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  • 1
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1612-1612
    Abstract: Abstract 1612 Poster Board I-638 Cytogenetically normal AML (CN-AML) is a heterogeneous disease with molecular markers impacting considerably on survival. Acquired gene mutations such as the internal tandem duplication (ITD) of the FLT3 gene has been shown to be associated with poor prognosis. Furthermore, it has been shown that the poor prognosis in the group of patients with high risk cytogenetics could be improved, when a consolidation therapy with allogeneic stem cell transplantation (HCT) was performed. To investigate the importance of a postremission consolidation therapy in CN-AML patients according their mutational status for the FLT3-ITD mutation we compared the clinical outcome in these patients on an intention to treat analysis. A total of 800 patients have been entered into two OSHO (East German study group for hematology and oncology) studies between 1997 and now. The first protocol (AML 96) compared two different induction schedules employing different schedules of intermediate AraC and Idarubicin. The second protocol (AML 2002) studied the role of two different induction therapies in patients failing to reach CR after the first induction therapy. From the 800 patients treated within these protocols 338 pts. had a normal karyotype. Complete remissions were obtained in 277 patients after one or two induction cycles. Out of these patients 78 pts received a consolidation therapy by allogeneic HCT whereas 169 pts were further treated by conventional chemotherapy or by autologous transplantation. HCT was performed after conditioning with cytoxan and 1200 cGy total body irradiation followed by GvH-D prophylaxis with cyclosporine and methotrexate. Material at the time of diagnosis to analyse the presence of a FLT3-ITD mutation was available in 116 pts. Of those, 70 patients received conventional chemotherapy whereas 46 pts. were transplanted from an allogeneic donor as postremission therapy. Data were analyzed on an intend-to-treat-analysis in 116/277 patients being in CR1 after induction therapy from whom a FLT3-ITD mutation analysis was available. The EFS in this cohort of 116 patients was 38% after 5 years. Within the subgroup of patients (n=46) who received a HCT from an allogeneic donor the EFS was 44% compared to 33% (p=0.19) within the subgroup of conventional treated patients(n=70). As previously described, the detection of a FLT3-ITD mutation had a negative impact on event free survival which was calculated with 25% after 5 years in contrast to 46% in FLT3-ITD negative patients (p=0.06). In a further step EFS was analyzed according to the FLT3 status and the postremission treatment given. The EFS in conventional treated patients was significantly different (FLT3-ITD negative: LFS=50% vs. FLT3-ITD positive: LFS=19%; p=0.05). But, allogeneic HCT in first complete remission equalizes this difference (FLT3-ITD negative: LFS=50% vs. FLT3-ITD positive: LFS=35%; p=0.58). Major significant differences were seen in relapse incidences (RI) between the four subgroups of patients (FLT3-ITD positive and negative, conventional postremission therapy or allogeneic HCT; p=0.003). FLT3-ITD positive patients treated with conventional chemotherapy had a RI of 80% that could be reduced to a RI of 48% in the group of HCT patients. Within the two different treatment groups of FLT3-ITD negative patients the RI in the conventional treated group was 55% compared to 26% in HCT patients. To conclude, the worse prognostic impact of the presence FLT3-ITD mutation on the outcome of CN-AML pts. can be improved by allogeneic HCT performed in first complete remission after two courses of induction therapy. Allogeneic HCT reduces the relapse incidence in FLT3-ITD positive as well as in FLT3-ITD negative pts. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
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  • 2
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 4593-4593
    Abstract: Abstract 4593 Orexin receptors are involved in the regulation of sleep-wake-rhythm, food intake and energy homeostasis and it was still recently believed that their expression is restricted to the nervous system. But, during the last years orexin receptors have been detected in an increasing number of peripheral tissues. We have earlier found orexin receptor 1 and 2 expression on human CD34+ hematopoietic stem and progenitor cells. Still, the sources of their physiological ligands, the peptides orexin A and B, seemed so far to be restricted to the central nerve system. Ca2+-dependent signaling and activation of mitogen-activated protein kinase (MAPK) and extracellular signal-related kinase 1/2 (ERK1/2) pathways are considered as main downstream signaling pathways of the orexin receptors. In this study, we investigated the signaling and functional role of orexin receptors in CD34+ hematopoietic stem and progenitor cells. Using confocal fluorescence microscopy and flow cytometry we found that stimulation of purified CD34+ cells with orexin A and B led to an increase of the intracellular calcium concentration due to both calcium influx and calcium release from intracellular stores. Of interest, incubation with orexin reduces the SDF-1β-induced calcium influx. Furthermore orexin receptor stimulation led to a decrease of the intracellular cAMP concentration. Following orexin receptor stimulation with orexin A and B, we observed an initial increase of ERK1/2 phosphorylation up to 30 minutes upon incubation with orexin followed by a decrease at several time points up to 8 hours in comparison to the unstimulated control. To investigate a potential impact on the functional properties of human CD34+ cells we performed proliferation and apoptosis assays, migration and adhesion assays as