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1.  Silencing DACH1 Promotes Esophageal Cancer Growth by Inhibiting TGF-β Signaling 
PLoS ONE  2014;9(4):e95509.
Human Dachshund homologue 1 (DACH1) is a major component of the Retinal Determination Gene Network. Loss of DACH1 expression was found in breast, prostate, lung, endometrial, colorectal and hepatocellular carcinoma. To explore the expression, regulation and function of DACH1 in human esophageal cancer, 11 esophageal cancer cell lines, 10 cases of normal esophageal mucosa, 51 cases of different grades of dysplasia and 104 cases of primary esophageal squamous cancer were employed. Methylation specific PCR, immunohistochemistry, western blot, flow cytometry, small interfering RNAs, colony formation techniques and xenograft mice model were used. We found that DACH1 expression was regulated by promoter region hypermethylation in esophageal cancer cell lines. 18.8% (6 of 32) of grade 1, 42.1% (8 of 19) of grade 2 and grade 3 dysplasia (ED2,3), and 61.5% (64 of 104) of esophageal cancer were methylated, but no methylation was found in 10 cases of normal esophageal mucosa. The methylation was increased in progression tendency during esophageal carcinogenesis (P<0.01). DACH1 methylation was associated with poor differentiation (P<0.05) and late tumor stage (P<0.05). Restoration of DACH1 expression inhibited cell growth and activated TGF-β signaling in KYSE150 and KYSE510 cells. DACH1 suppressed human esophageal cancer cell tumor growth in xenograft mice. In conclusion, DACH1 is frequently methylated in human esophageal cancer and methylation of DACH1 is involved in the early stage of esophageal carcinogenesis. DACH1 expression is regulated by promoter region hypermethylation. DACH1 suppresses esophageal cancer growth by activating TGF-β signaling.
doi:10.1371/journal.pone.0095509
PMCID: PMC3990688  PMID: 24743895
2.  Potential of Adipose-Derived Mesenchymal Stem Cells and Skeletal Muscle-Derived Satellite Cells for Somatic Cell Nuclear Transfer Mediated Transgenesis in Arbas Cashmere Goats 
PLoS ONE  2014;9(4):e93583.
Somatic cell nuclear transfer is used to generate genetic models for research and new, genetically modified livestock varieties. Goat fetal fibroblast cells (gFFCs) are the predominant nuclear donors in Cashmere goat transgenic cloning, but have disadvantages. We evaluated the potential of goat adipose-derived mesenchymal stem cells (gADSCs) and goat skeletal muscle-derived satellite cells (gMDSCs) for somatic cell nuclear transfer, evaluating their proliferation, pluripotency, transfection efficiency and capacity to support full term development of embryos after additive gene transfer or homologous recombination. gADSCs and gMDSCs were isolated by enzyme digestion and differentiated into neurocytes, myotube cells and insulin-producing cells. Neuron-specific enolase, fast muscle myosin and insulin expression were determined by immunohistochemistry. Following somatic cell nuclear transfer with donor cells derived from gADSCs, gMDSCs and gFFCs, transfection and cloning efficiencies were compared. Red fluorescent protein levels were determined by quantitative PCR and western blotting. 5-Methylcytosine, H4K5, H4K12 and H3K18 were determined immunohistochemically. gADSCs and gMDSCs were maintained in culture for up to 65 passages, whereas gFFCs could be passaged barely more than 15 times. gADSCs and gMDSCs had higher fluorescent colony forming efficiency and greater convergence (20%) and cleavage (10%) rates than gFFCs, and exhibited differing H4K5 histone modification patterns after somatic cell nuclear transfer and in vitro cultivation. After transfection with a pDsRed2-1 expression plasmid, the integrated exogenous genes did not influence the pluripotency of gADSCs–pDsRed2-1 or gMDSCs–pDsRed2-1. DsRed2 mRNA expression by cloned embryos derived from gADSCs–pDsRed2-1 or gMDSCs–pDsRed2-1 was more than twice that of gFFCs–pDsRed2-1 embryos (P<0.01). Pregnancy rates of gADSCs–pDsRed2-1 and gMDSCs–pDsRed2-1 recipients were higher than those of gFFCs–pDsRed2-1 recipients (P<0.01). With their high proliferative capacity and transfection efficiency, gADSCs and gMDSCs are a valuable cell source for breeding new, genetically modified varieties of livestock by somatic cell nuclear transfer.
doi:10.1371/journal.pone.0093583
PMCID: PMC3974752  PMID: 24699686
3.  Prevalence and Correlates of Sexual Risk Behaviors Among Drug Users in Western China: Implications for HIV Transmission 
Abstract
The prevalence and correlates of sexual risk behaviors among drug users in western China and the implications for HIV transmission in this population are described. A cross-sectional survey of male drug users was conducted in methadone maintenance therapy clinics and detoxification centers in three western provinces of China between September 2009 and December 2010. Participants in the study completed a questionnaire about demographics, HIV/AIDS knowledge, drug use history, sexual risk behaviors, and other psychosocial variables. Factors associated with HIV sexual risk behaviors were identified by multiple logistic regression analysis. Of 1,304 drug users surveyed, nearly 54% never used condoms during sexual intercourse with a spouse or cohabitant, and this behavior was associated with coming from Chongqing (OR=1.86, p<0.05), being aged 36 and older (OR=5.03, p<0.05), being married or cohabiting (OR=1.68, p<0.05), having first taken drugs at age 30 and above (OR=1.80, p<0.05), and having received AIDS advice or detection from authorities in the past year (OR=1.95, p<0.05). Twenty-six percent had had sex with casual sexual partners in the past year, and this behavior was associated with being married or cohabiting (OR=0.30, p<0.05), first taking drugs at age 31 and above (OR=0.42, p<0.05), and receiving AIDS advice or HIV detection from authorities in the past year (OR=0.70, p<0.05). About 34% never used a condom when having sex with casual sexual partners, and this behavior was associated with coming from Guangxi (OR=2.81, p<0.05) or Chongqing (OR=2.73, p<0.05). Almost 14% had had commercial sex in the past year, and this behavior was associated with coming from Guangxi (OR=6.26, p<0.05) or Chongqing (OR=5.44, p<0.05) and having exchanged needles or received clean needles from the Needle Exchange Centers in the past year (OR=2.76, p<0.05). Nearly 23% had never used condoms when having commercial sex, and this behavior was associated with having received free condoms from authorities in the past year (OR=0.26, p<0.05). Sexual risk behaviors among drug users in Guangxi, Chongqing, and Xinjiang are common. Additional intervention strategies are needed to control the spread of HIV in this population.
