The First Hospital of China Medical University

Chaoyang, China

The First Hospital of China Medical University

Chaoyang, China
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Wang Y.,The First Hospital of China Medical University | Ma Y.,University College of Applied Sciences | Hu J.,Essential Qualities Oriented Education College | Cheng W.,University College of Applied Sciences | And 5 more authors.
Neuroscience | Year: 2015

Chronic stress during critical periods of human fetal brain development is associated with cognitive, behavioral, and mood disorders in later life. Altered glutamate receptor (GluR) expression has been implicated in the pathogenesis of stress-dependent disorders. To test whether prenatal chronic mild stress (PCMS) enhances offspring's vulnerability to stress-induced behavioral and neurobiological abnormalities and if this enhanced vulnerability is sex-dependent, we measured depression-like behavior in the forced swimming test (FST) and regional changes in GluR subunit expression in PCMS-exposed adult male and female rats. Both male and female PCMS-exposed rats exhibited stronger depression-like behavior than controls. Males and females exhibited unique regional changes in GluR expression in response to PCMS alone, FST alone (CON-FST), and PCMS with FST (PCMS-FST). In females, PCMS alone did not alter N-methyl- d-aspartate receptor (NMDAR) or metabotropic glutamate receptor (mGluR) expression, while in PCMS males, higher mGluR2/3, mGluR5, and NR1 expression levels were observed in the prefrontal cortex. In addition, PCMS altered the change in GluR expression induced by acute stress (the FST test), and this too was sex-specific. Male PCMS-FST rats expressed significantly lower mGluR5 levels in the hippocampus, lower mGluR5, NR1, postsynaptic density protein (PSD)95, and higher mGluR2/3 in the prefrontal cortex, and higher mGluR5 and PSD95 in the amygdala than male CON-FST rats. Female PCMS-FST rats expressed lower NR1 in the hippocampus, lower NR2B and PSD95 in the prefrontal cortex, lower mGluR2/3 in the amygdala, and higher PSD95 in the amygdala than female CON-FST rats. PCMS may increase the offspring's vulnerability to depression by altering sex-specific stress-induced changes in glutamatergic signaling. © 2015.


Boku S.,Hokkaido University | Nakagawa S.,Hokkaido University | Masuda T.,Hokkaido University | Masuda T.,Dainippon Sumitomo | And 8 more authors.
Progress in Neuro-Psychopharmacology and Biological Psychiatry | Year: 2011

Neurogenesis in the adult dentate gyrus (DG) is considered to be partly involved in the action of mood stabilizers. However, it remains unclear how mood stabilizers affect neural precursor cells in adult DG. We have established a culture system of adult rat DG-derived neural precursor cells (ADP) and have shown that lithium, a mood stabilizer, and dexamethasone, an agonist of glucocorticoid receptor, reciprocally regulate ADP proliferation. Neurogenesis constitutes not only proliferation of neural precursor cells but also apoptosis and differentiation. To develop further understanding of mood stabilizer effects on neural precursor cells in adult DG, we investigated and compared the effects of four common mood stabilizers-lithium, valproate, carbamazepine, and lamotrigine-on ADP proliferation, apoptosis, and differentiation. ADP proliferation, decreased by dexamethasone, was examined using Alamar Blue assay. Using TUNEL assay, ADP apoptosis induced by staurosporine was examined. The differentiated ADP induced by retinoic acid was characterized by immunostaining with anti-GFAP or anti-Tuj1 antibody. Lithium and valproate, but not carbamazepine and lamotrigine, recovered ADP proliferation decreased by dexamethasone. All four mood stabilizers decreased ADP apoptosis. Retinoic acid differentiated ADP into both neurons and astrocytes. Lithium and carbamazepine increased the ratio of neurons and decreased that of astrocytes. However, valproate and lamotrigine increased the ratio of astrocytes and decreased that of neurons. Therefore, these four stabilizers exhibited both common and differential effects on ADP proliferation, apoptosis, and differentiation. © 2010 Elsevier Inc.


