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  • 1
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    A DNMT3A mutation common in AML exhibits dominant-negative effects in murine ES cells (2013)
    American Society of Hematology (ASH)
    In: Blood
    Details
    Publikationsdatum: 2013-12-13
    Beschreibung: Somatic heterozygous mutations of the DNA methyltransferase gene DNMT3A occur frequently in acute myeloid leukemia and other hematological malignancies, with the majority (~60%) of mutations affecting a single amino acid, Arg882 (R882), in the catalytic domain. Although the mutations impair DNMT3A catalytic activity in vitro, their effects on DNA methylation in cells have not been explored. Here, we show that exogenously expressed mouse Dnmt3a proteins harboring the corresponding R878 mutations largely fail to mediate DNA methylation in murine embryonic stem (ES) cells but are capable of interacting with wild-type Dnmt3a and Dnmt3b. Coexpression of the Dnmt3a R878H (histidine) mutant protein results in inhibition of the ability of wild-type Dnmt3a and Dnmt3b to methylate DNA in murine ES cells. Furthermore, expression of Dnmt3a R878H in ES cells containing endogenous Dnmt3a or Dnmt3b induces hypomethylation. These results suggest that the DNMT3A R882 mutations, in addition to being hypomorphic, have dominant-negative effects.
    Schlagwort(e): Myeloid Neoplasia, Brief Reports
    Print ISSN: 0006-4971
    Digitale ISSN: 1528-0020
    Thema: Biologie , Medizin
    Publiziert von American Society of Hematology (ASH)
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
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    Intraocular involvement of mycosis fungoides associated with immunophenotypic switch from CD4+ to CD8+ (2018)
    American Society of Hematology (ASH)
    In: Blood
    Details
    Publikationsdatum: 2018-02-23
    Schlagwort(e): Lymphoid Neoplasia
    Print ISSN: 0006-4971
    Digitale ISSN: 1528-0020
    Thema: Biologie , Medizin
    Publiziert von American Society of Hematology (ASH)
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
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    SMILE for natural killer/T-cell lymphoma: analysis of safety and efficacy from the Asia Lymphoma Study Group (2012)
    American Society of Hematology (ASH)
    In: Blood
    Details
    Publikationsdatum: 2012-10-12
    Beschreibung: Natural killer/T-cell lymphoma is rare and aggressive, with poor outcome. Optimal treatment remains unclear. A novel regimen dexamethasone, methotrexate, ifosfamide, l -asparaginase, and etoposide (SMILE) showed promise in phase 1/2 studies with restrictive recruitment criteria. To define the general applicability of SMILE, 43 newly diagnosed and 44 relapsed/refractory patients (nasal, N = 60, nonnasal, N = 21; disseminated, N = 6; male, N = 59; female, N = 28) at a median age of 51 years (23-83 years) were treated. Poor-risk factors included stage III/IV disease (56%), international prognostic index of 3 to 5 (43%), and Korean prognostic scores of 3 to 4 (41%). A median of 3 (0-6; total = 315) courses of SMILE were administered. Significant toxicities included grade 3/4 neutropenia (N = 57; 5 sepsis-related deaths); grade 3/4 thrombocytopenia (N = 36); and nephrotoxicity (N = 15; 1 acute renal failure and death). Interim analysis after 2 to 3 cycles showed complete remission rate of 56%, partial remission rate of 22%, giving an overall response rate of 78%. On treatment completion, the overall-response rate became 81% (complete remission = 66%, partial remission = 15%). Response rates were similar for newly diagnosed or relapsed/refractory patients. At a median follow-up of 31 months (1-84 months), the 5-year overall survival was 50% and 4-year disease-free-survival was 64%. Multivariate analysis showed that international prognostic index was the most significant factor impacting on outcome and survivals.
