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1.  Calpain-1 contributes to IgE-mediated mast cell activation 
Mast cells play a central role in allergy through secretion of both preformed and newly synthesized mediators. Mast cell mediator secretion is controlled by a complex network of signaling events. Despite intensive studies, signaling pathways in the regulation of mast cell mediator secretion remain incompletely defined. Here, we examined the role of calpain in IgE-dependent mast cell activation. IgE-mediated activation of mouse bone marrow-derived mast cells (BMMCs) enhanced calpain activity. Inhibition of calpain activity by a number of calpain inhibitors reduced IgE-mediated mast cell degranulation both in vitro and in vivo. Calpain inhibitors blocked IgE-mediated TNF and IL-6 production in vitro and reduced late-phase allergic response in vivo. Importantly, mouse calpain-1 null BMMCs showed reduced IgE-mediated mast cell degranulation in vitro and in vivo, diminished cytokine and chemokine production in vitro, and impaired late-phase allergic response in vivo. Further studies revealed that calpain-1-deficiency led to specific attenuation of IκB-NF-κB pathway and IKK-SNAP23 pathway, while calcium flux, MAP kinases, Akt, and NFAT pathway proceed normally in IgE-activated calpain-1 null mast cells. Thus, calpain-1 is identified as a novel regulator in IgE-mediated mast cell activation and could serve as a potential therapeutic target for the management of allergic inflammation.
PMCID: PMC4038093  PMID: 24760147
2.  Association between CYP1B1 Gene Polymorphisms and Risk Factors and Susceptibility to Laryngeal Cancer 
The aim of this study was to investigate the association between polymorphism of the cytochrome P450 1B1 (CYP1B1) gene, a metabolic enzyme gene, and the susceptibility to laryngeal cancer among the Chinese Han population.
In a case-control study, we investigated polymorphisms in the CYP1B1 gene (rs10012, rs1056827, and rs1056836) with a real-time quantitative polymerase chain reaction (PCR) assay (TaqMan). The study was conducted with 300 Chinese Han patients with laryngeal cancer and 300 healthy Chinese Han subjects in a control group. We also studied the interactions between genetic polymorphism and risk factors such as smoking and alcohol consumption in the pathogenesis of laryngeal cancer.
There were statistically significant differences in the distributions of the rs1056827 and rs1056836 genotypes between the 2 groups. Regarding rs1056827, carriers of the T allele had a significantly higher risk of laryngeal cancer than the G-allele carriers (OR=1.4339, 95% CI: 1.1268–1.8247; P=0.0034). The difference was still statistically significant after adjusting for factors such as age, sex, smoking, and drinking (adjusted OR=1.743, 95% CI: 1.124–3.743, P<0.001). However, regarding rs1056836, the G allele carriers had a significantly lower risk of laryngeal cancer than the C allele carriers (OR=0.5557, 95% CI: 0.3787–0.8154; P=0.0027). The difference was statistically significant even after adjusting for factors such as age, sex, smoking, and drinking (adjusted OR=0.5641, 95% CI: 0.3212–0.8121, P=0.001). Subjects who carry the C-T-C haplotype have a significantly increased incidence of laryngeal cancer. We also found that CYP1B1 rs1056827 polymorphism had synergistic effects with smoking or alcohol consumption regarding the risk of laryngeal cancer.
CYP1B1 gene polymorphism is closely related to the onset of laryngeal cancer. There is a mutually synergistic effect between smoking, alcohol consumption, and CYP1B1 gene polymorphisms regarding laryngeal cancer.
PMCID: PMC4307736  PMID: 25619313
Laryngeal Neoplasms; Polymorphism, Single Nucleotide; Steroid 11-beta-Hydroxylase
3.  Relationship Between Amounts of Daily Cigarette Consumption and Abdominal Obesity Moderated by CYP2A6 Genotypes in Chinese Male Current Smokers 
Cigarette smoking is an important risk factor for abdominal obesity. However, the degree to which the CYP2A6 genotype moderates the relationship between smoking and abdominal obesity has not been established.
This study aims to investigate whether or not the relationship between smoking quantity and abdominal obesity is influenced by CYP2A6 genotypes.
Nine hundred fifty-four male current smokers were selected. A venous specimen was collected to test serum cotinine and CYP2A6 genotype, and all smokers were divided into heavy (>15 cigarettes/day) and light smokers (≤15 cigarettes/day).
Heavy smoking increased the risk of abdominal obesity (odds ratio (OR)=1.57; 95% CI, 1.13–2.19) compared with light smoking. Furthermore, heavy smoking had a positive interactive effect with CYP2A6 poor metabolizer genotype on abdominal obesity (OR=3.90; 95% CI, 1.25– 12.18). Moreover, CYP2A6 poor metabolizer genotypes were associated with slower nicotine metabolism.
Heavy smoking may increase the risk of abdominal obesity—particularly in smokers with CYP2A6 poor metabolizer genotypes.
PMCID: PMC4114962  PMID: 22160797
Cigarette smoking; CYP2A6 genotypes; Abdominal obesity; Interaction
4.  Interaction between heavy smoking and CYP2A6 genotypes on type 2 diabetes and its possible pathways 
To explore the interactions between smoking and CYP2A6 genotypes on type 2 diabetes (T2DM) as well as potential pathways for smoking in causing T2DM.
