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1.  Design, Synthesis, and Biological Evaluation of Stable Colchicine Binding Site Tubulin Inhibitors as Potential Anticancer Agents 
Journal of Medicinal Chemistry  2014;57(17):7355-7366.
To block the metabolically labile sites of novel tubulin inhibitors targeting the colchicine binding site based on SMART, ABI, and PAT templates, we have designed, synthesized, and biologically tested three focused sets of new derivatives with modifications at the carbonyl linker, the para-position in the C ring of SMART template, and modification of A ring of the PAT template. Structure–activity relationships of these compounds led to the identification of new benzimidazole and imidazo[4,5-c]pyridine-fused ring templates, represented by compounds 4 and 7, respectively, which showed enhanced antitumor activity and substantially improved the metabolic stability in liver microsomes compared to SMART. MOM group replaced TMP C ring and generated a potent analogue 15, which showed comparable potency to the parent SMART compound. Further modification of PAT template yielded another potent analogue 33 with 5-indolyl substituent at A ring.
PMCID: PMC4161160  PMID: 25122533
2.  Development of BODIPY FL Vindoline as a Novel and High-Affinity Pregnane X Receptor Fluorescent Probe 
Bioconjugate Chemistry  2014;25(9):1664-1677.
The pregnane X receptor (PXR) regulates the metabolism and excretion of xenobiotics and endobiotics by regulating the expression of drug-metabolizing enzymes and transporters. The unique structure of PXR allows it to bind many drugs and drug leads, possibly causing undesired drug–drug interactions. Therefore, it is crucial to evaluate whether chemicals or drugs bind to PXR. Fluorescence-based assays are preferred because of their sensitivity and nonradioactive nature. On the basis of our previously characterized 4 (BODIPY FL vinblastine), a high-affinity PXR probe, we developed 20 (BODIPY FL vindoline) and showed that it is a novel and potent PXR fluorescent probe with Kd of 256 nM in a time-resolved fluorescence resonance energy transfer (TR-FRET) binding assay with PXR. By using 20 (BODIPY FL vindoline) in the PXR TR-FRET assay, we obtained a more than 7-fold signal-to-background ratio and high signal stability (signal was stable for at least 120 min, and Z′-factor > 0.85 from 30 to 240 min). The assay can tolerate DMSO up to 2%. This assay has been used to evaluate a panel of PXR ligands for their PXR-binding affinities. The performance of 20 (BODIPY FL vindoline) in the PXR TR-FRET assay makes it an ideal PXR fluorescent probe, and the newly developed PXR TR-FRET assay with 20 (BODIPY FL vindoline) as a fluorescent probe is suitable for high-throughput screening to identify PXR-binding ligands.
PMCID: PMC4166032  PMID: 25133934
3.  Comparison of apical and coronal extrusions using reciprocating and rotary instrumentation systems 
BMC Oral Health  2015;15:92.
The aim of this study was to compare the apical and coronal extrusions by using two reciprocating and two rotary instrumentation systems.
Eighty extracted human single-rooted anterior teeth were randomly assigned to four groups. Four different root canal instrumentation systems were used according to the manufacturers instructions, including two reciprocating single-file systems, Reciproc and WaveOne, and two full-sequence rotary BLX and ProTaper instruments. Debris collected from the coronal by the instruments and apical extrusions were quantified respectively. After drying the collections, the mean weight of debris collected from apical and coronal extrusions was assessed using an electronic balance and analyzed using the Kruskal–Wallis H and Mann–Whitney U tests.
Statistically significant differences in the apical extrusion were observed among the four groups. Reciproc and WaveOne instruments produced significantly less debris than BLX and ProTaper instruments (P < 0.05).
All of the systems produced apical extrusion of debris. However, reciprocating single-file systems produced less apical extrusion than full-sequence rotary systems. No relationship was observed between apical and coronal extrusions.
PMCID: PMC4527245  PMID: 26251234
4.  Controlled Multiple Growth Factor Delivery from Bone Tissue Engineering Scaffolds via Designed Affinity 
Tissue Engineering. Part A  2013;20(15-16):2077-2087.
It is known that angiogenesis plays an important role in bone regeneration and that release of angiogenic and osteogenic growth factors can enhance bone formation. Multiple growth factors play key roles in processes that lead to tissue formation/regeneration during natural tissue development and repair. Therefore, treatments aiming to mimic tissue regeneration can benefit from multiple growth factor release, and there remains a need for simple clinically relevant approaches for dual growth factor release. We hypothesized that mineral coatings could be used as a platform for controlled incorporation and release of multiple growth factors. Specifically, mineral-coated scaffolds were “dip coated” in multiple growth factor solutions, and growth factor binding and release were dictated by the growth factor-mineral binding affinity. Beta tricalcium phosphate (β-TCP) scaffolds were fabricated using indirect solid-free form fabrication techniques and coated with a thin conformal mineral layer. Mineral-coated β-TCP scaffolds were sequentially dipped in recombinant human vascular endothelial growth factor (rhVEGF) and a modular bone morphogenetic peptide, a mineral-binding version of bone morphogenetic protein 2 (BMP2), solutions to allow for the incorporation of each growth factor. The dual release profile showed sustained release of both growth factors for over more than 60 days. Scaffolds releasing either rhVEGF alone or the combination of growth factors showed an increase in blood vessel ingrowth in a dose-dependent manner in a sheep intramuscular implantation model. This approach demonstrates a “modular design” approach, in which a controllable biologics carrier is integrated into a structural scaffold as a thin surface coating.