    Schlagwort(e): Free Research Articles, Lymphoid Neoplasia, Clinical Trials and Observations
    Print ISSN: 0006-4971
    Digitale ISSN: 1528-0020
    Thema: Biologie , Medizin
    Publiziert von American Society of Hematology (ASH)
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 4
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    The Novel Role of IL-7 Ligation to IL-7 Receptor in Myeloid Cells of Rheumatoid Arthritis and Collagen-Induced Arthritis [INNATE IMMUNITY AND INFLAMMATION] (2013)
    The American Association of Immunologists (AAI)
    Details
    Publikationsdatum: 2013-05-04
    Beschreibung: Although the role of IL-7 and IL-7R has been implicated in the pathogenesis of rheumatoid arthritis (RA), the majority of the studies have focused on the effect of IL-7/IL-7R in T cell development and function. Our novel data, however, document that patients with RA and greater disease activity have higher levels of IL-7, IL-7R, and TNF-α in RA monocytes, suggesting a feedback regulation between IL-7/IL-7R and TNF-α cascades in myeloid cells that is linked to chronic disease progression. Investigations into the involved mechanism showed that IL-7 is a novel and potent chemoattractant that attracts IL-7R + monocytes through activation of the PI3K/AKT1 and ERK pathways at similar concentrations of IL-7 detected in RA synovial fluid. To determine whether ligation of IL-7 to IL-7R is a potential target for RA treatment and to identify their mechanism of action, collagen-induced arthritis (CIA) was therapeutically treated with anti–IL-7 Ab or IgG control. Anti–IL-7 Ab treatment significantly reduces CIA monocyte recruitment and osteoclast differentiation as well as potent joint monocyte chemoattractants and bone erosion markers, suggesting that both direct and indirect pathways might contribute to the observed effect. We also demonstrate that reduction in joint MIP-2 levels is responsible for suppressed vascularization detected in mice treated with anti–IL-7 Ab compared with the control group. To our knowledge, we show for the first time that expression of IL-7/IL-7R in myeloid cells is strongly correlated with RA disease activity and that ligation of IL-7 to IL-7R contributes to monocyte homing, differentiation of osteoclasts, and vascularization in the CIA effector phase.
    Print ISSN: 0022-1767
    Digitale ISSN: 1550-6606
    Thema: Medizin
    Publiziert von The American Association of Immunologists (AAI)
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 5
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    Ligation of TLR5 Promotes Myeloid Cell Infiltration and Differentiation into Mature Osteoclasts in Rheumatoid Arthritis and Experimental Arthritis [CLINICAL AND HUMAN IMMUNOLOGY] (2014)
    The American Association of Immunologists (AAI)
    Details
    Publikationsdatum: 2014-10-04
    Beschreibung: Our aim was to examine the impact of TLR5 ligation in rheumatoid arthritis (RA) and experimental arthritis pathology. Studies were conducted to investigate the role of TLR5 ligation on RA and mouse myeloid cell chemotaxis or osteoclast formation, and in addition, to uncover the significance of TNF-α function in TLR5-mediated pathogenesis. Next, the in vivo mechanism of action was determined in collagen-induced arthritis (CIA) and local joint TLR5 ligation models. Last, to evaluate the importance of TLR5 function in RA, we used anti-TLR5 Ab therapy in CIA mice. We show that TLR5 agonist, flagellin, can promote monocyte infiltration and osteoclast maturation directly through myeloid TLR5 ligation and indirectly via TNF-α production from RA and mouse cells. These two identified TLR5 functions are potentiated by TNF-α, because inhibition of both pathways can more strongly impair RA synovial fluid–driven monocyte migration and osteoclast differentiation compared with each factor alone. In preclinical studies, flagellin postonset treatment in CIA and local TLR5 ligation in vivo provoke homing and osteoclastic development of myeloid cells, which are associated with the TNF-α cascade. Conversely, CIA joint inflammation and bone erosion are alleviated when TLR5 function is blocked. We found that TLR5 and TNF-α pathways are interconnected, because TNF-α is produced by TLR5 ligation in RA myeloid cells, and anti–TNF-α therapy can markedly suppress TLR5 expression in RA monocytes. Our novel findings demonstrate that a direct and an indirect mechanism are involved in TLR5-driven RA inflammation and bone destruction.
