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Berlin Brandenburg

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  • 1
    Language: English
    In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, February 2012, Vol.26(2), pp.894-906
    Description: The JAK2 mutation V617F is detectable in a majority of patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). Enforced expression of JAK2 V617F in mice induces myeloproliferation and bone marrow (BM) fibrosis, suggesting a causal role for the JAK2 mutant in the pathogenesis of MPNs. However, little is known about mechanisms and effector molecules contributing to JAK2 V617F-induced myeloproliferation and fibrosis. We show that JAK2 V617F promotes expression of oncostatin M (OSM) in neoplastic myeloid cells. Correspondingly, OSM mRNA levels were increased in the BM of patients with MPNs (median 287% of ABL, range 22-1450%) compared to control patients (median 59% of ABL, range 12-264%; P 〈 0.0001). OSM secreted by JAK2 V617F+ cells stimulated growth of fibroblasts and microvascular endothelial cells and induced the production of angiogenic and profibrogenic cytokines (HGF, VEGF, and SDF-1) in BM fibroblasts. All effects of MPN cell-derived OSM were blocked by a neutralizing anti-OSM antibody, whereas the production of OSM in MPN cells was suppressed by a pharmacologic JAK2 inhibitor or RNAi-mediated knockdown of JAK2. In summary, JAK2 V617F-mediated up-regulation of OSM may contribute to fibrosis, neoangiogenesis, and the cytokine storm observed in MPNs, suggesting that OSM might serve as a novel therapeutic target molecule in these neoplasms.
    Keywords: Janus Kinase 2 -- Genetics ; Mutant Proteins -- Genetics ; Myeloproliferative Disorders -- Genetics ; Oncostatin M -- Metabolism
    ISSN: 08926638
    E-ISSN: 1530-6860
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  • 2
    Language: English
    In: Applied and Environmental Microbiology, 2011, Vol. 77(3), p.1151
    Description: Volume 76, no. 23, p. 7867-7869, 2010. Page 7868, legend to Fig. 1, line 2: “(day 1)” should read “(day −1).”
    Keywords: Engineering ; Biology ; Economics;
    ISSN: 0099-2240
    ISSN: 00992240
    E-ISSN: 10985336
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  • 3
    Language: English
    In: Applied and Environmental Microbiology, 2010, Vol. 76(23), p.7867
    ISSN: 0099-2240
    ISSN: 00992240
    Source: American Society of Microbiology
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  • 4
    Language: English
    In: PLoS ONE, 2012, Vol.7(1), p.e29925
    Description: The phosphoinositide 3-kinase (PI3-kinase) and the mammalian target of rapamycin (mTOR) are two major signaling molecules involved in growth and activation of mast cells (MC) and basophils (BA). We examined the effects of the dual PI3-kinase/mTOR blocker NVP-BEZ235 on growth of normal and neoplastic BA and MC as well as immunoglobulin E (IgE)-dependent cell activation. Growth of MC and BA were determined by measuring 3 H-thymidine uptake and apoptosis. Cell activation was determined in histamine release experiments and by measuring upregulation of CD63 and CD203c after challenging with IgE plus anti-IgE or allergen. We found that NVP-BEZ235 exerts profound inhibitory effects on growth of primary and cloned neoplastic MC. In the MC leukemia cell line HMC-1, NVP-BEZ235 showed similar IC 50 values in the HMC-1.1 subclone lacking KIT D816V (0.025 µM) and the HMC-1.2 subclone expressing KIT D816V (0.005 µM). Moreover, NVP-BEZ235 was found to exert strong growth-inhibitory effects on neoplastic MC in a xenotransplant-mouse model employing NMR1-Foxn1 nu mice. NVP-BEZ235 also exerted inhibitory effects on cytokine-dependent differentiation of normal BA and MC, but did not induce growth inhibition or apoptosis in mature MC or normal bone marrow cells. Finally, NVP-BEZ235 was found to inhibit IgE-dependent histamine release in BA and MC (IC 50 0.5–1 µM) as well as anti-IgE-induced upregulation of CD203c in BA and IgE-dependent upregulation of CD63 in MC. In summary, NVP-BEZ235 produces growth-inhibitory effects in immature neoplastic MC and inhibits IgE-dependent activation of mature BA and MC. Whether these potentially beneficial drug effects have clinical implications is currently under investigation.
