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1.  Interleukin-22 ameliorates liver fibrogenesis by attenuating hepatic stellate cell activation and downregulating the levels of inflammatory cytokines 
AIM: To investigate the effect of interleukin (IL)-22 on hepatic fibrosis in mice and the possible mechanism involved.
METHODS: Liver fibrosis was induced in male BALB/c mice by CCl4. Recombinant IL-22 (rmIL-22) was administered intraperitoneally in CCl4-treated mice. Fibrosis was assessed by histology and Masson staining. The activation of hepatic stellate cells (HSCs) was investigated by analysis of α-smooth muscle actin expression. The frequencies of T helper (Th) 22 cells, Th17 cells and Th1 cells, the expression of inflammatory cytokines [IL-22, IL-17A, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), IL-6, IL-1β] and transcription factors [aryl hydrocarbon receptor (AHR), RAR-related orphan receptor (RORγt), T-bet] mRNA in the liver were investigated. In addition, the plasma levels of IL-22, IL-17A, IFN-γ, TNF-α, IL-6 and IL-1β were evaluated.
RESULTS: Significant elevations in circulating Th22 cells, Th17 cells, Th1 cells, IL-22, IL-17A, and IFN-γ were observed in the hepatic fibrosis group compared with the control group (P < 0.01). Treatment with rmIL-22 in mice with hepatic fibrosis ameliorated the severity of hepatic fibrosis, which was confirmed by lower hepatic fibrosis pathological scores (P < 0.01). RmIL-22 decreased the frequencies of Th22 cells (6.71% ± 0.97% vs 8.09% ± 0.74%, P < 0.01), Th17 cells (4.34% ± 0.37% vs 5.71% ± 0.24%, P < 0.01), Th1 cells (3.09% ± 0.49% vs 4.91% ± 0.73%, P < 0.01), and the levels of IL-22 (56.23 ± 3.08 vs 70.29 ± 3.01, P < 0.01), IL-17A (30.74 ± 2.77 vs 45.68 ± 2.71, P < 0.01), and IFN-γ (74.78 ± 2.61 vs 124.89 ± 2.82, P < 0.01). Down-regulation of IL-22, IL-17A, IFN-γ, TNF-α, IL-6, IL-1β, AHR RORγt, and T-bet gene expression in the liver was observed in the rmIL-22 group (P < 0.01).
CONCLUSION: The frequencies of Th22, Th17 and Th1 cells are elevated in hepatic fibrosis. RmIL-22 can attenuate HSC activation and down-regulate the levels of inflammatory cytokines, thereby ameliorating liver fibrogenesis.
PMCID: PMC4316095  PMID: 25663772
T helper 22 cells; T helper 17 cells; T helper 1 cells; Interleukin-22; Hepatic fibrosis
2.  Hematopoietic Stem and Progenitor Cells Can Be Enriched by Implanting Biomaterial into Spatium Intermusculare 
BioMed Research International  2015;2015:398642.
Hematopoietic stem and progenitor cells (HSPCs) have been used successfully to treat patients with cancer and disorders of the blood and immune systems. In this study, we tried to enrich HSPCs by implanting biomaterials into the spatium intermusculare of mice hind limbs. Gelatine sponges were implanted into the spatium intermusculare of mice and then retrieved after 12 days. The presence of HSPCs in the migrating cells (MCs) was detected by phenotypically probing with CD34+Sca-1+ and functionally confirming the presence of using colony-forming cell assay and assessing the long-term reconstitution ability. The frequency of CD34+, Sca-1+, and CD34+Sca-1+ cells and colony formation unit in the MCs was much higher than that in the bone marrow (BM). Moreover, transplanted MCs were able to home to BM, muscle, and spleen, which induced an efficient long-term hematopoietic reconstitution in vivo. In addition, HSPCs within the MCs originated from the BM. Furthermore, the administration of G-CSF greatly reduced the time of implantation, and increased the number of MCs and frequency of HSPCs in the MCs. These data provide compelling evidence that HSPCs can be enriched by implanting biomaterial into spatium intermusculare. Implantation of biomaterial may be seen as the first step to a proof of their applicability to clinical practice in enriching HSPCs.
PMCID: PMC4324487
3.  A Re-evaluation of CD22 Expression by Human Lung Cancer 
Cancer research  2014;74(1):263-271.
CD22 is a transmembrane glycoprotein expressed by mature B cells. It inhibits signal transduction by the B cell receptor and its co-receptor CD19. Recently it was reported that most human lung cancer cells and cell lines express CD22 making it an important new lung cancer therapeutic target (Can Res 72:5556, 2012). The objective of our studies was to independently validate these results with the goal of testing the efficacy of our CD22 immunotoxins on lung cancer cell lines. As determined by qRT-PCR analysis, we found that levels of CD22 mRNA in a panel of human lung cancer cell lines were 200–60,000- fold lower than those observed in the human CD22+ Burkitt’s lymphoma cells, Daudi. Using flow cytometry with a panel of CD22 monoclonal antibodies and Western blot analyses, we could not detect surface or intracellular expression of CD22 protein in a panel of lung cancer cell lines. In addition, the in vitro proliferation of the lung tumor cell lines was not affected by CD22 antibodies or our highly potent anti-CD22 immunotoxin. By contrast, CD22+ Daudi cells expressed high levels of CD22 mRNA and protein and were sensitive to our CD22 immunotoxin. Importantly, primary non-small cell lung cancers from over 250 patient specimens did not express detectable levels of CD22 protein as assessed by immunohistochemistry. We conclude that CD22 is not expressed at measurable levels on the surface of lung cancer cells and that these cells can not be killed by anti-CD22 immunotoxins.