    Print ISSN: 0022-1767
    Digitale ISSN: 1550-6606
    Thema: Medizin
    Publiziert von The American Association of Immunologists (AAI)
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 6
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    HIF-1{alpha}-Mediated Upregulation of TASK-2 K+ Channels Augments Ca2+ Signaling in Mouse B Cells under Hypoxia [IMMUNE REGULATION] (2014)
    The American Association of Immunologists (AAI)
    Details
    Publikationsdatum: 2014-11-08
    Beschreibung: The general consensus is that immune cells are exposed to physiological hypoxia in vivo (PhyO 2 , 2–5% P O2 ). However, functional studies of B cells in hypoxic conditions are sparse. Recently, we reported the expression in mouse B cells of TASK-2, a member of pH-sensitive two-pore domain K + channels with background activity. In this study, we investigated the response of K + channels to sustained PhyO 2 (sustained hypoxia [SH], 3% P O2 for 24 h) in WEHI-231 mouse B cells. SH induced voltage-independent background K + conductance (SH-K bg ) and hyperpolarized the membrane potential. The pH sensitivity and the single-channel conductance of SH-K bg were consistent with those of TASK-2. Immunoblotting assay results showed that SH significantly increased plasma membrane expressions of TASK-2. Conversely, SH failed to induce any current following small interfering (si)TASK-2 transfection. Similar hypoxic upregulation of TASK-2 was also observed in splenic primary B cells. Mechanistically, upregulation of TASK-2 by SH was prevented by si hypoxia-inducible factor-1α (HIF-1α) transfection or by YC-1, a pharmacological HIF-1α inhibitor. In addition, TASK-2 current was increased in WEHI-231 cells overexpressed with O 2 -resistant HIF-1α. Importantly, [Ca 2+ ] c increment in response to BCR stimulation was significantly higher in SH-exposed B cells, which was abolished by high K + -induced depolarization or by siTASK-2 transfection. The data demonstrate that TASK-2 is upregulated under hypoxia via HIF-1α–dependent manner in B cells. This is functionally important in maintaining the negative membrane potential and providing electrical driving force to control Ca 2+ influx.
    Print ISSN: 0022-1767
    Digitale ISSN: 1550-6606
    Thema: Medizin
    Publiziert von The American Association of Immunologists (AAI)
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 7
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    Rise and Fall of Kir2.2 Current by TLR4 Signaling in Human Monocytes: PKC-Dependent Trafficking and PI3K-Mediated PIP2 Decrease [INNATE IMMUNITY AND INFLAMMATION] (2015)
    The American Association of Immunologists (AAI)
    Details
    Publikationsdatum: 2015-09-19
    Beschreibung: LPSs are widely used to stimulate TLR4, but their effects on ion channels in immune cells are poorly known. In THP-1 cells and human blood monocytes treated with LPS, inwardly rectifying K + channel current (I Kir,LPS ) newly emerged at 1 h, peaked at 4 h (–119 ± 8.6 pA/pF), and decayed afterward (–32 ± 6.7 pA/pF at 24 h). Whereas both the Kir2.1 and Kir2.2 mRNAs and proteins were observed, single-channel conductance (38 pS) of I Kir,LPS and small interfering RNA–induced knockdown commonly indicated Kir2.2 than Kir2.1. LPS-induced cytokine release and store-operated Ca 2+ entry were commonly decreased by ML-133, a Kir2 inhibitor. Immunoblot, confocal microscopy, and the effects of vesicular trafficking inhibitors commonly suggested plasma membrane translocation of Kir2.2 by LPS. Both I Kir,LPS and membrane translocation of Kir2.2 were inhibited by GF109203X (protein kinase C [PKC] inhibitor) or by transfection with small interfering RNA–specific PKC. Interestingly, pharmacological activation of PKC by PMA induced both Kir2.1 and Kir2.2 currents. The spontaneously decayed I Kir,LPS at 24 h was recovered by PI3K inhibitors but further suppressed by an inhibitor of phosphatidylinositol(3,4,5)-trisphosphate (PIP 3 ) phosphatase (phosphatase and tensin homolog). However, I Kir,LPS at 24 h was not affected by Akt inhibitors, suggesting that the decreased phosphatidylinositol(4,5)-bisphosphate availability, that is, conversion into PIP 3 by PI3K, per se accounts for the decay of I Kir,LPS . Taken together, to our knowledge these data are the first demonstrations that I Kir is newly induced by TLR4 stimulation via PKC-dependent membrane trafficking of Kir2.2, and that conversion of phosphatidylinositol(4,5)-bisphosphate to PIP 3 modulates Kir2.2. The augmentation of Ca 2+ influx and cytokine release suggests a physiological role for Kir2.2 in TLR4-stimulated monocytes.
