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  1. Article ; Online: Design and Characterization of Mutated Variants of the Oncotoxic Parvoviral Protein NS1.

    Hauswirth, Patrick / Graber, Philipp / Buczak, Katarzyna / Mancuso, Riccardo Vincenzo / Schenk, Susanne Heidi / Nüesch, Jürg P F / Huwyler, Jörg

    Viruses

    2023  Volume 15, Issue 1

    Abstract: Oncotoxic proteins such as the non-structural protein 1 (NS1), a constituent of the rodent parvovirus H1 (H1-PV), offer a novel approach for treatment of tumors that are refractory to other treatments. In the present study, mutated NS1 variants were ... ...

    Abstract Oncotoxic proteins such as the non-structural protein 1 (NS1), a constituent of the rodent parvovirus H1 (H1-PV), offer a novel approach for treatment of tumors that are refractory to other treatments. In the present study, mutated NS1 variants were designed and tested with respect to their oncotoxic potential in human hepatocellular carcinoma cell lines. We introduced single point mutations of previously described important residues of the wild-type NS1 protein and a deletion of 114 base pairs localized within the N-terminal domain of NS1. Cell-viability screening with HepG2 and Hep3B hepatocarcinoma cells transfected with the constructed NS1-mutants led to identification of the single-amino acid NS1-mutant NS1-T585E, which led to a 30% decrease in cell viability as compared to NS1 wildtype. Using proteomics analysis, we could identify new interaction partners and signaling pathways of NS1. We could thus identify new oncotoxic NS1 variants and gain insight into the modes of action of NS1, which is exclusively toxic to human cancer cells. Our in-vitro studies provide mechanistic explanations for the observed oncolytic effects. Expression of NS1 variants had no effect on cell viability in NS1 unresponsive control HepG2 cells or primary mouse hepatocytes. The availability of new NS1 variants in combination with a better understanding of their modes of action offers new possibilities for the design of innovative cancer treatment strategies.
    MeSH term(s) Animals ; Humans ; Mice ; Cell Line ; Liver Neoplasms/genetics ; Parvoviridae Infections ; Parvovirus/genetics ; Viral Nonstructural Proteins/metabolism
    Chemical Substances Viral Nonstructural Proteins
    Language English
    Publishing date 2023-01-11
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2516098-9
    ISSN 1999-4915 ; 1999-4915
    ISSN (online) 1999-4915
    ISSN 1999-4915
    DOI 10.3390/v15010209
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Zebrafish Larvae as an

    Hauswirth, Patrick / Buck, Jonas / Puligilla, Ramya / Alter, Claudio Luca / Sieber, Sandro / Claudi, Beatrice / Fanous, Joseph / Bumann, Dirk / Huwyler, Jörg

    Frontiers in bioscience (Landmark edition)

    2023  Volume 28, Issue 5, Page(s) 99

    Abstract: Introduction: Blood infections from multi-drug-resistant : Methods: We established suitable : Results: We detected : Conclusions: The zebrafish-larvae model enables testing of antimicrobials for efficacy against extra- and ... ...

    Abstract Introduction: Blood infections from multi-drug-resistant
    Methods: We established suitable
    Results: We detected
    Conclusions: The zebrafish-larvae model enables testing of antimicrobials for efficacy against extra- and intracellular
    MeSH term(s) Animals ; Zebrafish ; Larva ; Anti-Bacterial Agents/pharmacology ; Anti-Bacterial Agents/metabolism ; Macrophages/metabolism ; Salmonella/genetics
    Chemical Substances Anti-Bacterial Agents
    Language English
    Publishing date 2023-05-31
    Publishing country Singapore
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2704569-9
    ISSN 2768-6698 ; 2768-6698
    ISSN (online) 2768-6698
    ISSN 2768-6698
    DOI 10.31083/j.fbl2805099
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: MEndoB, a chimeric lysin featuring a novel domain architecture and superior activity for the treatment of staphylococcal infections.

    Roehrig, Christian / Huemer, Markus / Lorgé, Dominique / Arn, Fabienne / Heinrich, Nadine / Selvakumar, Lavanja / Gasser, Lynn / Hauswirth, Patrick / Chang, Chun-Chi / Schweizer, Tiziano A / Eichenseher, Fritz / Lehmann, Steffi / Zinkernagel, Annelies S / Schmelcher, Mathias

    mBio

    2024  Volume 15, Issue 2, Page(s) e0254023

    Abstract: Bacterial infections are a growing global healthcare concern, as an estimated annual 4.95 million deaths are associated with antimicrobial resistance (AMR). Methicillin- ... ...

    Abstract Bacterial infections are a growing global healthcare concern, as an estimated annual 4.95 million deaths are associated with antimicrobial resistance (AMR). Methicillin-resistant
    MeSH term(s) Humans ; Animals ; Mice ; Staphylococcus aureus ; Methicillin-Resistant Staphylococcus aureus ; Peptidoglycan ; Zebrafish ; Staphylococcal Infections/drug therapy ; Staphylococcal Infections/microbiology ; Anti-Bacterial Agents/pharmacology ; Anti-Bacterial Agents/therapeutic use ; Staphylococcus ; N-Acetylmuramoyl-L-alanine Amidase/genetics ; N-Acetylmuramoyl-L-alanine Amidase/therapeutic use ; Sepsis/drug therapy
    Chemical Substances Peptidoglycan ; Anti-Bacterial Agents ; N-Acetylmuramoyl-L-alanine Amidase (EC 3.5.1.28)
    Language English
    Publishing date 2024-01-26
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2557172-2
    ISSN 2150-7511 ; 2161-2129
    ISSN (online) 2150-7511
    ISSN 2161-2129
    DOI 10.1128/mbio.02540-23
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: High efficiency preparation of monodisperse plasma membrane derived extracellular vesicles for therapeutic applications.

