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1.  Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma 
Vithana, Eranga N | Khor, Chiea-Chuen | Qiao, Chunyan | Nongpiur, Monisha E | George, Ronnie | Chen, Li-Jia | Do, Tan | Abu-Amero, Khaled | Huang, Chor Kai | Low, Sancy | Tajudin, Liza-Sharmini A | Perera, Shamira A | Cheng, Ching-Yu | Xu, Liang | Jia, Hongyan | Ho, Ching-Lin | Sim, Kar Seng | Wu, Ren-Yi | Tham, Clement C Y | Chew, Paul T K | Su, Daniel H | Oen, Francis T | Sarangapani, Sripriya | Soumittra, Nagaswamy | Osman, Essam A | Wong, Hon-Tym | Tang, Guangxian | Fan, Sujie | Meng, Hailin | Huong, Dao T L | Wang, Hua | Feng, Bo | Baskaran, Mani | Shantha, Balekudaru | Ramprasad, Vedam L | Kumaramanickavel, Govindasamy | Iyengar, Sudha K | How, Alicia C | Lee, Kelvin Y | Sivakumaran, Theru A | Yong, Victor H K | Ting, Serena M L | Li, Yang | Wang, Ya-Xing | Tay, Wan-Ting | Sim, Xueling | Lavanya, Raghavan | Cornes, Belinda K | Zheng, Ying-Feng | Wong, Tina T | Loon, Seng-Chee | Yong, Vernon K Y | Waseem, Naushin | Yaakub, Azhany | Chia, Kee-Seng | Allingham, R Rand | Hauser, Michael A | Lam, Dennis S C | Hibberd, Martin L | Bhattacharya, Shomi S | Zhang, Mingzhi | Teo, Yik Ying | Tan, Donald T | Jonas, Jost B | Tai, E-Shyong | Saw, Seang-Mei | Hon, Do Nhu | Al-Obeidan, Saleh A | Liu, Jianjun | Chau, Tran Nguyen Bich | Simmons, Cameron P | Bei, Jin-Xin | Zeng, Yi-Xin | Foster, Paul J | Vijaya, Lingam | Wong, Tien-Yin | Pang, Chi-Pui | Wang, Ningli | Aung, Tin
Nature genetics  2012;44(10):1142-1146.
Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study including 1,854 PACG cases and 9,608 controls across 5 sample collections in Asia. Replication experiments were conducted in 1,917 PACG cases and 8,943 controls collected from a further 6 sample collections. We report significant associations at three new loci: rs11024102 in PLEKHA7 (per-allele odds ratio (OR) = 1.22; P = 5.33 × 10−12), rs3753841 in COL11A1 (per-allele OR = 1.20; P = 9.22 × 10−10) and rs1015213 located between PCMTD1 and ST18 on chromosome 8q (per-allele OR = 1.50; P = 3.29 × 10−9). Our findings, accumulated across these independent worldwide collections, suggest possible mechanisms explaining the pathogenesis of PACG.
PMCID: PMC4333205  PMID: 22922875
2.  Prognostic factors and survival in patients with gastric stump cancer 
AIM: To elucidate the clinicopathological characteristics and prognostic factors of gastric stump cancer (GSC).
METHODS: The clinical data for 92 patients with GSC were collected at Fudan University Shanghai Cancer Center. The prognostic factors were analyzed with Cox proportional hazard models.
RESULTS: GSC tended to occur within 25 years following the primary surgery, when the initial disease is benign, whereas it primarily occurred within the first 15 years post-operation for gastric cancer. Patients with regular follow-up after primary surgery had a better survival rate. The multivariate Cox regression analysis revealed that Borrmann type I/II (HR = 3.165, 95%CI: 1.055-9.500, P = 0.040) and radical resection (HR = 1.780, 95%CI: 1.061-2.987, P = 0.029) were independent prognostic factors for GSC. The overall 1-, 3-, and 5-year survival rates of the 92 patients were 78.3%, 45.6% and 27.6%, respectively. The 1-, 3-, and 5-year survival rates of those undergoing radical resection were 79.3%, 52.2%, and 37.8%, respectively. The 5-year survival rates for stages I, II, III, and IV were 85.7%, 47.4%, 16.0%, and 13.3%, respectively (P = 0.005).
CONCLUSION: The appearance of GSC occurs sooner in patients with primary malignant cancer than in patients with a primary benign disease. Therefore, close follow-up is necessary. The overall survival of patients with GSC is poor, and curative resection can improve their prognosis.
PMCID: PMC4323464
Gastric stump cancer; Clinicopathological characteristics; Prognosis
3.  The distance discordance metric - A novel approach to quantifying spatial uncertainties in intra- and inter-patient deformable image registration 
Physics in medicine and biology  2014;59(3):733-746.
