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Berlin Brandenburg

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  • 1
    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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  • 2
    Language: English
    In: International Archives of Allergy and Immunology, August 2012, Vol.159(1), pp.15-22
    Description: Background: Dasatinib is a multikinase inhibitor active against several tyrosine kinases including ABL, KIT, Lyn and Btk. Apart from its known antileukemic activity, the drug produces several side effects including edemas and pleural effusions, which are supposedly triggered by activated immune cells. Effusion formation can be treated effectively by glucocorticosteroids. We have recently shown that low concentrations of dasatinib (〈0.1 µM) promote IgE-dependent secretion of histamine in basophils, especially in allergic individuals. In the current study, we asked whether glucocorticosteroids inhibit dasatinib-induced activation of basophils. Methods: Basophils were preincubated with dexamethasone, prednisolone and hydrocortisone for 24 h, and were then exposed to an anti-IgE antibody (normal basophils) or the allergens Bet v 1 and Phl p 5 (allergic patients) with or without low concentrations of dasatinib (0.025 µM). After incubation, basophils were examined for histamine release and expression of CD63 and CD203c. Results: All three glucocorticosteroids were found to counteract IgE-dependent and dasatinib-enhanced histamine release in basophils in nonallergic and allergic individuals. In addition, glucocorticosteroids were found to inhibit anti-IgE-induced upregulation of CD63 and CD203c in the presence or absence of dasatinib. The inhibitory effects of glucocorticosteroids were dose-dependent (effective range: 1–10 µM) and seen in all donors examined. Conclusions: Glucocorticosteroids rescue IgE receptor cross-linked basophils from additional costimulatory effects of low-dose dasatinib which may have clinical implications in dasatinib-treated patients.
    Keywords: Original Paper ; Basophils ; Dasatinib ; Glucocorticosteroids ; Histamine ; Immunoglobulin E Receptor ; Medicine
    ISSN: 1018-2438
    E-ISSN: 1423-0097
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  • 3
    Language: English
    In: Blood, 03 May 2012, Vol.119(18), pp.4242-52
    Description: Aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) are advanced hematopoietic neoplasms with poor prognosis. In these patients, neoplastic mast cells (MCs) are resistant against various drugs. We examined the effects of 2 demethylating agents, 5-azacytidine and decitabine on growth and survival of neoplastic MCs and the MC line HMC-1. Two HMC-1 subclones were used, HMC-1.1 lacking KIT D816V and HMC-1.2 exhibiting KIT D816V. Both agents induced apoptosis in HMC-1.1 and HMC-1.2 cells. Decitabine, but not 5-azacytidine, also produced a G(2)/M cell-cycle arrest in HMC-1 cells. Drug-induced apoptosis was accompanied by cleavage of caspase-8 and caspase-3 as well as FAS-demethylation and FAS-re-expression in neoplastic MCs. Furthermore, both demethylating agents were found to synergize with the FAS-ligand in inducing apoptosis in neoplastic MCs. Correspondingly, siRNA against FAS was found to block drug-induced expression of FAS and drug-induced apoptosis in HMC-1 cells. Neither 5-azacytidine nor decitabine induced substantial apoptosis or growth arrest in normal MCs or normal bone marrow cells. Together, 5-azacytidine and decitabine exert growth-inhibitory and proapoptotic effects in neoplastic MCs. These effects are mediated through "FAS-re-expression" and are augmented by the FAS-ligand. Whether epigenetic drugs produce antineoplastic effects in vivo in patients with ASM and MCL remains to be determined.
    Keywords: Antimetabolites, Antineoplastic -- Pharmacology ; Apoptosis -- Drug Effects ; Azacitidine -- Analogs & Derivatives ; Leukemia, Mast-Cell -- Pathology ; Mast Cells -- Drug Effects ; Mastocytosis, Systemic -- Pathology ; Protein Processing, Post-Translational -- Drug Effects ; Fas Receptor -- Metabolism
    ISSN: 00064971
    E-ISSN: 1528-0020
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  • 4
    Language: English
    In: Neoplasia (New York, N.Y.), July 2012, Vol.14(7), pp.572-84
    Description: Chronic myeloid leukemia (CML) is a hematopoietic neoplasm characterized by the Philadelphia chromosome and the related BCR-ABL1 oncoprotein. Acceleration of CML is usually accompanied by basophilia. Several proangiogenic molecules have been implicated in disease acceleration, including the hepatocyte growth factor (HGF). However, little is known so far about the cellular distribution and function of HGF in CML. We here report that HGF is expressed abundantly in purified CML basophils and in the basophil-committed CML line KU812, whereas all other cell types examined expressed only trace amounts of HGF or no HGF. Interleukin 3, a major regulator of human basophils, was found to promote HGF expression in CML basophils. By contrast, BCR-ABL1 failed to induce HGF synthesis in CML cells, and imatinib failed to inhibit expression of HGF in these cells. Recombinant HGF as well as basophil-derived HGF induced endothelial cell migration in a scratch wound assay, and these effects of HGF were reverted by an anti-HGF antibody as well as by pharmacologic c-Met inhibitors. In addition, anti-HGF and c-Met inhibitors were found to suppress the spontaneous growth of KU812 cells, suggesting autocrine growth regulation. Together, HGF is a BCR-ABL1-independent angiogenic and autocrine growth regulator in CML. Basophils are a unique source of HGF in these patients and may play a more active role in disease-associated angiogenesis and disease progression than has so far been assumed. Our data also suggest that HGF and c-Met are potential therapeutic targets in CML.