Cross-sectional study.
A total of 1344 smokers with complete data from a community-based T2DM survey in Guangzhou and Zhuhai of China from July 2006 to June 2007 were interviewed with a structured questionnaire about socio-demographic status and daily cigarette consumption. Serum glucose, insulin, and cotinine were measured after an overnight fast. Subjects were genotyped for CYP2A6 and classified, according to genotype, into normal, intermediate, slow, or poor nicotine metabolizers based on prior knowledge of CYP2A6 allele associations with nicotine C-oxidation rate. Abdominal obesity was defined as a waist-to-hip ratio ≥0.90 for males or ≥0.85 for females. Type 2 diabetic patients (n=154) were diagnosed according to WHO 1999 criteria. Chi-square tests, multivariate logistic regression models, and a structural equation model were used in this study.
Multivariate analysis indicated that, compared with light smoking, heavy smoking significantly increased the risk of T2DM (odds ratio (OR)=1.75, 95% CI=1.01–3.05). There were significant interactions between heavy smoking and slow CYP2A6 (OR=5.12, 95% CI=1.08–24.23) and poor CYP2A6 metabolizer genotypes (OR=8.54, 95% CI=1.28–57.02) on T2DM. Structural equation modeling indicated that CYP2A6 moderation of smoking quantity risk on T2DM was mediated by the effects on serum cotinine, abdominal obesity, insulin resistance, and insulin secretion.
Heavy smoking was significantly associated with T2DM, and this association was moderated by CYP2A6 genotype and mediated by serum cotinine, abdominal obesity, insulin resistance, and insulin secretion.
PMCID: PMC4112659  PMID: 21964962
5.  Growth of Millimeter-Size Single Crystal Graphene on Cu Foils by Circumfluence Chemical Vapor Deposition 
Scientific Reports  2014;4:4537.
A simply and reproducible way is proposed to significantly suppress the nucleation density of graphene on the copper foil during the chemical vapor deposition process. By inserting a copper foil into a tube with one close end, the nucleation density on the copper foils can be reduced by more than five orders of magnitude and an ultra-low nucleation density of ~10 nucleus/cm2 has been achieved. The structural analyses demonstrate that single crystal monolayer graphene with a lateral size of 1.9 mm can be grown on the copper foils under the optimized growth condition. The electrical transport studies show that the mobility of such single crystal graphene is around 2400 cm2/Vs.
PMCID: PMC3971397  PMID: 24686949
6.  Associations of CYP2A6 genotype with smoking behaviors in southern China 
Addiction (Abingdon, England)  2011;106(5):985-994.
To investigate the association of CYP2A6 genetic polymorphisms with smoking-related phenotypes in Chinese smokers.
Case-only genetic association study.
Southern China
A total of 1,328 Han Chinese smokers who participated in a community-based chronic disease screening project in Guangzhou and Zhuhai from 2006 to 2007.
All participants were answered a structured questionnaire about socio-demographic status and smoking behaviors and informative alleles for the cytochrome P450 2A6 (CYP2A6) gene (CYP2A6 *4, *5, *7, *9 and *10) were genotyped.
The frequencies of CYP2A6 *4, *5, *7, *9 and *10 alleles were 8.5%, 1.2%, 6.3%, 13.5% and 2.4%, which corresponded to 48.9%, 15.4%, 24.2% and 11.5% of participants being classified as normal, intermediate, slow and poor metabolizers, respectively. Multivariate analyses demonstrated that compared with normal metabolizers, poor metabolizers reported smoking fewer cigarettes per day (adjusted OR = 0.49; 95% CI: 0.32–0.76), started smoking regularly later in life (adjusted OR = 1.55; 95% CI: 1.06–2.26) and, amongst former smokers, reported smoking for a shorter duration prior to quitting (adjusted OR = 0.33; 95% CI: 0.12–0.94). However, poor metabolizers were less likely to quit smoking and remain abstinent than normal metabolizers (OR = 0.54; 95% CI: 0.34–0.86).
Reduced metabolism function of CYP2A6 in smokers appears to be associated with fewer cigarettes smoked, later initiation of smoking regularly, shorter smoking duration and lower likelihood of smoking cessation.
PMCID: PMC3074015  PMID: 21205058
CYP2A6; genetic polymorphisms; smoking behavior; Chinese smokers
7.  Rapamycin enhances cetuximab cytotoxicity by inhibiting mTOR-mediated drug resistance in mesenchymal hepatoma cells 
Cancer Biology & Therapy  2014;15(8):992-999.
The synergistic effect of combined drug therapy provides an enhanced treatment for advanced liver cancer. We aimed to investigate the underlying mechanism of cetuximab sensitization by rapamycin in hepatoma cells. Four hepatoma cell lines, HepG2, HuH7, SNU-387, and SNU-449, were treated with cetuximab or cetuximab plus rapamycin and growth inhibition was evaluated by measuring relative cell viability and cell proliferation. The cell phenotype was determined for each hepatoma cell line by western blot analysis of E-cadherin and vimentin expression and mTOR activation status. To identify the role of mTOR signaling in cetuximab sensitization, we used deferoxamine-mediated hypoxia to induce epithelial–mesenchymal transition (EMT) in HuH7 and HepG2 cells and measured mTOR activity after rapamycin treatment.