Previous methods to estimate the inherent accuracy of deformable image registration (DIR) have typically been performed relative to a known ground truth, such as tracking of anatomic landmarks or known deformations in a physical or virtual phantom. In this study, we propose a new approach to estimate the spatial geometric uncertainty of DIR using statistical sampling techniques that can be applied to the resulting deformation vector fields (DVFs) for a given registration. The proposed DIR performance metric, the distance discordance metric (DDM), is based on the variability in the distance between corresponding voxels from different images, which are co-registered to the same voxel at location (X) in an arbitrarily chosen “reference” image. The DDM value, at location (X) in the reference image, represents the mean dispersion between voxels, when these images are registered to other images in the image set. The method requires at least four registered images to estimate the uncertainty of the DIRs, both for inter-and intra-patient DIR. To validate the proposed method, we generated an image set by deforming a software phantom with known DVFs. The registration error was computed at each voxel in the “reference” phantom and then compared to DDM, inverse consistency error (ICE), and transitivity error (TE) over the entire phantom. The DDM showed a higher Pearson correlation (Rp) with the actual error (Rp ranged from 0.6 to 0.9) in comparison with ICE and TE (Rp ranged from 0.2 to 0.8). In the resulting spatial DDM map, regions with distinct intensity gradients had a lower discordance and therefore, less variability relative to regions with uniform intensity. Subsequently, we applied DDM for intra-patient DIR in an image set of 10 longitudinal computed tomography (CT) scans of one prostate cancer patient and for inter-patient DIR in an image set of 10 planning CT scans of different head and neck cancer patients. For both intra- and inter-patient DIR, the spatial DDM map showed large variation over the volume of interest (the pelvis for the prostate patient and the head for the head and neck patients). The highest discordance was observed in the soft tissues, such as the brain, bladder, and rectum, due to higher variability in the registration. The smallest DDM values were observed in the bony structures in the pelvis and the base of the skull. The proposed metric, DDM, provides a quantitative tool to evaluate the performance of DIR when a set of images is available. Therefore, DDM can be used to estimate and visualize the uncertainty of intra- and/or inter-patient DIR based on the variability of the registration rather than the absolute registration error.
PMCID: PMC3995002  PMID: 24440838
Deformable image registration; distance discordance; uncertainty; inaccuracy
4.  Validation of the Chinese version of the Clinical Assessment Interview for Negative Symptoms (CAINS): a preliminary report 
The present study aimed to examine the psychometric properties of the Chinese version of the Clinical Assessment Interview for Negative Symptoms (CAINS). We recruited 68 patients with schizophrenia from the Chinese setting. The findings showed a generally consistent two-factor structure with the original version, namely “expression” and “motivation–pleasure.” There is a minor cultural variation in perceiving these items in the Chinese culture. However, the present study demonstrated that the Chinese version of the CAINS appears to be a valid and reliable clinical tool for the assessment of negative symptoms in the Chinese setting.
PMCID: PMC4313598
negative symptoms; schizophrenia; validation
5.  GneZ, a UDP-GlcNAc 2-Epimerase, Is Required for S-Layer Assembly and Vegetative Growth of Bacillus anthracis 
Journal of Bacteriology  2014;196(16):2969-2978.
Bacillus anthracis, the causative agent of anthrax, forms an S-layer atop its peptidoglycan envelope and displays S-layer proteins and Bacillus S-layer-associated (BSL) proteins with specific functions to support cell separation of vegetative bacilli and growth in infected mammalian hosts. S-layer and BSL proteins bind via the S-layer homology (SLH) domain to the pyruvylated secondary cell wall polysaccharide (SCWP) with the repeat structure [→4)-β-ManNAc-(1→4)-β-GlcNAc-(1→6)-α-GlcNAc-(1→]n, where α-GlcNAc and β-GlcNAc are substituted with two and one galactosyl residues, respectively. B. anthracis gneY (BAS5048) and gneZ (BAS5117) encode nearly identical UDP-GlcNAc 2-epimerase enzymes that catalyze the reversible conversion of UDP-GlcNAc and UDP-ManNAc. UDP-GlcNAc 2-epimerase enzymes have been shown to be required for the attachment of the phage lysin PlyG with the bacterial envelope and for bacterial growth. Here, we asked whether gneY and gneZ are required for the synthesis of the pyruvylated SCWP and for S-layer assembly. We show that gneZ, but not gneY, is required for B. anthracis vegetative growth, rod cell shape, S-layer assembly, and synthesis of pyruvylated SCWP. Nevertheless, inducible expression of gneY alleviated all the defects associated with the gneZ mutant. In contrast to vegetative growth, neither germination of B. anthracis spores nor the formation of spores in mother cells required UDP-GlcNAc 2-epimerase activity.
PMCID: PMC4135639  PMID: 24914184
6.  Transcriptome analysis of food habit transition from carnivory to herbivory in a typical vertebrate herbivore, grass carp Ctenopharyngodon idella 
BMC Genomics  2015;16(1):15.
Although feeding behavior and food habit are ecologically and economically important properties, little is known about formation and evolution of herbivory. Grass carp (Ctenopharyngodon idella) is an ecologically appealing model of vertebrate herbivore, widely cultivated in the world as edible fish or as biological control agents for aquatic weeds. Grass carp exhibits food habit transition from carnivory to herbivory during development. However, currently little is known about the genes regulating the unique food habit transition and the formation of herbivory, and how they could achieve higher growth rates on plant materials, which have a relatively poor nutritional quality.
We showed that grass carp fed with duckweed (modeling fish after food habit transition) had significantly higher relative length of gut than fish before food habit transition or those fed with chironomid larvae (fish without transition). Using transcriptome sequencing, we identified 10,184 differentially expressed genes between grass carp before and after transition in brain, liver and gut. By eliminating genes potentially involved in development (via comparing fish with or without food habit transition), we identified changes in expression of genes involved in cell proliferation and differentiation, appetite control, circadian rhythm, and digestion and metabolism between fish before and after food habit transition. Up-regulation of GHRb, Egfr, Fgf, Fgfbp1, Insra, Irs2, Jak, STAT, PKC, PI3K expression in fish fed with duckweed, consistent with faster gut growth, could promote the food habit transition. Grass carp after food habit transition had increased appetite signal in brain. Altered expressions of Per, Cry, Clock, Bmal2, Pdp, Dec and Fbxl3 might reset circadian phase of fish after food habit transition. Expression of genes involved in digestion and metabolism were significantly different between fish before and after the transition.
