The Experts below are selected from a list of 165 Experts worldwide ranked by ideXlab platform
Guy C Brown - One of the best experts on this subject based on the ideXlab platform.
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anti cd47 antibodies induce phagocytosis of live malignant b cells by macrophages via the fc domain resulting in cell death by phagoptosis
Oncotarget, 2017Co-Authors: Le Métayer, Anna Vilalta, G Amos A Burke, Guy C BrownAbstract:// Lucy E. Metayer 1 , Anna Vilalta 1 , G.A. Amos Burke 2 and Guy C. Brown 1 1 Department of Biochemistry, University of Cambridge, Cambridge, UK 2 Department of Pediatrics, University of Cambridge, Cambridge, UK Correspondence to: Guy C. Brown, email: // Keywords : phagocytosis, cell death, leukemia, antibodies, phagoptosis, Autophagy Received : December 15, 2015 Accepted : April 14, 2017 Published : June 15, 2017 Abstract When expressed on the surface of cells, CD47 inhibits phagocytosis of these cells by phagocytes. Most human cancers overexpress CD47, and antibodies to CD47 have shown a remarkable ability to clear a range of cancers in animal models. However, the mechanism by which these antibodies cause cancer cell death is unclear. We find that CD47 is expressed on the surface of three B-cell lines from human malignancies: 697 (pre-B-ALL Lymphoblasts), Ramos and DG-75 (both mature B-cells, Burkitt’s lymphoma), and anti-CD47 antibodies greatly increase the phagocytosis of all three cell line by macrophages. In the presence of macrophages, the antibodies cause clearance of the Lymphoblasts within hours, but in the absence of macrophages, the antibodies have no effect on Lymphoblast viability. Macrophages engulf viable Lymphoblasts containing mitochondria with a normal membrane potential, but following engulfment the mitochondrial membrane potential is lost indicating a loss of viability. Inhibition of phagocytosis protects Lymphoblasts from death indicating that phagocytosis is required for anti-CD47 mediated cell death. Blocking either the antibody Fc domain or Fc receptors inhibits antibody-induced phagocytosis. Antibodies against cell surface markers CD10 or CD19 also induced Fc-domain-dependent phagocytosis, but at a lower level commensurate with expression. Thus, phagoptosis may contribute to the efficacy of a number of therapeutic antibodies used in cancer therapy, as well as potentially endogenous antibodies. We conclude that anti-CD47 antibodies induce phagocytosis by binding CD47 on Lymphoblast and Fc receptors on macrophages, resulting in cell death by phagocytosis, i.e. phagoptosis.
Phatcharee Chukaew - One of the best experts on this subject based on the ideXlab platform.
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potential depression and antidepressant response biomarkers in human Lymphoblast cell lines from treatment responsive and treatment resistant subjects roles of ssris and omega 3 polyunsaturated fatty acids
Molecular Psychiatry, 2020Co-Authors: Phatcharee Chukaew, Alex D Leow, Witchuda Saengsawang, Mark M RasenickAbstract:While several therapeutic strategies exist for depression, most antidepressant drugs require several weeks before reaching full biochemical efficacy and remission is not achieved in many patients. Therefore, biomarkers for depression and drug-response would help tailor treatment strategies. This study made use of banked human Lymphoblast cell lines (LCLs) from normal and depressed subjects; the latter divided into remitters and non-remitters. Due to the fact that previous studies have shown effects on growth factors, cytokines, and elements of the cAMP-generating system as potential biomarkers for depression and antidepressant action, these were examined in LCLs. Initial gene and protein expression profiles for signaling cascades related to neuroendocrine and inflammatory functions differ among the three groups. Growth factor genes, including VEGFA and BDNF were significantly down-regulated in cells from depressed subjects. In addition, omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been reported to act as both antidepressants and anti-inflammatories, but the mechanisms for these effects are not established. Here we showed that n-3 PUFAs and escitalopram (selective serotonin reuptake inhibitors, SSRIs) treatment increased adenylyl cyclase (AC) and BDNF gene expression in LCLs. These data are consistent with clinical observations showing that n-3 PUFA and SSRI have antidepressant affects, which may be additive. Contrary to observations made in neuronal and glial cells, n-3 PUFA treatment attenuated cAMP accumulation in LCLs. However, while Lymphoblasts show paradoxical responses to neurons and glia, patient-derived Lymphoblasts appear to carry potential depression biomarkers making them an important tool for studying precision medicine in depressive patients. Furthermore, these data validate usefulness of n-3 PUFAs in treatment for depression.
