Nanjing Gulou Hospital

Nanjing, China

Nanjing Gulou Hospital

Nanjing, China
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Zhu W.-J.,Soochow University of China | Yang S.-D.,Soochow University of China | Qu C.-X.,Soochow University of China | Zhu Q.-L.,Soochow University of China | And 7 more authors.
International Journal of Nanomedicine | Year: 2017

Multidrug resistance (MDR) is a major obstacle for the clinical therapy of malignant human cancers. The discovery of RNA interference provides efficient gene silencing within tumor cells for reversing MDR. In this study, a new “binary polymer” low-density lipoprotein– N-succinyl chitosan–cystamine–urocanic acid (LDL–NSC–SS–UA) with dual pH/redox sensitivity and targeting effect was synthesized for the co-delivery of breast cancer resistance protein small interfering RNA (siRNA) and paclitaxel (PTX). In vivo, the co-delivering micelles can accumulate in tumor tissue via the enhanced permeability and retention effect and the specific recognition and combination of LDL and LDL receptor, which is overexpressed on the surface of tumor cell membranes. The siRNA–PTX-loaded micelles inhibited gene and drug release under physiological conditions while promoting fast release in an acid microenvironment or in the presence of glutathione. The micelles escaped from the lysosome through the proton sponge effect. Additionally, the micelles exhibited superior antitumor activity and downregulated the protein and mRNA expression levels of breast cancer resistance protein in MCF-7/Taxol cells. The biodistribution and antitumor studies proved that the siRNA–PTX-loaded micelles possessed prolonged circulation time with a remarkable tumor-targeting effect and effectively inhibited tumor growth. Therefore, the novel dual pH/redox-sensitive polymers co-delivering siRNA and PTX with excellent biocompatibility and effective reversal of MDR demonstrate a considerable potential in cancer therapy. © 2017 Zhu et al.

Fang C.-Y.,China Pharmaceutical University | Xu J.-B.,China Pharmaceutical University | Li J.,Nanjing GuLou Hospital | Fang H.-S.,China Pharmaceutical University
Chinese Journal of Pharmaceutical Biotechnology | Year: 2014

To study the impact of ouabain on the conformation change of Na+, K+-ATPase, a new method based on molecular dynamics simulation was proposed. Firstly, complex can be obtained through docking, then, simulate enzyme monomer and its compounds in the same environment. The results showed that after ouabain binding to Na+, K+-ATPase, αM1 and αM2 of Na+, K+-ATPase move toward to ouabain and the A domain is slightly moving toward to P domain in the E2P: ouabain form; and Hydrophobic residues Phe783, Thr797, Val322, Gly319, Ile320, Ile321, Leu125, Ile315, Ala112 in binding pocket form hydrophobic effect with ouabain and polar residues, Asp121, Thr797, Gln111 form hydrogen bonds with ouabain. Comparison of the E2P: ouabain complex with E2P structure, in E2P: ouabain complex, 212TGES215 loop of A domain and flanking residues bury the phosphorylated Asp369 residue, protecting it against spontaneous hydrolysis. This prevents E1and E2 conformational change necessary for the function of the protein, then inhibit the activity of enzyme and stimulate the calcium ion mediated signaling channel. The method proposed in the paper not only intuitively shows the conformational changes of Na+, K+-ATPase, but well explains the mechanism of interaction of ouabain and Na+, K+-ATPase, and those data play a guiding role for further study.

Yan S.-Q.,China Pharmaceutical University | Li J.,Nanjing Gulou hospital | Fang H.-S.,China Pharmaceutical University
Chinese Journal of Pharmaceutical Biotechnology | Year: 2015

Genome-scale metabolic networks are a hot topic in system biology. The network reconstruction contains all of the known metabolic reactions and genes that encode each enzyme in an organism. Flux balance analysis (FBA) is a mathematical approach for analyzing the fux of metabolites through a metabolic network. FBA calculates the flux of metabolites through this metabolic network, thereby making it possible to predict the growth rate of an organism or the rate of production of a biotechnologically important metabolite. This paper reviews theories and modeling steps of flux balance analysis algorithms, flux balance analysis of mycolic acid pathways and, commonly used flux balance analysis softwares, and then compares the flux balance analysis tools, from installation requirements, availability, functionality, model interchange, network visualization, to guide the user to select the right software tools. © 2015, Editorial Board of Pharmaceutical Biotechnology. All right reserved.

