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  • 1
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    German Medical Science; Düsseldorf, Köln
    In:  122. Kongress der Deutschen Gesellschaft für Chirurgie; 20050405-20050408; München; DOC05dgch3007 /20050615/
    Publication Date: 2005-06-16
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 2
    Keywords: EXPRESSION ; SURVIVAL ; COMBINATION ; Germany ; MODEL ; THERAPY ; RISK ; PATIENT ; IMPACT ; INDUCTION ; ACID ; NO ; DIFFERENCE ; AGE ; RATES ; chemotherapy ; leukemia ; MULTIVARIATE ; RISK GROUP ; COMPLETE REMISSION ; INITIATION ; COLONY-STIMULATING FACTOR ; Bcl-2 ; SOUTHWEST-ONCOLOGY-GROUP ; ACUTE MYELOGENOUS LEUKEMIA ; acute myeloid leukemia ; INDUCTION THERAPY ; ELDERLY-PATIENTS ; PHASE-III ; DEHYDROGENASE ; overall survival ; all-trans retinoic acid ; COUNCIL AML11 TRIAL ; CYTOSINE-ARABINOSIDE ; elderly patients ; IDARUBICIN
    Abstract: The purpose of our study was (i) to evaluate the impact of all-trans retinoic acid ( ATRA) given as adjunct to chemotherapy and (ii) to compare second consolidation vs maintenance therapy in elderly patients with acute myeloid leukemia (AML). A total of 242 patients aged greater than or equal to61 years (median, 66.6 years) with AML were randomly assigned to ATRA beginning on day +3 after the initiation of chemotherapy (ATRA-arm, n = 122) or no ATRA (standard-arm, n 120) in combination with induction and first consolidation therapy. A total of 61 patients in complete remission (CR) were randomly assigned to second intense consolidation (n = 31) or 1-year oral maintenance therapy ( n 30). After induction therapy the intention-to-treat analysis revealed a significant difference in CR rates between the ATRA- and the standard-arm (52 vs 39%; P = 0.05). Event-free (EFS) and overall survival ( OS) were significantly better in the ATRA- compared to the standard-arm (P = 0.03 and 0.01, respectively). OS after second randomization was significantly better for patients assigned to intensive consolidation therapy (P〈0.001). The multivariate model for survival revealed lactate dehydrogenase, cytogenetic risk group, age, and first and second randomization as prognostic variables. In conclusion, the addition of ATRA to induction and consolidation therapy may improve CR rate, EFS and OS in elderly patients with AML
    Type of Publication: Journal article published
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  • 3
    Keywords: CELLS ; EXPRESSION ; GROWTH ; POPULATION ; GENE ; GENES ; PROTEIN ; TISSUE ; PATIENT ; ACTIVATION ; microarrays ; ONCOLOGY ; HEMOGLOBIN
    Abstract: In this study, we provide a molecular signature of highly enriched CD34+ cells from bone marrow of untreated patients with chronic myelogenous leukemia (CML) in chronic phase in comparison with normal CD34+ cells using microarrays covering 8746 genes. Expression data reflected several BCR-ABL-induced effects in primary CML progenitors, such as transcriptional activation of the classical mitogen-activated protein kinase pathway and the phosphoinositide-3 kinase/AKT pathway as well as downregulation of the proapoptotic gene IRF8. Moreover, novel transcriptional changes in comparison with normal CD34+ cells were identified. These include upregulation of genes involved in the transforming growth factorbeta pathway, fetal hemoglobin genes, leptin receptor, sorcin, tissue inhibitor of metalloproteinase 1, the neuroepithelial cell transforming gene 1 and downregulation of selenoprotein P. Additionally, genes associated with early hematopoietic stem cells (HSC) and leukemogenesis such as HoxA9 and MEIS1 were transcriptionally activated. Differential expression of differentiation-associated genes suggested an altered composition of the CD34+ cell population in CML. This was confirmed by subset analyses of chronic phase CML CD34+ cells showing an increase of the proportion of megakaryocyte-erythroid progenitors, whereas the proportion of HSC and granulocyte-macrophage progenitors was decreased in CML. In conclusion, our results give novel insights into the biology of CML and could provide the basis for identification of new therapeutic targets.Leukemia (2007) 21, 494-504. doi:10.1038/sj.leu.2404549; published online 25 January 2007
    Type of Publication: Journal article published
