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Dive into the research topics where Yafeng Shen is active.

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Featured researches published by Yafeng Shen.


Environmental Toxicology and Pharmacology | 2015

In vitro cytotoxicity of gold nanorods in A549 cells

Ying Tang; Yafeng Shen; Libin Huang; Gaojian Lv; Changhai Lei; Xiaoyan Fan; Fangxing Lin; Yuxia Zhang; Lihui Wu; Yongji Yang

Gold nanoparticles, which have unique physicochemical characteristics, are being used for an increasingly wide range of applications in biomedical research. In this study, gold nanorods (width of 25 nm, length of 52 nm) were found to be internalized by A549 cells and were primarily localized in the lysosomes and membranous vesicles. The integrity of the membranes of A549 cells exposed to gold nanorods for 4h was damaged, as indicated by laser scanning confocal microscopy (LSCM). Increased lactate dehydrogenase (LDH) leakage and decreased cell viability further indicated the concentration-dependent cytotoxicity of the gold nanorods to the A549 cells. Reactive oxygen species (ROS) production was induced in the A549 cells by the gold nanorods, and this effect was positively correlated with the concentration of the gold nanorods. The results of this study indicated that exposure to gold nanorods caused dose-dependent cytotoxicity in A549 cells and that oxidative stress may be the main factor causing cytotoxicity.


Science Translational Medicine | 2017

Antagonism of EGFR and Notch limits resistance to EGFR inhibitors and radiation by decreasing tumor-initiating cell frequency

Shi Hu; Wenyan Fu; Tian Li; Qingning Yuan; Feifei Wang; Gaojian Lv; Yuanyuan Lv; Xiaoyan Fan; Yafeng Shen; Fangxing Lin; Ying Tang; Xuting Ye; Yongji Yang; Changhai Lei

An anti-EGFR/Notch antibody limits acquired resistance to EGFR inhibitors and radiation by reducing tumor-initiating cell frequency. Two targets for a bigger punch The epidermal growth factor receptor (EGFR) is a common target of therapeutics for a variety of different tumors, but tumors eventually become resistant to these drugs. One route to resistance is an increase in the number of cancer stem cells driven by the Notch pathway. To overcome this type of resistance, Hu et al. created a customized antibody called CT16, which can recognize both EGFR and Notch, simultaneously inhibiting both pathways. The authors tested this antibody in mouse models of non–small cell lung cancer, showing that it inhibits cancer stem cells and is more effective than antibodies against the individual pathways alone and in combination, particularly in the presence of radiation treatment. Epidermal growth factor receptor (EGFR) blockade and radiation are efficacious in the treatment of cancer, but resistance is commonly reported. Studies have suggested that dysregulation of Notch signaling and enrichment of the cancer stem cell population underlie these treatment challenges. Our data show that dual targeting of EGFR and Notch2/3 receptors with antibody CT16 not only inhibited signaling mediated by these receptors but also showed a strong anti–stem cell effect both in vitro and in vivo. Treatment with CT16 prevented acquired resistance to EGFR inhibitors and radiation in non–small cell lung cancer (NSCLC) cell line models and patient-derived xenograft tumors. CT16 also had a superior radiosensitizing impact compared with EGFR inhibitors. CT16 in combination with radiation had a larger antitumor effect than the combination of radiation with EGFR inhibitors or tarextumab. Mechanistically, CT16 treatment inhibits the stem cell–like subpopulation, which has a high mesenchymal gene expression and DNA repair activity, and reduces tumor-initiating cell frequency. This finding highlights the capacity of a combined blockade of EGFR and Notch signaling to augment the response to radiation and suggests that CT16 may achieve clinical efficacy when combined with radiation in NSCLC treatment.


Cancer Letters | 2016

Broad RTK-targeted therapy overcomes molecular heterogeneity-driven resistance to cetuximab via vectored immunoprophylaxis in colorectal cancer

Shi Hu; Haibin Dai; Tian Li; Ying Tang; Wenyan Fu; Qingning Yuan; Feifei Wang; Gaojian Lv; Yuanyuan Lv; Xiaoyan Fan; Sheng Zhang; Ruobing Jin; Yafeng Shen; Fangxing Lin; Xuting Ye; Min Ding; Yongji Yang; Changhai Lei