PMCID: PMC4137333  PMID: 24350567
5.  Long-Term Effectiveness of Antiretroviral Therapy in China: An Observational Cohort Study from 2003–2014 
In order to assess the effectiveness of the Chinese government’s expanded access program, a cohort study on all adult HIV patients in Shenzhen was conducted from December 2003 to February 2014 to estimate the effects of antiretroviral therapy (ART) on mortality, tuberculosis and CD4 cell counts. Marginal structural regression models adjusted for baseline and time-varying covariates. Of the 6897 patients enrolled and followed up for a maximum of 178 months, 44.92% received ART. Among patients who commenced receiving ART during the study, there were 98 deaths and 59 new tuberculosis diagnoses, while there were 410 deaths and 201 new tuberculosis diagnoses among those without ART. ART was associated with both lower mortality (hazard ratio [HR] = 0.18; 95% confidence interval [CI] = 0.11–0.27) and the presence of tuberculosis (HR = 0.27; 95% CI = 0.19–0.37). Each month of ART was associated with an average increase in CD4 cell count of 6.52 cells/µL (95% CI = 6.08–7.12 cells/µL). In conclusions, the effectiveness of ART provided by China government health services is the same as that in higher-income countries. Accounting to higher mortality rates from the delay of starting ART, faster expansion and timely imitation of ART are urgent.
PMCID: PMC4555246  PMID: 26213959
HIV; ART; mortality; observational cohort study; China
6.  In vivo antimicrobial activity of marbofloxacin against Pasteurella multocida in a tissue cage model in calves 
Marbofloxacin is a fluoroquinolone specially developed for use in veterinary medicine with broad-spectrum antibacterial activity. The objective of our study was to re-evaluate in vivo antimicrobial activity of marbofloxacin against Pasteurella multocida using subcutaneously implanted tissue cages in calves. Calves were infected by direct injection into tissue cages with P. multocida(type B, serotype 2), then intramuscularly received a range of marbofloxacin doses 24 h after inoculation. The ratio of 24 h area under the concentration-time curve divided by the minimum inhibitory concentration or the mutant prevention concentration (AUC24 h/MIC or AUC24 h/MPC) was the pharmacokinetic-pharmacodynamic (PK/PD) index that best described the effectiveness of marbofloxacin against P. multocida (R2 = 0.8514) by non-linear regression analysis. Marbofloxacin exhibited a good antimicrobial activity in vivo. The levels of AUC24 h/MIC and AUC24 h/MPC that produced 50% (1.5log10 CFU/mL reduction) and 90% (3log10 CFU/mL reduction) of maximum response were 18.60 and 50.65 h, 4.67 and 12.89 h by using sigmoid Emax model WINNONLIN software, respectively. The in vivo PK/PD integrated methods by tissue cage model display the advantage of the evaluation of antimicrobial activity and the optimization of the dosage regimen for antibiotics in the presence of the host defenses, especially in target animal of veterinary interest.
PMCID: PMC4513234  PMID: 26257726
marbofloxacin; Pasteurella multocida; tissue cage model; in vivo antimicrobial activity; calves
7.  Antithyroid Antibodies Are Implicated in Epileptogenesis of Adult Patients With Epilepsy 
Medicine  2015;94(26):e1059.
Antithyroid antibodies (Abs) are associated with epilepsy in steroid-responsive encephalopathy, but have been rarely studied in unselected epilepsy patients. This study aimed to characterize the prevalence and associated factors of antithyroid Abs and other auto-Abs in adult patients with epilepsy.
Epilepsy patients without autoimmune disorders were surveyed for antinuclear antibody (ANA), anti-β2 glycoprotein 1 antibody (aβ2GP1), anticardiolipin IgG Ab, antimicrosomal antibody (AMA), antithyroglobulin antibody (ATA), and thyroid function test.
Of 319 patients, 75 (23.5%) were positive for at least 1 Ab. The most common Ab was anticardiolipin antibody (aCL) (30/319, 9.4%), followed by AMA (24/319, 7.5%), ANA (18/319, 5.6%), aβ2GP1 (18/319, 6.5%), and ATA (6/319, 3.25%). Antimicrosomal Abs were significantly more frequent in patients who were female, older at disease onset, older at the time of study, and had unknown seizure etiology. The presence of aCL was significantly associated with more frequent seizures. Most patients with antithyroid Ab were female and had focal seizures with unknown etiology.