We suggest that the food habit transition from carnivory to herbivory in grass carp might be due to enhanced gut growth, increased appetite, resetting of circadian phase and enhanced digestion and metabolism. We also found extensive alternative splicing and novel transcript accompanying food habit transition. These differences together might account for the food habit transition and the formation of herbivory in grass carp.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1217-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4307112  PMID: 25608568
Food habit transition; Carnivory; Herbivory; Grass carp; Transcriptome sequencing
7.  Serum soluble CD40 is associated with liver injury in patients with chronic hepatitis B 
Soluble cluster of differentiation 40 (sCD40) is proteolytically cleaved from membrane-bound CD40 and binds to CD154, thereby inhibiting CD40-CD154-mediated immune responses. The aim of the present study was to clarify the role of sCD40 in chronic hepatitis B (CHB). The sCD40 levels in sera from 132 patients with CHB and 33 healthy individuals were retrospectively measured. sCD40 concentrations in patients with CHB were higher than those in healthy controls, and sCD40 levels correlated positively with serum levels of the liver dysfunction biomarkers alanine transaminase (ALT) and aspartate transaminase (AST). sCD40 concentrations increased with a rise in the severity of liver necroinflammation and fibrosis. Patients with >75% liver tissue staining positive for hepatitis B virus (HBV) antigen expression showed significantly lower sCD40 levels than those who stained negative for the HBV antigen. The area under the receiver operating characteristic curve of sCD40 was greater than that of ALT and AST; thus, sCD40 levels have a high diagnostic accuracy for detecting severe liver inflammation in patients with CHB, and could serve as an immunological marker of hepatic tissue injury.
PMCID: PMC4316966  PMID: 25667667
fibrosis; hepatocyte; immune; necroinflammatory
8.  SAHA Enhances Proteostasis of Epilepsy-Associated α1(A322D)β2γ2 GABAa Receptors 
Chemistry & biology  2013;20(12):10.1016/j.chembiol.2013.09.020.
GABAa receptors are the primary inhibitory ion channels in the mammalian central nervous system. The A322D mutation in the α1 subunit of GABAa receptors is known to result in its degradation and reduce its cell surface expression, leading to loss of GABAa receptor function in autosomal dominant juvenile myoclonic epilepsy. Here, we show that SAHA, a FDA-approved drug, increases the transcription of the α1(A322D) subunit, enhances its folding and trafficking post-translationally, increases its cell surface level, and restores the GABA-induced maximal current in HEK293 cells expressing α1(A322D)β2γ2 receptors to 10% of that for wild type receptors. To enhance the trafficking efficiency of the α1(A322D) subunit, SAHA increases the BiP protein level and the interaction between the α1(A322D) subunit and calnexin. SAHA is the first reported drug that enhances epilepsy-associated GABAa receptor proteostasis.
PMCID: PMC3872227  PMID: 24211135
9.  Effect of titanium dioxide nanoparticles on zebrafish embryos and developing retina 
To investigate the impact of titanium dioxide nanoparticles (TiO2 NPs) on embryonic development and retinal neurogenesis.
The agglomeration and sedimentation of TiO2 NPs solutions at different dilutions were observed, and the ultraviolet-visible spectra of their supernatants were measured. Zebrafish embryos were experimentally exposed to TiO2 NPs until 72h postfertilization (hpf). The retinal neurogenesis and distribution of the microglia were analyzed by immunohistochemistry and whole mount in situ hybridization.
The 1 mg/L was determined to be an appropriate exposure dose. Embryos exposed to TiO2 NPs had a normal phenotype. The neurogenesis was initiated on time, and ganglion cells, cones and rods were well differentiated at 72 hpf. The expression of fms mRNA and the 4C4 antibody, which were specific to microglia in the central nervous system (CNS), closely resembled their endogenous profile.
These data demonstrate that short-term exposure to TiO2 NPs at a low dose does not lead to delayed embryonic development or retinal neurotoxicity.
PMCID: PMC4270981  PMID: 25540739
titanium dioxide nanoparticles; retina; microglia; zebrafish
10.  Altered MicroRNA Expression Profile in Exosomes during Osteogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells 
PLoS ONE  2014;9(12):e114627.
The physiological role of microRNAs (miRNAs) in osteoblast differentiation remains elusive. Exosomal miRNAs isolated from human bone marrow-derived mesenchymal stem cells (BMSCs) culture were profiled using miRNA arrays containing probes for 894 human matured miRNAs. Seventy-nine miRNAs (∼8.84%) could be detected in exosomes isolated from BMSC culture supernatants when normalized to endogenous control genes RNU44. Among them, nine exosomal miRNAs were up regulated and 4 miRNAs were under regulated significantly (Relative fold>2, p<0.05) when compared with the values at 0 day with maximum changes at 1 to 7 days. Five miRNAs (miR-199b, miR-218, miR-148a, miR-135b, and miR-221) were further validated and differentially expressed in the individual exosomal samples from hBMSCs cultured at different time points. Bioinformatic analysis by DIANA-mirPath demonstrated that RNA degradation, mRNA surveillance pathway, Wnt signaling pathway, RNA transport were the most prominent pathways enriched in quantiles with differential exosomal miRNA patterns related to osteogenic differentiation. These data demonstrated exosomal miRNA is a regulator of osteoblast differentiation.
PMCID: PMC4263734  PMID: 25503309
11.  Identification of GABAC Receptor Protein Homeostasis Network Components from Three Tandem Mass Spectrometry Proteomics Approaches 
Journal of proteome research  2013;12(12):10.1021/pr400535z.