    PubMed ID: 17252012
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  • 4
    Keywords: IN-VITRO ; INHIBITION ; DNA methylation ; PROGENITOR CELLS ; ABNORMALITIES ; microenvironment ; ACUTE MYELOID-LEUKEMIA ; MYELODYSPLASTIC SYNDROMES ; BONE-MARROW NICHE ; HEMATOPOIETIC STEM-CELL
    Abstract: Ineffective hematopoiesis is a major characteristic of myelodysplastic syndromes (MDS) causing relevant morbidity and mortality. Mesenchymal stromal cells (MSC) have been shown to physiologically support hematopoiesis, but their contribution to the pathogenesis of MDS remains elusive. We show that MSC from patients across all MDS subtypes (n=106) exhibit significantly reduced growth and proliferative capacities accompanied by premature replicative senescence. Osteogenic differentiation was significantly reduced in MDS-derived MSC, indicated by cytochemical stainings and reduced expressions of Osterix and Osteocalcin. This was associated with specific methylation patterns that clearly separated MDS-MSC from healthy controls and showed a strong enrichment for biological processes associated with cellular phenotypes and transcriptional regulation. Furthermore, in MDS-MSC, we detected altered expression of key molecules involved in the interaction with hematopoietic stem and progenitor cells (HSPC), in particular Osteopontin, Jagged1, Kit-ligand and Angiopoietin as well as several chemokines. Functionally, this translated into a significantly diminished ability of MDS-derived MSC to support CD34+ HSPC in long-term culture-initiating cell assays associated with a reduced cell cycle activity. Taken together, our comprehensive analysis shows that MSC from all MDS subtypes are structurally, epigenetically and functionally altered, which leads to impaired stromal support and seems to contribute to deficient hematopoiesis in MDS.
    Type of Publication: Journal article published
    PubMed ID: 23797473
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  • 5
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; GROWTH ; tumor ; BLOOD ; CELL ; Germany ; human ; cell line ; LINES ; FLOW ; CELL-LINES ; LINKAGE ; bone marrow ; BONE-MARROW ; ACID ; GLYCOPROTEIN ; ASSAY ; CELL-LINE ; leukemia ; LINE ; EXTRACELLULAR-MATRIX ; SURFACE ; ADHESION ; CLASS-I ; sialic acid ; PROGENITOR CELLS ; SIALIC-ACID ; LIVE CELLS ; DE-NOVO ; CELL-SURFACE ; HEMATOPOIETIC PROGENITOR CELLS ; PERIPHERAL-BLOOD ; PNA ; MATRIX ; PROGRAM ; RESIDUES ; SURFACE GLYCOPROTEIN ; extracellular matrix ; regulation ; GLYCOPROTEINS ; SIALOGLYCANS ; CD34 progenitor ; ecto-sialyltransferase ST6GaI 1 ; hematopoietic precursor cells ; HUMAN HEMATOPOIETIC PROGENITORS ; lactosamine ; surface sialylation
    Abstract: Surface expressed negatively charged sialoglycans contribute to the regulation of adhesive cellular interactions and are thus involved in the growth and differentiaton of hematopoietic progenitor cells. In particular, the cell surface sialylation state may govern the liberation of CD34+ hematopoietic precursors from bone marrow stroma cells and extracellular matrix. In order to assess the overall surface sialylation of live human CD34+ hematopoietic precursor cells, we applied a previously described flow cytometric enzyme assay. Cells with and without sialidase pretreatment were incubated in the presence of fluorescent CMP-sialic acid and exogenous ST6GalI. Thus sialylation of surface-expressed lactosamine residues was analysed. We demonstrated that surface lactosamines of CD34+ precursors derived from bone marrow and peripheral blood are over 95% sialylated, predominantly in alpha2-6 linkage. These results are in accordance with flow cytometric analysis of surface lectin staining. Sialic acid specific lectins MAA and SNA were strongly bound whereas SBA, VVA, and PNA became reactive only after sialidase pretreatment. CD34+ leukemia cell lines TF1 and KG1a also showed a high degree of surface sialylation, whereas cell line KG1 expressed to the largest extent free lactosamines. In these cell lines, alpha2-6 and alpha2-3 sialylated residues were present in equal amounts. In a variation of the flow cytometric enzyme assay, live cells were incubated without exogenous STGal I to measure the activity of endogenous ecto-sialyltransferase. Ecto sialyltransferase activity was observed in all CD34+ cells which was able to resialylate major surface glycoproteins such as HLA Class I, CD45, CD43, and CD34. The ecto-sialyltransferase may serve to maintain or increase surface sialylation rapidly without de novo synthesis