PMCID: PMC3903042  PMID: 24395821
lung cancer; CD22 expression
4.  In-vivo assessment of the morphology and hemodynamic functions of the BioValsalva™ composite valve-conduit graft using cardiac magnetic resonance imaging and computational modelling technology 
The evaluation of any new cardiac valvular prosthesis should go beyond the classical morbidity and mortality rates and involve hemodynamic assessment. As a proof of concept, the objective of this study was to characterise for the first time the hemodynamics and the blood flow profiles at the aortic root in patients implanted with BioValsalva™ composite valve-conduit using comprehensive MRI and computer technologies.
Four male patients implanted with BioValsalva™ and 2 age-matched normal controls (NC) underwent cardiac magnetic resonance imaging (MRI). Phase-contrast imaging with velocity-mapping in 3 orthogonal directions was performed at the level of the aortic root and descending thoracic aorta. Computational fluid dynamic (CFD) simulations were performed for all the subjects with patient-specific flow information derived from phase-contrast MR data.
The maximum and mean flow rates throughout the cardiac cycle at the aortic root level were very comparable between NC and BioValsalva™ patients (541 ± 199 vs. 567 ± 75 ml/s) and (95 ± 46 vs. 96 ± 10 ml/s), respectively. The maximum velocity (cm/s) was higher in patients (314 ± 49 vs. 223 ± 20; P = 0.06) due to relatively smaller effective orifice area (EOA), 2.99 ± 0.47 vs. 4.40 ± 0.24 cm2 (P = 0.06), however, the BioValsalva™ EOA was comparable to other reported prosthesis. The cross-sectional area and maximum diameter at the root were comparable between the two groups. BioValsalva™ conduit was stiffer than the native aortic wall, compliance (mm2 • mmHg−1 • 10−3) values were (12.6 ± 4.2 vs 25.3 ± 0.4.; P = 0.06). The maximum time-averaged wall shear stress (Pa), at the ascending aorta was equivalent between the two groups, 17.17 ± 2.7 (NC) vs. 17.33 ± 4.7 (BioValsalva™ ). Flow streamlines at the root and ascending aorta were also similar between the two groups apart from a degree of helical flow that occurs at the outer curvature at the angle developed near the suture line.
BioValsalva™ composite valve-conduit prosthesis is potentially comparable to native aortic root in structural design and in many hemodynamic parameters, although it is stiffer. Surgeons should pay more attention to the surgical technique to maximise the reestablishment of normal smooth aortic curvature geometry to prevent unfavourable flow characteristics.
PMCID: PMC4263057  PMID: 25488105
Composite valve-conduit; Aortic valve; Aortic root; Aortic prosthesis; BioValsalva; Computational fluid dynamic
5.  miR-429 inhibits migration and invasion of breast cancer cells in vitro 
International Journal of Oncology  2014;46(2):531-538.
Accumulating evidence indicates that microRNAs (miRNAs) are involved in regulating cancer invasion and metastasis, and an increasing number of research demonstrates that miRNAs can promote or inhibit cell motility depending on genetic background of different cancers and the microenvironment. In the present study, we established an in vivo bone metastasis model of breast cancer by injecting MDA-MB-231 cells into the left ventricle of nude mice, and then screened the differentially expressed miRNAs between parental and bone-metastatic MDA-MB-231 cells using miRNA array. The results revealed that decreased expression of miR-429 was probably involved in negatively regulating bone metastasis of breast cancer cells. On the other hand, overexpression of miR-429 in MDA-MB-231 cells remarkably suppressed invasion in vitro. We identified ZEB1 and CRKL as potential targets of miR-429 by analyzing combined results from in silico search and global expression array of the same RNA samples. Immunoblot assay confirmed that miR-429 reduced their expression at protein level. Taken together, our results offer an opportunity for further understanding of the recondite mechanisms underlying the bone metastasis of breast cancer.
PMCID: PMC4277243  PMID: 25405387
miR-429; ZEB1; CRKL; breast cancer bone metastasis
6.  Absence of DICER1, CTCF, RPL22, DNMT3A, TRRAP, IDH1 and IDH2 hotspot mutations in patients with various subtypes of ovarian carcinomas 
Biomedical Reports  2014;3(1):33-37.
Cancer is caused by multiple genetic alterations within cells. Recently, large-scale sequencing has identified frequent ribonuclease type III (DICER1), CCCTC-binding factor (CTCF), ribosomal protein L22 (RPL22), DNA (cytosine-5-)-methyltransferase 3α (DNMT3A), transformation/transcription domain-associated protein (TRRAP), isocitrate dehydrogenase (IDH)1 and IDH2 hotspot mutations in diverse types of cancer. However, it remains largely unknown whether these mutations also exist in ovarian carcinomas. In the present study, a collection of 251 patients with distinct subtypes of ovarian carcinomas were recruited and sequenced for the presence of these hotspot mutations. However, no mutations in the seven genes were detected in the samples. These negative results, together with certain recent reports, indicate that the hotspot mutations in the CTCF, RPL22, DNMT3A, TRRAP, IDH1 and IDH2 genes may not be actively involved in the carcinogenesis of ovarian carcinoma. Of note, the DICER1 mutation frequency in Sertoli-Leydig cell tumor in the present study was significantly lower compared to prior observation, and therefore, it is speculated that this discrepancy may be mainly due to the small sample size analyzed in the study. In addition, among these samples, frequent polymerase (DNA directed) ε, catalytic subunit (POLE1) and ring finger protein 43 (RNF43) mutations were identified in endometrioid and mucinous ovarian carcinomas, respectively; thus DICER1, CTCF, RPL22, DNMT3A, TRRAP, IDH1 and IDH2 hotspot mutations may not play synergistic roles with POLE1 or RNF43 mutations in the carcinogenesis of endometrioid or mucinous ovarian carcinomas.
