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Xiaojiang S Chen - One of the best experts on this subject based on the ideXlab platform.
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mechanism of origin dna recognition and assembly of an initiator helicase complex by sv40 large Tumor Antigen
Cell Reports, 2013Co-Authors: Paul Y Chang, Ana Carolina Dantas Machado, Remo Rohs, Xiaojiang S ChenAbstract:Summary The DNA Tumor virus Simian virus 40 (SV40) is a model system for studying eukaryotic replication. SV40 large Tumor Antigen (LTag) is the initiator/helicase that is essential for genome replication. LTag recognizes and assembles at the viral replication origin. We determined the structure of two multidomain LTag subunits bound to origin DNA. The structure reveals that the origin binding domains (OBDs) and Zn and AAA+ domains are involved in origin recognition and assembly. Notably, the OBDs recognize the origin in an unexpected manner. The histidine residues of the AAA+ domains insert into a narrow minor groove region with enhanced negative electrostatic potential. Computational analysis indicates that this region is intrinsically narrow, demonstrating the role of DNA shape readout in origin recognition. Our results provide important insights into the assembly of the LTag initiator/helicase at the replication origin and suggest that histidine contacts with the minor groove serve as a mechanism of DNA shape readout.
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mechanisms of conformational change for a replicative hexameric helicase of sv40 large Tumor Antigen
Cell, 2004Co-Authors: Xiaojiang S Chen, Dahai Gai, Rui Zhao, Carla V FinkielsteinAbstract:Abstract The large Tumor Antigen (LTag) of simian virus 40, an AAA + protein, is a hexameric helicase essential for viral DNA replication in eukaryotic cells. LTag functions as an efficient molecular machine powered by ATP binding and hydrolysis for origin DNA melting and replication fork unwinding. To understand how ATP binding and hydrolysis are coupled to conformational changes, we have determined high-resolution structures (∼1.9 A) of LTag hexamers in distinct nucleotide binding states. The structural differences of LTag in various nucleotide states detail the molecular mechanisms of conformational changes triggered by ATP binding/hydrolysis and reveal a potential mechanism of concerted nucleotide binding and hydrolysis. During these conformational changes, the angles and orientations between domains of a monomer alter, creating an "iris"-like motion in the hexamer. Additionally, six unique β hairpins on the channel surface move longitudinally along the central channel, possibly serving as a motor for pulling DNA into the LTag double hexamer for unwinding.
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mechanisms of conformational change for a replicative hexameric helicase of sv40 large Tumor Antigen
Cell, 2004Co-Authors: Dahai Gai, Xiaojiang S Chen, Rui Zhao, Carla V FinkielsteinAbstract:The large Tumor Antigen (LTag) of simian virus 40, an AAA(+) protein, is a hexameric helicase essential for viral DNA replication in eukaryotic cells. LTag functions as an efficient molecular machine powered by ATP binding and hydrolysis for origin DNA melting and replication fork unwinding. To understand how ATP binding and hydrolysis are coupled to conformational changes, we have determined high-resolution structures ( approximately 1.9 A) of LTag hexamers in distinct nucleotide binding states. The structural differences of LTag in various nucleotide states detail the molecular mechanisms of conformational changes triggered by ATP binding/hydrolysis and reveal a potential mechanism of concerted nucleotide binding and hydrolysis. During these conformational changes, the angles and orientations between domains of a monomer alter, creating an "iris"-like motion in the hexamer. Additionally, six unique beta hairpins on the channel surface move longitudinally along the central channel, possibly serving as a motor for pulling DNA into the LTag double hexamer for unwinding.
Ting Liu - One of the best experts on this subject based on the ideXlab platform.