doi:10.1089/aid.2012.0272
PMCID: PMC3607904  PMID: 23210514
4.  Exploring the complex mechanical properties of xanthan scaffolds by AFM-based force spectroscopy 
Summary
The polysaccharide xanthan has been extensively studied owing to its potential application in tissue engineering. In this paper, xanthan scaffold structures were investigated by atomic force microscope (AFM) in liquid, and the mechanical properties of the complex xanthan structures were investigated by using AFM-based force spectroscopy (FS). In this work, three types of structures in the xanthan scaffold were identified based on three types of FS stretching events. The fact that the complex force responses are the combinations of different types of stretching events suggests complicated intermolecular interactions among xanthan fibrils. The results provide crucial information to understand the structures and mechanical properties of the xanthan scaffold.
doi:10.3762/bjnano.5.42
PMCID: PMC3999747  PMID: 24778961
atomic force microscopy (AFM); force spectroscopy (FS); mechanical properties; xanthan scaffold
5.  Attitudes Toward HIV Pre-Exposure Prophylaxis Among Men Who Have Sex with Men in Western China 
AIDS Patient Care and STDs  2013;27(3):137-141.
Abstract
Pre-exposure prophylaxis (PrEP), as demonstrated in recently published clinical trials, is one promising approach for controlling the emerging epidemic among men who have sex with men (MSM). We evaluated the attitudes towards use of PrEP among MSM in western China. A total of 1402 participants completed a self-administered questionnaire. Overall, 22% of the participants reported that they had heard of PrEP, <1% had ever used medicine to prevent HIV, and 64% reported that they were absolutely willing to use PrEP if it were proven to be safe and effective. The predictors of willingness to use PrEP included lower education, moderate income compared with the lowest income, never or rarely finding sexual partners through the Internet in the past 6 months, sexually transmitted infection (STI) history, more knowledge of AIDS, worrying about HIV as a threat to themselves and their family, having previously heard of PrEP, and believing that PrEP was effective in preventing HIV. This study demonstrates that Chinese MSM have moderate awareness of PrEP and a high interest in using it.
doi:10.1089/apc.2012.0412
PMCID: PMC3595955  PMID: 23425017
6.  Scientific publications in respiratory journals from Chinese authors in various parts of North Asia: a 10-year survey of literature 
BMJ Open  2014;4(2):e004201.
Objectives
Respiratory disease remains one of the leading causes of morbidity and mortality in China. However, little is known about the research status of respirology in three major regions of China—Mainland (ML), Hong Kong (HK) and Taiwan (TW). A 10-year survey of literature was conducted to compare the three regions’ outputs in the research of respirology.
Design
A bibliometric study.
Setting
China.
Participants and outcome measures
A literature search in PubMed database, updated as of September 2012, led to the identification of the related articles from 2000 to 2009. The number of total articles, randomised controlled trials, case reports, meta-analysis, impact factors (IF), citations and articles published in top general medicine journals was collected for quantity and quality comparisons.
Results
2208 articles were collected, 814 from ML, 909 from TW and 485 from HK. The total number of articles from the three regions has increased significantly from 2000 to 2009. The number of articles published per year from ML has exceeded that from HK in 2005 and TW in 2008. The accumulated IF of articles from TW (3192.417) was much higher than that from ML (2409.956) and HK (1898.312). HK got the highest average IF of respirology articles and the majority of articles were published in top general medicine journals.
Conclusions
The total number of published articles from the three major regions of China has increased notably from 2000 to 2009. The annual number of publications by ML researchers exceeded those from TW and HK. However, the quality of articles from TW and HK is better than that from ML.
doi:10.1136/bmjopen-2013-004201
PMCID: PMC3939649  PMID: 24583761
Internal Medicine; Medical History; Respiratory Medicine (see Thoracic Medicine)
7.  LRP-1 polymorphism is associated with global and regional amyloid load in Alzheimer's disease in humans in-vivo 
NeuroImage : Clinical  2014;4:411-416.
Objective
Impaired amyloid clearance has been proposed to contribute to β-amyloid deposition in sporadic late-onset Alzheimer's disease (AD). Low density lipoprotein receptor-related protein 1 (LRP-1) is involved in the active outward transport of β-amyloid across the blood–brain barrier (BBB). The C667T polymorphism (rs1799986) of the LRP-1 gene has been inconsistently associated with AD in genetic studies.
We aimed to elucidate the association of this polymorphism with in-vivo brain amyloid load of AD patients using amyloid PET with [11C]PiB.
Materials and methods
72 patients with very mild to moderate AD were examined with amyloid PET and C667T polymorphism was obtained using TaqMan PCR assays. The association of C667T polymorphism with global and regional amyloid load was calculated using linear regression and voxel based analysis, respectively. The effect of the previously identified modulator of amyloid uptake, the apolipoprotein E genotype, on this association was also determined.
Results
The regression analysis between amyloid load and C667T polymorphism was statistically significant (p = 0.046, β = 0.236). In an additional analysis ApoE genotype and gender were identified to explain further variability of amyloid load. Voxel based analysis revealed a significant (p < 0.05) association between C667T polymorphism and amyloid uptake in the temporo-parietal cortex bilaterally. ApoE did not interact significantly with the LRP-1 polymorphism.
