Kooperativer Bibliotheksverbund

Berlin Brandenburg

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  • 1
    Language: English
    In: Trends in Molecular Medicine, 2011, Vol.17(8), pp.433-441
    Description: Malignant gliomas (MGs) are deadly brain tumors with a median survival after resection, radiotherapy and chemotherapy of only 12 months. The natural immunosuppressive state of MG patients and the locally restricted growth of MGs render this neoplasm an excellent target for immunotherapy. Consequently, several failed attempts were made to treat MGs with immune cells. Recent preclinical experimental studies, however, demonstrate that natural killer (NK) cells can kill MGs and therefore hold promise in immunotherapy of MGs. This review describes the experimental and clinical evidence that support the potential of NK cells in therapy of MGs as well as the limitations to NK therapy. Finally, we propose strategies that could circumvent mitigating factors and enhance NK cell therapy for MG patients.
    Keywords: Medicine ; Biology
    ISSN: 1471-4914
    E-ISSN: 1471-499X
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  • 2
    Language: English
    In: Biochemical Pharmacology, 2011, Vol.81(2), pp.251-258
    Description: Enzastaurin is a selective protein kinase Cβ inhibitor which is shown to have direct antitumor effect as well as suppress glycogen synthase kinase-3β (GSK-3β) phosphorylation (resulting in its activation) in both tumor tissues and peripheral blood mononuclear cells (PBMC). It is currently used in phase II trials for the treatment of colon cancer, refractory glioblastoma and diffuse large B cell lymphoma. In this study, the direct effect of enzastaurin on effector function of human natural killer (NK) cells was investigated. The results obtained showed that enzastaurin suppressed both natural and antibody-dependent cellular cytotoxicity (ADCC) of NK cells against different tumor targets. This inhibition was associated with a specific down-regulation of surface expression of NK cell activating receptor NKG2D and CD16 involved in natural cytotoxicity and ADCC respectively, as well as the inhibition of perforin release. Analysis of signal transduction revealed that enzastaurin activated GSK-3β by inhibition of GSK-3β phosphorylation. Treatment of NK cells with GSK-3β-specific inhibitor TDZD-8 prevented enzastaurin-induced inhibition of NK cell cytotoxicity. Apart from the known antitumor and antiangiogenic effects, these results demonstrate that enzastaurin suppresses NK cell activity and may therefore interfere with NK cell-mediated tumor control in enzastaurin-treated cancer patients.
    Keywords: Antibody-Dependent Cellular Cytotoxicity ; Natural Cytotoxicity ; Nkg2d ; Protein Kinase Cβ ; Glycogen Synthase Kinase-3β ; Pharmacy, Therapeutics, & Pharmacology ; Chemistry
    ISSN: 0006-2952
    E-ISSN: 1873-2968
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  • 3
    Language: English
    In: PLoS ONE, 2011, Vol.6(11), p.e27390
    Description: Since the isolation of Helicobacter species in biliary system, a hypothetical question was raised about the role of these agents in the development of cholelithiasis. This meta-analysis is to explore the association between the Helicobacter infection and biliary lithiasis. ; A systematic literature search was performed to identify all eligible articles. Meta-analysis which was carried out using odds ratio and random effect model, 95% confidence intervals for odds ratio was calculated. Quantitative assessment of heterogeneity was explored by chi-square test with significance set at P value 0.10 and was measured using statistic. Eighteen studies published between 1998 and 2011 were finally eligible for meta-analysis. and were studied. With heterogeneity ( = 69.5%, P〈0.0001), significantly higher pooled infection rates of (OR: 2.59, 35.82% versus 26.75%, P = 0.01) and (OR: 3.13, 31.30% versus 12.12%, P = 0.02) were observed in lithiasis group. Higher prevalence of in cholelithiasis patients were reported by studies from East Asia, South Asia and South America. Evidences supporting the higher presence of in cholelithiasis patients could be found by PCR for detecting 16s rRNA in bile, 26kDa protein gene in biliary tissue and immunohistochemistry. Using multiple detection tests could increase the detection rate of . ; Our meta-analysis suggests a trend of higher presence of in cholelithiasis patients than control group and this trend was significant in the regions with higher prevalence of this agent. Evidences supporting the association between and cholelithiasis could be found by using different tests but the gold standard for the identification of these bacteria in biliary system has yet to be established. Considering obvious heterogeneity, a large multi-center study will facilitate us to further clarify the association between the infection and cholelithiasis.
