Zsuzsanna Nagy | University of Birmingham (original) (raw)
Papers by Zsuzsanna Nagy
The Journal of Pathology: Clinical Research
Journal of Neural Transmission Supplementum, Feb 1, 1999
There is growing evidence that neuronal death in Down's syndrome is due to apoptotic mech... more There is growing evidence that neuronal death in Down's syndrome is due to apoptotic mechanisms. The phenomena, however, that trigger and regulate programmed cell death in the Down's syndrome-related neurodegeneration are still much debated. In vitro evidence has suggested that the main factor responsible for neuronal death in this condition is the accumulation of beta-amyloid, due to the overexpression of its precursor protein. Another hypothesis argues for the importance of reactive oxygen species in neuronal death. However, the in vivo findings do not entirely support either theories. We propose that neuronal apoptosis, as well as the formation of Alzheimer-type pathology, in Down's syndrome is due to an aberrant re-entry of neurones into the cell division cycle. Due to the simultaneous overexpression of conflicting cell cycle regulatory signals the mitogenic amyloid precursor and the differentiation factor S100, the cell cycle is abandoned. Subsequently the cell cycle arrest may lead to either the formation of Alzheimer-related pathology or to apoptotic cell death.
Int Psychogeriatr, 2003
The link between Alzheimer&am... more The link between Alzheimer's disease and cerebrovascular disease has been long recognized. However, the mechanisms that lead to the development of the two seemingly different pathologies are still elusive. Our studies concentrate on the understanding of the interaction between the two diseases and the deciphering of a possible common pathogenic mechanism. In this context the role of shared risk factors, such as ApoE and elevated plasma homocysteine, is also discussed.
Angiogenesis, 2014
Tumor endothelial specific expression of Robo4 in adults identifies this plasma membrane protein ... more Tumor endothelial specific expression of Robo4 in adults identifies this plasma membrane protein as an anticancer target for immunotherapeutic approaches, such as vaccination. In this report, we describe how vaccination against Robo4 inhibits angiogenesis and tumor growth. To break tolerance to the auto-antigen Robo4, mice were immunised with the extracellular domain of mouse Robo4, fused to the Fc domain of human immunoglobulin within an adjuvant. Vaccinated mice show a strong antibody response to Robo4, with no objectively detectable adverse effects on health. Robo4 vaccinated mice showed impaired fibrovascular invasion and angiogenesis in a rodent sponge implantation assay, as well as a reduced growth of implanted syngeneic Lewis lung carcinoma. The anti-tumor effect of Robo4 vaccination was present in CD8 deficient mice but absent in B cell or IgG1 knockout mice, suggesting antibody dependent cell mediated cytotoxicity as the anti-vascular/ anti-tumor mechanism. Finally, we show that an adjuvant free soluble Robo4-carrier conjugate can retard tumor growth in carrier primed mice. These results point to appropriate Robo4 conjugates as potential anti-angiogenic vaccines for cancer patients.
Acta neuropathologica communications, Jan 8, 2013
The development of disease-modifying therapies for Alzheimer's disease is hampered by our lac... more The development of disease-modifying therapies for Alzheimer's disease is hampered by our lack of understanding of the early pathogenic mechanisms and the lack of early biomarkers and risk factors.We have documented the expression pattern of mTOR regulated genes in the frontal cortex of…
The advent of functional genomics has enabled the genome-wide characterization of the molecular s... more The advent of functional genomics has enabled the genome-wide characterization of the molecular state of cells and tissues, virtually at every level of biological organization. The difficulty in organizing and mining this unprecedented amount of information has stimulated the development of computational methods designed to infer the underlying structure of regulatory networks from observational data. These important developments had a profound impact in biological sciences since they triggered the development of a novel data-driven investigative approach. In cancer research, this strategy has been particularly successful. It has contributed to the identification of novel biomarkers, to a better characterization of disease heterogeneity and to a more in depth understanding of cancer pathophysiology. However , so far these approaches have not explicitly addressed the challenge of identifying networks representing the interaction of different cell types in a complex tissue. Since thes...