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the plant alkaloid tetrandrine inhibits metastasis via autophagy dependent wnt β catenin and metastatic Tumor Antigen 1 signaling in human liver cancer cells
Journal of Experimental & Clinical Cancer Research, 2018Co-Authors: Zhenxing Zhang, Ting LiuAbstract:Tetrandrine is a bisbenzylisoquinoline alkaloid isolated from the Chinese medicinal herb Stephania tetrandra S. Moore. We previously demonstrated that tetrandrine exhibits potent antiTumor effects in many types of cancer cells. In this study, we investigated the effects of tetrandrine on human hepatocellular carcinoma (HCC) metastasis. The invasion and migration effects were evaluated via wound healing and transwell assays. Immunofluorescence and western blotting analyses were used to investigate the levels of epithelial-mesenchymal transition (EMT)-related protein. A metastasis model was established to investigate the inhibitory effect of tetrandrine on hepatocellular carcinoma metastasis in vivo. Tetrandrine inhibits HCC invasion and migration by preventing cell EMT. The underlying mechanism was closely associated with tetrandrine-induced human liver cell autophagy, which inhibits Wnt/β-catenin pathway activity and decreases metastatic Tumor Antigen 1 (MTA1) expression to modulate cancer cell metastasis. Our findings demonstrate, for the first time, that tetrandrine plays a significant role in the inhibition of human hepatocellular carcinoma metastasis and provide novel insights into the application of tetrandrine in clinical HCC treatment.
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The plant alkaloid tetrandrine inhibits metastasis via autophagy-dependent Wnt/β-catenin and metastatic Tumor Antigen 1 signaling in human liver cancer cells
BMC, 2018Co-Authors: Zhenxing Zhang, Ting LiuAbstract:Abstract Background Tetrandrine is a bisbenzylisoquinoline alkaloid isolated from the Chinese medicinal herb Stephania tetrandra S. Moore. We previously demonstrated that tetrandrine exhibits potent antiTumor effects in many types of cancer cells. In this study, we investigated the effects of tetrandrine on human hepatocellular carcinoma (HCC) metastasis. Methods The invasion and migration effects were evaluated via wound healing and transwell assays. Immunofluorescence and western blotting analyses were used to investigate the levels of epithelial-mesenchymal transition (EMT)-related protein. A metastasis model was established to investigate the inhibitory effect of tetrandrine on hepatocellular carcinoma metastasis in vivo. Results Tetrandrine inhibits HCC invasion and migration by preventing cell EMT. The underlying mechanism was closely associated with tetrandrine-induced human liver cell autophagy, which inhibits Wnt/β-catenin pathway activity and decreases metastatic Tumor Antigen 1 (MTA1) expression to modulate cancer cell metastasis. Conclusion Our findings demonstrate, for the first time, that tetrandrine plays a significant role in the inhibition of human hepatocellular carcinoma metastasis and provide novel insights into the application of tetrandrine in clinical HCC treatment
Devin B Lowe - One of the best experts on this subject based on the ideXlab platform.
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the role of gamma interferon in dna vaccine induced Tumor immunity targeting simian virus 40 large Tumor Antigen
Cancer Immunology Immunotherapy, 2013Co-Authors: Joel F Aldrich, Devin B Lowe, Michael H Shearer, Cynthia A Jumper, Ronald C Kennedy, Richard Winn, Robert K BrightAbstract:The central role of CD4+ T lymphocytes in mediating DNA vaccine-induced Tumor immunity against the viral oncoprotein simian virus 40 (SV40) large Tumor Antigen (Tag) has previously been described by our laboratory. In the present study, we extend our previous findings by examining the roles of IFN-γ and Th1-associated effector cells within the context of DNA immunization in a murine model of pulmonary metastasis. Immunization of BALB/c mice with plasmid DNA encoding SV40 Tag (pCMV-Tag) generated IFN-γ-secreting T lymphocytes that produced this cytokine upon in vitro stimulation with mKSA Tumor cells. The role of IFN-γ as a mediator of protection against mKSA Tumor development was assessed via in vivo IFN-γ neutralization, and these experiments demonstrated a requirement for this cytokine in the induction immune phase. Neutralization of IFN-γ was associated with a reduction in Th1 cytokine-producing CD4+ and CD8+ splenocytes, as assessed by flow cytometry analysis, and provided further evidence for the role of CD4+ T lymphocytes as drivers of the cellular immune response. Depletion of NK cells and CD8+ T lymphocytes demonstrated the expendability of these cell types individually, but showed a requirement for a resident cytotoxic cell population within the immune effector phase. Our findings demonstrate the importance of IFN-γ in the induction of protective immunity stimulated by pCMV-Tag DNA-based vaccine and help to clarify the general mechanisms by which DNA vaccines trigger immunity to Tumor cells.