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potential depression and antidepressant response biomarkers in human Lymphoblast cell lines from treatment responsive and treatment resistant subjects roles of ssris and omega 3 polyunsaturated fatty acids
bioRxiv, 2020Co-Authors: Phatcharee Chukaew, Alex D Leow, Witchuda Saengsawang, Mark M RasenickAbstract:Abstract While several therapeutic strategies exist for depression, most antidepressant drugs require several weeks before reaching full biochemical efficacy and remission is not entirely achieved in many patients. Therefore, biomarkers for depression and drug-response would help tailor treatment strategies. This study made use of banked human Lymphoblast cell lines (LCLs) from normal and depressed subjects; the latter divided into remitters and non-remitters. Due to the fact that previous studies have shown effects on growth factors, cytokines and elements of the cAMP generating system as potential biomarkers for depression and antidepressant action, these were examined in LCLs. Initial gene and protein expression profiles for signaling cascades related to neuroendocrine and inflammatory functions differ among the three groups. Growth factor genes, including VEGFA and BDNF were significantly down-regulated in cells from depressed subjects. In addition, omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been reported to act as both antidepressants and anti-inflammatories, but the mechanisms for these effects are not established. Here we showed that n-3 PUFAs and escitalopram (selective serotonin reuptake inhibitors, SSRIs) treatment increased adenylyl cyclase (AC) and BDNF gene expression in LCLs. These data are consistent with clinical observations showing that n-3 PUFA and SSRI have antidepressant affects, which may be additive. Contrary to observations made in neuronal and glial cells, n-3 PUFA treatment attenuated cAMP accumulation in LCLs. However, while Lymphoblasts show paradoxical responses to neurons and glia, patient-derived Lymphoblasts appear to carry potential depression biomarkers making them an important tool for studying precision medicine in depressive patients. Furthermore, these data validate usefulness of n-3 PUFAs in treatment for depression.
Le Métayer - One of the best experts on this subject based on the ideXlab platform.
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anti cd47 antibodies induce phagocytosis of live malignant b cells by macrophages via the fc domain resulting in cell death by phagoptosis
Oncotarget, 2017Co-Authors: Le Métayer, Anna Vilalta, G Amos A Burke, Guy C BrownAbstract:// Lucy E. Metayer 1 , Anna Vilalta 1 , G.A. Amos Burke 2 and Guy C. Brown 1 1 Department of Biochemistry, University of Cambridge, Cambridge, UK 2 Department of Pediatrics, University of Cambridge, Cambridge, UK Correspondence to: Guy C. Brown, email: // Keywords : phagocytosis, cell death, leukemia, antibodies, phagoptosis, Autophagy Received : December 15, 2015 Accepted : April 14, 2017 Published : June 15, 2017 Abstract When expressed on the surface of cells, CD47 inhibits phagocytosis of these cells by phagocytes. Most human cancers overexpress CD47, and antibodies to CD47 have shown a remarkable ability to clear a range of cancers in animal models. However, the mechanism by which these antibodies cause cancer cell death is unclear. We find that CD47 is expressed on the surface of three B-cell lines from human malignancies: 697 (pre-B-ALL Lymphoblasts), Ramos and DG-75 (both mature B-cells, Burkitt’s lymphoma), and anti-CD47 antibodies greatly increase the phagocytosis of all three cell line by macrophages. In the presence of macrophages, the antibodies cause clearance of the Lymphoblasts within hours, but in the absence of macrophages, the antibodies have no effect on Lymphoblast viability. Macrophages engulf viable Lymphoblasts containing mitochondria with a normal membrane potential, but following engulfment the mitochondrial membrane potential is lost indicating a loss of viability. Inhibition of phagocytosis protects Lymphoblasts from death indicating that phagocytosis is required for anti-CD47 mediated cell death. Blocking either the antibody Fc domain or Fc receptors inhibits antibody-induced phagocytosis. Antibodies against cell surface markers CD10 or CD19 also induced Fc-domain-dependent phagocytosis, but at a lower level commensurate with expression. Thus, phagoptosis may contribute to the efficacy of a number of therapeutic antibodies used in cancer therapy, as well as potentially endogenous antibodies. We conclude that anti-CD47 antibodies induce phagocytosis by binding CD47 on Lymphoblast and Fc receptors on macrophages, resulting in cell death by phagocytosis, i.e. phagoptosis.