The human epidermal growth factor receptor (EGFR) targeting chimeric monoclonal antibody, cetuximab (Erbitux®), is a widely used drug in the treatment of metastatic colorectal cancer. However, the activation of the extensive crosstalk among the EGFR family receptors as well as other tyrosine kinase receptors (RTKs) impairs the efficacy of the drug by fueling acquired resistance. To identify the responsible potential activation pathway underlying cetuximab resistance and generate novel treatment strategies, cetuximab-resistant colorectal cancer cell lines were generated and validated and a functional RNAi screen targeting human RTKs was used to identify extensive receptor tyrosine kinase signaling networks established in resistant cancer cells. MET, Axl, and IGF-1R were identified as contributors to the acquired resistance to cetuximab. Targeting vectored immunoprophylaxis (VIPs) to different RTKs were generated and characterized. Different VIP approaches were evaluated in vivo with parental and cetuximab-resistance xenografts and the RTKs in resistant cancer xenografts were inhibited with VIPs via re-sensitization to cetuximab treatment. Combination of VIPs was more broadly efficacious, mechanistically, due to co-blocking the EGFR/Axl/MET signaling pathway, which was cross-activated in the resistant cell lines. Moreover, a VIP-based procedural treatment strategy not only eliminated the tumor but also afforded long-lasting protection from tumor recurrence and resistance. Overall, EGFR-related RTK pathway-network activation represents a novel mechanism underlying cetuximab resistance. A broad VIP combination strategy and VIP-based procedural treatment strategy may be a recommended addition to cetuximab-based targeted therapy. Our results establish a new principle to achieve combined RTK inhibition and reverse drug resistance using a VIP approach.


Scientific Reports | 2017

TRIM14 regulates cell proliferation and invasion in osteosarcoma via promotion of the AKT signaling pathway

Guoxing Xu; Yongfei Guo; Dabo Xu; Yi Wang; Yafeng Shen; Feifei Wang; Yuanyuan Lv; Fanglong Song; Dawei Jiang; Yinquan Zhang; Yi Lou; Yake Meng; Yongji Yang; Yifan Kang

Recent studies have shown that some members of the tripartite motif-containing protein (TRIM) family serve as important regulators of tumorigenesis. However, the biological role of TRIM14 in osteosarcoma remains to be established. In this study, we showed that TRIM14 is upregulated in human osteosarcoma specimens and cell lines, and correlated with osteosarcoma progression and shorter patient survival times. Functional studies demonstrated that overexpression of TRIM14 enhances osteosarcoma cell proliferation, clone formation, cell cycle procession, migration and invasion in vitro and promotes tumor growth in vivo, and conversely, its silencing has the opposite effects. Furthermore, TRIM14 overexpression induced activation of the AKT pathway. Inhibition of AKT expression reversed the TRIM14-mediated promotory effects on cell growth and mobility, in addition to TRIM14-induced epithelial-to-mesenchymal transition (EMT) and cyclin D1 upregulation. Our findings collectively suggest that TRIM14 functions as an oncogene by upregulating the AKT signaling pathway in osteosarcoma cells, supporting its potential utility as a therapeutic target for this disease.


Molecular Immunology | 2017

Targeting EGFR/HER2 heterodimerization with a novel anti-HER2 domain II/III antibody

Xiaojie Yu; Lingfei Wang; Yafeng Shen; Chao Wang; Yajun Zhang; Yanchun Meng; Yang Yang; Beibei Liang; Bo Zhou; Huajing Wang; Huafeng Wei; Changhai Lei; Shi Hu; Bohua Li

HighlightsA novel anti‐HER2 antibody was developed.There was a structural conformation change in HER2 in complex with 7C3.The antibody could block HER2/EGFR heterodimerization and signaling.It reveals a unique potential to complement current anti‐HER2 treatment strategy. Abstract HER2, a ligand‐free tyrosine kinase receptor of the HER family, is frequently overexpressed in breast cancer. The anti‐HER2 antibody trastuzumab has shown significant clinical benefits in metastatic breast cancer. Despite the effectiveness of trastuzumab, its efficacy remains variable and often modest. Thus, there is an urgent need to improve ErbB2‐targeting therapy. Here, we describe a novel anti‐HER2 antibody, 7C3, which was developed using hybridoma technique. Structural analysis confirms that the epitope of this antibody is in domain II/III of HER2. Moreover, a structural conformation change was observed in HER2 in complex with 7C3. Interestingly, this novel anti‐HER2 antibody exhibits efficacy in blocking HER2/EGFR heterodimerization and signaling. The results highlight the different function role of HER2 domains and the unique potential of 7C3 to inhibit the HER2/EGFR heterodimer, which may complement current anti‐HER2 treatments.


