susceptibility in Kcne2−/− mice were alleviated by injections of myo-inositol. Suspecting a defect in myo-inositol transport, we found that KCNE2 and KCNQ1, a voltage-gated potassium channel α subunit, colocalized and coimmunoprecipitated with SMIT1, a Na+-coupled myo-inositol transporter, in the choroid plexus epithelium. Heterologous coexpression demonstrated that myo-inositol transport by SMIT1 was augmented by coexpression of KCNQ1 but inhibited by coexpression of both KCNQ1 and KCNE2, which form a constitutively active, heteromeric K+ channel. SMIT1 and the related transporter SMIT2 were also inhibited by a constitutively active mutant form of KCNQ1. The activity of KCNQ1 and KCNQ1-KCNE2 were augmented by SMIT1 and the glucose transporter SGLT1, but suppressed by SMIT2. Channel-transporter signaling complexes may be a widespread mechanism to facilitate solute transport and electrochemical crosstalk.
PMCID: PMC4063528  PMID: 24595108
16.  Analysis of interactions between SNARE proteins using imaging ellipsometer coupled with microfluidic array 
Scientific Reports  2014;4:5341.
The soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins are small and abundant membrane-bound proteins, whose specific interactions mediate membrane fusion during cell fusion or cellular trafficking. In this study, we report the use of a label-free method, called imaging ellipsometer to analyze the interactions among three SNAREs, namely Sec22p, Ykt6p and Sso2p. The SNAREs were immobilized on the silicon wafer and then analyzed in a pairwise mode with microfluidic array, leading us to discover the interactions between Ykt6p and Sso2p, Sec22p and Sso2p. Moreover, by using the real-time function of the imaging ellipsometer, we were able to obtain their association constants (KA) of about 104 M−1. We argue that the use of imaging ellipsometer coupled with microfluidic device will deepen our understanding of the molecular mechanisms underlying membrane fusion process.
PMCID: PMC4061542  PMID: 24938428
17.  The Common Variant rs4444235 near BMP4 Confers Genetic Susceptibility of Colorectal Cancer: An Updated Meta-Analysis Based on a Comprehensive Statistical Strategy 
PLoS ONE  2014;9(6):e100133.
We performed an updated meta-analysis, using a comprehensive strategy of a logistic regression and a model-free approach, to evaluate more precisely the role of the rs4444235 variant near the Bone morphogenetic protein-4 (BMP4) gene in susceptibility to colorectal cancer (CRC).
A total of 19 studies with 28770 cases and 28234 controls were included. Metagen system with logistic regression was applied to choose the most plausible genetic model for rs4444235. Generalized odds ratio (ORG) metric was used to provide a global test of relationship between rs4444235 and CRC risk.
Metagen analysis suggested the rs4444235 fitted best to an additive model. In assessment of the additive model, heterogeneity was observed (P = 0.059, I2 = 36.1), and pooled per-allele OR was 1.08 (95% CI = 1.05–1.11). Based on the model-free approach, pooled ORG was 1.09 (95% CI = 1.05–1.14) under a random-effect model. Stratified analyses suggested heterogeneity could be in part explained by population ethnicity, study design, sources of controls, and sample size. Sensitivity analysis further supported the robust stability of the current results, by showing similar pooled estimates before and after sequential removal of each study.
This meta-analysis provides a robust estimate of the positive association between the rs4444235 and CRC risk and further emphasizes the importance of the rs4444235 in CRC risk prediction.
PMCID: PMC4059743  PMID: 24932582
18.  A multi-layer inference approach to reconstruct condition-specific genes and their regulation 
Bioinformatics  2013;29(12):1541-1552.
An important topic in systems biology is the reverse engineering of regulatory mechanisms through reconstruction of context-dependent gene networks. A major challenge is to identify the genes and the regulations specific to a condition or phenotype, given that regulatory processes are highly connected such that a specific response is typically accompanied by numerous collateral effects. In this study, we design a multi-layer approach that is able to reconstruct condition-specific genes and their regulation through an integrative analysis of large-scale information of gene expression, protein interaction and transcriptional regulation (transcription factor-target gene relationships). We establish the accuracy of our methodology against synthetic datasets, as well as a yeast dataset. We then extend the framework to the application of higher eukaryotic systems, including human breast cancer and Arabidopsis thaliana cold acclimation. Our study identified TACSTD2 (TROP2) as a target gene for human breast cancer and discovered its regulation by transcription factors CREB, as well as NFkB. We also predict KIF2C is a target gene for ER−/HER2− breast cancer and is positively regulated by E2F1. The predictions were further confirmed through experimental studies.