PMCID: PMC4251111  PMID: 25469243
hotspot mutations; absence; ovarian carcinoma
7.  Time-Course Changes of Steroidogenic Gene Expression and Steroidogenesis of Rat Leydig Cells after Acute Immobilization Stress 
Leydig cells secrete testosterone, which is essential for male fertility and reproductive health. Stress increases the secretion of glucocorticoid (corticosterone, CORT; in rats), which decreases circulating testosterone levels in part through a direct action by binding to the glucocorticoid receptors (NR3C1) in Leydig cells. The intratesticular CORT level is dependent on oxidative inactivation of glucocorticoid by 11β-hydroxysteroid dehydrogenase 1 (HSD11B1) in Leydig cells. In the present study, we investigated the time-course changes of steroidogenic gene expression levels after acute immobilization stress in rats. The plasma CORT levels were significantly increased 0.5, 1, 3 and 6 h after immobilization stress, while plasma testosterone levels were significantly reduced 3 and 6 h, after stress and luteinizing hormone (LH) did not change. Immobilization stress caused the down-regulation of Scarb1, Star and Cyp17a1 expression levels in the rat testis starting at the first hour of stress, ahead of the significant decreases of plasma testosterone levels. Other mRNA levels, including Cyp11a1, Hsd3b1 and Hsd17b3, began to decline after 3 h. Hsd11b1 and Nos2 mRNA levels did not change during the course of stress. Administration of glucocorticoid antagonist RU486 significantly restored plasma testosterone levels. In conclusion, Scarb1, Star and Cyp17a1 expression levels are more sensitive to acute stress, and acute immobilization stress causes the decline of the steroidogenic pathway via elevating the levels of glucocorticoid, which binds to NR3C1 in Leydig cells to inhibit steroidogenic gene expression.
PMCID: PMC4264210  PMID: 25405735
acute stress; Leydig cell; steroidogenic enzymes; rat; corticosterone; StAR
8.  Zinc-Finger Protein 545 Inhibits Cell Proliferation as a Tumor Suppressor through Inducing Apoptosis and is Disrupted by Promoter Methylation in Breast Cancer 
PLoS ONE  2014;9(10):e110990.
Krüppel-associated box-containing zinc finger proteins (KRAP-ZFPs) are well recognized as key regulators of transcription, which play a crucial role in the regulation of cell proliferation, differentiation, apoptosis and tumorigenesis. We previously identified a KRAP-ZFP protein ZNF545 acting as a tumor suppressor involved in tumor pathogenesis. However, its expression and biological function in breast cancer remain elusive. In this study, we found that ZNF545 was frequently downregulated in estrogen receptor-positive (ER+), progesterone receptor-positive (PR+) and human epidermal growth factor receptor 2-negative (HER2−) breast tumor tissues compared with paired adjacent non-tumor tissues. We further examined its expression and methylation in breast cancer cell lines by semi-quantitative RT-PCR and methylation-specific PCR. We found that ZNF545 was silenced by promoter methylation in MCF7 cell line, and its expression could be restored by demethylation, concomitant with increased unmethylated alleles. ZNF545 methylation was detected in 29% of breast tumor tissues, but not in normal breast tissues, suggesting tumor-specific methylation of ZNF545 in breast cancer. Ectopic expression of ZNF545 in MCF7 cells inhibited cell proliferation through inducing cell cycle G0/G1 arrest and apoptosis, thus as a tumor suppressor. Moreover, ZNF545 upregulated mRNA and protein levels of c-Jun/AP1, BAX, p53 and Caspase 3. Taken together, these results demonstrate that ZNF545 inhibits breast tumor cell proliferation through inducing apoptosis and is disrupted by promoter methylation in breast cancer.
PMCID: PMC4215924  PMID: 25360542
9.  Contrast-enhanced ultrasound: Improving the preoperative staging of hepatocellular carcinoma and guiding individual treatment 
World Journal of Gastroenterology : WJG  2014;20(35):12628-12636.
AIM: To investigate the clinical role of contrast-enhanced ultrasound (CEUS) combined with contrast-enhanced computed tomography (CE-CT) or magnetic resonance imaging to improve the preoperative staging of hepatocellular carcinoma (HCC) and guide surgical decision-making.
METHODS: Sixty-nine patients who underwent liver resection for HCC in our center were enrolled prospectively in the study. CEUS and CE-CT/MRI were performed before surgery. Intraoperative ultrasound (IOUS) was carried out after liver mobilization. Lesions depicted by each imaging modality were counted and mapped. To investigate the impact of tumor size on the study, we divided the patients into two groups, the “Smaller group”(S-group, ≤ 5 cm in diameter) and the “Larger-group” (L-group, > 5 cm in diameter). The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of CE-CT/MRI, CEUS, IOUS, CEUS+CE-CT/MRI and the tumor node metastasis staging of tumors were calculated and compared. Changes in the surgical strategy as a result of CEUS and IOUS were analyzed.