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in vitro simian virus 40 large Tumor Antigen expression correlates with differential immune responses following dna immunization
Virology, 2005Co-Authors: Devin B Lowe, Michael H Shearer, James Tarbox, Hyun Seok Kang, Cynthia A Jumper, Robert K Bright, Ronald C KennedyAbstract:Simian virus 40 (SV40) contains an essential protein, large Tumor Antigen (Tag), which assists in viral replication and causes cell transformation and immortalization. Our laboratory has examined plasmid DNA, expressing SV40 Tag under two different promoters, for use in potential cancer vaccination strategies. One plasmid, pSV3-neo, failed to induce SV40 Tag antibody, produced a weak cell-mediated response, and only partial protection in murine experimental Tumor challenge systems. The second plasmid, pCMV-Tag, induced antibodies to SV40 Tag, produced a robust cell-mediated response, and invoked complete Tumor immunity in vivo. The induction of CD4+ and CD8+ T cell responses following plasmid DNA immunization and Tumor cell challenge reflected a type 1 cytokine secretion profile. Our hypothesis for this differential immune response is that pCMV-Tag exhibits a higher level of transgene expression due to a more efficient promoter. We determined that pCMV-Tag levels of SV40 Tag mRNA and protein expression were higher when compared to pSV3-neo. A threshold amount of SV40 Tag may be required to stimulate antibody production and provide complete systemic Tumor immunity.
Julien Fourcade - One of the best experts on this subject based on the ideXlab platform.
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tigit and pd 1 impair Tumor Antigen specific cd8 t cells in melanoma patients
Journal of Clinical Investigation, 2015Co-Authors: Joemarc Chauvin, Ornella Pagliano, Julien Fourcade, Zhaojun Sun, Hong Wang, Cindy Sander, John M Kirkwood, Tsenghui Timothy Chen, Mark Maurer, Alan J KormanAbstract:T cell Ig and ITIM domain (TIGIT) is an inhibitory receptor expressed by activated T cells, Tregs, and NK cells. Here, we determined that TIGIT is upregulated on Tumor Antigen-specific (TA-specific) CD8⁺ T cells and CD8⁺ Tumor-infiltrating lymphocytes (TILs) from patients with melanoma, and these TIGIT-expressing CD8⁺ T cells often coexpress the inhibitory receptor PD-1. Moreover, CD8⁺ TILs from patients exhibited downregulation of the costimulatory molecule CD226, which competes with TIGIT for the same ligand, supporting a TIGIT/CD226 imbalance in metastatic melanoma. TIGIT marked early T cell activation and was further upregulated by T cells upon PD-1 blockade and in dysfunctional PD-1⁺TIM-3⁺ TA-specific CD8⁺ T cells. PD-1⁺TIGIT⁺, PD-1⁻TIGIT⁺, and PD-1⁺TIGIT⁻ CD8⁺ TILs had similar functional capacities ex vivo, suggesting that TIGIT alone, or together with PD-1, is not indicative of T cell dysfunction. However, in the presence of TIGIT ligand-expressing cells, TIGIT and PD-1 blockade additively increased proliferation, cytokine production, and degranulation of both TA-specific CD8⁺ T cells and CD8⁺ TILs. Collectively, our results show that TIGIT and PD-1 regulate the expansion and function of TA-specific CD8⁺ T cells and CD8⁺ TILs in melanoma patients and suggest that dual TIGIT and PD-1 blockade should be further explored to elicit potent antiTumor CD8⁺ T cell responses in patients with advanced melanoma.