Availability: The implementation and detailed protocol of the layer approach is available at
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC3673221  PMID: 23610368
19.  Comparison of different surgical approaches of functional endoscopic sinus surgery on patients with chronic rhinosinusitis 
Chronic rhinosinusitis (CRS) is not a life-threatening disorder but may have a great impact on the patients. This study intended to evaluate the impact of functional endoscopic sinus surgery (FESS), and compare the effect and quality of life (QOL) after two different surgical approaches on patients with CRS. Sixty patients of CRS were analyzed before and after FESS. The extent of disease was evaluated by the Lund-Mackay scoring system using computed tomography (CT) and endoscopy. Subjective patient QOL scores were assessed by SF-36 questionnaire and symptom scores were recorded using the SNOT-20 questionnaire. Forty patients of multiunit CRS were randomly allocated to two groups in order to be taken radical FESS (RFESS) and conservative FESS (CFESS), respectively. The Lund-Mackay score and degree of preoperative polyps did not differ statistically between the two groups. In the 1 months follow-up settings, such domains as role physical, mental health, role emotional and general health of SF-36, and total of the SNOT-20 items scores and the most important 5-item scores of SNOT-20 all began to get better markedly (P<0.05); in the 6-12 months follow-up settings, the indices of QOL and symptoms status entirely improved from the baseline, and CFESS scope surgery is no significantly difference with RFESS in improving the QOL and symptoms of patients. The results of this study suggesting that nasal polyps have a significant negative impact on the patients with CRS. FESS is a reliable and effective method for improving a patient’s QOL and symptoms after 6 months of surgery, regardless of approaches.
PMCID: PMC4100969  PMID: 25035783
Chronic rhinosinusitis; functional endoscopic sinus surgery; surgical approaches; quality of life; symptoms
20.  Comparative Transcriptional Analysis of Asexual and Sexual Morphs Reveals Possible Mechanisms in Reproductive Polyphenism of the Cotton Aphid 
PLoS ONE  2014;9(6):e99506.
Aphids, the destructive insect pests in the agriculture, horticulture and forestry, are capable of reproducing asexually and sexually upon environmental change. However, the molecular basis of aphid reproductive mode switch remains an enigma. Here we report a comparative analysis of differential gene expression profiling among parthenogenetic females, gynoparae and sexual females of the cotton aphid Aphis gossypii, using the RNA-seq approach with next-generation sequencing platforms, followed by RT-qPCR. At the cutoff criteria of fold change ≥2 and P<0.01, we identified 741 up- and 879 down-regulated genes in gynoparae versus parthenogenetic females, 2,101 up- and 2,210 down-regulated genes in sexual females compared to gynoparae, and 1,614 up- and 2,238 down-regulated genes in sexual females relative to parthenogenetic females. Gene ontology category and KEGG pathway analysis suggest the involvement of differentially expressed genes in multiple cellular signaling pathways into the reproductive mode transition, including phototransduction, cuticle composition, progesterone-mediated oocyte maturation and endocrine regulation. This study forms a basis for deciphering the molecular mechanisms underlying the shift from asexual to sexual reproduction in the cotton aphid. It also provides valuable resources for future studies on this host-alternating aphid species, and the insight into the understanding of reproductive mode plasticity in different aphid species.
PMCID: PMC4051768  PMID: 24915491
21.  IGFBPrP1 induces liver fibrosis by inducing hepatic stellate cell activation and hepatocyte apoptosis via Smad2/3 signaling 
AIM: To investigate the role and mechanism of insulin-like growth factor binding protein-related protein 1 (IGFBPrP1) in the development of liver fibrosis.
METHODS: An in vitro model using hepatic stellate cell (HSC)-T6 cells and an in vivo model of rat liver overexpressing IGFBPrP1 were established using an IGFBPrP1-expressing recombinant adenovirus. The expression of IGFBPrP1 was examined by immunofluorescence, and the expression of collagen I and fibronectin was measured by real-time reverse transcription-polymerase chain reaction and Western blot analysis. The expression of Smad2/3 and p-Smad2/3 was examined by Western blot and immunohistochemistry. A shSmad3-expressing recombinant adenovirus (AdshSmad3) was designed and used to knockdown the Smad3 gene in HSC-T6 cells and rat liver fibrosis transfected with IGFBPrP1. The expression of collagen I, fibronectin, and α-smooth muscle actin (α-SMA) was determined by Western blot analysis and immunohistochemistry. Hepatocyte apoptosis was assessed using TUNEL assay.