RESULTS: One hundred and twenty-seven nodules, comprising 94 HCCs confirmed by histopathology and 33 benign lesions confirmed by histopathology and follow-up, were identified in 69 patients. The overall diagnostic sensitivity rates of CE-CT/MRI, CEUS, IOUS and CEUS+ CE-CT/MRI were 78.7%, 89.4%, 89.4% and 89.4%, respectively. There was a significant difference between CEUS + CE-CT/MRI and CE-CT/MRI (P = 0.046). Combining CEUS with CT or MRI increased, the diagnostic specificity compared with CT/MRI, CEUS and IOUS, and this difference was statistically significant (100%, 72.7%, 97.0%, and 69.7%, P = 0.004, P = 0.002, P = 0.002, respectively). The diagnostic accuracy was significantly higher for CEUS + CT/MRI compared with CT/MRI (92.1% vs 77.2%, P = 0.001). The TNM staging of tumors based on CEUS + CE-CT/MRI approximated to the final pathological TNM staging (P = 0.977). There was a significant difference in the accuracy of TNM staging when comparing CEUS + CE-CT/MRI with CE-CT/MRI (P = 0.002). Before surgery, strategies were changed in 15.9% (11/69) of patients as a result of CEUS. Finally, only 5.7% (4/69) of surgical strategies were changed because of IOUS findings. In the S-group, CEUS revealed 12 false positive lesions, including seven false positive lesions that were diagnosed by preoperative imaging examinations and five by IOUS. In contrast, in the L-group, IUOS revealed eight new malignant lesions; six of these lesions were true HCCs that were also identified by preoperative CEUS.
CONCLUSION: CEUS combined with CT or MRI improves the accuracy of preoperative staging for hepatocellular carcinoma and may help to guide individualized treatment for patients with HCC. CEUS may better identify non-malignant lesions in patients with small tumors and discover new malignant lesions in patients with large tumors.
PMCID: PMC4168101  PMID: 25253968
Hepatocellular carcinoma; Contrast-enhanced ultrasound; Tumor node metastasis staging; Intraoperative ultrasound; Liver resection
10.  Integrating Multi-Omics for Uncovering the Architecture of Cross-Talking Pathways in Breast Cancer 
PLoS ONE  2014;9(8):e104282.
Cross-talk among abnormal pathways widely occurs in human cancer and generally leads to insensitivity to cancer treatment. Moreover, alterations in the abnormal pathways are not limited to single molecular level. Therefore, we proposed a strategy that integrates a large number of biological sources at multiple levels for systematic identification of cross-talk among risk pathways in cancer by random walk on protein interaction network. We applied the method to multi-Omics breast cancer data from The Cancer Genome Atlas (TCGA), including somatic mutation, DNA copy number, DNA methylation and gene expression profiles. We identified close cross-talk among many known cancer-related pathways with complex change patterns. Furthermore, we identified key genes (linkers) bridging these cross-talks and showed that these genes carried out consistent biological functions with the linked cross-talking pathways. Through identification of leader genes in each pathway, the architecture of cross-talking pathways was built. Notably, we observed that linkers cooperated with leaders to form the fundamentation of cross-talk of pathways which play core roles in deterioration of breast cancer. As an example, we observed that KRAS showed a direct connection to numerous cancer-related pathways, such as MAPK signaling pathway, suggesting that it may be a central communication hub. In summary, we offer an effective way to characterize complex cross-talk among disease pathways, which can be applied to other diseases and provide useful information for the treatment of cancer.
PMCID: PMC4138095  PMID: 25137136
11.  Beclin 1 Expression is Closely Linked to Colorectal Carcinogenesis and Distant Metastasis of Colorectal Carcinoma 
Beclin 1 participates in development, autophagy, differentiation, anti- apoptosis, neurodegeneration, tumorigenesis and cancer progression. The roles of Beclin 1 in colorectal carcinogenesis and its subsequent progression are still unclear. Here, the mRNA and protein expression of Beclin 1 were determined in colorectal carcinoma and matched mucosa by Reverse transcriptase-polymerase chain reaction and Western blot. Immunohistochemistry and in situ hybridization (ISH) were performed on tissue microarryer with colorectal carcinoma, adenoma and mucosa. The expression of Beclin 1 mRNA and protein was found to be higher in colorectal carcinoma than matched mucosa by real-time PCR and Western blot (p < 0.05). According to the ISH data, Beclin 1 expression was lower in colorectal non-neoplastic mucosa (NNM) than adenoma and carcinoma (p < 0.05). Immunohistochemically, primary carcinoma showed stronger Beclin 1 expression than NNM and metastatic carcinoma in the liver (p < 0.05). Beclin 1 protein expression was negatively related to liver and distant metastasis (p < 0.05), but not correlated with age, sex, depth of invasion, lymphatic or venous invasion, lymph node metastasis, tumor-node-metastasis (TNM) staging, differentiation or serum carcinoembryonic antigen (CEA) concentration (p > 0.05). Survival analysis indicated that Beclin 1 expression was not linked to favorable prognosis of the patients with colorectal carcinoma (p > 0.05). Cox’s model indicated that depth of invasion and distant metastasis were independent prognostic factors for colorectal carcinomas (p < 0.05). It was suggested that Beclin 1 expression is closely linked to colorectal carcinogenesis and distant metastasis of colorectal carcinoma.