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Anti-CD47 antibodies induce phagocytosis of live, malignant B cells by macrophages via the Fc domain, resulting in cell death by phagoptosis
'Organisation for Economic Co-Operation and Development (OECD)', 2017Co-Authors: Le Métayer, Vilalta A, Burke Gaa, Brown GuyAbstract:When expressed on the surface of cells, CD47 inhibits phagocytosis of these cells by phagocytes. Most human cancers overexpress CD47, and antibodies to CD47 have shown a remarkable ability to clear a range of cancers in animal models. However, the mechanism by which these antibodies cause cancer cell death is unclear. We find that CD47 is expressed on the surface of three B-cell lines from human malignancies: 697 (pre-B-ALL Lymphoblasts), Ramos and DG-75 (both mature B-cells, Burkitt's lymphoma), and anti-CD47 antibodies greatly increase the phagocytosis of all three cell line by macrophages. In the presence of macrophages, the antibodies cause clearance of the Lymphoblasts within hours, but in the absence of macrophages, the antibodies have no effect on Lymphoblast viability. Macrophages engulf viable Lymphoblasts containing mitochondria with a normal membrane potential, but following engulfment the mitochondrial membrane potential is lost indicating a loss of viability. Inhibition of phagocytosis protects Lymphoblasts from death indicating that phagocytosis is required for anti-CD47 mediated cell death. Blocking either the antibody Fc domain or Fc receptors inhibits antibody-induced phagocytosis. Antibodies against cell surface markers CD10 or CD19 also induced Fc-domain-dependent phagocytosis, but at a lower level commensurate with expression. Thus, phagoptosis may contribute to the efficacy of a number of therapeutic antibodies used in cancer therapy, as well as potentially endogenous antibodies. We conclude that anti-CD47 antibodies induce phagocytosis by binding CD47 on Lymphoblast and Fc receptors on macrophages, resulting in cell death by phagocytosis, i.e. phagoptosis.This research was funded by the Leukaemia & Lymphoma Research (Bloodwise, 10027) UK
Mark M Rasenick - One of the best experts on this subject based on the ideXlab platform.
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potential depression and antidepressant response biomarkers in human Lymphoblast cell lines from treatment responsive and treatment resistant subjects roles of ssris and omega 3 polyunsaturated fatty acids
Molecular Psychiatry, 2020Co-Authors: Phatcharee Chukaew, Alex D Leow, Witchuda Saengsawang, Mark M RasenickAbstract:While several therapeutic strategies exist for depression, most antidepressant drugs require several weeks before reaching full biochemical efficacy and remission is not achieved in many patients. Therefore, biomarkers for depression and drug-response would help tailor treatment strategies. This study made use of banked human Lymphoblast cell lines (LCLs) from normal and depressed subjects; the latter divided into remitters and non-remitters. Due to the fact that previous studies have shown effects on growth factors, cytokines, and elements of the cAMP-generating system as potential biomarkers for depression and antidepressant action, these were examined in LCLs. Initial gene and protein expression profiles for signaling cascades related to neuroendocrine and inflammatory functions differ among the three groups. Growth factor genes, including VEGFA and BDNF were significantly down-regulated in cells from depressed subjects. In addition, omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been reported to act as both antidepressants and anti-inflammatories, but the mechanisms for these effects are not established. Here we showed that n-3 PUFAs and escitalopram (selective serotonin reuptake inhibitors, SSRIs) treatment increased adenylyl cyclase (AC) and BDNF gene expression in LCLs. These data are consistent with clinical observations showing that n-3 PUFA and SSRI have antidepressant affects, which may be additive. Contrary to observations made in neuronal and glial cells, n-3 PUFA treatment attenuated cAMP accumulation in LCLs. However, while Lymphoblasts show paradoxical responses to neurons and glia, patient-derived Lymphoblasts appear to carry potential depression biomarkers making them an important tool for studying precision medicine in depressive patients. Furthermore, these data validate usefulness of n-3 PUFAs in treatment for depression.
