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  • 1
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  GMS Current Posters in Otorhinolaryngology - Head and Neck Surgery; VOL: 11; DOC214 /20150416/
    Publication Date: 2015-04-17
    Description: Einleitung: Stimmprothesen sind als Hilfsmittel nach dem MPG zugelassen. Sie werden in eine ösophagotracheale Fistel eingesetzt und müssen Aspiration sicher verhindern. Die Zulassung neuer Prothesen in Deutschland erfolgte bisher ohne technisch-physikalische Prüfung, da keine DIN-Norm hierfür existierte. Die Folge waren ab Werk mangelhafte Stimmprothesen mit undichten oder schwergängigen Ventilen. Ein Schutz der Patienten vor billigen Plagiaten aus Niedriglohnländern bestand nicht.Methoden: Nach umfangreicher technischer Prüfung fabrikneuer Stimmprothesen in der Hochschule Esslingen wurde 2011 ein ausführlich begründeter Normierungsantrag für Stimmprothesen beim DIN gestellt und vom Arbeitsausschuss Medizinprodukte für das Atemwegssystem des DIN-Normenausschuss Rettungsdienst und Krankenhaus (NARK) bearbeitet. Ergebnis: Es entstanden zwei Normen für Stimmprothesen. Die DIN 13200-1 normiert Maßeinheiten und die Testverfahren zur Prüfung der Dichtigkeit des Ventils, des Ventilöffnungsdrucks sowie zur Messung der Durchfluss-Druckabfall-Kennlinie. Die DIN 13200-2 definiert die Anforderungen an Begleitinformationen, Beschriftung und Verpackung von Stimmprothesen. Schlussfolgerungen: Durch die DIN Normen 13200-1 und 13200-2 wird sicher gestellt, dass in Deutschland neu zugelassene Stimmprothesen qualitative Mindestanforderungen erfüllen. Das in Verkehr bringen billiger und qualitativ minderwertiger Plagiate ist deutlich erschwert. Die Normen bauen keine Hindernisse auf, sondern bieten eine physikalisch technische Basis für die weitere Entwicklung von Stimmprothesen. Die Normen DIN 13200-1 und 13200-2 wurden direkt in englischer Sprache formuliert um zeitnah auch die ISO Zertifizierung anzustreben.Der Erstautor gibt keinen Interessenkonflikt an.
    Keywords: ddc: 610
    Language: German
    Type: article
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  • 2
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  79. Jahresversammlung der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie; 20080430-20080504; Bonn; DOC08hnod295 /20080422/
    Publication Date: 2008-04-21
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 3
    Abstract: Smac mimetics antagonize IAP proteins, which are highly expressed in several cancers. Recent reports indicate that Smac mimetics trigger a broad cytokine response and synergize with immune modulators to induce cell death. Here, we identify a differential requirement of TRAIL or TNFalpha as mediators of IFNalpha/Smac mimetic-induced cell death depending on the cellular context. Subtoxic concentrations of Smac mimetics cooperate with IFNalpha to induce cell death in various solid tumor cell lines in a highly synergistic manner as determined by combination index. Mechanistic studies show that IFNalpha/BV6 cotreatment promotes the formation of a caspase-8-activating complex together with the adaptor protein FADD and RIP1. Assembly of this RIP1/FADD/caspase-8 complex represents a critical event, since RIP1 silencing inhibits IFNalpha/BV6-induced cell death. Strikingly, pharmacological inhibition of paracrine/autocrine TNFalpha signaling by the TNFalpha scavenger Enbrel rescues HT-29 colon carcinoma cells, but not A172 glioblastoma cells from IFNalpha/BV6-induced cell death. By comparison, A172 cells are significantly protected against IFNalpha/BV6 treatment by blockage of TRAIL signaling through genetic silencing of TRAIL or its cognate receptor TRAIL receptor 2 (DR5). Despite this differential requirement of TNFalpha and TRAIL signaling, mRNA and protein expression is increased by IFNalpha/BV6 cotreatment in both cell lines. Interestingly, A172 cells turn out to be resistant to exogenously added recombinant TNFalpha even in the presence of BV6, whereas they display a high sensitivity towards TRAIL/BV6. In contrast, BV6 efficiently sensitizes HT-29 cells to TNFalpha while TRAIL only had limited efficacy. This demonstrates that a differential sensitivity towards TRAIL or TNFalpha determines the dependency on either death receptor ligand for IFNalpha/Smac mimetic-induced cell death. Thus, by concomitant stimulation of both death receptor systems IFNalpha/Smac mimetic combination treatment is an effective strategy to induce cell death in TNFalpha- or TRAIL-responsive cancers.