Rapamycin significantly increased cetuximab cytotoxicity in hepatoma cell lines with differential sensitivities. Phenotypic differences among hepatoma cell lines, specifically epithelial (HuH7and HepG2) and mesenchymal (SNU-387 and SNU-449), correlated with the efficacy of rapamycin cotreatment, although rapamycin treatment did not affect cell phenotype. We further showed that rapamycin inhibits mTOR in mesenchymal SNU-387 and SNU-449 cells. In addition, the induction of EMT in HuH7 and HepG2 cells significantly decreased cetuximab cytotoxicity; however, rapamycin treatment significantly restored cetuximab sensitivity and decreased mTOR signaling in these cells.
In conclusion, we identified significant differences in rapamycin-induced cetuximab sensitization between epithelial and mesenchymal hepatoma cells. We therefore report that rapamycin cotreatment enhances cetuximab cytotoxicity by inhibiting mTOR signaling in mesenchymal cells.
PMCID: PMC4119084  PMID: 24800850
cetuximab; rapamycin; liver neoplasms; combined therapy; mTOR pathway
8.  Genetic variants in Fanconi Anemia Pathway Genes BRCA2 and FANCA Predict Melanoma Survival 
Cutaneous melanoma (CM) is the most lethal skin cancer. The Fanconi Anemia (FA) pathway involved in DNA crosslinks repair may affect CM susceptibility and prognosis. Using data derived from published genome-wide association study, we comprehensively analyzed the associations of 2339 common single nucleotide polymorphisms (SNPs) in 14 autosomal FA genes with overall survival (OS) in 858 CM patients. By performing false-positive report probability corrections and stepwise Cox proportional hazards regression analyses, we identified significant associations between CM OS and four putatively functional SNPs: BRCA2 rs10492396 [AG vs. GG: adjusted hazard ratio (adjHR)=1.85, 95% confident interval (CI)=1.16-2.95, P=0.010], rs206118 (CC vs. TT+TC: adjHR=2.44, 95% CI=1.27-4.67, P=0.007), rs3752447 (CC vs. TT+TC: adjHR=2.10, 95% CI=1.38-3.18, P=0.0005), and FANCA rs62068372 (TT vs. CC+CT: adjHR=1.85, 95% CI=1.27-2.69, P=0.001). Moreover, patients with an increasing number of unfavorable genotypes (NUG) of these loci had markedly reduced OS and melanoma-specific survival (MSS). The final model incorporating with NUG, tumor stage and Breslow thickness showed an improved discriminatory ability to classify both 5-year OS and 5-year MSS. Additional investigations, preferably prospective studies, are needed to validate our findings.
PMCID: PMC4289462  PMID: 25243787
cutaneous melanoma; Fanconi Anemia pathway; survival; single nucleotide polymorphisms; Cox regression
9.  Serum Prognostic Biomarkers in Head and Neck Cancer Patients 
The Laryngoscope  2014;124(8):1819-1826.
A reliable estimate of survival is important as it may impact treatment choice. The objective of this study is to identify serum autoantibody biomarkers that can be used to improve prognostication for patients affected with head and neck squamous cell carcinoma (HNSCC).
Study Design
Prospective cohort study.
A panel of 130 serum biomarkers, previously selected for cancer detection using microarray-based serological profiling and specialized bioinformatics, were evaluated for their potential as prognostic biomarkers in a cohort of 119 HNSCC patients followed for up to 12.7 years. A biomarker was considered positive if its reactivity to the particular patient’s serum was greater than one standard deviation above the mean reactivity to sera from the other 118 patients, using a leave-one-out cross-validation model. Survival curves were estimated according to the Kaplan-Meier method, and statistically significant differences in survival were examined using the log rank test. Independent prognostic biomarkers were identified following analysis using multivariate Cox proportional hazards models.
Poor overall survival was associated with African Americans (hazard ratio [HR] for death =2.61; 95% confidence interval [CI]: 1.58–4.33; P =.000), advanced stage (HR =2.79; 95% CI: 1.40–5.57; P =.004), and recurrent disease (HR =6.66; 95% CI: 2.54–17.44; P =.000). On multivariable Cox analysis adjusted for covariates (race and stage), six of the 130 markers evaluated were found to be independent prognosticators of overall survival.
The results shown here are promising and demonstrate the potential use of serum biomarkers for prognostication in HNSCC patients. Further clinical trials to include larger samples of patients across multiple centers may be warranted.
PMCID: PMC4129948  PMID: 24347532
Head and neck squamous cell carcinoma; prognostic biomarkers; prognosis; proteomic
10.  Bladder Acellular Matrix Conjugated with Basic Fibroblast Growth Factor for Bladder Regeneration 
Tissue Engineering. Part A  2014;20(15-16):2234-2242.
Basic fibroblast growth factor (bFGF) plays an important role in wound repair and tissue regeneration. Considerable research has been focused on the exploration of bFGF delivery systems for maintaining efficient local concentration at the injury sites. In this study, bFGF was chemically crosslinked to the bladder acellular matrix (BAM) to create specific binding between bFGF and BAM. The BAM scaffold conjugated with bFGF (CL-BAM/bFGF) could bind more bFGF and achieve controlled release of bFGF, which promoted human fibroblasts to proliferate in vitro and accelerated cellularization and vascularization after subcutaneous implantation. Using the rat bladder reconstruction model, the CL-BAM/bFGF group showed better tissue regeneration compared with the other groups. In summary, CL-BAM/bFGF could prevent the diffusion of bFGF from BAM and maintain its activity. Thus, the scaffold conjugated with growth factor systems could be an effective way for maintaining local therapy dosage at the target site in wound repair and tissue regeneration.
