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Douglas S Lyles - One of the best experts on this subject based on the ideXlab platform.
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oncolytic vesicular stomatitis virus induces apoptosis in u87 glioblastoma cells by a type ii death Receptor Mechanism and induces cell death and tumor clearance in vivo
Journal of Virology, 2011Co-Authors: Zachary D Cary, Mark C Willingham, Douglas S LylesAbstract:Vesicular stomatitis virus (VSV) is a potential oncolytic virus for treating glioblastoma multiforme (GBM), an aggressive brain tumor. Matrix (M) protein mutants of VSV have shown greater selectivity for killing GBM cells versus normal brain cells than VSV with wild-type M protein. The goal of this research was to determine the contribution of death Receptor and mitochondrial pathways to apoptosis induced by an M protein mutant (M51R) VSV in U87 human GBM tumor cells. Compared to controls, U87 cells expressing a dominant negative form of Fas (dnFas) or overexpressing Bcl-X L had reduced caspase-3 activation following infection with M51R VSV, indicating that both the death Receptor pathway and mitochondrial pathways are important for M51R VSV-induced apoptosis. Death Receptor signaling has been classified as type I or type II, depending on whether signaling is independent (type I) or dependent on the mitochondrial pathway (type II). Bcl-X L overexpression inhibited caspase activation in response to a Fas-inducing antibody, similar to the inhibition in response to M51R VSV infection, indicating that U87 cells behave as type II cells. Inhibition of apoptosis in vitro delayed, but did not prevent, virus-induced cell death. Murine xenografts of U87 cells that overexpress Bcl-X L regressed with a time course similar to that of control cells following treatment with M51R VSV, and tumors were not detectable at 21 days postinoculation. Immunohistochemical analysis demonstrated similar levels of viral antigen expression but reduced activation of caspase-3 following virus treatment of Bcl-X L-overexpressing tumors compared to controls. Further, the pathological changes in tumors following treatment with virus were quite different in the presence versus the absence of Bcl-X L overexpression. These results demonstrate that M51R VSV efficiently induces oncolysis in GBM tumor cells despite deregulation of apoptotic pathways, underscoring its potential use as a treatment for GBM. Vesicular stomatitis virus (VSV) is a well-studied negativestrand RNA virus that has been identified as a potential oncolytic virus therapy for brain tumors (29, 30, 51, 53). Oncolytic virus therapy is an emerging therapy for cancers that currently lack effective treatment (7, 11). Glioblastoma multiforme (GBM) is a common and highly aggressive brain tumor that has a median survival of approximately 1 year once diagnosed (15). Thus, GBM is a cancer that is widely considered likely to benefit from oncolytic virus therapy. Several clinical trials of oncolytic viruses are ongoing or have already been conducted in patients with GBM (14, 30, 31, 33, 45, 56). To date, at least two VSV oncolytic viruses have been considered by the NIH Recombinant DNA Advisory Committee, a key step toward beginning clinical trials in a variety of cancer types (47, 48). The selectivity of VSV for cancerous versus normal tissue is due to defects in antiviral responses that cancers develop
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oncolytic vesicular stomatitis virus induces apoptosis in u87 glioblastoma cells by a type ii death Receptor Mechanism and induces cell death and tumor clearance in vivo
Journal of Virology, 2011Co-Authors: Zachary D Cary, Mark C Willingham, Douglas S LylesAbstract:Vesicular stomatitis virus (VSV) is a potential oncolytic virus for treating glioblastoma multiforme (GBM), an aggressive brain tumor. Matrix (M) protein mutants of VSV have shown greater selectivity for killing GBM cells versus normal brain cells than VSV with wild-type M protein. The goal of this research was to determine the contribution of death Receptor and mitochondrial pathways to apoptosis induced by an M protein mutant (M51R) VSV in U87 human GBM tumor cells. Compared to controls, U87 cells expressing a dominant negative form of Fas (dnFas) or overexpressing Bcl-X(L) had reduced caspase-3 activation following infection with M51R VSV, indicating that both the death Receptor pathway and mitochondrial pathways are important for M51R VSV-induced apoptosis. Death Receptor signaling has been classified as type I or type II, depending on whether signaling is independent (type I) or dependent on the mitochondrial pathway (type II). Bcl-X(L) overexpression inhibited caspase activation in response to a Fas-inducing antibody, similar to the inhibition in response to M51R VSV infection, indicating that U87 cells behave as type II cells. Inhibition of apoptosis in vitro delayed, but did not prevent, virus-induced cell death. Murine xenografts of U87 cells that overexpress Bcl-X(L) regressed with a time course similar to that of control cells following treatment with M51R VSV, and tumors were not detectable at 21 days postinoculation. Immunohistochemical analysis demonstrated similar levels of viral antigen expression but reduced activation of caspase-3 following virus treatment of Bcl-X(L)-overexpressing tumors compared to controls. Further, the pathological changes in tumors following treatment with virus were quite different in the presence versus the absence of Bcl-X(L) overexpression. These results demonstrate that M51R VSV efficiently induces oncolysis in GBM tumor cells despite deregulation of apoptotic pathways, underscoring its potential use as a treatment for GBM.
