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1.  Disorganized vascular structures in sporadic venous malformations: a possible correlation with balancing effect between Tie2 and TGF-β 
Scientific Reports  2014;4:5457.
Venous malformations (VMs) are among the most common slow-flow vascular malformations characterized by irregular venous channels, luminal thrombi, and phleboliths. To systematically manifest the disorganized vascular structures in sporadic VMs, we initially evaluated histopathological characteristics, perivascular cell coverage, adhesion molecules expression and vascular ultrastructures. Then, the expression of Tie2 and TGF-β in VMs was detected. Meanwhile, the in vitro studies were performed for mechanism investigation. Our data showed that the perivascular α-SMA+ cell coverage and expression of adhesion molecules in VMs were significantly decreased compared with those in the normal skin tissues. We also found that the expression and phosphorylation levels of Tie2 were upregulated, whereas TGF-β was downregulated in VMs, and they were negatively correlated. Moreover, the in vitro results also revealed a possible balancing effect between Tie2 and TGF-β, as demonstrated by the findings that Ang-1 (agonist of Tie2) treatment significantly downregulated TGF-β expression, and treatment with recombinant TGF-β could also suppress Tie2 expression and phosphorylation. This study provided strong evidence supporting the disorganized vascular structures and dysregulation of related molecules in sporadic VMs, and demonstrated a possible balancing effect between Tie2 and TGF-β, which might help to develop novel therapeutics for vascular disorganization-related disorders.
PMCID: PMC4071312  PMID: 24966004
2.  The NMR Structure of an Internal Loop from 23S Ribosomal RNA Differs from its Structure in Crystals of 50S Ribosomal Subunits 
Biochemistry  2006;45(39):11776-11789.
Internal loops play an important role in structure and folding of RNA and in RNA recognition by other molecules such as proteins and ligands. An understanding of internal loops with propensities to form a particular structure will help predict RNA structure, recognition, and function. The structures of internal loops 5'1009CUAAG10133'3'1168GAAGC11645' and 5'998CUAAG10023'3'1157GAAGC11535' from helix 40 of the large subunit rRNA in Deinococcus radiodurans and Escherichia coli, respectively, are phylogenetically conserved, suggesting functional relevance. The energetics and NMR solution structure of the loop were determined in the duplex, 5'1GGCUAAGAC93'3'18CCGAAGCUG105' The internal loop forms a different structure in solution than in the crystal structures of the ribosomal subunits. In particular, the crystal structures have a bulged out adenine at the equivalent of position A15 and a reverse Hoogsteen UA pair (trans Watson-Crick/Hoogsteen UA) at the equivalent of U4 and A14, whereas the solution structure has a single hydrogen bond UA pair (cis Watson-Crick/sugar edge A15U4) between U4 and A15 and a sheared AA pair (trans Hoogsteen/sugar edge A14A5) between A5 and A14. There is cross-strand stacking between A6 and A14 (A6/A14/A15 stacking pattern) in the NMR structure. All three structures have a sheared GA pair (trans Hoogsteen/sugar edge A6G13) at the equivalent of A6 and G13. The internal loop has contacts with ribosomal protein L20 and other parts of the RNA in the crystal structures. These contacts presumably provide the free energy to rearrange the base pairing in the loop. Evidently, molecular recognition of this internal loop involves induced fit binding, which could confer several advantages. The predicted thermodynamic stability of the loop agrees with the experimental value, even though the thermodynamic model assumes a Watson–Crick UA pair.
PMCID: PMC4070884  PMID: 17002278
3.  Indoleamides are active against drug-resistant Mycobacterium tuberculosis 
Nature communications  2013;4:2907.
Responsible for nearly two million deaths each year, the infectious disease tuberculosis remains a serious global health challenge. The emergence of multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis confounds control efforts, and new drugs with novel molecular targets are desperately needed. Here we describe lead compounds, the indoleamides, with potent activity against both drug-susceptible and drug-resistant strains of M. tuberculosis by targeting the mycolic acid transporter MmpL3. We identify a single mutation in mmpL3 which confers high resistance to the indoleamide class while remaining susceptible to currently used first- and second-line tuberculosis drugs, indicating a lack of cross-resistance. Importantly, an indoleamide derivative exhibits dose-dependent anti-mycobacterial activity when orally administered to M. tuberculosis-infected mice. The bioavailability of the indoleamides, combined with their ability to kill tubercle bacilli, indicates great potential for translational developments of this structure class for the treatment of drug-resistant tuberculosis.
PMCID: PMC3909880  PMID: 24352433
4.  Do bisphosphonates affect bone healing? A meta-analysis of randomized controlled trials 
Whether bisphosphonates affect indirect bone healing is still unclear.
We carried out a comprehensive search strategy. Only randomized controlled trials were included. Two reviewers independently assessed methodological qualities and extracted outcome data. Analysis was performed with RevMan 5.2.
