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1.  Genetic variants in Fas signaling pathway genes and risk of gastric cancer 
Populations in north central China are at high risk for gastric cancers (GC), and altered FAS-mediated cell signaling and/or apoptosis may contribute to this risk. We examined the association of 554 single nucleotide polymorphisms (SNPs) in 53 Fas signaling-related genes using a pathway-based approach in 1758 GC cases (1126 gastric cardia adenocarcinomas (GCA) and 632 gastric noncardia adenocarcinomas (GNCA)), and 2111 controls from a genome-wide association study (GWAS) of GC in ethnic Chinese. SNP associations with risk of overall GC, GCA and GNCA were evaluated using unconditional logistic regressions controlling for age, sex and study. Gene- and pathway-based associations were tested using the adaptive rank-truncated product (ARTP) method. Statistical significance was evaluated empirically by permutation. Significant pathway-based associations were observed for Fas signaling with risk of overall GC (P = 5.5E-04) and GCA (P = 6.3E-03), but not GNCA (P = 8.1E-02). Among examined genes in the Fas signaling pathway, MAP2K4, FAF1, MAPK8, CASP10, CASP8, CFLAR, MAP2K1, CAP8AP2, PAK2 and IKBKB were associated with risk of GC (nominal P < 0.05), and FAF1 and MAPK8 were significantly associated with risk of both GCA and GNCA (nominal P < 0.05). Our examination of genetic variation in the Fas signaling pathway is consistent with an association of altered Fas signaling and/or apoptosis with risk of GC. As one of the first attempts to investigate a pathway-level association, our results suggest that these genes and the Fas signaling pathway warrant further evaluation in relation to GC risk in other populations.
doi:10.1002/ijc.28415
PMCID: PMC3858487  PMID: 23921907
Gastric cancer; gastric cardia; gastric noncardia; Fas signaling; genetic variants; GWAS; single nucleotide polymorphisms; pathway genes
2.  Case-case comparison of smoking and alcohol risk associations with Epstein-Barr virus-positive gastric cancer 
Helicobacter pylori is the primary cause of gastric cancer. However, monoclonal Epstein-Barr virus (EBV) nucleic acid is also present in up to 10% of these tumors worldwide. EBV prevalence is increased with male sex, non-antral localization and surgically disrupted anatomy. To further examine associations between EBV and gastric cancer, we organized an international consortium of 11 studies with tumor EBV status assessed by in situ hybridization. We pooled individual-level data on 2,648 gastric cancer patients, including 184 (7%) with EBV-positive cancers; all studies had information on cigarette use (64% smokers) and 9 had data on alcohol (57% drinkers). We compared patients with EBV-positive and EBV-negative tumors to evaluate smoking and alcohol interactions with EBV status. To account for within-population clustering, multi-level logistic regression models were used to estimate interaction odds ratios (OR) adjusted for distributions of sex (72% male), age (mean 59 years), tumor histology (56% Lauren intestinal-type), anatomic subsite (61% noncardia) and year of diagnosis (1983–2012). In unadjusted analyses, the OR of EBV positivity with smoking was 2.2 (95% confidence interval [CI], 1.6–3.2). The OR was attenuated to 1.5 (95% CI, 1.01–2.3) by adjustment for the possible confounders. There was no significant interaction of EBV status with alcohol drinking (crude OR, 1.4; adjusted OR, 1.0). Our data indicate the smoking association with gastric cancer is stronger for EBV-positive than EBV-negative tumors. Conversely, the null association with alcohol does not vary by EBV status. Distinct epidemiologic characteristics of EBV-positive cancer further implicate the virus as a co-factor in gastric carcinogenesis.
doi:10.1002/ijc.28402
PMCID: PMC3961829  PMID: 23904115
Alcohol; EBV; gastric cancer; smoking; pooled-analysis
3.  Quantification of myocardial perfusion with self-gated cardiovascular magnetic resonance 
Background
Current myocardial perfusion measurements make use of an ECG-gated pulse sequence to track the uptake and washout of a gadolinium-based contrast agent. The use of a gated acquisition is a problem in situations with a poor ECG signal. Recently, an ungated perfusion acquisition was proposed but it is not known how accurately quantitative perfusion estimates can be made from such datasets that are acquired without any triggering signal.
Methods
An undersampled saturation recovery radial turboFLASH pulse sequence was used in 7 subjects to acquire dynamic contrast-enhanced images during free-breathing. A single saturation pulse was followed by acquisition of 4–5 slices after a delay of ~40 msec. This was repeated without pause and without any type of gating. The same pulse sequence, with ECG-gating, was used to acquire gated data as a ground truth. An iterative spatio-temporal constrained reconstruction was used to reconstruct the undersampled images. After reconstruction, the ungated images were retrospectively binned (“self-gated”) into two cardiac phases using a region of interest based technique and deformably registered into near-systole and near-diastole. The gated and the self-gated datasets were then quantified with standard methods.
