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Berlin Brandenburg

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  • Biology
  • ScienceDirect Journals (Elsevier)  (31)
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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: Antiviral Research, January 2013, Vol.97(1), pp.41-48
    Description: ► 22 Flavonoids were examined for activity against H5N1 influenza A viruses. ► Biochanin A and baicalein exerted the highest potency. ► Biochanin A and baicalein interfered with H5N1 replication. ► Biochanin A and baicalein interfered with virus-induced cytokine expression. ► Biochanin A and baicalein differ in their molecular antiviral mechanisms. From a panel of 22 flavonoids, we identified six compounds (apigenin, baicalein, biochanin A, kaempferol, luteolin, naringenin) that inhibited influenza A nucleoprotein production in human lung epithelial (A549) cells infected with the highly pathogenic avian influenza H5N1 virus strain A/Thailand/Kan-1/04 in non-toxic concentrations. Baicalein ( : 18.79 ± 1.17 μM, selectivity index 5.82) and biochanin A ( 8.92 ± 1.87 μM, selectivity index 5.60) were selected for further experiments. Both compounds reduced H5N1 infectious titres (baicalein 40 μM: 29-fold reduction, biochanin A 40 μM: 55-fold reduction after infection at MOI 0.01), virus-induced caspase 3 cleavage, nuclear export of viral RNP complexes, and enhanced the effects of the neuraminidase inhibitor zanamivir. Biochanin A and baicalein also inhibited the replication of the H5N1 strain A/Vietnam/1203/04. Time of addition experiments indicated that both compounds interfere with H5N1 replication after the adsorption period. Further mechanistic investigations revealed clear differences between these two flavonoids. Only baicalein interfered with the viral neuraminidase activity (39 ± 7% inhibition at 100 μM, the maximum concentration tested). In contrast to baicalein, biochanin A affected cellular signalling pathways resulting in reduced virus-induced activation of AKT, ERK 1/2, and NF-kB. Moreover, biochanin A inhibited the virus-induced production of IL-6, IL-8, and IP-10 while baicalein inhibited IL-6 and IL-8 production without affecting IP-10 levels. In primary human monocyte-derived macrophages, only baicalein but not biochanin A impaired H5N1 virus replication. Both flavonoids interfered with the H5N1-induced production of IL-6, IP-10, and TNF-α but not of IL-8 in macrophages. These findings indicate that closely related flavonoids can exert anti-H5N1 effects by different molecular mechanisms.
    Keywords: H5n1 ; Biochanin A ; Baicalein ; Antiviral ; Anti-Inflammatory ; Flavonoid ; Medicine ; Biology
    ISSN: 0166-3542
    E-ISSN: 1872-9096
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  • 3
    Language: English
    In: Biochemical and Biophysical Research Communications, 2006, Vol.339(1), pp.375-379
    Description: The measurement of natural killer (NK) cells toxicity against tumor or virus-infected cells especially in cases with small blood samples requires highly sensitive methods. Here, a coupled luminescent method (CLM) based on glyceraldehyde-3-phosphate dehydrogenase release from injured target cells was used to evaluate the cytotoxicity of interleukin-2 activated NK cells against neuroblastoma cell lines. In contrast to most other methods, CLM does not require the pretreatment of target cells with labeling substances which could be toxic or radioactive. The effective killing of tumor cells was achieved by low effector/target ratios ranging from 0.5:1 to 4:1. CLM provides highly sensitive, safe, and fast procedure for measurement of NK cell activity with small blood samples such as those obtained from pediatric patients.
    Keywords: Nk Cells ; Cytotoxicity ; Polio Virus Receptor ; Coupled Luminescent Method ; Neuroblastoma Cells ; Biology ; Chemistry ; Anatomy & Physiology
    ISSN: 0006-291X
    E-ISSN: 1090-2104
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  • 4
    Language: English
    In: FEBS Letters, 03 April 2007, Vol.581(7), pp.1317-1322
    Description: Treatment of transformed cells from leukemia or solid tumors with histone deacetylase inhibitors (HDACi) was shown to increase their sensitivity to NK cell lysis. In this study, treatment of IL-2-activated NK cells with HDACi including suberoylanilide hydroxamic acid and valproic acid was studied. Both drugs at therapeutic concentrations inhibited NK cell cytotoxicity on human leukemic cells. This inhibition was associated with decreased expression and function of NK cell activating receptors NKp46 and NKp30 as well as impaired granule exocytosis. NFκB activation in IL-2-activated NK cells was inhibited by both HDACi. Pharmacologic inhibition of NFκB activity resulted in similar effects on NK cell activity like those observed for HDACi. These results demonstrate for the first time that HDACi prevent NK cytotoxicity by downregulation of NK cell activating receptors probably through the inhibition of NFκB activation.