well as colony forming and long-term culture assays. Remarkably, stimulation with orexin A and B led to a significant higher proportion of early pluripotent hematopoietic progenitor (CFU-GEMM) colonies and a significant reduction of erythroid precursors. A more immature phenotype of orexin-stimulated CD34+ cells is also reflected by array-based gene expression profiling. Long-term culture assays revealed a significant higher frequency of LTC-IC indicating also a more immature phenotype of orexin-stimulated cells. In line, orexin receptor stimulation led to a significant increase of the proportion of Lin-, CD34+, CD38- HSC in the G0-phase of the cell cycle. Furthermore, stimulation with orexin A and B increased the number of apoptotic cells in the Lin-, CD34+, CD38- HSC fraction and the total hematopoietic stem and progenitor population determined by flowcytometric analysis of intracellular cleaved caspase 3 content. The adhesive capacity of CD34+ cells to fibronectin and collagen coated dishes and the migratory capacity was significantly decreased upon orexin receptor stimulation. Concurrent incubation with the selective Gi-protein inhibitor pertussis toxin abrogated these effects. Given the functional impact of the orexin system on CD34+ cells, we asked if orexins are secreted locally in the bone marrow or autocrine by CD34+ cells or if they are humorally transported to the bone marrow cavity. Using FACS analysis, immunfluorescent staining and western blotting we could detect prepro-Orexin in CD34+ cells and using ELISA orexin was found in the serum obtained by bone marrow biopsies and peripheral blood. Taken together, the phenotype of orexin-stimulated hematopoietic stem and progenitor cells suggest a mobilizing effect of the orexin receptor stimulation as well as an increased repopulation capacity which might be of relevance in clinical stem cell mobilization and transplantation and is currently verified in murine models. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 53, No. 10 ( 2009-10), p. 4464-4471
    Abstract: Bacteria can defend themselves against β-lactam antibiotics through the expression of class B β-lactamases, which cleave the β-lactam amide bond and render the molecule harmless. There are three subclasses of class B β-lactamases (B1, B2, and B3), all of which require Zn 2+ for activity and can bind either one or two zinc ions. Whereas the B1 and B3 metallo-β-lactamases are most active as dizinc enzymes, subclass B2 enzymes, such as Aeromonas hydrophila CphA, are inhibited by the binding of a second zinc ion. We crystallized A. hydrophila CphA in order to determine the binding site of the inhibitory zinc ion. X-ray data from zinc-saturated crystals allowed us to solve the crystal structures of the dizinc forms of the wild-type enzyme and N220G mutant. The first zinc ion binds in the cysteine site, as previously determined for the monozinc form of the enzyme. The second zinc ion occupies a slightly modified histidine site, where the conserved His118 and His196 residues act as metal ligands. This atypical coordination sphere probably explains the rather high dissociation constant for the second zinc ion compared to those observed with enzymes of subclasses B1 and B3. Inhibition by the second zinc ion results from immobilization of the catalytically important His118 and His196 residues, as well as the folding of the Gly232-Asn233 loop into a position that covers the active site.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
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    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2009
    detail.hit.zdb_id: 1496156-8
    SSG: 12
    SSG: 15,3
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  • 4
    In: Transplantation, Ovid Technologies (Wolters Kluwer Health), Vol. 87, No. 9 ( 2009-05-15), p. 1415-1421
    Type of Medium: Online Resource
    ISSN: 0041-1337
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    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2009
    detail.hit.zdb_id: 2035395-9
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  • 5
    Online Resource
    Online Resource
    Microbiology Society ; 2009
    In:  Journal of General Virology Vol. 90, No. 6 ( 2009-06-01), p. 1440-1449
    In: Journal of General Virology, Microbiology Society, Vol. 90, No. 6 ( 2009-06-01), p. 1440-1449
    Abstract: Herpesvirus glycoproteins often form specific heterodimers that can fulfil functions that cannot be carried out by either of the partners acting alone. This study showed that interactions between the Epstein–Barr virus (EBV) multi-spanning transmembrane envelope protein BMRF2 and type II membrane protein BDLF2 influence the way in which these proteins are trafficked in the cell, and hence the subcellular compartment in which they accumulate. When expressed transiently in mammalian cells, BDLF2 accumulated in the endoplasmic reticulum (ER), whereas BMRF2 accumulated in the ER and Golgi apparatus. However, when the two proteins were co-expressed, BDLF2 was transported with BMRF2 to the Golgi apparatus and from there to the plasma membrane, where the proteins co-localized extensively. The distribution of the two proteins at the plasma membrane was reproducibly associated with dramatic changes in cellular morphology, including the formation of enlarged membrane protrusions and cellular processes whose adhesion extremities were organized by the actin cytoskeleton. A dominant-active form of the small GTPase RhoA was epistatic to this morphological phenotype, suggesting that RhoA is a central component of the signalling pathway that reorganizes the cytoskeleton in response to BDLF2–BMRF2. It was concluded that EBV produces a glycoprotein heterodimer that induces changes in cellular morphology through reorganization of the actin cytoskeleton and may facilitate virion spread between cells.