PMCID: PMC4137349  PMID: 24483233
11.  Frequent Use of Chlorhexidine-Based Body Wash Associated with a Reduction in Methicillin-Resistant Staphylococcus aureus Nasal Colonization among Military Trainees 
In a field-based trial among military trainees, personal hygiene measures, including chlorhexidine (CHG) body wash, did not prevent overall and methicillin-resistant Staphylococcus aureus (MRSA) skin and soft-tissue infections (SSTI). We conducted a secondary analysis of anterior nares cultures obtained during the trial to evaluate the impact of hygiene measures on Staphylococcus aureus colonization. A cluster-randomized trial for SSTI prevention was conducted among U.S. Army infantry trainees from May 2010 to January 2012. There were three study groups with incrementally increasing education- and hygiene-based components: standard (S), enhanced standard (ES), and CHG. Anterior nares cultures were obtained from participants to determine the prevalence of S. aureus colonization. A total of 1,706 participants (469 S, 597 ES, and 640 CHG) without SSTI were included in the colonization analysis. Of those randomized to the CHG group, 360 (56.3%) reported frequent use of body wash. Frequent use of body wash had no effect on overall S. aureus colonization (53.3% versus 56.8% among infrequent/nonusers; P = 0.25). MRSA colonization prevalence was marginally lower among frequent users (2.5% versus 4.7%; P = 0.07). In multivariable analysis, the odds of MRSA colonization were lower among frequent users (odds ratio [OR], 0.36; 95% confidence interval [CI], 0.16 to 0.77). This CHG-associated reduction was not observed when comparing colonization with USA300 to that with non-USA300 types (OR, 0.59; 95% CI, 0.06 to 5.76). Frequent use of CHG body wash was associated with a reduction in MRSA nasal colonization among high-risk military trainees. Topical chlorhexidine may contribute to MRSA SSTI prevention by reducing colonization. However, further studies evaluating the pathogenesis of SSTI are needed. (This study has been registered at under registration no. NCT01105767).
PMCID: PMC4335831  PMID: 25421482
12.  Sex and Race (Black-White) Differences in the Relationship of Childhood Risk Factors to Adulthood Arterial Stiffness: The Bogalusa Heart Study 
Background and aim
Cardiovascular risk factors in childhood are predictive of adulthood arterial stiffness. However, it is unknown whether this relationship varies by race or sex.
Six hundred and eighty adults aged 24–43 had been followed for an average of 26.3 years, from the Bogalusa Heart Study. Brachial to ankle pulse wave velocity (baPWV) measured by an automatic oscillometric technique was used as the outcome variable for arterial stiffness during adulthood. Body mass index (BMI), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), glucose, and systolic blood pressure (SBP), all measured in childhood, were used as predictors. The average values of childhood measurements at multiple time points were used, standardized to age, race, and sex-specific z-scores.
In the total sample, childhood SBP was the only significant predictor (p<0.001) for adult baPWV. Significant interactions between sex and BMI (p=0.001), between sex and LDL-C (p=0.035), and between race and HDL-C (p=0.002) on adult baPWV were identified. Childhood predictors of adult baPWV were BMI (30.9 cm/second reduction in baPWV per standard deviation increase, 95% confidence interval (CI): −55.0, −6.9 cm/second), LDL-C (30.8 cm/second increase, 95% CI: 2.9, 59.5 cm/second) and HDL-C (46.8 cm/second reduction, 95% CI: −76.2, −17.4 cm/second) in white males, systolic blood pressure (38.2 cm/second increase, 95% CI: 11.0, 65.4 cm/second) in white females, BMI (71.3 cm/second reduction, 95% CI: −119.9, −22.7 cm/second) in black males, and none in black females.
The associations of childhood cardiovascular risk factors with adult arterial stiffness varied by race and sex.
PMCID: PMC4108517  PMID: 24762753
Race (black–white); sex; childhood CV risk factors; adult arterial stiffness
13.  Electromechanical and atrial and ventricular antiarrhythmic actions of CIJ-3-2F, a novel benzyl-furoquinoline vasodilator in rat heart 
British Journal of Pharmacology  2014;171(16):3918-3937.
This study was designed to examine the antiarrhythmic efficacy and the underlying mechanisms of the benzyl-furoquinoline vasodilator, CIJ-3-2F, in rat cardiac preparations.
Conduction electrograms and left ventricular pressure were determined in Langendorff-perfused hearts. Action potentials were assessed with microelectrode techniques, calcium transients by fura-2 fluorescence and ionic currents by whole-cell patch-clamp techniques.