    Keywords: Research Article ; Biology ; Medicine ; Infectious Diseases ; Microbiology ; Surgery ; Gastroenterology And Hepatology
    E-ISSN: 1932-6203
    Source: PLoS
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  • 4
    Language: English
    In: The Journal of biological chemistry, 25 March 2016, Vol.291(13), pp.6912-22
    Description: The activity of Rac in leukocytes is essential for immunity. However, its role in NK cell-mediated anti-microbial signaling remains unclear. In this study, we investigated the role of Rac in NK cell mediated anti-cryptococcal killing. We found thatCryptococcus neoformansindependently activates both Rac and SFK pathways in NK cells, and unlike in tumor killing,Cryptococcusinitiated a novel Rac → PI3K → Erk cytotoxicity cascade. Remarkably, Rac was not required for conjugate formation, despite its essential role in NK cytotoxicity againstC. neoformans Taken together, our data show that, unlike observations with tumor cells, NK cells use a novel Rac cytotoxicity pathway in conjunction with SFK, to killC. neoformans.
    Keywords: Cellular Signaling ; Cryptococcus ; Rac (Rac Gtpase) ; Src ; Adhesion ; Fungi ; Natural Killer Cells (Nk Cells) ; Phosphatidylinositide 3-Kinase (PI 3-Kinase) ; Cytotoxicity, Immunologic ; Class Ia Phosphatidylinositol 3-Kinase -- Immunology ; Cryptococcus Neoformans -- Physiology ; Killer Cells, Natural -- Immunology ; Rac Gtp-Binding Proteins -- Immunology ; Rac1 Gtp-Binding Protein -- Immunology ; Src-Family Kinases -- Immunology
    E-ISSN: 1083-351X
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  • 5
    Language: English
    In: Journal of immunology (Baltimore, Md. : 1950), 15 October 2018, Vol.201(8), pp.2369-2376
    Description: is a fungal pathogen that causes fatal meningitis and pneumonia. During host defense to , NK cells directly recognize and kill using cytolytic degranulation analogous to killing of tumor cells. This fungal killing requires independent activation of Src family kinase (SFK) and Rac1-mediated pathways. Recognition of requires the natural cytotoxicity receptor, NKp30; however, it is not known whether NKp30 activates both signal transduction pathways or whether a second receptor is involved in activation of one of the pathways. We used primary human NK cells and a human NK cell line and found that NKp30 activates SFK → PI3K but not Rac1 cytotoxic signaling, which led to a search for the receptor leading to Rac1 activation. We found that NK cells require integrin-linked kinase (ILK) to activate Rac1 for effective fungal killing. This observation led to our identification of β1 integrin as an essential anticryptococcal receptor. These findings demonstrate that multiple receptors, including β1 integrins and NKp30 and their proximal signaling pathways, are required for recognition of , which activates a central cytolytic antimicrobial pathway leading to fungal killing.
    Keywords: Cryptococcosis -- Immunology ; Cryptococcus Neoformans -- Physiology ; Integrin Beta1 -- Metabolism ; Killer Cells, Natural -- Immunology ; Rac1 Gtp-Binding Protein -- Metabolism
    ISSN: 00221767
    E-ISSN: 1550-6606
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  • 6
    In: PLoS ONE, 2011, Vol.6(11)
    Description: Background Since the isolation of Helicobacter species in biliary system, a hypothetical question was raised about the role of these agents in the development of cholelithiasis. This meta-analysis is to explore the association between the Helicobacter infection and biliary lithiasis. Methodology/Principal Findings A systematic literature search was performed to identify all eligible articles. Meta-analysis which was carried out using odds ratio and random effect model, 95% confidence intervals for odds ratio was calculated. Quantitative assessment of heterogeneity was explored by chi-square test with significance set at P value 0.10 and was measured using I 2 statistic. Eighteen studies published between 1998 and 2011 were finally eligible for meta-analysis. H. Pylori, H. Bilis, H. Hepaticus, H. Pullorum and H. Ganmani were studied. With heterogeneity ( I 2  = 69.5%, P〈0.0001), significantly higher pooled infection rates of H. Pylori (OR: 2.59, 35.82% versus 26.75%, P = 0.01) and H. Hepaticus (OR: 3.13, 31.30% versus 12.12%, P = 0.02) were observed in lithiasis group. Higher prevalence of H. Pylori in cholelithiasis patients were reported by studies from East Asia, South Asia and South America. Evidences supporting the higher presence of H. Pylori in cholelithiasis patients could be found by PCR for detecting 16s rRNA in bile, 26kDa protein gene in biliary tissue and immunohistochemistry. Using multiple detection tests could increase the detection rate of H. Pylori . Conclusions/Significances Our meta-analysis suggests a trend of higher presence of H. Pylori in cholelithiasis patients than control group and this trend was significant in the regions with higher prevalence of this agent. Evidences supporting the association between Helicobacter and cholelithiasis could be found by using different tests but the gold standard for the identification of these bacteria in biliary system has yet to be established. Considering obvious heterogeneity, a large multi-center study will facilitate us to further clarify the association between the Helicobacter infection and cholelithiasis.