    Type of Publication: Journal article published
    PubMed ID: 15750786
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  • 6
    Keywords: CELLS ; EXPRESSION ; IN-VITRO ; INHIBITOR ; proliferation ; CELL ; CELL-PROLIFERATION ; Germany ; COMMON ; POPULATION ; GENE ; GENE-EXPRESSION ; GENES ; transcription ; ADHESION MOLECULES ; MOLECULES ; PATIENT ; TRANSCRIPTION FACTOR ; DOWN-REGULATION ; MOLECULE ; BONE-MARROW ; TRANSCRIPTION FACTORS ; gene expression ; ASSAY ; affymetrix ; leukemia ; ADHESION ; MIGRATION ; STEM-CELLS ; PHENOTYPE ; PROGENITOR CELLS ; PROTEIN-KINASE-C ; expression profiling ; FIBRONECTIN ; INHIBITORS ; cell proliferation ; ASSAYS ; PHASE ; BCR-ABL ; CML ; BONE ; STEM-CELL ; PROGENITORS ; CXCR4 ; MARROW ; QUIESCENCE ; TRANSCRIPTION-FACTOR ; myeloid ; stem and progenitor cells ; POSITIVE CELLS ; PROPORTION
    Abstract: We found that composition of cell subsets within the CD34+ cell population is markedly altered in chronic phase (CP) chronic myeloid leukemia (CML). Specifically, proportions and absolute cell counts of common myeloid progenitors (CMP) and megakaryocyte-erythrocyte progenitors (MEP) are significantly greater in comparison to normal bone marrow whereas absolute numbers of hematopoietic stem cells (HSC) are equal. To understand the basis for this, we performed gene expression profiling (Affymetrix HU-133A 2.0) of the distinct CD34+ cell subsets from six patients with CP CML and five healthy donors. Euclidean distance analysis revealed a remarkable transcriptional similarity between the CML patients' HSC and normal progenitors, especially CMP. CP CML HSC were transcriptionally more similar to their progeny than normal HSC to theirs, suggesting a more mature phenotype. Hence, the greatest differences between CP CML patients and normal donors were apparent in HSC including downregulation of genes encoding adhesion molecules, transcription factors, regulators of stem-cell fate and inhibitors of cell proliferation in CP CML. Impaired adhesive and migratory capacities were functionally corroborated by fibronectin detachment analysis and transwell assays, respectively. Based on our findings we propose a loss of quiescence of the CML HSC on detachment from the niche leading to expansion of myeloid progenitors. Leukemia (2009) 23, 892-899; doi:10.1038/leu.2008.392; published online 22 January 2009
    Type of Publication: Journal article published
    PubMed ID: 19158832
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  • 7
    Keywords: ACTIVATION ; SUPPRESSION ; GROWTH-FACTOR-BETA ; microenvironment ; TGF-BETA ; thalidomide ; ANEMIA ; PLASMA-CELLS ; NICHES ; I KINASE INHIBITOR
    Abstract: Multiple myeloma (MM) is a clonal plasma cell disorder frequently accompanied by hematopoietic impairment. We show that hematopoietic stem and progenitor cells (HSPCs), in particular megakaryocyte-erythrocyte progenitors, are diminished in the BM of MM patients. Genomic profiling of HSPC subsets revealed deregulations of signaling cascades, most notably TGF beta signaling, and pathways involved in cytoskeletal organization, migration, adhesion, and cell-cycle regulation in the patients. Functionally, proliferation, colony formation, and long-term self-renewal were impaired as a consequence of activated TGF beta signaling. In accordance, TGF beta levels in the BM extracellular fluid were elevated and mesenchymal stromal cells (MSCs) had a reduced capacity to support long-term hematopoiesis of HSPCs that completely recovered on blockade of TGF beta signaling. Furthermore, we found defective actin assembly and down-regulation of the adhesion receptor CD44 in MM HSPCs functionally reflected by impaired migration and adhesion. Still, transplantation into myeloma-free NOG mice revealed even enhanced engraftment and normal differentiation capacities of MM HSPCs, which underlines that functional impairment of HSPCs depends on MM-related microenvironmental cues and is reversible. Taken together, these data implicate that hematopoietic suppression in MM emerges from the HSPCs as a result of MM-related microenvironmental alterations.