In isolated hearts, CIJ-3-2F prolonged sinus cycle length, QT interval, Wenckebach cycle length, atrio-His bundle and His bundle-ventricular conduction intervals, refractory periods in atrium, AV node, His-Purkinje system and ventricle, and also increased left ventricular pressure. CIJ-3-2F reduced the incidences of both ischaemic and reperfusion-induced ventricular arrhythmias and prevented the induction of atrial tachyarrhythmias. In both atrial and papillary muscles, CIJ-3-2F decreased upstroke velocity and prolonged duration of the action potential. In ventricular myocytes, CIJ-3-2F moderately increased the amplitude of [Ca2+]i transients and cell shortening. CIJ-3-2F inhibited the transient outward K+ current (Ito) (IC50 = 4.4 μM) with accelerated inactivation, a slower rate of recovery from inactivation and use-dependency. CIJ-3-2F also suppressed the steady-state outward K+ current (Iss, IC50 = 3.6 μM, maximum inhibition = 65.7%) and both the inward Na+ current (INa, IC50 = 2.8 μM) and L-type Ca2+ current (ICa,L, IC50 = 4.9 μM, maximum inhibition = 69.4%).
CIJ-3-2F blocked Na+ and Ito channels and, to some extent, also blocked Ca2+ and Iss channels, modifying cardiac electromechanical function. These effects are likely to underlie its antiarrhythmic properties.
PMCID: PMC4128053  PMID: 24820856
14.  Suicide and Other-Cause Mortality after Early Exposure to Smoking and Second Hand Smoking: A 12-Year Population-Based Follow-Up Study 
PLoS ONE  2015;10(7):e0130044.
The association between smoking and suicide is still controversial, particular for early life cigarette smoking exposure. Few studies have investigated this association in adolescents using population-based cohorts, and the relationship with second hand smoking (SHS) exposure has not been addressed.
Methods and Findings
In this study, we followed a large population-based sample of younger people to investigate the association between smoking, SHS exposure and suicide mortality. Between October 1995 and June 1996, 162,682 junior high school students ages 11 to 16 years old living in a geographic catchment area in Taiwan were enrolled and then followed till December 2007 (1,948,432 person-years) through linkage to the National Death Certification System. Participants who were currently smoking at baseline had a greater than six-fold higher suicide mortality than those who did not smoke (29.5 vs. 4.8 per 100,000 person-years, p<0.001) as well as higher natural mortality (33.7 vs. 10.3 per 100,000 person-years, p<0.001). After controlling for gender, age, parental education, asthma, allergic rhinitis, and alcohol consumption, the adjusted hazard ratios for suicide were 3.69 (95% CI 1.85-7.39) in current smokers, and 1.47 (95% CI 0.94-2.30) and 2.83 (95% CI 1.54-5.20) respectively in adolescents exposed to SHS of 1-20 cigarettes and >20 cigarettes/per day. The estimated depression-adjusted odds ratio did not change substantially. The population attributable fractions for suicide associated with smoking and heavy SHS exposure (>20 cigarettes/per day) were 9.6% and 10.6%, respectively.
This study showed evidence of excess suicide mortality among young adults exposed to active or passive early life cigarette smoking.
PMCID: PMC4519334  PMID: 26222448
15.  PDIA3 Knockdown Exacerbates Free Fatty Acid-Induced Hepatocyte Steatosis and Apoptosis 
PLoS ONE  2015;10(7):e0133882.
Nonalcoholic fatty liver disease (NAFLD) has emerged as one of the most common chronic liver disease over the past decades. Endoplasmic reticulum stress (ERS) plays a pivotal role during the development of NAFLD. This study aims to analyze the potential role of protein disulfide isomerase A3 precursor (PDIA3), one of the ER chaperones, in free fatty acid-induced cell model of NAFLD. Human liver L02 cell line was treated with sodium palmitate for 24 hours, which developed severe intracellular lipid accumulation. The increased protein level of PDIA3 was detected via immunoblotting analysis in the fat loaded cell models of NAFLD. siRNA-mediated knockdown of PDIA3 in L02 cells not only increased the cellular lipid accumulation, but also exacerbated hepatocytes apoptosis induced by sodium palmitate. Further investigation revealed that knockdown of PDIA3 up-regulated protein expression of fatty acid synthase (FAS), a key enzyme involved in fatty acid synthesis. PDIA3 knockdown also up-regulated key molecules of ERS pathway, including glucose-regulated protein 78 (GRP78), phospho-PKR-like ER kinase (p-PERK), and C/EBP homologous protein (CHOP). Our results suggested that ER chaperone PDIA3 plays a pivotal role in FFA-induced hepatocyte steatosis and apoptosis.
PMCID: PMC4516249  PMID: 26214517
16.  TLR4-HMGB1-, MyD88- and TRIF-dependent signaling in mouse intestinal ischemia/reperfusion injury 
AIM: To characterize high-mobility group protein 1-toll-like receptor 4 (HMGB1-TLR4) and downstream signaling pathways in intestinal ischemia/reperfusion (I/R) injury.
METHODS: Forty specific-pathogen-free male C57BL/6 mice were randomly divided into five groups (n = 8 per group): sham, control, anti-HMGB1, anti-myeloid differentiation gene 88 (MyD88), and anti-translocating-chain-associating membrane protein (TRIF) antibody groups. Vehicle with the control IgG antibody, anti-HMGB1, anti-MyD88, or anti-TRIF antibodies (all 1 mg/kg, 0.025%) were injected via the caudal vein 30 min prior to ischemia. After anesthetization, the abdominal wall was opened and the superior mesenteric artery was exposed, followed by 60 min mesenteric ischemia and then 60 min reperfusion. For the sham group, the abdominal wall was opened for 120 min without I/R. Levels of serum nuclear factor (NF)-κB p65, interleukin (IL)-6, and tumor necrosis factor (TNF)-α were measured, along with myeloperoxidase activity in the lung and liver. In addition,morphologic changes that occurred in the lung and intestinal tissues were evaluated. Levels of mRNA transcripts encoding HMGB1 and NF-κB were measured by real-time quantitative PCR, and levels of HMGB1 and NF-κB protein were measured by Western blot. Results were analyzed using one-way analysis of variance.