Danoy P.,University of Queensland | Wei M.,Shanghai University | Johanna H.,University of Queensland | Jiang L.,Shanghai University | And 6 more authors.
Annals of the Rheumatic Diseases | Year: 2011

Background: The genome-wide association study era has made great progress in identifying susceptibility genes and genetic loci for rheumatoid arthritis (RA) in populations of White European ancestry. However, few studies have tried to dissect disease aetiopathogenesis in other ethnic populations. Objective: To investigate these associations in the Han Chinese population. Methods: Haplotypes from the HapMap database Chinese population were used to select tag-single-nucleotide polymorphisms (SNPs) (r2 =0.8) across 19 distinct RA genomic regions. A two phase case-control association study was performed, with 169 SNPs genotyped in phase I (n=571 cases, n=880 controls), and 64 SNPs achieving p<0.2 in the first phase being genotyped in phase II (n=464 cases, n=822 controls). Association statistics were calculated using permutation tests both unadjusted and adjusted for the number of markers studied. Results: Robust association was detected for MMEL1 and CTLA4 , and modest association was identified for another six loci: PADI4 , STAT4 , PRDM1 , CDK6 , TRAF1-C5 and KIF5A-PIP4K2C. All three markers genotyped in MMEL1 demonstrated association, with peak signal for rs3890745 (p=2.6×10 -5unadjusted, p=0.003 adjusted, OR=0.79). For CTLA4 , significance was detected for three of five variants showing association, with peak association for marker rs12992492 (p=4.3×10-5 unadjusted, p=0.0021 adjusted, OR=0.77). Lack of association of common variants in PTPN22 with RA in Han Chinese was confirmed. Conclusion: This study identifies MMEL1 and CTLA4 as RA susceptibility genes, provides suggestive evidence of association for a further six loci in the Han Chinese population and confirms lack of PTPN22 association in Asian populations. It also confirms the value of multiethnic population studies to help dissect disease aetiopathogenesis.

Davidson S.I.,University of Queensland | Liu Y.,Shanghai University | Danoy P.A.,University of Queensland | Wu X.,Shanghai University | And 15 more authors.
Annals of the Rheumatic Diseases | Year: 2011

Objectives: Recent association studies by the Australo-Anglo-American Spondyloarthritis Consortium (TASC) in Caucasian European populations from Australia, North America and the UK have identified a number of genes as being associated with ankylosing spondylitis (AS). A candidate gene study in a Han Chinese population was performed based on these findings to identify associated genes in this population. Methods: A case-control study was performed in a Han Chinese population of patients with AS (n=775) and controls (n=1587) from Shanghai and Nanjing. All patients met the modified New York criteria for AS. The cases and controls were genotyped for 115 single nucleotide polymorphisms (SNPs) tagging IL23R, ERAP1, STAT3, JAK2, TNFRSF1A and TRADD, as well as other confirmation SNPs from the TASC study, using the Sequenom iPlex and the ABI OpenArray platforms. Statistical analysis of genotyped SNPs was performed using the Cochran - Armitage test for trend and meta-analysis was performed using METAL. SNPs in AS-associated genes in this study were then imputed using MaCH, and association with AS tested by logistic regression. Results: SNPs in TNFRSF1A (rs4149577, p=8.2×10-4), STAT3 (rs2293152, p=0.0015; rs1053005, p=0.017) and ERAP1 (rs27038, p=0.0091; rs27037, p=0.0092) were significantly associated with AS in Han Chinese. Association was also observed between AS and the intergenic region 2p15 (rs10865331, p=0.023). The lack of association between AS and IL23R in Han Chinese was confirmed (all SNPs p>0.1). Conclusions: The study results demonstrate for the first time that genetic polymorphisms in STAT3, TNFRSF1A and 2p15 are associated with AS in Han Chinese, suggesting common pathogenic mechanisms for the disease in Chinese and Caucasian European populations. Furthermore, previous findings demonstrating that ERAP1, but not IL23R, is associated with AS in Chinese patients were confirmed.