Eight eligible randomized controlled trials with 2,508 patients were included. Meta-analysis results showed that no statistically significant differences were founded in indirect bone healing in short time (within 3 months) (relative risk (RR) 1.40, relative the control group; 95% CI 0.36 to 5.49) and in long-term (more than 12 months) postoperation (RR 1.0; 95% CI 0.98 to 1.02) between bisphosphonates infusion groups and control groups. There were no statistically significant differences of indirect bone healing between early and delay bisphosphonates administration groups. Bisphosphonates infusion after lumbar infusion surgery could promote bone healing and shorten fusion time in 6 months postoperation (RR 1.35; 95% CI 1.11 to 1.66).
There was no clinically detectable delay to fracture healing via external callus formation following bisphosphonates treatment. Considering the benefit aspects of bisphosphonates for osteoporosis treatment, we recommend bisphosphonates infusion after fracture fixation surgery and lumbar fusion surgery.
PMCID: PMC4058448  PMID: 24902588
Bisphosphonates; Indirect bone healing; Lumbar fusion; Randomized controlled trials; Meta-analysis
5.  Linear mixed-effects modeling approach to FMRI group analysis 
NeuroImage  2013;73:176-190.
Conventional group analysis is usually performed with Student-type t-test, regression, or standard AN(C)OVA in which the variance–covariance matrix is presumed to have a simple structure. Some correction approaches are adopted when assumptions about the covariance structure is violated. However, as experiments are designed with different degrees of sophistication, these traditional methods can become cumbersome, or even be unable to handle the situation at hand. For example, most current FMRI software packages have difficulty analyzing the following scenarios at group level: (1) taking within-subject variability into account when there are effect estimates from multiple runs or sessions; (2) continuous explanatory variables (covariates) modeling in the presence of a within-subject (repeated measures) factor, multiple subject-grouping (between-subjects) factors, or the mixture of both; (3) subject-specific adjustments in covariate modeling; (4) group analysis with estimation of hemodynamic response (HDR) function by multiple basis functions; (5) various cases of missing data in longitudinal studies; and (6) group studies involving family members or twins.
Here we present a linear mixed-effects modeling (LME) methodology that extends the conventional group analysis approach to analyze many complicated cases, including the six prototypes delineated above, whose analyses would be otherwise either difficult or unfeasible under traditional frameworks such as AN(C)OVA and general linear model (GLM). In addition, the strength of the LME framework lies in its flexibility to model and estimate the variance–covariance structures for both random effects and residuals. The intraclass correlation (ICC) values can be easily obtained with an LME model with crossed random effects, even at the presence of confounding fixed effects. The simulations of one prototypical scenario indicate that the LME modeling keeps a balance between the control for false positives and the sensitivity for activation detection. The importance of hypothesis formulation is also illustrated in the simulations. Comparisons with alternative group analysis approaches and the limitations of LME are discussed in details.
PMCID: PMC3638840  PMID: 23376789
FMRI group analysis; GLM; AN(C)OVA; LME; ICC; AFNI; R
6.  Assessing the Impact of the NIH CTSA Program on Institutionally Sponsored Clinical Trials 
To assess the impact of the NIH CTSA program on patient enrollment in clinical trials sponsored/collaborated by CTSA consortium institutions.
Material and Methods
Using publicly available clinical trial data at, we identify positive trend changes in the number of patients enrolled in clinical trials performed at CTSA consortium institutions over the years before and after their respective CTSA award dates. CTSA consortium institutions were matched with similar non-CTSA institutions.
As compared to matched non-CTSA institutions CTSA consortium sites noted an increase in patient enrollment after the CTSA awards. In particular, we detected a change-point, where a new enrollment trend emerged, 338 days after the CTSA award. No such trend was noted over the same period in the non CTSA institutions.
Our analysis provides evidence that the NIH CTSA funding program made a positive impact on patient enrollment.
PMCID: PMC3684971  PMID: 23751024
CTSA; Clinical and Translational Science; Clinical trials
7.  Stop violence against medical workers in China 
Journal of Thoracic Disease  2014;6(6):E141-E145.
The incidence of patient-doctor disputes are alarmingly increasing in China, this article reviews the current status and causes of violence against medical workers in China, six strategies to tackle the daily worrying problems have been proposed and hopefully could improve the medical working environment in China.
PMCID: PMC4073378  PMID: 24977026
Violent attacks; threats; assaults; hospitals; medical workers in China
8.  Consecutive GA Pairs Stabilize Medium Size RNA Internal Loops† 
Biochemistry  2006;45(12):4025-4043.
Internal loops in RNA are important for folding and function. Consecutive non-canonical pairs can form in internal loops having at least two nucleotides on each side. Thermodynamic and structural insights for such internal loops should improve approximations for their stabilities and predictions of secondary and three-dimensional structures. Most natural internal loops are purine rich. A series of oligoribonucleotides that form purine rich internal loops of 5 – 10 nucleotides, including kink-turn loops, were studied by UV melting, exchangeable proton and phosphorus NMR. Three consecutive GA pairs with the motif of 5′YGGA¯3′RAAG or GGA¯R3′AAGY5′ (i.e. 5′GGA¯3′3′AAG5′ closed on at least one side with a CG, UA, or UG pair with Y representing C or U and R representing A or G) stabilize internal loops having six to ten nucleotides. Certain motifs with two consecutive GA pairs are also stabilizing. In internal loops with three or more nucleotides on each side, the motif 5′UG¯3′GA has stability similar to 5′CG¯3′GA. A revised model for predicting stabilities of internal loops with 6 – 10 nucleotides is derived by multiple linear regression. Loops with 2 × 3 nucleotides are predicted well by a previous thermodynamic model.