RESULTS: Blocking HMGB1, MyD88, and TRIF expression by injecting anti-HMGB1, anti-MyD88, or anti-TRIF antibodies prior to ischemia reduced the levels of inflammatory cytokines in serum; NF-κB p65: 104.64 ± 11.89, 228.53 ± 24.85, 145.00 ± 33.63, 191.12 ± 13.22, and 183.73 ± 10.81 (P < 0.05); IL-6: 50.02 ± 6.33, 104.91 ± 31.18, 62.28 ± 6.73, 85.90 ± 17.37, and 78.14 ± 7.38 (P < 0.05); TNF-α, 43.79 ± 4.18, 70.81 ± 6.97, 52.76 ± 5.71, 63.19 ± 5.47, and 59.70 ± 4.63 (P < 0.05) for the sham, control, anti-HMGB1, anti-MyD88, and anti-TRIF groups, respectively (all in pg/mL).Antibodies also alleviated tissue injury in the lung and small intestine compared with the control group in the mouse intestinal I/R model. The administration of anti-HMGB1, anti-MyD88, and anti-TRIF antibodies markedly reduced damage caused by I/R, for which anti-HMGB1 antibody had the most obvious effect.
CONCLUSION: HMGB1 and its downstream signaling pathway play important roles in the mouse intestinal I/R injury, and the effect of the TRIF-dependent pathway is slightly greater.
PMCID: PMC4507101  PMID: 26217083
C57BL/6 mouse; High-mobility group protein 1; Intestinal ischemia-reperfusion injury; Myeloid differentiation gene 88; Nuclear factor-κB translocating-chain-associating membrane protein
17.  All-carbon based graphene field effect transistor with graphitic electrodes fabricated by e-beam direct writing on PMMA 
Scientific Reports  2015;5:12198.
A so called all-carbon based graphene field effect transistor (GFET) in which the electrodes are composed of graphite-like nano-sheets instead of metals in the traditional devices is fabricated by one-step e-beam direct writing (EBDW). It is also found that the graphite-like nano-sheets in electrodes are perpendicular to the channel graphene, which is confirmed by the transmission electron microscopy (HRTEM). The one-step fabrication of the carbonaceous electrodes is more convenient and lower-cost comparing to the preparation of traditional metal electrodes and can be applied to many other nano-electronic devices.
PMCID: PMC4508849  PMID: 26195033
18.  Epidural anesthesia for laparoscopic bariatric surgery: a case report 
SpringerPlus  2015;4:363.
Rapid and uneventful postoperative recovery following general anesthesia in morbidly obese patients undergoing bariatric surgery may offer challenges to anesthesiologists. With improved surgical techniques and shorter pneumoperitoneum, regional anesthesia may be considered for this laparoscopic procedure in selected cases.
Case description
The first patient was a 60-year-old male (body mass index: 39 kg/m2) who was scheduled for laparoscopic sleeve gastrectomy. The second patient was a 46-year-old female (body mass index: 47 kg/m2) who was scheduled for laparoscopic gastric bypass. After standard intraoperative monitoring was applied, epidural anesthesia was performed at thoracic level T9–T10. Surgical technique modification included insufflation of CO2 at a low flow rate and avoidance of orogastric tube use. During the procedure, both patients breathed spontaneously without difficulty. One hypotension episode occurred and was successfully treated with a 12-mg bolus of ephedrine in case 1. Shoulder pain occurred intraoperatively in case 2 and was successfully treated with a 50-μg bolus of fentanyl. Postoperatively, 2 mg epidural morphine was administered for postoperative analgesia. Both patients were satisfied with the anesthesia technique and was discharged uneventfully.
Discussion and evaluation
This anesthetic technique may maintain pre-operative respiratory function, increase alertness, and reduce the use of rescue analgesics, which is crucial for optimal outcomes in morbidly obese patients. Conversion of epidural anesthesia to general anesthesia may be required if patients can not tolerate the laparoscopic procedure (e.g. intolerable shoulder pain) or the increased respiratory rate during pneumoperitoneum leading to difficulty in performing laparoscopic surgery. Further studies are needed to elucidate this issue.
General anesthesia is widely used for laparoscopic bariatric surgery, but epidural anesthesia may be a viable alternative to general anesthesia in selected cases. Further prospective studies may be required to elucidate the relative advantages and disadvantages of epidural anesthesia in this surgical population.
PMCID: PMC4504868  PMID: 26203409
Epidural anesthesia; Laparoscopic bariatric surgery; Obesity
The metaplastic intestinal epithelium in Barrett esophagus (BE) occasionally contains Paneth cells; however, little is known regarding the prevalence and significance of Paneth cell metaplasia (PCM) in BE.
We evaluated 757 esophageal biopsy specimens with intestinal metaplasia (IM) for PCM. Outcome analysis was performed in 299 cases with complete clinical data using multinomial logistic regression.