Wu Y.-L.,Guangdong Academy of Medical science | Lee J.S.,National Cancer Center | Thongprasert S.,Maharaj Nakorn Chiang Mai Hospital | Yu C.-J.,National Taiwan University Hospital | And 28 more authors.
The Lancet Oncology | Year: 2013

Background: The results of FASTACT, a randomised, placebo-controlled, phase 2 study, showed that intercalated chemotherapy and erlotinib significantly prolonged progression-free survival (PFS) in patients with advanced non-small-cell lung cancer. We undertook FASTACT-2, a phase 3 study in a similar patient population. Methods: In this phase 3 trial, patients with untreated stage IIIB/IV non-small-cell lung cancer were randomly assigned in a 1:1 ratio by use of an interactive internet response system with minimisation algorithm (stratified by disease stage, tumour histology, smoking status, and chemotherapy regimen) to receive six cycles of gemcitabine (1250 mg/m2 on days 1 and 8, intravenously) plus platinum (carboplatin 5 × area under the curve or cisplatin 75 mg/m2 on day 1, intravenously) with intercalated erlotinib (150 mg/day on days 15-28, orally; chemotherapy plus erlotinib) or placebo orally (chemotherapy plus placebo) every 4 weeks. With the exception of an independent group responsible for monitoring data and safety monitoring board, everyone outside the interactive internet response system company was masked to treatment allocation. Patients continued to receive erlotinib or placebo until progression or unacceptable toxicity or death, and all patients in the placebo group were offered second-line erlotinib at the time of progression. The primary endpoint was PFS in the intention-to-treat population. This trial is registered with, number NCT00883779. Findings: From April 29, 2009, to Sept 9, 2010, 451 patients were randomly assigned to chemotherapy plus erlotinib (n=226) or chemotherapy plus placebo (n=225). PFS was significantly prolonged with chemotherapy plus erlotinib versus chemotherapy plus placebo (median PFS 7·6 months [95% CI 7·2-8·3], vs 6·0 months [5·6-7·1], hazard ratio [HR] 0·57 [0·47-0·69]; p<0·0001). Median overall survival for patients in the chemotherapy plus erlotinib and chemotherapy plus placebo groups was 18·3 months (16·3-20·8) and 15·2 months (12·7-17·5), respectively (HR 0·79 [0·64-0·99]; p=0·0420). Treatment benefit was noted only in patients with an activating EGFR gene mutation (median PFS 16·8 months [12·9-20·4] vs 6·9 months [5·3-7·6], HR 0·25 [0·16-0·39]; p<0·0001; median overall survival 31·4 months [22·2-undefined], vs 20·6 months [14·2-26·9], HR 0·48 [0·27-0·84]; p=0·0092). Serious adverse events were reported by 76 (34%) of 222 patients in the chemotherapy plus placebo group and 69 (31%) of 226 in the chemotherapy plus erlotinib group. The most common grade 3 or greater adverse events were neutropenia (65 [29%] patients and 55 [25%], respectively), thrombocytopenia (32 [14%] and 31 [14%], respectively), and anaemia (26 [12%] and 21 [9%], respectively). Interpretation: Intercalated chemotherapy and erlotinib is a viable first-line option for patients with non-small-cell lung cancer with EGFR mutation-positive disease or selected patients with unknown EGFR mutation status. Funding: F Hoffmann-La Roche. © 2013 Elsevier Ltd.

Wu S.,Nanjing Medical University | Yu W.,Nanjing Medical University | Qu X.,Nanjing Medical University | Wang R.,Nanjing Medical University | And 4 more authors.
Journal of Hematology and Oncology | Year: 2014

