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1.  Human Beta-Defensin-1 Suppresses Tumor Migration and Invasion and Is an Independent Predictor for Survival of Oral Squamous Cell Carcinoma Patients 
PLoS ONE  2014;9(3):e91867.
Human beta-defensin-1 (hBD-1) has recently been considered as a candidate tumor suppressor in renal and prostate cancer. The aim of this study was to investigate the role of hBD-1 in the progression of oral squamous cell carcinoma (OSCC) and its potential as diagnostic/prognostic biomarker and therapeutic target for OSCC.
HBD-1 expression in tissues at different stages of oral carcinogenesis, as well as OSCC cell lines was examined. HBD-1 was overexpressed in HSC-3, UM1, SCC-9 and SCC-25 cells and subjected to cell growth, apoptosis, migration and invasion assays. Tissue microarray constructed with tissues from 175 patients was used to examine clinicopathological significance of hBD-1 expression in OSCC.
HBD-1 expression decreased from oral precancerous lesions to OSCC and was lower in OSCC with lymph node metastasis than those without metastasis. In vitro, the expression of hBD-1 was related to the invasive potential of OSCC cell lines. Induction of exogenous expression of hBD-1 inhibited migration and invasion of OSCC cells, probably by regulation of RhoA, RhoC and MMP-2; but had no significant effect on proliferation or apoptosis. In a cohort of patients with primary OSCC, cases with no expression of hBD-1 had more chance to be involved in lymph node metastasis. Eventually, the positive expression of hBD-1 was associated with longer survival of patients with OSCC, and multivariate analysis and ROC curve analysis confirmed hBD-1 positivity to be an independent prognostic factor of OSCC, especially OSCC at early stage.
Overall, these data indicated that hBD-1 suppressed tumor migration and invasion of OSCC and was likely to be a prognostic biomarker and a potential target for treatment of OSCC.
PMCID: PMC3962354  PMID: 24658581
2.  Tea polyphenols alleviate high fat and high glucose-induced endothelial hyperpermeability by attenuating ROS production via NADPH oxidase pathway 
BMC Research Notes  2014;7:120.
Hyperglycemia-induced endothelial hyperpermeability is crucial to cardiovascular disorders and macro-vascular complications in diabetes mellitus. The objective of this study is to investigate the effects of green tea polyphenols (GTPs) on endothelial hyperpermeability and the role of nicotinamide adenine dinucleotide phosphate (NADPH) pathway.
Male Wistar rats fed on a high fat diet (HF) were treated with GTPs (0, 0.8, 1.6, 3.2 g/L in drinking water) for 26 weeks. Bovine aortic endothelial cells (BAECs) were treated with high glucose (HG, 33 mmol/L) and GTPs (0.0, 0.4, or 4 μg/mL) for 24 hours in vitro. The endothelial permeabilities in rat aorta and monolayer BAECs were measured by Evans blue injection method and efflux of fluorescein isothiocyanate (FITC)-dextran, respectively. The reactive oxygen species (ROS) levels in rat aorta and monolayer BAECs were measured by dihydroethidium (DHE) and 2′, 7′-dichloro-fluorescein diacetate (DCFH-DA) fluorescent probe, respectively. Protein levels of NADPH oxidase subunits were determined by Western-blot.
HF diet-fed increased the endothelial permeability and ROS levels in rat aorta while HG treatments increased the endothelial permeability and ROS levels in cultured BAECs. Co-treatment with GTPs alleviated those changes both in vivo and in vitro. In in vitro studies, GTPs treatments protected against the HG-induced over-expressions of p22phox and p67phox. Diphenylene iodonium chloride (DPI), an inhibitor of NADPH oxidase, alleviated the hyperpermeability induced by HG.
GTPs could alleviate endothelial hyperpermeabilities in HF diet-fed rat aorta and in HG treated BAECs. The decrease of ROS production resulting from down-regulation of NADPH oxidase contributed to the alleviation of endothelial hyperpermeability.
PMCID: PMC3944679  PMID: 24580748
Green tea polyphenols; High fat; High glucose; Hyperpermeability; NADPH oxidase
4.  Correction: Genome-Wide Sequence Characterization and Expression Analysis of Major Intrinsic Proteins in Soybean (Glycine max L.) 
PLoS ONE  2014;9(1):10.1371/annotation/e3307d0c-bb59-4f75-89b4-8e0d5af087d5.
PMCID: PMC3894297
5.  MAPK pathway mediates the induction of visfatin in neonatal SD rat cardiomyocytes pretreated with glucose 
Biomedical Reports  2014;2(2):282-286.