The association of different auto-Abs with different factors suggests that they may have different roles in adult patients with epilepsy. Recurrent seizures and certain antiepileptic medications may cause the production of aCL. The role of antithyroid Abs in adult focal epilepsy with unknown cause, especially in females, warrants further evaluation because of the potential implications on treatment.
PMCID: PMC4504585  PMID: 26131823
8.  Association of ADRB1 gene polymorphisms with pain sensitivity in a Chinese population 
Objective: The present study aims to observe the influence of single-nucleotide polymorphisms (SNPs) in the ADRB1 gene on individual differences in pain sensitivity. Methods: We analyzed the associations between pain sensitivity and ADRB1 gene SNPs (A145 G and G1165 C) in 324 Chinese patients who underwent surgery. The genotyping was performed using PCR-RFLP technique. Results: The patients who carried the A-allele of the A145 G SNP were more sensitive to cold pressor-induced pain than those who did not carry this allele (P < 0.05). We did not found G1165 C polymorphism associated with pain sensitive in the present study. The haplotype analysis revealed A-C haplotype carriers have reduced fentanyl use in 24-h postoperative (P < 0.05). Conclusion: ADRB1 gene polymorphisms are associated with pain and analgesic sensitivity.
PMCID: PMC4565355  PMID: 26379972
β1-adrenergic receptor; gene polymorphism; opioid; pain; individual difference
9.  The Biomimetic Shark Skin Optimization Design Method for Improving Lubrication Effect of Engineering Surface 
Journal of Tribology  2014;136(3):0317031-03170313.
Nature has long been an important source of inspiration for mankind to develop artificial ways to mimic the remarkable properties of biological systems. In this work, a new method was explored to fabricate a biomimetic engineering surface comprising both the shark-skin, the shark body denticle, and rib morphology. It can help reduce water resistance and the friction contact area as well as accommodate lubricant. The lubrication theory model was established to predict the effect of geometric parameters of a biomimetic surface on tribological performance. The model has been proved to be feasible to predict tribological performance by the experimental results. The model was then used to investigate the effect of the grid textured surface on frictional performance of different geometries. The investigation was aimed at providing a rule for deriving the design parameters of a biomimetic surface with good lubrication characteristics. Results suggest that: (i) the increase in depression width ratio Λ decreases its corresponding coefficient of friction, and (ii) the small coefficient of friction is achievable when Λ is beyond 0.45. Superposition of depth ratio Γ and angle's couple under the condition of Λ < 0.45 affects the value of friction coefficient. It shows the decrease in angle decreases with the increase in dimension depth Γ.
PMCID: PMC4095752  PMID: 25053867
hydrodynamic lubrication; biomimetic surface; hydrodynamic friction; surface texture design; effect of texture geometry
10.  Deregulated HOXB7 Expression Predicts Poor Prognosis of Patients with Esophageal Squamous Cell Carcinoma and Regulates Cancer Cell Proliferation In Vitro and In Vivo 
PLoS ONE  2015;10(6):e0130551.
We observed abnormal HOXB7 expression in esophageal squamous cell carcinoma (ESCC) previously. This study was to evaluate the prognostic significance of HOXB7 and reveal the potential mechanism.
Immunohistochemistry was used to confirm the abnormal expression of HOXB7 in ESCC. The prognostic significance of HOXB7 expression was analyzed in two independent cohorts. RNAi was used to establish two stable HOXB7-knockdown cell strains. CCK8 assay, cell growth curve assay, colony formation assay, flow cycle analysis and tumorigenicity assay in nude mice were employed to investigate the effect of HOXB7 on proliferation in vitro and in vivo.
Immunohistochemistry confirmed the abnormal expression of HOXB7 in ESCC compared with paracancerous mucosa (18/23 vs. 9/23, p=0.039). HOXB7 expression was positively correlated with the T stage, lymph node metastasis and TNM stage. The median survival of patients with high HOXB7 expression was significantly shorter than that with low expression (45 months vs. 137 months, p = 0.007 for cohort 1; 19 months vs. 34 months, p = 0.001 for cohort 2). Multivariate survival analysis showed that HOXB7 expression was another independent prognostic factor (HR [95% CI] = 0.573 [0.341–0.963], p = 0.036 for cohort 1; HR [95%CI] = 0.543 [0.350–0.844], p = 0.024 for cohort 2). Experiments in vitro and in vivo showed that after knockdown of HOXB7, the proliferation rate dropped, growth rate descended, colony-formation ability reduced, G1-phase arrest occurred and the tumorigenicity reduced remarkably.
HOXB7 could promote cancer cell proliferation and might be an independent prognostic factor for patients with ESCC.