    Print ISSN: 0022-1767
    Digitale ISSN: 1550-6606
    Thema: Medizin
    Publiziert von The American Association of Immunologists (AAI)
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 8
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    Platelets and neutrophil extracellular traps collaborate to promote intravascular coagulation during sepsis in mice (2017)
    American Society of Hematology (ASH)
    In: Blood
    Details
    Publikationsdatum: 2017-03-10
    Beschreibung: Neutrophil extracellular traps (NETs; webs of DNA coated in antimicrobial proteins) are released into the vasculature during sepsis where they contribute to host defense, but also cause tissue damage and organ dysfunction. Various components of NETs have also been implicated as activators of coagulation. Using multicolor confocal intravital microscopy in mouse models of sepsis, we observed profound platelet aggregation, thrombin activation, and fibrin clot formation within (and downstream of) NETs in vivo. NETs were critical for the development of sepsis-induced intravascular coagulation regardless of the inciting bacterial stimulus (gram-negative, gram-positive, or bacterial products). Removal of NETs via DNase infusion, or in peptidylarginine deiminase-4–deficient mice (which have impaired NET production), resulted in significantly lower quantities of intravascular thrombin activity, reduced platelet aggregation, and improved microvascular perfusion. NET-induced intravascular coagulation was dependent on a collaborative interaction between histone H4 in NETs, platelets, and the release of inorganic polyphosphate. Real-time perfusion imaging revealed markedly improved microvascular perfusion in response to the blockade of NET-induced coagulation, which correlated with reduced markers of systemic intravascular coagulation and end-organ damage in septic mice. Together, these data demonstrate, for the first time in an in vivo model of infection, a dynamic NET–platelet–thrombin axis that promotes intravascular coagulation and microvascular dysfunction in sepsis.