Results
Regional myocardial blood flow estimates (MBFs) obtained using self-gated systole (0.64 ± 0.26 ml/min/g), self-gated diastole (0.64 ± 0.26 ml/min/g), and ECG-gated scans (0.65 ± 0.28 ml/min/g) were similar. Based on the criteria for interchangeable methods listed in the statistical analysis section, the MBF values estimated from self-gated and gated methods were not significantly different.
Conclusion
The self-gated technique for quantification of regional myocardial perfusion matched ECG-gated perfusion measurements well in normal subjects at rest. Self-gated systolic perfusion values matched ECG-gated perfusion values better than did diastolic values.
Electronic supplementary material
The online version of this article (doi:10.1186/s12968-015-0109-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12968-015-0109-1
PMCID: PMC4325943
Cardiovascular magnetic resonance; Myocardial perfusion; Quantitative perfusion; ECG-gating; Self-gated
4.  Polymorphisms of the WRN gene and DNA damage of peripheral lymphocytes in age-related cataract in a Han Chinese population 
Age  2013;35(6):2435-2444.
Werner syndrome is caused by mutations in the DNA repair Werner helicase (WRN) gene and characterized by accelerated aging including cataracts. Age-related cataract (ARC) cases (N = 504) and controls (N = 244) were recruited from a population-based study to evaluate the association of single-nucleotide polymorphisms (SNPs) of WRN and another DNA repair gene (human 8-oxoguanine DNA N-glycosylase 1) with ARC. Among the five SNPs tested, only WRN rs1346044 was found to be significantly associated between cases and controls before multiple-testing adjustment. The minor C allele of rs1346044 was associated with ARC with an odds ratio (OR) of 0.66, suggesting a protective role of the C allele for developing ARC. The stratification analysis on the subtypes of ARC showed that rs1346044 was significantly associated with cortical cataract, but not with nuclear, posterior subcapsular, and mixed types after multiple-testing adjustment (OR = 0.51, p < 0.01). The genetic model analysis showed that the results fit the dominant model (OR = 0.44, p < 0.001). The comet assay used to assess the extent of DNA damage in peripheral lymphocytes of ARC cases found that the DNA damage in lymphocytes from patients with CC genotype was significantly less than that in patients with TT genotype. We concluded that the C allele of rs1346044, a non-synonymous SNP resulting in the conversion of Cys to Arg at amino acid position 1367 of WRN, alters susceptibility to ARC, especially the cortical type of the disease, in the Han Chinese. The underlying mechanism of its protective role might be related to the improved DNA repair function.
doi:10.1007/s11357-013-9512-4
PMCID: PMC3824989  PMID: 23334603
Age-related cataract (ARC); WRN; Single-nucleotide polymorphism; Comet assay; DNA damage; Cortical cataract
5.  A method for generating large datasets of organ geometries for radiotherapy treatment planning studies 
Radiology and Oncology  2014;48(4):408-415.
Background
With the rapidly increasing application of adaptive radiotherapy, large datasets of organ geometries based on the patient’s anatomy are desired to support clinical application or research work, such as image segmentation, re-planning, and organ deformation analysis. Sometimes only limited datasets are available in clinical practice. In this study, we propose a new method to generate large datasets of organ geometries to be utilized in adaptive radiotherapy.
Methods
Given a training dataset of organ shapes derived from daily cone-beam CT, we align them into a common coordinate frame and select one of the training surfaces as reference surface. A statistical shape model of organs was constructed, based on the establishment of point correspondence between surfaces and non-uniform rational B-spline (NURBS) representation. A principal component analysis is performed on the sampled surface points to capture the major variation modes of each organ.
Results
A set of principal components and their respective coefficients, which represent organ surface deformation, were obtained, and a statistical analysis of the coefficients was performed. New sets of statistically equivalent coefficients can be constructed and assigned to the principal components, resulting in a larger geometry dataset for the patient’s organs.
Conclusions
These generated organ geometries are realistic and statistically representative.
doi:10.2478/raon-2014-0003
PMCID: PMC4230563  PMID: 25435856
non-uniform rational B-spline technique; new geometries; statistical shape model; adaptive radiotherapy
6.  A novel serine hydroxymethyltransferase from Arthrobacter nicotianae: characterization and improving catalytic efficiency by rational design 
BMC Biotechnology  2014;14(1):93.
Background
Serine hydroxymethyltransferase (SHMT) is the key enzyme in L-serine enzymatic production, suggesting the importance of obtaining a SHMT with high activity.
Results
Here, a novel SHMT gene, glyA, was obtained through degenerate oligonucleotide-primed PCR and encoded a novel SHMT with 54.3% similarity to the known SHMT from Escherichia coli. The obtained protein AnSHMT showed the optimal activity at 40°C and pH 7.5, and was more stable in weakly alkali conditions (pH 6.5-8.5) than Hyphomicrobium methylovorum’s SHMT (pH 6.0-7.5), In order to improve the catalytic efficiency of the wild type, the site-directed mutagenesis based on sequences alignment and bioinformatics prediction, was used and the catalytic efficiency of the mutant I249L was found to be 2.78-fold higher than that of the wild-type, with the replacement of isoleucine by leucine at the 249 position.