PMCID: PMC4468077  PMID: 26076456
11.  Genetics and gastric cancer susceptibility 
Gastric cancer has high morbidity and mortality in China. It is ranked first in malignant tumors of the digestive system. Its etiology and pathogenesis are still unclear, but they may be associated with a variety of factors. Genetic susceptibility genes have become a research hotspot in China. Elucidating the genetic mechanisms of gastric cancer can facilitate achieving individualized prevention and developing more effective methods to reduce clinical adverse consequences, which has important clinical significance. Genetic susceptibility results from the influence of genetic factors or specific genetic defects that endow an individual’s offspring with certain physiological and metabolic features that are prone to certain diseases. Currently, studies on the genetic susceptibility genes of gastric cancer have become a hotspot. The purpose is to screen for the etiology of gastric cancer, search for gene therapy methods, and ultimately provide a scientific basis for the prevention and control of gastric cancer. This article reviews the current progress of studies on genetic susceptibility genes for gastric cancer.
PMCID: PMC4538020  PMID: 26309491
Gastric cancer; genetics; susceptibility
12.  deGPS is a powerful tool for detecting differential expression in RNA-sequencing studies 
BMC Genomics  2015;16(1):455.
The advent of the NGS technologies has permitted profiling of whole-genome transcriptomes (i.e., RNA-Seq) at unprecedented speed and very low cost. RNA-Seq provides a far more precise measurement of transcript levels and their isoforms compared to other methods such as microarrays. A fundamental goal of RNA-Seq is to better identify expression changes between different biological or disease conditions. However, existing methods for detecting differential expression from RNA-Seq count data have not been comprehensively evaluated in large-scale RNA-Seq datasets. Many of them suffer from inflation of type I error and failure in controlling false discovery rate especially in the presence of abnormal high sequence read counts in RNA-Seq experiments.
To address these challenges, we propose a powerful and robust tool, termed deGPS, for detecting differential expression in RNA-Seq data. This framework contains new normalization methods based on generalized Poisson distribution modeling sequence count data, followed by permutation-based differential expression tests. We systematically evaluated our new tool in simulated datasets from several large-scale TCGA RNA-Seq projects, unbiased benchmark data from compcodeR package, and real RNA-Seq data from the development transcriptome of Drosophila. deGPS can precisely control type I error and false discovery rate for the detection of differential expression and is robust in the presence of abnormal high sequence read counts in RNA-Seq experiments.
Software implementing our deGPS was released within an R package with parallel computations ( deGPS is a powerful and robust tool for data normalization and detecting different expression in RNA-Seq experiments. Beyond RNA-Seq, deGPS has the potential to significantly enhance future data analysis efforts from many other high-throughput platforms such as ChIP-Seq, MBD-Seq and RIP-Seq.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1676-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4465298  PMID: 26070955
Next-generation sequencing; Differential expression; Generalized Poisson; RNA-Seq
13.  Design, Synthesis and Structure-Activity Relationship Studies of Novel Survivin Inhibitors with Potent Anti-Proliferative Properties 
PLoS ONE  2015;10(6):e0129807.
The anti-apoptotic protein survivin is highly expressed in most human cancer cells, but has very low expression in normal differentiated cells. Thus survivin is considered as an attractive cancer drug target. Herein we report the design and synthesis of a series of novel survivin inhibitors based on the oxyquinoline scaffold from our recently identified hit compound UC-112. These new analogs were tested against a panel of cancer cell lines including one with multidrug-resistant phenotype. Eight of these new UC-112 analogs showed IC50 values in the nanomole range in anti-proliferative assays. The best three compounds among them along with UC-112 were submitted for NCI-60 cancer cell line screening. The results indicated that structural modification from UC-112 to our best compound 4g has improved activity by four folds (2.2 μM for UC-112 vs. 0.5 μM for 4g, average GI50 values over all cancer cell lines in the NCI-60 panel).Western blot analyses demonstrated the new compounds maintained high selectivity for survivin inhibition over other members in the inhibition of apoptosis protein family. When tested in an A375 human melanoma xenograft model, the most active compound 4g effectively suppressed tumor growth and strongly induced cancer cell apoptosis in tumor tissues. This novel scaffold is promising for the development of selective survivin inhibitors as potential anticancer agents.
PMCID: PMC4466525  PMID: 26070194
14.  Extent, Nature, and Risk Factors of Workplace Violence in Public Tertiary Hospitals in China: A Cross-Sectional Survey 
Using a cross-sectional survey design from 11 public tertiary hospitals (a specialist hospital, four Chinese medicine hospitals, and six general hospitals) in the urban areas of Heilongjiang, we determined the nature of workplace violence that medical staff have encountered in Chinese hospitals and identified factors associated with those experiences of violence. A total of 1129 health workers participated. The specialist hospital had the highest prevalence of physical violence (35.4%), while the general hospitals had the highest prevalence of non-physical violence (76%). Inexperienced medical staff (p < 0.001) were more likely to suffer non-physical violence than physical violence in Chinese medicine hospitals compared to experienced staff. Medical units (p = 0.001) had a high risk of non-physical violence, while surgical units (p = 0.005) had a high risk of physical violence. In general hospitals, staff with higher levels of anxiety about workplace violence were more vulnerable to both physical violence (1.67, 95% CI 1.36–2.10) and non-physical violence (1.309, 95% CI 1.136–1.508) compared to those with lower levels of anxiety, while rotating shift workers had a higher odds of physical violence (2.2, 95% CI 1.21–4.17) and non-physical violence (1.65, 95% CI 1.13–2.41) compared to fixed day shift workers. Thus, prevention should focus not only on high-risk sections of hospitals, but also on the nature of the hospital itself.