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potential depression and antidepressant response biomarkers in human Lymphoblast cell lines from treatment responsive and treatment resistant subjects roles of ssris and omega 3 polyunsaturated fatty acids
bioRxiv, 2020Co-Authors: Phatcharee Chukaew, Alex D Leow, Witchuda Saengsawang, Mark M RasenickAbstract:Abstract While several therapeutic strategies exist for depression, most antidepressant drugs require several weeks before reaching full biochemical efficacy and remission is not entirely achieved in many patients. Therefore, biomarkers for depression and drug-response would help tailor treatment strategies. This study made use of banked human Lymphoblast cell lines (LCLs) from normal and depressed subjects; the latter divided into remitters and non-remitters. Due to the fact that previous studies have shown effects on growth factors, cytokines and elements of the cAMP generating system as potential biomarkers for depression and antidepressant action, these were examined in LCLs. Initial gene and protein expression profiles for signaling cascades related to neuroendocrine and inflammatory functions differ among the three groups. Growth factor genes, including VEGFA and BDNF were significantly down-regulated in cells from depressed subjects. In addition, omega-3 polyunsaturated fatty acids (n-3 PUFAs) have been reported to act as both antidepressants and anti-inflammatories, but the mechanisms for these effects are not established. Here we showed that n-3 PUFAs and escitalopram (selective serotonin reuptake inhibitors, SSRIs) treatment increased adenylyl cyclase (AC) and BDNF gene expression in LCLs. These data are consistent with clinical observations showing that n-3 PUFA and SSRI have antidepressant affects, which may be additive. Contrary to observations made in neuronal and glial cells, n-3 PUFA treatment attenuated cAMP accumulation in LCLs. However, while Lymphoblasts show paradoxical responses to neurons and glia, patient-derived Lymphoblasts appear to carry potential depression biomarkers making them an important tool for studying precision medicine in depressive patients. Furthermore, these data validate usefulness of n-3 PUFAs in treatment for depression.
Charles A Stanley - One of the best experts on this subject based on the ideXlab platform.
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hyperinsulinism hyperammonemia syndrome in children with regulatory mutations in the inhibitory guanosine triphosphate binding domain of glutamate dehydrogenase
The Journal of Clinical Endocrinology and Metabolism, 2001Co-Authors: Courtney Macmullen, Jie Fang, Andrea Kelly, Pascale De Lonlaydebeney, Jeanmarie Saudubray, Arupa Ganguly, Thomas J Smith, Charles A StanleyAbstract:The hyperinsulinism/hyperammonemia (HI/HA) syndrome is a form of congenital hyperinsulinism in which affected children have recurrent symptomatic hypoglycemia together with asymptomatic, persistent elevations of plasma ammonium levels. We have shown that the disorder is caused by dominant mutations of the mitochondrial enzyme, glutamate dehydrogenase (GDH), that impair sensitivity to the allosteric inhibitor, GTP. In 65 HI/HA probands screened for GDH mutations, we identified 19 (29%) who had mutations in a new domain, encoded by exons 6 and 7. Six new mutations were found: Ser217Cys, Arg221Cys, Arg265Thr, Tyr266Cys, Arg269Cys, and Arg269His. In all five mutations tested, Lymphoblast GDH showed reduced sensitivity to allosteric inhibition by GTP (IC50, 60–250 vs. 20–50 nmol/L in normal subjects), consistent with a gain of enzyme function. Studies of ATP allosteric effects on GDH showed a triphasic response with a decrease in high affinity inhibition of enzyme activity in HI/HA Lymphoblasts. All of the res...
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hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene
The New England Journal of Medicine, 1998Co-Authors: Charles A Stanley, Yen K Lieu, Alberto Burlina, Cheryl R Greenberg, Nancy J Hopwood, Kusiel Perlman, Barry H Rich, Enrico Zammarchi, Mortimer PonczAbstract:Background A new form of congenital hyperinsulinism characterized by hypoglycemia and hyperammonemia was described recently. We hypothesized that this syndrome of hyperinsulinism and hyperammonemia was caused by excessive activity of glutamate dehydrogenase, which oxidizes glutamate to α-ketoglutarate and which is a potential regulator of insulin secretion in pancreatic beta cells and of ureagenesis in the liver. Methods We measured glutamate dehydrogenase activity in Lymphoblasts from eight unrelated children with the hyperinsulinism–hyperammonemia syndrome: six with sporadic cases and two with familial cases. We identified mutations in the glutamate dehydrogenase gene by sequencing glutamate dehydrogenase complementary DNA prepared from Lymphoblast messenger RNA. Site-directed mutagenesis was used to express the mutations in COS-7 cells. Results The sensitivity of glutamate dehydrogenase to inhibition by guanosine 5'-triphosphate was a quarter of the normal level in the patients with sporadic hyperinsul...