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pd 1 and tim 3 regulate the expansion of Tumor Antigen specific cd8 t cells induced by melanoma vaccines
Cancer Research, 2014Co-Authors: Julien Fourcade, Joemarc Chauvin, Ornella Pagliano, Zhaojun Sun, Cindy Sander, John M Kirkwood, Bratislav Janjic, Ahmad A Tarhini, Hussein Tawbi, Stergios J MoschosAbstract:Although melanoma vaccines stimulate Tumor Antigen-specific CD8(+) T cells, objective clinical responses are rarely observed. To investigate this discrepancy, we evaluated the character of vaccine-induced CD8(+) T cells with regard to the inhibitory T-cell coreceptors PD-1 and Tim-3 in patients with metastatic melanoma who were administered Tumor vaccines. The vaccines included incomplete Freund's adjuvant, CpG oligodeoxynucleotide (CpG), and the HLA-A2-restricted analog peptide NY-ESO-1 157-165V, either by itself or in combination with the pan-DR epitope NY-ESO-1 119-143. Both vaccines stimulated rapid Tumor Antigen-specific CD8(+) T-cell responses detected ex vivo, however, Tumor Antigen-specific CD8(+) T cells produced more IFN-γ and exhibited higher lytic function upon immunization with MHC class I and class II epitopes. Notably, the vast majority of vaccine-induced CD8(+) T cells upregulated PD-1 and a minority also upregulated Tim-3. Levels of PD-1 and Tim-3 expression by vaccine-induced CD8(+) T cells at the time of vaccine administration correlated inversely with their expansion in vivo. Dual blockade of PD-1 and Tim-3 enhanced the expansion and cytokine production of vaccine-induced CD8(+) T cells in vitro. Collectively, our findings support the use of PD-1 and Tim-3 blockades with cancer vaccines to stimulate potent antiTumor T-cell responses and increase the likelihood of clinical responses in patients with advanced melanoma.
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pd 1 and tim 3 regulate the expansion of Tumor Antigen specific cd8 t cells induced by melanoma vaccines
Cancer Research, 2014Co-Authors: Julien Fourcade, Joemarc Chauvin, Ornella Pagliano, Cindy Sander, John M Kirkwood, Bratislav Janjic, Ahmad A Tarhini, Hussein Tawbi, Stergios J Moschos, Hong WangAbstract:Although melanoma vaccines stimulate Tumor Antigen–specific CD8 + T cells, objective clinical responses are rarely observed. To investigate this discrepancy, we evaluated the character of vaccine-induced CD8 + T cells with regard to the inhibitory T-cell coreceptors PD-1 and Tim-3 in patients with metastatic melanoma who were administered Tumor vaccines. The vaccines included incomplete Freund9s adjuvant, CpG oligodeoxynucleotide (CpG), and the HLA-A2–restricted analog peptide NY-ESO-1 157-165V, either by itself or in combination with the pan-DR epitope NY-ESO-1 119-143. Both vaccines stimulated rapid Tumor Antigen–specific CD8 + T-cell responses detected ex vivo , however, Tumor Antigen–specific CD8 + T cells produced more IFN-γ and exhibited higher lytic function upon immunization with MHC class I and class II epitopes. Notably, the vast majority of vaccine-induced CD8 + T cells upregulated PD-1 and a minority also upregulated Tim-3. Levels of PD-1 and Tim-3 expression by vaccine-induced CD8 + T cells at the time of vaccine administration correlated inversely with their expansion in vivo . Dual blockade of PD-1 and Tim-3 enhanced the expansion and cytokine production of vaccine-induced CD8 + T cells in vitro . Collectively, our findings support the use of PD-1 and Tim-3 blockades with cancer vaccines to stimulate potent antiTumor T-cell responses and increase the likelihood of clinical responses in patients with advanced melanoma. Cancer Res; 74(4); 1045–55. ©2013 AACR .