PMCID: PMC4483731  PMID: 26086703
Chinese medicine hospitals; general hospitals; specialist hospitals; workplace violence; risk factor
15.  Effect of curcumin on permeability of coronary artery and expression of related proteins in rat coronary atherosclerosis heart disease model 
Objective: Our objective is to explore the effect of curcumin on permeability of coronary artery and expression of related proteins in rat coronary atherosclerosis heart disease model. Methods: 45 healthy male Wistar rats of clean grade were selected and divided into treatment group, model control group and blank control group. The rats in the treatment group and model control group received high-fat diet for 12 weeks and intraperitoneal injection of VD3 to establish rat coronary atherosclerosis heart disease model. After modeling, the rats in the treatment group received gavage of 100 mg/(kg·d) curcimin, and the rats in the model control group and blank control group received gavage of 5 ml/(kg·d) distilled water, the intervention time was 4 weeks. After intervention, the rats were killed, and the hearts were dissected to obtain the samples of coronary artery. After embedding and frozen section, immunofluorescence method was used to detect the change of endarterium permeability in 3 groups, Western blot was used to detect matrix metalloproteinase-9 (MMP-9) and CD40L in coronary artery tissue, and enzyme linked immunosorbent assay (ELISA) was used to detect serum tumor necrosis factor-α (TNF-α) and C reaction protein (CRP). Results: After modeling, compared with the blank control group, total cholesterol (TC), triglyceride (TG) and low density lipoprotein cholesterin (LDL-c) in the treatment group and model control group were significantly higher (P<0.05), however, high density lipoprotein cholesterin (HDL-c) was significantly lower. The pathological sections showed that there was lipidosis in rat coronary artery in treatment group and model control group, indicating that the modeling was successful. Immunofluorescence showed that there was only a little fluorochrome permeability in artery in blank control group, there was some fluorochrome permeability in artery in the treatment group and there was a lot of fluorochrome permeability in artery in the model control group. MMP-9 and CD40L in coronary artery tissue in the model control group were significantly higher than the treatment group (P<0.05), MMP-9 and CD40L in coronary artery tissue in the treatment group were significantly higher than the blank control group (P<0.05); serum TNF-α and CRP in the model control group were significantly higher than the treatment group (P<0.05), which were significantly higher in the treatment group than the blank control group (P<0.05). Conclusion: Rat coronary atherosclerosis heart disease model can be successfully established by feeding with high-fat diet and intraperitoneal injection of VD3, the permeability of coronary artery in coronary heart disease rat model is significantly increased, which may be related to up-regulation of MMP-9, CD40L, TNF-α and CRP expression. Application of curcumin can inhibit expression of MMP-9, CD40L, TNF-α and CRP to improve the permeability of coronary artery.
PMCID: PMC4525956  PMID: 26261622
Curcumin; coronary atherosclerosis heart disease; coronary artery; permeability; MMP-9; CD40L; TNF-α; CRP
16.  Outcomes of antiretroviral treatment in HIV-infected adults: a dynamic and observational cohort study in Shenzhen, China, 2003–2014 
BMJ Open  2015;5(5):e007508.
To report 10-year outcomes of virological and immunological treatment failure rates and risk factors.
Prospective cohort study.
Shenzhen, China.
2172 HIV-positive adults in the national treatment database of Shenzhen from December 2003 to January 2014.
Antiretroviral therapy according to the Chinese national treatment guidelines.
Outcome measures
Virological and immunological treatment failure rates.
Of the 3099 patients surveyed, 2172 (70.1%) were included in the study. The median age was 33 years; 78.2% were male and 51.8% were infected through heterosexual contact. The median follow-up time was 31 months (IQR, 26–38). A total of 81 (3.7%) patients died, whereas 292 (13.4%) and 400 (18.4%) patients experienced virological and immunological failures, respectively. Adjusted Cox regression analysis indicated that baseline viral load (HR=2.19, 95% CI 1.52 to 4.48 for patients with a baseline viral load greater than or equal to 1 000 000 copies/mL compared to those with less than 10 000 copies/mL) and WHO stage (HR=4.16, 95% CI 2.01 to 10.57 for patients in WHO stage IV compared with those in stage I) were significantly associated with virological failure. The strongest risk factors for immunological treatment failure were a low CD4 cell count (HR=0.46, 95% CI 0.32 to 0.66 for patients with CD4 cell counts of 50–99 cells/mm3 compared to those with less than 50 cells/mm3) and higher baseline WHO stage at treatment initiation (HR=2.15, 95% CI 1.38 to 3.34 for patients in WHO stage IV compared to those in stage I).
