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  • 1
    Publication Date: 2018-04-28
    Description: Middle East respiratory syndrome coronavirus (MERS-CoV) causes a highly lethal pulmonary infection with ~35% mortality. The potential for a future pandemic originating from animal reservoirs or health care-associated events is a major public health concern. There are no vaccines or therapeutic agents currently available for MERS-CoV. Using a probe-based single B cell cloning strategy, we have identified and characterized multiple neutralizing monoclonal antibodies (MAbs) specifically binding to the receptor-binding domain (RBD) or S1 (non-RBD) regions from a convalescent MERS-CoV-infected patient and from immunized rhesus macaques. RBD-specific MAbs tended to have greater neutralizing potency than non-RBD S1-specific MAbs. Six RBD-specific and five S1-specific MAbs could be sorted into four RBD and three non-RBD distinct binding patterns, based on competition assays, mapping neutralization escape variants, and structural analysis. We determined cocrystal structures for two MAbs targeting the RBD from different angles and show they can bind the RBD only in the "out" position. We then showed that selected RBD-specific, non-RBD S1-specific, and S2-specific MAbs given prophylactically prevented MERS-CoV replication in lungs and protected mice from lethal challenge. Importantly, combining RBD- and non-RBD MAbs delayed the emergence of escape mutations in a cell-based virus escape assay. These studies identify MAbs targeting different antigenic sites on S that will be useful for defining mechanisms of MERS-CoV neutralization and for developing more effective interventions to prevent or treat MERS-CoV infections. IMPORTANCE MERS-CoV causes a highly lethal respiratory infection for which no vaccines or antiviral therapeutic options are currently available. Based on continuing exposure from established reservoirs in dromedary camels and bats, transmission of MERS-CoV into humans and future outbreaks are expected. Using structurally defined probes for the MERS-CoV spike glycoprotein (S), the target for neutralizing antibodies, single B cells were sorted from a convalescent human and immunized nonhuman primates (NHPs). MAbs produced from paired immunoglobulin gene sequences were mapped to multiple epitopes within and outside the receptor-binding domain (RBD) and protected against lethal MERS infection in a murine model following passive immunization. Importantly, combining MAbs targeting distinct epitopes prevented viral neutralization escape from RBD-directed MAbs. These data suggest that antibody responses to multiple domains on CoV spike protein may improve immunity and will guide future vaccine and therapeutic development efforts.
    Print ISSN: 0022-538X
    Electronic ISSN: 1098-5514
    Topics: Medicine
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  • 2
    Publication Date: 2018-05-16
    Description: Purpose: One third of ER-positive breast cancer patients who initially respond to endocrine therapy become resistant to treatment. Such treatment failure is associated with poor prognosis and remains an area of unmet clinical need. Here, we identify a specific posttranslational modification that occurs during endocrine resistance and which results in tumor susceptibility to the apoptosis-inducer TRAIL. This potentially offers a novel stratified approach to targeting endocrine-resistant breast cancer. Experimental Design: Cell line and primary-derived xenograft models of endocrine resistance were investigated for susceptibility to TRAIL. Tumor viability, cancer stem cell (CSC) viability (tumorspheres), tumor growth kinetics, and metastatic burden were assessed. Western blots for the TRAIL-pathway inhibitor, c-FLIP, and upstream regulators were performed. Results were confirmed in primary culture of 26 endocrine-resistant and endocrine-naïve breast tumors. Results: Breast cancer cell lines with acquired resistance to tamoxifen (TAMR) or faslodex were more sensitive to TRAIL than their endocrine-sensitive controls. Moreover, TRAIL eliminated CSC-like activity in TAMR cells, resulting in prolonged remission of xenografts in vivo . In primary culture, TRAIL significantly depleted CSCs in 85% endocrine-resistant, compared with 8% endocrine-naïve, tumors, whereas systemic administration of TRAIL in endocrine-resistant patient-derived xenografts reduced tumor growth, CSC-like activity, and metastases. Acquired TRAIL sensitivity correlated with a reduction in intracellular levels of c-FLIP, and an increase in Jnk-mediated phosphorylation of E3-ligase, ITCH, which degrades c-FLIP. Conclusions: These results identify a novel mechanism of acquired vulnerability to an extrinsic cell death stimulus, in endocrine-resistant breast cancers, which has both therapeutic and prognostic potential. Clin Cancer Res; 24(10); 2452–63. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 3
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  Gemeinsame Jahrestagung der Deutschen, Österreichischen und Schweizer Gesellschaft für Thoraxchirurgie; 20101007-20101009; Wien, Österreich; DOC10dgtP12 /20100930/
    Publication Date: 2010-10-06
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 4
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  54. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie (gmds); 20090907-20090910; Essen; DOC09gmds248 /20090831/
    Publication Date: 2009-08-31
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 5
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  GMS Current Posters in Otorhinolaryngology - Head and Neck Surgery; VOL: 11; DOC059 /20150416/
    Publication Date: 2015-04-17
    Description: Einleitung: Das Konzept der minimal-invasiven Cochlea-Implantation über Bohrkanäle ist Gegenstand aktueller Forschung. Durch Anlegen von kleinsten und präzisen Bohrkanälen sollen Operationtrauma und Risiken minimiert werden. Solche minimal-invasiven Eingriffe bei Kindern stellen aufgrund unterschiedlicher Anatomie im Vergleich zum Erwachsenen besondere Herausforderungen dar. In der vorliegenden Arbeit wird die generelle Durchführbarkeit sowie die Limitationen von minimal-invasiven multi-port Zugängen zur Cochlea bei Kindern unterschiedlichen Alters untersucht und der dafür verfügbare mastoidale Raum in Abhängigkeit von dem Alter definiert.Methoden: Ausgehend von CT-Datensätzen von Kindern unterschiedlicher Altersgruppen (Säugling, Kleinkind, Schulkind) wurden die anatomischen Strukturen im Felsenbein segmentiert und ein 3D-Modell erstellt. Mittels einer speziellen Planungssoftware erfolgte die Berechnung und Visualisierung möglicher kollisionsfreier Bohrkanäle von der Mastoidoberfläche zum Zielort Cochlea. Die Ergebnisse wurden mit einem erwachsenen Patientenkollektiv verglichen.Ergebnisse und Schlussfolgerungen: Präsentiert wird eine Evaluation der Bohrkanäle hinsichtlich des anatomischen Verlaufs und der möglichen Durchmesser in Abhängigkeit von der individuellen Patientenanatomie und des Alters. Limitationen im Vergleich mit dem erwachsenen Patientenkollektiv werden diskutiert. Die Ergebnisse definieren den grundsätzlich verfügbaren Raum für Zugänge zur Cochlea bei Kindern.Der Erstautor gibt keinen Interessenkonflikt an.