The protein visfatin is an insulin mimetic that has been shown to reduce plasma glucose levels, increase cytokine production and induce angiogenesis. However, few studies have focused on visfatin expression in cardiomyocytes at the cellular level. Therefore, the aim of the present study was to investigate visfatin expression and its potential mechanisms in cultured neonatal rat cardiomyocytes exposed to high-glucose concentrations. Primary cultures of 2-to 3-day-old Sprague Dawley (SD) rat cardiomyocytes were pretreated with increasing concentrations of glucose. P38 mitogen-activated protein kinase (MAPK) pathway inhibitor SB203580, extra cellular signal-regulated kinase (ERK1/2) pathway inhibitor PD098059 and c-Jun NH 2-terminal kinase (JNK) pathway inhibitor SP600125 were used to block the effect of glucose on visfatin expression. Cell viability following each glucose treatment was determined using the MTT assay. Expression of visfatin was detected using RT-PCR and western blot analysis. Increased glucose concentration directly correlated with an increased expression of visfatin mRNA and protein in neonatal rat cardiomyocytes. Following high doses of glucose, visfatin mRNA and protein expression peaked after 24 h with no significant change thereafter. Increased visfatin expression was blocked by the P38 MAPK inhibitor SB203580, suggesting a potential mechanism not yet identified. Expression of visfatin in cardiomyocytes was increased through the P38 MAPK pathway in the presence of high-glucose concentrations.
PMCID: PMC3917739  PMID: 24649111
visfatin; myocyte; glucose; insulin
6.  A Large Cohort Study Reveals the Association of Elevated Peripheral Blood Lymphocyte-to-Monocyte Ratio with Favorable Prognosis in Nasopharyngeal Carcinoma 
PLoS ONE  2013;8(12):e83069.
Nasopharyngeal carcinoma (NPC) is an endemic neoplasm in southern China. Although NPC sufferers are sensitive to radiotherapy, 20–30% of patients finally progress with recurrence and metastases. Elevated lymphocyte-to-monocyte ratio (LMR) has been reported to be associated with favorable prognosis in some hematology malignancies, but has not been studied in NPC. The aim of this study was to evaluate whether LMR could predict the prognosis of NPC patients.
A retrospective cohort of 1,547 non-metastatic NPC patients was recruited between January 2005 and June 2008. The counts for peripheral lymphocyte and monocyte were retrieved, and the LMR was calculated. Receiver operating characteristic curve analysis, univariate and multivariate COX proportional hazards analyses were applied to evaluate the associations of LMR with overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS) and loco-regional recurrence-free survival (LRRFS), respectively.
Univariate analysis revealed that higher LMR level (≥5.220) was significantly associated with superior OS, DFS and DMFS (P values <0.001). The higher lymphocyte count (≥2.145×109/L) was significantly associated with better OS (P = 0.002) and DMFS (P = 0.031), respectively, while the lower monocyte count (<0.475×109/L) was associated with better OS (P = 0.012), DFS (P = 0.011) and DMFS (P = 0.003), respectively. Multivariate Cox proportional hazard analysis showed that higher LMR level was a significantly independent predictor for superior OS (hazard ratio or HR  = 0.558, 95% confidence interval or 95% CI  = 0.417–0.748; P<0.001), DFS (HR  = 0.669, 95% CI  = 0.535–0.838; P<0.001) and DMFS (HR = 0.543, 95% CI  = 0.403–0.732; P<0.001), respectively. The advanced T and N stages were also independent indicators for worse OS, DFS, and DMFS, except that T stage showed borderline statistical significance for DFS (P = 0.053) and DMFS (P = 0.080).
The elevated pretreatment peripheral LMR level was a significant favorable factor for NPC prognosis and this easily accessed variable may serve as a potent marker to predict the outcomes of NPC patients.
PMCID: PMC3873908  PMID: 24386144
7.  Whole Genome Sequencing in Autism Identifies Hotspots for De Novo Germline Mutation 
Cell  2012;151(7):1431-1442.
De novo mutation plays an important role in Autism Spectrum Disorders (ASDs). Notably, pathogenic copy number variants (CNVs) are characterized by high mutation rates. We hypothesize that hypermutability is a property of ASD genes, and may also include nucleotide-substitution hotspots. We investigated global patterns of germline mutation by whole genome sequencing of monozygotic twins concordant for ASD and their parents. Mutation rates varied widely throughout the genome (by 100-fold) and could be explained by intrinsic characteristics of DNA sequence and chromatin structure. Dense clusters of mutations within individual genomes were attributable to compound mutation or gene conversion. Hypermutability was a characteristic of genes involved in ASD and other diseases. In addition, genes impacted by mutations in this study were associated with ASD in independent exome-sequencing datasets. Our findings suggest that regional hypermutation is a significant factor shaping patterns of genetic variation and disease risk in humans.