PMCID: PMC4159856  PMID: 25196438
colorectal carcinoma; Beclin 1; tumorigenesis; pathogenesis; prognosis
12.  Identifying dysfunctional miRNA-mRNA regulatory modules by inverse activation, cofunction, and high interconnection of target genes: A case study of glioblastoma 
Neuro-Oncology  2013;15(7):818-828.
Accumulating evidence demonstrates that complex diseases may arise from cooperative effects of multiple dysfunctional miRNAs. Thus, identifying abnormal functions cooperatively regulated by multiple miRNAs is useful for understanding the pathogenesis of complex diseases.
In this study, we proposed a multistep method to identify dysfunctional miRNA-mRNA regulatory modules (dMiMRMs) in a specific disease, in which a group of miRNAs cooperatively regulate a group of target genes involved in a specific function. We identified dysfunctional miRNAs, which were differentially expressed and inversely regulated most of their target genes, by integrating paired miRNA and mRNA expression profiles and miRNA target information. Then, we identified cooperative functional units, in each of which a pair of miRNAs cooperatively repressed function-enriched and highly interconnected target genes. Finally, the cooperative functional units were assembled into dMiMRMs.
We applied our method to glioblastoma (GBM) and identified GBM-associated dMiMRMs at the population, subtype, and individual levels. We identified 5 common dMiMRMs using all GBM samples, 3 of which were associated with the prognosis in patients with GBM and were better predictors of prognosis than were miRNAs or mRNAs alone. By applying our approach to GBM subtypes, we found consistent dMiMRMs across GBM subtypes, and some subtype-specific dMiMRMs were observed. Furthermore, personalized dMiMRMs were identified, suggesting significant individual differences in different patients with GBM.
Our method provides the capability to identify miRNA-mediated dysfunctional mechanisms underlying complex diseases.
PMCID: PMC3688007  PMID: 23516263
cooperation; glioblastoma; miRNA-mRNA regulatory module; miRNA and mRNA expression profiles
13.  Biowire: a new platform for maturation of human pluripotent stem cell derived cardiomyocytes 
Nature methods  2013;10(8):781-787.
Directed differentiation protocols enable derivation of cardiomyocytes from human pluripotent stem cells (hPSC) and permit engineering of human myocardium in vitro. However, hPSC-derived cardiomyocytes are reflective of very early human development, limiting their utility in the generation of in vitro models of mature myocardium. Here, we developed a new platform that combines three-dimensional cell cultivation in a microfabricated system with electrical stimulation to mature hPSC-derived cardiac tissues. We utilized quantitative structural, molecular and electrophysiological analyses to elucidate the responses of immature human myocardium to electrical stimulation and pacing. We demonstrated that the engineered platform allowed for the generation of 3-dimensional, aligned cardiac tissues (biowires) with frequent striations. Biowires submitted to electrical stimulation markedly increased myofibril ultrastructural organization, displayed elevated conduction velocity and altered both the electrophysiological and Ca2+ handling properties versus non-stimulated controls. These changes were in agreement with cardiomyocyte maturation and were dependent on the stimulation rate.
PMCID: PMC4071061  PMID: 23793239 CAMSID: cams3996
14.  Elevated Urinary Levels of Cystatin C and Neutrophil Gelatinase-Associated Lipocalin in Henoch-Schönlein Purpura Patients with Renal Involvement 
PLoS ONE  2014;9(6):e101026.
Henoch-Schönlein purpura (HSP) is a commonest systemic vasculitis in childhood. The long-term prognosis of HSP is determined by the degree of renal involvement. The aim of this study is to search novel clinically applicable biomarkers to evaluate renal involvement in HSP patients. 20 bio-indexes in urine samples were simultaneously screened by antibody array assay. We indicated that urinary levels of cystatin C (Cys C) and neutrophil gelatinase-associated lipocalin (NGAL) in HSP patients with renal involvement were significantly higher than those without renal involvement and healthy controls. Furthermore, ELISA was used to analyze urinary Cys C and NGAL levels in HSP patients with or without renal involvement, atopic dermatitis (AD) patients and healthy controls. Our results demonstrated that urinary Cys C and NGAL levels in HSP patients with renal involvement were significantly elevated, when compared with those without renal involvement, AD patients and control subjects. In addition, by receiver operating characteristic (ROC) curve analysis, we demonstrated that the area under the ROC curve of NGAL (0.789) was larger than that of Cys C (0.692). Taken together, we show firstly that urinary Cys C and NGAL levels is abnormally elevated in HSP patients with renal involvement. We suggest that urinary Cys C and NGAL are novel useful biomarkers of renal involvement in HSP patients.
