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1. chinaXiv:201605.01515 [pdf]

Intratumoral Delivery of IL-21 Overcomes Anti-Her2/Neu Resistance through Shifting Tumor-Associated Macrophages from M2 to M1 Phenotype

Xu, Meng; Liu, Mingyue; Du, Xuexiang; Li, Sirui; Li, Hang; Li, Xiaozhu; Li, Ying; Qin, Zhihai; Fu, Yang-Xin; Wang, Shengdian; Xu, Meng; Liu, Mingyue; Du, Xuexiang; Li, Sirui; Wang, Yang; Fu, Yang-Xin
Subjects: Biology >> Biophysics >> Immunology

Tumor resistance is a major hurdle to anti-Her2/neu Ab-based cancer therapy. Current strategies to overcome tumor resistance focus on tumor cell-intrinsic resistance. However, the extrinsic mechanisms, especially the tumor microenvironment, also play important roles in modulating the therapeutic response and resistance of the Ab. In this study, we demonstrate that tumor progression is highly associated with TAMs with immune-suppressive M2 phenotypes, and deletion of TAMs markedly enhanced the therapeutic effects of anti-Her2/neu Ab in a HER2/neu-dependent breast cancer cell TUBO model. Tumor local delivery of IL-21 can skew TAM polarization away from the M2 phenotype to a tumor-inhibiting M1 phenotype, which rapidly stimulates T cell responses against tumor and dramatically promotes the therapeutic effect of anti-Her2 Ab. Skewing of TAM polarization by IL-21 relies substantially on direct action of IL-21 on TAMs rather than stimulation of T and NK cells. Thus, our findings identify the abundant TAMs as a major extrinsic barrier for anti-Her2/neu Ab therapy and present a novel approach to combat this extrinsic resistance by tumor local delivery of IL-21 to skew TAM polarization. This study offers a therapeutic strategy to modulate the tumor microenvironment to overcome tumor-extrinsic resistance.

submitted time 2016-05-12 Hits1071Downloads517 Comment 0

2. chinaXiv:201605.01249 [pdf]

Specific binding of Clostridium perfringens enterotoxin fragment to Claudin-b and modulation of zebrafish epidermal barrier

Zhang, Jingjing; Yang, Zhenguo; Chen, Huapu; Wang, Sijie; Fan, Yiming; Zhang, Jingjing; Piontek, Anna; Qin, Zhihai; Piontek, Joerg; Ni, Chen
Subjects: Biology >> Biophysics

Claudins (Cldn) are the major components of tight junctions (TJs) sealing the paracellular cleft in tissue barriers of various organs. Zebrafish Cldnb, the homolog of mammalian Cldn4, is expressed at epithelial cell-cell contacts and is important for regulating epidermal permeability. The bacterial toxin Clostridium perfringens enterotoxin (CPE) has been shown to bind to a subset of mammalian Cldns. In this study, we used the Cldn-binding C-terminal domain of CPE (194-319 amino acids, cCPE(194-319)) to investigate its functional role in modulating zebrafish larval epidermal barriers. In vitro analyses show that cCPE(194-319) removed Cldn4 from epithelial cells and disrupted the monolayer tightness, which could be rescued by the removal of cCPE(194-319). Incubation of zebrafish larvae with cCPE(194-319) removed Cldnb specifically from the epidermal cell membrane. Dye diffusion analysis with 4-kDa fluorescent dextran indicated that the permeability of the epidermal barrier increased due to cCPE(194-319) incubation. Electron microscopic investigation revealed reversible loss of TJ integrity by Cldnb removal. Collectively, these results suggest that cCPE(194-319) could be used as a Cldnb modulator to transiently open the epidermal barrier in zebrafish. In addition, zebrafish might be used as an invivo system to investigate the capability of cCPE to enhance drug delivery across tissue barriers.

submitted time 2016-05-11 Hits185Downloads129 Comment 0

3. chinaXiv:201605.00729 [pdf]

Identification of Liver Epithelial Cell-derived Ig Expression in mu chain-deficient mice

Shao, Wenwei; Zhang, Chi; Ma, Junfan; Zhu, Zhu; Gong, Xiaoting; Qiu, Xiaoyan; Liu, Enyang; Zhang, Long; Qiu, Xiaoyan; Qin, Zhihai;
Subjects: Biology >> Biophysics

Growing evidence indicates that B cells are not the only source of immunoglobulin (Ig). To investigate this discovery further, we used mu MT mice, which have a disruption of the first transmembrane exon of the mu heavy chain and do not express the membrane form of IgM. These mice lack mature B cells and thus serve as a good model to explore Ig expression by liver epithelial cells. We found that Ig heavy chains (mu, delta, gamma and alpha) and light chains (kappa and lambda) were expressed in sorted liver epithelial cells of mu MT mice. Surprisingly, each heavy chain class showed its respective variable region sequence characteristics in their variable region, instead of sharing the same VDJ usage, which suggests that class switching does not occur in liver epithelial cells. Moreover, the gamma and alpha chains, but not the mu and delta chains, showed mutations in the variable region, thus indicating that different classes of Ig have different activities. Our findings support the concept that non-B cells, liver epithelial cells here, can produce different classes of Ig.

submitted time 2016-05-05 Hits196Downloads133 Comment 0

4. chinaXiv:201605.00705 [pdf]

Transformable Peptide Nanocarriers for Expeditious Drug Release and Effective Cancer Therapy via Cancer-Associated Fibroblast Activation

Ji, Tianjiao; Zhao, Ying; Ding, Yanping; Wang, Jing; Zhao, Ruifang; Lang, Jiayan; Qin, Hao; Shi, Jian; Nie, Guangjun; Zhao, Yuliang; Liu, Xiaoman; Tao, Ning; Qin, Zhihai;
Subjects: Biology >> Biophysics

A novel cleavable amphiphilic peptide (CAP) was designed to be specifically responsive to fibroblast activation protein- (FAP-), a protease specifically expressed on the surface of cancer-associated fibroblasts. The CAP self-assembled into fiber-like nanostructures in solution, while the presence of hydrophobic chemotherapeutic drugs readily transformed the assemblies into drug-loaded spherical nanoparticles. The disassembly of these nanoparticles (CAP-NPs) upon FAP- cleavage resulted in rapid and efficient release of the encapsulated drugs specifically at tumor sites. This Transformers-like drug delivery strategy could allow them to disrupt the stromal barrier and enhance local drug accumulation. Therapeutic results suggested that drug-loaded CAP-NPs hold promising tumor specificity and therapeutic efficacy for various solid tumor models, confirming its potential utility and versatility in antitumor therapy.

submitted time 2016-05-05 Hits260Downloads185 Comment 0

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