    Keywords: Cytotoxicity ; Nk Cells ; Histone Deacetylase Inhibitors ; Nk Cell Activating and Inhibitory Receptors ; Nuclear Factor Kappa B ; Biology ; Chemistry ; Anatomy & Physiology
    ISSN: 0014-5793
    E-ISSN: 1873-3468
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  • 5
    Language: English
    In: Immunobiology, 2011, Vol.216(3), pp.334-342
    Description: Posttrauma apoptosis resistance of neutrophils (PMN) is related to overshooting immune responses, systemic inflammatory response syndrome (SIRS) and multiple organ failure (MOF). Recently, we have shown that the apoptosis resistance in circulating PMN from severely injured patients which is known to be mediated by high serum levels of pro-inflammatory cytokines can be overcome by the activation of Fas death receptor. Here, we aimed to study whether stimulation of surface Fas leads to the inactivation of hyperactivated PMN from critically ill patients with SIRS. PMN from 23 multiple trauma patients (mean injury severity score (ISS) 34 ± 1.9) were isolated at day 1 after admission to the trauma center. PMN from 17 volunteer blood donors served as controls. Neutrophil activity has been determined after short (1 h) and long-term (4 h) stimulation of freshly isolated PMN with immobilized agonistic anti-Fas antibodies. We found neutrophil chemotactic migration in response to IL-8, phagocytosis and oxidative burst to be significantly inhibited in control cells already after short-term (1 h) Fas stimulation. In contrast, inactivation of trauma PMN by agonistic anti-Fas antibodies was found to be efficient only after long-term (4 h) incubation of cells with agonistic antibodies. Thus, in trauma PMN down-regulation of neutrophil activity seems to be delayed when compared to cells isolated from healthy controls, suggesting impaired susceptibility for Fas stimulation in these cells. Interestingly, whereas Fas-mediated inhibition of phagocytosis and oxidative burst could be prevented by the broad range caspase inhibitor t-butoxycarbonyl-aspartyl(O-methyl)-fluoromethyl ketone (BocD-fmk), the chemotactic activity in response to IL-8 was unaffected. In conclusion, we demonstrate that stimulation of neutrophil Fas does not only initiate apoptosis but also induces inhibition of neutrophil functions, partially by non-apoptotic signaling.
    Keywords: Caspases ; Chemotaxis ; Neutrophils ; Oxidative Burst ; Phagocytosis ; Sirs ; Biology
    ISSN: 0171-2985
    E-ISSN: 1878-3279
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  • 6
    Language: English
    In: Neoplasia, January 2009, Vol.11(1), pp.1-9
    Description: Although human cytomegalovirus (HCMV) is generally not regarded to be an oncogenic virus, HCMV infection has been implicated in malignant diseases from different cancer entities. On the basis of our experimental findings, we developed the concept of “oncomodulation” to better explain the role of HCMV in cancer. Oncomodulation means that HCMV infects tumor cells and increases their malignancy. By this concept, HCMV was proposed to be a therapeutic target in a fraction of cancer patients. However, the clinical relevance of HCMV-induced oncomodulation remains to be clarified. One central question that has to be definitively answered is if HCMV establishes persistent virus replication in tumor cells or not. In our eyes, recent clinical findings from different groups in glioblastoma patients and especially the detection of a correlation between the numbers of HCMV-infected glioblastoma cells and tumor stage (malignancy) strongly increase the evidence that HCMV may exert oncomodulatory effects. Here, we summarize the currently available knowledge about the molecular mechanisms that may contribute to oncomodulation by HCMV as well as the clinical findings that suggest that a fraction of tumors from different entities is indeed infected with HCMV.