PMCID: PMC4070996  PMID: 24963810
15.  Prioritising risk pathways of complex human diseases based on functional profiling 
Analysis of the biological pathways involved in complex human diseases is an important step in elucidating the pathogenesis and mechanism of diseases. Most pathway analysis approaches identify disease-related biological pathways using overlapping genes between pathways and diseases. However, these approaches ignore the functional biological association between pathways and diseases. In this paper, we designed a novel computational framework for prioritising disease-risk pathways based on functional profiling. The disease gene set and biological pathways were translated into functional profiles in the context of GO annotations. We then implemented a semantic similarity measurement for calculating the concordance score between a functional profile of disease genes and a functional profile of pathways (FPP); the concordance score was then used to prioritise and infer disease-risk pathways. A freely accessible web toolkit, ‘Functional Profiling-based Pathway Prioritisation' (FPPP), was developed ( During validation, our method successfully identified known disease–pathway pairs with area under the ROC curve (AUC) values of 96.73 and 95.02% in tests using both pathway randomisation and disease randomisation. A robustness analysis showed that FPPP is reliable even when using data containing noise. A case study based on a dilated cardiomyopathy data set indicated that the high-ranking pathways from FPPP are well known to be linked with this disease. Furthermore, we predicted the risk pathways of 413 diseases by using FPPP to build a disease similarity landscape that systematically reveals the global modular organisation of disease associations.
PMCID: PMC3658188  PMID: 23047740
complex human diseases; prioritising risk pathways; functional profiling; concordance score
16.  Comparison of long non-coding RNAs, microRNAs and messenger RNAs involved in initiation and progression of esophageal squamous cell carcinoma 
Molecular Medicine Reports  2014;10(2):652-662.
Traditionally, cancer research has focused on protein-coding genes, which are considered the principal effectors and regulators of tumorigenesis. Non-coding RNAs, in particular microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have been widely reported to be important in the regulation of tumorigenesis and cancer development. However, to the best of our knowledge, investigation of the expression profiles of lncRNAs and a comparison of the involvement of lncRNAs, miRNAs and messenger RNAs (mRNAs) in esophageal tumorigenesis and development have not previously been performed. In the current study, intrinsic associations among the expression profiles of lncRNAs, miRNAs and mRNAs from normal esophageal tissues and those from cancer tissues were investigated. Oligonucleotide microarrays were used to detect the expression profiles of the three types of RNA in the canceration processes of human esophageal squamous cell carcinoma (ESCC) tissues. It was demonstrated that the different RNAs exhibit associated patterns of expression among normal esophageal epithelium, low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), and carcinoma tissues, particularly in the critical period of canceration (HGIN to ESCC). Furthermore, the results indicated a high level of similarity in the potential function of lncRNAs, miRNAs and mRNAs in the processes of ESCC development. In the current study, a first generation atlas of lncRNA profiling and its association with miRNAs and mRNAs in the canceration processes of ESCC were presented.
PMCID: PMC4094766  PMID: 24888564
long non-coding RNA; microRNA; messenger RNA; esophageal squamous cell carcinoma; canceration processes; bioinformatic analysis
17.  Banana ethylene response factors are involved in fruit ripening through their interactions with ethylene biosynthesis genes 
Journal of Experimental Botany  2013;64(8):2499-2510.
The involvement of ethylene response factor (ERF) transcription factor (TF) in the transcriptional regulation of ethylene biosynthesis genes during fruit ripening remains largely unclear. In this study, 15 ERF genes, designated as MaERF1–MaERF15, were isolated and characterized from banana fruit. These MaERFs were classified into seven of the 12 known ERF families. Subcellular localization showed that MaERF proteins of five different subfamilies preferentially localized to the nucleus. The 15 MaERF genes displayed differential expression patterns and levels in peel and pulp of banana fruit, in association with four different ripening treatments caused by natural, ethylene-induced, 1-methylcyclopropene (1-MCP)-delayed, and combined 1-MCP and ethylene treatments. MaERF9 was upregulated while MaERF11 was downregulated in peel and pulp of banana fruit during ripening or after treatment with ethylene. Furthermore, yeast-one hybrid (Y1H) and transient expression assays showed that the potential repressor MaERF11 bound to MaACS1 and MaACO1 promoters to suppress their activities and that MaERF9 activated MaACO1 promoter activity. Interestingly, protein–protein interaction analysis revealed that MaERF9 and -11 physically interacted with MaACO1. Taken together, these results suggest that MaERFs are involved in banana fruit ripening via transcriptional regulation of or interaction with ethylene biosynthesis genes.
PMCID: PMC3654433  PMID: 23599278
Banana; ERF; ethylene biosynthesis; fruit ripening; interaction; transcriptional regulation.
18.  The DNA Methylome and Transcriptome of Different Brain Regions in Schizophrenia and Bipolar Disorder 
PLoS ONE  2014;9(4):e95875.
Extensive changes in DNA methylation have been observed in schizophrenia (SC) and bipolar disorder (BP), and may contribute to the pathogenesis of these disorders. Here, we performed genome-scale DNA methylation profiling using methylated DNA immunoprecipitation followed by sequencing (MeDIP-seq) on two brain regions (including frontal cortex and anterior cingulate) in 5 SC, 7 BP and 6 normal subjects. Comparing with normal controls, we identified substantial differentially methylated regions (DMRs) in these two brain regions of SC and BP. To our surprise, different brain regions show completely distinct distributions of DMRs across the genomes. In frontal cortex of both SC and BP subjects, we observed widespread hypomethylation as compared to normal controls, preferentially targeting the terminal ends of the chromosomes. In contrast, in anterior cingulate, both SC and BP subjects displayed extensive gain of methylation. Notably, in these two brain regions of SC and BP, only a few DMRs overlapped with promoters, whereas a greater proportion occurs in introns and intergenic regions. Functional enrichment analysis indicated that important psychiatric disorder-related biological processes such as neuron development, differentiation and projection may be altered by epigenetic changes located in the intronic regions. Transcriptome analysis revealed consistent dysfunctional processes with those determined by DMRs. Furthermore, DMRs in the same brain regions from SC and BP could successfully distinguish BP and/or SC from normal controls while differentially expressed genes could not. Overall, our results support a major role for brain-region-dependent aberrant DNA methylation in the pathogenesis of these two disorders.