BMC Genomics, 2008
Background: Targeting tumor angiogenesis and vasculature is a promising strategy for the inhibiti... more Background: Targeting tumor angiogenesis and vasculature is a promising strategy for the inhibition of tumor growth and dissemination. Evidence suggests that tumor vasculature expresses unique markers that distinguish it from normal vasculature. Our efforts focused on the molecular characterization of endothelial cells (EC) in the search for selective markers of tumor vasculature that might be helpful for the development of effective therapeutic approaches.
Journal of Neuropathology and Experimental Neurology, 1997
The diagnosis of Alzheimer disease (AD) according to current criteria is a combined clinical and ... more The diagnosis of Alzheimer disease (AD) according to current criteria is a combined clinical and pathological exercise. The clinical discrimination of AD from other types of dementia may be complicated when the patient suffers from more than one disease. In particular the concomitant presence of other neurological conditions may significantly influence the severity of cognitive deficit. In this study we analyze the extent of the influence of vascular and other neurodegenerative pathology on the cognitive deficit in a consecutive series of 88 prospectively assessed elderly subjects. We find that, for any given level of cognitive deficit, the densities of either all plaques or neuritic plaques alone in the neocortex are significantly lower in cases of AD mixed with other CNS pathology than in cases of AD with no other CNS pathology. In AD combined with cerebrovascular disease, the total plaque density makes a significant contribution to cognitive deficit, while neurofibrillary tangle (NFT) densities do not. In contrast, in pure AD tangle density is the major determinant of cognitive deficit. Our findings draw attention to the influence of coexisting brain pathologies on the clinical manifestation of dementia in subjects with AD. These findings indicate that pathological diagnostic criteria for AD should take into account such additional pathology in demented subjects. They also improve understanding of the circumstances in which the amyloid component of AD can play a decisive role in precipitating clinical dementia.
Cancer Research, 2014
ABSTRACT Chimeric antigen receptor (CAR) therapy combines the specificity of a monoclonal antibod... more ABSTRACT Chimeric antigen receptor (CAR) therapy combines the specificity of a monoclonal antibody with the potent cytotoxic and immune regulatory activity of self-replicating T cells. This approach has shown remarkable efficacy in recent clinical trials targeting T cells to hematological cancers. More limited benefit has been reported with solid tumors, possibly because of lack of suitable target antigens, immune evasion mechanisms in the malignant cells and/or lack of T cell infiltration into the tumor tissue. An alternative approach that avoids some of these problems is to use a CAR that targets the tumor vasculature rather than the malignant cells directly. CLEC14A is a glycoprotein recently identified to be selectively overexpressed on the surface of the tumor vasculature in a wide range of human cancers, including ovarian, liver, bladder, prostate, breast and kidney, and is therefore of considerable interest for tumor therapy. Here we explore for the first time the feasibility of targeting the tumor vasculature using CLEC14A-specific CARs. Initially we generated CARs from several CLEC14A-specific monoclonal antibodies and then expressed them in T cells. In vitro T cell functional assays demonstrated that these CARs can trigger potent antigen-specific activation including cytotoxicity in engineered T cells. These CARs recognize both human and mouse forms of CLEC14A, so safety/efficacy studies could be conducted using mouse models. Following infusion of escalating doses of engineered T cells into healthy mice, circulating CAR-T cells persisted for at least the next 5 weeks without signs of toxicity. To explore anti-tumor effects, Lewis lung carcinoma cells were subcutaneously implanted into C57BL6 mice and 4 days later mice received a single dose of CLEC14A-specific CAR-T cells. Our recent data demonstrate statistically significant inhibition of tumor growth in mice treated with CAR-T cells compared with mock-transduced T cells. The engineered cells also appeared to expand/accumulate at the tumor site. These data suggest CLEC14A can be safely and effectively targeted with CAR-T cells, potentially offering a potent and widely applicable cancer therapy.