Soria J.-C.,University Paris - Sud | Wu Y.-L.,Guangdong General Hospital and Guangdong Academy of Medical science | Nakagawa K.,Kinki University | Kim S.-W.,University of Ulsan | And 15 more authors.
The Lancet Oncology | Year: 2015

Optimum management strategies for patients with advanced non-small-cell lung cancer (NSCLC) with acquired resistance to EGFR tyrosine-kinase inhibitors are undefined. We aimed to assess the efficacy and safety of continuing gefitinib combined with chemotherapy versus chemotherapy alone in patients with EGFR-mutation-positive advanced NSCLC with acquired resistance to first-line gefitinib. Methods: The randomised, phase 3, multicentre IMPRESS study was done in 71 centres in 11 countries in Europe and the Asia-Pacific region. Eligible patients were aged at least 18 years with histologically confirmed, chemotherapy-naive, stage IIIB-IV EGFR-mutation-positive advanced NSCLC with previous disease control with first-line gefitinib and recent disease progression (Response Evaluation Criteria in Solid Tumors version 1.1). Participants were randomly assigned (1:1) by central block randomisation to oral gefitinib 250 mg or placebo once daily in tablet form; randomisation did not include stratification factors. All patients also received the platinum-based doublet chemotherapy cisplatin 75 mg/m2 plus pemetrexed 500 mg/m2 on the first day of each cycle. After completion of a maximum of six chemotherapy cycles, patients continued their randomly assigned treatment until disease progression or another discontinuation criterion was met. All study investigators and participants were masked to treatment allocation. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The study has completed enrolment, but patients are still in follow-up for overall survival. This trial is registered with ClinicalTrials.gov, number NCT01544179. Findings: Between March 29, 2012, and Dec 20, 2013, 265 patients were randomly assigned: 133 to the gefitinib group and 132 to the placebo group. At the time of data cutoff (May 5, 2014), 98 (74%) patients had disease progression in the gefitinib group compared with 107 (81%) in the placebo group (hazard ratio 0·86, 95% CI 0·65-1·13; p=0·27; median progression-free survival 5·4 months in both groups [95% CI 4·5-5·7 in the gefitinib group and 4·6-5·5 in the placebo group]). The most common adverse events of any grade were nausea (85 [64%] of 132 patients in the gefitinib group and 81 [61%] of 132 patients in the placebo group) and decreased appetite (65 [49%] and 45 [34%]). The most common adverse events of grade 3 or worse were anaemia (11 [8%] of 132 patients in the gefitinib group and five [4%] of 132 patients in the placebo group) and neutropenia (nine [7%] and seven [5%]). 37 (28%) of 132 patients in the gefitinib group and 28 (21%) of 132 patients in the placebo group reported serious adverse events. Interpretation: Continuation of gefitinib after radiological disease progression on first-line gefitinib did not prolong progression-free survival in patients who received platinum-based doublet chemotherapy as subsequent line of treatment. Platinum-based doublet chemotherapy remains the standard of care in this setting. Funding: AstraZeneca. © 2015 Elsevier Ltd.


Wu F.,University of Alberta | Zhang J.,University of Alberta | Zhang J.,The First Hospital of China Medical University | Wang P.,University of Alberta | And 9 more authors.
Cellular Signalling | Year: 2012

Sox2 (sex-determining region Y-box protein 2) is a transcription factor regulating pluripotency in embryonic stem cells. Sox2 is aberrantly expressed in breast and other cancers, though its biological significance remains widely unexplored. To understand the significance of this aberrancy, we assessed the transcription activity of Sox2 in two Sox2-expressing breast cancer cell lines, MCF7 and ZR751, using a lentiviral Sox2 GFP reporter vector. Surprisingly, Sox2 transcription activity, as measured by GFP expression encoded in a Sox2 reporter construct, was detectable only in a small subset of cells in both cell lines. Purification of GFP. + cells (cells with Sox2 activity) and GFP. - cells (cells without Sox2 activity) was enriched for two phenotypically distinct cell populations in both MCF7 and ZR751 cell lines. Specifically, GFP. + cells formed significantly more colonies in methylcellulose and more mammospheres in vitro compared to GFP. - cells. These phenotypic differences are directly linked to Sox2 as siRNA knockdown of Sox2 in GFP. + cells abolished these abilities. To provide a mechanistic explanation to our observations, we performed gel shift and chromatin immunoprecipitation studies; Sox2 was found to bind to its DNA binding consensus sequence and the promoters of Cyclin D1 and Nanog (two known Sox2 downstream targets) only in GFP. + cells. GFP. + cells also up-regulated CD49f, phospho-GSK3β, and β-catenin. In summary, we have identified two novel phenotypically distinct cell subsets in two breast cancer cell lines based on their differential Sox2 transcription activity. We demonstrate that Sox2 transcription activity, and not its protein expression alone, underlies the tumorigenicity and cancer stem cell-like phenotypes in breast cancers. © 2012 Elsevier Inc.


