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  • 1
    Keywords: brain ; APOPTOSIS ; EXPRESSION ; SURVIVAL ; tumor ; Germany ; DISEASE ; MORTALITY ; PROTEIN ; RESOLUTION ; MICE ; TUMOR-NECROSIS-FACTOR ; NITRIC-OXIDE ; murine ; T-CELLS ; NUMBER ; RATES ; NECROSIS-FACTOR-ALPHA ; IMMUNE-RESPONSE ; CENTRAL-NERVOUS-SYSTEM ; pathology ; TNF-ALPHA ; protein expression ; TNF ; FACTOR-ALPHA ; SYNTHASE ; development ; REACTIVE OXYGEN ; PHASE ; NITRIC-OXIDE-SYNTHASE ; NECROSIS-FACTOR ; TUMOR NECROSIS FACTOR ; nitric oxide synthase ; brain abscess ; INTRACEREBRAL IMMUNE-RESPONSE ; NEUTROPHIL APOPTOSIS ; RECEPTOR-TYPE 1 ; Staphylococcus aureus ; TOXOPLASMA ENCEPHALITIS
    Abstract: Tumor necrosis factor-alpha (TNF-alpha) is a central mediator of the immune response to pathogens, but may also exert neurotoxic effects, thereby contributing to immunopathology. To define the role of TNF during the course of brain abscess, TNF-deficient (TNF0/0) truce were stereotaxically infected with Staphylococcus (S.) aureus-laden agarose beads. In comparison to 100% survival of wild type (WT) mice, TNF0/0 mice displayed high mortality rates (54%) in the initial phase of abscess development as well as significantly increased morbidity in the course of the disease. The worse clinical outcome was due to an increased intracerebral (i.e.) bacterial load in TNF0/0 mice as compared to WT mice. The impaired control of S. aureus was associated with reduced inductible nitric oxide synthase (iNOS) mRNA and protein expression in TNF0/0 mice. Similarly, numbers of inflammatory leukocytes, cytokine expression of IL-6, IL-12p40, IFNgamma, IL-1beta mRNA, and brain edema were significantly increased in TNF0/0 mice as compared to WT animals. In addition, resolution of i.e. infiltrates was delayed in TNF0/0 mice correlating with reduced apoptosis of inflammatory leukocytes and formation of a fibrous abscess capsule. Collectively, these data demonstrate that TNF is of key importance for the control of S. aureus-induced brain abscess and regulates the ensuing host immune response
    Type of Publication: Journal article published
    PubMed ID: 15715082
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  • 2
    Keywords: ANGIOGENESIS ; CELLS ; EXPRESSION ; ENDOTHELIAL GROWTH-FACTOR ; INHIBITION ; POPULATION ; PROTEIN ; mechanisms ; DOWN-REGULATION ; HYPERMETHYLATION ; MALIGNANT GLIOMAS ; astrocytoma ; SUBTYPES ; PROMOTER METHYLATION ; GLIOBLASTOMA ; AKAP12 ; Gravin ; SSeCKS ; SSECKS/GRAVIN/AKAP12
    Abstract: The scaffold protein A-kinase anchor protein 12 (AKAP12) exerts tumor suppressor activity and is downregulated in several tumor entities. We characterized AKAP12 expression and regulation in astrocytomas, including pilocytic and diffusely infiltrating astrocytomas. We examined 194 human gliomas and 23 normal brain white matter samples by immunohistochemistry or immunoblotting for AKAP12 expression. We further performed quantitative methylation analysis of the AKAP12 promoter by MassARRAY (R) of normal brain, World Health Organization (WHO) grade I to IV astrocytomas, and glioma cell lines. Our results show that AKAP12 is expressed in a perivascular distribution in normal CNS, strongly upregulated in tumor cells in pilocytic astrocytomas, and weakly expressed in diffuse astrocytomas of WHO grade II to IV. Methylation analyses revealed specific hypermethylation of AKAP12 alpha promoter in WHO grade II to IV astrocytomas. Restoration experiments using 5-aza-2'-deoxycytidine in primary glioblastoma cells decreased AKAP12 alpha promoter methylation and markedly increased AKAP12 alpha mRNA levels. In summary, we demonstrate that AKAP12 is differentially expressed in human astrocytomas showing high expression in pilocytic but low expression in diffuse astrocytomas of all WHO-grades. Our results further indicate that epigenetic mechanisms are involved in silencing AKAP12 in diffuse astrocytomas; however, a tumor suppressive role of AKAP12 in distinct astrocytoma subtypes remains to be determined
    Type of Publication: Journal article published
    PubMed ID: 24042196
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  • 3
    Keywords: proliferation ; SYSTEM ; DISEASE ; PROTEIN ; MICE ; PATIENT ; MARKER ; ANTIGEN ; ANTIGENS ; T cell ; T cells ; T-CELL ; T-CELLS ; culture ; antibodies ; antibody ; MOUSE ; NERVOUS-SYSTEM ; LESIONS ; NUMBER ; COMPONENT ; DAMAGE ; cytoskeleton ; NETHERLANDS ; CD8(+) ; CENTRAL-NERVOUS-SYSTEM ; pathology ; AMYOTROPHIC-LATERAL-SCLEROSIS ; MULTIPLE-SCLEROSIS ; INTERFERON-GAMMA ; inflammation ; CD4(+) T-CELLS ; AUTOIMMUNE ENCEPHALOMYELITIS ; SERUM ; AUTOIMMUNITY ; IMMUNIZATION ; CYTOKINE ; RECOMBINANT ; RE ; SERUM ANTIBODIES ; LEVEL ; multiple sclerosis ; USA ; animal model ; central nervous system ; DEGENERATION ; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS ; correlates ; SENSORY NEURONOPATHY ; axonal damage ; MS LESIONS ; neurofilament light ; PROGRESSIVE MULTIPLE-SCLEROSIS ; spastic paresis