PMCID: PMC4032320  PMID: 16548530
9.  Tert-Butylhydroquinone Alleviates Early Brain Injury and Cognitive Dysfunction after Experimental Subarachnoid Hemorrhage: Role of Keap1/Nrf2/ARE Pathway 
PLoS ONE  2014;9(5):e97685.
Tert-butylhydroquinone (tBHQ), an Nrf2 activator, has demonstrated neuroprotection against brain trauma and ischemic stroke in vivo. However, little work has been done with respect to its effect on early brain injury (EBI) after subarachnoid hemorrhage (SAH). At the same time, as an oral medication, it may have extensive clinical applications for the treatment of SAH-induced cognitive dysfunction. This study was undertaken to evaluate the influence of tBHQ on EBI, secondary deficits of learning and memory, and the Keap1/Nrf2/ARE pathway in a rat SAH model. SD rats were divided into four groups: (1) Control group (n = 40); (2) SAH group (n = 40); (3) SAH+vehicle group (n = 40); and (4) SAH+tBHQ group (n = 40). All SAH animals were subjected to injection of autologous blood into the prechiasmatic cistern once in 20 s. In SAH+tBHQ group, tBHQ was administered via oral gavage at a dose of 12.5 mg/kg at 2 h, 12 h, 24 h, and 36 h after SAH. In the first set of experiments, brain samples were extracted and evaluated 48 h after SAH. In the second set of experiments, changes in cognition and memory were investigated in a Morris water maze. Results shows that administration of tBHQ after SAH significantly ameliorated EBI-related problems, such as brain edema, blood-brain barrier (BBB) impairment, clinical behavior deficits, cortical apoptosis, and neurodegeneration. Learning deficits induced by SAH was markedly alleviated after tBHQ therapy. Treatment with tBHQ markedly up-regulated the expression of Keap1, Nrf2, HO-1, NQO1, and GSTα1 after SAH. In conclusion, the administration of tBHQ abated the development of EBI and cognitive dysfunction in this SAH model. Its action was probably mediated by activation of the Keap1/Nrf2/ARE pathway.
PMCID: PMC4029824  PMID: 24848277
10.  Efficacy of ilaprazole in the treatment of duodenal ulcers: A meta-analysis 
AIM: To compare the efficacy and tolerance of ilaprazole compared with other proton pump inhibitors (PPIs) in the treatment of duodenal ulcer.
METHODS: An electronic database search of Medline, Embase, the Cochrane controlled trials register, Web of Science, PubMed, and the Chinese Biomedical Literature Database (updated to July 2013), and manual searches were conducted. A meta-analysis of randomized controlled trials comparing the efficacy and tolerance of ilaprazole and other PPIs in the treatment of duodenal ulcers was performed.
RESULTS: Five articles involving 1481 patients were included. The meta-analysis showed no difference in the 4-wk healing rate between ilaprazole and other PPIs [89.7% vs 87.0%; relative risk (RR) = 1.02; 95%CI: 0.98-1.06; Z = 1.00; P = 0.32]. The results did not change in the sensitivity analyses. The meta-analysis indicated that the adverse effect rate in the ilaprazole group was lower than that in the control group, but the difference was not significant (9.7% vs 13.0%; RR = 0.81; 95%CI: 0.60-1.07; Z = 1.47; P = 0.14).
CONCLUSION: Ilaprazole is a highly effective and safe PPI in the treatment of duodenal ulcers. Ilaprazole can be recommended as a therapy for acid-related disorders, especially in Asian populations.
PMCID: PMC4009550  PMID: 24803828
Ilaprazole; Proton pump inhibitor; Duodenal ulcer; Meta-analysis
11.  Synergistic Effect of MiR-146a Mimic and Cetuximab on Hepatocellular Carcinoma Cells 
BioMed Research International  2014;2014:384121.
Previously, we found that the expression of microRNA-146a (miR-146a) was downregulated in hepatocellular carcinoma (HCC) formalin-fixed paraffin-embedded (FFPE) tissues compared to the adjacent noncancerous hepatic tissues. In the current study, we have explored the in vitro effect of miR-146a on the malignant phenotypes of HCC cells. MiR-146a mimic could suppress cell growth and increase cellular apoptosis in HCC cell lines HepG2, HepB3, and SNU449, as assessed by spectrophotometry, fluorimetry, and fluorescence microscopy, respectively. Furthermore, western blot showed that miR-146a mimic downregulated EGFR, ERK1/2, and stat5 signalings. These effects were less potent compared to that of a siRNA targeting EGFR, a known target gene of miR-146a. Moreover, miR-146a mimic could enhance the cell growth inhibition and apoptosis induction impact of various EGFR targeting agents. The most potent combination was miR-146a mimic with cetuximab, presenting a synergistic effect. In conclusion, miR-146a plays a vital role in the cell growth and apoptosis of HCC cells and inducing miR-146a level might be a critical targeted molecular therapy strategy for HCC.
