The Experts below are selected from a list of 192 Experts worldwide ranked by ideXlab platform
Laurence Lagneaux - One of the best experts on this subject based on the ideXlab platform.
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effect of the deacetylase inhibitor suberoylanilide hydroxamic acid saha on chronic lymphocytic leukemia cells apoptosis migration impairment and Drug Sensitization
Blood, 2009Co-Authors: Basile Stamatopoulos, Nathalie Meuleman, Cecile De Bruyn, Alain Delforge, Dominique Bron, Laurence LagneauxAbstract:Abstract 3435 Poster Board III-323 Chronic lymphocytic leukemia (CLL) is a neoplastic disorder that arises largely as a result of defective apoptosis leading to chemoresistance. Furthermore, SDF-1 and its receptor CXCR4 has been shown to play an important role in CLL cell trafficking and survival. Since histone acetylation is involved in the modulation of gene expression, cellular differentiation, and survival, we evaluated the effects of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on CLL cells in vitro and in particular on cell survival, CXCR4 expression, migration and in combination with different chemotherapies. Here, we showed that a 48-hour treatment of SAHA induced a dose-dependent decrease in CLL cell viability via apoptosis (n=20, p = 0.0032 ). This effect was also seen in previously untreated and chemoresistant CLL patients. Using specific caspase inhibitors, we demonstrated the participation of caspases-3, -6 and -8, suggesting an activation of the extrinsic pathway. Additionally, SAHA decreased actin polymerization (about 45%) in response to SDF-1 (n=6, p = 0.0313 ). SAHA also significantly decreased CXCR4 mRNA (n=10, p = 0.0010 ) and protein expression (n=25, p<0.0001 ). Consequently, CLL cell migration in response to SDF-1 (n=17, p = 0.0003 ) or through bone marrow stromal cells (pseudoemperipolesis) was dramatically impaired. Finally, SAHA at low concentration (5μM) could increase sensitivity of CLL cells to fludarabine, flavopiridol, thalidomide or bortezomib. In conclusion, SAHA induces apoptosis in CLL cells via the extrinsic pathway and downregulates CXCR4 expression leading to decreased cell migration. SAHA (alone or in combination with other Drugs) represents thus a promising therapeutic approach to inhibiting migration, inducing apoptosis in CLL cell and potentially overcoming Drug resistance. Disclosures No relevant conflicts of interest to declare.
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Effect of the Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid (SAHA) On Chronic Lymphocytic Leukemia Cells: Apoptosis, Migration Impairment and Drug Sensitization.
Blood, 2009Co-Authors: Basile Stamatopoulos, Nathalie Meuleman, Cecile De Bruyn, Alain Delforge, Dominique Bron, Laurence LagneauxAbstract:Abstract 3435 Poster Board III-323 Chronic lymphocytic leukemia (CLL) is a neoplastic disorder that arises largely as a result of defective apoptosis leading to chemoresistance. Furthermore, SDF-1 and its receptor CXCR4 has been shown to play an important role in CLL cell trafficking and survival. Since histone acetylation is involved in the modulation of gene expression, cellular differentiation, and survival, we evaluated the effects of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on CLL cells in vitro and in particular on cell survival, CXCR4 expression, migration and in combination with different chemotherapies. Here, we showed that a 48-hour treatment of SAHA induced a dose-dependent decrease in CLL cell viability via apoptosis (n=20, p = 0.0032 ). This effect was also seen in previously untreated and chemoresistant CLL patients. Using specific caspase inhibitors, we demonstrated the participation of caspases-3, -6 and -8, suggesting an activation of the extrinsic pathway. Additionally, SAHA decreased actin polymerization (about 45%) in response to SDF-1 (n=6, p = 0.0313 ). SAHA also significantly decreased CXCR4 mRNA (n=10, p = 0.0010 ) and protein expression (n=25, p
H F Merk - One of the best experts on this subject based on the ideXlab platform.