Gamma-amino butyric acid type C (GABAC) receptors inhibit neuronal firing primarily in retina. Maintenance of GABAC receptor protein homeostasis in cells is essential for its function. However, a systematic study of GABAC receptor protein homeostasis (proteostasis) network components is absent. Here, co-immunoprecipitation of human GABAC-ρ1 receptor complexes was performed in HEK293 cells overexpressing ρ1 receptors. To enhance the coverage and reliability of identified proteins, immunoisolated ρ1 receptor complexes were subjected to three tandem mass spectrometry (MS)-based proteomic analyses: namely, gel-based tandem MS (GeLC-MS/MS), solution-based tandem MS (SoLC-MS/MS), and multidimensional protein identification technology (MudPIT). From the 107 identified proteins, we assembled GABAC-ρ1 receptor proteostasis network components, including proteins with protein folding, degradation, and trafficking functions. We studied representative individual ρ1 receptor interacting proteins, including calnexin, a lectin chaperone that facilitates glycoprotein folding, and LMAN1, a glycoprotein trafficking receptor, and global effectors that regulate protein folding in cells based on bioinformatics analysis, including HSF1, a master regulator of the heat shock response, and XBP1, a key transcription factor of the unfolded protein response. Manipulating selected GABAC receptor proteostasis network components is a promising strategy to regulate GABAC receptor folding, trafficking, degradation and thus function to ameliorate related retinal diseases.
PMCID: PMC3864119  PMID: 24079818
GABAC receptor; tandem mass spectrometry; interactome; proteostasis; folding; trafficking; degradation; heat shock response; unfolded protein response
12.  Isolation and epithelial co-culture of mouse renal peritubular endothelial cells 
BMC Cell Biology  2014;15(1):40.
Endothelial-mesenchymal transition (EndoMT) has been shown to be a major source of myofibroblasts, contributing to kidney fibrosis. However, in vitro study of endothelial cells often relies on culture of isolated primary endothelial cells due to the unavailability of endothelial cell lines. Our recent study suggested that peritubular endothelial cells could contribute to kidney fibrosis through EndoMT. Therefore, successful isolation and culture of mouse peritubular endothelial cells could provide a new platform for studying kidney fibrosis. This study describes an immunomagnetic separation method for the isolation of mouse renal peritubular endothelial cells using anti-CD146 MicroBeads, followed by co-culture with mouse renal proximal tubular epithelial cells to maintain endothelial phenotype.
Flow cytometry showed that after isolation and two days of culture, about 95% of cells were positive for endothelial-specific marker CD146. The percentage of other cells, including dendritic cells (CD11c) and macrophages (F4/80), was less than 1%. Maintenance of endothelial cell phenotype required vascular endothelial growth factor (VEGF) and co-culture with mouse proximal tubular epithelial cells.
In this study, we established a method for the isolation of mouse renal peritubular endothelial cells by using immunomagnetic separation with anti-CD146 MicroBeads, followed by co-culture with mouse renal proximal tubular epithelial cells to maintain phenotype.
Electronic supplementary material
The online version of this article (doi:10.1186/s12860-014-0040-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4260259  PMID: 25433516
Peritubular endothelial cells; Tubular epithelial cells; CD146; Co-culture; Vascular endothelial growth factor
13.  Circulating Programmed Death-1 as a Marker for Sustained High Hepatitis B Viral Load and Risk of Hepatocellular Carcinoma 
PLoS ONE  2014;9(11):e95870.
Recent evidence indicates a crucial role of the immunoinhibitory receptor programmed death-1 (PD-1) in enforcing T-cell dysfunction during chronic viral infection and cancer. We assessed the impact of circulating soluble PD-1 (sPD-1) levels on long-term dynamics of hepatitis B virus (HBV) load and hepatocellular carcinoma (HCC) risk.
In a case-cohort study on longitudinal analysis of viral load within a cohort of 2903 men chronically infected with HBV, followed up from baseline (1989–1992) through 2010, we determined sPD-1 levels in baseline plasma with enzyme-linked immunosorbent assay from 126 men who subsequently developed HCC and 1155 men who did not develop HCC. To evaluate whether patients' characteristics involved the use of sPD-1 as a biomarker, sPD-1 was also tested in 614 newly-diagnosed patients with HBV-related HCC recruited from a multicenter study for comparison with the 1155 noncases in the case-cohort study.
Plasma quartile levels of sPD-1 were positively associated with HCC risk for men in the case-cohort analysis (vs. quartile 1: adjusted odds ratios [95% confidence intervals] for quartile 2-quartile 4 were 1.51 [0.75–3.03], 2.15 [1.12–4.13], and 2.29 [1.20–4.38], respectively), and in the case-control study regardless of age-of-onset and clinical stage. Furthermore, we found longitudinal effect of elevated sPD-1 levels to maintain higher viral load for 4 or more years, with greater and more prolonged effect among HBV genotype C- vs. non-C-infected participants. High levels of viral load and sPD-1 (vs. absence of both) was associated with a 6.29-fold increase in risk of HCC, and combining both conditions with HBV genotype C yielded an odds ratio of 30.47 with significant additive interaction (relative excess risk due to interaction: 27.08 [95% confidence interval = 8.76–45.41]).
Our data suggest plasma sPD-1 as an important immune-related marker for assessment of HBV activity and HCC risk.
PMCID: PMC4245192  PMID: 25427199
14.  Ten-Year Cumulative Incidence of Diabetic Retinopathy. The Beijing Eye Study 2001/2011 
PLoS ONE  2014;9(10):e111320.
To assess the cumulative 10-year incidence of diabetic retinopathy (DR) and its associated factors in a population living in Greater Beijing.
The population-based longitudinal Beijing Eye Study, which included 4439 subjects (age in 2001: 40+years) in 2001, was repeated in 2011 with 2695 subjects participating (66.4% of the survivors). The study participants underwent a detailed ophthalmic examination. Fundus photographs were examined for the new development of DR.