Conclusions
This research provides useful information about the interesting site, and the application of DOP-PCR in cloning a novel glyA gene.
doi:10.1186/s12896-014-0093-9
PMCID: PMC4260256  PMID: 25394480
Arthrobacter nicotianae; SHMT; Characterization; Site-directed mutagenesis; Catalytic efficiency
7.  Post-Contrast Myocardial T1 and ECV Disagree in a Longitudinal Canine Study 
NMR in biomedicine  2014;27(8):988-995.
Both post-contrast myocardial T1 and extracellular volume (ECV) measurements have been associated with interstitial fibrosis. The cardiovascular magnetic resonance (CMR) field is migrating towards ECV, because it is largely insensitive to confounders that affect post-contrast myocardial T1. Despite the theoretical advantages of myocardial ECV over post-contrast myocardial T1, systematic experimental studies comparing the two measurements are largely lacking. We sought to measure the temporal changes in post-contrast myocardial T1 and ECV in an established canine model with chronic atrial fibrillation.
Seventeen mongrel dogs, implanted with a pacemaker to induce chronic atrial fibrillation via rapid atrial pacing, were scanned multiple times for a total of 46 CMR scans at 3T. These dogs with different disease durations (0–22 months) were part of a separate longitudinal study aimed at studying the relationship between AF and patho-physiology. In each animal, we measured native and post-contrast T1s and hematocrit. Temporal changes in post-contrast myocardial T1 and ECV, as well as other CMR parameters, were modeled with linear mixed effect models to account for repeated measurements over disease duration.
In 17 animals, post-contrast myocardial T1 decreased significantly from 872 to 698 ms (p< 0.001), which corresponds to a 24.9% relative reduction. In contrast, ECV increased from 21.0 to 22.0% (p=0.38), which corresponds to only a 4.5% relative increase. To partially investigate this discrepancy, we quantified collagen volume fraction (CVF) in post-mortem heart tissues of 6 canines sacrificed at different disease duration (0–22 months). CVF quantified by histology increased from 0.9 to 1.9% (p=0.56), which agrees more with ECV than post-contrast myocardial T1. This study shows that post-contrast myocardial T1 and ECV may disagree in a longitudinal canine study. A more comprehensive study, including histologic, cardiac, and renal functional analyses, is warranted to test rigorously which CMR parameter (ECV or post-contrast myocardial T1) agrees more with CVF.
doi:10.1002/nbm.3135
PMCID: PMC4227501  PMID: 24865566
Diffuse myocardial fibrosis; post-contrast myocardial T1; extracellular volume fraction; MRI; heart failure; atrial fibrillation; collagen volume fraction
8.  Magnetic Nanoclusters with Hydrophilic Spacing for Dual Drug Delivery and Sensitive Magnetic Resonance Imaging 
Magnetic Block Ionomer Clusters (MBIClusters) with hydrophilic ionic cores and nonionic coronas have been prepared that have ultrahigh transverse NMR relaxivities together with capacities for incorporating high concentrations of polar antibiotic payloads. Magnetite-polymer nanoparticles were assembled by adsorbing the polyacrylate block of an aminofunctional poly(ethylene oxide-b-acrylate) (H2N-PEO-b-PAA) copolymer onto magnetite nanoparticles. The PEO blocks extended into aqueous media to keep the nanoparticles dispersed. Amines at the tips of the H2N-PEO corona were then linked through reaction with a PEO diacrylate oligomer to yield MBIClusters where the metal oxide in the precursor nanoparticles were distinctly separated by the hydrophilic polymer. The intensity average spacing between the magnetite nanoparticles within the clusters was estimated to be ~50 nm. These MBIClusters with hydrophilic intra-cluster space had transverse relaxivities (r2’s) that increased from 190 to 604 s−1 mM Fe−1 measured at 1.4 T and 37 °C as their average sizes increased. The clusters were loaded with up to ~38 wt% of the multi-cationic drug gentamicin. MRI scans focused on the livers of mice demonstrated that these MBIClusters are sensitive contrast agents.
doi:10.1039/C2TB00275B
PMCID: PMC4199085  PMID: 25328679
magnetite; block ionomer; relaxivity; contrast agent; MRI
9.  A cross-sectional study on health-related knowledge and its predictors among Chinese vocational college students 
BMJ Open  2014;4(10):e005182.
Objectives
This study sought to examine the level of health-related knowledge and its predictors among vocational college students in China.
Study design
A cross-sectional study.
Methods
A survey was performed to collect data on heath-related knowledge and potential risk factors among 708 students in four higher vocational colleges at Nanyang, Henan, China. Linear regression models were conducted to identify the predictors of the level of health-related knowledge.