Zachary D Cary - One of the best experts on this subject based on the ideXlab platform.
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oncolytic vesicular stomatitis virus induces apoptosis in u87 glioblastoma cells by a type ii death Receptor Mechanism and induces cell death and tumor clearance in vivo
Journal of Virology, 2011Co-Authors: Zachary D Cary, Mark C Willingham, Douglas S LylesAbstract:Vesicular stomatitis virus (VSV) is a potential oncolytic virus for treating glioblastoma multiforme (GBM), an aggressive brain tumor. Matrix (M) protein mutants of VSV have shown greater selectivity for killing GBM cells versus normal brain cells than VSV with wild-type M protein. The goal of this research was to determine the contribution of death Receptor and mitochondrial pathways to apoptosis induced by an M protein mutant (M51R) VSV in U87 human GBM tumor cells. Compared to controls, U87 cells expressing a dominant negative form of Fas (dnFas) or overexpressing Bcl-X L had reduced caspase-3 activation following infection with M51R VSV, indicating that both the death Receptor pathway and mitochondrial pathways are important for M51R VSV-induced apoptosis. Death Receptor signaling has been classified as type I or type II, depending on whether signaling is independent (type I) or dependent on the mitochondrial pathway (type II). Bcl-X L overexpression inhibited caspase activation in response to a Fas-inducing antibody, similar to the inhibition in response to M51R VSV infection, indicating that U87 cells behave as type II cells. Inhibition of apoptosis in vitro delayed, but did not prevent, virus-induced cell death. Murine xenografts of U87 cells that overexpress Bcl-X L regressed with a time course similar to that of control cells following treatment with M51R VSV, and tumors were not detectable at 21 days postinoculation. Immunohistochemical analysis demonstrated similar levels of viral antigen expression but reduced activation of caspase-3 following virus treatment of Bcl-X L-overexpressing tumors compared to controls. Further, the pathological changes in tumors following treatment with virus were quite different in the presence versus the absence of Bcl-X L overexpression. These results demonstrate that M51R VSV efficiently induces oncolysis in GBM tumor cells despite deregulation of apoptotic pathways, underscoring its potential use as a treatment for GBM. Vesicular stomatitis virus (VSV) is a well-studied negativestrand RNA virus that has been identified as a potential oncolytic virus therapy for brain tumors (29, 30, 51, 53). Oncolytic virus therapy is an emerging therapy for cancers that currently lack effective treatment (7, 11). Glioblastoma multiforme (GBM) is a common and highly aggressive brain tumor that has a median survival of approximately 1 year once diagnosed (15). Thus, GBM is a cancer that is widely considered likely to benefit from oncolytic virus therapy. Several clinical trials of oncolytic viruses are ongoing or have already been conducted in patients with GBM (14, 30, 31, 33, 45, 56). To date, at least two VSV oncolytic viruses have been considered by the NIH Recombinant DNA Advisory Committee, a key step toward beginning clinical trials in a variety of cancer types (47, 48). The selectivity of VSV for cancerous versus normal tissue is due to defects in antiviral responses that cancers develop
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oncolytic vesicular stomatitis virus induces apoptosis in u87 glioblastoma cells by a type ii death Receptor Mechanism and induces cell death and tumor clearance in vivo
Journal of Virology, 2011Co-Authors: Zachary D Cary, Mark C Willingham, Douglas S LylesAbstract:Vesicular stomatitis virus (VSV) is a potential oncolytic virus for treating glioblastoma multiforme (GBM), an aggressive brain tumor. Matrix (M) protein mutants of VSV have shown greater selectivity for killing GBM cells versus normal brain cells than VSV with wild-type M protein. The goal of this research was to determine the contribution of death Receptor and mitochondrial pathways to apoptosis induced by an M protein mutant (M51R) VSV in U87 human GBM tumor cells. Compared to controls, U87 cells expressing a dominant negative form of Fas (dnFas) or overexpressing Bcl-X(L) had reduced caspase-3 activation following infection with M51R VSV, indicating that both the death Receptor pathway and mitochondrial pathways are important for M51R VSV-induced apoptosis. Death Receptor signaling has been classified as type I or type II, depending on whether signaling is independent (type I) or dependent on the mitochondrial pathway (type II). Bcl-X(L) overexpression inhibited caspase activation in response to a Fas-inducing antibody, similar to the inhibition in response to M51R VSV infection, indicating that U87 cells behave as type II cells. Inhibition of apoptosis in vitro delayed, but did not prevent, virus-induced cell death. Murine xenografts of U87 cells that overexpress Bcl-X(L) regressed with a time course similar to that of control cells following treatment with M51R VSV, and tumors were not detectable at 21 days postinoculation. Immunohistochemical analysis demonstrated similar levels of viral antigen expression but reduced activation of caspase-3 following virus treatment of Bcl-X(L)-overexpressing tumors compared to controls. Further, the pathological changes in tumors following treatment with virus were quite different in the presence versus the absence of Bcl-X(L) overexpression. These results demonstrate that M51R VSV efficiently induces oncolysis in GBM tumor cells despite deregulation of apoptotic pathways, underscoring its potential use as a treatment for GBM.