    Type of Publication: Journal article published
    PubMed ID: 26788912
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  • 4
    Abstract: Necroptosis is a form of programmed cell death that critically depends on RIP3 and MLKL. However, the contribution of mitochondria to necroptosis is still poorly understood. In the present study, we discovered that mitochondrial perturbations play a critical role in Smac mimetic/Dexamethasone (Dexa)-induced necroptosis independently of death receptor ligands. We demonstrate that the Smac mimetic BV6 and Dexa cooperate to trigger necroptotic cell death in acute lymphoblastic leukemia (ALL) cells that are deficient in caspase activation due to absent caspase-8 expression or pharmacological inhibition by the caspase inhibitor zVAD.fmk, since genetic silencing or pharmacological inhibition of RIP3 or MLKL significantly rescue BV6/Dexa-induced necroptosis. In addition, RIP3 or MLKL knockout mouse embryonic fibroblasts (MEFs) are protected from BV6/Dexa/zVAD.fmk-induced cell death. In contrast, antagonistic antibodies against the death receptor ligands TNFalpha, TRAIL or CD95 ligand fail to rescue BV6/Dexa-triggered cell death. Kinetic studies revealed that prior to cell death BV6/Dexa treatment causes hyperpolarization of the mitochondrial membrane potential (MMP) followed by loss of MMP, reactive oxygen species (ROS) production, Bak activation and disruption of mitochondrial respiration. Importantly, knockdown of Bak significantly reduces BV6/Dexa-induced loss of MMP and delays cell death, but not ROS production, whereas ROS scavengers attenuate Bak activation, indicating that ROS production occurs upstream of BV6/Dexa-mediated Bak activation. Consistently, BV6/Dexa treatment causes oxidative thiol modifications of Bak protein. Intriguingly, knockdown or knockout of RIP3 or MLKL protect ALL cells or MEFs from BV6/Dexa-induced ROS production, Bak activation, drop of MMP and disruption of mitochondrial respiration, demonstrating that these mitochondrial events depend on RIP3 and MLKL. Thus, mitochondria might serve as an amplification step in BV6/Dexa-induced necroptosis. These findings provide new insights into the role of mitochondrial dysfunctions during necroptosis and have important implications for the development of novel treatment approaches to overcome apoptosis resistance in ALL.
    Type of Publication: Journal article published
    PubMed ID: 27834956
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  • 5
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  44. Jahrestagung der Deutschen Gesellschaft der Plastischen, Rekonstruktiven und Ästhetischen Chirurgen (DGPRÄC), 17. Jahrestagung der Vereinigung der Deutschen Ästhetisch-Plastischen Chirurgen (VDÄPC); 20130912-20130914; Münster; DOCP 35 /20130910/
    Publication Date: 2013-09-11
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 6
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  130. Kongress der Deutschen Gesellschaft für Chirurgie; 20130430-20130503; München; DOC13dgch627 /20130426/
    Publication Date: 2013-04-27
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 7
    Abstract: Therapeutic targeting of inhibitor of apoptosis (IAP) proteins by small-molecule inhibitors such as Smac mimetic is considered as a promising anticancer strategy to elicit apoptosis. Recent advances have renewed the interest in exploiting the antileukemic activity of interferon (IFN)alpha for the treatment of acute myeloid leukemia (AML). Here, we identify a novel synergistic interaction of the Smac mimetic BV6 and IFNalpha to trigger cell death in AML cells. Calculation of combination index (CI) confirms the synergism of BV6 and IFNalpha. In contrast to AML cells, no synergistic toxicity of BV6 and IFNalpha at equimolar concentrations is found against normal peripheral blood lymphocytes. BV6 and IFNalpha act in concert to stimulate expression of tumor necrosis factor (TNF)alpha and its secretion into the supernatant, thereby initiating an autocrine/paracrine TNFalpha/TNF receptor 1 (TNFR1) loop that drives cell death by BV6 and IFNalpha. Consistently, pharmacological inhibition of TNFalpha by the TNFalpha-blocking antibody Enbrel or genetic silencing of TNFR1 significantly reduces BV6/IFNalpha-induced cell death. In addition, BV6/IFNalpha-induced cell death depends on interferon regulatory factor (IRF)1, since RNA interference-imposed knockdown of IRF1 significantly rescues cell death. In conclusion, the identification of a novel synergistic antileukemic combination of Smac mimetic and IFNalpha has important implications for the development of innovative treatment strategies in AML.
