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Fu D.-Y.,Breast Cancer Institute | Fu D.-Y.,Peoples Hospital of Jiangsu Province | Wang Z.-M.,Chinese National Human Genome Center at Shanghai | Wang B.-L.,Chinese National Human Genome Center at Shanghai | And 5 more authors.
Human Pathology | Year: 2010

EphA5 is a member of the Eph receptor tyrosine kinase family, which plays a critical role in the regulation of carcinogenesis. Our previous DNA methylation microarray results suggested that the CpG islands in the EphA5 promoter exhibited higher methylation levels in breast cancer tissues. In this study, we further analyzed EphA5 gene expression profiles, methylation status, and clinical implications in breast cancer. We found that the level of EphA5 mRNA was dramatically decreased in 5 different breast cancer cell lines. After treating the cell lines with 5-aza-2′-deoxycytidine (5-aza-dC, a demethylation agent), the levels of EphA5 mRNA and protein were significantly increased. Bisulfite sequencing and methylation-specific polymerase chain reaction detection showed that decreased expression of EphA5 was associated with its methylation status. We also found a significant correlation (P = .017) between the reduction of EphA5 mRNA levels and aberrant methylation of EphA5 in 31 paired tissue samples. In clinical samples, EphA5 methylation was detected in 64.1% (75/117) of breast tumors and 28.2% (33/117) of paired normal tissues (P < .001), which was associated with higher tumor grade (P = .024), lymph node metastasis (P = .004), and progesterone receptor-negative status (P = .008). Our data indicate that EphA5 might be a potential target for epigenetic silencing in primary breast cancer and a valuable molecular marker for breast cancer carcinogenesis and progression. © 2010 Elsevier Inc. All rights reserved. Source


Hou Y.,CAS Institute of Chemistry | Qiao R.,CAS Institute of Chemistry | Fang F.,CAS Wuhan Institute of Physics and Mathematics | Wang X.,CAS Wuhan Institute of Physics and Mathematics | And 7 more authors.
ACS Nano | Year: 2013

Differently sized NaGdF4 nanocrystals with narrow particle size distributions were synthesized by a high temperature approach. Upon ligand exchange, the as-prepared hydrophobic NaGdF4 nanocrystals were transferred into water by using asymmetric PEGs simultaneously bearing phosphate and maleimide groups. Further investigations demonstrated that the water-soluble NaGdF4 nanocrystals, coated by PEG bearing two phosphate groups on the same side, exhibit not only excellent colloidal stability in water and PBS buffer, but also higher T1 relaxivity than Gd-DTPA (Magnevist). Through "click" reaction between the maleimide residue on particle surface and thiol group from the partly reduced anti-EGFR monoclonal antibody (mAb), NaGdF4-PEG-mAb nanoprobes were constructed, and their biocompatibility and binding specificity were evaluated through in vitro experiments. A series of in vivo experiments were then carried out for detecting intraperitoneal tumor xenografts in nude mice by using magnetic resonance (MR) imaging technique. The results revealed that the NaGdF4-PEG-mAb probes possessed satisfying tumor-specific targeting ability and strong MR contrast enhancement effects. © 2012 American Chemical Society. Source


Herbst R.S.,University of Houston | Sun Y.,Cancer Hospital | Eberhardt W.E.E.,University of Duisburg - Essen | Germonpre P.,University of Antwerp | And 14 more authors.
The Lancet Oncology | Year: 2010

Background: Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), and rearranged during transfection (RET) tyrosine kinases. In a randomised phase 2 study in patients with previously treated non-small-cell lung cancer (NSCLC), adding vandetanib 100 mg to docetaxel significantly improved progression-free survival (PFS) compared with docetaxel alone, including a longer PFS in women. These results supported investigation of the combination in this larger, definitive phase 3 trial (ZODIAC). Methods: Between May, 2006, and April, 2008, patients with locally advanced or metastatic (stage IIIB-IV) NSCLC after progression following first-line chemotherapy were randomly assigned 1:1 through a third-party interactive voice system to receive vandetanib (100 mg/day) plus docetaxel (75 mg/m2 intravenously every 21 days; maximum six cycles) or placebo plus docetaxel. The primary objective was comparison of PFS between the two groups in the intention-to-treat population. Women were a coprimary analysis population. This study has been completed and is registered with ClinicalTrials.gov, number NCT00312377. Findings: 1391 patients received vandetanib plus docetaxel (n=694 [197 women]) or placebo plus docetaxel (n=697 [224 women]). Vandetanib plus docetaxel led to a significant improvement in PFS versus placebo plus docetaxel (hazard ratio [HR] 0·79, 97·58% CI 0·70-0·90; p<0·0001); median PFS was 4·0 months in the vandetanib group versus 3·2 months in placebo group. A similar improvement in PFS with vandetanib plus docetaxel versus placebo plus docetaxel was seen in women (HR 0·79, 0·62-1·00, p=0·024); median PFS was 4·6 months in the vandetanib group versus 4·2 months in the placebo group. Among grade 3 or higher adverse events, rash (63/689 [9%] vs 7/690 [1%]), neutropenia (199/689 [29%] vs 164/690 [24%]), leukopenia (99/689 [14%] vs 77/690 [11%]), and febrile neutropenia (61/689 [9%] vs 48/690 [7%]) were more common with vandetanib plus docetaxel than with placebo plus docetaxel. The most common serious adverse event was febrile neutropenia (46/689 [7%] in the vandetanib group vs 38/690 [6%] in the placebo group). Interpretation: The addition of vandetanib to docetaxel provides a significant improvement in PFS in patients with advanced NSCLC after progression following first-line therapy. Funding: AstraZeneca. © 2010 Elsevier Ltd. Source