PubMed | The First hospital of China Medical University, University of Alberta, National Research Center of Egypt and University of Toronto
Type: | Journal: Scientific reports | Year: 2016

Various forms of oncogenic ALK proteins have been identified in various types of human cancers. While Crizotinib, an ALK inhibitor, has been found to be therapeutically useful against a subset of ALK(+) tumours, clinical resistance to this drug has been well recognized and the mechanism of this phenomenon is incompletely understood. Using the cellular thermal shift assay (CETSA), we measured the Crizotinib-ALK binding in a panel of ALK(+) cell lines, and correlated the findings with the ALK structure and its interactions with specific binding proteins. The Crizotinib IC50 significantly correlated with Crizotinib-ALK binding. The suboptimal Crizotinib-ALK binding in Crizotinib-resistant cells is not due to the cell-specific environment, since transfection of NPM-ALK into these cells revealed substantial Crizotinib-NPM-ALK binding. Interestingly, we found that the resistant cells expressed higher protein level of -catenin and siRNA knockdown restored Crizotinib-ALK binding (correlated with a significant lowering of IC50). Computational analysis of the crystal structures suggests that -catenin exerts steric hindrance to the Crizotinib-ALK binding. In conclusion, the Crizotinib-ALK binding measurable by CETSA is useful in predicting Crizotinib sensitivity, and Crizotinib-ALK binding is in turn dictated by the structure of ALK and some of its binding partners.


Liu L.-L.,The First Hospital of China Medical University | Jiang Y.,Central University of Costa Rica | Wang L.-N.,The First Hospital of China Medical University | Liu N.,The First Hospital of China Medical University
Clinical and Experimental Immunology | Year: 2012

Complement system activation is associated with immunoglobulin A nephropathy (IgAN) activity and progression. The aim of the present study was to investigate the importance of urinary mannose-binding lectin (MBL), at the time of renal biopsy, for evaluating disease severity and predicting the progression of IgAN. A total of 162 patients with biopsy-proven IgAN were enrolled and 50 healthy individuals were selected as normal controls. Urinary MBL was measured by sandwich enzyme-linked immunosorbent assay (ELISA) and normalized for urinary creatinine concentration. Urinary MBL was significantly higher in IgAN patients than that in normal controls, and elevated as histopathological phenotypes upgraded. Urinary MBL was correlated significantly with the well-known clinical predictors for the prognosis of IgAN; that is, renal function (represented by serum creatinine and estimated glomerular filtration rate), proteinuria and arterial hypertension. Urinary MBL was demonstrated to be correlated with the histopathological parameters which have independent value in predicting renal outcome of IgAN according to the Oxford classification; that is, mesangial hypercellularity, segmental glomerulosclerosis, endocapillary hypercellularity and tubular atrophy/interstitial fibrosis. More importantly, non-remission patients at the end of follow-up had significantly higher levels of urinary MBL compared with patients in remission. In conclusion, urinary MBL can be a reliable non-invasive biomarker for evaluating disease severity and predicting the prognosis of IgAN. This is the first report on this issue. However, our conclusions should be verified further in large-scale studies with long-term follow-up. © 2012 The Authors. Clinical and Experimental Immunology © 2012 British Society for Immunology.


Zhang J.,University of Alberta | Zhang J.,The First Hospital of China Medical University | Wang P.,University of Alberta | Wu F.,University of Alberta | And 7 more authors.
Cellular Signalling | Year: 2012