Journal of Cellular Physiology | 2018

Conditionally Targeted Deletion of PSEN1 Leads to Diastolic Heart Dysfunction

Xiao-Wei Song; Qingning Yuan; Ying Tang; Mi Cao; Yafeng Shen; Zhen-Yu Zeng; Changhai Lei; SongHua Li; Xianxian Zhao; Yongji Yang

Recently, PSEN1 has been reported to have mutations in dilated cardiomyopathy pedigrees. However, the function and mechanism of PSEN1 in cardiomyopathy remains unresolved. Here, we established four types of genetically modified mice to determine the function of PSEN1 in cardiac development and pathology. PSEN1 null mutation resulted in perinatal death, retardation of heart growth, ventricular dilatation, septum defects, and valvular thickening. PSEN1 knockout in adults led to decreased muscle fibers, widened sarcomere Z lines and reduced lengths of sarcomeres in cardiomyocytes. Cardiovascular loss of function of PSEN1 induced by Sm22a‐Cre or Myh6‐Cre/ER/tamoxifen also resulted in severe ultrastructural abnormalities, such as relaxed gap junctions between neighboring cardiomyocytes. Functionally, cardiovascular deletion of PSEN1 caused spontaneous mortality from birth to adulthood and led to diastolic heart dysfunction, including decreased volume of the left ventricle at the end‐systolic and end‐diastolic stages. Additionally, in a myocardial ischemia model, deletion of PSEN1 in the cardiovascular system first protected mice by inducing adaptive hypertrophy but ultimately resulted in severe heart failure. Furthermore, a collection of genes was abnormally expressed in the hearts of cardiac‐specific PSEN1 knockout mice. They were enriched in cell proliferation, calcium regulation, and so on. Taken together, dynamic regulation and abnormal function of PSEN1 underlie the pathogenesis of cardiovascular diseases due to ultrastructural abnormality of cardiomyocytes.


bioRxiv | 2018

Targeting RyR2 with a phosphorylation site-specific nanobody Reverses Dysfunction of Failing Cardiomyocytes in Rat

Tian Li; Yafeng Shen; Fangxing Lin; Wenyan Fu; Shuowu Liu; Xiaoyan Fan; Xuting Ye; Ying Tang; Min Ding; Yongji Yang; Changhai Lei; Shi Hu

Chronic PKA phosphorylation of RyR2 has been shown to increased diastolic SR Ca2+ leak and lead to cardiac dysfunction. Since the change of phosphorylation level of RyR2 is a biomarker of failing heart, we attempted to verify the hypothesis that intracellular gene delivery of a RyR2 targeting phosphorylation site-specific nanobody could preserve contractility of failing myocardium. In present study, we acquired the RyR2-specific nanobodies from a phage display library which are variable domains of camellidae heavy chain-only antibodies (VHH). One of the monoclonal nanobodies, AR185, inhibiting RyR2 phosphorylation in an in vitro assay was then chosen for further investigation. We investigated the potential of adeno-associated virus (AAV)-9-mediated cardiac expression of AR185 against post-ischemic heart failure. Adeno-associated virus gene delivery elevated the intracellular expression AR185 protein in the ischemic heart failure model of rats, and this treatment normalized the systolic and diastolic dysfunction of the failing myocardium in vivo and in vitro by reversing myocardial Ca2+ handling. Furthermore, AR185 gene transfer to failing cardiomyocytes reduced the frequency of sarcoplasmic reticulum (SR) calcium leak, thereby restoring the attenuated intracellular calcium transients and SR calcium load. Moreover, AR185 gene transfer inhibited PKA phosphorylation of RyR2 in failing cardiomyocytes. Our results provided strong pre-clinical experimental evidence of the cardiac expression of RyR2 nanobody with AAV9 vectors as a promising therapeutic strategy for ischemic heart failure.