    Type of Publication: Journal article published
    PubMed ID: 22517906
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  • 8
    Abstract: Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) has been identified as high-risk subgroup of acute T-lymphoblastic leukemia (T-ALL) with a high rate of FLT3-mutations in adults. To unravel the underlying pathomechanisms and the clinical course we assessed molecular alterations and clinical characteristics in a large cohort of ETP-ALL (n = 68) in comparison to non-ETP T-ALL adult patients. Interestingly, we found a high rate of FLT3-mutations in ETP-ALL samples (n = 24, 35%). Furthermore, FLT3 mutated ETP-ALL was characterized by a specific immunophenotype (CD2+/CD5-/CD13+/CD33-), a distinct gene expression pattern (aberrant expression of IGFBP7, WT1, GATA3) and mutational status (absence of NOTCH1 mutations and a low frequency, 21%, of clonal TCR rearrangements). The observed low GATA3 expression and high WT1 expression in combination with lack of NOTCH1 mutations and a low rate of TCR rearrangements point to a leukemic transformation at the pluripotent prothymocyte stage in FLT3 mutated ETP-ALL. The clinical outcome in ETP-ALL patients was poor, but encouraging in those patients with allogeneic stem cell transplantation (3-year OS: 74%). To further explore the efficacy of targeted therapies, we demonstrate that T-ALL cell lines transfected with FLT3 expression constructs were particularly sensitive to tyrosine kinase inhibitors. In conclusion, FLT3 mutated ETP-ALL defines a molecular distinct stem cell like leukemic subtype. These data warrant clinical studies with the implementation of FLT3 inhibitors in addition to early allogeneic stem cell transplantation for this high risk subgroup.
    Type of Publication: Journal article published
    PubMed ID: 23359050
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  • 9
    Abstract: Hematopoietic insufficiency is the hallmark of acute myeloid leukemia (AML) and predisposes patients to life-threatening complications such as bleeding and infections. Addressing the contribution of mesenchymal stromal cells (MSC) to AML-induced hematopoietic failure we show that MSC from AML patients (n=64) exhibit significant growth deficiency and impaired osteogenic differentiation capacity. This was molecularly reflected by a specific methylation signature affecting pathways involved in cell differentiation, proliferation and skeletal development. In addition, we found distinct alterations of hematopoiesis-regulating factors such as Kit-ligand and Jagged1 accompanied by a significantly diminished ability to support CD34+ hematopoietic stem and progenitor cells in long-term culture-initiating cells (LTC-ICs) assays. This deficient osteogenic differentiation and insufficient stromal support was reversible and correlated with disease status as indicated by Osteocalcin serum levels and LTC-IC frequencies returning to normal values at remission. In line with this, cultivation of healthy MSC in conditioned medium from four AML cell lines resulted in decreased proliferation and osteogenic differentiation. Taken together, AML-derived MSC are molecularly and functionally altered and contribute to hematopoietic insufficiency. Inverse correlation with disease status and adoption of an AML-like phenotype after exposure to leukemic conditions suggests an instructive role of leukemic cells on bone marrow microenvironment.
    Type of Publication: Journal article published
    PubMed ID: 26601782
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  • 10
    Abstract: Epigenetic changes represent an attractive mechanism for understanding the phenotypic changes associated with human aging. Age-related changes in DNA methylation at the genome scale have been termed 'epigenetic drift', but the defining features of this phenomenon remain to be established. Human epidermis represents an excellent model for understanding age-related epigenetic changes because of its substantial cell-type homogeneity and its well-known age-related phenotype. We have now generated and analyzed the currently largest set of human epidermis methylomes (N = 108) using array-based profiling of 450 000 methylation marks in various age groups. Data analysis confirmed that age-related methylation differences are locally restricted and characterized by relatively small effect sizes. Nevertheless, methylation data could be used to predict the chronological age of sample donors with high accuracy. We also identified discontinuous methylation changes as a novel feature of the aging methylome. Finally, our analysis uncovered an age-related erosion of DNA methylation patterns that is characterized by a reduced dynamic range and increased heterogeneity of global methylation patterns. These changes in methylation variability were accompanied by a reduced connectivity of transcriptional networks. Our findings thus define the loss of epigenetic regulatory fidelity as a key feature of the aging epigenome.
    Type of Publication: Journal article published
    PubMed ID: 27004597
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