Discussion
In conclusion, C667T polymorphism of LRP-1 is moderately but significantly associated with global and regional amyloid deposition in AD. The relationship appears to be independent of the ApoE genotype. This finding is compatible with the hypothesis that impaired amyloid clearance contributes to amyloid deposition in late-onset sporadic AD.
Highlights
•Impaired drainage systems are discussed to be causative for AD.•LRP-1 transports Aß from the brain.•LRP-1 polymorphism is associated with amyloid deposition in-vivo in-human.•Results are compatible with the hypothesis of impaired drainage systems in AD.
doi:10.1016/j.nicl.2014.01.016
PMCID: PMC3939495  PMID: 24596678
Alzheimer's disease (AD); Low density lipoprotein receptor related protein 1 (LRP-1); C667T polymorphism; Apolipoprotein E (ApoE); Pittsburgh compound B ([11C]PiB); Positron emission tomography (PET)
8.  Pre-Exposure Prophylaxis for the Prevention of HIV Infection in High Risk Populations: A Meta-Analysis of Randomized Controlled Trials 
PLoS ONE  2014;9(2):e87674.
Background
Nearly ten randomized controlled trials (RCTs) of pre-exposure prophylaxis (PrEP) have been completed or are ongoing worldwide to evaluate the effectiveness of PrEP in HIV transmission among HIV-uninfected high risk populations. The purpose of this study was to evaluate the role of PrEP to prevent HIV transmission through a Mata-analysis.
Methods
A comprehensive computerized literature search was carried out in PubMed, EMbase, Ovid, Web of Science, Science Direct, Wan Fang, CNKI and related websites to collect relevant articles (from their establishment date to August 30, 2013). The search terms were “pre-exposure prophylaxis”, “high risk population”, “HIV infection”, “reduction”, “relative risk” and “efficacy”. We included any RCT assessing PrEP for the prevention of HIV infection in high risk populations. Interventions of the studies were continuously daily or intermittent doses of single or compound antiretrovirals (ARVs) before HIV exposure or during HIV exposure. A meta-analysis was conducted using Stata 10.0. A random-effects method was used to calculate the pooled relative risk (RR) and 95% confidence intervals (CI) for all studies included.
Results
Seven RCTs involving 14,804 individuals in high risk populations were eligible for this study. The number of subjects in the experimental groups was 8,195, with HIV infection rate of 2.03%. The number of subjects in the control groups was 6,609, with HIV infection rate of 4.07%. The pooled RR was 0.53 (95% CI = 0.40∼0.71, P<0.001). The re-analyzed pooled RR were 0.61 (95% CI = 0.48∼0.77, P<0.001), 0.49 (95% CI = 0.38∼0.63, P<0.001), respectively, by excluding the largest study or two studies without statistical significance. Publication bias analysis revealed a symmetry funnel plot. The fail-safe number was 1,022.
Conclusion
These results show that PrEP is an effective strategy for reducing new HIV infections in high risk populations.
doi:10.1371/journal.pone.0087674
PMCID: PMC3912017  PMID: 24498350
9.  HIV Pre-Exposure Prophylaxis Interest among Female Sex Workers in Guangxi, China 
PLoS ONE  2014;9(1):e86200.
Objectives
Acceptability of pre-exposure prophylaxis (PrEP) and willingness to participate in a clinical trial for both safety and efficacy of PrEP were investigated among female sex workers (FSWs) in Guangxi, China.
Methods
A cross-sectional study was performed in three cities in Guangxi. Structured, self-administered questionnaires were used to assess the acceptability of PrEP and the willingness to participate in a clinical trial. Multivariable logistic regression models were fitted to identify predictors.
Results
Among 405 participants, 15.1% had heard of PrEP. If PrEP was deemed to be effective, safe and provided for free, 85.9% reported that they would accept it, and 54.3% of those who accepted PrEP said that they would participate in a clinical trial. The increased acceptability of PrEP was associated with working in male dominated venues, higher income, a poor family relationship, better HIV/AIDS knowledge, not realizing HIV risk from unfamiliar clients, not being forced to use condoms by the gatekeepers, consistent use of condoms, and use of drugs to prevent STD infection. The increased willingness to participate in a clinical trial was associated with a poor family relationship, better HIV/AIDS knowledge, not realizing HIV risk from unfamiliar clients, a willingness to adhere to daily PreP use, and not being concerned about discrimination by others. The main reason for rejecting PrEP or participating in a clinical trial was the concern about the side effects of PrEP.
Conclusions
Acceptability of PrEP among Guangxi FSWs is relatively high, indicating that PrEP intervention programs may be feasible for Chinese FSWs. Given the fact that most of the participants had never heard of PrEP before, and that family, gatekeepers, and social discrimination could significantly affect its acceptability, a comprehensive mix of multiple interventions is necessary for the successful implementation of a PrEP program among this population in Guangxi.
doi:10.1371/journal.pone.0086200
PMCID: PMC3899205  PMID: 24465956
10.  Molecular characterisation of murine acute myeloid leukaemia induced by 56Fe ion and 137Cs gamma ray irradiation 
Mutagenesis  2012;28(1):71-79.
