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PubMed | Chongqing Zhongshan Hospital and Zhejiang University
Type: Journal Article | Journal: Oncology letters | Year: 2017

Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) that has been demonstrated to be clinically useful for the treatment of patients with non-small cell lung cancer (NSCLC). However, ~50% of patients do not respond to EGFR TKI treatment through the emergence of mutations, such as T790M. Therefore, it is important to determine which patients are eligible for treatment with gefitinib. As a preferred dimerization partner for EGFR, the role of EGFR 2 (HER2) in mediating sensitivity to gefitinib is poorly understood. In the present study, full-length human HER2 cDNA was introduced to the NSCLC cell lines H1975 and H1299, which have a low endogenous expression level of HER2. In addition, it was observed in the present study that the H1975 cell line harbored the L858R and T790M mutations in the EGFR kinase domain. Western blot analysis and MTT assay were used to evaluate the TKI sensitivity of HER2 expression status, and the activation of HER3 and HER2 downstream effectors. The results indicated that the sensitivity of H1975 cells to gefitinib was restored by the overexpression of HER2, which stimulated HER2-driven signaling cascades accompanied by the activation of protein kinase B. By contrast, ectopic HER2 overexpression in H1299 cells did not significantly alter the sensitivity to gefitinib treatment. In conclusion, the current study results suggested that the relatively resistance of the H1975 cell line to gefitinib could be reversed by the overexpression of HER2. Therefore, the expression of HER2 could also be considered when evaluate the patients potential response to gefitinib, particularly in the subgroup of lung cancer patients who harbor an EGFR mutation.


Wang J.,Tongji University | Ma L.,Tongji University | Weng W.,Tongji University | Qiao Y.,Shanghai JiaoTong University | And 9 more authors.
Hepatology | Year: 2013

Yes-associated protein (YAP), the downstream effecter of the Hippo-signaling pathway as well as cyclic adenosine monophosphate response element-binding protein (CREB), has been linked to hepatocarcinogenesis. However, little is known about whether and how YAP and CREB interact with each other. In this study, we found that YAP-CREB interaction is critical for liver cancer cell survival and maintenance of transformative phenotypes, both in vitro and in vivo. Moreover, both CREB and YAP proteins are highly expressed in a subset of human liver cancer samples and are closely correlated. Mechanistically, CREB promotes YAP transcriptional output through binding to -608/-439, a novel region from the YAP promoter. By contrast, YAP promotes protein stabilization of CREB through interaction with mitogen-activated protein kinase 14 (MAPK14/p38) and beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC). Gain-of-function and loss-of-function studies demonstrated that phosphorylation of CREB by MAPK14/p38 at ser133 ultimately leads to its degradation. Such effects can be enhanced by BTRC through phosphorylation of MAPK14/p38 at Thr180/Tyr182. However, YAP negatively controls phosphorylation of MAPK14/p38 through inhibition of BTRC expression. Conclusion: There is a novel positive autoregulatory feedback loop underlying the interaction between YAP and CREB in liver cancer, suggesting that YAP and CREB form a nexus to integrate the protein kinase A, Hippo/YAP, and MAPK14/p38 pathways in cancer cells and thus may be helpful in the development of effective diagnosis and treatment strategies against liver cancer. (Hepatology 2013;53:1011-1020). © 2013 by the American Association for the Study of Liver Diseases.


Li L.,Tongji University | Li L.,Chongqing Zhongshan Hospital | Wang J.,Tongji University | Zhang Y.,Tongji University | And 9 more authors.
FEBS Letters | Year: 2013

Mitogen-activated protein kinase kinase 1 (MAP2K1/MEK1) as well as Yes-associated protein (YAP), the downstream effector of Hippo signaling pathway, is linked to hepatocarcinogenesis. However, little is known about whether and how MEK1 interacts with YAP. In this study, we find that MEK1-YAP interaction is critical for liver cancer cell proliferation and maintenance of transformed phenotypes both in vitro and in vivo. Moreover, MEK1 and YAP proteins are closely correlated in human liver cancer samples. Mechanistically, inhibition of MEK1 by both PD98059 and U0126 as well as RNAi reduces beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC), which acts as a potential endogenous YAP protector. © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.