The Journal of Pathology: Clinical Research
Journal of Neural Transmission Supplementum, Feb 1, 1999
There is growing evidence that neuronal death in Down's syndrome is due to apoptotic mech... more There is growing evidence that neuronal death in Down's syndrome is due to apoptotic mechanisms. The phenomena, however, that trigger and regulate programmed cell death in the Down's syndrome-related neurodegeneration are still much debated. In vitro evidence has suggested that the main factor responsible for neuronal death in this condition is the accumulation of beta-amyloid, due to the overexpression of its precursor protein. Another hypothesis argues for the importance of reactive oxygen species in neuronal death. However, the in vivo findings do not entirely support either theories. We propose that neuronal apoptosis, as well as the formation of Alzheimer-type pathology, in Down's syndrome is due to an aberrant re-entry of neurones into the cell division cycle. Due to the simultaneous overexpression of conflicting cell cycle regulatory signals the mitogenic amyloid precursor and the differentiation factor S100, the cell cycle is abandoned. Subsequently the cell cycle arrest may lead to either the formation of Alzheimer-related pathology or to apoptotic cell death.
Int Psychogeriatr, 2003
The link between Alzheimer&am... more The link between Alzheimer's disease and cerebrovascular disease has been long recognized. However, the mechanisms that lead to the development of the two seemingly different pathologies are still elusive. Our studies concentrate on the understanding of the interaction between the two diseases and the deciphering of a possible common pathogenic mechanism. In this context the role of shared risk factors, such as ApoE and elevated plasma homocysteine, is also discussed.
Angiogenesis, 2014
Tumor endothelial specific expression of Robo4 in adults identifies this plasma membrane protein ... more Tumor endothelial specific expression of Robo4 in adults identifies this plasma membrane protein as an anticancer target for immunotherapeutic approaches, such as vaccination. In this report, we describe how vaccination against Robo4 inhibits angiogenesis and tumor growth. To break tolerance to the auto-antigen Robo4, mice were immunised with the extracellular domain of mouse Robo4, fused to the Fc domain of human immunoglobulin within an adjuvant. Vaccinated mice show a strong antibody response to Robo4, with no objectively detectable adverse effects on health. Robo4 vaccinated mice showed impaired fibrovascular invasion and angiogenesis in a rodent sponge implantation assay, as well as a reduced growth of implanted syngeneic Lewis lung carcinoma. The anti-tumor effect of Robo4 vaccination was present in CD8 deficient mice but absent in B cell or IgG1 knockout mice, suggesting antibody dependent cell mediated cytotoxicity as the anti-vascular/ anti-tumor mechanism. Finally, we show that an adjuvant free soluble Robo4-carrier conjugate can retard tumor growth in carrier primed mice. These results point to appropriate Robo4 conjugates as potential anti-angiogenic vaccines for cancer patients.
Acta neuropathologica communications, Jan 8, 2013
The development of disease-modifying therapies for Alzheimer's disease is hampered by our lac... more The development of disease-modifying therapies for Alzheimer's disease is hampered by our lack of understanding of the early pathogenic mechanisms and the lack of early biomarkers and risk factors.We have documented the expression pattern of mTOR regulated genes in the frontal cortex of…
The advent of functional genomics has enabled the genome-wide characterization of the molecular s... more The advent of functional genomics has enabled the genome-wide characterization of the molecular state of cells and tissues, virtually at every level of biological organization. The difficulty in organizing and mining this unprecedented amount of information has stimulated the development of computational methods designed to infer the underlying structure of regulatory networks from observational data. These important developments had a profound impact in biological sciences since they triggered the development of a novel data-driven investigative approach. In cancer research, this strategy has been particularly successful. It has contributed to the identification of novel biomarkers, to a better characterization of disease heterogeneity and to a more in depth understanding of cancer pathophysiology. However , so far these approaches have not explicitly addressed the challenge of identifying networks representing the interaction of different cell types in a complex tissue. Since thes...