Results
The level of health-related knowledge among Chinese vocational college students is extremely low (only 1.4% students have an adequate level of health-related knowledge). According to the multivariate analysis, major, year of class, place of origin and a mother's education level are significantly associated with health-related knowledge in Chinese vocational college students.
Conclusions
Health education and health promotion efforts are encouraged to improve the level of health-related knowledge in this population. Attention and efforts to improve health-related knowledge of Chinese vocational college students who come from rural areas, whose mothers have a lower level of education, who are in non-medicine majors and during the first few years of vocational college is warranted.
doi:10.1136/bmjopen-2014-005182
PMCID: PMC4194799  PMID: 25311037
PUBLIC HEALTH
10.  RAD51B Activity and Cell Cycle Regulation in Response to DNA Damage in Breast Cancer Cell Lines 
Common genetic variants mapping to two distinct regions of RAD51B, a paralog of RAD51, have been associated with breast cancer risk in genome-wide association studies (GWAS). RAD51B is a plausible candidate gene because of its established role in the homologous recombination (HR) process. How germline genetic variation in RAD51B confers susceptibility to breast cancer is not well understood. Here, we investigate the molecular function of RAD51B in breast cancer cell lines by knocking down RAD51B expression by small interfering RNA and treating cells with DNA-damaging agents, namely cisplatin, hydroxyurea, or methyl-methanesulfonate. Our results show that RAD51B-depleted breast cancer cells have increased sensitivity to DNA damage, reduced efficiency of HR, and altered cell cycle checkpoint responses. The influence of RAD51B on the cell cycle checkpoint is independent of its role in HR and further studies are required to determine whether these functions can explain the RAD51B breast cancer susceptibility alleles.
doi:10.4137/BCBCR.S17766
PMCID: PMC4213955  PMID: 25368520
RAD51B; breast cancer; DNA damage; homologous recombination
11.  MicroRNA-21 inhibits platelet-derived growth factor-induced human aortic vascular smooth muscle cell proliferation and migration through targeting activator protein-1 
Objectives: This study is to investigate whether microRNA (miR)-21 inhibits platelet-derived growth factor-induced human aortic vascular smooth muscle cell (VSMC) proliferation and migration through targeting activator protein-1 (AP-1). Methods: VSMCs were transfected with the miR-21 or miR-21 inhibitor. Cell proliferation was determined using methyl thiazolyl tetrazolium assay. Cell migration was detected by transwell assay. Luciferase reporter assay was used to study the interaction between miR-21 and AP-1. The levels of mRNA were determined using quantitative real-time polymerase chain reaction, while protein expression was measured using Western blotting assay. Results: Low expression of miR-21 significantly inhibited VSMC proliferation, invasion and migration. The mRNA levels and protein expression of α-SMA and AP-1 were down-regulated by low expression of miR-21. In addition, luciferase reporter assay demonstrated that AP-1 might be a direct target gene of miR-21 in VSMC initiation and development. Moreover, up-regulation of AP-1 was critical for miR-21-mediated inhibitory effects on platelet-derived growth factor-induced cell proliferation and migration in human VSMCs. Conclusions: In summary, miR-21 is a key molecule in regulating human VSMC proliferation and migration by targeting AP-1, suggesting that specific modulation of miR-21 in human VSMCs may become an attractive approach for the treatment of proliferative vascular diseases.
PMCID: PMC4212925  PMID: 25360215
microRNA-21; vascular smooth muscle cells; proliferation; migration; activator protein-1; platelet-derived growth factor
12.  Behavioral and Psychological Symptoms in Alzheimer's Disease 
BioMed Research International  2014;2014:927804.
Neuropsychiatric symptoms (NPS) such as depression, apathy, aggression, and psychosis are now recognized as core features of Alzheimer's disease (AD), and there is a general consensus that greater symptom severity is predictive of faster cognitive decline, loss of independence, and even shorter survival. Whether these symptoms result from the same pathogenic processes responsible for cognitive decline or have unique etiologies independent of AD-associated neurodegeneration is unclear. Many structural and metabolic features of the AD brain are associated with individual neuropsychiatric symptoms or symptom clusters. In addition, many genes have been identified and confirmed that are associated with symptom risk in a few cases. However, there are no single genes strongly predictive of individual neuropsychiatric syndromes, while functional and structural brain changes unique to specific symptoms may reflect variability in progression of the same pathological processes. Unfortunately, treatment success for these psychiatric symptoms may be lower when comorbid with AD, underscoring the importance of future research on their pathobiology and treatment. This review summarizes some of the most salient aspects of NPS pathogenesis.