Tang C.,Chongqing University of Technology | Wang G.,Chongqing University of Technology | Wu X.,Chongqing University of Technology | Li Z.,Chongqing Zhongshan Hospital | And 3 more authors.
Journal of Vascular Surgery | Year: 2011

Objectives The purpose of this study was to investigate the effects of gene transfection of endothelial cells with vascular endothelial growth factor (VEGF) on re-endothelialization and inhibiting in-stent restenosis. Methods Stents coated with human umbilical vein endothelial cells (HUVECs) transfected with VEGF121 were studied both in vitro and in vivo. In vitro studies were performed using a homemade extracorporeal circulation system. In vivo studies were performed using the rabbit abdominal aorta model. Results In vitro studies confirmed that VEGF121-transfected cells adhered on the surface of stainless steel stents with over 90% of the surface covered within 24 hours of seeding. In vivo results showed that VEGF121-transfected HUVECs-coated stents were covered with seeding cells after implanting, and almost completely covered with cells after stent implantation for 1 week. In contrast, the non-endothelialized areas of bare metal stents and glutin/poly-L-lysine-coated stents were covered at 4 weeks, and the monolayers of cells were not observed, but fragile neointima was found on the surface. After 12 weeks, VEGF121-transfected HUVECs-coated stents significantly reduced the neointima area (0.78 ± 0.03 mm2) and stenosis (15.69 ± 2.61%) as compared with those for bare metal stents (neointima area = 2.26 ± 0.67 mm2; the percentage of stenosis = 47.55 ± 7.10%;P < .01) and glutin/poly-L-lysine-coated stents (neointima area = 1.40 ± 0.37 mm2; the percentage of stenosis = 31.37 ± 8.18%;P < .01). Conclusion In this small animal study, VEGF transfected human endothelial cells, when coated on stainless steel stents, reduce neointimal hyperplasia, promote endothelialization, and reduce in-stent restenosis. Additional studies with this technology are necessary to determine its ultimate utility in improving stents performance. © 2011 Society for Vascular Surgery.


Luo J.-H.,Chongqing Zhongshan Hospital | Kuang Y.,Chongqing Zhongshan Hospital
International Eye Science | Year: 2015

AIM: To investigate the status of visual disability population in Yuzhong district of Chongqing, in order to provide a counter measure for improving their quality of life. METHODS: The data of visual disability population was analyzed, which was registered in federation of the disabled of Yuzhong district of Chongqing from January 21, 2009 to July 17, 2013, collected the information of their gender and age constituent ratio, visual disability level differences, and the differences of their disability pathogeny. RESULTS: There was no significant difference between the total numbers of male and female visual disability, and before the age of 60, the number of male was more than female, but after 60, it was opposite. The grade four of visual disability accounted for the largest proportion, followed by a level of grade one, two, and three. The main causes of visual disability in proper order were: ametropia (high myopia), retina and pigment membrane disease, ocular trauma, optic nerve disease, glaucoma, corneal disease, congenital anomaly or eccyliosis, cataract, amblyopia, agnogenic, methysis, trachoma, and the others (hyperpyrexia). CONCLUSION: The diagnosis and treatment of juvenile in Yuzhong district must be strengthened, also include retina and pigment membrane disease, to reduce the visual disability caused by these diseases. ©, 2015, International Journal of Ophthalmology (c/o Editorial Office). All right reserved.