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determination of interleukin 5 secretion from Drug specific activated ex vivo peripheral blood mononuclear cells as a test system for the in vitro detection of Drug Sensitization
Clinical & Experimental Allergy, 2002Co-Authors: B Sachs, Stephan Erdmann, Malte J Baron, Mark M Neis, Al T Masaoudi, H F MerkAbstract:Summary BackgroundIn vitro detection of Drug Sensitization is still limited. The lymphocyte transformation test, which determines Drug-specific proliferation, is the only in vitro test for detecting Drug Sensitization at the cellular level irrespective of the reaction's clinical phenotype. Accumulation of eosinophils following IL-5 secretion from Drug-specific stimulated T cells is a characteristic histological feature of Drug-induced skin eruptions. Objective We determined whether in vitro Drug-specific activation of ex vivo peripheral blood mononuclear cells from 10 patients with Drug-induced maculopapular exanthems and three patients with severe skin reactions results in secretion of IL-5, IL-10 or IFN-γ and assessed the sensitivity and specificity of Drug-specific IL-5 secretion as a test system compared with the lymphocyte transformation test and patch tests. Furthermore, the subsets of CD4+ and CD8+ T cells involved in Drug-specific proliferation, IL-5 secretion and mRNA expression were examined in three patients. Methods Drug-specific proliferation of peripheral blood mononuclear cells in the lymphocyte transformation test was investigated by 3H-thymidine uptake, and culture supernatants taken after 5 days were analysed for IL-5, IL-10 and IFN-γ concentrations by ELISA technique. IL-5 mRNA expression was determined by RT-PCR. Results Drug-specific activation of peripheral blood mononuclear cells consistently resulted in IL-5 and to a lesser extent in IL-10 and IFN-γ secretion. The sensitivities of the patch test, lymphocyte transformation test and assessment of Drug-specific IL-5 secretion for the detection of Drug Sensitization were 55%, 75% and 92%, respectively. Conclusion These data suggest a role for the determination of Drug-specific IL-5 secretion by ex vivo peripheral blood mononuclear cells for the in vitro detection of Drug-Sensitization in Drug-induced maculopapular exanthems.
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Determination of interleukin‐5 secretion from Drug‐specific activated ex vivo peripheral blood mononuclear cells as a test system for the in vitro detection of Drug Sensitization
Clinical & Experimental Allergy, 2002Co-Authors: B Sachs, Stephan Erdmann, Mark M Neis, J. Malte Baron, T. Al Masaoudi, H F MerkAbstract:Summary BackgroundIn vitro detection of Drug Sensitization is still limited. The lymphocyte transformation test, which determines Drug-specific proliferation, is the only in vitro test for detecting Drug Sensitization at the cellular level irrespective of the reaction's clinical phenotype. Accumulation of eosinophils following IL-5 secretion from Drug-specific stimulated T cells is a characteristic histological feature of Drug-induced skin eruptions. Objective We determined whether in vitro Drug-specific activation of ex vivo peripheral blood mononuclear cells from 10 patients with Drug-induced maculopapular exanthems and three patients with severe skin reactions results in secretion of IL-5, IL-10 or IFN-γ and assessed the sensitivity and specificity of Drug-specific IL-5 secretion as a test system compared with the lymphocyte transformation test and patch tests. Furthermore, the subsets of CD4+ and CD8+ T cells involved in Drug-specific proliferation, IL-5 secretion and mRNA expression were examined in three patients. Methods Drug-specific proliferation of peripheral blood mononuclear cells in the lymphocyte transformation test was investigated by 3H-thymidine uptake, and culture supernatants taken after 5 days were analysed for IL-5, IL-10 and IFN-γ concentrations by ELISA technique. IL-5 mRNA expression was determined by RT-PCR. Results Drug-specific activation of peripheral blood mononuclear cells consistently resulted in IL-5 and to a lesser extent in IL-10 and IFN-γ secretion. The sensitivities of the patch test, lymphocyte transformation test and assessment of Drug-specific IL-5 secretion for the detection of Drug Sensitization were 55%, 75% and 92%, respectively. Conclusion These data suggest a role for the determination of Drug-specific IL-5 secretion by ex vivo peripheral blood mononuclear cells for the in vitro detection of Drug-Sensitization in Drug-induced maculopapular exanthems.