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immunization with analog peptide in combination with cpg and montanide expands Tumor Antigen specific cd8 t cells in melanoma patients
Journal of Immunotherapy, 2008Co-Authors: Julien Fourcade, Arthur M. Krieg, Pedro Andrade A Filho, Cindy Sander, Bratislav Janjic, Pavol Kudela, Stephanie R Land, Albert D Donnenberg, Hongmei Shen, John M KirkwoodAbstract:Analog peptides represent a promising tool to further optimize peptide-based vaccines in promoting the expansion of Tumor Antigen-specific cytotoxic T lymphocytes. Here, we report the results of a pilot trial designed to study the immunogenicity of the analog peptide NY-ESO-1 157-165V in combination
Ronald C Kennedy - One of the best experts on this subject based on the ideXlab platform.
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the role of gamma interferon in dna vaccine induced Tumor immunity targeting simian virus 40 large Tumor Antigen
Cancer Immunology Immunotherapy, 2013Co-Authors: Joel F Aldrich, Devin B Lowe, Michael H Shearer, Cynthia A Jumper, Ronald C Kennedy, Richard Winn, Robert K BrightAbstract:The central role of CD4+ T lymphocytes in mediating DNA vaccine-induced Tumor immunity against the viral oncoprotein simian virus 40 (SV40) large Tumor Antigen (Tag) has previously been described by our laboratory. In the present study, we extend our previous findings by examining the roles of IFN-γ and Th1-associated effector cells within the context of DNA immunization in a murine model of pulmonary metastasis. Immunization of BALB/c mice with plasmid DNA encoding SV40 Tag (pCMV-Tag) generated IFN-γ-secreting T lymphocytes that produced this cytokine upon in vitro stimulation with mKSA Tumor cells. The role of IFN-γ as a mediator of protection against mKSA Tumor development was assessed via in vivo IFN-γ neutralization, and these experiments demonstrated a requirement for this cytokine in the induction immune phase. Neutralization of IFN-γ was associated with a reduction in Th1 cytokine-producing CD4+ and CD8+ splenocytes, as assessed by flow cytometry analysis, and provided further evidence for the role of CD4+ T lymphocytes as drivers of the cellular immune response. Depletion of NK cells and CD8+ T lymphocytes demonstrated the expendability of these cell types individually, but showed a requirement for a resident cytotoxic cell population within the immune effector phase. Our findings demonstrate the importance of IFN-γ in the induction of protective immunity stimulated by pCMV-Tag DNA-based vaccine and help to clarify the general mechanisms by which DNA vaccines trigger immunity to Tumor cells.
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in vitro simian virus 40 large Tumor Antigen expression correlates with differential immune responses following dna immunization
Virology, 2005Co-Authors: Devin B Lowe, Michael H Shearer, James Tarbox, Hyun Seok Kang, Cynthia A Jumper, Robert K Bright, Ronald C KennedyAbstract:Simian virus 40 (SV40) contains an essential protein, large Tumor Antigen (Tag), which assists in viral replication and causes cell transformation and immortalization. Our laboratory has examined plasmid DNA, expressing SV40 Tag under two different promoters, for use in potential cancer vaccination strategies. One plasmid, pSV3-neo, failed to induce SV40 Tag antibody, produced a weak cell-mediated response, and only partial protection in murine experimental Tumor challenge systems. The second plasmid, pCMV-Tag, induced antibodies to SV40 Tag, produced a robust cell-mediated response, and invoked complete Tumor immunity in vivo. The induction of CD4+ and CD8+ T cell responses following plasmid DNA immunization and Tumor cell challenge reflected a type 1 cytokine secretion profile. Our hypothesis for this differential immune response is that pCMV-Tag exhibits a higher level of transgene expression due to a more efficient promoter. We determined that pCMV-Tag levels of SV40 Tag mRNA and protein expression were higher when compared to pSV3-neo. A threshold amount of SV40 Tag may be required to stimulate antibody production and provide complete systemic Tumor immunity.