After excluding individuals with DR at baseline (n = 87) or no sufficient fundus photographs in 2011 (n = 6), the study included 2602 subjects with a mean age of 64.6±9.7 years (median: 64.0 years; range: 50 to 93 years). In the 10-year period, 109 subjects (39 men) developed new DR with an incidence of 4.2% (95% confidence interval (CI): 3.45,5.03). In multiple logistic regression analysis, incident DR was significantly associated with higher HbA1c value (P<0.001; Odds Ratio (OR): 1.73; 95% Confidence Interval (CI): 1.35,2.21), longer duration of diabetes mellitus (P<0.001; OR: 1.16; 95% CI: 1.10,1.22), higher serum concentration of creatinine (P = 0.02; OR: 1.01; 95% CI: 1.002,1.022), lower educational level (P = 0.049; OR: 0.74; 95% CI: 0.55,0.99), higher estimated cerebrospinal fluid pressure (P = 0.038; OR: 1.10; 95% CI: 1.01,1.22), and shorter axial length (P<0.001; OR: 0.48; 95% CI: 0.33,0.71).
The cumulative 10-year incidence (mean: 4.2%) of DR in a North Chinese population was significantly associated with a higher HbA1c value, longer known duration of diabetes mellitus, higher estimated CSFP and shorter axial length (P<0.001). Shorter axial length (or hyperopia) and, potentially, higher CSFP may be additional risk factors to be taken into account when counseling and treating patients with diabetes mellitus.
PMCID: PMC4210166  PMID: 25347072
15.  Cigarette smoke affects dendritic cell maturation in the small airways of patients with chronic obstructive pulmonary disease 
Molecular Medicine Reports  2014;11(1):219-225.
The aim of the present study was to characterize and quantify the numbers and expression levels of cells markers associated with dendritic cell (DC) maturation in small airways in current smokers and non-smokers with or without chronic obstructive pulmonary disease (COPD). Lung tissues from the following 32 patients were obtained during resection for lung cancer: Eight smokers with COPD, eight non-smokers with COPD, eight current smokers without COPD and eight non-smokers without COPD, serving as a control. The tissue sections were immunostained for cluster of differentiation (CD)83+ and CD1a+ to delineate mature and immature DCs, and chemokine receptor type 7 (CCR7+) to detect DC migratory ability. Myeloid DCs were collected from the lung tissues, and subsequently the CD83+ and CCR7+ expression levels in the lung myeloid DCs were detected using flow cytometry. The expression levels of CD83+, CD1a+ and CCR7+ mRNA in total lung RNA were evaluated by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Evident chronic bronchitis and emphysema pathological changes were observed in the lung tissues of patients with COPD. The results revealed that the numbers of CD83+ and CCR7+ DCs were reduced but the numbers of CD1a+ DCs were significantly increased in the COPD group as compared with the control group (P<0.05, respectively). Using RT-qPCR, the expression levels of CCR7+ and CD83+ mRNA were found to be reduced in the smokers with COPD as compared with the non-smokers without COPD group (P<0.05, respectively). Excessive local adaptive immune responses are key elements in the pathogenesis of COPD. Cigarette smoke may stimulate immune responses by impairing the homing of airway DCs to the lymph nodes and reduce the migratory potential of DCs. The present study revealed that COPD is associated with reduced numbers of mature CD83+ DCs and lower CCR7+ expression levels in small airways.
PMCID: PMC4237095  PMID: 25338516
chronic obstructive pulmonary disease; reverse transcription polymerase chain reaction; chemokine receptor type 7; dendritic cells; cluster of differentiation 83; cluster of differentiation 1a
16.  Compound Danshen Dripping Pill Pretreatment to Prevent Contrast-Induced Nephropathy in Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention 
Background. Contrast-induced nephropathy (CIN) limits the outcome of percutaneous coronary intervention (PCI). Objective. To investigate whether pretreatment with Compound Danshen Dripping Pills (CDDP) will decrease the incidence of CIN after PCI. Methods. A total of 229 patients with acute coronary syndrome (ACS) undergoing PCI were divided into the control group (n = 114) and the CDDP (containing salvia miltiorrhiza and sanqi) group (n = 115; given 20 CDDP pills, three times daily before PCI). Serum creatinine, creatinine clearance (CrCl), high-sensitivity C-reactive protein (hsCRP), P-selectin, and intercellular adhesion molecule-1 (ICAM-1) were measured at admission and 24 and 48 h after PCI. Results. CrCl decreased after PCI but recovered after 48 h. In the CDDP group, CrCl recovered more rapidly (P < 0.05). The procedure increased the hsCRP, P-selectin, and ICAM-1 levels, but these levels were less in the CDDP group (P < 0.05). Conclusions. Pretreatment with CDDP can decrease the occurrence of CIN in patients undergoing PCI, suggesting that the early use of CDDP is an appropriate adjuvant pharmacological therapy before PCI.
PMCID: PMC4216665  PMID: 25386219
17.  Cholinergic Modulation of Large-Conductance Calcium-Activated Potassium Channels Regulates Synaptic Strength and Spine Calcium in Cartwheel Cells of the Dorsal Cochlear Nucleus 
The Journal of Neuroscience  2014;34(15):5261-5272.