    Type of Publication: Journal article published
    PubMed ID: 25179908
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  • 8
    Abstract: Rhabdomyosarcoma (RMS), the most common cancer of connective tissues in pediatrics, is often resistant to conventional therapies. One underlying mechanism of this resistance is the overexpression of Inhibitor of Apoptosis (IAP) proteins, leading to a dysfunctional cell death program within tumor cells. Smac mimetics (SM) are small molecules that can reactivate the cell death program by antagonizing IAP proteins and thereby compensating their overexpression. Here, we report that SM sensitize two RMS cell lines (RD and RH30) toward natural killer (NK) cell-mediated killing on the one hand, and increase the cytotoxic potential of NK cells on the other. The SM-induced sensitization of RH30 cells toward NK cell-mediated killing is significantly reduced through blocking tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on NK cells prior to coculture. In addition, the presence of zVAD.fmk, a pancaspase inhibitor, rescues tumor cells from the increase in killing, indicating an apoptosis-dependent cell death. On the NK cell side, the presence of SM in addition to IL-2 during the ex vivo expansion leads to an increase in their cytotoxic activity against RH30 cells. This effect is mainly TNFalpha-dependent and partially mediated by NK cell activation, which is associated with transcriptional upregulation of NF-kappaB target genes such as IkappaBalpha and RelB. Taken together, our findings implicate that SM represent a novel double-hit strategy, sensitizing tumor and activating NK cells with one single drug.
    Type of Publication: Journal article published
    PubMed ID: 28326081
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  • 9
    Abstract: Since cancer cells often evade apoptosis, induction of necroptosis as another mode of programmed cell death is considered a promising therapeutic alternative. Here, we identify a novel synergistic interaction of Smac mimetics that antagonize x-linked Inhibitor of Apoptosis (XIAP), cellular Inhibitor of Apoptosis (cIAP) 1 and 2 with interferon (IFN)gamma to induce necroptosis in apoptosis-resistant cancer cells in which caspase activation is blocked. This synergism is confirmed by calculation of combination indices (CIs) and found in both solid and hematological cancer cell lines as well as for different Smac mimetics (i.e. BV6, Birinapant), pointing to a broader relevance. Importantly, individual genetic knockdown of key components of necroptosis signaling, i.e. receptor-interacting protein (RIP) 1, RIP3 or mixed lineage kinase domain-like pseudokinase (MLKL), significantly protects from BV6/IFNgamma-induced cell death. Similarly, pharmacological inhibitors of RIP1 (necrostatin-1(Nec-1)), RIP3 (GSK'872) or MLKL (necrosulfonamide (NSA)) significantly reduce BV6/IFNgamma-stimulated cell death. Of note, IFN-regulatory factor (IRF)1 is required for BV6/IFNgamma-mediated necroptosis, as IRF1 silencing provides protection from cell death. By comparison, antibodies blocking tumor necrosis factor (TNF)alpha, TNF-related apoptosis-inducing ligand (TRAIL) or CD95 ligand fail to inhibit BV6/IFNgamma-induced cell death, pointing to a mechanism independently of death receptor ligands. This is the first report showing that Smac mimetics synergize with IFNgamma to trigger necroptosis in apoptosis-resistant cancer cells with important implications for Smac mimetic-based strategies for the treatment of cancer.
    Type of Publication: Journal article published
    PubMed ID: 28923396
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  • 10
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  86. Jahresversammlung der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie; 20150513-20150516; Berlin; DOC15hnod032 /20150326/
    Publication Date: 2015-03-27
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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