    Keywords: Research Article ; Biology ; Immunology ; Molecular Biology ; Cell Biology ; Developmental Biology
    E-ISSN: 1932-6203
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  • 5
    Language: English
    In: European Journal of Nuclear Medicine and Molecular Imaging, 2018, Vol.45(10), pp.1645-1648
    Description: To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1007/s00259-018-4060-x Byline: Marcus Hacker (1,2), Gregor Hoermann (3,4), Lukas Kenner (2,5,6,7) Author Affiliation: (1) 0000 0000 9259 8492, grid.22937.3d, Division of Nuclear Medicine, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria (2) 0000 0000 9259 8492, grid.22937.3d, CBMed Core Lab2, Medical University of Vienna, Vienna, Austria (3) 0000 0000 9259 8492, grid.22937.3d, Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria (4) 0000 0000 9259 8492, grid.22937.3d, Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria (5) 0000 0000 9259 8492, grid.22937.3d, Clinical Institute of Pathology, Department for Experimental and Laboratory Animal Pathology, Medical University of Vienna, Vienna, Austria (6) 0000 0004 0436 8814, grid.454387.9, Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria (7) 0000 0000 9686 6466, grid.6583.8, Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, Austria Article History: Registration Date: 25/05/2018 Online Date: 02/06/2018
    Keywords: Medical Schools ; Diagnostic Imaging ; Resveratrol;
    ISSN: 1619-7070
    E-ISSN: 1619-7089
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  • 6
    Language: English
    In: Blood, 01 November 2018, Vol.132(18), pp.1936-1950
    Description: The Hermes receptor CD44 is a multifunctional adhesion molecule that plays an essential role in the homing and invasion of neoplastic stem cells in various myeloid malignancies. Although mast cells (MCs) reportedly express CD44, little is known about the regulation and function of this receptor in neoplastic...
    Keywords: Gene Expression Regulation, Neoplastic ; Signal Transduction ; Hyaluronan Receptors -- Genetics ; Mastocytosis, Systemic -- Genetics ; Neoplasm Invasiveness -- Genetics ; Stat5 Transcription Factor -- Metabolism ; Ras Proteins -- Metabolism
    E-ISSN: 1528-0020
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  • 7
    Language: English
    In: Blood, 19 January 2017, Vol.129(3), pp.371-382
    Description: Systemic mastocytosis (SM) is characterized by abnormal accumulation of neoplastic mast cells harboring the activating KIT mutation D816V in the bone marrow and other internal organs. As found in other myeloproliferative neoplasms, increased production of profibrogenic and angiogenic cytokines and related alterations of the bone marrow microenvironment are commonly found in SM. However, little is known about mechanisms and effector molecules triggering fibrosis and angiogenesis in SM. Here we show that KIT D816V promotes expression of the proangiogenic cytokine CCL2 in neoplastic mast cells. Correspondingly, the KIT-targeting drug midostaurin and RNA interference-mediated knockdown of KIT reduced expression of CCL2. We also found that nuclear factor κB contributes to KIT-dependent upregulation of CCL2 in mast cells. In addition, CCL2 secreted by KIT D816V mast cells was found to promote the migration of human endothelial cells in vitro. Furthermore, knockdown of CCL2 in neoplastic mast cells resulted in reduced microvessel density and reduced tumor growth in vivo compared with CCL2-expressing cells. Finally, we measured CCL2 serum concentrations in patients with SM and found that CCL2 levels were significantly increased in mastocytosis patients compared with controls. CCL2 serum levels were higher in patients with advanced SM and were found to correlate with poor survival. In summary, we have identified CCL2 as a novel KIT D816V-dependent key regulator of vascular cell migration and angiogenesis in SM. CCL2 expression correlates with disease severity and prognosis. Whether CCL2 may serve as a therapeutic target in advanced SM remains to be determined in forthcoming studies.
    Keywords: Bone Marrow -- Pathology ; Chemokine Ccl2 -- Blood ; Mastocytosis, Systemic -- Pathology ; Proto-Oncogene Proteins C-Kit -- Genetics
    E-ISSN: 1528-0020
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  • 8
    Language: English
    In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, August 2014, Vol.28(8), pp.3540-51
    Description: Advanced systemic mastocytosis (SM) is an aggressive hematopoietic neoplasm with poor prognosis and short survival times. So far, no curative therapy is available for affected patients. We have identified the cell surface antigen CD52 (CAMPATH-1) as a molecular target expressed abundantly on the surface of primary neoplastic mast cells (MCs) in patients with advanced SM. In contrast, neoplastic MCs of patients with indolent SM and normal MCs expressed only low levels or did not express CD52. To study the mechanisms of CD52 expression and the value of this antigen as a potential therapeutic target, we generated a human MC cell line, designated MCPV-1, by lentiviral immortalization of cord blood-derived MC progenitor cells. Functional studies revealed that activated RAS profoundly promotes surface expression of CD52. The CD52-targeting antibody alemtuzumab induced cell death in CD52(+) primary neoplastic MCs obtained from patients with SM as well as in MCPV-1 cells. NSG mice xenotransplanted with MCPV-1 cells survived significantly longer after treatment with alemtuzumab (median survival: 31 d untreated vs. 46 d treated; P=0.0012). We conclude that CD52 is a novel marker and potential therapeutic target in neoplastic MCs in patients with advanced SM.