    Abstract: Axonal damage is the major cause of irreversible neurologic disability in patients with multiple sclerosis. Although axonal damage correlates with antibodies against neurotilament light (NF-L) protein, a major component of the axonal cytoskeleton, the possible pathogenic role of autoirnmunity to axonal antigens such as NF-L has so far been ignored. Here we show that Biozzi ABH mice immunized with NF-L protein develop neurologic disease characterized by spastic paresis and paralysis concomitant with axonal degeneration and inflammation primarily in the dorsal column of the spinal cord. The inflammatory central nervous system lesions were dominated by F4/80' macrophages/microglia and relatively low numbers of CD4(+) and CD8(+) T-cells. In splenocyte cultures, proliferation to NF-L was observed in CD4(+) T-cells accompanied by the production of the proinflammatory cytokine interferon-gamma. Elevated levels of circulating antibodies recognizing recombinant mouse NF-L were present in the serum, and immunoglobulin deposits were observed within axons in spinal cord lesions of mice exhibiting clinical disease. These data provide evidence that autoimmunity to NF-L protein induces axonal degeneration and clinical neurologic disease in mice, indicating that autoimmunity to axonal antigens, as described in multiple sclerosis, may be pathogenic rather than acting merely as a surrogate marker for axonal degeneration
    Type of Publication: Journal article published
    PubMed ID: 17413320
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  • 4
    Keywords: CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; SYSTEM ; GENE ; PROTEIN ; DIFFERENTIATION ; primary ; DOMAIN ; MATURATION ; NERVOUS-SYSTEM ; IDENTIFICATION ; LYMPHOMA ; PLASMA ; MUTATION ; inactivation ; LYMPHOCYTES ; MUTATIONS ; PHENOTYPE ; CENTRAL-NERVOUS-SYSTEM ; SERIES ; B-CELL LYMPHOMA ; protein expression ; molecular ; FEATURES ; PATTERN ; TUMOR-SUPPRESSOR ; diffuse large B-cell lymphoma ; REPRESSOR ; SUPPRESSOR ; USA ; B-CELL LYMPHOMAS ; PCNSL ; B-CELL ; central nervous system ; systemic ; tumor suppressor ; BLIMP-1 ; BLIMP1 ; PRDM1 ; PRDM1/BLIMP-1 ; primary central nervous system lymphoma
    Abstract: Primary lympbomas of the CNS (PCNSLs) show molecular features of the late germinal center exit B-cell phenotype and are impaired in their terminal differentiation as indicated by a lack of immunoglobulin class switching. Because the positive regulatory domain I protein with ZNF domain (PRDM1/BLIMP1) is a master regulator of terminal B-cell differentiation into plasma cells, we investigated a series of 21 PCNSLs for the presence of mutations in the PRDM1 gene and alterations in the expression pattern of the PRDM1 protein. Direct sequencing of all coding exons of the PRDM1 gene identified deleterious mutations associated with abrogation of PRDM1 protein expression in 4 of 21 (19%) PCNSLs. Thus, similar to systemic diffuse large B-cell lymphomas, PRDM1 may be a tumor suppressor in some PCNSL and contribute to lymphomagenesis by impairing terminal differentiation
    Type of Publication: Journal article published
    PubMed ID: 18596541
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  • 5
    Keywords: CELLS ; EXPRESSION ; SURVIVAL ; tumor ; TUMOR-CELLS ; CELL ; Germany ; SYSTEM ; GENE ; GENE-EXPRESSION ; PROTEIN ; transcription ; PATIENT ; MECHANISM ; TRANSCRIPTION FACTOR ; cell signaling ; prognosis ; mechanisms ; NERVOUS-SYSTEM ; immunohistochemistry ; LYMPHOMA ; gene expression ; B-CELLS ; CENTRAL-NERVOUS-SYSTEM ; pathology ; OVEREXPRESSION ; POOR-PROGNOSIS ; B-CELL LYMPHOMA ; signaling ; SUBSET ; regulation ; diffuse large B-cell lymphoma ; USA ; outcome ; DLBCL ; primary central nervous system lymphoma ; gene expression analysis ; 3 ; TRANSCRIPTION-FACTOR ; Forkhead box P1
    Abstract: Forkhead box PI (FOXP1) protein is a transcription factor involved in cell signaling and regulation of gene expression. The overexpression of FOXP1 in a subgroup of systemic diffuse large B-cell lymphomas has been associated with an exceptionally poor clinical outcome. Data on FOXP1 expression in primary central nervous system lymphomas (PCNSL), that is, diffuse large B-cell lymphomas confined to the central nervous system, are not yet available. We analyzed 43 PCNSL from immunocompetent patients. Immunohistochemistry showed expression of FOXP1 protein in 21 (88%) of 24 cases. All 19 PCNSL analyzed by quantitative gene expression analysis showed overexpression of truncated FOXP1 Isoforms 3 and 9 and downregulation of normal-size FOXP1 compared with nonmalignant germinal center B cells, the normal counterpart of PCNSL tumor cells. Thus, truncated FOXP1 isoforms are preferentially overexpressed in PCNSL as they are in diffuse large B-cell lymphomas. Although the mechanisms are presently unclear, this overexpression may contribute to a poor prognosis in PCNSL
    Type of Publication: Journal article published
    PubMed ID: 19680146
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