    Keywords: Basophils -- Metabolism ; Hepatocyte Growth Factor -- Metabolism ; Leukemia, Myelogenous, Chronic, BCR-Abl Positive -- Metabolism
    E-ISSN: 1476-5586
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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  • 5
    Language: English
    In: Critical Reviews in Oncology / Hematology, April 2014, Vol.90(1), pp.1-16
    Description: Disordered stem cell epigenetics and apoptosis-regulating mechanisms contribute essentially to the pathogenesis of myelodysplastic syndromes (MDS) and may trigger disease-progression to secondary acute myeloid leukemia (AML). Expression of apoptosis-mediators FAS (CD95) and DAPK1 the latter being also known for its association with autophagy are upregulated in neoplastic cells in patients with low-risk MDS and epigenetically silenced and downregulated in high-risk MDS and AML as confirmed by a study 50 MDS and 30 AMLs complementing this review. 5-Azacytidine (AZA) and 5-aza-2′deoxycytidine (DAC), promoted FAS and DAPK1 gene demethylation and their (re)expression as well as apoptosis in leukemic cell lines (HL-60, KG1) which can be reversed by siRNA against FAS. Thus, promoter-demethylation of FAS and DAPK1 represents a critical mechanism of drug-induced apoptosis in neoplastic cells in MDS and AML which underscores the clinical implication of epigenetically active therapies.
    Keywords: Epigenetics ; Apoptosis ; Autophagy ; Demethylating Drugs ; Medicine
    ISSN: 1040-8428
    E-ISSN: 1879-0461
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  • 6
    Language: English
    In: Neoplasia, July 2012, Vol.14(7), pp.572,IN7-584,IN10
    Description: Chronic myeloid leukemia (CML) is a hematopoietic neoplasm characterized by the Philadelphia chromosome and the related BCR-ABL1 oncoprotein. Acceleration of CML is usually accompanied by basophilia. Several proangiogenic molecules have been implicated in disease acceleration, including the hepatocyte growth factor (HGF). However, little is known so far about the cellular distribution and function of HGF in CML. We here report that HGF is expressed abundantly in purified CML basophils and in the basophil-committed CML line KU812, whereas all other cell types examined expressed only trace amounts of HGF or no HGF. Interleukin 3, a major regulator of human basophils, was found to promote HGF expression in CML basophils. By contrast, BCR-ABL1 failed to induce HGF synthesis in CML cells, and imatinib failed to inhibit expression of HGF in these cells. Recombinant HGF as well as basophil-derived HGF induced endothelial cell migration in a scratch wound assay, and these effects of HGF were reverted by an anti-HGF antibody as well as by pharmacologic c-Met inhibitors. In addition, anti-HGF and c-Met inhibitors were found to suppress the spontaneous growth of KU812 cells, suggesting autocrine growth regulation. Together, HGF is a BCR-ABL1-independent angiogenic and autocrine growth regulator in CML. Basophils are a unique source of HGF in these patients and may play a more active role in disease-associated angiogenesis and disease progression than has so far been assumed. Our data also suggest that HGF and c-Met are potential therapeutic targets in CML.
    Keywords: Medicine
    ISSN: 1476-5586
    ISSN: 15228002
    E-ISSN: 1476-5586
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  • 7
    Language: English
    In: Middleton's Allergy, Chapter Appendix A, pp.1663-1687
    ISBN: 978-0-323-08593-9
    ISBN: 978-0-323-11332-8
    ISBN: 978-0-323-24503-6
    ISBN: 978-0-323-32497-7
    ISBN: 978-0-323-39793-3
    Source: ScienceDirect (Elsevier B.V.)
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  • 8
    Language: English
    In: Virus-Insect-Plant Interactions, Chapter 1, pp.1,I-27,I
    Description: Plant viruses replicate in their insect host (propagative circulative transmission) and can be considered as plant as well as insect viruses. The phytoarbovirus group contains members that replicate in their aphid or leafhopper vectors, for example, replication of tomato spotted wilt tospovirus in thrips. A number of phytoarboviruses impair vector longevity and fecundity. Some are even transmitted from parent insect vector to progeny. Horizontal venereal transmission of a plant virus among insects has never been reported. However, transmission of virus through gametes of insects has been documented, especially for Drosophila spp. The Drosophila S virus (DSV), a reolike virus, invades differentiating male and female germ cells, causing developmental malformation. The baculovirus-like gonad-specific virus (GSV) causes abnormalities in the male and female reproductive systems of two species, Helicoverpazae and H. armigera. In both cases, the sperm and the egg could carry virions that could be transmitted to progeny at the time of fertilization. It is generally believed that geminiviruses do not affect their insect vectors. Nonetheless, the relationship between the whitefly Bemisia tabaci and an isolate of tomato yellow leaf curl geminivirus from Israel (TYLCV-Is) is reminiscent of an insect–pathogen relationship. This chapter presents and discusses some of the recent investigations on whether TYLCV is a sexually transmitted pathogen of B. tabaci.
    ISBN: 978-0-12-327681-0
    Source: ScienceDirect (Elsevier B.V.)
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