    Keywords: Campath-1 ; Ras G12v ; Alemtuzumab ; Mast Cell Leukemia ; Molecular Targeted Therapy ; Antibodies, Monoclonal, Humanized -- Therapeutic Use ; Antigens, CD -- Analysis ; Antigens, Neoplasm -- Analysis ; Antineoplastic Agents -- Therapeutic Use ; Glycoproteins -- Analysis ; Mastocytosis, Systemic -- Metabolism
    ISSN: 08926638
    E-ISSN: 1530-6860
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  • 9
    Language: English
    In: The Journal of Allergy and Clinical Immunology, February 2016, Vol.137(2), pp.601-609.e8
    Description: Late allergic reactions are common in the course of allergen-specific immunotherapy and even occur with allergy vaccines with reduced IgE reactivity. We sought to study atopy patch test (APT) reactions and T-cell responses to the recombinant birch pollen allergen Bet v 1 and recombinant hypoallergenic T-cell epitope–containing Bet v 1 fragments in patients with birch pollen allergy with and without atopic dermatitis (AD). A clinical study was conducted in 15 patients with birch pollen allergy with AD (group 1), 5 patients with birch pollen allergy without AD (group 2), 5 allergic patients without birch pollen allergy (group 3), and 5 nonallergic subjects (group 4) by performing skin prick tests and APTs with rBet v 1 and hypoallergenic rBet v 1 fragments. T-cell, cutaneous lymphocyte antigen (CLA) and CCR4 T-cell and cytokine responses were studied by thymidine uptake, carboxyfluorescein diacetate succinimidyl ester staining, and Luminex technology, respectively. rBet v 1 and hypoallergenic rBet v 1 fragments induced APT reactions in not only most of the patients with birch pollen allergy with AD (11/15) but also in most of those without AD (4/5). Patients with birch pollen allergy with AD had higher Bet v 1–specific proliferation of CLA and CCR4 T cells compared with patients with birch pollen allergy without AD. There were no differences in Bet v 1–specific CLA and CCR4 proliferation and cytokine secretion in patients with and without APT reactions. Hypoallergenic rBet v 1 fragments induce T cell–dependent late reactions not only in patients with birch pollen allergy with AD but also in those without AD, which can be determined based on APT results but not based on parameters.
    Keywords: Allergy ; Allergen ; Recombinant Hypoallergens ; Atopy Patch Testing ; Late-Phase Reaction ; T-Cell Proliferation ; Cutaneous Lymphocyte Antigen ; Ccr4 ; Birch Pollen Allergy ; Rbet V 1 ; Rbet V 1 Fragments ; Specific Immunotherapy ; Medicine
    ISSN: 0091-6749
    E-ISSN: 1097-6825
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  • 10
    Language: English
    In: Mediators of Inflammation, 2015-12-01, 2015卷 (Issue 2015), pp.626-642
    Description: The term myeloproliferative neoplasms (MPN) refers to a heterogeneous group of diseases including not only polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), but also chronic myeloid leukemia (CML), and systemic mastocytosis (SM). Despite the clinical and biological differences between these diseases, common pathophysiological mechanisms have been identified in MPN. First, aberrant tyrosine kinase signaling due to somatic mutations in certain driver genes is common to these MPN. Second, alterations of the bone marrow microenvironment are found in all MPN types and have been implicated in the pathogenesis of the diseases. Finally, elevated levels of proinflammatory and microenvironment-regulating cytokines are commonly found in all MPN-variants. In this paper, we review the effects of MPN-related oncogenes on cytokine expression and release and describe common as well as distinct pathogenetic mechanisms underlying microenvironmental changes in various MPN. Furthermore, targeting of the microenvironment in MPN is discussed. Such novel therapies may enhance the efficacy and may overcome resistance to established tyrosine kinase inhibitor treatment in these patients. Nevertheless, additional basic studies on the complex interplay of neoplastic and stromal cells are required in order to optimize targeting strategies and to translate these concepts into clinical application.
    Keywords: Tumor Microenvironment ; Cytokines -- Metabolism ; Myeloproliferative Disorders -- Pathology ; Neoplasms -- Pathology;
    ISSN: 0962-9351
    E-ISSN: 14661861
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