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Nagashima S.,Tokyo Medical and Dental University | Bao Y.,First Hospital of China Medical University | Hata Y.,Tokyo Medical and Dental University
Current Drug Targets | Year: 2016

Yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ) co-operate with numerous transcription factors to regulate gene transcriptions. YAP1 and TAZ are negatively regulated by the tumor suppressive Hippo pathway. In human cancers, the Hippo pathway is frequently deregulated and YAP1 and TAZ escape the inhibition by the Hippo pathway. The up-regulation of YAP1 and TAZ induces epithelial-mesenchymal transition and increases drug resistance in cancer cells. TAZ is implicated in cancer stemness. In consequence cancers with hyperactive YAP1 and TAZ are associated with poor clinical prognosis. Inhibitors of YAP1 and TAZ are reasoned to be beneficial in cancer therapy. On the other hand, since YAP1 and TAZ play important roles in the regulation of various tissue stem cells and in tissue repair, activators of YAP1 and TAZ are useful in the regenerative medicine. We discuss the potential application of inhibitors and activators of YAP1 and TAZ in human diseases and review the progress of drug screenings to search for them. © 2016 Bentham Science Publishers.


Wang P.,University of Alberta | Zhang J.D.,University of Alberta | Zhang J.D.,First Hospital of China Medical University | Wu F.,University of Alberta | And 10 more authors.
Cellular Signalling | Year: 2012

SALL4 is one of the master transcriptional factors that are crucial in maintaining the pluripotency of embryonic stem cells (ESCs). While the expression of SALL4 is normally restricted to ESCs and somatic stem cells, we found that it is aberrantly expressed in ALK-positive anaplastic large cell lymphoma (ALK+ ALCL), a type of lymphoid malignancy carrying a mature T-cell immunophenotype. shRNA knockdown of SALL4 in ALK+ ALCL cell lines resulted in apoptosis and cell-cycle arrest, and significantly decreased colony formation on soft agar. These changes correlated with the downregulation of several anti-apoptotic proteins and facilitators of cell-cycle progression. Based on the differential response to a SALL4 reporter construct, we were able to separate two distinct cell subsets in Karpas 299 (an ALK+ ALCL cell line), namely SALL4high and SALL4low. Importantly, the biological effects induced by SALL4 knock-down in Karpas 299 were restricted to the purified SALL4high cells, and this finding further supports the concept that SALL4 is biologically important in ALK+ ALCL. Lastly, the expression of SALL4 was not dependent on the nucleophosmin (NPM)-anaplastic lymphoma kinase (ALK)/STAT3 signaling axis, the key oncogenic driver in ALK+ ALCL. To conclude, for the first time, our study has revealed the oncogenic contributions of an ESC protein in the pathogenesis of ALK+ ALCL. © 2012 Elsevier Inc.


PubMed | First Hospital of China Medical University and Shenyang University
Type: | Journal: OncoTargets and therapy | Year: 2016

The prognostic significance of claudin 4 (CLDN4) in patients with gastric cancer (GC) is controversial. This meta-analysis aims to assess the correlation between CLDN4 expression and clinicopathological characteristics and assess the prognostic significance of CLDN4 in GC.We searched the PubMed and Embase databases. We performed the meta-analysis with odds ratio (OR), hazard ratio (HR), and 95% confidence interval (CI) as effect values.Fourteen studies containing 2,106 patients with GC were analyzed. The overall analysis showed that CLDN4 expression was associated with increasing pT category, tumor size, and lymph node metastasis in patients with GC (pT3-T4 vs pT1-T2: OR =1.56, 95% CI =1.13-2.16; P<0.01; large tumor size vs small tumor size: OR =1.64, 95% CI =1.15-2.34; P<0.01; positive lymph node metastasis vs negative lymph node metastasis: OR =1.49, 95% CI =1.12-1.97; P<0.01). CLDN4 expression was associated with histological differentiation (differentiated type vs undifferentiated type: OR =2.90, 95% CI =1.32-6.37; P=0.01; Lauren intestinal type vs diffuse type: OR =3.51, 95% CI =1.48-8.28; P<0.01). CLDN4 expression was also strongly associated with sex and age. This meta-analysis found no significant association between CLDN4 expression and prognosis for overall survival in patients with GC (HR =0.74, 95% CI =0.43-1.27; P=0.28).Present study indicates that aberrant CLDN4 expression plays an important role in the clinicopathological characteristics of GC.


