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  • 1
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; SURVIVAL ; BLOOD ; CELL ; Germany ; human ; IN-VIVO ; VIVO ; DEATH ; POPULATION ; GENE ; microarray ; MONOCLONAL-ANTIBODY ; CUTTING EDGE ; MARKER ; CONTRAST ; DENDRITIC CELLS ; T cell ; T cells ; T-CELL ; T-CELLS ; FLOW ; MEMORY ; antibodies ; antibody ; HUMANS ; resistance ; CD95 ligand ; CELL-DEATH ; UP-REGULATION ; RATES ; MARKERS ; MONOCLONAL-ANTIBODIES ; POPULATIONS ; INDIVIDUALS ; CHILDREN ; FLOW-CYTOMETRY ; PERIPHERAL-BLOOD ; MULTIPLE-SCLEROSIS ; HIGH-LEVEL ; CD95 ; cord blood ; INCREASE ; FOXP3 ; LEVEL ; monoclonal antibodies ; RESISTANT ; in vivo ; regulatory T cells ; peripheral blood ; regulatory T cell ; CD4(+)CD25(+) ; CD95L ; CORD ; NEWBORN
    Abstract: Most CD4(+)CD25(hi)FOXP3(+) regulatory T cells (T-regs) from adult peripheral blood express high levels of CD45RO and CD95 and are prone to CD95L-mediated apoptosis in contrast to conventional T cells (T-convs). However, a T-reg subpopulation remained consistently apoptosis resistant. Gene microarray and 6-color flow cytometry analysis including FOXP3 revealed an increase in naive T-cell markers on the CD95L-resistant T-regs compared with most T-regs. In contrast to T-regs found in adult humans, most CD4(+)CD25(+)FOXP3(+) T cells found in cord blood are naive and exhibit low CD95 expression. Furthermore, most of these newborn T-reg are not sensitive toward CD95L similar to naive T-regs from adult individuals. After short stimulation with anti-CD3/CD28 monoclonal antibodies (mAbs), cord blood T-regs strongly up-regulated CD95 and were sensitized toward CD95L. This functional change was paralleled by a rapid up-regulation of memory T-cell markers on cord blood T-regs that are frequently found on adult memory T-reg. In summary, we show a clear functional difference between naive and memory Tregs that could result in different survival rates of those 2 cell populations in vivo. This new observation could be crucial for the planning of therapeutic application of T-reg
    Type of Publication: Journal article published
    PubMed ID: 16868256
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  • 2
    Keywords: EXPRESSION ; DISTINCT ; DIFFERENTIATION ; MUTATIONS ; DE-NOVO ; METHYLATION ; GENETIC PROFILES ; HOXA CLUSTER ; MOLECULAR SUBGROUPS ; CROSS-SPECIES GENOMICS
    Abstract: Medulloblastoma is a malignant embryonal brain tumor with highly variable outcome. In order to study the biology of this tumor and to perform preclinical treatment studies, a lot of effort has been put into the generation of appropriate mouse models. The usage of these models, however, has become debatable with the advances in human medulloblastoma subgrouping. This study brings together multiple relevant mouse models and matches genetic alterations and gene expression data of 140 murine tumors with 423 human medulloblastomas in a global way. Using AGDEX analysis and k-means clustering, we show that the Blbp-cre::Ctnnb1(ex3)(Fl/+)Trp53 (Fl/Fl) mouse model fits well to human WNT medulloblastoma, and that, among various Myc- or Mycn-based mouse medulloblastomas, tumors in Glt1-tTA::TRE-MYCN/Luc mice proved to be most specific for human group 3 medulloblastoma. None of the analyzed models displayed a significant match to group 4 tumors. Intriguingly, mice with Ptch1 or Smo mutations selectively modeled SHH medulloblastomas of adulthood, although such mutations occur in all human age groups. We therefore suggest that the infantile or adult gene expression pattern of SHH MBs are not solely determined by specific mutations. This is supported by the observation that human medulloblastomas with PTCH1 mutations displayed more similarities to PTCH1 wild-type tumors of the same age group than to PTCH1-mutated tumors of the other age group. Together, we provide novel insights into previously unrecognized specificity of distinct models and suggest these findings as a solid basis to choose the appropriate model for preclinical studies on medulloblastoma.
    Type of Publication: Journal article published
    PubMed ID: 24871706
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