Exposure to sparsely ionising gamma- or X-ray irradiation is known to increase the risk of leukaemia in humans. However, heavy ion radiotherapy and extended space exploration will expose humans to densely ionising high linear energy transfer (LET) radiation for which there is currently no understanding of leukaemia risk. Murine models have implicated chromosomal deletion that includes the hematopoietic transcription factor gene, PU.1 (Sfpi1), and point mutation of the second PU.1 allele as the primary cause of low-LET radiation-induced murine acute myeloid leukaemia (rAML). Using array comparative genomic hybridisation, fluorescence in situ hybridisation and high resolution melt analysis, we have confirmed that biallelic PU.1 mutations are common in low-LET rAML, occurring in 88% of samples. Biallelic PU.1 mutations were also detected in the majority of high-LET rAML samples. Microsatellite instability was identified in 42% of all rAML samples, and 89% of samples carried increased microsatellite mutant frequencies at the single-cell level, indicative of ongoing instability. Instability was also observed cytogenetically as a 2-fold increase in chromatid-type aberrations. These data highlight the similarities in molecular characteristics of high-LET and low-LET rAML and confirm the presence of ongoing chromosomal and microsatellite instability in murine rAML.
doi:10.1093/mutage/ges055
PMCID: PMC3716295  PMID: 22987027
11.  TFIIB Co-Localizes and Interacts with α-Tubulin during Oocyte Meiosis in the Mouse and Depletion of TFIIB Causes Arrest of Subsequent Embryo Development 
PLoS ONE  2013;8(11):e80039.
TFIIB (transcription factor IIB) is a transcription factor that provides a bridge between promoter-bound TFIID and RNA polymerase II, and it is a target of various transcriptional activator proteins that stimulate the pre-initiation complex assembly. The localization and/or attachment matrix of TFIIB in the cytoplast is not well understood. This study focuses on the function of TFIIB and its interrelationship with α-tubulins in a mouse model. During oocyte maturation TFIIB distributes throughout the entire nucleus of the germinal vesicle (GV). After progression to GV breakdown (GVBD), TFIIB and α-tubulin co-localize and accumulate in the vicinity of the condensed chromosomes. During the MII stage, the TFIIB signals are more concentrated at the equatorial plate and the kinetochores. Colcemid treatment of oocytes disrupts the microtubule (MT) system, although the TFIIB signals are still present with the altered MT state. Injection of oocytes with TFIIB antibodies and siRNAs causes abnormal spindle formation and irregular chromosome alignment. These findings suggest that TFIIB dissociates from the condensed chromatids and then tightly binds to microtubules from GVBD to the MII phase. The assembly and disassembly of TFIIB may very well be associated with and driven by microtubules. TFIIB maintains its contact with the α-tubulins and its co-localization forms a unique distribution pattern. Depletion of Tf2b in oocytes results in a significant decrease in TFIIB expression, although polar body extrusion does not appear to be affected. Knockdown of Tf2b dramatically affects subsequent embryo development with more than 85% of the embryos arrested at the 2-cell stage. These arrested embryos still maintain apparently normal morphology for at least 96h without any obvious degeneration. Analysis of the effects of TFIIB in somatic cells by co-transfection of BiFC plasmids pHA-Tf2b and pFlag-Tuba1α further confirms a direct interaction between TFIIB and α-tubulins.
doi:10.1371/journal.pone.0080039
PMCID: PMC3828216  PMID: 24244602
12.  Hilar hematoma after extracorporeal shock wave lithotripsy for pancreatic stones 
doi:10.7178/jig.133
PMCID: PMC3896577  PMID: 24498532
extracorporeal shock wave lithotripsy; pancreatic stones; hematoma
13.  Comparison of Three Intervention Models for Promoting Circumcision among Migrant Workers in Western China to Reduce Local Sexual Transmission of HIV 
PLoS ONE  2013;8(9):e76107.
Objective
Three models for promoting male circumcision (MC) as a preventative intervention against HIV infection were compared among migrant worker populations in western China.
Methods
A cohort study was performed after an initial cross-sectional survey among migrant workers in three provincial level districts with high HIV prevalence in western China. A total of 1,670 HIV seronegative male migrants were cluster-randomized into three intervention models, in which the dissemination of promotional materials and expert- and volunteer-led discussions are conducted in one, two, and three stage interventions. Changes in knowledge of MC, acceptability of MC, MC surgery uptake, and the costs of implementation were analyzed at 6-month and 9-month follow-up visits.
Results
All three models significantly increased the participants’ knowledge about MC. The three-stage model significantly increased the acceptability of MC among participants and led to greatest increase in MC uptake. At the end of follow-up, 9.2% (153/1,670) of participants underwent MC surgery; uptake among the one-, two-, and three-stage models were 4.9%, 9.3%, and 14.6%, respectively. Multivariable Cox regression analysis showed that three-stage model was the most effective method to scale up MC, with RR = 2.0 (95% CI, 1.3-3.1, P=0.002) compared to the on-site session model. The two-stage intervention model showed no significant difference with either the on-site session model (RR=1.5, 95% CI, 0.92-2.4, P=0.12) or three-stage model (P=0.10).
Conclusions
A three-stage intervention with gradual introduction of knowledge led to the significantly increase in MC uptake among migrant workers in western China, and was also the most cost-effective method among the three models.
doi:10.1371/journal.pone.0076107
PMCID: PMC3786908  PMID: 24098770
14.  Systematic Review of Anastomotic Leakage Rate According to an International Grading System Following Anterior Resection for Rectal Cancer 
PLoS ONE  2013;8(9):e75519.
Background
A generally acceptable definition and a severity grading system for anastomotic leakages (ALs) following rectal resection were not available until 2010, when the International Study Group of Rectal Cancer (ISGRC) proposed a definition and a grading system for AL.
Methods
A search for published data was performed using the MEDLINE database (2000 to December 5, 2012) to perform a systematic review of the studies that described AL, grade AL according to the grading system, pool data, and determine the average rate of AL for each grade after anterior resection (AR) for rectal cancer.
Results
A total of 930 abstracts were retrieved; 40 articles on AR, 25 articles on low AR (LAR), and 5 articles on ultralow AR (ULAR) were included in the review and analysis. The pooled overall AL rate of AR was 8.58% (2,085/24,288); the rate of the asymptomatic leakage (Grade A) was 2.57%, that of AL that required active intervention without relaparotomy (Grade B) was 2.37%, and that of AL that required relaparotomy (Grade C) was 5.40%. The pooled rate of AL that required relaparotomy was higher in AR (5.40%) than in LAR (4.70%) and in ULAR (1.81%), which could be attributed to the higher rate of protective defunctioning stoma in LAR (40.72%) and ULAR (63.44%) compared with that in AR (30.11%).