Liu L.-L.,China Medical University at Heping | Jiang Y.,First Hospital of China Medical University | Wang L.-N.,China Medical University at Heping | Yao L.,China Medical University at Heping | Li Z.-L.,China Medical University at Heping
Drugs | Year: 2012

Introduction: Whether mycophenolate mofetil is superior to cyclophosphamide as induction therapy for lupus nephritis (LN) remains controversial. Objective: Our objective was to investigate the efficacy and safety of mycophenolate mofetil compared with cyclophosphamide as induction therapy for LN patients. Methods: Randomized controlled trials (RCTs) on humans were identified in searches of PubMed/MEDLINE,EMBASE and theCochraneCentralRegister of Controlled Trials (all to 1 December 2011). Studies that compared the efficacy and safety between mycophenolate mofetil and cyclophosphamide as induction therapy in LN patients were selected. Methodological quality of the included trials was assessed according to Cochrane criteria and Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. The fixed effects model was applied for pooling where there was no significant heterogeneity, otherwise the random effects model (Dersimonian and Laird method) was performed. Results: Seven trials were identified, including 725 patients. The Dersimonian and Laird method was applied for renal remission in the presence of significant heterogeneity, and no statistically significant differences were distinguished between mycophenolate mofetil and cyclophosphamide. To explore the possible source of heterogeneity, meta-regression was performed. It was suggested that no obvious study- or patient-level factors could explain interstudy heterogeneity with statistical significance. Among all these factors, the mode of administration of cyclophosphamide could explain most of the heterogeneity, although the coefficient was insignificant. Therefore, we performed a sensitivity analysis by excluding the trial in which cyclophosphamide was administered orally instead of intravenously, which suggested that mycophenolatemofetil was more effective than intravenous cyclophosphamide for inducing complete remission (relative risk [RR] 1.72; 95% CI 1.17, 2.55; p = 0.006) and complete or partial remission (RR 1.18; 95% CI 1.04, 1.35; p = 0.01). In addition, mycophenolate mofetil was superior to cyclophosphamide for significantly reducing end-stage renal disease (ESRD) or death (RR 0.64; 95% CI 0.41, 0.98; p = 0.04). For the safety comparison, lower risks of leukopenia, amenorrhoea and alopecia, and a higher risk of diarrhoea were found with mycophenolate mofetil. No statistical differences in infection and gastrointestinal symptoms were distinguished between mycophenolate mofetil and cyclophosphamide. The relatively small number and the open-label fashion of eligible RCTs may limit the value of our meta-analysis. Conclusions: Mycophenolate mofetil is superior to intravenous cyclophosphamide for inducing renal remission, and has a significant advantage over cyclophosphamide for reducing ESRD or death. Furthermore, mycophenolate mofetil has lower risks of leukopenia, amenorrhoea and alopecia, but a higher risk of diarrhoea than cyclophosphamide. However, our conclusions need to be proved further in larger well designed trials. Adis © 2012 Springer International Publishing AG. All rights reserved.


Liu H.,University of Toronto | Liu H.,First Hospital of China Medical University | Yang P.S.,University of Toronto | Zhu T.,University of Toronto | And 9 more authors.
International Journal of Biochemistry and Cell Biology | Year: 2013