Basile Stamatopoulos - One of the best experts on this subject based on the ideXlab platform.
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effect of the deacetylase inhibitor suberoylanilide hydroxamic acid saha on chronic lymphocytic leukemia cells apoptosis migration impairment and Drug Sensitization
Blood, 2009Co-Authors: Basile Stamatopoulos, Nathalie Meuleman, Cecile De Bruyn, Alain Delforge, Dominique Bron, Laurence LagneauxAbstract:Abstract 3435 Poster Board III-323 Chronic lymphocytic leukemia (CLL) is a neoplastic disorder that arises largely as a result of defective apoptosis leading to chemoresistance. Furthermore, SDF-1 and its receptor CXCR4 has been shown to play an important role in CLL cell trafficking and survival. Since histone acetylation is involved in the modulation of gene expression, cellular differentiation, and survival, we evaluated the effects of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on CLL cells in vitro and in particular on cell survival, CXCR4 expression, migration and in combination with different chemotherapies. Here, we showed that a 48-hour treatment of SAHA induced a dose-dependent decrease in CLL cell viability via apoptosis (n=20, p = 0.0032 ). This effect was also seen in previously untreated and chemoresistant CLL patients. Using specific caspase inhibitors, we demonstrated the participation of caspases-3, -6 and -8, suggesting an activation of the extrinsic pathway. Additionally, SAHA decreased actin polymerization (about 45%) in response to SDF-1 (n=6, p = 0.0313 ). SAHA also significantly decreased CXCR4 mRNA (n=10, p = 0.0010 ) and protein expression (n=25, p<0.0001 ). Consequently, CLL cell migration in response to SDF-1 (n=17, p = 0.0003 ) or through bone marrow stromal cells (pseudoemperipolesis) was dramatically impaired. Finally, SAHA at low concentration (5μM) could increase sensitivity of CLL cells to fludarabine, flavopiridol, thalidomide or bortezomib. In conclusion, SAHA induces apoptosis in CLL cells via the extrinsic pathway and downregulates CXCR4 expression leading to decreased cell migration. SAHA (alone or in combination with other Drugs) represents thus a promising therapeutic approach to inhibiting migration, inducing apoptosis in CLL cell and potentially overcoming Drug resistance. Disclosures No relevant conflicts of interest to declare.
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Effect of the Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid (SAHA) On Chronic Lymphocytic Leukemia Cells: Apoptosis, Migration Impairment and Drug Sensitization.
Blood, 2009Co-Authors: Basile Stamatopoulos, Nathalie Meuleman, Cecile De Bruyn, Alain Delforge, Dominique Bron, Laurence LagneauxAbstract:Abstract 3435 Poster Board III-323 Chronic lymphocytic leukemia (CLL) is a neoplastic disorder that arises largely as a result of defective apoptosis leading to chemoresistance. Furthermore, SDF-1 and its receptor CXCR4 has been shown to play an important role in CLL cell trafficking and survival. Since histone acetylation is involved in the modulation of gene expression, cellular differentiation, and survival, we evaluated the effects of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on CLL cells in vitro and in particular on cell survival, CXCR4 expression, migration and in combination with different chemotherapies. Here, we showed that a 48-hour treatment of SAHA induced a dose-dependent decrease in CLL cell viability via apoptosis (n=20, p = 0.0032 ). This effect was also seen in previously untreated and chemoresistant CLL patients. Using specific caspase inhibitors, we demonstrated the participation of caspases-3, -6 and -8, suggesting an activation of the extrinsic pathway. Additionally, SAHA decreased actin polymerization (about 45%) in response to SDF-1 (n=6, p = 0.0313 ). SAHA also significantly decreased CXCR4 mRNA (n=10, p = 0.0010 ) and protein expression (n=25, p
Steven M Albelda - One of the best experts on this subject based on the ideXlab platform.