RESULTS: IGFBPrP1 overexpression induced collagen deposition and up-regulated the expression of α-SMA and p-Smad2/3, and AdshSmad3 inhibited IGFBPrP1-stimulated p-Smad2/3 activation and the expression of α-SMA, collagen I and fibronectin in HSC-T6 cells. Similarly, increased hepatocyte apoptosis (38.56% ± 3.42% vs 0.24% ± 0.03%, P < 0.05), α-SMA positive stained cells (29.84% ± 1.36% vs 5.83% ± 1.47%, P < 0.05), and increased numbers of Smad3 (35.88% ± 2.15% vs 10.24% ± 1.31%, P < 0.05) and p-Smad2/3 positive cells (28.87% ± 2.73% vs 8.23% ± 0.98%, P < 0.05) were detected in the livers of IGFBPrP1-overexpressing rats compared with the control group. Moreover, AdshSmad3 reduced IGFBPrP1-stimulated Smad3 expression and attenuated α-SMA expression (29.84% ± 1.36% vs 8.23% ± 1.28%, P < 0.05), hepatocyte apoptosis (38.56% ± 3.42% vs 6.75% ± 0.52%, P < 0.05), and both collagen I and fibronectin deposition in the livers of AdIGFBPrP1-treated rats.
CONCLUSION: IGFBPrP1 induces liver fibrosis by mediating the activation of hepatic stellate cells and hepatocyte apoptosis in a Smad3-dependent mechanism.
PMCID: PMC4047337  PMID: 24914373
Insulin-like growth factor binding protein-related protein 1; Liver fibrosis; Hepatic stellate cells; Hepatocyte apoptosis; Smad pathway
22.  Projecting dynamic trends for HIV/AIDS in a highly endemic area of China: Estimation models for Liangshan Prefecture, Sichuan Province 
Current HIV research  2009;7(4):390-397.
This study describes the current situation and projects dynamic trends for HIV prevalence in a highly endemic area of China, Liangshan Prefecture, Sichuan Province. Epidemiological, behavioral, and population census data from multiple sources were analyzed to extract input for an Asian Epidemic Model (AEM). Fitting curves to historical trends in HIV prevalence were used as a baseline, and future intervention scenarios were explored using the AEM. For 2007, modeled data suggested ≈0.5% adult HIV prevalence in Liangshan, with an estimated 17,450 people living with HIV/AIDS and 3,400 new infections. With current high risk behaviors, the model predicts that adult prevalence will rise to 1.5% by 2020. Increased condom use and clean needle exchange among injection drug users (IDUs) have slowed the epidemic. The source of new HIV infections will change from a preponderance of IDU-related infections in 2007 (65.9%) to a mixed epidemic in 2020 (general population heterosexuals 45.2%, IDU 38.6%, homosexual transmission between men 12.7%, female sex workers and their clients 3.5%). We anticipate rising prevalence, stable incidence, and higher representation of sexual transmission over time. Prevention investments should target specific interventions toward sub-groups at highest risk, given that both IDUs and men who have sex with men will likely represent a majority of cases and serve as a bridge population.
PMCID: PMC4048065  PMID: 19601774
HIV; Asian Epidemic Model; epidemiologic modeling; substance abuse; homosexuality; China
23.  Comparison of Efficacy and Safety of Tenofovir and Entecavir in Chronic Hepatitis B Virus Infection: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(6):e98865.
Tenofovir (TDF) and entecavir (ETV) are both potent antiviral agents for the treatment of chronic hepatitis B virus (HBV) infection. Multiple studies have compared efficacy and safety of these two agents, but yielded inconsistent results. Hence, we conducted a meta-analysis to discern comparative efficacy and safety.
Published data relevant to a comparison of TDF and ETV used in HBV were included. HBV DNA suppression rate, ALT normalization rate, and HBeAg seroconversion rate at 24 weeks and 48 weeks were reviewed. Drug safety profiles and resistance were also discussed.