PMCID: PMC3712641  PMID: 23260136
8.  Organizational Culture and Its Relationship with Hospital Performance in Public Hospitals in China 
Health Services Research  2011;46(6 Pt 2):2139-2160.
To measure perceptions of organizational culture among employees of public hospitals in China and to determine whether perceptions are associated with hospital performance.
Data Sources
Hospital, employee, and patient surveys from 87 Chinese public hospitals conducted during 2009.
Study Design
Developed and administered a tool to assess organizational culture in Chinese public hospitals. Used factor analysis to create measures of organizational culture. Analyzed the relationships between employee type and perceptions of culture and between perceptions of culture and hospital performance using multivariate models.
Principal Findings
Employees perceived the culture of Chinese public hospitals as stronger in internal rules and regulations, and weaker in empowerment. Hospitals in which employees perceived that the culture emphasized cost control were more profitable and had higher rates of outpatient visits and bed days per physician per day but also had lower levels of patient satisfaction. Hospitals with cultures perceived as customer-focused had longer length of stay but lower patient satisfaction.
Managers in Chinese public hospitals should consider whether the culture of their organization will enable them to respond effectively to their changing environment.
PMCID: PMC3392996  PMID: 22092228
Business and management; comparative health systems/international health; hospitals; organization theory
9.  An Evaluation of Association between a Novel Hippocampal Biology Related SNP (rs7294919) and Schizophrenia 
PLoS ONE  2013;8(11):e80696.
Recent genetic analyses have implicated several candidate susceptibility variants for schizophrenia. The single nucleotide polymorphism (SNP) rs7294919 is likely a schizophrenia-susceptibility variant according to its significant association with hippocampal volume, hippocampus function, and cognitive performance as well as the nominal association with schizophrenia. However, all previous analyses were conducted only in Europeans, and whether rs7294919 is associated with schizophrenia in other populations are yet to be tested. Here, we conducted a case-control analysis of rs7294919 with schizophrenia in six independent Chinese (N = 3) and Japanese (N = 3) samples, including a total of 7,352 cases and 10,824 controls. The results of our association analysis were not able to confirm the association of rs7294919 with schizophrenia (p = 0.51 in total samples, odds ratio = 1.02 for allele[C]). The absence of rs7294919’s association in Chinese and Japanese suggest a potential genetic heterogeneity in the susceptibility of schizophrenia on this locus and also demonstrate the difficulties in replicating associations of schizophrenia across different ethnic populations.
PMCID: PMC3838413  PMID: 24278305
10.  Preliminary Experimental Results from a MARS Micro-CT System 
The Medipix All Resolution System (MARS) system is a commercial spectral/multi-energy micro-CT scanner designed and assembled by the MARS Bioimaging, Ltd. in New Zealand. This system utilizes the state-of-the-art Medipix photon-counting, energy-discriminating detector technology developed by a collaboration based at European Organization for Nuclear Research (CERN). In this paper, we report our preliminary experimental results using this system, including geometrical alignment, photon energy characterization, protocol optimization, and spectral image reconstruction. We produced our scan datasets with a multi-material phantom, and then applied ordered subset-simultaneous algebraic reconstruction technique (OS-SART) to reconstruct images in different energy ranges and principal component analysis (PCA) to evaluate spectral deviation between the energy ranges.
PMCID: PMC3789250  PMID: 22635175
Spectral/Multi-Energy Micro-CT; OS-SART; Multi-Material Phantom; PCA
11.  Influence of the mixture of Epimedii Herba and Ginkgo Folium extracts on the coronary flow of isolated hearts in rats 
Pharmacognosy Magazine  2013;9(36):290-293.
In clinical practice, Epimedii Herba and Ginkgo Folium preparations are widely used in treatment of diseases such as coronary heart disease (angina) in China. However, there are no studies on the two-drug combination.
To explore the effect of the mixture of the Epimedii Herba extract (EE) and Ginkgo Folium extract (GE) on coronary flow of isolated hearts in rats.
Materials and Methods:
EE and GE were prepared by reflux in alcohol, and processed with HPD-100 macro-reticular resins; icariin from EE and total bilobalides from GE were determined by high performance liquid chromatography (HPLC). Fifty male Sprague–Dawley (SD) mice were subdivided into five groups (10 rats each): Normal control group (NC), EE – 10 mg group, GE – 10 mg group, EE – 5 mg + GE – 5 mg group, and EE – 10 mg + GE – 10 mg group. Isolated hearts uniform pressure perfusion was proceeded with Langendorff system.