BMC Genomics, 2008
Background: Targeting tumor angiogenesis and vasculature is a promising strategy for the inhibiti... more Background: Targeting tumor angiogenesis and vasculature is a promising strategy for the inhibition of tumor growth and dissemination. Evidence suggests that tumor vasculature expresses unique markers that distinguish it from normal vasculature. Our efforts focused on the molecular characterization of endothelial cells (EC) in the search for selective markers of tumor vasculature that might be helpful for the development of effective therapeutic approaches.
Journal of Neuropathology and Experimental Neurology, 1997
The diagnosis of Alzheimer disease (AD) according to current criteria is a combined clinical and ... more The diagnosis of Alzheimer disease (AD) according to current criteria is a combined clinical and pathological exercise. The clinical discrimination of AD from other types of dementia may be complicated when the patient suffers from more than one disease. In particular the concomitant presence of other neurological conditions may significantly influence the severity of cognitive deficit. In this study we analyze the extent of the influence of vascular and other neurodegenerative pathology on the cognitive deficit in a consecutive series of 88 prospectively assessed elderly subjects. We find that, for any given level of cognitive deficit, the densities of either all plaques or neuritic plaques alone in the neocortex are significantly lower in cases of AD mixed with other CNS pathology than in cases of AD with no other CNS pathology. In AD combined with cerebrovascular disease, the total plaque density makes a significant contribution to cognitive deficit, while neurofibrillary tangle (NFT) densities do not. In contrast, in pure AD tangle density is the major determinant of cognitive deficit. Our findings draw attention to the influence of coexisting brain pathologies on the clinical manifestation of dementia in subjects with AD. These findings indicate that pathological diagnostic criteria for AD should take into account such additional pathology in demented subjects. They also improve understanding of the circumstances in which the amyloid component of AD can play a decisive role in precipitating clinical dementia.
Cancer Research, 2014
ABSTRACT Chimeric antigen receptor (CAR) therapy combines the specificity of a monoclonal antibod... more ABSTRACT Chimeric antigen receptor (CAR) therapy combines the specificity of a monoclonal antibody with the potent cytotoxic and immune regulatory activity of self-replicating T cells. This approach has shown remarkable efficacy in recent clinical trials targeting T cells to hematological cancers. More limited benefit has been reported with solid tumors, possibly because of lack of suitable target antigens, immune evasion mechanisms in the malignant cells and/or lack of T cell infiltration into the tumor tissue. An alternative approach that avoids some of these problems is to use a CAR that targets the tumor vasculature rather than the malignant cells directly. CLEC14A is a glycoprotein recently identified to be selectively overexpressed on the surface of the tumor vasculature in a wide range of human cancers, including ovarian, liver, bladder, prostate, breast and kidney, and is therefore of considerable interest for tumor therapy. Here we explore for the first time the feasibility of targeting the tumor vasculature using CLEC14A-specific CARs. Initially we generated CARs from several CLEC14A-specific monoclonal antibodies and then expressed them in T cells. In vitro T cell functional assays demonstrated that these CARs can trigger potent antigen-specific activation including cytotoxicity in engineered T cells. These CARs recognize both human and mouse forms of CLEC14A, so safety/efficacy studies could be conducted using mouse models. Following infusion of escalating doses of engineered T cells into healthy mice, circulating CAR-T cells persisted for at least the next 5 weeks without signs of toxicity. To explore anti-tumor effects, Lewis lung carcinoma cells were subcutaneously implanted into C57BL6 mice and 4 days later mice received a single dose of CLEC14A-specific CAR-T cells. Our recent data demonstrate statistically significant inhibition of tumor growth in mice treated with CAR-T cells compared with mock-transduced T cells. The engineered cells also appeared to expand/accumulate at the tumor site. These data suggest CLEC14A can be safely and effectively targeted with CAR-T cells, potentially offering a potent and widely applicable cancer therapy.