    Keywords: ddc: 610
    Language: German
    Type: article
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  • 6
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  49. Jahrestagung der Deutschen Gesellschaft der Plastischen, Rekonstruktiven und Ästhetischen Chirurgen (DGPRÄC), 23. Jahrestagung der Vereinigung der Deutschen Ästhetisch-Plastischen Chirurgen (VDÄPC); 20180913-20180915; Bochum; DOC093 /20180920/
    Publication Date: 2018-09-21
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 7
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  46. Jahrestagung der Deutschen Gesellschaft der Plastischen, Rekonstruktiven und Ästhetischen Chirurgen (DGPRÄC), 20. Jahrestagung der Vereinigung der Deutschen Ästhetisch-Plastischen Chirurgen (VDÄPC); 20151001-20151003; Berlin; DOC146 /20150928/
    Publication Date: 2015-09-29
    Keywords: Neurales Gleitgewebe ; Neurolyse ; Nervenkompressionsyndrome ; Sulcus ulnaris Syndrom ; ddc: 610
    Language: German
    Type: conferenceObject
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  • 8
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  53. Kongress der Deutschen Gesellschaft für Handchirurgie; 20121011-20121013; Lübeck; DOC12dgh23 /20121009/
    Publication Date: 2012-10-10
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 9
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  16. Jahrestagung der Deutschen Gesellschaft für Thoraxchirurgie; 20071004-20071006; Konstanz; DOC07dgtF3 /20100322/
    Publication Date: 2010-03-23
    Keywords: ddc: 610
    Type: conferenceObject
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  • 10
    Keywords: APOPTOSIS ; CELLS ; BLOOD ; CELL ; Germany ; IN-VIVO ; KINASE ; PATHWAY ; PATHWAYS ; SYSTEM ; DEATH ; PROTEIN ; PROTEINS ; RNA ; MICE ; NF-KAPPA-B ; ACTIVATION ; MECHANISM ; FAMILY ; primary ; INDUCTION ; T cell ; T cells ; T-CELL ; T-CELLS ; MEMBER ; MEMBERS ; TRANSGENIC MICE ; CD95 ligand ; CELL-DEATH ; INDUCED APOPTOSIS ; LYMPHOCYTES ; B-CELLS ; SIGNALING COMPLEX ; Bcl-2 ; molecular ; MOLECULAR-BASIS ; RE ; FAMILIES ; LIFE ; LEVEL ; cell death ; ANTIGEN RECEPTORS ; progenitor ; SUPPRESSOR ; FAS LIGAND ; AICD ; HEMATOPOIETIC PROGENITOR KINASE-1 ; USA ; B-LYMPHOCYTES ; FATE ; FRAGMENT ; FAMILY-MEMBER BIM ; B-CELL ; KINASE-1 ; EXPANSION ; caspase-3 ; block ; B cells ; BCL-2 FAMILY ; COMPLEMENT ; FULL-LENGTH ; MEDIATED CLEAVAGE ; SMALL INTERFERING RNA
    Abstract: Life and death of peripheral lymphocytes is strictly controlled to maintain physiologic levels of T and B cells. Activation-induced cell death (AICD) is one mechanism to delete superfluous lymphocytes by restimulation of their immunoreceptors and it depends partially on the CD95/CD95L system. Recently, we have shown that hematopoietic progenitor kinase 1 (HPK1) determines T-cell fate. While full-length HPK1 is essential for NF-KB activation in T cells, the C-terminal fragment of HPK1, HPK1-C, suppresses NF-KB and sensitizes toward AICD by a yet undefined cell death pathway. Here we show that upon IL-2-driven expansion of primary T cells, HPK1 is converted to HPK1-C by a caspase-3 activity below the threshold of apoptosis induction. HPK1-C selectively blocks induction of NF-kappa B-dependent antiapoptotic Bcl-2 family members but not of the proapoptotic Bcl-2 family member Bim.Interestingly, T and B lymphocytes from HPK1-C transgenic mice undergo AICD independently of the CD95/CD95L system but involving caspase-9. Knock down of HPK1/HPK1-C or Bim by small interfering RNA shows that CD95L-dependent and HPK1/HPK1-C-dependent cell death pathways complement each other in AICD of primary T cells. Our results define HPK1-C as a suppressor of antiapoptotic Bcl-2 proteins and provide a molecular basis for our understanding of CD95L-independent AICD of lymphocytes
    Type of Publication: Journal article published
    PubMed ID: 17712048
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