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Liu Y.,Shenyang University | Ren W.,Shenyang University | Liu C.,The First Hospital of China Medical University | Huang K.,Shenyang University | And 3 more authors.
Oncology Letters | Year: 2012

The accuracy of diagnosing t umors may be improved significantly by detecting the microvascular distri- bution. Indeed, contrast-enhanced ultrasonography (CEUS) has shown a distinct advantage in detecting microvasculature. This study aimed to determine the angiogenic characteristics of VX2 tumors in rabbits using CEUS. A total of 17 rabbits were injected with 0.5 ml VX2 cell suspension into the muscles of both hind legs to prepare the VX2 tumor models. At 14, 21, 28 and 35 days after tumor inoculation, CEUS was performed on the rabbits with 0.3 ml SonoVue following a local anesthesia. The pathological findings of the tumors were compared. A total of 12 rabbits survived after being inocu- lated with the tumor cells and developed a total of 38 tumors. The size of the tumors ranged from 1.12 to 10.85 cm. Using CEUS, all tumors demonstrated rim enhancement with some unenhanced regions. Enhancement began from the periph- eral region and quickly showed internal reticular vessels. Regardless of the tumor size or the presence of necrosis, no complete enhancement of the tumors was observed. On microscopic examination, VX2 tumor cells were detected in striated muscles, immature blood capillaries and fibrosis tissues scattered in tumor nests. Im munohistochem ical examination revealed that CD34+ cells appeared mainly in the muscles adjacent to vessels. In conclusion, CEUS may be an efficient method to evaluate angiogenesis and blood perfusion in VX2 tumors. Source

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. Source

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. Source

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. Source

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. Source

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