Wang H.,Chongqing Medical University | He Y.,Chongqing Zhongshan Hospital | Xia Y.,Chongqing Medical University | Wang L.,Chongqing Medical University | Liang S.,Chongqing Medical University
Molecular Biology Reports | Year: 2014

Acinetobacter baumannii causes common and severe community- and hospital-acquired infections. The increasing emergence of multidrug-resistant (MDR) and pan-drug resistant A. baumannii has limited the therapeutic options, highlighting the need for new therapeutic strategies. The goal of this study was to investigate whether antisense peptide nucleic acids (PNAs) could mediate gene-specific inhibition effects in MDR A. baumannii. We described a screening strategy based on computational prediction and dot hybridization for identifying potential inhibitory PNAs, and evaluated the in vitro growth inhibition potency of two PNAs conjugated to the (KFF)3K peptide (pPNA1 and pPNA2), both of which targeted the growth essential gene gyrA of A. baumannii. Both pPNAs showed strong inhibition effects on bacterial growth and gyrA mRNA expression in a dose-dependent manner. The lowest inhibitory and bactericidal concentration were 5 and 10 μM, respectively. Combination of the two pPNAs showed superimposed effect other than synergistic effect. Control PNAs without (KFF)3K peptide conjugation or with mismatched antisense sequence had no inhibition effects on bacterial growth or mRNA expression. Our study suggests that anti-gyrA pPNAs can efficiently inhibit gene expression and bacterial growth, and has the potential as a new therapeutic option for MDR A. baumannii. © 2014, Springer Science+Business Media Dordrecht.


Yan J.,Chongqing Medical University | Shang X.,Chongqing Zhongshan Hospital | Rong X.,Chongqing Medical University
International Journal of Clinical and Experimental Medicine | Year: 2015

Objective: To investigate the relationship between IL-27 gene polymorphism and the susceptibility of rheumatoid arthritis (RA) in a Chinese Hans population. Methods: 310 RA patients and 310 healthy controls were examined in this study. Polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) technique was used in the detection of the genotype in three loci of IL-27 gene (-964A/G, 2905T/G, and 4730T/C). We compared genotype and allele frequency and distribution of these two groups. Results: The genotype distribution of the case group and the control group were all in accordance with Hardy-Weinberg equilibrium (P>0.05). The difference of genotype and allele frequencies of three loci between these two groups showed no statistically significant (P>0.05). But the frequencies of G-T-C haplotype was significantly higher in the case group than in the control group, the difference showed statistically significant (OR=2.001, 95% CI: 1.121~3.573; P=0.0170). G-T-T haplotype in case group was significantly lower than that in the control group, the difference showed statistically significant (OR=0.715, 95% CI: 0.527~0.970, P=0.030). Conclusion: In Chinese Hans population, IL-27 gene haplotypes were correlated with the risk of RA. G-T-C haplotype was the risk factors for the incidence of RA, but G-T-T haplotype maybe was the protective factor of RA. © 2015, E-Century Publishing Corporation. All rights reserved.


Liang S.,Chongqing Medical University | He Y.,Chongqing Zhongshan Hospital | Xia Y.,Chongqing Medical University | Wang H.,Chongqing Medical University | And 3 more authors.
International Journal of Infectious Diseases | Year: 2015

Background: The increasing emergence of clinical infections caused by methicillin-resistant Staphylococcus aureus (MRSA) challenges existing therapeutic options and highlights the need to develop novel treatment strategies. The ftsZ gene is essential to bacterial cell division. Methods: In this study, two antisense peptide nucleic acids (PNAs) conjugated to a cell-penetrating peptide were used to inhibit the growth of MRSA. PPNA1, identified with computational prediction and dot-blot hybridization, is complementary to nucleotides 309-323 of the ftsZ mRNA. PPNA2 was designed to target the region that includes the translation initiation site and the ribosomal-binding site (Shine-Dalgarno sequence) of the ftsZ gene. Scrambled PPNA was constructed with mismatches to three bases within the antisense PPNA1 sequence. Results: PPNA1 and PPNA2 caused concentration-dependent growth inhibition and had bactericidal effects. The minimal bactericidal concentrations of antisense PPNA1 and PPNA2 were 30. μmol/l and 40. μmol/l, respectively. The scrambled PPNA had no effect on bacterial growth, even at higher concentrations, confirming the sequence specificity of the probes. RT-PCR showed that the antisense PPNAs suppressed ftsZ mRNA expression in a dose-dependent manner. Conclusion: Our results demonstrate that the potent effects of PNAs on bacterial growth and cell viability were mediated by the down-regulation or even knock-out of ftsZ gene expression. This highlights the utility of ftsZ as a promising target for the development of new antisense antibacterial agents to treat MRSA infections. © 2014 The Authors.