Mark C Willingham - One of the best experts on this subject based on the ideXlab platform.
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oncolytic vesicular stomatitis virus induces apoptosis in u87 glioblastoma cells by a type ii death Receptor Mechanism and induces cell death and tumor clearance in vivo
Journal of Virology, 2011Co-Authors: Zachary D Cary, Mark C Willingham, Douglas S LylesAbstract:Vesicular stomatitis virus (VSV) is a potential oncolytic virus for treating glioblastoma multiforme (GBM), an aggressive brain tumor. Matrix (M) protein mutants of VSV have shown greater selectivity for killing GBM cells versus normal brain cells than VSV with wild-type M protein. The goal of this research was to determine the contribution of death Receptor and mitochondrial pathways to apoptosis induced by an M protein mutant (M51R) VSV in U87 human GBM tumor cells. Compared to controls, U87 cells expressing a dominant negative form of Fas (dnFas) or overexpressing Bcl-X L had reduced caspase-3 activation following infection with M51R VSV, indicating that both the death Receptor pathway and mitochondrial pathways are important for M51R VSV-induced apoptosis. Death Receptor signaling has been classified as type I or type II, depending on whether signaling is independent (type I) or dependent on the mitochondrial pathway (type II). Bcl-X L overexpression inhibited caspase activation in response to a Fas-inducing antibody, similar to the inhibition in response to M51R VSV infection, indicating that U87 cells behave as type II cells. Inhibition of apoptosis in vitro delayed, but did not prevent, virus-induced cell death. Murine xenografts of U87 cells that overexpress Bcl-X L regressed with a time course similar to that of control cells following treatment with M51R VSV, and tumors were not detectable at 21 days postinoculation. Immunohistochemical analysis demonstrated similar levels of viral antigen expression but reduced activation of caspase-3 following virus treatment of Bcl-X L-overexpressing tumors compared to controls. Further, the pathological changes in tumors following treatment with virus were quite different in the presence versus the absence of Bcl-X L overexpression. These results demonstrate that M51R VSV efficiently induces oncolysis in GBM tumor cells despite deregulation of apoptotic pathways, underscoring its potential use as a treatment for GBM. Vesicular stomatitis virus (VSV) is a well-studied negativestrand RNA virus that has been identified as a potential oncolytic virus therapy for brain tumors (29, 30, 51, 53). Oncolytic virus therapy is an emerging therapy for cancers that currently lack effective treatment (7, 11). Glioblastoma multiforme (GBM) is a common and highly aggressive brain tumor that has a median survival of approximately 1 year once diagnosed (15). Thus, GBM is a cancer that is widely considered likely to benefit from oncolytic virus therapy. Several clinical trials of oncolytic viruses are ongoing or have already been conducted in patients with GBM (14, 30, 31, 33, 45, 56). To date, at least two VSV oncolytic viruses have been considered by the NIH Recombinant DNA Advisory Committee, a key step toward beginning clinical trials in a variety of cancer types (47, 48). The selectivity of VSV for cancerous versus normal tissue is due to defects in antiviral responses that cancers develop
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oncolytic vesicular stomatitis virus induces apoptosis in u87 glioblastoma cells by a type ii death Receptor Mechanism and induces cell death and tumor clearance in vivo
Journal of Virology, 2011Co-Authors: Zachary D Cary, Mark C Willingham, Douglas S LylesAbstract:Vesicular stomatitis virus (VSV) is a potential oncolytic virus for treating glioblastoma multiforme (GBM), an aggressive brain tumor. Matrix (M) protein mutants of VSV have shown greater selectivity for killing GBM cells versus normal brain cells than VSV with wild-type M protein. The goal of this research was to determine the contribution of death Receptor and mitochondrial pathways to apoptosis induced by an M protein mutant (M51R) VSV in U87 human GBM tumor cells. Compared to controls, U87 cells expressing a dominant negative form of Fas (dnFas) or overexpressing Bcl-X(L) had reduced caspase-3 activation following infection with M51R VSV, indicating that both the death Receptor pathway and mitochondrial pathways are important for M51R VSV-induced apoptosis. Death Receptor signaling has been classified as type I or type II, depending on whether signaling is independent (type I) or dependent on the mitochondrial pathway (type II). Bcl-X(L) overexpression inhibited caspase activation in response to a Fas-inducing antibody, similar to the inhibition in response to M51R VSV infection, indicating that U87 cells behave as type II cells. Inhibition of apoptosis in vitro delayed, but did not prevent, virus-induced cell death. Murine xenografts of U87 cells that overexpress Bcl-X(L) regressed with a time course similar to that of control cells following treatment with M51R VSV, and tumors were not detectable at 21 days postinoculation. Immunohistochemical analysis demonstrated similar levels of viral antigen expression but reduced activation of caspase-3 following virus treatment of Bcl-X(L)-overexpressing tumors compared to controls. Further, the pathological changes in tumors following treatment with virus were quite different in the presence versus the absence of Bcl-X(L) overexpression. These results demonstrate that M51R VSV efficiently induces oncolysis in GBM tumor cells despite deregulation of apoptotic pathways, underscoring its potential use as a treatment for GBM.