PMCID: PMC4002434  PMID: 24776767
19.  Experimental Study of Local Inner Ear Gene Therapy for Controlling Autoimmune Sensorineural Hearing Loss 
BioMed Research International  2014;2014:134658.
This study aimed to investigate the efficacy of gene therapy for treating autoimmune sensorineural hearing loss (ASHL) via local administration of a recombinant adenovirus vector containing the Fas ligand or interleukin IL-10 gene. Guinea pigs were divided into four groups, with different microinjections in the scala tympani. Group A were injected with FasL-EGFP, B with IL-10-EGFP, C with EGFP, and D with artificial perilymph. Seven days later, auditory brain-stem response (ABR) was tested, and the temporal bone was stained and observed by light microscopy. The spiral ligament and basement membrane were observed using transmission electron microscopy. FasL and IL-10 expression were examined using immunofluorescence histochemistry. Immunohistochemical analysis showed that the recombinant adenovirus vector in Groups A, B, and C can transfect the stria vascularis, the spiral ligament, the organ of Corti, the spiral ganglion, the region surrounding the small blood vessel in the modiolus, and the cochlear bone wall. Compared with those in Groups C and D, the ABR wave III mean thresholds were significantly lower and the inner ear immunoinflammatory responses in Groups A and B were significantly alleviated. Inhibition of immunoinflammatory response alleviated immunoinflammatory injury and auditory dysfunction. This technique shows potential as a novel therapy for ASHL.
PMCID: PMC3997895  PMID: 24804196
20.  Downregulated inhibitor of growth 3 (ING3) expression during colorectal carcinogenesis 
Background & objectives:
ING3 (inhibitor of growth protein 3) overexpression decreased S-phase cell population and colony-forming efficiency, and induced apoptosis at a p53-mediated manner. The aim of this study was to investigate the clinicopathological and prognostic significance of ING3 expression in colorectal carcinogenesis and subsequent progression.
ING3 expression was examined by immunohistochemistry on tissue microarray containing colorectal non-neoplastic mucosa (NNM), adenoma and adenocarcinoma. Colorectal carcinoma tissue and cell lines were studied for ING3 expression by Western blot or RT-PCR.
ING3 mRNA was differentially expressed in Colo201, Colo205, DLD-1, HCT-15, HCT-116, HT-29, KM-12, SW480, SW620 and WiDr cells. Carcinomas showed significantly lower ING3 expression than matched NNM at mRNA level (P< 0.05), but not at protein level. Immunohistochemically, ING3 expression was significantly decreased from NNM, adenoma to adenocarcinoma (P< 0.05). ING3 expression was not correlated with age, sex, tumour size, depth of invasion, lymphatic or venous invasion, lymph node metastasis, tumour- node- metastasis staging or differentiation. Kaplan-Meier analysis indicated that ING3 protein expression was not associated the prognosis of the patients with colorectal carcinoma (P< 0.05).
Interpretation & conclusions:
Our study showed that downregulated ING3 expression might play an important role in colorectal adenoma-adenocarcinoma sequence. Further studies are required to understand the mechanism.
PMCID: PMC4078494  PMID: 24927342
Carcinogenesis; colorectal carcinoma; ING3; prognosis; progression
21.  Anti-cocaine antibody and butyrylcholinesterase-derived cocaine hydrolase exert cooperative effects on cocaine pharmacokinetics and cocaine-induced locomotor activity in mice 
Chemico-biological interactions  2012;203(1):212-216.
We are investigating treatments for cocaine abuse based on viral gene transfer of a cocaine hydrolase (CocH) derived from human butyrylcholinesterase, which can reduce cocaine-stimulated locomotion and cocaine-primed reinstatement of drug-seeking behavior in rats for many months. Here, in mice, we explored the possibility that anti-cocaine antibodies can complement the actions of CocH to reduce cocaine uptake in brain and block centrally-evoked locomotor stimulation. Direct injections of test proteins showed that CocH (0.3 or 1 mg/kg) was effective by itself in reducing drug levels in plasma and brain of mice given cocaine (10 mg/kg, s.c., or 20 mg/kg, i.p). Administration of cocaine antibody per se at a low dose (8 mg/kg, i.p.) exerted little effect on cocaine distribution. However, a higher dose of antibody (12 mg/kg) caused peripheral trapping (increased plasma drug levels), which led to increased cocaine metabolism by CocH, as evidenced by a 6-fold rise in plasma benzoic acid. Behavioral tests with small doses of CocH and antibody (1 and 8 mg/kg, respectively) showed that neither agent alone reduced mouse locomotor activity triggered by a very large cocaine dose (100 mg/kg, i.p.). However, dual treatment completely suppressed the locomotor stimulation. Altogether, we found cooperative and possibly synergistic actions that warrant further exploration of dual therapies for treatment of cocaine abuse.
PMCID: PMC3572300  PMID: 22960160
22.  The Prognostic Value of CXCR4 in Ovarian Cancer: A Meta-Analysis 
PLoS ONE  2014;9(3):e92629.