Seven articles met entry criteria. Four and six articles included data for 24 and 48-week HBV DNA suppression rates, respectively, and no significant differences for the rates between the two drugs were found in chronic HBV patients (TDF vs. ETV: relative risk [RR] = 1.10, 95% CI = 0.91–1.33 and RR = 1.07, 95% CI = 0.99–1.17 for 24 weeks and 48 weeks, respectively). For the ALT normalization rate (three studies for 24 weeks, four articles for 48 weeks) and HBeAg seroconversion rate (two and four studies for 24 weeks and 48 weeks, respectively), no difference was observed between TDF and ETV. Additionally, no significant distinction in short term safety was found for CHB patients.
TDF and ETV are similarly effective and safe in chronic HBV patients after 24 weeks and 48 weeks of anti-viral therapy. Nevertheless, the long-term efficacy and safety of TDF and ETV should be monitored in prolonged therapy.
PMCID: PMC4048232  PMID: 24905092
24.  Bidirectional regulation of angiogenesis and miR-18a expression by PNS in the mouse model of tumor complicated by myocardial ischemia 
Panax Notoginseng Saponins (PNS) is the major class of active constituents of notoginseng, a natural product extensively used as a therapeutic agent in China. Tumor when accompanied by cardiovascular disorders poses a greater challenge for clinical management given the paradoxical involvement of angiogenesis, therefore gaining increased research attention. This study aim to investigate effects of PNS and its activity components in the mouse model of tumor complicated with myocardial ischemia.
Tumor complexed with myocardial ischemia mouse model was first established, which was followed by histological and immunohistochemistry examination to assess the effect of indicated treatments on tumor, myocardial ischemia and tissue specific angiogenesis. MicroRNA (miRNA) profiling was further carried out to identify potential miRNA regulators that might mechanistically underline the therapeutic effects of PNS in this complex model.
PNS and its major activity components Rg1, Rb1 and R1 suppressed tumor growth and simultaneously attenuated myocardial ischemia. PNS treatment led to decreased expression of CD34 and vWF in tumor and increased expression of these vascular markers in heart. PNS treatment resulted in reduced expression of miR-18a in tumor and upregulated expression of miR-18a in heart.
Our data demonstrated for the first time that PNS exerts tissue specific regulatory effects on angiogenesis in part through modulating the expression of miR-18a, which could be responsible for its bidirectional effect on complex disease conditions where paradoxical angiogenesis is implicated. Therefore, our study provides experimental evidence warranting evaluation of PNS and related bioactive component as a rational therapy for complex disease conditions including co-manifestation of cancer and ischemic cardiovascular disease.
PMCID: PMC4060854  PMID: 24903055
Myocardial ischemia; Tumor; Angiogenesis; PNS; Bidirectional regulation; miR-18a
25.  Correlation of CD146 expression and clinicopathological characteristics in esophageal squamous cell carcinoma 
Oncology Letters  2014;8(2):859-863.
CD146, a cell adhesion molecule, is found in normal and tumor tissues. The level of its expression has been found to directly correlate with tumor progression and metastatic potential. The objective of this study was to investigate the expression of CD146 in esophageal squamous cell carcinoma (ESCC) and its correlation with clinicopathological parameters. Tumor specimens were collected from 63 patients with ESCC who underwent complete resection. We analyzed the CD146 expression levels in ESCC by immunohistochemistry. The expression of CD146 was detected and it was observed to correlate with clinicopathological parameters. Sixty-three cases of normal squamous mucosa were included for comparison. CD146 expression was identified in 46.0% (29/63) of the ESCC samples, and no positive (weak to moderate or moderate to strong) expression was found in the normal squamous epithelium samples (χ2=27.248; P<0.0001). CD146 expression was associated with lymph node metastasis (χ2=5.117; P=0.024) and advanced clinical stage (χ2=4.661; P=0.031). CD146 expression was one of the significant predictors of survival (hazard ratio, 2.838; 95% confidence interval 1.102–7.305). The overexpression of the CD146 gene was one of the important phenotypes and characteristics in ESCC carcinomatous change. We found that CD146 expression was associated with lymph node metastasis and advanced clinical stage, and was an indicator of poor prognosis in ESCC patients. CD146 may prove to be an important tumor marker for the individualized treatment for ESCC.
PMCID: PMC4081421  PMID: 25009662
CD146; esophageal squamous cell cancer; clinicopathological characteristics; immunohistochemistry

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