The content of icariin in EE was 20.8%. The total content including four kinds of bilobalides (ginkolide A–C and bilobalide) in GE was 8.6%. The coronary flow in the NC group remained stable before and after treatment, and the coronoray flow in the EE, GE, EE + GE groups was increased and the relative magnitude of heightening was 25.0–33.3%, and the coronary flow in EE + GE was significantly different from that in the single EE or GE group.
EE or GE itself can heighten coronary flow of isolated hearts in rats. The activity of the mixture including EE and GE is better than that of single EE or GE, and the activity becomes larger when the dosage is doubled, and is related with dosage.
PMCID: PMC3793332  PMID: 24124279
Bilobalide; Coronary flow; icariin; macro-reticular resins; traditional Chinese medicine
12.  β-cyclodextrin assistant flavonoid glycosides enzymatic hydrolysis 
Pharmacognosy Magazine  2013;9(Suppl 1):S11-S18.
The content of icaritin and genistein in herba is very low, preparation with relatively large quantities is an important issue for extensive pharmacological studies.
This study focuses on preparing and enzymic hydrolysis of flavonoid glycosides /β-cyclodextrin inclusion complex to increase the hydrolysis rate.
Materials and Methods:
The physical property of newly prepared inclusion complex was tested by differential scanning calorimetry (DSC). The conditions of enzymatic hydrolysis were optimized for the bioconversion of flavonoid glycosides /β-cyclodextrin inclusion complex by mono-factor experimental design. The experiments are using the icariin and genistein as the model drugs.
The solubility of icariin and genistein were increased almost 17 times from 29.2 μg/ml to 513.5 μg/ml at 60°C and 28 times from 7.78 μg/ml to 221.46 μg/ml at 50°C, respectively, demonstrating that the inclusion complex could significantly increase the solubility of flavonoid glycosides. Under the optimal conditions, the reaction time of icariin and genistin decreased by 68% and 145%, when compared with that without β-CD inclusion. By using this enzymatic condition, 473 mg icaritin (with the purity of 99.34%) and 567 mg genistein(with the purity of 99.46%), which was finally determined by melt point, ESI-MS, UV, IR, 1H NMR and 13C NMR, was obtained eventually by transforming the inclusion complex(contains 1.0 g substrates).
This study can clearly indicate a new attempt to improve the speed of enzyme-hydrolysis of poorly water-soluble flavonoid glycosides and find a more superior condition which is used to prepare icaritin and genistein.
PMCID: PMC3798134  PMID: 24143039
Cellulase; enzymatic hydrolysis; flavonoid glycosides; snailase; β-CD inclusion complex
13.  Correction: Green Tea Polyphenols Reduced Fat Deposits in High Fat-Fed Rats via erk1/2-PPARγ-Adiponectin Pathway 
PLoS ONE  2013;8(9):10.1371/annotation/83355f31-f12d-4b8e-9310-b60d11e37482.
PMCID: PMC3779281  PMID: 24073189
14.  Interior Tomography With Continuous Singular Value Decomposition 
IEEE transactions on medical imaging  2012;10.1109/TMI.2012.2213304.
The long-standing interior problem has important mathematical and practical implications. The recently developed interior tomography methods have produced encouraging results. A particular scenario for theoretically exact interior reconstruction from truncated projections is that there is a known subregion in the region of interest (ROI). In this paper, we improve a novel continuous singular value decomposition (SVD) method for interior reconstruction assuming a known subregion. First, two sets of orthogonal eigen-functions are calculated for the Hilbert and image spaces respectively. Then, after the interior Hilbert data are calculated from projection data through the ROI, they are projected onto the eigen-functions in the Hilbert space, and an interior image is recovered by a linear combination of the eigen-functions with the resulting coefficients. Finally, the interior image is compensated for the ambiguity due to the null space utilizing the prior subregion knowledge. Experiments with simulated and real data demonstrate the advantages of our approach relative to the projection onto convex set type interior reconstructions.
PMCID: PMC3773972  PMID: 22907966
Hilbert transform; interior tomography; singular value decomposition (SVD); X-ray computed tomography (CT)
15.  Role of podocalyxin in astrocytoma: Clinicopathological and in vitro evidence 
Oncology Letters  2013;6(5):1390-1396.