doi:10.1155/2014/927804
PMCID: PMC4123596  PMID: 25133184
13.  Maternal Nutrient Restriction Predisposes Ventricular Remodeling in Adult Sheep Offspring 
Maternal nutrient restriction during pregnancy is associated with the development of a “thrifty phenotype” in offspring, conferring increased prevalence of metabolic diseases in adulthood. To explore the possible mechanisms behind heart diseases in adulthood following maternal nutrient restriction, dams were fed a nutrient restricted (NR: 50%) or control (100%) diet from 28 to 78 d of gestation. Both groups were then fed 100% of requirements to lambing. At 6 yrs of age, female offspring of NR and control ewes of similar weight and body condition were subject to ad libitum feeding of a highly palatable diet for 12 wks. Cardiac geometry, post-insulin receptor signaling, autophagy and pro-inflammatory cytokines were evaluated in hearts from adult offspring. Our results indicated that maternal nutrient restriction overtly increased body weight gain and triggered cardiac remodeling in offspring following the 12-week ad libitum feeding. Phosphorylation of IRS1 was increased in left but not right ventricles from NR offspring. Levels of STAT3 were upregulated in left ventricles whereas expression of TNFα and TLR4 was enhanced in right ventricles in adult offspring of maternal nutrition restricted ewes. No significant differences were found in pan IRS-1, pan AMPK, pan Akt, pAMPK, pAkt, GLUT4, phosphorylated mTOR, Beclin-1 and LC3 II proteins in left and right ventricle between the control and NR offspring. These data revealed that maternal nutrient restriction during early to mid gestation may predispose adult offspring to cardiac remodeling possibly associated with phosphorylation of IRS1 as well as proinflammatory cytokines but not autophagy.
doi:10.1016/j.jnutbio.2012.10.001
PMCID: PMC3633637  PMID: 23333094
nutrition restriction; gestation; offspring; insulin signaling
14.  Genetic variants in DNA repair pathway genes and risk of esophageal squamous cell carcinoma and gastric adenocarcinoma in a Chinese population 
Carcinogenesis  2013;34(7):1536-1542.
The DNA repair pathways help to maintain genomic integrity and therefore genetic variation in the pathways could affect the propensity to develop cancer. Selected germline single nucleotide polymorphisms (SNPs) in the pathways have been associated with esophageal cancer and gastric cancer (GC) but few studies have comprehensively examined the pathway genes. We aimed to investigate associations between DNA repair pathway genes and risk of esophageal squamous cell carcinoma (ESCC) and GC, using data from a genome-wide association study in a Han Chinese population where ESCC and GC are the predominant cancers. In sum, 1942 ESCC cases, 1758 GC cases and 2111 controls from the Shanxi Upper Gastrointestinal Cancer Genetics Project (discovery set) and the Linxian Nutrition Intervention Trials (replication set) were genotyped for 1675 SNPs in 170 DNA repair-related genes. Logistic regression models were applied to evaluate SNP-level associations. Gene- and pathway-level associations were determined using the resampling-based adaptive rank-truncated product approach. The DNA repair pathways overall were significantly associated with risk of ESCC (P = 6.37 × 10− 4), but not with GC (P = 0.20). The most significant gene in ESCC was CHEK2 (P = 2.00 × 10− 6) and in GC was CLK2 (P = 3.02 × 10− 4). We observed several other genes significantly associated with either ESCC (SMUG1, TDG, TP53, GTF2H3, FEN1, POLQ, HEL308, RAD54B, MPG, FANCE and BRCA1) or GC risk (MRE11A, RAD54L and POLE) (P < 0.05). We provide evidence for an association between specific genes in the DNA repair pathways and the risk of ESCC and GC. Further studies are warranted to validate these associations and to investigate underlying mechanisms.
doi:10.1093/carcin/bgt094
PMCID: PMC3697889  PMID: 23504502
15.  Differential Expression of Granulopoiesis Related Genes in Neutrophil Subsets Distinguished by Membrane Expression of CD177 
PLoS ONE  2014;9(6):e99671.
Objective
Differential gene expression in CD177+ and CD177− neutrophils was investigated, in order to detect possible differences in neutrophil function which could be related to the pathogenesis of ANCA-associated Vasculitides (AAV).
Methods
Neutrophils were isolated from healthy controls (HC) with high, negative or bimodal CD177 expression, and sorted into CD177+ and CD177− subpopulations. Total RNA was screened for expression of 24,000 probes with Illumina Ref-8 Beadchips. Genes showing differential expression between CD177+ and CD177− subsets in microarray analysis were re-assessed using quantitative-PCR. CD177 expression on neutrophil precursors in bone marrow was analyzed using quantitative PCR and flowcytometry.
Results
The proportion of CD177+ cells increased during neutrophil maturation in bone marrow. Fold change analysis of gene expression profile of sorted CD177+ and CD177− neutrophils resulted in 14 genes with fold change (fc) >3 difference in expression. Interestingly, 10 of these genes have been reported to change significantly in expression during neutrophil maturation, and most of these genes were granule protein (GP) coding genes. mRNA expression levels measured by RT-PCR of a number of these GP, and of PR3 and MPO were higher in the CD177− neutrophil subset in HC, however, particular granule protein amounts were comparable between CD177+ and CD177− neutrophil subsets. AAV patients had higher amounts of CD177+ neutrophils, but contrary to neutrophils from HC expression of GP-genes was increased, possibly due to activation.