    Type of Medium: Online Resource
    ISSN: 0022-1317 , 1465-2099
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    Language: English
    Publisher: Microbiology Society
    Publication Date: 2009
    detail.hit.zdb_id: 2007065-2
    SSG: 12
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  • 6
    Online Resource
    Online Resource
    Physicians Postgraduate Press, Inc ; 2009
    In:  The Journal of Clinical Psychiatry Vol. 70, No. 4 ( 2009-04-15), p. 500-508
    In: The Journal of Clinical Psychiatry, Physicians Postgraduate Press, Inc, Vol. 70, No. 4 ( 2009-04-15), p. 500-508
    Type of Medium: Online Resource
    ISSN: 0160-6689
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    Language: English
    Publisher: Physicians Postgraduate Press, Inc
    Publication Date: 2009
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  • 7
    In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 1799-1799
    Abstract: Abstract 1799 Poster Board I-825 Multiple myeloma (MM) patients often present with anemia at the time of initial diagnosis. This has so far only attributed to a physically marrow suppression by the invading malignant plasma cells and the overexpression of Fas-L and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by malignant plasma cells triggering the death of immature erythroblasts. Still the impact of MM on hematopoietic stem cells and their niches is scarcely established. In this study we analyzed highly purified CD34+ hematopoietic stem and progenitor cell subsets from the bone marrow of newly diagnosed MM patients in comparison to normal donors. Quantitative flowcytometric analyses revealed a significant reduction of the megakaryocyte-erythrocyte progenitor (MEP) proportion in MM patients, whereas the percentage of granulocyte-macrophage progenitors (GMP) was significantly increased. Proportions of hematopoietic stem cells (HSC) and myeloid progenitors (CMP) were not significantly altered. We then asked if this is also reflected by clonogenic assays and found a significantly decreased percentage of erythroid precursors (BFU-E and CFU-E). Using Affymetrix HU133 2.0 gene arrays, we compared the gene expression signatures of stem cells and progenitor subsets in MM patients and healthy donors. The most striking findings so far reflect reduced adhesive and migratory potential, impaired self-renewal capacity and disturbed B-cell development in HSC whereas the MEP expression profile reflects decreased in cell cycle activity and enhanced apoptosis. In line we found a decreased expression of the adhesion molecule CD44 and a reduced actin polymerization in MM HSC by immunofluorescence analysis. Accordingly, in vitro adhesion and transwell migration assays showed reduced adhesive and migratory capacities. The impaired self-renewal capacity of MM HSC was functionally corroborated by a significantly decreased long-term culture initiating cell (LTC-IC) frequency in long term culture assays. Cell cycle analyses revealed a significantly larger proportion of MM MEP in G0-phase of the cell cycle. Furthermore, the proportion of apoptotic cells in MM MEP determined by the content of cleaved caspase 3 was increased as compared to MEP from healthy donors. Taken together, our findings indicate an impact of MM on the molecular phenotype and functional properties of stem and progenitor cells. Anemia in MM seems at least partially to originate already at the stem and progenitor level. Disclosures Off Label Use: AML with multikinase inhibitor sorafenib, which is approved by EMEA + FDA for renal cell carcinoma.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2009
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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