The present study examined the expression of podocalyxin (PODX) in surgically-resected astrocytomas, associated the levels of PODX expression with the clinicopathological characteristics and survival outcomes of astrocytoma and assessed how PODX affected the viability of astrocytoma cells following the administration of chemotherapeutic agents. The immunohistochemical analysis of 102 patient samples revealed that a high expression of PODX was significantly associated with high-grade astrocytomas (P<0.001) and a high Ki-67 labeling index (LI; P<0.001). A Kaplan-Meier survival analysis demonstrated that the high PODX expression group had significantly shorter disease-free survival (DFS) and overall survival (OS) rates compared with the low expression group (P<0.001). The multivariate analysis using the Cox’s proportional hazards model revealed that a high expression of PODX, a high World Health Organization grade and a high Ki-67 LI were independent factors for shorter DFS and OS times. A subsequent in vitro study using SW1783 and U-87 human astrocytoma cell lines revealed that knocking down PODX decreased astrocytoma cell viability against temozolomide-induced apoptotic stress through the inhibition of the Akt survival signaling pathway. In conclusion, the in vivo findings indicated that a high expression of PODX is predictive of a poor survival outcome and, thus, may be used as a prognostic factor to predict the survival outcomes of astrocytoma patients. The in vitro findings indicated that PODX may promote astrocytoma cell viability against chemotherapeutic agent-induced apoptotic stress through the Akt pathway, indicating that PODX may be a novel target for overcoming chemoresistance in astrocytomas.
PMCID: PMC3813577  PMID: 24179530
astrocytoma; podocalyxin; overall survival; disease-free survival; Ki-67; temozolomide; cell survival; Akt
16.  Exome Sequencing and Linkage Analysis Identified Tenascin-C (TNC) as a Novel Causative Gene in Nonsyndromic Hearing Loss 
PLoS ONE  2013;8(7):e69549.
In this study, a five-generation Chinese family (family F013) with progressive autosomal dominant hearing loss was mapped to a critical region spanning 28.54 Mb on chromosome 9q31.3-q34.3 by linkage analysis, which was a novel DFNA locus, assigned as DFNA56. In this interval, there were 398 annotated genes. Then, whole exome sequencing was applied in three patients and one normal individual from this family. Six single nucleotide variants and two indels were found co-segregated with the phenotypes. Then using mass spectrum (Sequenom, Inc.) to rank the eight sites, we found only the TNC gene be co-segregated with hearing loss in 53 subjects of F013. And this missense mutation (c.5317G>A, p.V1773M ) of TNC located exactly in the critical linked interval. Further screening to the coding region of this gene in 587 subjects with nonsyndromic hearing loss (NSHL) found a second missense mutation, c.5368A>T (p. T1796S), co-segregating with phenotype in the other family. These two mutations located in the conserved region of TNC and were absent in the 387 normal hearing individuals of matched geographical ancestry. Functional effects of the two mutations were predicted using SIFT and both mutations were deleterious. All these results supported that TNC may be the causal gene for the hearing loss inherited in these families. TNC encodes tenascin-C, a member of the extracellular matrix (ECM), is present in the basilar membrane (BM), and the osseous spiral lamina of the cochlea. It plays an important role in cochlear development. The up-regulated expression of TNC gene in tissue repair and neural regeneration was seen in human and zebrafish, and in sensory receptor recovery in the vestibular organ after ototoxic injury in birds. Then the absence of normal tenascin-C was supposed to cause irreversible injuries in cochlea and caused hearing loss.
PMCID: PMC3728356  PMID: 23936043
17.  Delphinidin-3-Glucoside Protects against Oxidized Low-Density Lipoprotein-Induced Mitochondrial Dysfunction in Vascular Endothelial Cells via the Sodium-Dependent Glucose Transporter SGLT1 
PLoS ONE  2013;8(7):e68617.
Delphinidin-3-glucoside (Dp) is a member of a family of bioactive compounds known as anthocyanins that occur naturally in pigmented plants and are known to ameliorate oxidative stress. Previous studies have showed that Dp decreased oxidative stress in vascular endothelial cells, however, the underlying mechanisms remain largely unknown. In the present study, we showed that pretreatment with Dp significantly suppressed oxidized low-density lipoprotein (oxLDL)-induced cell proliferation inhibition and apoptosis in primary human umbilical vein endothelial cells (HUVECs). Also, Dp pretreatment attenuated oxLDL-induced mitochondrial dysfunction via decreased reactive oxygen species (ROS) and superoxide anion generation, thereby repressing mitochondrial membrane potential and closing mitochondrial permeability transition pore. Furthermore, in vitro and in vivo data showed that Dp was transported into endothelial cells in a temperature, concentration, and time-dependent manner via the sodium-dependent glucose transporter (SGLT1). Suppression of SGLT1 by its substrate glucose, its inhibitor phlorizin or SGLT1 siRNA blocked Dp transportation. Repression of SGLT1 significantly inhibited Dp function of ameliorating mitochondrial dysfunction induced by pro-apoptotic factors (Apoptosis-inducing factor, Cytochrome c, Caspase-3 and Bax/Bcl-2 ratio). Taken together, our data indicate that Dp protects VECs via the SGLT1-ROS-mitochodria pathway. This new insight may help to elucidate the molecular mechanisms underlying the vascular protection afforded by Dp, and anthocyanins in general, in the context of prevention of endothelial dysfunction and atherosclerosis.