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differential sensitivity of thoracic malignant tumors to adenovirus mediated Drug Sensitization gene therapy
The Journal of Thoracic and Cardiovascular Surgery, 1995Co-Authors: Roy W Smythe, Harry C Hwang, A A Elshami, Kunjlata M Amin, Steven M Albelda, Larry R KaiserAbstract:Abstract Malignant mesothelioma may prove to be an attractive candidate for somatic gene therapy with replication-deficient recombinant adenovirus transfer of a toxic, or Drug Sensitization gene. Transfer of the herpes simplex thymidine kinase type I gene (HSV tk ), followed by exposure to the acyclic nucleoside Drug ganciclovir, has been shown to be an effective tumor cell killing system. To study generalized applicability, we tested a number of thoracic malignant cell lines for their sensitivity to gancyclovir after infection with an adenoviral vector containing the HSV tk gene (Ad.RSV tk ). Using the concentration of gancyclovir required to kill 50% of the cells (IC50) as a measure of sensitivity, we detected variable sensitivity among cell lines, with mesothelioma most sensitive (IC50 = 0.075 to 2.8 μmol/L gancyclovir), and non-small-cell carcinoma lines having an intermediate sensitivity (IC50 = 1.5 to 100 μmol/L). In contrast, an ovarian carcinoma line was extremely resistant (IC50 > 2000 μmol/L). To study the possible mechanisms for these differences, we studied cell lines with regard to their ability to be infected with an adenoviral vector containing a marker gene (Ad.CMV lacZ ) and expression of the vitronectin receptor α v (an integrin cell adhesion molecule shown to be required for adenovirus internalization after initial binding). We found that the degree of lacZ transduction correlated with HSV tk sensitivity, whereas vitronectin receptor expression did not, suggesting that differences in initial viral binding ability, rather than internalization, may explain the sensitivity differences seen in vitro. (J THORAC CARDIOVASC SURG 1995;109:626-31)
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use of recombinant adenovirus to transfer the herpes simplex virus thymidine kinase hsvtk gene to thoracic neoplasms an effective in vitro Drug Sensitization system
Cancer Research, 1994Co-Authors: Roy W Smythe, Harry C Hwang, Kunjlata M Amin, Larry R Kaiser, Beverly L Davidson, James M Wilson, Steven M AlbeldaAbstract:Transfer of the herpes simplex virus thymidine kinase ( HSVtk ) gene into tumor cells using retroviral vectors followed by administration of ganciclovir provides a potential strategy for the treatment of malignancy. Because of the limitations of using retroviral vectors for clinical application, the feasibility of using a recombinant adenovirus containing HSVtk was examined. Cell lines derived from human malignant mesotheliomas and non-small cell lung cancers infected with a recombinant adenovirus containing HSVtk showed strong expression of HSVtk protein as determined by immunohistochemical staining. Infection with a recombinant adenovirus containing HSVtk rendered cells sensitive to doses of ganciclovir that were 2–3 logs lower than uninfected cells or those infected with a control virus. A strong “bystander effect” was noted in mesothelioma lines; there was no diminution in the efficacy of ganciclovir treatment until the ratio of infected:uninfected cells fell below 1:10. This study thus demonstrates in vitro efficacy of an adenovirus-transduced HSVtk Drug Sensitization gene therapy system in thoracic malignancies. Recombinant adenovirus transfer of the HSVtk gene followed by ganciclovir may have promise as an in situ treatment for tumors.
B Sachs - One of the best experts on this subject based on the ideXlab platform.