Acetylcholine is a neuromodulatory transmitter that controls synaptic plasticity and sensory processing in many brain regions. The dorsal cochlear nucleus (DCN) is an auditory brainstem nucleus that integrates auditory signals from the cochlea with multisensory inputs from several brainstem nuclei and receives prominent cholinergic projections. In the auditory periphery, cholinergic modulation serves a neuroprotective function, reducing cochlear output under high sound levels. However, the role of cholinergic signaling in the DCN is less understood. Here we examine postsynaptic mechanisms of cholinergic modulation at glutamatergic synapses formed by parallel fiber axons onto cartwheel cells (CWCs) in the apical DCN circuit from mouse brainstem slice using calcium (Ca) imaging combined with two-photon laser glutamate uncaging onto CWC spines. Activation of muscarinic acetylcholine receptors (mAChRs) significantly increased the amplitude of both uncaging-evoked EPSPs (uEPSPs) and spine Ca transients. Our results demonstrate that mAChRs in CWC spines act by suppressing large-conductance calcium-activated potassium (BK) channels, and this effect is mediated through the cAMP/protein kinase A signaling pathway. Blocking BK channels relieves voltage-dependent magnesium block of NMDA receptors, thereby enhancing uEPSPs and spine Ca transients. Finally, we demonstrate that mAChR activation inhibits L-type Ca channels and thus may contribute to the suppression of BK channels by mAChRs. In summary, we demonstrate a novel role for BK channels in regulating glutamatergic transmission and show that this mechanism is under modulatory control of mAChRs.
PMCID: PMC3983802  PMID: 24719104
18.  Cetrotide administration in the early luteal phase in patients at high risk of ovarian hyperstimulation syndrome: A controlled clinical study 
The aim of the present pilot study was to assess the feasibility and efficacy of Cetrotide administration in the early luteal phase in patients at high risk of ovarian hyperstimulation syndrome (OHSS), undergoing embryo cryopreservation following superovulation. A total of 135 patients at high risk of OHSS and undergoing embryo cryopreservation were divided into two groups. In the treatment group (n=39), the patients received daily subcutaneous injections of 0.25 mg Cetrotide between days 1 and 5 following ooctye retrieval, and volume expansion and symptomatic treatment were also provided. In the control group (n=96), the patients received routine treatments, including volume expansion therapy. The serum steroid hormone concentrations of the patients were measured on days 2, 5 and 8 following ooctye retrieval, while the incidence of moderate or severe OHSS, self-evaluated clinical symptoms and various clinical indicators were recorded. The serum estradiol (E2), luteinizing hormone and progesterone levels in the treatment group on days 2, 5 and 8 following oocyte retrieval were not found to differ significantly when compared with the patients in the control group (P>0.05). The incidence of severe OHSS did not differ significantly between the two groups (P>0.05). The average length of hospital stay and length of luteal phase were not found to be significantly different between the treatment and control groups (P>0.05). In conclusion, Cetrotide injections in the early luteal phase did not alter the serum steroid levels of patients at high risk of OHSS undergoing embryo cryopreservation, and were unable to reduce the incidence of severe early OHSS. However, further randomized studies are required to evaluate the effectiveness of Cetrotide in the prevention of OHSS.
PMCID: PMC4217764  PMID: 25371744
gonadotropin-releasing hormone antagonist; ovarian hyperstimulation syndrome; in vitro fertilization; luteal phase; prevention
19.  Correlations between brachial endothelial function and cardiovascular risk factors: a survey of 2,511 Chinese subjects 
Journal of Thoracic Disease  2014;6(10):1441-1451.
We examined the relationship of several cardiovascular risk factors (CVRF) to brachial artery flow-mediated dilatation (FMD) in Chinese subjects.
This was a cross-sectional study. In 2,511 Chinese adults (age 46.86±9.52 years, 1,891 men and 620 women) recruited from people who underwent health screening at The Third Xiangya Hospital, patients’ CVRF [age, body mass index (BMI), waist circumference (WC), blood pressure (BP), cholesterol parameters, creatinine (Cr), uric acid (UA), glucose level and smoking] and prevalence of present disease (hypertension, diabetes mellitus, coronary heart disease and hyperlipidemia) were investigated.
Multivariate analysis revealed that FMD negative correlated with age (β=–0.29, P<0.001), gender (β=–0.12, P<0.001), BMI (β=–0.12, P=0.001), WC (β=–0.10, P=0.011), systolic BP (SBP) (β=–0.12, P<0.001), fasting glucose (β=–0.04, P=0.009), total cholesterol (TC) (β=–0.04, P=0.014), smoking (β=–0.05, P=0.003), and baseline brachial artery diameter (β=–0.35, P<0.001). FMD decreased with increasing age in both genders. In women, FMD was higher than men and age-related decline in FMD was steepest after age 40; FMD was similar in men above 55 years old.
In Chinese subjects, FMD may be a usefully marker of CVRF. Age, gender, BMI, WC, SBP, fasting glucose, TC, smoking, and baseline brachial artery diameter were independent variables related to the impairment of FMD. The influence of CVRF on endothelial function is more in women than men.
PMCID: PMC4215131  PMID: 25364521
Endothelial function; brachial artery flow-mediated dilatation (FMD); cardiovascular risk factors (CVRF)
20.  Delta-like ligand 4: A predictor of poor prognosis in clear cell renal cell carcinoma 
Oncology Letters  2014;8(6):2627-2633.