The transcriptional factor Twist1 has been shown to play a key role in regulating epithelial mesenchymal transition, invasiveness and migratory properties in solid tumors. We found that Twist1 is aberrantly expressed in ALK-positive anaplastic large cell lymphoma (ALK + ALCL), a type of T-cell lymphoid malignancy. Using RT-PCR and Western blots, Twist1 was detectable in all 3 ALK + ALCL cell lines examined but absent in normal T-cells. By immunohistochemistry, Twist1 was detectable in all 10 cases of ALK + ALCL examined; benign lymphoid tissues were consistently negative. Twist1 expression in ALK + ALCL cells can be attributed to the NPM-ALK/STAT3 signaling axis, the key oncogenic driving force in this tumor type. Twist1 is biologically important in ALK + ALCL cells, as Twist1 knockdown resulted in a significant decrease in their invasiveness in an in-vitro assay. Further investigation revealed that this increase in invasiveness is linked to the activation of AKT and down-regulation of p66Shc, two signaling proteins known to be involved in NPM-ALK-mediated oncogenesis. Lastly, knockdown of Twist1 sensitizes ALK + ALCL cells to the growth inhibitory effect of PF-2341066 (Crizotinib®), an ALK inhibitor being used in clinical trials. In conclusion, Twist1 expression, owing to the abnormal NPM-ALK/STAT3 signaling, contributes to its invasiveness and decreased sensitivity to PF-2341066 in ALK + ALCL. © 2011 Elsevier Inc.


Xia M.,The First Hospital of China Medical University | Zhu Y.,The First Hospital of China Medical University
Journal of Neuroscience Research | Year: 2014

After spinal cord injury (SCI), the formation of glial scar is a complex process that is attributed primarily to astrocytic proliferation, but the mechanism of astrocytes proliferation is still unclear. Fibronectin is a large extracellular glycoprotein that helps organize the matrix protein, and its main membrane receptor is the α5β1 integrin subunit. In this study, fibronectin stimulated spinal cord astrocytic proliferation from two directions: fibronectin increased astrocytic proliferation via α5β1 integrin receptor, and fibronectin upregulated the expression of P2Y1 receptor, and adenosine triphosphate (ATP) could enhance the astrocytic proliferation and induce more release of arachidonic acid and prostaglandin E2 via P2Y1. The upregulation of P2Y1 by fibronectin required [Ca2+]i and the activation of integrin link kinase (ILK) and Akt. We found that [Ca2+]i stimulated by fibronectin was α5β1 integrin receptor dependent and that the phosphorylation of Akt or extracellular signal-regulated protein kinase (ERK1/2) induced by fibronectin mediated the activation of cAMP response element-binding protein (CREB) and signal transducer and activator of transcription 3 (Stat3). Our research suggests that the release of fibronectin and ATP could stimulate the spinal cord astrocytic proliferation after SCI, and the expression of P2Y1 increased by fibronectin would provide more sites for ATP, which could aggravate the proliferation and inflammation of spinal cord astrocytes. © 2014 Wiley Periodicals, Inc.


PubMed | the First Hospital of China Medical University
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016

e21024 Background: Receptor activator for nuclear factor kappa B ligand/receptor activator for nuclear factor kappa B (RANKL/RANK) pathway is critical for RANK-expressing cancer cells to home to bones, and c-Src is critical for cancer progression. However, there are no data currently available about the effect of RANK/c-Src on breast cancer patient prognosis. This study was aimed to evaluate the effect of RANK and c-Src on prognosis in metastatic breast cancer patients.RANK and c-Src expression were evaluated by immunohistochemical staining in primary breast cancer tissues of 102 patients with distant metastasis. The median follow-up period was 40 (range 7-143) months. The relationship between RANK and/or c-Src expression and clinical outcome were explored. The log-rank test and the Kaplan-Meier method were used for the patient survival analysis. Multivariate analysis was performed according to the Cox proportional hazards model.The RANK and c-Src positive expression rates were 47.1% and 54.9%, respectively, in breast cancer tissues. All patients developed distant metastases, in which 62 patients developed bone metastases. Patients with RANK positive expression showed significantly poorer progression-free survival (p=0.023) and disease-specific survival (p=0.001). Similarly, patients with c-Src positive expression also showed significantly poorer progression-free survival (p=0.044) and disease-specific survival (p=0.017). Subgroup analysis demonstrated that the signicant difference in prognosis completely related to the occurrence of bone metastasis. Furthermore, RANK and c-Src co-expression correlated to poorer bone metastasis-free rate (p=0.007) and disease-specific survival rate (p=0.002) in bone metastasis patients. Multivariate analysis demonstrated that co-expression of RANK and c-Src was an independent predictor of bone metastasis-free survival (RR=2.281; 95%CI: 1.105-4.710; p=0.026) and disease-specific survival (RR=4.434; 95%CI: 1.697-11.586; p=0.002).Co-expression of RANK and c-Src might be an independent predictor of poor prognosis in breast cancer patients with bone metastasis.

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