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determination of interleukin 5 secretion from Drug specific activated ex vivo peripheral blood mononuclear cells as a test system for the in vitro detection of Drug Sensitization
Clinical & Experimental Allergy, 2002Co-Authors: B Sachs, Stephan Erdmann, Malte J Baron, Mark M Neis, Al T Masaoudi, H F MerkAbstract:Summary BackgroundIn vitro detection of Drug Sensitization is still limited. The lymphocyte transformation test, which determines Drug-specific proliferation, is the only in vitro test for detecting Drug Sensitization at the cellular level irrespective of the reaction's clinical phenotype. Accumulation of eosinophils following IL-5 secretion from Drug-specific stimulated T cells is a characteristic histological feature of Drug-induced skin eruptions. Objective We determined whether in vitro Drug-specific activation of ex vivo peripheral blood mononuclear cells from 10 patients with Drug-induced maculopapular exanthems and three patients with severe skin reactions results in secretion of IL-5, IL-10 or IFN-γ and assessed the sensitivity and specificity of Drug-specific IL-5 secretion as a test system compared with the lymphocyte transformation test and patch tests. Furthermore, the subsets of CD4+ and CD8+ T cells involved in Drug-specific proliferation, IL-5 secretion and mRNA expression were examined in three patients. Methods Drug-specific proliferation of peripheral blood mononuclear cells in the lymphocyte transformation test was investigated by 3H-thymidine uptake, and culture supernatants taken after 5 days were analysed for IL-5, IL-10 and IFN-γ concentrations by ELISA technique. IL-5 mRNA expression was determined by RT-PCR. Results Drug-specific activation of peripheral blood mononuclear cells consistently resulted in IL-5 and to a lesser extent in IL-10 and IFN-γ secretion. The sensitivities of the patch test, lymphocyte transformation test and assessment of Drug-specific IL-5 secretion for the detection of Drug Sensitization were 55%, 75% and 92%, respectively. Conclusion These data suggest a role for the determination of Drug-specific IL-5 secretion by ex vivo peripheral blood mononuclear cells for the in vitro detection of Drug-Sensitization in Drug-induced maculopapular exanthems.
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Determination of interleukin‐5 secretion from Drug‐specific activated ex vivo peripheral blood mononuclear cells as a test system for the in vitro detection of Drug Sensitization
Clinical & Experimental Allergy, 2002Co-Authors: B Sachs, Stephan Erdmann, Mark M Neis, J. Malte Baron, T. Al Masaoudi, H F MerkAbstract:Summary BackgroundIn vitro detection of Drug Sensitization is still limited. The lymphocyte transformation test, which determines Drug-specific proliferation, is the only in vitro test for detecting Drug Sensitization at the cellular level irrespective of the reaction's clinical phenotype. Accumulation of eosinophils following IL-5 secretion from Drug-specific stimulated T cells is a characteristic histological feature of Drug-induced skin eruptions. Objective We determined whether in vitro Drug-specific activation of ex vivo peripheral blood mononuclear cells from 10 patients with Drug-induced maculopapular exanthems and three patients with severe skin reactions results in secretion of IL-5, IL-10 or IFN-γ and assessed the sensitivity and specificity of Drug-specific IL-5 secretion as a test system compared with the lymphocyte transformation test and patch tests. Furthermore, the subsets of CD4+ and CD8+ T cells involved in Drug-specific proliferation, IL-5 secretion and mRNA expression were examined in three patients. Methods Drug-specific proliferation of peripheral blood mononuclear cells in the lymphocyte transformation test was investigated by 3H-thymidine uptake, and culture supernatants taken after 5 days were analysed for IL-5, IL-10 and IFN-γ concentrations by ELISA technique. IL-5 mRNA expression was determined by RT-PCR. Results Drug-specific activation of peripheral blood mononuclear cells consistently resulted in IL-5 and to a lesser extent in IL-10 and IFN-γ secretion. The sensitivities of the patch test, lymphocyte transformation test and assessment of Drug-specific IL-5 secretion for the detection of Drug Sensitization were 55%, 75% and 92%, respectively. Conclusion These data suggest a role for the determination of Drug-specific IL-5 secretion by ex vivo peripheral blood mononuclear cells for the in vitro detection of Drug-Sensitization in Drug-induced maculopapular exanthems.