Conclusion
The neutrophil population can be distinguished by membrane expression of CD177 into subsets that are different in expression of GP mRNA but not in GP protein production. GP gene expression is also elevated in AAV patients, which is not explained by skewed distribution of CD177+ and CD177− subsets but may be associated with neutrophil activation during on-going inflammation.
doi:10.1371/journal.pone.0099671
PMCID: PMC4057222  PMID: 24926686
16.  Chronic Akt Activation Attenuated Lipopolysaccharide-Induced Cardiac Dysfunction via Akt/GSK3β-Dependent Inhibition of Apoptosis and ER Stress 
Biochimica et biophysica acta  2013;1832(6):848-863.
Sepsis is characterized by systematic inflammation and contributes to cardiac dysfunction. This study was designed to examine the effect of Akt activation on LPS-induced cardiac anomalies and underlying mechanism(s) involved. Mechanical and intracellular Ca2+ properties were examined in myocardium from wild-type and transgenic mice with cardiac-specific chronic Akt overexpression following LPS (4 mg/kg, i.p.) challenge. Akt signaling cascade (Akt, PTEN, GSK3β), stress signal (ERK, JNK, p38), apoptotic markers (BAX, caspase-3/-9), ER stress markers (GRP78, GADD153, eIF2α), inflammatory markers (TNFα, IL-1β, IL-6) and autophagic markers (Beclin-1, LC3B, Atg7 and p62) were evaluated. Our results revealed that LPS induced marked decrease in ejection fraction, fractional shortening, cardiomyocyte contractile capacity with dampened intracellular Ca2+ release and clearance, elevated ROS generation and decreased GSH/GSSG ratio, increased ERK, JNK, p38, GRP78, GADD153, eIF2α, BAX, caspase-3 and - 9, downregulated Bcl-2, the effects of which were significantly attenuated or obliterated by Akt activation. Akt activation itself did not affect cardiac contractile and intracellular Ca2+ properties, ROS production, oxidative stress, apoptosis and ER stress. In addition, LPS upregulated levels of Beclin-1, LC3B and Atg7, while suppressing p62 accumulation. Akt activation did not affect Beclin-1, LC3B, Atg7 and p62 in the presence or absence of LPS. Akt overexpression promoted phosphorylation of Akt and GSK3β. In vitro study using the GSK3β inhibitor SB216763 mimicked the response elicited by chronic Akt activation. Taken together, these data showed that Akt activation ameliorated LPS-induced cardiac contractile and intracellular Ca2+ anomalies through inhibition of apoptosis and ER stress, possibly involving an Akt/GSK3β-dependent mechanism.
doi:10.1016/j.bbadis.2013.02.023
PMCID: PMC3653446  PMID: 23474308
Sepsis; heart; contractile function; Akt; ER stress; apoptosis
17.  miR-21 inhibitor suppresses proliferation and migration of nasopharyngeal carcinoma cells through down-regulation of BCL2 expression 
This study is to investigate the expression of miR-21 in nasopharyngeal carcinoma (NPC) cells, and the effect of miR-21 in the biological behavior and expression of B-cell lymphoma 2 (BCL2) in NPC cells. Paired NPC and adjacent non-tumor tissues were obtained from 53 patients who underwent primary surgical resection of NPC tissues. Luciferase reporter assay was performed to test whether BCL2 is a direct target of miR-21. Methylthiazolyl blue tetrazolium assay and colony assay were used to evaluate the effect of miR-21 on NPC cell proliferation. Transwell and wound-healing assays were carried out to test the effect of low expression of miR-21 on cancer cell migration and invasion. QRT-PCR and Western blotting were used to measure the levels of mRNA and protein expression, respectively. Tumor tissues showed a positive correlation between the levels of miR-21 and BCL2 protein expression. Cells transfected with miR-21 inhibitor healed slower compared the control (P < 0.05). In addition, cell migration was notably inhibited by the down-regulation of miR-21 in vitro (P < 0.05). The reduction in miR-21 expression showed a remarkable effect on the biological behavior of NPC cell clone formation (P < 0.05). Low expression of miR-21 by transfection with miRNA expression plasmid led to a decrease in BCL2 expression, which was accompanied by reduced migration and proliferation of the cancer cells. Our results demonstrated that miR-21 inhibitor down-regulated BCL2 expression level, suggesting that BCL2 might be a target gene for the initiation and development of NPC cells.
PMCID: PMC4097257  PMID: 25031780
MicroRNA; miR-21; nasopharyngeal carcinoma; B-cell lymphoma 2
18.  Genetic variants in sex hormone metabolic pathway genes and risk of esophageal squamous cell carcinoma 
Carcinogenesis  2013;34(5):1062-1068.