Thirty-one percent (234/757) of the IM cases showed PCM. Paneth cells are decreased when BE epithelium becomes increasingly dysplastic. Long-segment BE shows significantly more PCM than short-segment BE. On follow-up biopsies, patients without PCM (NPCM) are three times more likely to regress than patients with PCM, regardless of dysplasia, BE segment length, age, or sex. However, there is no significant difference in terms of progression to dysplasia/adenocarcinoma between the PCM and NPCM groups.
The presence of PCM is associated with less disease regression and is not associated with more disease progression.
PMCID: PMC4504017  PMID: 25873500
Paneth cell; Barrett esophagus; Dysplasia; Esophageal adenocarcinoma; GERD
20.  Introgression of the crtRB1 gene into quality protein maize inbred lines using molecular markers 
Molecular Breeding  2015;35(8):154.
Quality protein maize (QPM; Zea mays L.) has effectively enhanced levels of the amino acids, lysine, and tryptophan, over normal maize and provided balanced dietary protein for the health and development of monogastric animals and humans. However, as in normal maize, QPM varieties are low in provitamin A (ProVA), a precursor of vitamin A, which can lead to vitamin A deficiency in humans when maize is a significant part of their diet. In this study, maize inbred Hp321-1 carrying the favorable alleles crtRB1-5′TE-2 and crtRB1-3′TE-1 that can enhance levels of ProVA, was used as donor for improving ProVA in QPM inbred lines CML161 and CML171. Functional markers for identifying the favorable alleles crtRB1-5′TE-2 and crtRB1-3′TE-1 were used in foreground selection, and simple sequence repeat markers were used in background selection for the BC1F1, BC2F1, and BC2F2 generations. The background recovery rates were 77.4 and 84.5 % for CML161 and CML171 populations, respectively, in the BC1F1 generation, and 89.9 and 92.1 % in the BC2F2 generation. With foreground and background selection, the mean ProVA concentration has been improved from 1.60 µg g−1 in the parent of CML161 to 5.25 µg g−1 in its BC2F3 offspring, from 1.80 µg g−1 in the parent of CML171 to 8.14 µg g−1 in its BC2F3 offspring while maintaining similar QPM characteristics of the recurrent parents. The success from this study offers maize breeders a procedure for increasing ProVA in QPM lines, which will greatly mitigate vitamin A deficiency and protein-energy malnutrition in developing countries.
Electronic supplementary material
The online version of this article (doi:10.1007/s11032-015-0349-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4503869  PMID: 26190934
Provitamin A; crtRB1 gene; Functional markers; Foreground selection; Background selection; Maize (Zea mays L.)
21.  Balancing the Expression and Production of a Heterodimeric Protein: Recombinant Agkisacutacin as a Novel Antithrombotic Drug Candidate 
Scientific Reports  2015;5:11730.
Agkisacucetin extracted from the venom of Agkistrodon acutus has been demonstrated to be a promising antithrombotic drug candidate in clinical studies due to its function as a novel platelet membrane glycoprotein (GP) Ib inhibitor. Agkisacucetin is a heterodimeric protein composed of α- and β-subunits with seven disulphide bonds. Both subunits form inactive homodimeric products, which cause difficulties for recombinant production. In this study, Agkisacucetin α- and β-subunits were inserted sequentially into the chromosome of Pichia pastoris at the mutant histidinol dehydrogenase gene and ribosomal DNA repeat sites, respectively. By optimizing the gene copies and productivity of each subunit by drug screening, we successfully obtained a recombinant strain with balanced expression of the two subunits. Using this strain, a yield greater than 100 mg/L recombinant Agkisacucetin in fed-batch fermentation was reached. The recombinant Agkisacucetin possessed extremely similar binding affinity to recombinant GPIb and human platelets in in vitro assays, and its ristocetin-induced platelet aggregation activity ex vivo was identical to that of the extracted native Agkisacucetin, demonstrating that the yeast-derived Agkisacucetin could be an effective alternative to native Agkisacucetin. Moreover, this study provides an effective strategy for balancing the expression and production of heterodimeric proteins in P. pastoris.
PMCID: PMC4491848  PMID: 26144864
22.  Hepatitis B Virus Infection Rate and Distribution in Chinese Systemic Lupus Erythematosus Patients 
The aim of this study was to investigate the hepatitis B virus (HBV) infection rate in systemic lupus erythematosus (SLE) patients in China, and to determine the age and sex distribution.
A total of 3981 SLE patients diagnosed in The First Affiliated Hospital of Sun Yat-sen University from January 1996 to December 2011 were retrospectively investigated for evaluation of the HBV infection rate. The HBV infection rate and the positive rate of hepatitis B surface antibody (HBsAb) and hepatitis B core antibody (HBcAb) were standardized to national census data in 2000 and compared with the prevalence found in the 2006 national survey.
The age and sex standardized HBV infection rate in Chinese SLE patients was 3.3%. The age and sex standardized positive rate of HBsAb and HBcAb were 58.1% and 26.1%, respectively. As compared with the prevalence from the 2006 national survey, the HBV infection rate and the positive rate of HBcAb were lower and the positive rate of HBsAb was higher in SLE patients aged 15–49 years old compared to peers in the general population. There was no difference in HBV infection rate between males and females (4.2% vs. 2.8%, p=0.088) in SLE patients.