Delta-like ligand 4 (Dll4)-Notch signaling is important in tumor angiogenesis; however, the prognostic value of D114 detection in patients with clear cell renal cell carcinoma (CCRCC) remains unclear. The present study aimed to determine whether the presence of high Dll4 expression levels was correlated with poor prognosis in CCRCC following curative resection. The D114 expression levels in four paired samples of CCRCC tissues and adjacent normal renal tissues were assayed by western blotting. Surgical specimens comprised 121 CCRCC tissue samples and 65 normal renal tissue samples, obtained from patients with CCRCC. The specimens were immunohistochemically assessed to determine Dll4 and vascular endothelial growth factor receptor 2 (VEGFR-2) expression levels. The prognostic significance of Dll4 expression levels was evaluated by the Kaplan-Meier method and Cox regression analysis. The correlation between Dll4 expression levels and VEGFR-2 expression levels, tumor stage, tumor grade and metastasis, was examined by χ2 test and multivariate logistic regression. As determined by the western blotting results, Dll4 protein expression levels were significantly increased in CCRCC tissues compared with those in adjacent non-cancerous tissues. From the analysis of the surgical specimens, 53 (43.8%) CCRCC patients exhibited immunohistochemically high Dll4 expression levels and 68 (56.2%) patients exhibited low Dll4 expression levels. The survival curves revealed that the patients with high Dll4 expression levels had significantly shorter survival times than the patients with low Dll4 expression levels (P<0.001). Multivariate survival analysis demonstrated that the presence of high Dll4 expression levels was independently associated with reduced overall survival and progression-free survival times (P=0.021 and 0.034, respectively). A positive correlation was also identified between Dll4 and VEGFR-2 expression levels (P=0.001). In conclusion, the results show that the presence of high Dll4 expression levels was clearly associated with high VEGFR-2 expression levels, tumor grade, tumor stage and poor prognosis in CCRCC patients. Therefore, inhibition of Dll4 may exert potent growth inhibitory effects on tumors resistant to anti-VEGF therapies for CCRCC.
PMCID: PMC4214437  PMID: 25364440
delta-like ligand 4; clear cell renal cell carcinoma; survival; prognosis
21.  The Association of the Vanin-1 N131S Variant with Blood Pressure Is Mediated by Endoplasmic Reticulum-Associated Degradation and Loss of Function 
PLoS Genetics  2014;10(9):e1004641.
High blood pressure (BP) is the most common cardiovascular risk factor worldwide and a major contributor to heart disease and stroke. We previously discovered a BP-associated missense SNP (single nucleotide polymorphism)–rs2272996–in the gene encoding vanin-1, a glycosylphosphatidylinositol (GPI)-anchored membrane pantetheinase. In the present study, we first replicated the association of rs2272996 and BP traits with a total sample size of nearly 30,000 individuals from the Continental Origins and Genetic Epidemiology Network (COGENT) of African Americans (P = 0.01). This association was further validated using patient plasma samples; we observed that the N131S mutation is associated with significantly lower plasma vanin-1 protein levels. We observed that the N131S vanin-1 is subjected to rapid endoplasmic reticulum-associated degradation (ERAD) as the underlying mechanism for its reduction. Using HEK293 cells stably expressing vanin-1 variants, we showed that N131S vanin-1 was degraded significantly faster than wild type (WT) vanin-1. Consequently, there were only minimal quantities of variant vanin-1 present on the plasma membrane and greatly reduced pantetheinase activity. Application of MG-132, a proteasome inhibitor, resulted in accumulation of ubiquitinated variant protein. A further experiment demonstrated that atenolol and diltiazem, two current drugs for treating hypertension, reduce the vanin-1 protein level. Our study provides strong biological evidence for the association of the identified SNP with BP and suggests that vanin-1 misfolding and degradation are the underlying molecular mechanism.
Author Summary
Hypertension (HTN) or high blood pressure (BP) is common worldwide and a major risk factor for cardiovascular disease and all-cause mortality. Identification of genetic variants of consequence for HTN serves as the molecular basis for its treatment. Using admixture mapping analysis of the Family Blood Pressure Program data, we recently identified that the VNN1 gene (encoding the protein vanin-1), in particular SNP rs2272996 (N131S), was associated with BP in both African Americans and Mexican Americans. Vanin-1 was reported to act as an oxidative stress sensor using its pantetheinase enzyme activity. Because a linkage between oxidative stress and HTN has been hypothesized for many years, vanin-1's pantetheinase activity offers a physiologic rationale for BP regulation. Here, we first replicated the association of rs2272996 with BP in the Continental Origins and Genetic Epidemiology Network (COGENT), which included nearly 30,000 African Americans. We further demonstrated that the N131S mutation in vanin-1 leads to its rapid degradation in cells, resulting in loss of function on the plasma membrane. The loss of function of vanin-1 is associated with reduced BP. Therefore, our results indicate that vanin-1 is a new candidate to be manipulated to ameliorate HTN.
PMCID: PMC4169380  PMID: 25233454
22.  Subfoveal Choroidal Thickness and Glaucoma. The Beijing Eye Study 2011 
PLoS ONE  2014;9(9):e107321.
To examine subfoveal choroidal thickness (SFCT) in eyes with glaucoma, using enhanced depth imaging spectral domain optical coherence tomography.
The population-based Beijing Eye Study 2011 included 3468 individuals with a mean age of 64.6±9.8 years (range: 50–93 years). A detailed ophthalmic examination was performed including spectral-domain optical coherence tomography (SD-OCT) with enhanced depth imaging for measurement of SFCT, and assessment of fundus photographs for presence of glaucoma. In addition, the group of patients with chronic angle-closure glaucoma (ACG) from the Beijing Eye Study (n = 37) was merged with a group of patients with chronic ACG from the Tongren hospital (n = 52).
Assessments of SFCT and glaucoma were available for 3232 (93.2%) subjects. After adjusting for age, axial length, gender, anterior chamber and lens thickness, SFCT was not significantly associated with presence of glaucoma (P = 0.08; regression coefficient B:−15.7). As a corollary, in logistic regression analysis with adjustment for age, axial length and intraocular pressure, presence of glaucoma was not significantly associated with SFCT (P = 0.20). If only open-angle glaucoma was considered, multivariate analysis revealed no significant association between SFCT and presence of open-angle glaucoma (P = 0.44). As a corollary, in logistic regression analysis, open-angle glaucoma was not significantly associated with SFCT (P = 0.91). In a similar manner if only ACG was taken into account, SFCT was not significantly associated with the presence of ACG (P = 0.27) in multivariate analysis. As a corollary in binary regression analysis, presence of ACG was not significantly associated with SFCT (P = 0.27).