Recent reports have shown that C-X-C chemokine receptor 4 (CXCR4) is expressed in ovarian cancer and plays an important role in metastasis. However, the prognostic value of CXCR4 in ovarian cancer remains controversial and has not been emphasized. The aim of this study is to evaluate the prognostic significance of CXCR4 in ovarian cancer by performing a meta-analysis.
We systematically searched for studies evaluating the relationship between CXCR4 expression and the outcome of ovarian cancer patients. Only articles in which CXCR4 expression was detected by immunohistochemical staining were included. Hazard ratios (HRs) and relative risk (RR) with 95% confidence intervals (CIs) were pooled as effect size (ES) across studies for overall survival (OS) and progression-free survival (PFS).
A total of 729 patients from 7 studies (6 articles) were included in this meta-analysis. Our results showed that high CXCR4 expression was significantly associated with poor prognosis in terms of OS (ES, 2.81; 95% CI, 1.16–6.80; p = 0.022) and PFS (ES, 8.48; 95% CI, 2.13–33.70; p = 0.002) in ovarian cancer patients. The association between high CXCR4 expression and poor ovarian cancer prognosis in OS was also statistically significant in subgroups of Asian and III-IV patients constituting 70%.
The present meta-analysis indicated that high CXCR4 expression was associated with poor prognosis in ovarian cancer. More studies, especially larger scale and well-matched researches, are warranted to clarify the prognostic effect of CXCR4 on the outcome of ovarian cancer.
PMCID: PMC3962452  PMID: 24658065
23.  Cancer-Risk Module Identification and Module-Based Disease Risk Evaluation: A Case Study on Lung Cancer 
PLoS ONE  2014;9(3):e92395.
Gene expression profiles have drawn broad attention in deciphering the pathogenesis of human cancers. Cancer-related gene modules could be identified in co-expression networks and be applied to facilitate cancer research and clinical diagnosis. In this paper, a new method was proposed to identify lung cancer-risk modules and evaluate the module-based disease risks of samples. The results showed that thirty one cancer-risk modules were closely related to the lung cancer genes at the functional level and interactional level, indicating that these modules and genes might synergistically lead to the occurrence of lung cancer. Our method was proved to have good robustness by evaluating the disease risk of samples in eight cancer expression profiles (four for lung cancer and four for other cancers), and had better performance than the WGCNA method. This method could provide assistance to the diagnosis and treatment of cancers and a new clue for explaining cancer mechanisms.
PMCID: PMC3958511  PMID: 24643254
24.  Distribution of endothelial progenitor cells in tissues from patients with gastric cancer 
Oncology Letters  2014;7(5):1695-1700.
It is accepted that endothelial progenitor cells (EPCs) are recruited into tumor sites and take part in the neovascularization of tumors. However, few articles have discussed the specific distribution of EPCs in vivo in tissues of gastric cancer patients. For this reason, the present study sought to elucidate EPC distribution in vivo in tissues of patients with gastric cancer. Fresh tumor tissues were collected from 26 newly diagnosed patients with histologically confirmed gastric cancer (mean age, 51 years; range, 21–81 years; 7 females, 19 males). All patients were treated surgically with curative intent. One portion of the fresh tissues was prepared for flow cytometric analysis and another was immediately snap frozen in liquid nitrogen and stored at −80°C for later use in quantitative polymerase chain reaction. The analysis was based on two groups of tissues, namely the cancer group and cancer-adjacent group. The presence of CD34/CD133 double-positive cells was determined in cancer-adjacent and cancer tissues by flow cytometry. The analysis revealed that the total number of EPCs in cancer tissue was slightly greater than the number in the cancer-adjacent tissue, but not to the point of statistical significance. The number of EPCs in cancer-adjacent and cancer tissues of patients with early-stage gastric cancer was higher than the EPC count in late-stage gastric cancer patients, and significant differences were identified in the number of EPCs in cancer tissue between patients of different tumor stages. Levels of cluster of differentiation (CD)34, CD133 and vascular endothelial growth factor receptor 2 were not significantly different in cancer-adjacent tissue compared with cancer tissue. These results suggest that cancer-adjacent and cancer tissue of gastric cancer patients may be used as a reference index in the clinical and pathological staging of tumors.
PMCID: PMC3997668  PMID: 24765203
endothelial progenitor cells; gastric cancer; distribution
25.  Changed trends of major causes of visual impairment in Sichuan, China from 1987 to 2006 
To study the trends of major causes of visual impairment (VI) in adults in Sichuan, China and evaluate the effect of aging on the trends.
We used data from the National Sample Survey on Disabilities (NSSD) in Sichuan province conducted in 1987 and 2006. The age-adjusted prevalence of major causes of VI and the prevalence stratified by age in each cause were calculated and compared. The association between age and each cause of VI was also analyzed.
Retinal disease increased and became the second leading cause of VI in 2006 while blinding trachoma decreased markedly. Cataract and non-trachomatous corneal diseases were among the leading causes of VI in both years. We found associations between age and causes of VI, with age showing the strongest association with cataract and relatively lower associations with other causes.
In the last two decades, dramatic changes occurred in the major causes of VI with significantly increased retinal disease and decreased blinding trachoma. Aging of the population might be an important factor accounting for the changed trends of VI. Understanding the prevalence of VI, its major causes and trends over time can assist in prioritizing and developing effective interventional strategies and monitoring their impact.
PMCID: PMC3949475  PMID: 24634880
visual impairment; prevalence; trachoma; non-trachomatous corneal disease; cataract; retinal disease; glaucoma; eye trauma

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