Conclusions
The new grading system is simple that the ALs of each grade can be easily extracted from past publications, therefore likely to be accepted and applied in future studies.
doi:10.1371/journal.pone.0075519
PMCID: PMC3783382  PMID: 24086552
15.  Comprehensive screening for PRSS1, SPINK1, CFTR, CTRC and CLDN2 gene mutations in Chinese paediatric patients with idiopathic chronic pancreatitis: a cohort study 
BMJ Open  2013;3(9):e003150.
Objective
Genetic alterations may contribute to chronic pancreatitis (CP) in Chinese young patients. This study was designed to investigate mutations of cationic trypsinogen (PRSS1), pancreatic secretory trypsin inhibitor or serine protease inhibitor Kazal type 1 (SPINK1), cystic fibrosis transmembrane conductance regulator (CFTR), chymotrypsin C (CTRC) and CLDN2 genes and the copy number variations (CNVs) of PRSS1 and asses associations with the development of idiopathic CP (ICP) in Chinese children.
Design
Retrospective.
Setting
A single center.
Participants
75 ICP Chinese children (40 boys and 35 girls).
Primary and secondary outcome measures
Mutations of PRSS1, SPINK1, CFTR, CTRC and CLDN2 genes and CNVs.
Results
7 patients had heterozygous mutations in PRSS1, that is, N29I (n=1), R122H or R122C (n=6). The CNVs of PRSS1 in five patients had abnormal copies (1 copy (n=4), five copies (n=1)). 43 patients had IVS3+2T>C (rs148954387) (10 homozygous and 33 heterozygous) in SPINK1. None of the PRSS1 mutation patients carried a SPINK1 mutation. Frequency of PRSS1 and SPINK1 mutations was 9.3% and 57.3%, respectively, with an overall frequency of 66.6% (50/75). In addition, one patient had a novel deletion of CFTR (GCTTCCTA from c.500 to c.508 leading to the shortened polypeptide molecule via a stop codon). Another patient had a novel missense in CLDN2 exon 2 (c.592A>C mutation). Clinically, patients with SPINK1 mutations had a higher rate of pancreatic duct stones, pancreatic pseudocyst and pancreatic calcification than those without SPINK1 mutations (p<0.05).
Conclusions
SPINK1 mutations were more commonly associated with Chinese children with ICP. SPINK1 IVS3+2T>C mutation may play an important role in the pathogenesis of Chinese paediatric ICP. However, further study is needed to confirm and to investigate the role of these genes in the development of Chinese ICP.
doi:10.1136/bmjopen-2013-003150
PMCID: PMC3773632  PMID: 24002981
Gastroenterology; Genetics
16.  The Clinical Profile of Merkel Cell Carcinoma in Mainland China 
International journal of dermatology  2012;51(9):1054-1059.
Background
Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy, but little is known about the presence or characteristics of MCC in mainland China. A retrospective chart review was conducted to describe the clinical profile of Merkel cell carcinoma in China.
Methods
At 18 cancer or dermatology hospitals in metropolitan centers from the six geographical regions of mainland China, approximately 3,100,000 pathology database and medical records were searched for cases that had a pathological diagnosis of MCC between 1970 and 2009. A case series was compiled from retrospective chart reviews of identified MCC patients.
Results
Eight out of 18 participating hospitals reported at least one record of a patient with a pathological diagnosis of MCC, and a total of 22 cases were identified. The median age of patients was 65.5, and 59% were female. The median time from the appearance of a lesion to the time of biopsy was 6 months, and the most common location of lesions was the head and neck. The most common treatment used was surgery alone.
Conclusions
MCC appears to be uncommon in mainland China. Patients in this series are elderly, often had lesions on the head/neck region, and most commonly received surgery alone as treatment. In contrast with MCC in Western countries, the current series' patients were all of Asian ethnicity, had larger lesions at presentation, and none were documented as having HIV or other forms of immunosuppression.
doi:10.1111/j.1365-4632.2011.05251.x
PMCID: PMC3732818  PMID: 22909358
Merkel cell carcinoma; China; skin cancer; case-series
17.  Progenitor Cell Line (hPheo1) Derived from a Human Pheochromocytoma Tumor 
PLoS ONE  2013;8(6):e65624.
Background
Pheochromocytomas are rare tumors generally arising in the medullary region of the adrenal gland. These tumors release excessive epinephrine and norepinephrine resulting in hypertension and cardiovascular crises for which surgery is the only definitive treatment. Molecular mechanisms that control tumor development and hormone production are poorly understood, and progress has been hampered by the lack of human cellular model systems. To study pheochromocytomas, we developed a stable progenitor pheochromocytoma cell line derived from a primary human tumor.
Methods
After IRB approval and written informed consent, human pheochromocytoma tissue was excised, minced, dispersed enzymatically, and cultured in vitro. Primary pheochromocytoma cells were infected with a lentivirus vector carrying the catalytic subunit of human telomerase reverse transcriptase (hTERT). The hTERT immortalized cells (hPheo1) have been passaged >300 population doublings. The resulting cell line was characterized morphologically, biochemically and for expression of neuroendocrine properties. The expression of marker enzymes and proteins was assessed by immunofluorescence staining and immunoblotting. Telomerase activity was determined by using the telomeric repeat amplification protocol (TRAP) assay.
Results
We have established a human pheochromocytoma precursor cell line that expresses the neuroendocrine marker, chromogranin A, when differentiated in the presence of bone morphogenic protein 4 (BMP4), nerve growth factor (NGF), and dexamethasone. Phenylethanolamine N-methyltransferase (PNMT) expression is also detected with this differentiation regimen. CD-56 (also known as NCAM, neural cell adhesion molecule) is expressed in these cells, but CD31 (also known as PECAM-1, a marker of endothelial cells) is negative.