    Schlagwort(e): Phagocytes, Granulocytes, and Myelopoiesis, Platelets and Thrombopoiesis, Thrombosis and Hemostasis
    Print ISSN: 0006-4971
    Digitale ISSN: 1528-0020
    Thema: Biologie , Medizin
    Publiziert von American Society of Hematology (ASH)
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 9
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    PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing L-asparaginase (2017)
    American Society of Hematology (ASH)
    In: Blood
    Details
    Publikationsdatum: 2017-04-28
    Beschreibung: Natural killer (NK)/T-cell lymphomas failing L-asparaginse regimens have no known salvage and are almost invariably fatal. Seven male patients with NK/T-cell lymphoma (median age, 49 years; range, 31-68 years) for whom a median of 2 (range, 1-5) regimens (including l -asparaginase regimens and allogeneic hematopoietic stem-cell transplantation [HSCT] in 2 cases) failed were treated with the anti–programmed death 1 (PD1) antibody pembrolizumab. All patients responded, according to various clinical, radiologic (positron emission tomography), morphologic, and molecular (circulating Epstein-Barr virus [EBV] DNA) criteria. Two patients achieved complete response (CR) in all parameters. Three patients achieved clinical and radiologic CRs, with two having molecular remission (undetectable EBV DNA) but minimal EBV-encoded RNA-positive cells in lesions comprising predominantly CD3 + CD4 + and CD3 + CD8 + T cells (which ultimately disappeared, suggesting they represented pseudoprogression) and one having detectable EBV DNA despite morphologic CR. Two patients achieved partial response (PR). After a median of 7 (range, 2-13) cycles of pembrolizumab and a follow-up of a median of 6 (range, 2-10) months, all five CR patients were still in remission. The only adverse event was grade 2 skin graft-versus-host disease in one patient with previous allogeneic HSCT. Expression of the PD1 ligand was strong in 4 patients (3 achieving CR) and weak in 1 (achieving PR). PD1 blockade with pembrolizumab was a potent strategy for NK/T-cell lymphomas failing l -asparaginase regimens.
    Schlagwort(e): Immunobiology, Free Research Articles, Lymphoid Neoplasia, Brief Reports, Clinical Trials and Observations
    Print ISSN: 0006-4971
    Digitale ISSN: 1528-0020
    Thema: Biologie , Medizin
    Publiziert von American Society of Hematology (ASH)
    Standort Signatur Einschränkungen Verfügbarkeit
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    PAPER CURRENT
  • 10
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    mTOR- and SGK-Mediated Connexin 43 Expression Participates in Lipopolysaccharide-Stimulated Macrophage Migration through the iNOS/Src/FAK Axis [INFECTIOUS DISEASE AND HOST RESPONSE] (2018)
    The American Association of Immunologists (AAI)
    Details
    Publikationsdatum: 2018-11-06
    Beschreibung: Connexin 43 (Cx43) deficiency was found to increase mortality in a mouse model of bacterial peritonitis, and Cx43 is upregulated in macrophages by LPS treatment. In this study, we characterized a novel signaling pathway for LPS-induced Cx43 expression in RAW264.7 cells and thioglycolate-elicited peritoneal macrophages (TGEMs). LPS alone or LPS-containing conditioned medium (CM) upregulated Cx43. Overexpression or silencing of Cx43 led to the enhancement or inhibition, respectively, of CM-induced TGEM migration. This response involved the inducible NO synthase (iNOS)/focal adhesion kinase (FAK)/Src pathways. Moreover, CM-induced migration was compromised in TGEMs from Cx43 +/– mice compared with TGEMs from Cx43 +/+ littermates. Cx43 was upregulated by a serum/glucocorticoid-regulated kinase 1 (SGK) activator and downregulated, along with inhibition of CM-induced TGEM migration, by knockdown of the SGK gene or blockade of the SGK pathway. LPS-induced SGK activation was abrogated by Torin2, whereas LPS-induced Cx43 was downregulated by both Torin2 and rapamycin. Analysis of the effects of FK506 and methylprednisolone, common immunosuppressive agents following organ transplantation, suggested a link between these immunosuppressive drugs and impaired macrophage migration via the Cx43/iNOS/Src/FAK pathway. In a model of Escherichia coli infectious peritonitis, GSK650349-, an SGK inhibitor, or Torin2-treated mice showed less accumulation of F4/80 + CD11b + macrophages in the peritoneal cavity, with a delay in the elimination of bacteria. Furthermore, following pretreatment with Gap19, a selective Cx43 hemichannel blocker, the survival of model mice was significantly reduced. Taken together, our study suggested that Cx43 in macrophages was associated with macrophage migration, an important immune process in host defense to infection.
    Print ISSN: 0022-1767
    Digitale ISSN: 1550-6606
    Thema: Medizin
    Publiziert von The American Association of Immunologists (AAI)
    Standort Signatur Einschränkungen Verfügbarkeit
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