Sustained virological and immunological outcomes show that patients have responded positively to long-term antiretroviral treatment with low mortality. This 10-year data study provides important information for clinicians and policymakers in the region as they begin to evaluate and plan for the future needs of their own rapidly expanding programmes.
PMCID: PMC4442238  PMID: 26002691
HIV; antiretroviral; virologic failure; immunologic failure; China
17.  Hepatitis B virus X protein induces expression of alpha-fetoprotein and activates PI3K/mTOR signaling pathway in liver cells 
Oncotarget  2015;6(14):12196-12208.
The hepatitis B virus (HBV)-X protein (HBx) induces malignant transformation of liver cells, and elevated expression of alpha-fetoprotein (AFP) is a significant biomarker of hepatocarcinogenesis. However, the role of AFP in HBV-related hepatocarcinogenesis is unclear. In this study, we investigated the regulatory impact of AFP expression on HBx-mediated malignant transformation of human hepatocytes. We found that HBV induced the expression of AFP before that of oncogenes, e.g., Src, Ras and chemokine (C-X-C motif) receptor 4 (CXCR4), and AFP activated protein kinase B (AKT) and mammalian target of rapamycin (mTOR) in HBV-related HCC tissues and in human liver cells transfected with HBx. Cytoplasmic AFP interacted with and inhibited phosphatase and tensin homolog deleted on chromosome 10 (PTEN), activating the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway and promoting mTOR-mediated stimulation of the transcription factor hypoxia inducible factor-1α (HIF-1α), and therefore led to the activation of the promoters of Src, CXCR4, and Ras genes. On the contrary, reduced expression of AFP by siRNA resulted in the repression of p-mTOR, pAKT, Src, CXCR4, and Ras in human malignant liver cells. Taken together, for the first time our study indicates that HBx-induced AFP expression critically promote malignant transformation in liver cells through the activation of PI3K/mTOR signaling.
PMCID: PMC4494932  PMID: 25682869
AFP; HBx; PI3K/mTOR signaling; Liver cells; Hepatocarcinogenesis
18.  HBx induced AFP receptor expressed to activate PI3K/AKT signal to promote expression of Src in liver cells and hepatoma cells 
BMC Cancer  2015;15:362.
Hepatitis B virus (HBV)-X protein(HBx) is a transactivator of host several cellular genes including alpha-fetoprotein(AFP) and AFP receptor(AFPR) which contributes to HBV-associated tumor development. The expression of AFP/AFPR are correlated with hepatocellular carcinoma(HCC)-initial cells. But the role of AFP and AFPR in promoting occurrence of HBV-related HCC were still unclear.
A total of 71 clinical patients’ liver specimens, normal human liver cells L-02 and HCC cell lines, PLC/PRF/5 were selected for analyzing the effects of HBx on expression of AFP, AFPR and Src. The expression of goal proteins were detected by Immunohistochemical stained and Western blotting; HBx-expressed vectors were constructed and transfected into L-02 cells, laser confocal microscopy was applied to observe expression and location of AFP, AFPR and Src in the normal liver cells and HCC cells, soft agar colony formation assay was used to observe colonies formed of the cells.
We confirmed HBx gives preference to promote the expression of AFP and AFPR; HBx priors to up-regulate the expression of AFPR and AFP in L-02 cells and in normal liver specimens; AFPR signal been able to stimulate Src expression. The results also indicated that phosphatidylinositol 3-kinase(PI3K) inhibitors Ly294002 and GDC0941 effectively suppress AFPR mediated up-regulation expression of Src in AFPR positive HCC lines.
HBx priors to drive the expression of AFP and AFPR to promote expression of Src in normal liver cells and hepatoma cells; AFP and AFPR maybe play pivotal role in HBV-related hepatocarcinogenesis; Targeting AFPR is an available therapeutic strategy of HCC.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1384-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4427932  PMID: 25943101
Hepatitis B virus-x(HBx); Alpha fetoprotein(AFP)/AFP receptor; PI3K/AKT signal; Hepatoma cells
19.  MicroRNA-135b Regulates Leucine Zipper Tumor Suppressor 1 in Cutaneous Squamous Cell Carcinoma 
PLoS ONE  2015;10(5):e0125412.
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin malignancy and it presents a therapeutic challenge in organ transplant recipient patients. Despite the need, there are only a few targeted drug treatment options. Recent studies have revealed a pivotal role played by microRNAs (miRNAs) in multiple cancers, but only a few studies tested their function in cSCC. Here, we analyzed differential expression of 88 cancer related miRNAs in 43 study participants with cSCC; 32 immunocompetent, 11 OTR patients, and 15 non-lesional skin samples by microarray analysis. Of the examined miRNAs, miR-135b was the most upregulated (13.3-fold, 21.5-fold; p=0.0001) in both patient groups. Similarly, the miR-135b expression was also upregulated in three cSCC cell lines when evaluated by quantitative real-time PCR. In functional studies, inhibition of miR-135b by specific anti-miR oligonucleotides resulted in upregulation of its target gene LZTS1 mRNA and protein levels and led to decreased cell motility and invasion of both primary and metastatic cSCC cell lines. In contrast, miR-135b overexpression by synthetic miR-135b mimic induced further down-regulation of LZTS1 mRNA in vitro and increased cancer cell motility and invasiveness. Immunohistochemical evaluation of 67 cSCC tumor tissues demonstrated that miR-135b expression inversely correlated with LZTS1 staining intensity and the tumor grade. These results indicate that miR-135b functions as an oncogene in cSCC and provide new understanding into its pathological role in cSCC progression and invasiveness.