The HBV infection rate was relatively lower in SLE patients compared with the general population, but there was no difference in pediatric patients or patients aged above 50 years old. Unlike in the general population, the HBV infection rate had no statistical differences between males and females in SLE patients.
PMCID: PMC4501635  PMID: 26148056
Age; Hepatitis B Antibodies; Systemic Lupus Erythematosus
23.  Treatment Response Evaluation using 18F-FDOPA PET in Patients with Recurrent Malignant Glioma on Bevacizumab Therapy 
This study compares the value of 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-FDOPA) PET and MRI in assessing outcome during antiangiogenic treatment in patients with recurrent high-grade gliomas.
Experimental Design
Thirty patients were prospectively studied with 18F-FDOPA PET scans immediately before, and two and six weeks after start of bevacizumab therapy. 18F-FDOPA metabolic tumor volumes (MTV) as well as max and mean SUVs within this MTV were obtained. MRI treatment response was assessed at 6 weeks. The predictive ability of 18F-FDOPA PET and MRI response assessment were evaluated with regard to progression-free survival (PFS) and overall survival (OS).
30, 28, and 24 18F-FDOPA PET scans at baseline, 2 weeks, and 6 weeks, were available for analysis, respectively. 18F-FDOPA PET SUVs as well as their changes through therapy were not predictive of outcome. However, metabolic tumor volume (MTV) parameters such as MTV changes were highly prognostic. Interestingly, absolute MTV at the first follow up scan provides the most significant prediction for increased OS (P < 0.0001) as well as PFS (P = 0.001). This surprising result was scrutinized with cross-validation and simulation analysis. Responders based on 18F-FDOPA PET data survived 3.5 times longer (12.1 vs. 3.5 months median OS, P < 0.001) than non-responders (17 vs. 11 patients, respectively). In comparison, responders based on MRI data lived 1.5 times longer (11.4 vs 7.7 mo, P = 0.03) than non-responders (22 vs. 7 patients, respectively).
18F-FDOPA PET identifies treatment responders to antiangiogenic therapy as early as two weeks after treatment initiation.
PMCID: PMC4079729  PMID: 24687922
24.  Haplotype Analysis of the XRCC1 Gene and Laryngeal Cancer 
Objective: Several polymorphisms in DNA repair genes have been extensively studied in association with various human cancers, including laryngeal cancer. The present study aimed to investigate the association between polymorphisms of the XRCC1 gene and laryngeal cancer in a Chinese population. Methods: Five polymorphisms of the XRCC1 gene (rs3213403, rs1799778, rs1001581, rs3213282, and rs3810378) were genotyped by TaqMan in 234 patients with larynx cancer and 230 age- and sex-matched controls without cancer. Results: The rs3213403, rs1799778, and rs3213282 polymorphisms of XRCC1 were associated with larynx cancer. Haplotype analysis indicated that CCA (odds ratio [OR], 5.707; 95% confidence interval [CI], 3.277–9.938; p<0.001), TGG (OR, 4.344; 95% CI, 2.804–6.732; p<0.001), ACA (OR, 1.615; 95% CI, 1.159–2.250; p=0.004), and GCG (OR, 1.702; 95% CI, 1.164–2.489; p=0.005) were associated with an increased risk for larynx cancer, respectively. However, TGA (OR, 0.518; 95% CI, 0.398–0.673; p<0.001) and ACC (OR, 0.314; 95% CI, 0.215–0.457; p<0.001) were associated with a decreased risk for larynx cancer. Conclusions: The results indicated that XRCC1 genetic polymorphisms were associated with larynx cancer in a Chinese population.
PMCID: PMC4094024  PMID: 24956286
25.  Genotoxicity and Cytotoxicity of Cadmium Sulfide Nanomaterials to Mice: Comparison Between Nanorods and Nanodots 
Environmental Engineering Science  2014;31(7):373-380.
Cadmium sulfide (CdS) nanomaterials (such as CdS nanodots or nanorods) are widely used in optical, electronic, and biological applications. Large-scale production and use of these materials will likely result in accidental and incidental releases, which raise concerns about their potential environmental and human-health impacts. Most studies on toxicity of Cd-containing nanomaterials have focused on nanodots, and the relative toxicity of Cd-containing nanorods is not well understood. Here, we compared genotoxicity and cytotoxicity of CdS nanorods (30–50 nm diameter, 500–1100 nm length) and cubic CdS nanodots (3–5 nm) in mice by examining total cadmium accumulation in organs, acute toxicity, DNA damage, spermatozoon viability and abnormality, kidney and liver damage, and oxidative stress. Compared with (smaller) nanodots, nanorods resulted in relatively low bioaccumulation, acute toxicity, and damage to spermatozoa and the tested organs. Differences in toxicity between CdS nanodots and nanorods could not be fully explained by differences in their metal ion (Cd2+) release patterns, based on control tests with mice gavaged with dissolved CdCl2 at equivalent concentrations. This underscores that toxicity of metallic nanomaterials could not be solely predicted based either on their elemental composition or on the amount of ions released before receptor intake. Particle morphology (including size) may also need to be considered.
PMCID: PMC4098819  PMID: 25053877
cadmium sulfide; cytotoxicity; genotoxicity; nanodots; nanorods

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