Gildas Loussouarn - One of the best experts on this subject based on the ideXlab platform.
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Up-regulation of voltage-gated sodium channels by peptides mimicking S4-S5 linkers reveals a variation of the ligand-Receptor Mechanism
Scientific Reports, 2020Co-Authors: Olfat Malak, Fayal Abderemane-ali, Yue Wei, Fabien Coyan, Gilyane Pontus, David Shaya, Céline Marionneau, Gildas LoussouarnAbstract:Prokaryotic NaV channels are tetramers and eukaryotic NaV channels consist of a single subunit containing four domains. Each monomer/domain contains six transmembrane segments (S1-S6), S1-S4 being the voltage-sensor domain and S5-S6 the pore domain. A crystal structure of NaVMs, a prokaryotic NaV channel, suggests that the S4-S5 linker (S4-S5L) interacts with the C-terminus of S6 (S6T) to stabilize the gate in the open state. However, in several voltage-gated potassium channels, using specific S4-S5L-mimicking peptides, we previously demonstrated that S4-S5L/S6T interaction stabilizes the gate in the closed state. Here, we used the same strategy on another prokaryotic NaV channel, NaVSp1, to test whether equivalent peptides stabilize the channel in the open or closed state. A NaVSp1-specific S4-S5L peptide, containing the residues supposed to interact with S6T according to the NaVMs structure, induced both an increase in NaVSp1 current density and a negative shift in the activation curve, consistent with S4-S5L stabilizing the open state. Using this approach on a human NaV channel, hNaV1.4, and testing 12 hNaV1.4 S4-S5L peptides, we identified four activating S4-S5L peptides. These results suggest that, in eukaryotic NaV channels, the S4-S5L of DI, DII and DIII domains allosterically modulate the activation gate and stabilize its open state.
Mark A. Goldsmith - One of the best experts on this subject based on the ideXlab platform.
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A trans-Receptor Mechanism for infection of CD4-negative cells by human immunodeficiency virus type 1.
Current biology : CB, 1999Co-Authors: Roberto F. Speck, Ursula Esser, Michael L. Penn, Daniel A. Eckstein, Lynn Pulliam, Stephen Y. Chan, Mark A. GoldsmithAbstract:Abstract Chemokine Receptors, particularly CCR5 and CXCR4, act as essential coReceptors in concert with CD4 for cellular entry by human immunodeficiency virus type 1 (HIV-1; reviewed in [1]). But infection of CD4 − cells has also been encountered in various tissues in vivo , including astrocytes, neurons and microvascular endothelial cells of the brain [2–6], epithelial cells [5,7], CD4 − lymphocytes and thymocytes [8,9], and cardiomyocytes [10]. Here, we present evidence for the infection of CD4 − cell lines bearing coReceptors by well-known HIV-1 strains when co-cultured with CD4 + cells. This process requires contact between the coReceptor-bearing and CD4 + cells and supports the full viral replication cycle within the coReceptor-bearing target cell. Furthermore, CD4 provided in trans facilitates infection of primary human cells, such as brain-derived astrocytes. Although the pathobiological significance of infection of CD4 − cells in vivo remains to be elucidated, this trans -Receptor Mechanism may facilitate generation of hidden reservoirs of latent virus that confound antiviral therapies and that contribute to specific AIDS-associated clinical syndromes.