PMCID: PMC4033429  PMID: 24895573
12.  SPDEF Functions as a Colorectal Tumor Suppressor by Inhibiting β-Catenin Activity 
Gastroenterology  2013;144(5):1012-1023.e6.
Expression of the SAM pointed domain containing ETS transcription factor (SPDEF or prostate-derived ETS factor) is regulated by Atoh1 and is required for the differentiation of goblet and Paneth cells. SPDEF has been reported to suppress the development of breast, prostate, and colon tumors. We analyzed levels of SPDEF in colorectal tumor samples from patients and its tumor-suppressive functions in mouse models of colorectal cancer (CRC).
We analyzed levels of SPDEF messenger RNA and protein in more than 500 human CRC samples and more than 80 nontumor controls. Spdef−/− and wild-type mice (controls) were either bred with ApcMin/+ mice, or given azoxymethane (AOM) and dextran sodium sulfate (DSS), or 1,2-dimethylhydrazine and DSS, to induce colorectal tumors. Expression of Spdef also was induced transiently by administration of tetracycline to Spdefdox-intestine mice with established tumors, induced by the combination of AOM and DSS or by breeding with ApcMin/+ mice. Colon tissues were collected and analyzed for tumor number, size, grade, and for cell proliferation and apoptosis. We also analyzed the effects of SPDEF expression in HCT116 and SW480 human CRC cells.
In colorectal tumors from patients, loss of SPDEF was observed in approximately 85% of tumors and correlated with progression from normal tissue, to adenoma, to adenocarcinoma. Spdef−/−; ApcMin/+ mice developed approximately 3-fold more colon tumors than Spdef+/+; ApcMin/+ mice. Likewise, Spdef−/− mice developed approximately 3-fold more colon tumors than Spdef+/+ mice after administration of AOM and DSS. After administration of 1,2-dimethylhydrazine and DSS, invasive carcinomas were observed exclusively in Spdef−/− mice. Conversely, expression of SPDEF was sufficient to promote cell-cycle exit in cells of established adenomas from Spdefdox-intestine; ApcMin/+ mice and in Spdefdox-intestine mice after administration of AOM + DSS. SPDEF inhibited the expression of β-catenin–target genes in mouse colon tumors, and interacted with β-catenin to block its transcriptional activity in CRC cell lines, resulting in lower levels of cyclin D1 and c-MYC.
SPDEF is a colon tumor suppressor and a candidate therapeutic target for colon adenomas and adenocarcinoma.
PMCID: PMC3738069  PMID: 23376423
Notch Signaling; Differentiation Factor; Colon Cancer; Colitis-Associated Cancer
13.  Loss of p53 in Stromal Fibroblasts Promotes Epithelial Cell Invasion through Redox-Mediated ICAM1 Signal 
Tumor microenvironment plays a major role in cancer development. Understanding how the stroma affects epithelial transformation will provide a basis for new preventive strategies. Recent evidences suggest that oxidative stress in stroma may play a role in cancer progression and loss of p53 function in the stromal cells were associated with poor prognosis and high tumor recurrence. However, the underlying mechanisms remain poorly understood. Here, we investigated the role of p53 loss in fibroblasts on epithelial transformation and the mechanistic involvement of reactive species. Using 3D-organotypic culture and other assays, we report that the stroma containing p53-deficient fibroblasts could transform the non-tumorigenic epithelial cells of oral and ovarian tissues origins to become invasive through reactive nitrogen species (RNS)-mediated release of cytokine ICAM1. The p53-deficient fibroblasts have increased RNS production and accumulation of oxidative DNA damage products associated with specific up-regulation of endothelial nitric oxide synthase (eNOS). Suppression of RNS production by siRNA of eNOS or antioxidant NAC reduced ICAM1 expression and prevented the stroma-mediated epithelial invasion. Our study uncovers the novel mechanism by which redox alteration associated with loss of p53 in stromal fibroblasts function as a key inducer of epithelial transformation and invasion via RNS-mediated-ICAM1 signaling. Thus, modulation of the redox signaling in microenvironment may serve as a new approach to prevent epithelial transformation and suppress cancer invasion.
PMCID: PMC3622735  PMID: 23376231
fibroblast; ICAM1; Invasion; RNS; p53; eNOS
14.  The Role of BRCA Status on the Prognosis of Patients with Epithelial Ovarian Cancer: A Systematic Review of the Literature with a Meta-Analysis 
PLoS ONE  2014;9(5):e95285.