In multivariate analysis with adjustment for age, axial length, gender, anterior chamber and lens thickness, neither OAG nor ACG was associated with an abnormal SFCT.
PMCID: PMC4161421  PMID: 25210857
23.  Uniaxial Cyclic Stretch Promotes Osteogenic Differentiation and Synthesis of BMP2 in the C3H10T1/2 Cells with BMP2 Gene Variant of rs2273073 (T/G) 
PLoS ONE  2014;9(9):e106598.
Ossification of the posterior longitudinal ligament of the cervical spine (OPLL) is characterized by the replacement of ligament tissues with ectopic bone formation, and this result is strongly affected by genetic and local factors. Two single nucleotide polymorphisms (SNPs) of rs2273073 (T/G) and rs235768 (A/T) of bone morphogenetic protein 2 (BMP2) gene which are associated with OPLL have been reported in our previous report. In this study, we confirmed the connection in 18 case samples analysis of BMP2 gene in OPLL patients; additionally, it was also shown from the OPLL patients with ligament tissues that enchondral ossification and expression of BMP2 were significantly higher compared with the non-OPLL patients by histological examination, immunohistochemistry and Western blotting analysis. To investigate the underlying mechanism, we studied the effect of SNPs in cell model. The C3H10T1/2 cells with different BMP2 gene variants were constructed and then subjected to uniaxial cyclic stretch (0.5 Hz, 10% stretch). In the presence of mechanical stress, the expression of BMP2 protein in C3H10T1/2 cells transfected by BMP2 (rs2273073 (T/G)) and BMP2 (rs2273073 (T/G), rs235768 (A/T)) were significantly higher than the corresponding static groups (P<0.05). In conclusion, these results suggested that BMP2 gene variant of rs2273073 (T/G) could not only increase cell susceptibility to bone transformation similar to pre-OPLL change, but also increase the sensibility to mechanical stress which might play an important role during the progression of OPLL.
PMCID: PMC4156358  PMID: 25191703
24.  Sleep, Mood, and Quality of Life in Patients Receiving Treatment for Lung Cancer 
Oncology nursing forum  2013;40(5):441-451.
To distinguish relationships among subjective and objective characteristics of sleep, mood, and quality of life (QOL) in patients receiving treatment for lung cancer.
Descriptive, correlational study.
Two ambulatory oncology clinics.
35 patients with lung cancer.
The following instruments were used to measure the variables of interest: Pittsburgh Sleep Quality Index (PSQI), Hospital Anxiety and Depression Scale, Functional Assessment of Cancer Treatment–Lung (FACT-L), a sleep diary, and a motionlogger actigraph.
Main Research Variables
Sleep, mood, and QOL.
Significant differences were found between sleep diary and actigraph measures of sleep efficiency (p = 0.002), sleep latency (p = 0.014), sleep duration (p < 0.001), and wake after sleep onset (p < 0.001). Poor sleepers (PSQI score greater than 5) were significantly different from good sleepers (PSQI score of 5 or lower) on sleep diary measures of sleep efficiency and sleep latency and the FACT-L lung cancer symptom subscale, but not on mood or actigraphy sleep measures.
Although patients with lung cancer may report an overall acceptable sleep quality when assessed by a single question, those same patients may still have markedly increased sleep latencies or reduced total sleep time. The findings indicate the complexity of sleep disturbances in patients with lung cancer. Lung cancer symptoms had a stronger association with sleep than mood. Research using prospective methods will help to elucidate their clinical significance.
Implications for Nursing
Patients receiving treatment for lung cancer are at an increased risk for sleep disturbances and would benefit from routine sleep assessment and management. In addition, assessment and management of common symptoms may improve sleep and, ultimately, QOL.
Knowledge Translation
A high frequency of sleep disturbances in patients receiving treatment for lung cancer was evident, and poor sleepers had lower QOL. Sleep disturbances may be more related to lung cancer symptoms than anxiety or depression. Improving lung cancer symptoms such as dyspnea may improve sleep.
PMCID: PMC4080434  PMID: 23989018
25.  The Adenosine Deaminase Gene Polymorphism Is Associated with Chronic Heart Failure Risk in Chinese 
Adenosine (Ado) is an important cardioprotective agent. Since endogenous Ado levels are affected by the enzyme Ado deaminase (ADA), polymorphisms within the ADA gene may exert some effect on chronic heart failure (CHF). This study applied a case-control investigation to 300 northern Chinese Han CHF patients and 400 ethnicity-matched healthy controls in which nine single-nucleotide polymorphisms (SNPs) of ADA were genotyped and association analyses were performed. Odds ratios (ORs) with 95% confidence intervals (CI) were used to assess the association. Overall, rs452159 polymorphism in ADA gene was significantly associated with susceptibility to CHF under the dominant model (p = 0.013, OR = 1.537, 95% CI = 1.10–2.16), after adjustment for age, sex, and traditional cardiovascular risk factors. No difference in genotype distribution and allele frequency for the rs452159 according to the functional New York Heart Association class was found. Furthermore, the values of left ventricular ejection fraction, left-ventricle end-diastolic diameter or left-ventricle end-systolic diameter did not differ significantly among the different rs452159 genotype CHF patients. Although further studies with larger cohorts and other ethnicities are required to validate the conclusions, the findings of this study potentially provide novel insight into the pathogenesis of CHF.
PMCID: PMC4200810  PMID: 25170811
ADA; adenosine; chronic heart failure; SNP; rs452159

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