In China, esophageal cancer is the fourth leading cause of cancer death where essentially all cases are histologically esophageal squamous cell carcinoma (ESCC), in contrast to esophageal adenocarcinoma in the West. Globally, ESCC is 2.4 times more common among men than women and recently it has been suggested that sex hormones may be associated with the risk of ESCC. We examined the association between genetic variants in sex hormone metabolic genes and ESCC risk in a population from north central China with high-incidence rates. A total of 1026 ESCC cases and 1452 controls were genotyped for 797 unique tag single-nucleotide polymorphisms (SNPs) in 51 sex hormone metabolic genes. SNP-, gene- and pathway-based associations with ESCC risk were evaluated using unconditional logistic regression adjusted for age, sex and geographical location and the adaptive rank truncated product (ARTP) method. Statistical significance was determined through use of permutation for pathway- and gene-based associations. No associations were observed for the overall sex hormone metabolic pathway (P = 0.14) or subpathways (androgen synthesis: P = 0.30, estrogen synthesis: P = 0.15 and estrogen removal: P = 0.19) with risk of ESCC. However, six individual genes (including SULT2B1, CYP1B1, CYP3A7, CYP3A5, SHBG and CYP11A1) were significantly associated with ESCC risk (P < 0.05). Our examination of genetic variation in the sex hormone metabolic pathway is consistent with a potential association with risk of ESCC. These positive findings warrant further evaluation in relation to ESCC risk and replication in other populations.
doi:10.1093/carcin/bgt030
PMCID: PMC3643422  PMID: 23358850
19.  Global Changes in Gene Expression of Barrett's Esophagus Compared to Normal Squamous Esophagus and Gastric Cardia Tissues 
PLoS ONE  2014;9(4):e93219.
Background
Barrett's esophagus (BE) is a metaplastic precursor lesion of esophageal adenocarcinoma (EA), the most rapidly increasing cancer in western societies. While the prevalence of BE is increasing, the vast majority of EA occurs in patients with undiagnosed BE. Thus, we sought to identify genes that are altered in BE compared to the normal mucosa of the esophagus, and which may be potential biomarkers for the development or diagnosis of BE.
Design
We performed gene expression analysis using HG-U133A Affymetrix chips on fresh frozen tissue samples of Barrett's metaplasia and matched normal mucosa from squamous esophagus (NE) and gastric cardia (NC) in 40 BE patients.
Results
Using a cut off of 2-fold and P<1.12E-06 (0.05 with Bonferroni correction), we identified 1324 differentially-expressed genes comparing BE vs NE and 649 differentially-expressed genes comparing BE vs NC. Except for individual genes such as the SOXs and PROM1 that were dysregulated only in BE vs NE, we found a subset of genes (n = 205) whose expression was significantly altered in both BE vs NE and BE vs NC. These genes were overrepresented in different pathways, including TGF-β and Notch.
Conclusion
Our findings provide additional data on the global transcriptome in BE tissues compared to matched NE and NC tissues which should promote further understanding of the functions and regulatory mechanisms of genes involved in BE development, as well as insight into novel genes that may be useful as potential biomarkers for the diagnosis of BE in the future.
doi:10.1371/journal.pone.0093219
PMCID: PMC3979678  PMID: 24714516
20.  Association of eNOS Polymorphisms with Anterior Chamber Depth in Han Chinese: Jiangsu Eye Study 
Journal of Ophthalmology  2014;2014:164104.
Recently, a study reported that single nucleotide polymorphisms (SNP) in endothelial nitric oxide synthase (eNOS) were associated with primary angle closure glaucoma (PACG) in Australian cohort. In this study, we aimed to investigate whether those eNOS SNPs are associated with primary angle closure (PAC) or ocular biometric characteristics such as axial length (AL), anterior chamber depth (ACD), and diopter of spherical power (DS) in Han Chinese. The samples consisted of 232 PAC subjects and 306 controls collected from a population-based prevalence survey conducted in Funing County of Jiangsu, China. The rs3793342 and rs11771443 in eNOS were genotyped by TaqMan-MGB probe using the RT-PCR system. Our data did not identify any association of the eNOS SNPs with PAC. However, the analysis on the quantitative traits of ocular biometrics showed that the ACD of rs11771443 AA and GA carriers is significantly deeper than that of rs11771443 GG carriers (P = 0.0025), even though the AL and DS are not associated with rs11771443 genotypes. Rs3793342 was not associated with any biometric parameters including ACD, AL and DS. In summary, our data indicates that eNOS rs11771443 is associated with ACD and its role in the pathogenesis of PACG warranted further study.
doi:10.1155/2014/164104
PMCID: PMC3944786  PMID: 24688788
22.  Genetic/Epigenetic Modulation, Ocular Diseases, and Therapeutic Prospective 
Journal of Ophthalmology  2013;2013:980608.