PMCID: PMC3715513  PMID: 23874689
18.  Sequencing of Fifty Human Exomes Reveals Adaptation to High Altitude 
Science (New York, N.Y.)  2010;329(5987):75-78.
Residents of the Tibetan Plateau show heritable adaptations to extreme altitude. We sequenced 50 exomes of ethnic Tibetans, encompassing coding sequences of 92% of human genes, with an average coverage of 18X per individual. Genes showing population-specific allele frequency changes, which represent strong candidates for altitude adaptation, were identified. The strongest signal of natural selection came from EPAS1, a transcription factor involved in response to hypoxia. One SNP at EPAS1 shows a 78% frequency difference between Tibetan and Han samples, representing the fastest allele frequency change observed at any human gene to date. This SNP’s association with erythrocyte abundance supports the role of EPAS1 in adaptation to hypoxia. Thus, a population genomic survey has revealed a functionally important locus in genetic adaptation to high altitude.
PMCID: PMC3711608  PMID: 20595611
19.  Effects of Fluid Shear Stress on Expression of Smac/DIABLO in Human Umbilical Vein Endothelial Cells☆ 
To investigate the molecular mechanisms of laminar shear stress on inhibition of apoptosis in endothelial cells, human umbilical vein endothelial cells (HUVECs) were starved in medium containing 2% fetal bovine serum and 20 dyne/cm2 shear stress.
HUVECs were subjected to shear stress or incubated in a static condition and then Smac/DIABLO expression was quantified by reverse-transcription polymerase chain reaction, real-time PCR, and western blot. The effect of shear stress on the migration of Smac/DIABLO proteins was detected by immunofluorescence microscopy.
Results demonstrated that 20 dyne/cm2 shear stress inhibited the expression of Smac/DIABLO at both the mRNA and protein levels in cultured HUVECs. Furthermore, release of Smac/DIABLO from mitochondria was induced by removal of basic fibroblast growth factor and decrease of fetal bovine serum in the medium, whereas shear stress inhibited its release under the same conditions.
These results suggest that down-regulation of Smac/DIABLO may contribute to the potent antiatherosclerotic effect of shear stress by preventing endothelial cells from entering apoptosis.
PMCID: PMC3862198  PMID: 24384678
apoptosis; atherosclerosis; human umbilical vein endothelial cells; shear stress; Smac/DIABLO
20.  Decrease expression of microRNA-20a promotes cancer cell proliferation and predicts poor survival of hepatocellular carcinoma 
Growing evidences indicate microRNAs play important roles in cancer development, progression, metastasis and may constitute robust biomarkers for cancer prognosis. The aim of this study was to identify the clinical and functional association of microRNA-20a (miR-20a) in hepatocellular carcinoma (HCC).
MiR-20a was detected using Taqman real-time polymerase chain reaction. Kaplan-Meier and Cox proportional regression analyses were utilized to determine the association of miR-20a with survival of patients. The potential functions of miR-20a on proliferation were evaluated by proliferation and flow cytometry analysis. The direct target gene of miR-20a was also identified by luciferase reporter assays.
MiR-20a was lower in primary HCC than normal liver, and were further decreased in those with post-liver transplantation (LT) HCC recurrence compared with those with non-recurrence (p = 0.001). Patients with lower miR-20a expression had significantly poorer recurrence-free survival (RFS, Log rank p < 0.001) and overall survival (OS, Log rank p < 0.001). Multivariate analysis revealed that lower miR-20a was an independent predictor of poor prognosis. MiR-20a restoration could suppress HepG2 and SMMC-7721 cells proliferation and induce cell cycle G1 arrest and apoptosis. Subsequent investigations revealed that miR-20a directly targeted myeloid cell leukemia sequence 1 (Mcl-1) and reduced the endogenous protein level of Mcl-1 in HCC cells.
MiR-20a is decreased in HCCs and correlates with HCC recurrence and prognosis. Down-regulation of miR-20a increases the proliferation abilities of HCC cells. Our findings suggest miR-20a may represent a novel potential therapeutic target and biomarker for survival of HCC patients.