The role of BRCA dysfunction on the prognosis of patients with epithelial ovarian cancer (EOCs) remains controversial. This systematic review tried to assess the role of BRCA dysfunction, including BRCA1/2 germline, somatic mutations, low BRCA1 protein/mRNA expression or BRCA1 promoter methylation, as prognostic factor in EOCs.
Studies were selected for analysis if they provided an independent assessment of BRCA status and prognosis in EOC. To make it possible to aggregate survival results of the published studies, their methodology was assessed using a modified quality scale.
Of 35 evaluable studies, 23 identified BRCA dysfucntion status as a favourable prognostic factor. No significant differences were detected in the global score of quality assessment. The aggregated hazard ratio (HR) of overall survival (OS) of 34 evaluable studies suggested that BRCA dysfunction status had a favourable impact on OS (HR = 0.69, 95% CI 0.61–0.79), and when these studies were categorised into BRCA1/2 mutation and low protein/mRNA expression of BRCA1 subgroups, all of them demonstrated positive results (HR = 0.67, 95% CI: 0.57–0.78; HR = 0.62, 95% CI: 0.51–0.75; and HR = 0.51, 95% CI: 0.33–0.78, respectively), except for the subgroup of BRCA1 promoter methylation (HR = 1.59, 95% CI: 0.72–3.50). The meta-analysis of progression-free survival (PFS), which included 18 evaluable studies, demonstrated that BRCA dysfunction status was associated with a longer PFS in EOC (HR = 0.69, 95% CI: 0.63–0.76).
Patients with BRCA dysfunction status tend to have a better outcome, but further prospective clinical studies comparing the different BRCA statuses in EOC is urgently needed to specifically define the most effective treatment for the separate patient groups.
PMCID: PMC4006804  PMID: 24788697
15.  Disposable circumcision suture device: clinical effect and patient satisfaction 
Asian Journal of Andrology  2014;16(3):453-456.
In our experience patients undergoing circumcision are mostly concerned about pain and penile appearances. We conducted a prospective randomized trial to assess the benefits of a new disposable circumcision suture device (DCSD). A total of 942 patients were equally divided into three groups (conventional circumcision, Shang ring and disposable suture device group). Patients in the DCSD group were anesthetized with compound 5% lidocaine cream, the others with a 2% lidocaine penile block. Operation time, intra-operative blood loss, incision healing time, intra-operative and post-operative pain, the penile appearance and overall satisfaction degree were measured. Operation time and intra-operative blood loss were significantly lower in the Shang ring and suture device groups compared to the conventional group (P < 0.001). Intra-operative pain was less in the suture device group compared with the other two groups (P < 0.001); whereas post-operative pain was higher in the conventional group compared to the other two groups (P < 0.001). Patients in the suture device (80.57%) and Shang ring (73.57%) groups were more satisfied with penile appearances compared with the conventional circumcision group (20.06%, P < 0.05). Patients in suture device group also healed markedly faster than the conventional group (P < 0.01). The overall satisfaction rate was better in the suture device group (78.66%) compared with the conventional (47.13%) and Shang ring (50.00%) groups (P < 0.05). The combination of DCSD and lidocaine cream resulted in shorter operation and incision healing times, reduced intra-operative and post-operative pain and improved patient satisfaction with the cosmetic appearances.
PMCID: PMC4023377  PMID: 24759586
circumcision; disposable circumcision suture device; patient satisfaction; penis appearance; pre-operative and postoperative pain; Shang ring
16.  Primary diffuse large B-cell lymphoma of the chest wall: a case report 
Reports of primary diffuse large B-cell lymphomas of the chest wall are extremely rare in the literature. We report the case of a 62-year-old Chinese woman presenting with left-sided chest pain. A computed tomography scan showed a solid, round mass in the left anterior chest wall, involving the second and third costal cartilages. Complete resection and reconstruction of the chest wall was performed. The histological and immunohistochemical features of the mass were used to diagnose a primary diffuse large B-cell lymphoma.
PMCID: PMC3999458  PMID: 24755347
Chest wall; Diffuse large B-cell lymphoma
17.  The Effect of Urban Basic Medical Insurance on Health Service Utilisation in Shaanxi Province, China: A Comparison of Two Schemes 
PLoS ONE  2014;9(4):e94909.
Urban population in China is mainly covered by two medical insurance schemes: the Urban Employee Basic Medical Insurance (UEBMI) for urban employees in formal sector and the Urban Resident Basic Medical Insurance (URBMI) for the left urban residents, mainly the unemployed, the elderly and children. This paper studies the effects of UEBMI and URBMI on health services utilisation in Shaanxi Province, Western China.
Cross-sectional data from the 4th National Health Services Survey - Shaanxi Province was studied. The propensity score matching and the coarsened exact matching methods have been used to estimate the average medical insurance effect on the insured.
Compared to the uninsured, robust results suggest that UEBMI had significantly increased the outpatient health services utilisation in the last two weeks (p<0.10), whilst the significant effect on hospitalisation was evident in the CEM method (p<0.10). The effect of URBMI was limited in that although being insured was associated with higher health services utilisation, compared with the uninsured, none of the improvement was statistically significant (p>0.10). It was also found that compared with the uninsured, basic medical insurance enrollees were more likely to purchase inpatient treatments in lower levels of hospitals, consistent with the incentive of the benefit package design.