Chen S.,Chongqing Medical University | Yin Y.,Chongqing Medical University | Lan X.,Chongqing Medical University | Liu Z.,Chongqing Medical University | And 8 more authors.
European Journal of Heart Failure | Year: 2013

AimsThe aim of this study was to investigate the predictive ability of paced QRS duration (pQRSd) for heart failure events among patients receiving right ventricular apical pacing (RVAP).Methods and resultsA total of 194 patients with complete atrioventricular block receiving pacemaker treatment were enrolled and stratified to group 1, pQRSd < 160 ms, n = 53; group 2, 160 ≤ pQRSd < 190 ms, n = 97; and group 3, pQRSd ≥ 190 ms, n = 44. Study outcomes were heart failure events, changes in pQRSd, and changes in left ventricular ejection fraction (LVEF). During the 3-year follow-up, the incidence of heart failure events was 9.4, 27.8, and 56.8% in groups 1, 2, and 3, respectively (P < 0.001). Among the patients without heart failure events, the pQRSd at 3 years remained longer than that at baseline (162.1 ± 22.6 vs. 160.9 ± 22.1 ms, P < 0.05), whereas among patients who experienced heart failure events, the prolonged pQRSd at 3 years seemed more pronounced as compared with baseline (184.1 ± 21.1 vs. 179.8 ± 21 ms, P < 0.001). Linear regression demonstrated that a decrease in LVEF was positively correlated with pQRSd over time (relative risk 0.423; P < 0.05). The receiver operating charactersitic curve showed that the cut-off value of pQRSd was 165 ms with a sensitivity of 0.789.ConclusionA prolonged pQRSd has a detrimental effect on long-term cardiac function during RVAP in patients with complete atrioventricular block. pQRSd could be a useful predictor to identify patients who are at risk for heart failure events during RVAP. © 2012 Published on behalf of the European Society of Cardiology. All rights reserved.


PubMed | Chongqing Zhongshan Hospital and Chongqing Medical University
Type: | Journal: Journal of the neurological sciences | Year: 2016

Transplanted Schwann cells have the potential to serve as a support for regenerating neurites after spinal cord injury. However, implanted Schwann cells die off rapidly once transplanted partly owing to the absence of a proper matrix support, with a glia scar and a cavity being present instead at the injury site. For this report, we evaluated aligned electrospun poly(methyl methacrylate) nanofibers as a Schwann cell-loading scaffold in vitro. By monitoring the fluorescence of green fluorescence protein-containing Schwann cells cultured on nanofibers, we found that aligned nanofibers provided better support for the cells than did non-aligned nanofibers. The cells elongated along the long axes of the aligned nanofibers and formed longer cell processes than when the substrate was non-aligned nanofibers. By coculturing Schwann cells with dorsal root ganglion neurons, it was also found that Schwann cells and neurites of dorsal root ganglion neurons could share and both elongate along the orientation of aligned nanofibers and thus they had a higher chance of colocalization than cocultured on film and non-aligned fibers, which might be beneficial to the ensuring process of myelination. The results of the study indicate that aligned electrospun nanofibers may serve as a Schwann cell-loading scaffold for future implantation research.

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