PMCID: PMC3699415  PMID: 23594563
MicroRNA-20a; Hepatocellular Carcinoma; Recurrence; Prognosis; Liver transplantation
21.  Different dorsal striatum circuits mediate action discrimination and action generalization 
The European Journal of Neuroscience  2012;35(7):1105-1114.
Generalization is an important process that allows animals to extract rules from regularities of past experience and apply them to analogous situations. In particular, the generalization of previously learned actions to novel instruments allows animals to use past experience to act faster and more efficiently in an ever-changing environment. However, generalization of actions to a dissimilar instrument or situation may also be detrimental. In this study, we investigate the neural bases of action generalization and discrimination in mice trained on a lever-pressing task. Using specific schedules of reinforcement known to bias animals towards habitual or goal-directed behaviors, we confirmed that action generalization is more prominent in animals using habitual rather than goal-directed strategies. We uncovered that selective excitotoxic lesions of the dorsolateral and dorsomedial striatum have opposite effects on the generalization of a previously learned action to a novel lever. While lesions of the dorsolateral striatum impair action generalization, dorsomedial striatum lesions affect action discrimination and bias subjects towards action generalization. Importantly, these lesions do not affect the ability of animals to explore or match their lever-pressing rate to the reinforcement rate, or the ability to distinguish between different levers. The data presented here reveal that dorsolateral and dorsomedial striatal circuits have opposing roles in the generalization of previously learned actions to novel instruments, and suggest that these circuits compete for the expression of generalization in novel situations.
PMCID: PMC3325510  PMID: 22487040
habit; goal-directed; basal ganglia; motor; learning; memory
22.  Prognostic assessment of different metastatic lymph node staging methods for gastric cancer after D2 resection 
AIM: To compare the prognostic assessment of lymph node ratio and absolute number based staging system for gastric cancer after D2 resection.
METHODS: The clinical, pathologic, and long-term follow-up data of 427 patients with gastric cancer that underwent D2 curative gastrectomy were retrospectively analyzed. The relationships between the metastatic lymph node ratio (MLR), log odds of positive lymph nodes (LODDS), and positive lymph nodes (pN) staging methods and the long-term prognoses of the patients were compared. In addition, the survival curves, accuracy, and homogeneity were compared with stratification to evaluate the prognostic assessment of the 3 methods when the number of tested lymph nodes was insufficient (< 10 and 10-15).
RESULTS: MLR [hazard ratio (HR) = 1.401, P = 0.012], LODDS (HR = 1.012, P = 0.034), and pN (HR = 1.376, P = 0.005) were independent risk factors for gastric cancer patients. The receiver operating characteristic (ROC) curves showed that the prognostic accuracy of the 3 methods was comparable (P > 0.05). Spearman correlation analysis confirmed that MLR, LODDS, and pN were all positively correlated with the total number of tested lymph nodes. When the number of tested lymph node was < 10, the value of survival curves staged by MLR and LODDS was superior to those of pN staging. However, the difference in survival curves between adjacent stages was not significant. In addition, the survival rate of stage 4 patients using the MLR and LODDS staging methods was 26.7% and 27.3% with < 10 lymph node, respectively which were significantly higher than the survival rate of patients with > 15 tested lymph nodes (< 4%). The ROC curve showed that the accuracy of the prognostic assessment of MLR, LODDS, and pN staging methods was comparable (P > 0.05), and the area under the ROC curve of all 3 methods were increased progressively with the enhanced levels of examined lymph nodes. In addition, the homogeneity of the 3 methods in patients with ≤ 15 tested lymph nodes also showed no significant difference.
CONCLUSION: Neither MLR or LODDS could reduce the staging bias. A sufficient number of tested lymph nodes is key to ensure an accurate prognosis for patients underwent D2 radical gastrectomy.
PMCID: PMC3613114  PMID: 23569344
Gastric cancer; Metastatic lymph node ratio; Lymph node metastasis; Prognosis
23.  Resveratrol ameliorates high-glucose-induced hyperpermeability mediated by caveolae via VEGF/KDR pathway 
Genes & Nutrition  2012;8(2):231-239.