PMCID: PMC4418692  PMID: 25938461
20.  Mesenchymal-endothelial-transition contributes to cardiac neovascularization 
Nature  2014;514(7524):585-590.
Endothelial cells contribute to a subset of cardiac fibroblasts by undergoing endothelial-to-mesenchymal-transition, but whether cardiac fibroblasts can adopt an endothelial cell fate and directly contribute to neovascularization after cardiac injury is not known. Here, using genetic fate map techniques, we demonstrate that cardiac fibroblasts rapidly adopt an endothelial cell like phenotype after acute ischemic cardiac injury. Fibroblast derived endothelial cells exhibit anatomical and functional characteristics of native endothelial cells. We show that the transcription factor p53 regulates such a switch in cardiac fibroblast fate. Loss of p53 in cardiac fibroblasts severely decreases the formation of fibroblast derived endothelial cells, reduces post infarct vascular density and worsens cardiac function. Conversely, stimulation of the p53 pathway in cardiac fibroblasts augments mesenchymal to endothelial transition, enhances vascularity and improves cardiac function. These observations demonstrate that mesenchymal-to-endothelial-transition contributes to neovascularization of the injured heart and represents a potential therapeutic target for enhancing cardiac repair.
PMCID: PMC4214889  PMID: 25317562
21.  Gene expression profiling via bioinformatics analysis reveals biomarkers in laryngeal squamous cell carcinoma 
Molecular Medicine Reports  2015;12(2):2457-2464.
The present study aimed to identify key genes and relevant microRNAs (miRNAs) involved in laryngeal squamous cell carcinoma (LSCC). The gene expression profiles of LSCC tissue samples were analyzed with various bioinformatics tools. A gene expression data set (GSE51985), including ten laryngeal squamous cell carcinoma (LSCC) tissue samples and ten adjacent non-neoplastic tissue samples, was downloaded from the Gene Expression Omnibus. Differential analysis was performed using software package limma of R. Functional enrichment analysis was applied to the differentially expressed genes (DEGs) using the Database for Annotation, Visualization and Integrated Discovery. Protein-protein interaction (PPI) networks were constructed for the protein products using information from the Search Tool for the Retrieval of Interacting Genes/Proteins. Module analysis was performed using ClusterONE (a software plugin from Cytoscape). MicroRNAs (miRNAs) regulating the DEGs were predicted using WebGestalt. A total of 461 DEGs were identified in LSCC, 297 of which were upregulated and 164 of which were downregulated. Cell cycle, proteasome and DNA replication were significantly over-represented in the upregulated genes, while the ribosome was significantly over-represented in the downregulated genes. Two PPI networks were constructed for the up- and downregulated genes. One module from the upregulated gene network was associated with protein kinase. Numerous miRNAs associated with LSCC were predicted, including miRNA (miR)-25, miR-32, miR-92 and miR-29. In conclusion, numerous key genes and pathways involved in LSCC were revealed, which may aid the advancement of current knowledge regarding the pathogenesis of LSCC. In addition, relevant miRNAs were also identified, which may represent potential biomarkers for use in the diagnosis or treatment of the disease.
PMCID: PMC4464462  PMID: 25936657
laryngeal squamous cell carcinoma; differentially expressed genes; functional enrichment analysis; protein-protein interaction network; microRNA
22.  Femtosecond laser-assisted anterior lamellar keratoplasty for the treatment of stromal corneal pathology 
BMC Ophthalmology  2015;15:15.
To describe the initial outcomes and safety of anterior lamellar keratoplasty (ALK) assisted by a femtosecond laser for stromal corneal pathology.
A non-comparative case series of 14 eyes (13 patients) with various stromal corneal diseases underwent ALK with a femtosecond laser. Femtosecond laser settings, technique, uncorrected visual acuity (UCVA), best-corrected visual acuity (BCVA), and endothelial cell density (ECD) were measured.
All eyes were successfully treated without intraoperative complications. The UCVA improved in 11 eyes (78.6%) compared with preoperative UCVA. The mean difference between preoperative and postoperative UCVA was a gain of 1.7 lines (range, unchanged to 6 lines). The BCVA improved in all eyes compared with preoperative levels. The mean difference between preoperative and postoperative BCVA was a gain of 2.4 lines (range, 1–8 lines). In 3 eyes, phototherapeutic keratectomy was performed. The mean reduction in endothelial cell density was 3.7% after a mean 7.3 months of follow-up. No graft rejection, infection, or epithelial ingrowth was found.