Basic Medical insurance schemes have shown a positive but limited effect on increasing health services utilisation in Shaanxi Province. The benefit package design of higher reimbursement rates for lower level hospitals has induced the insured to use medical services in lower level hospitals for inpatient services.
PMCID: PMC3989255  PMID: 24740282
18.  Training-associated changes and stability of attention bias in youth: Implications for Attention Bias Modification Treatment for pediatric anxiety 
Attention Bias Modification Treatment (ABMT), an emerging treatment for anxiety disorders, is thought to modify underlying, stable patterns of attention. Therefore, ABMT research should take into account the impact of attention bias stability on attention training response, especially in pediatric populations. ABMT research typically relies on the dot-probe task, where individuals detect a probe following an emotional-neutral stimulus pair. The current research presents two dot-probe experiments relevant to ABMT and attention-bias stability. In Experiment 1, anxious youth receiving 8-weeks of cognitive-behavioral therapy (CBT) were randomly assigned to ABMT that trains attention towards happy faces (n=18) or placebo (n=18). Two additional comparison groups, anxious youth receiving only CBT (n=17) and healthy comparison youth (n=16), were studied. Active attention training towards happy faces did not augment clinician-rated response to CBT; however, individuals receiving training exhibited reductions on self-report measures of anxiety earlier than individuals receiving CBT only. In Experiment 2, healthy youth (n=12) completed a dot-probe task twice while undergoing functional magnetic resonance imaging. Intra class-correlation demonstrated stability of neural activation in response to attention bias in the ventrolateral prefrontal cortex and amygdala. Together, these two studies investigate the ways in which attention-bias stability may impact future work on ABMT.
PMCID: PMC3606014  PMID: 23200784
dot-probe; attention training; test-retest reliability; fMRI
19.  HMGB1-Promoted and TLR2/4-Dependent NK Cell Maturation and Activation Take Part in Rotavirus-Induced Murine Biliary Atresia 
PLoS Pathogens  2014;10(3):e1004011.
Recent studies show that NK cells play important roles in murine biliary atresia (BA), and a temporary immunological gap exists in this disease. In this study, we found high-mobility group box-1 (HMGB1) and TLRs were overexpressed in human and rotavirus-induced murine BA. The overexpressed HMGB1 released from the nuclei of rotavirus-infected cholangiocytes, as well as macrophages, activated hepatic NK cells via HMGB1-TLRs-MAPK signaling pathways. Immature NK cells had low cytotoxicity on rotavirus-injured cholangiocytes due to low expression of TLRs, which caused persistent rotavirus infection in bile ducts. HMGB1 up-regulated the levels of TLRs of NK cells and promoted NK cell activation in an age-dependent fashion. As NK cells gained increasing activation as mice aged, they gained increasing cytotoxicity on rotavirus-infected cholangiocytes, which finally caused BA. Adult NK cells eliminated rotavirus-infected cholangiocytes shortly after infection, which prevented persistent rotavirus infection in bile ducts. Moreover, adoptive transfer of mature NK cells prior to rotavirus infection decreased the incidence of BA in newborn mice. Thus, the dysfunction of newborn NK cells may, in part, participate in the immunological gap in the development of rotavirus induced murine BA.
Author Summary
Biliary atresia (BA) is the most common precipitating factor for liver transplantation in infants. BA is caused by the obstruction of hepatic bile ducts, leading to progressive obstructive jaundice and liver fibrosis. A well-recognized theory is that rotavirus injures biliary epithelia in a mouse model of BA, followed by attack of immunocytes, such as NK cells. We performed this research to investigate whether maturation and activation of NK cells take part in the development of BA. We identified that rotavirus induced HMGB1 release from injured bile ducts. HMGB1 induced NK cell activation in an age-dependent fashion via HMGB1-TLRs-MAPK signaling pathways. Newborn NK cells were unable to eliminate rotavirus-infected cholangiocytes, which caused persistent biliary infection; maturated NK cells were activated gradually and caused persistent biliary injury, which finally led to BA. We identify HMGB1 as an important pro-inflammatory initiator and a critical inducer for maturation of NK cells in the development of BA. HMGB1-induced activation of NK cells may, in part, plays crucial roles in the development of murine BA. Novel therapies targeting HMGB1 or TLRs in patients with BA may be applied in the future to decrease the activity of NK cells in order to inhibit the progression of BA.
PMCID: PMC3961347  PMID: 24651485
20.  Adipose transplant for inborn errors of branched chain amino acid metabolism in mice 
Molecular genetics and metabolism  2013;109(4):345-353.