Conclusions
We have maintained hTERT-immortalized progenitor cells derived from a pheochromocytoma (hPheo1) in culture for over 300 population doublings. This progenitor human cell line is normal diploid except for a deletion in the p16 region and has inducible neuroendocrine biomarkers. These cells should be a valuable reagent for studying mechanisms of tumor development and for testing novel therapeutic approaches.
doi:10.1371/journal.pone.0065624
PMCID: PMC3681983  PMID: 23785438
18.  Distinct transcriptome profiles identified in normal human bronchial epithelial cells after exposure to γ-rays and different elemental particles of high Z and energy 
BMC Genomics  2013;14:372.
Background
Ionizing radiation composed of accelerated ions of high atomic number (Z) and energy (HZE) deposits energy and creates damage in cells in a discrete manner as compared to the random deposition of energy and damage seen with low energy radiations such as γ- or x-rays. Such radiations can be highly effective at cell killing, transformation, and oncogenesis, all of which are concerns for the manned space program and for the burgeoning field of HZE particle radiotherapy for cancer. Furthermore, there are differences in the extent to which cells or tissues respond to such exposures that may be unrelated to absorbed dose. Therefore, we asked whether the energy deposition patterns produced by different radiation types would cause different molecular responses. We performed transcriptome profiling using human bronchial epithelial cells (HBECs) after exposure to γ-rays and to two different HZE particles (28Si and 56Fe) with different energy transfer properties to characterize the molecular response to HZE particles and γ-rays as a function of dose, energy deposition pattern, and time post-irradiation.
Results
Clonogenic assay indicated that the relative biological effectiveness (RBE) for 56Fe was 3.91 and for 28Si was 1.38 at 34% cell survival. Unsupervised clustering analysis of gene expression segregated samples according to the radiation species followed by the time after irradiation, whereas dose was not a significant parameter for segregation of radiation response. While a subset of genes associated with p53-signaling, such as CDKN1A, TRIM22 and BTG2 showed very similar responses to all radiation qualities, distinct expression changes were associated with the different radiation species. Gene enrichment analysis categorized the differentially expressed genes into functional groups related to cell death and cell cycle regulation for all radiation types, while gene pathway analysis revealed that the pro-inflammatory Acute Phase Response Signaling was specifically induced after HZE particle irradiation. A 73 gene signature capable of predicting with 96% accuracy the radiation species to which cells were exposed, was developed.
Conclusions
These data suggest that the molecular response to the radiation species used here is a function of the energy deposition characteristics of the radiation species. This novel molecular response to HZE particles may have implications for radiotherapy including particle selection for therapy and risk for second cancers, risk for cancers from diagnostic radiation exposures, as well as NASA’s efforts to develop more accurate lung cancer risk estimates for astronaut safety. Lastly, irrespective of the source of radiation, the gene expression changes observed set the stage for functional studies of initiation or progression of radiation-induced lung carcinogenesis.
doi:10.1186/1471-2164-14-372
PMCID: PMC3680091  PMID: 23724988
Gene expression; HZE particles; Ionizing radiation; Human bronchial epithelial cells
19.  Multiple carcinosarcomas of the esophagus and stomach 
Oncology Letters  2012;5(3):1017-1021.
Carcinosarcoma is an uncommon biphasic malignant neoplasm consisting of both carcinomatous and sarcomatous components. We report a case of an 84-year-old male with multiple carcinosarcomas occurring in the esophagus and stomach. Endoscopically, a bulky pedunculated polypoid lesion was observed in the middle of the esophagus and a huge discoid lesion in the lesser curvature. The patient received esophageal endoscopic mucosal resection, and the specimen measured 4×2.5×1.5 cm. Microscopically, the esophageal tumor consisted of several polymorphic spindle cells mixed with squamous cells, while the gastric biopsies revealed carcinomatous cells with evident abnormal karyokinesis and polymorphous spindle cells. Immunohistochemically, the resected tumor stained positively for the epithelial markers, epithelial membrane antigen (EMA) and cytokeratin 19 (CK 19), and the mesenchymal markers, smooth muscle actin (SMA) and vimentin. The gastric lesion stained positively for CK AE1/AE3, actin and vimentin, but was negative for EMA. Both lesions were positive for neuron specific enolase (NSE), demonstrating neuroendocrine differentiation. The patient succumbed seven months after being discharged from hospital. To our knowledge, this is the first case in the literature that describes multiple carcinosarcomas arising from the esophagus and stomach. A review of the available literature is also presented.
doi:10.3892/ol.2012.1095
PMCID: PMC3576283  PMID: 23426899
carcinosarcoma; upper gastrointestinal tract; immunohistochemistry
20.  Impact of SORL1 Single Nucleotide Polymorphisms on Alzheimer's Disease Cerebrospinal Fluid Markers 
Background
Recently, genetic variants of the neuronal sortilin-related receptor with A-type repeats (SORL1, also called LR11 or sorLA) have emerged as risk factors for the development of Alzheimer's disease (AD).
Methods
In this study, SORL1 gene polymorphisms, which have been shown to be related to AD, were analyzed for associations with cerebrospinal fluid (CSF) amyloid beta1–42 (Aβ1–42), phosphorylated tau181, and total tau levels in a non-Hispanic Caucasian sample, which encompassed 100 cognitively healthy elderly individuals, 166 patients with mild cognitive impairment, and 87 patients with probable AD. The data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (www.loni.ucla.edu/ADNI). Moreover, the impact of gene-gene interactions between SORL1 single nucleotide polymorphisms (SNPs) and the apolipoprotein E (APOE) ∊4 allele, the major genetic risk factor for sporadic AD, on Aβ1–42 concentrations was investigated.