Endothelial hyperpermeability induced by hyperglycemia is the initial step in the development of atherosclerosis, one of the most serious cardiovascular complications in diabetes. In the present study, we investigated the effects of resveratrol (RSV), a bioactive ingredient extracted from Chinese herb rhizoma polygonum cuspidatum, on permeability in vitro and the molecular mechanisms involved. Permeability was assessed by the efflux of fluorescein isothiocyanate (FITC)-dextran permeated through the monolayer endothelial cells (ECs). The mRNA levels, protein expressions, and secretions were measured by quantitative real-time PCR, western blot, and ELISA, respectively. Increased permeability and caveolin-1 (cav-1) expression were observed in monolayer ECs exposed to high glucose. Resveratrol treatment alleviated the hyperpermeability and the overexpression of cav-1 induced by high glucose in a dose-dependent manner. β-Cyclodextrin, a structural inhibitor of caveolae, reduced the hyperpermeability caused by high glucose. Resveratrol also down-regulated the increased expressions of vascular endothelial growth factor (VEGF) and kinase insert domain receptor (KDR, or VEGF receptor-2) induced by high glucose. Inhibition of VEGF/KDR pathway by using SU5416, a selective inhibitor of KDR, alleviated the hyperpermeability and the cav-1 overexpression induced by high glucose. The above results demonstrate that RSV ameliorates caveolae-mediated hyperpermeability induced by high glucose via VEGF/KDR pathway.
PMCID: PMC3575886  PMID: 22983702
Resveratrol; Diabetes; Atherosclerosis; Hyperpermeability; Caveolae; VEGF
24.  Genome-Wide Sequence Characterization and Expression Analysis of Major Intrinsic Proteins in Soybean (Glycine max L.) 
PLoS ONE  2013;8(2):e56312.
Water is essential for all living organisms. Aquaporin proteins are the major facilitator of water transport activity through cell membranes of plants including soybean. These proteins are diverse in plants and belong to a large major intrinsic (MIP) protein family. In higher plants, MIPs are classified into five subfamilies including plasma membrane intrinsic proteins (PIP), tonoplast intrinsic proteins (TIP), NOD26-like intrinsic proteins (NIP), small basic intrinsic proteins (SIP), and the recently discovered X intrinsic proteins (XIP). This paper reports genome wide assembly of soybean MIPs, their functional prediction and expression analysis. Using a bioinformatic homology search, 66 GmMIPs were identified in the soybean genome. Phylogenetic analysis of amino acid sequences of GmMIPs divided the large and highly similar multi-gene family into 5 subfamilies: GmPIPs, GmTIPs, GmNIPs, GmSIPs and GmXIPs. GmPIPs consisted of 22 genes and GmTIPs 23, which showed high sequence similarity within subfamilies. GmNIPs contained 13 and GmSIPs 6 members which were diverse. In addition, we also identified a two member GmXIP, a distinct 5th subfamily. GmMIPs were further classified into twelve subgroups based on substrate selectivity filter analysis. Expression analyses were performed for a selected set of GmMIPs using semi-quantitative reverse transcription (semi-RT-qPCR) and qPCR. Our results suggested that many GmMIPs have high sequence similarity but diverse roles as evidenced by analysis of sequences and their expression. It can be speculated that GmMIPs contains true aquaporins, glyceroporins, aquaglyceroporins and mixed transport facilitators.
PMCID: PMC3577755  PMID: 23437113
25.  Developing Genetic Epidemiological Models to Predict Risk for Nasopharyngeal Carcinoma in High-Risk Population of China 
PLoS ONE  2013;8(2):e56128.
To date, the only established model for assessing risk for nasopharyngeal carcinoma (NPC) relies on the sero-status of the Epstein-Barr virus (EBV). By contrast, the risk assessment models proposed here include environmental risk factors, family history of NPC, and information on genetic variants. The models were developed using epidemiological and genetic data from a large case-control study, which included 1,387 subjects with NPC and 1,459 controls of Cantonese origin. The predictive accuracy of the models were then assessed by calculating the area under the receiver-operating characteristic curves (AUC). To compare the discriminatory improvement of models with and without genetic information, we estimated the net reclassification improvement (NRI) and integrated discrimination index (IDI). Well-established environmental risk factors for NPC include consumption of salted fish and preserved vegetables and cigarette smoking (in pack years). The environmental model alone shows modest discriminatory ability (AUC = 0.68; 95% CI: 0.66, 0.70), which is only slightly increased by the addition of data on family history of NPC (AUC = 0.70; 95% CI: 0.68, 0.72). With the addition of data on genetic variants, however, our model’s discriminatory ability rises to 0.74 (95% CI: 0.72, 0.76). The improvements in NRI and IDI also suggest the potential usefulness of considering genetic variants when screening for NPC in endemic areas. If these findings are confirmed in larger cohort and population-based case-control studies, use of the new models to analyse data from NPC-endemic areas could well lead to earlier detection of NPC.
PMCID: PMC3574061  PMID: 23457511

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