Chen S.,Shantou University | Huo X.,Shantou University | Lin Y.,Cancer Hospital | Ban H.,Shantou University | And 4 more authors.
International Journal of Hygiene and Environmental Health | Year: 2010

Among the cancer patient population, resistance to therapy is a major cause for therapeutic failure and for human sufferings, especially for the cancer with poor prognosis. Therefore, finding factors that contribute to drug resistance is a major research interest. In this study, we have investigated whether polymorphisms in genes that control import/export of drugs (MDR1) and that repair DNA adducts (ERCC1) are involved with drug resistance in non-small cell lung cancer (NSCLC) patients. We have recruited 95 patients with advanced NSCLC (stages IIIB-IV) who were specifically treated with platinum-based chemotherapy. We used the ligase detection reactions assay (LDR) to detect polymorphisms in ERCC1 118C/T, and MDR1 2677T/A, E1/-129T/C, and C3435T in peripheral blood lymphocytes from the patients. The haplotype of MDR1 gene single nucleotide polymorphisms (SNPs) were analyzed using the SHEsis software platform on line. We found that none of the single polymorphisms was associated with treatment response or related toxicity. However, patients carrying at least one variant MDR1 2677 T allele was associated with a significantly increased risk of drug resistance (OR=1.844, 95% CI=1.01-3.53, P=0.04) but also with a significantly increased risk of gastrointestinal toxicity (P=0.03) but not hemato-, hepato- or nephro-toxicities. Moreover, we analyzed the haplotypes of the three polymorphisms in MDR1. The patients harboring the E1/-129T-2677T-3435C haplotype had a significantly better response to chemotherapy compared with those having the other haplotypes (P=0.02, 95% CI=1.20-25.87), and a marginally significant association with increased risk of gastrointestinal toxicity (P=0.02, 95% CI=1.15-3.88). Our results suggested that gene polymorphisms in MDR1G2677T/A may be a predictive marker of platinum-based treatment response and of secondary effects, especially gastrointestinal toxicity for advanced NSCLC patients. © 2010 Elsevier GmbH. All rights reserved. Source


Xu J.-J.,Cancer Hospital | Gan N.,Cancer Hospital
World Chinese Journal of Digestology | Year: 2015

AIM: To investigate the effect of simultaneous Sirtinol and K-ras knockdown on the proliferation and apoptosis of pancreatic cancer PANC-1 cells. METHODS: PANC-1 cells were divided into three groups and treated with 50 μmol/L Sirtinol (S), 50 nmol K-ras siRNA (K), and 50 μmol/L Sirtinol plus 50 nmol K-ras siRNA (K + S) for 48 h, respectively. Non-treated cells were used as a normal control (C). The expression level of SIRT1 protein was measured by Western blot. The expression levels of K-ras and Cyclin D1 mRNAs were measured by Q-PCR. Cell proliferation was detected by MTT assay. Cell apoptosis was detected by flow cytometry. RESULTS: Western blot analysis showed that the expression of SIRT1 decreased significantly in the S group and K + S group, compared with the C group and K group. Q-PCR showed that the K-ras mRNA level in the K group and K + S group was 0.454 ± 0.037 and 0.413 ± 0.032 times of that in the C group. MTT results showed that the A values in the K group, S group and K + S group were significantly decreased compared with the C group, with the K + S group decreasing most obviously. Q-PCR results showed that the Cyclin D1 mRNA level in the K group, S group and K + S group was 0.693 ± 0.046, 0.634 ± 0.032, and 0.400 ± 0.034 times of group C and the K + S group had the greatest reduction. Flow cytometry analysis showed that the apoptosis rates in the K group, S group and K + S group increased significantly compared with the C group (4.290% ± 0.246% vs 7.469% ± 0.457%, 8.206% ± 0.490% and 12.272% ± 0.675%), and the increase was most obvious in the K + S group. CONCLUSION: Simultaneous Sirtinol and K-ras knockdown could induce cell proliferation inhibition and apoptosis in PANC-1 cells. © 2015 Baishideng Publishing Group Inc. All rights reserved. Source

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