Results
Significant associations between CSF Aβ1–42 levels and the SORL1 SNPs 23 (rs3824968) and 24 (rs2282649) were detected in the AD group. The latter association became marginally statistically insignificant after Bonferroni correction for multiple comparisons. Carriers of the SORL1 SNP24 T allele and the SNP23 A allele both had lower CSF Aβ1–42 concentrations than non-carriers of these alleles. The analysis of the impact of interactions between APOE ∊4 allele and SORL1 SNPs on CSF Aβ1–42 levels unraveled significant influences of APOE.
Conclusions
Our findings provide further support for the notion that SORL1 genetic variants are related to AD pathology, probably by regulating the amyloid cascade.
doi:10.1159/000332017
PMCID: PMC3696367  PMID: 21997402
Dementia; Mild cognitive impairment; Healthy aging; Amyloid cascade; Association
21.  Feasibility and safety of magnetic-controlled capsule endoscopy system in examination of human stomach: a pilot study in healthy volunteers 
Objective
To assess the feasibility and safety of magnetic-controlled capsule endoscopy (MCE) system for examination of human stomach.
Methods
This pilot study enrolled 34 healthy volunteers. All subjects swallowed the MCE and gas-producing powder for gastric distention. An external robot was used to generate magnetic field to manipulate MCE inside the stomach. The primary measurements included safety, gastric preparation, maneuverability and visualization of gastric mucosa.
Results
Gastric preparation and examination was well accepted by subjects and there were no adverse events. The examination in the stomach takes 43.8±10.0min (27–60). The cleanliness was evaluated as good in the 30 (88.2%) subjects and as moderate in 4 (11.8%) subjects. The distention of gastric cavity was evaluated as good in the 29 (85.3%) subjects and moderate in 5 (14.7%) subjects. Maneuverability of the MCE to movements of the guidance magnet robot was graded as good in 29 (85.3%) subjects and moderate in 5 (14.7%) subjects. More than 75% gastric mucosa was visualized in 27 (79.4%) subjects and 50% to 75% in 7 (20.6%) subjects. Visualization of the gastric cardia, fundus, body, angulus, antrum and pylorus was subjectively assessed as complete in 82.4%, 85.3%, 100.0%, 100.0%, 100.0% and 100.0%, respectively. Polyp and erosive lesions were found in 7 subjects.
Conclusion
Magnetic-controlled capsule endoscopy used for examination of the human stomach is feasible and safe.
doi:10.4161/jig.23751
PMCID: PMC3655386  PMID: 23687601
capsule endoscopy; magnetic-controlled; robot; feasibility studies
22.  Willingness to use pre-exposure prophylaxis for HIV prevention among female sex workers: a cross-sectional study in China 
HIV/AIDS (Auckland, N.Z.)  2012;4:149-158.
Background
Pre-exposure prophylaxis (PrEP) is a strategy developed to prevent individuals who are human immunodeficiency virus (HIV)-negative from developing HIV infection. In China, while conducting a clinical trial to investigate the effectiveness and safety of PrEP, we performed this survey to assess the willingness of female sex workers to use PrEP, and identify predictors of this willingness.
Methods
From July 2009 to April 2010, a cross-sectional study was carried out in four provinces of China. We recruited 1611 female sex workers who completed a self-administered survey to assess their awareness of and intention to use PrEP. The survey also canvassed demographic, behavioral, and psychosocial variables. Bivariate and multivariable logistic regression models were fitted to identify predictors of intent to use PrEP.
Results
In total, 69% of the women (95% confidence interval [CI] 66.7–71.3) reported intent to use PrEP, and 12% (95% CI 10.5–13.7) had used drugs in the past to prevent a sexually transmitted infection. Further, 16.5% (95% CI 14.7–18.4) had previously heard of PrEP, and 1.4% (95% CI 0.9–2.1) had used PrEP previously to prevent HIV infection. Multivariate analysis indicated the following significant predictors of intent to use PrEP: Han ethnicity (adjusted odds ratio [AOR] 1.446; P = 0.011), urban residence (AOR 1.302; P = 0.027), knowledge about transmission of HIV/acquired immune deficiency virus syndrome (AIDS, AOR 1.817; P = 0.0007), a history of sexually transmitted infection (AOR 1.830; P < 0.0001), a history of using medication to prevent a sexually transmitted disease (AOR 2.547; P < 0.0001), and willingness to access knowledge about HIV/AIDS (AOR 2.153; P < 0.0001).
Conclusion
The majority of female sex workers reported intent to use PrEP if it is safe and effective. Given that most of the participants had never heard of PrEP before, we strongly recommend that educational materials be developed with detailed introduction of PrEP. The risks and benefits of PrEP use should be fully explained to potential users when promoting PrEP in the future.
doi:10.2147/HIV.S33445
PMCID: PMC3463398  PMID: 23055781
human immunodeficiency virus; infection; pre-exposure prophylaxis; PrEP; willingness; female sex workers
23.  Comparing serum levels of cardiac biomarkers in cancer patients receiving chemotherapy and subjects with chronic periodontitis 
Journal of Translational Medicine  2012;10(Suppl 1):S5.
Background
Chronic periodontitis (CP) is a chronic inflammation associated with elevations of several inflammatory and cardiac markers. Studies implicated CP as one of the etiologies in coronary heart disease (CHD). Cardiotoxicity is a major complication of anticancer drugs, including anthracyclines and 5-fluorouracil (5FU). The most severe cardiac complications are heart failure, arrhythmia and coronary heart disease (CHD). In this study, we compared the level of inflammatory factors and cardiac markers between chronic periodontitis patients and cancer patients receiving chemotherapy.