Fibrinogen-like protein 2 (FGL2), a novel effector molecule of CD4 +CD25+Foxp3+ regulatory T cells (Treg), mediates its suppressive activity through binding to low affinity Fcγ receptors expressed on antigen presenting cells (APCs). FGL2 has been implicated in the pathogenesis of viral hepatitis, xeno- and allotransplant rejection, and rheumatoid arthritis. Here we fully analyzed the structure-function relationships of recombinant murine FGL2 generated in COS-7 cells and identified the receptor binding domains. Native FGL2 exists as an oligomer with a molecular weight of approximately 260 kDa, while under reducing conditions, FGL2 has a molecular weight of 65 kDa suggesting that native FGL2 is composed of four monomers. By site-directed mutation, cysteines at positions 94, 97, 184 and 187, found in the coiled-coil domain were shown to be crucial for FGL2 oligomerization. Monomeric FGL2 had a lower affinity binding to APCs, but increased immunosuppressive activity compared to oligomeric FGL2. Deglycosylation demonstrated that sugar moieties are critical for maintaining solubility of FGL2. SWISS-MODEL analysis suggested that FGL2 has a similar tertiary structure with other members of the fibrinogen family such as fibrinogen and tachylectin. Mutational analysis of cysteine residues and Western blots suggested an asymmetric bouquet-shaped quaternary structure for oligomeric FGL2, resembling many pattern-recognition molecules in the lectin pathway of innate immunity. The functional motifs of FGL2 were mapped to the C terminal globular domain, using a peptide blockade assay. These results collectively define the biochemical and immunological determinants of FGL2, an important immunosuppressive molecule of Treg providing important insights for designing FGL2-related therapeutics. © 2012 Elsevier Ltd. All rights reserved.


Bao Y.,Harbin Medical University | Miao Y.,Harbin Medical University | Wang W.,Harbin Medical University | Qiu B.,First Hospital of China Medical University
HealthMED | Year: 2012

The pandemic influenza A (H1N1) virus emerged since 2009, and has reached worldwide. Pulmonary complications of H1N1 influenza A severely endanger survival of pregnant women. we successfully rescued a pregnant woman complicated with influenza A/H1N1 and severe pneumonia. A 32-year-old pregnant woman 36w+ was presented with fever, productive cough and dyspnea, and was diagnosed with influenza A subtype H1N1 with severe pneumonia and respiratory failure. She received assisted ventilation and other therapies and fetus was successfully delivered by cesarian section. After 39 days, the patient was clinically supported and discharged. In this report, we have discussed the greater risks to pregnant women infected with the H1N1 virus, and emphasize the importance of cesarean section to improve ventilation.


Liu L.-L.,First Hospital of China Medical University | Liu N.,First Hospital of China Medical University | Chen Y.,Central University of Costa Rica | Wang L.-N.,First Hospital of China Medical University | And 6 more authors.
Clinical and Experimental Immunology | Year: 2013

Summary: There is accumulating evidence to support a hypothesis of the activation of the lectin complement pathway in immunoglobulin A nephropathy (IgAN). The glomerular deposition of mannose-binding lectin (MBL), an initiator of the lectin pathway, has been identified, but its clinical significance has not been defined consistently. The aim of the present study was to investigate the value of glomerular MBL deposition as a useful histological biomarker in evaluating the severity and predicting the prognosis of IgAN. We included all consecutive patients with biopsy-proven primary IgAN from December 2008 to July 2010. Renal deposition of MBL was detected by immunofluorescence. The biopsy material from 131 patients (72 men) was thus used for MBL staining. The deposition of MBL was observed in a predominantly mesangial pattern in 45 patients (34·35%), which presented as global or segmental deposition. Compared with the patients without glomerular MBL deposition, those with glomerular MBL deposition had more severe proteinuria, decreased renal function, lower levels of serum albumin and a greater possibility of hypertension at the time of renal biopsy; they had more severe histological changes according to the Oxford classification (i.e. mesangial hypercellularity, segmental glomerulosclerosis, endocapillary hypercellularity and tubular atrophy/interstitial fibrosis), and their ratio presented an increase as the histopathological phenotypes segregated according to Lee's classification; furthermore, the follow-up data demonstrated that they had a lower renal remission rate. In conclusion, glomerular MBL deposition may predict a poor prognosis, and thus can be a new prognostic factor in IgA nephropathy. © 2013 British Society for Immunology.

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