doi:10.1155/2013/980608
PMCID: PMC3871509  PMID: 24381749
23.  Influence of Long-Term Caloric Restriction on Myocardial and Cardiomyocyte Contractile Function and Autophagy in Mice 
Both clinical and experimental evidence has revealed that calorie restriction (CR) is capable of improving heart function. However, most the reports are focused on the effect of CR on the pathological states such as obesity while the effect of CR on heart function in otherwise healthy subjects are not well understood. This study examined the long-term CR effect on cardiac contractile function and possible underlying mechanisms involved. C57BL/6 mice were subjected to a 40% CR or ad libitum feeding for 20 weeks. Echocardiographic and cardiomyocyte contractile properties were evaluated. Intracellular signaling pathways were examined using western blot analysis. Our results showed that CR overtly lessened glucose intolerance, body and heart weights (although not heart size), lowered fat tissue density, decreased left ventricular (LV) wall thickness (septum and posterior wall) in both systole and diastole, and reduced LV mass (not normalized LV mass) without affecting fractional shortening. Cardiomyocyte cell length and cross-sectional area were reduced while peak shortening amplitude was increased following CR. CR failed to affect maximal velocity of shortening/relengthening, duration of shortening and relengthening. Immunoblotting data depicted decreased and increased phosphorylation of Akt/GSK-3β and AMPK/ACC, respectively, following CR. CR also dampened the phosphorylation of mTOR, ERK1/2 and c-Jun while it increased the phosphorylation of JNK. Last but not least, CR significantly promoted cardiac autophagy as evidenced by increased expression of LC3B-II (and LC3B-IIto-LC3B-I ratio) and Beclin-1. In summary, our data suggested that long-term CR may preserve cardiac contractile function with improved cardiomyocyte function, lessen cardiac remodeling and promote autophagy.
doi:10.1016/j.jnutbio.2011.11.002
PMCID: PMC3386480  PMID: 22444502
Calorie restriction; Cardiac function; Remodeling; Insulin signaling; Autophagy
24.  An Extensive Replication Study on Three New Susceptibility Loci of Primary Angle Closure Glaucoma in Han Chinese: Jiangsu Eye Study 
Journal of Ophthalmology  2013;2013:641596.
Genome-wide association study (GWAS) analysis identified three new susceptibility loci for PACG. In this study, we aimed to investigate whether these three loci in PLEKHA7, COL11A1, and PCMTD1-ST18 are associated with PAC and ocular biometric characteristics, such as axial length (AL), anterior chamber depth (ACD), and diopter of spherical power (DS). The study was a part of the Jiangsu Eye Study. The samples were collected from 232 PAC subjects and 306 controls from a population-based prevalence survey conducted in Funing County of Jiangsu, China. The single nucleotide polymorphisms (SNPs) of rs11024102 in PLEKHA7, rs3753841 in COL11A1, and rs1015213 in PCMTD1-ST18 were genotyped by TaqMan-MGB probe using the RT-PCR system. None of the three polymorphisms showed differences in the distribution of genotypes and allele frequencies between the PAC group and the control group. No significant association was determined between the 3 SNPs and AL, ACD, or DS of PAC subjects. We concluded that even though PLEKHA7 rs11024102, COL11A1 rs3753841, and PCMTD1-ST18 rs1015213 are associated with PACG, those sequence variations are not associated with PAC in a Han Chinese population. Our results also did not support a significant role for these three SNPs in ocular biometry such as AL, ACD, and DS.
doi:10.1155/2013/641596
PMCID: PMC3824414  PMID: 24282630
25.  Genome-wide association studies of gastric adenocarcinoma and esophageal squamous cell carcinoma identify a shared susceptibility locus in PLCE1 at 10q23 
Nature genetics  2012;44(10):1090-1097.
We conducted a genome-wide association study of gastric cancer (GC) and esophageal squamous cell carcinoma (ESCC) in ethnic Chinese subjects in which we genotyped 551,152 single nucleotide polymorphisms (SNPs). We report a combined analysis of 2,240 GC cases, 2,115 ESCC cases, and 3,302 controls drawn from five studies. In logistic regression models adjusted for age, sex, and study, multiple variants at 10q23 had genome-wide significance for GC and ESCC independently. A notable signal was rs2274223, a nonsynonymous SNP located in PLCE1, for GC (P=8.40×1010; per allele odds ratio (OR) = 1.31) and ESCC (P=3.85×10−9; OR = 1.34). The association with GC differed by anatomic subsite. For tumors located in the cardia the association was stronger (P=4.19 × 10−15; OR= 1.57) and for those located in the noncardia stomach it was absent (P=0.44; OR=1.05). Our findings at 10q23 could provide insight into the high incidence rates of both cancers in China.
doi:10.1038/ng.2411
PMCID: PMC3513832  PMID: 22960999

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