Liver transplantation appears to be quite beneficial for treatment of Maple Syrup Urine Disease (MSUD, an inherited disorder of branched chain amino acid metabolism); however, there is a limited availability of donor livers worldwide and the first year costs of liver transplants are quite high. Recent studies have suggested that intact adipose tissue, already widely used in reconstructive surgery, may have an underappreciated high capacity for branched chain amino acid (BCAA) metabolism. Here we examined the potential for adipose tissue transplant to lower circulating BCAAs in two models of defective BCAA metabolism, BCATm and PP2Cm [branched chain keto acid dehydrogenase complex (BCKDC) phosphatase] knockout (KO) mice. After 1–2 g fat transplant, BCATm and PP2Cm KO mice gained or maintained body weight 3 weeks after surgery and consumed similar or more food/BCAAs the week before phlebotomy. Transplant of fat into the abdominal cavity led to a sterile inflammatory response and nonviable transplanted tissue. However when 1–2 g of fat was transplanted subcutaneously into the back, either as small (0.1–0.3g) or finely minced pieces introduced with a 18 ga. needle, plasma BCAAs decreased compared to Sham operated mice. In two studies on BCATm KO mice and one study on PP2Cm KO mice, fat transplant led to 52–81% reductions in plasma BCAAs compared to baseline plasma BCAA concentrations of untreated WT type siblings. In PP2Cm KO mice, individual BCAAs in plasma were also significantly reduced by fat transplant, as were the alloisoleucine/Phe ratios. Therefore, subcutaneous fat transplantation may have merit as an adjunct to dietary treatment of MSUD. Additional studies are needed to further refine this approach.
PMCID: PMC3955948  PMID: 23800641
Alloisoleucine; Adipose tissue; Branched chain amino acids; Maple Syrup Urine Disease; Transplantation; Mice
21.  Cell-surface processing of extracellular human immunodeficiency virus type 1 Vpr by proprotein convertases 
Virology  2007;372(2):384-397.
Increasing evidence suggests that extracellular Vpr could contribute to HIV pathogenesis through its effect on bystander cells. Soluble forms of Vpr have been detected in the sera and cerebrospinal fluids of HIV-1-infected patients, and in vitro studies have implicated extracellular Vpr as an effector of cellular responses, including G2 arrest, apoptosis and induction of cytokines and chemokines production, presumably through its ability to transduce into multiple cell types. However, the mechanism underlying Vpr release from HIV-1-producing cells remains undefined and the biological modifications that the extracellular protein may undergo are largely unknown. We provide evidence indicating that soluble forms of Vpr are present in the extracellular medium of HIV-1-producing cells. Release of Vpr in the extracellular medium did not originate from decaying or disrupted HIV-1 virions that package Vpr but rather appeared associated with HIV-1-mediated cytopathicity. Interestingly, Vpr was found to undergo proteolytic processing at a very well conserved proprotein convertase (PC) cleavage site, R85QRR88↓, located within the functionally important C-terminal arginine-rich domain of the protein. Vpr processing occurred extracellularly upon close contact to cells and most likely involved a cell surface-associated PC. Consistently, PC inhibitors suppressed Vpr processing, while expression of extracellular matrix-associated PC5 and PACE4 enhanced Vpr cleavage. PC-mediated processing of extracellular Vpr led to the production of a truncated Vpr product that was defective for the induction of cell cycle arrest and apoptosis when expressed in human cells. Collectively, these results suggest that cell surface processing of extracellular Vpr by PCs might regulate the levels of active soluble Vpr.
PMCID: PMC3955186  PMID: 18061232 CAMSID: cams4183
HIV-1; Vpr; Extracellular processing; Proprotein convertase; Protease; Extracellular matrix
22.  786-0 Renal cancer cell line-derived exosomes promote 786-0 cell migration and invasion in vitro 
Oncology Letters  2014;7(5):1576-1580.
Emerging evidence indicates that cancer-derived exosomes contribute to angiogenesis, tumor immunology and invasion. However, whether cancer cell-derived exosomes regulate the migration and invasion of the cancer cell itself, and the underlying mechanisms are not well understood. In the present study, exosomes derived from the 786-0 human renal cancer cell line were isolated, purified and 100 μg/ml were co-cultured with 786-0 cells for 24 h. The 786-0 cells were harvested for a cell invasion and migration assay. The expression of chemokine receptor type 4 (CXCR4) and matrix metalloproteinase-9 (MMP-9) in the 786-0 cells was examined by western blot analysis and revealed that the migration and invasion capabilities of the 786-0 cells were increased, however, the cell adhesion abilities were decreased as a result of the 24-h treatment with 786-0-derived exosomes. Furthermore, the expression levels of CXCR4 and MMP-9 in the 786-0 cells were increased. In conclusion, the 786-0 renal cancer cell line-derived exosomes increased migration and invasion, however, they decreased the adhesion ability of the 786-0 cells. The exosomes may have increased the CXCR4 and MMP-9 expression levels in the 786-0 cells. These findings indicated that renal tumor-derived exosomes may contribute to renal cancer development and progression.