Molecular Biology | 2018

Development and Optimization of Therapeutic Analogues of Anti-TNFα Antibody Infliximab

Xiaojie Yu; Yafeng Shen; Jian Dong; T. Li; Chao Wang; Yajun Zhang; Lingfei Wang; Yanchun Meng; Yongji Yang; Huajing Wang; Changhai Lei; Shi Hu; B.-H. Li

Previously, we have reported the crystal structures of Fab fragment of Infliximab in complex with TNFα. The structurally identified epitope on TNFα revealed the mechanism of TNFα inhibition by partially overlapping with the TNFα-receptor interface and the possibility to optimize the binding affinity. In this study, we launched a screen of a phage display library to isolate novel anti-TNFα antibodies based on the infliximab epitope. To develop novel anti-TNFα antibodies, structural analysis, the phage display antibody isolation, step by step antibody optimization, CDR residues random mutagenesis, and binding affinity characterization were performed. One of the novel antibodies generated on the backbone of infliximab, Inf3D6, has the superior binding affinity to TNFα, thus, demonstrating the potential for structure guided optimization for improvement of existing antibody-based therapeutics.


Journal of Drug Targeting | 2018

Cardiac adenovirus-associated viral Presenilin 1 gene delivery protects the left ventricular function of the heart via regulating RyR2 function in post-ischaemic heart failure

Tian Li; Yafeng Shen; Li Su; Xiaoyan Fan; Fangxing Lin; Xuting Ye; Dianer Ding; Ying Tang; Yongji Yang; Changhai Lei; Shi Hu

Abstract Post-ischaemic heart failure is a major cause of death worldwide. Reperfusion of infarcted heart tissue after myocardial infarction has been an important medical intervention to improve outcomes. However, disturbances in Ca2+ and redox homeostasis at the cellular level caused by ischaemia/reperfusion remain major clinical challenges. In this study, we investigated the potential of adeno-associated virus (AAV)-9-mediated cardiac expression of a Type-2 ryanodine receptor (RyR2) degradation-associated gene, Presenilin 1 (PSEN1), to combat post-ischaemic heart failure. Adeno-associated viral PSEN1 gene delivery elevated PSEN1 protein expression in a post-infarction rat heart failure model, and this administration normalised the contractile dysfunction of the failing myocardium in vivo and in vitro by reversing myocardial Ca2+ handling and function. Moreover, PSEN1 gene transfer to failing cardiomyocytes reduced sarcoplasmic reticulum (SR) Ca2+ leak, thereby restoring the diminished intracellular Ca2+ transients and SR Ca2+ load. Moreover, PSEN1 gene transfer reversed the phosphorylation of RyR2 in failing cardiomyocytes. However, selective autophagy inhibition did not prevent the PSEN1-induced blockade of RyR2 degradation, making the participation of autophagy in PSEN1-associated RyR2 degradation unlikely. Our results established a role of the cardiac expression of PSEN1 with AAV9 vectors as a promising therapeutic approach for post-ischaemic heart failure.


International Journal of Biological Macromolecules | 2016

In situ visualizing T-Tubule/SR junction reveals the ultra-structures of calcium storage and release machinery

XiaoWei Song; Ying Tang; Changhai Lei; Mi Cao; Yafeng Shen; Yongji Yang

In skeletal muscle, Ca(2+) release from sarcoplasmic reticulum (SR) following the action potential relies on the delicate architecture of the T-Tubule/SR junction. The T-Tubule/SR junction comprises two membrane systems: the integral proteins DHPR and RyR1 and the Ca(2+)-buffering apparatus within the SR lumen. The arrangement and interactions of the components have remained elusive due to technological limitations. Here, we determined whether electron tomography is effective fort the in situ determination of the relationships between RyR1 and DHPR, the SR membrane and other involved structures. First, we visually confirmed that RyR1 and DHPR are close neighbors that are mutually staggered with each other and directly interact with one of RyR1 subunits. Second, the Ca(2+) storage network within the SR lumen is directly correlated with RyR1. These results suggest that the excitation of the T-Tubule may induce Ca(2+) release through a direct interaction among DHPR, RyR1 and the Ca(2+) buffering apparatus. These results indicate that electron tomography has potential as an efficient method for the in situ characterization of the complex architecture and arrangement of two integral-integral-membrane proteins in the context of the surrounding phospholipid-bilayer and proteins.

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Changhai Lei

Second Military Medical University

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Ying Tang

Second Military Medical University

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Yongji Yang

Second Military Medical University

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Shi Hu

Second Military Medical University

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Fangxing Lin

Second Military Medical University

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Xiaoyan Fan

Second Military Medical University

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Yong-Ji Yang

Second Military Medical University

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Tian Li

Second Military Medical University

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Xuting Ye

Second Military Medical University

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Feifei Wang

Second Military Medical University

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