Methods
108 blood samples of periodontally healthy subjects were obtained on random from Hong Kong Red Cross, and these represented the controlled population. Forty-four patients diagnosed with chronic periodontitis were recruited from the West China Hospital of Stomatology, Sichuan University. They have received scaling and root planning with mean pocket depths of 6.05 mm. Thirty breast cancer patients diagnosed with invasive ductal carcinoma from UNIMED Medical Institute, Hong Kong gave consent to participate in this study. They received 4 cycles of 500mg/m2 5-fluorouracil, 75 mg/m2 epirubicin and 500mg/m2 cyclophosphamide at a 3-week interval between each cycle. Peripheral venous blood from each group was taken for measurement of blood cells, inflammatory marker (P-selectin, high sensitvity C-reactive protein) and cardiac markers (troponin T; troponin I; N-terminal pro brain natriuretic peptide (Nt-proBNP) and Lactate dehydrogenase (LDH).
Results
The lymphocyte count was higher (p < 0.05) in periodontitis patients than the other two groups, and more neutrophils (p < 0.05) were seen in cancer patients receiving chemotherapy. The two test groups demonstrated higher levels (p < 0.01) of inflammatory and cardiac markers than the control group.
Conclusions
The elevated cardiac markers found in periodontitis patients suggested that they may carry potential risks in developing cardiac lesions. Troponin T, troponin I, pro-BNP, LDH and high sensitvity C-reactive protein may be used as markers to monitor cardiac lesions in chronic inflammatory patients.
doi:10.1186/1479-5876-10-S1-S5
PMCID: PMC3445855  PMID: 23046680
24.  Gene polymorphism and protein of human pro- and anti-inflammatory cytokines in Chinese healthy subjects and chronic periodontitis patients 
Journal of Translational Medicine  2012;10(Suppl 1):S8.
Background
Periodontal disease is thought to arise from the interaction of various factors, including the susceptibility of the host, the presence of pathogenic organisms, and the absence of beneficial species. The genetic factors may play a significant role in the risk of periodontal diseases. Cytokines initiate, mediate and control immune and inflammatory responses. The aim of this study is to compare genotypes and soluble protein of pro and anti-inflammatory cytokines (IL-1α, IL-1β, IL-6, IFN-γ, IL-10, TNF-α and IL-4) in subjects with or free of chronic periodontitis.
Methods
A total of 1,290 Chinese subjects were recruited to this clinical trial: 850 periodontally healthy controls and 440 periodontal patients. All subjects were free of systemic diseases. Oral examinations were performed, and the following parameters were recorded for each subject: supragingival/subgingival calculus, gingival recession, bleeding on probing (BOP), probing depth (PD), clinical attachment loss (CAL), gingival recession and tooth mobility. The peripheral blood samples were collected for genetic and enzyme linked immunosorbent assay (ELISA) analysis. Restriction enzymes were used for digestion of amplified fragments of IL-1α, IL-1β, IL-6, IFN-γ, IL-10, TNF-α and IL-4.
Results
The protein expressions of patient and control samples for IL-1α, IL-1β, IL-6, TNF-α, IFN-γ, IL-10, and IL-4 measured by ELISA confirmed a statistically significant difference (p < 0.001). The digestion of fragments of various genes showed that the pro-inflammatory cytokines IL-1α and TNF-α, and the anti-inflammatory cytokines IL-4 and IL-10 demonstrated a correlation with chronic inflammation in patients (X2: p < 0.001). The remaining genes investigated in patients and healthy subjects (IL-1β, IL-6, IFN-γ and IL-10) did not show any significant difference.
Conclusions
The cytokine gene polymorphisms may be used as a marker for periodontitis susceptibility, clinical behaviour and severity. This detection offers early diagnosis and induction of prophylaxis to other family members against disease progression.
doi:10.1186/1479-5876-10-S1-S8
PMCID: PMC3445856  PMID: 23046796
25.  Clinical application of human β-defensin and CD14 gene polymorphism in evaluating the status of chronic inflammation 
Journal of Translational Medicine  2012;10(Suppl 1):S9.
Background
Periodontitis is a common disease that affects the periodontal tissue supporting the teeth. This disease is attributed to multiple risk factors, including diabetes, cigarette smoking, alcohol, pathogenic microorganisms, genetics and others. Human beta-defensin-1 (hBD-1) is a cationic antimicrobial peptide with cysteine-rich ß-sheets and broad-spectrum antimicrobial activity. CD14 is a protein involved in the detection of bacterial lipopolysaccharide (LPS) and has also been associated with periodontitis. This study investigates the single nucleotide polymorphic (SNP) region, -1654(V38I), of the human beta-defensin-1 (hBD-1) gene as well as the -159 region of the CD14 gene in subjects with chronic periodontitis.
Methods
Blood samples from periodontally healthy subjects and periodontitis patients were obtained. DNA was extracted from the blood and was used to perform restriction digest at the polymorphic G1654A site of DEFB1 with the enzyme HincII. The polymorphic site 159TT of CD14 was digested with the enzyme AvaII. Enzyme-linked immunosorbent assay (ELISA) was performed on soluble samples to determine the protein expressions.
Results
The control and patient groups expressed 35% and 38% 1654 A/A genotype of DEFB1, respectively. The A allele frequency of the control group was 40%, while the patient blood group was 54%. The mean hBD-1 protein levels of the control and patient samples were 102.83 pg/mL and 252.09 pg/mL, respectively. The genotype distribution of CD14 in healthy subjects was 16% for C/C, 26% for T/T and 58% for C/T. The genotype frequencies of CD14 in periodontitis patients were 10% for C/C, 43% for T/T and 47% for C/T. The CD14 protein expression determined by ELISA showed a mean protein level of the control samples at 76.28ng/mL and the patient blood samples at 179.27ng/mL with a p value of 0.001.
Our study demonstrated that patients suffering from chronic periodontitis present more commonly with the 1654A/A genotype on the DEFB1 gene and the 159T/T genotype on the CD14 gene.
Conclusions
This study purely investigated the association between periodontitis and one polymorphic site on both DEFB1 and CD14 gene, with the purpose of expanding knowledge for the future development in diagnostic markers or therapeutic interventions to combat this disease.
doi:10.1186/1479-5876-10-S1-S9
PMCID: PMC3445860  PMID: 23046822

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