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  • pathology  (6)
  • 1
    Keywords: brain ; CELLS ; tumor ; Germany ; PATHWAY ; PATHWAYS ; CLASSIFICATION ; SYSTEM ; SYSTEMS ; GENE ; GENES ; TUMORS ; PATIENT ; MECHANISM ; CONTRAST ; mechanisms ; FREQUENCY ; polymorphism ; POLYMORPHISMS ; VARIANTS ; IDENTIFICATION ; LESIONS ; WHITE-MATTER ; SERIES ; pathology ; NEOPLASTIC TRANSFORMATION ; molecular ; VARIANT ; MUTATIONAL ANALYSIS ; ALLELES ; DYSPLASIA ; epilepsy ; focal cortical dysplasia ; FOCAL EPILEPSIES ; GANGLIOGLIOMAS ; glio-neuronal lesion ; GLIONEURONAL TUMORS ; tuberous sclerosis ; TUBEROUS SCLEROSIS COMPLEX
    Abstract: Epilepsy-associated malformations of cortical development (MCDs) comprise a variety of dysplastic and neoplastic lesions of yet undetermined molecular pathology. Histopathologic similarities between MCDs and dysplastic brain lesions in the autosomal inherited neurocutaneous phacomatosis tuberous sclerosis (TSC), which affects the TSC1 and/or TSC2 genes, suggest common pathogenetic mechanisms. Previous studies revealed different alterations of TSC1 and TSC2 in epilepsy-associated malformations and glio-neuronal tumors despite histopathologic similarities. In order to examine current clinico-pathologic classification systems of cortical malformations on the molecular level, we carried out a mutational analysis of TSC1 and TSC2 in a series of surgical specimens obtained from patients with FCD without Taylor type balloon cells (FCDIIa; n = 20), architectural dysplasias (FCDI; n = 15), nodular cortical heterotopias (NCH; It = 4), and heterotopic white matter neurons (WMNH; It = 19). In FCDIIa, abundant genomic polymorphisms were detected in TSC2 (intron 4) but no allelic variants observed in exon 17 of TSCL This allelic distribution pattern is in contrast to findings in FCDI and WMNH but also to those previously reported in FCDIIb (Taylor's balloon cell type). The latter revealed increased frequencies of specific alleles only in TSCL The determination of characteristic molecular genetic alterations in specific epilepsy-associated malformations will support a comprehensive clinico-pathologic classification system and help to identify molecular pathways with potential pathogenetic relevance. Our work is supported by DFG (SFB TRB [AJB], DFG B1 42 1/1-1 [113]), BONFOR, and Deutsche Krebshilfe
    Type of Publication: Journal article published
    PubMed ID: 16042315
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  • 2
    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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  • 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: CANCER ; radiotherapy ; SURVIVAL ; tumor ; COMBINATION ; THERAPY ; GENE-EXPRESSION ; HYBRIDIZATION ; TUMORS ; SURGERY ; PATIENT ; MECHANISM ; prognosis ; TARGET ; IN-SITU ; AGE ; MUTATION ; chemotherapy ; leukemia ; MUTATIONS ; pathology ; GLIOMAS ; MULTIFORME ; HETEROGENEITY ; overall survival ; PROGNOSTIC-FACTOR ; SUBTYPES ; telomere ; temozolomide ; HUMAN-CELLS ; GLIOBLASTOMA ; retrospective ; MAINTENANCE ; ELONGATION ; IDH1 ; Genetic ; ISOCITRATE DEHYDROGENASE ; Type ; prognostic ; Alternative lengthening of telomeres ; Glioblastoma subtypes
    Abstract: Patients with glioblastoma (GBM) have variable clinical courses, but the factors that underlie this heterogeneity are not understood. To determine whether the presence of the telomerase-independent alternative lengthening of telomeres (ALTs) mechanism is a significant prognostic factor for survival, we performed a retrospective analysis of 573 GBM patients. The presence of ALT was identified in paraffin sections using a combination of immunofluorescence for promyelocytic leukemia body and telomere fluorescence in situ hybridization. Alternative lengthening of telomere was present in 15% of the GBM patients. Patients with ALT had longer survival that was independent of age, surgery, and other treatments. Mutations in isocitrate dehydrogenase (IDH1mut) 1 frequently accompanied ALT, and in the presence of both molecular events, there was significantly longer overall survival. These data suggest that most ALT+ tumors may be less aggressive proneural GBMs, and the better prognosis may relate to the set of genetic changes associated with this tumor subtype. Despite improved overall survival of patients treated with the addition of chemotherapy to radiotherapy and surgery, ALT and chemotherapy independently provided a survival advantage, but these factors were not found to be additive. These results suggest a critical need for developing new therapies to target these specific GBM subtypes
    Type of Publication: Journal article published
    PubMed ID: 205350338
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  • 5
    Keywords: APOPTOSIS ; EXPRESSION ; SURVIVAL ; CELL ; Germany ; PATHWAY ; SYSTEM ; DISTINCT ; GENE ; GENE-EXPRESSION ; GENES ; NF-KAPPA-B ; ACTIVATION ; FAMILY ; MEMBER ; TARGET ; NERVOUS-SYSTEM ; LYMPHOMA ; gene expression ; FACTOR-KAPPA-B ; RT-PCR ; CENTRAL-NERVOUS-SYSTEM ; NF-kappa B ; TARGETS ; pathology ; fluorescence in situ hybridization ; signaling ; FAMILIES ; CELL LYMPHOMA ; LEVEL ; NUCLEAR ; USA ; B-CELL ; germinal center ; central nervous system ; quantitative ; nuclear factor-kappa B ; primary central nervous system lymphomas (PCNSL)
    Abstract: Recent studies point to a role of nuclear factor (NF)-kappa B signaling in a subset of diffuse large B cell lymphomas. We have analyzed the expression of 21 genes encoding NF-kappa B family members, upstream modulators, and targets in 32 primary central nervous system lymphomas (PCNSLs) by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), Compared with nonmalignant germinal center centroblasts, expression of BCL10, REL, IAP1, and TRAF1 was significantly lower in PCNSLs, whereas that of BAX, BCLXL, BCL2, MALT1, CARD9, CARD10, CARD11, CARD14, CCND2, cFLIP, RELA, RELB, NFKB1, NFK82, and IRF4 was higher. Hierarchical clustering of gene expression data revealed two distinct subgroups of PCNSLs, which were characterized by significantly different transcriptional levels, predominantly of BCL10, but also of REL and IAPI. Thus, these quantitative RT-PCR data with expression of genes of the NF-kappa B family as well as NF-kappa B-regulated genes together with immunohistochemical detection of nuclear RELA and REL indicate activation of the NF-kappa B pathway in PCNSLs, which may contribute to their high proliferative activity and the low level of apoptosis
    Type of Publication: Journal article published
    PubMed ID: 17356384
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  • 6
    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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