    Keywords: Medicine
    ISSN: 1476-5586
    ISSN: 20452322
    E-ISSN: 1476-5586
    E-ISSN: 20452322
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  • 7
    Language: English
    In: Cell Reports, 05 June 2018, Vol.23(10), pp.3042-3055
    Description: Primary cilia are microtubule-based organelles that detect mechanical and chemical stimuli. Although cilia house a number of oncogenic molecules (including Smoothened, KRAS, EGFR, and PDGFR), their precise role in cancer remains unclear. We have interrogated the role of cilia in acquired and resistance to a variety of kinase inhibitors, and found that, in several examples, resistant cells are distinctly characterized by an increase in the number and/or length of cilia with altered structural features. Changes in ciliation seem to be linked to differences in the molecular composition of cilia and result in enhanced Hedgehog pathway activation. Notably, manipulating cilia length via Kif7 knockdown is sufficient to confer drug resistance in drug-sensitive cells. Conversely, targeting of cilia length or integrity through genetic and pharmacological approaches overcomes kinase inhibitor resistance. Our work establishes a role for ciliogenesis and cilia length in promoting cancer drug resistance and has significant translational implications. Jenks et al. demonstrate that enhanced ciliogenesis can facilitate resistance to a number of kinase inhibitors. Both acquired and resistant cells show increases in cilia numbers and length and increased Hedgehog signaling. Targeting ciliogenesis or ciliary signaling overcomes kinase inhibitor resistance.
    Keywords: Cilia ; Kinase Inhibitor ; Resistance ; Hedgehog Pathway ; Fgfr ; Biology
    ISSN: 2211-1247
    E-ISSN: 2211-1247
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  • 8
    Language: English
    In: International Journal for Parasitology, March 2018, Vol.48(3-4), pp.197-201
    Description: parasites are a major cause of diarrhoea that pose a particular threat to children in developing areas and immunocompromised individuals. Curative therapies and vaccines are lacking, mainly due to lack of a long-term culturing system of this parasite. Here, we show that COLO-680N cells infected with two different strains produce sufficient infectious oocysts to infect subsequent cultures, showing a substantial fold increase in production, depending on the experiment, over the most optimistic HCT-8 models. Oocyst identity was confirmed using a variety of microscopic- and molecular-based methods. This culturing system will accelerate research on and the development of anti- drugs.
    Keywords: Cryptosporidium ; Cell Culture ; Colo-680n ; Lipidomics ; Proteomics ; Atomic Force Microscopy ; Immunofluorescence Microscopy ; Electron Microscopy ; Biology ; Zoology
    ISSN: 0020-7519
    E-ISSN: 1879-0135
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  • 9
    Language: English
    In: Virology, 2007, Vol.362(1), pp.26-37
    Description: Infection with the SARS-associated coronavirus (SARS-CoV) induces an atypical pulmonary disease with a high lethality rate. Although the initial SARS epidemic was contained, sporadic outbreaks of the disease still occur, suggesting a continuous need for a vaccine against this virus. We therefore explored exosome-based vaccines containing the spike S proteins of SARS-CoV. S-containing exosomes were obtained by replacing the transmembrane and cytoplasmic domains of the S protein by those of VSV-G. The immunogenicity and efficacy of the S-containing exosomes were tested in mice and compared to an adenoviral vector vaccine expressing the S protein. Both, S-containing exosomes and the adenoviral vector vaccine induced neutralizing antibody titers. After priming with the SARS-S exosomal vaccine and boosting with the adenoviral vector the neutralizing antibody titers exceeded those observed in the convalescent serum of a SARS patient. Both approaches were effective in a SARS-S-expressing tumor challenge model and thus warrant further investigation.
    Keywords: Sars-Cov ; S Spike ; Vaccine ; Exosome ; Adenoviral Vector ; Biology
    ISSN: 0042-6822
    E-ISSN: 1096-0341
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  • 10
    Language: English
    In: Trends in Microbiology, 2003, Vol.11(4), pp.171-178
    Description: Human cytomegalovirus (HCMV) retinitis frequently occurs in severely naturally and iatrogenically immunocompromised patients. It has been shown that the immune-privileged retinal pigment epithelium (RPE) is a major site of persistent HCMV. Recently, evidence has accumulated to show that HCMV immediate early (IE) gene expression in RPE cells deviates ocular antiviral inflammation via FasL. Moreover, unlike in other cell types, the HCMV major IE1/2 enhancer promoter (MIEP) resists activation by proinflammatory stimuli mediated by the transcription factor NF- Kappa B. However, tumor necrosis factor- alpha (TNF- alpha ) and interferon- gamma (IFN- gamma ) found at elevated levels in transplant recipients and AIDS patients with retinitis sensitize RPE cells and other retinal cells to FasL-mediated apoptosis, thus contributing to retina destruction and necrosis rather than inflammation. These specific features of RPE cells in conjunction with deregulated immune responses of immunocompromised patients seem to contribute to virus persistence and pathogenesis within the immune-privileged ocular retina.
    Keywords: Biology
    ISSN: 0966-842X
    E-ISSN: 1878-4380
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