PMCID: PMC3997692  PMID: 24765179
renal cancer; cancer cell derived-exosomes; invasion; migration; chemokine receptor type 4
23.  The effects of China’s urban basic medical insurance schemes on the equity of health service utilisation: evidence from Shaanxi Province 
In order to alleviate the problem of “Kan Bing Nan, Kan Bing Gui” (medical treatment is difficult to access and expensive) and improve the equity of health service utilisation for urban residents in China, the Urban Employee Basic Medical Insurance scheme (UEBMI) and Urban Resident Basic Medical Insurance scheme (URBMI) were established in 1999 and 2007, respectively. This study aims to analyse the effects of UEBMI and URBMI on the equity of outpatient and inpatient utilisation in Shaanxi Province, China.
Using the data from the fourth National Health Services Survey in Shaanxi Province, the method of Propensity Score Matching was employed to generate comparable samples between the insured and uninsured residents, through a one-to-one match algorithm. Next, based on the matched data, the method of decomposition of the concentration index was employed to compare the horizontal inequity indexes of health service utilisation between the UEBMI/URBMI insured and the matched uninsured residents.
For the UEBMI insured and matched uninsured residents, the horizontal inequity indexes of outpatient visits are 0.1256 and -0.0511 respectively, and the horizontal inequity indexes of inpatient visits are 0.1222 and 0.2746 respectively. Meanwhile, the horizontal inequity indexes of outpatient visits are -0.1593 and 0.0967 for the URBMI insured and matched uninsured residents, and the horizontal inequity indexes of inpatient visits are 0.1931 and 0.3199 respectively.
The implementation of UEBMI increased the pro-rich inequity of outpatient utilisation (rich people utilise outpatient facilities more than the poor people) and the implementation of URBMI increased the pro-poor inequity of outpatient utilisation. Both of these two health insurance schemes reduced the pro-rich inequity of inpatient utilisation.
PMCID: PMC4016277  PMID: 24606592
24.  Overexpression of DcR3 and Its Significance on Tumor Cell Differentiation and Proliferation in Glioma 
The Scientific World Journal  2014;2014:605236.
Background. Overexpression of decoy receptor 3 (DcR3) have been reported in various classes of malignancies. However, its expression and clinicopathological contribution in gliomas has not been fully elucidated. Objective. To explore the expression and clinical significance of DcR3 protein in relation to tumor cell differentiation and proliferation in glioma cell lines and tissues. Methods. One hundred and twenty-five samples of glioma patients and 18 cases of normal brain tissues were recruited. The expression of DcR3 protein was detected using immunohistochemistry. Tumor differentiation was assessed by histologic characters and the status of glial fibrillary acidic protein (GFAP). Tumor cell labeling indexes (LIs) of Ki-67 and PCNA were also obtained. The relationship between the DcR3 level and clinicopathological features was investigated, including tumor differentiation, LIs, and survival. Meanwhile, the expression of DcR3 protein was also measured in the supernatants of 8 glioma cell lines and glioma cells freshly prepared from 8 human glioblastoma specimens by using western blot. Results. The level of DcR3 protein in gliomas was significantly higher than that in normal brain tissues (P < 0.01). DcR3 expression showed positive correlations with tumor pathological grade (r = 0.621, P < 0.01) and negative with GFAP expression (r = −0.489, P < 0.01). Furthermore, there were positive correlations between DcR3 expression and Ki-67, PCNA LIs (r = 0.529, P < 0.01; r = 0.556, P < 0.01). The survival in the DcR3 negative group was 50 ± 1.79 months, longer than that of the DcR3 positive group (48.36 ± 2.90), however, without significance (P = 0.149). Different levels of DcR3 could also be detected in the culturing supernatants of all the 8 glioma cell lines and glioma cells freshly obtained from 8 human glioblastoma specimens. Conclusions. The overexpression of DcR3 might play a crucial role in the tumorigenesis, differentiation, and proliferation of glioma.
PMCID: PMC3972858  PMID: 24741354
25.  Expression and clinicopathological significance of miR-146a in hepatocellular carcinoma tissues 
Aberrant expression of microRNA-146a (miR-146a) has been found in several classes of cancers. However, its expression and clinicopathological contribution in hepatocellular carcinoma (HCC) has not been fully elucidated.
To explore the clinicopathological significance of the miR-146a level in HCC formalin-fixed paraffin-embedded (FFPE) tissue.
Eighty-five HCC samples and their para-cancerous normal liver tissues were collected. Total mRNA including miRNA was extracted, and miR-146a expression was determined using real-time RT-PCR. Furthermore, the correlation between the miR-146a expression and clinicopathological parameters was investigated.
MicroRNA-146a expression in HCC tissues was lower compared with that in adjacent non-cancerous hepatic tissues. MicroRNA-146a expression was also related to clinical TNM stage, metastasis, portal vein tumor embolus, and number of tumor nodes.
Down-regulation of miR-146a is related to HCC carcinogenesis and deterioration of HCC. MicroRNA-146a may act as a suppressor miRNA of HCC, and it is therefore a potential prognostic biomarker for HCC patients.
PMCID: PMC3916713  PMID: 24172202
Hepatocellular carcinoma; metastasis; miR-146a; oncogenes; paraffin-embedded tissues; pathology; RT-qPCR; tumor biology

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