Background: Dysregulated microRNA (miRNA) expression contributes to cancer cell proliferation, apoptosis and angiogenesis. Angiogenesis is a hallmark of multiple myeloma (MM) development and progression. Argonaute 2 (AGO2) protein, a core component of the RNA-induced silencing complex (RISC), can directly bind to miRNAs and mediate target messenger RNA (mRNA) degradation. A previous study showed that AGO2 knockdown suppressed human umbilical vein endothelial cell (HUVEC) growth and tube formation. However, the roles and molecular mechanisms of AGO2-induced myeloma angiogenesis are not yet fully understood. The aim of this study was to characterize these roles and effects and their associated mechanisms. Results: Supernatants from AGO2-overexpressing MM lines induced HUVEC migration and accelerated tube formation. Conversely, supernatants from AGO2-knockdown MM lines suppressed HUVEC cell migration and tube formation. Moreover, a chick chorioallantoic membrane (CAM) assay was used to demonstrate that AGO2 could drive neovessel formation in MM lines in vivo. Using an miRNA microarray, we observed that 25 miRNAs were upregulated and 7 were downregulated in response to AGO2. Most let-7 family members and 2 miR-17/92 cluster members (miR-17a and miR-92-1), all known pro-angiogenic miRNAs, were positively regulated by AGO2 whereas anti-angiogenic miRNAs such as miR-145 and miR-361 were negatively regulated by AGO2. Conclusions: We conclude that AGO2 can drive neovessel formation in vitro and in vivo by dysregulating the expression of some angiogenic miRNAs. The pro-angiogenic miRNAs of the let-7 family and the miR-17/92 cluster, along with the anti-angiogenic miRNA miR-145, play crucial roles in AGO2-mediated angiogenesis by targeting angiogenesis-related genes. © 2014 Wu et al.; licensee BioMed Central Ltd.

Xu F.,Nanjing Medical University | Yang T.,Nanjing Medical University | Sheng Y.,Nanjing Medical University | Zhong T.,Nanjing Medical University | And 2 more authors.
Journal of Proteome Research | Year: 2014

As one of the most studied post-translational modifications (PTM), protein phosphorylation plays an essential role in almost all cellular processes. Current methods are able to predict and determine thousands of phosphorylation sites, whereas stoichiometric quantification of these sites is still challenging. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS)-based targeted proteomics is emerging as a promising technique for site-specific quantification of protein phosphorylation using proteolytic peptides as surrogates of proteins. However, several issues may limit its application, one of which relates to the phosphopeptides with different phosphorylation sites and the same mass (i.e., isobaric phosphopeptides). While employment of site-specific product ions allows for these isobaric phosphopeptides to be distinguished and quantified, site-specific product ions are often absent or weak in tandem mass spectra. In this study, linear algebra algorithms were employed as an add-on to targeted proteomics to retrieve information on individual phosphopeptides from their common spectra. To achieve this simultaneous quantification, a LC-MS/MS-based targeted proteomics assay was first developed and validated for each phosphopeptide. Given the slope and intercept of calibration curves of phosphopeptides in each transition, linear algebraic equations were developed. Using a series of mock mixtures prepared with varying concentrations of each phosphopeptide, the reliability of the approach to quantify isobaric phosphopeptides containing multiple phosphorylation sites (≥2) was discussed. Finally, we applied this approach to determine the phosphorylation stoichiometry of heat shock protein 27 (HSP27) at Ser78 and Ser82 in breast cancer cells and tissue samples. © 2014 American Chemical Society.

Yang T.,Nanjing Medical University | Xu F.,Nanjing Medical University | Zhao Y.,Nanjing Medical University | Wang S.,Nanjing Medical University | And 2 more authors.
Proteomics - Clinical Applications | Year: 2014

Purpose: Overexpression of human transferrin receptor (TfR) has been described qualitatively in various cancers, including breast cancer. Since TfR is also expressed to some extent under normal physiological conditions, increase of specificity and reproducibility in TfR quantification could improve the early detection and prognostic evaluation of cancers. Experimental design: A LC-MS/MS-based targeted proteomics assay was developed for the determination of TfR in human breast cells and tissue samples. Results: We selected the tryptic peptide 681VEYHFLSPYVSPK693 as the surrogate peptide for quantification and used a stable isotope-labeled synthetic peptide with this sequence as an internal standard. Quality control data indicated acceptable accuracy and precision. Finally, this assay was successfully applied to the quantitative analysis of TfR in three breast cell lines and 36 matched pairs of breast tissue samples. The experimental values were compared with those obtained from conventional analytical methods, including immunofluorescence microscopy, Western blotting, flow cytometry, and immunohistochemistry. Conclusions and clinical relevance: Not only is the LC-MS/MS-based targeted proteomics assay a more accurate method for the determination of TfR levels, but may afford more reliable quantification of TfR at low concentrations in clinical practice. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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