Femtosecond laser-assisted ALK improved UCVA and BCVA in patients with stromal corneal pathology. Our early results indicated that the femtosecond laser produced an effective and smooth dissection through opaque corneas even deeper corneal tissue.
PMCID: PMC4354740  PMID: 25884506
Femotosecond laser; Anterior lamellar keratoplasty; Corneal stromal pathology; Opacity
23.  Globular adiponectin reduces vascular calcification via inhibition of ER-stress-mediated smooth muscle cell apoptosis 
Objective: This study aims to explore the mechanism of globular adiponectin inhibiting vascular calcification. Methods: We established drug-induced rat vascular calcification model, globular adiponectin was given to observe the effect of globular Adiponectin on the degree of calcification. The markers of vascular calcification and apoptosis were also investigated. Meanwhile, the in vitro effect of globular Adiponectin on vascular calcification was also evaluated using primary cultured rat vascular smooth muscle cells. Results: We found that globular adiponectin could inhibit drug-induced rat vascular calcification significantly in vivo. The apoptosis of vascular smooth muscle cells was also reduced. The possible mechanism could be the down-regulation of endoplasmic reticulum stress by globular adiponectin. Experiments in primary cultured vascular smooth muscle cells also confirmed that globular adiponectin could reduce cell apoptosis to suppress vascular calcification via inhibition of endoplasmic reticulum stress. Conclusions: This study confirmed that globular adiponectin could suppress vascular calcification; one of the mechanisms could be inhibition of endoplasmic reticulum stress to reduce cell apoptosis. It could provide an effective method in the therapy of vascular calcification-associated diseases.
PMCID: PMC4440069  PMID: 26045760
Vascular calcification; globular adiponectin; cell apoptosis; endoplasmic reticulum stress
24.  Association between Glaucoma and Obstructive Sleep Apnea Syndrome: A Meta-Analysis and Systematic Review 
PLoS ONE  2015;10(2):e0115625.
Obstructive sleep apnea syndrome (OSAS) is a common disease that increases the risk of diabetes, heart disease, and stroke. However, studies of an association between OSAS and glaucoma neuropathy have reported controversial findings.
The main purpose of this study was to evaluate whether a significant association exists between OSAS and glaucoma by performing a meta-analysis of previous studies.
A comprehensive literature search using the PubMed and Embase databases was performed to identify cross-sectional, case-control, and cohort studies related to the topic. We estimated a pooled odds ratio (OR) for the association between OSAS and glaucoma, by a fixed- or random-effects model.
In total, 16 studies with 2,278,832 participants met the inclusion criteria: one retrospective cohort study reported an adjusted hazard ratio of glaucoma of 1.67 (95% CI = 1.30–2.17). Using a fixed-effects model, the pooled OR of six case-control studies was 1.96 (95% CI = 1.37 2.80). A significant association was also identified in a meta-analysis of nine cross-sectional studies using a random-effects model, which showed a pooled OR of 1.41 (95% CI = 1.11 1.79). However, the reported pooled estimates for case control studies and cross-sectional studies were based on unadjusted ORs.
Our results suggest that OSAS is associated with the prevalence of glaucoma. However, this result was based only on unadjusted estimates. Prospective cohort studies designed to take into consideration potential confounders, or examination of data from interventional trials to determine whether a reduction in OSAS status is associated with a reduced incidence of glaucoma, are needed to clarify whether OSAS is an independent risk factor for glaucoma.
PMCID: PMC4338237  PMID: 25705901
25.  Thinner changes of the retinal nerve fiber layer in patients with mild cognitive impairment and Alzheimer’s disease 
BMC Neurology  2015;15:14.
Alzheimer’s disease (AD) is the most common form of dementia and patients often have visual disorders. Mild cognitive impairment (MCI) is characterized by a memory deficit when compared with those of a similar age and education level which could indicate an earlier onset of AD. The aim of this study is to measure the changes of the retinal nerve fiber layer (RNFL) thickness of AD and MCI patients in comparison with the normal age controls.
The RNFL thickness was assessed using optical coherence tomography (OCT) in patients with MCI, AD (mild, moderate and severe) and the age matched controls.
The thickness of RNFL in the superior quadrant and total mean values are gradually and significantly decreased from MCI to severe AD when compared to that in the controls. There is also a significant reduction of the retinal nerve fiber layer in the inferior quadrant in severe AD patients.
Our data indicate that the retinal nerve fiber layer degeneration is paralleled with dementia progression. Owing to its non-invasive and cost effective nature, monitoring RNFL thickness may have a value in assessing disease progression and the efficacy of any treatments.
PMCID: PMC4342899  PMID: 25886372
Alzheimer’s disease; Mild cognitive impairment; Retinal nerve fiber layer; Optical coherence tomography

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