    Keywords: Research Article ; Biology ; Medicine ; Infectious Diseases ; Microbiology ; Surgery ; Gastroenterology And Hepatology
    E-ISSN: 1932-6203
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  • 7
    Language: English
    In: Biochemical Pharmacology, 15 January 2010, Vol.79(2), pp.188-197
    Description: Ribavirin, a broad-spectrum anti-viral drug, exhibits immunomodulatory activities. To study direct effects of ribavirin on natural killer (NK) cell effector functions and signaling, resting NK cells and interleukin (IL)-15-activated NK cells were treated for 5 days with therapeutic ribavirin concentrations ranging from 5 μg/ml to 20 μg/ml. Both resting and IL-15-activated NK cells that were not treated with ribavirin were used as control. Cytotoxicity assays, flow cytometry, enzyme linked immunosorbent assays, and Western blot experiments were performed to elucidate ribavirin effect on NK cells. Results showed that ribavirin (not toxic at concentrations tested; IC 〉 80 μg/ml) had no influence on lysis of target cells by freshly isolated NK cells. Conversely, ribavirin dose-dependently inhibited lysis of target cells by up to 66% and impaired interferon gamma production when IL-15-activated NK cells were used. IL-15-induced increased expression and hence function of NK cell activating receptors including NKp30, NKp44, NKp46 and NKG2D were selectively down-regulated and impaired. These inhibitory effects were associated with the down-regulation of IL-15 receptor beta and gamma expression. Accordingly, downstream events involved in NK cell signaling via IL-15 receptors including the activation of Janus kinase (Jak)-1, signal transducer and activator of transcription STAT-1, STAT-3, and STAT-5 as well as pathways responsible for NK cell degranulation including extracellular signal-regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK) were impaired. These results reveal a novel mechanism by which ribavirin exerts its immunomodulatory activities.
    Keywords: Nk Cell Activating Receptors ; Nk Cell Signaling ; Nk Cell Degranulation ; Perforin and Granzyme B Release ; Il-15 Receptors ; Pharmacy, Therapeutics, & Pharmacology ; Chemistry
    ISSN: 0006-2952
    E-ISSN: 1873-2968
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  • 8
    Language: English
    In: Cancer Research, 04/15/2012, Vol.72(8 Supplement), pp.1558-1558
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 9
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(6), p.e66825
    Description: Myxoma virus (MYXV) is a well-established oncolytic agent against different types of tumors. MYXV is also known for its immunomodulatory properties in down-regulating major histocompatibility complex (MHC) I surface expression (via the M153R...
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 10
    Language: English
    In: Medical Microbiology and Immunology, 2010, Vol.199(2), pp.93-101
    Description: Tumor resistance to lysis by resting natural killer (NK) cells may be overcome by priming of NK cells with cytokines or by binding of NK activating receptors to ligands expressed on target cells. In this study, major histocompatibility complex class I (MHC-I)-negative LNCaP and MHC-I-positive DU145 cells were infected with genetically modified influenza A virus lacking the non-structural gene 1 (∆NS1 IAV). The cells were used to investigate the influence of ∆NS1 IAV infection on NK cell lysis of tumor cells as well as to prime NK cells for lysis of LNCaP and DU145 cells. While LNCaP cells infected with ΔNS1 IAV showed enhanced lysis when compared with mock-infected cells (93% ± 1.47 vs. 52% ± 0.74), both mock-infected and ΔNS1 IAV-infected DU145 cells were resistant to NK cell lysis. Moreover, NK cells primed with ΔNS1 IAV-infected LNCaP/DU145 cells effectively lysed resistant DU145 and sensitive LNCaP cells to a greater extent than NK cells primed with mock-infected LNCaP/DU145 or non-primed NK cells. Also, NK cell priming with ΔNS1 IAV-infected tumor cells enhanced extracellular signal-regulated kinase phosphorylation and increased granule release in NK cells. The increased granule release was specifically mediated by NKp46, which eventually potentiated NK cells primed with ΔNS1 IAV-infected tumor cells to overcome the inhibitory effects posed by MHC-I expression on DU145 cells. These findings show that in addition to direct lytic activity of NK cells, ΔNS1 IAV may influence anti-tumoral responses by priming NK cells.
    Keywords: Cytotoxicity ; NK cell priming ; Major histocompatibility complex class I ; Degranulation ; Oncolytic influenza A virus
    ISSN: 0300-8584
    E-ISSN: 1432-1831
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