    Alter, Claudio L / Detampel, Pascal / Schefer, Roman B / Lotter, Claudia / Hauswirth, Patrick / Puligilla, Ramya D / Weibel, Vera J / Schenk, Susanne H / Heusermann, Wolf / Schürz, Melanie / Meisner-Kober, Nicole / Palivan, Cornelia / Einfalt, Tomaž / Huwyler, Jörg

    Communications biology

    2023  Volume 6, Issue 1, Page(s) 478

    Abstract: Extracellular vesicles (EVs) are highly interesting for the design of next-generation therapeutics. However, their preparation methods face challenges in standardization, yield, and reproducibility. Here, we describe a highly efficient and reproducible ... ...

    Abstract Extracellular vesicles (EVs) are highly interesting for the design of next-generation therapeutics. However, their preparation methods face challenges in standardization, yield, and reproducibility. Here, we describe a highly efficient and reproducible EV preparation method for monodisperse nano plasma membrane vesicles (nPMVs), which yields 10 to 100 times more particles per cell and hour than conventional EV preparation methods. nPMVs are produced by homogenizing giant plasma membrane vesicles following cell membrane blebbing and apoptotic body secretion induced by chemical stressors. nPMVs showed no significant differences compared to native EVs from the same cell line in cryo-TEM analysis, in vitro cellular interactions, and in vivo biodistribution studies in zebrafish larvae. Proteomics and lipidomics, on the other hand, suggested substantial differences consistent with the divergent origin of these two EV types and indicated that nPMVs primarily derive from apoptotic extracellular vesicles. nPMVs may provide an attractive source for developing EV-based pharmaceutical therapeutics.
    MeSH term(s) Animals ; Reproducibility of Results ; Tissue Distribution ; Zebrafish ; Extracellular Vesicles/metabolism ; Cell Membrane/metabolism
    Language English
    Publishing date 2023-05-03
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2399-3642
    ISSN (online) 2399-3642
    DOI 10.1038/s42003-023-04859-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Virus-Derived Peptides for Hepatic Enzyme Delivery.

    Pratsinis, Anna / Uhl, Philipp / Bolten, Jan Stephan / Hauswirth, Patrick / Schenk, Susanne Heidi / Urban, Stephan / Mier, Walter / Witzigmann, Dominik / Huwyler, Jörg

    Molecular pharmaceutics

    2021  Volume 18, Issue 5, Page(s) 2004–2014

    Abstract: Recently, a lipopeptide derived from the hepatitis B virus (HBV) large surface protein has been developed as an HBV entry inhibitor. This lipopeptide, called MyrcludexB (MyrB), selectively binds to the sodium taurocholate cotransporting polypeptide (NTCP) ...

    Abstract Recently, a lipopeptide derived from the hepatitis B virus (HBV) large surface protein has been developed as an HBV entry inhibitor. This lipopeptide, called MyrcludexB (MyrB), selectively binds to the sodium taurocholate cotransporting polypeptide (NTCP) on the basolateral membrane of hepatocytes. Here, the feasibility of coupling therapeutic enzymes to MyrB was investigated for the development of enzyme delivery strategies. Hepatotropic targeting shall enable enzyme prodrug therapies and detoxification procedures. Here, horseradish peroxidase (HRP) was conjugated to MyrB via maleimide chemistry, and coupling was validated by SDS-PAGE and reversed-phase HPLC. The specificity of the target recognition of HRP-MyrB could be shown in an NTCP-overexpressing liver parenchymal cell line, as demonstrated by competitive inhibition with an excess of free MyrB and displayed a strong linear dependency on the applied HRP-MyrB concentration.
    MeSH term(s) Animals ; Calcium-Binding Proteins/metabolism ; Cell Line, Tumor ; Drug Carriers/chemistry ; Drug Carriers/pharmacology ; Embryo, Nonmammalian ; Enzyme Therapy/methods ; Enzymes/administration & dosage ; Enzymes/pharmacokinetics ; HEK293 Cells ; Hepatocytes/metabolism ; Humans ; Lipopeptides/chemistry ; Lipopeptides/pharmacology ; Liver/cytology ; Liver/metabolism ; Mice ; Models, Animal ; Organic Anion Transporters, Sodium-Dependent/metabolism ; Prodrugs/administration & dosage ; Prodrugs/pharmacokinetics ; Symporters/metabolism ; Tissue Distribution ; Zebrafish ; Zebrafish Proteins/metabolism
    Chemical Substances Calcium-Binding Proteins ; Drug Carriers ; Enzymes ; Lipopeptides ; Organic Anion Transporters, Sodium-Dependent ; Prodrugs ; Symporters ; Zebrafish Proteins ; myrcludex-B ; stab2 protein, zebrafish ; sodium-bile acid cotransporter (145420-23-1)
    Language English
    Publishing date 2021-04-12
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2138405-8
    ISSN 1543-8392 ; 1543-8384
    ISSN (online) 1543-8392
    ISSN 1543-8384
    DOI 10.1021/acs.molpharmaceut.0c01222
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6250: Show issues Location:
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    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  6. Article ; Online: Non-viral gene delivery of the oncotoxic protein NS1 for treatment of hepatocellular carcinoma.

    Witzigmann, Dominik / Grossen, Philip / Quintavalle, Cristina / Lanzafame, Manuela / Schenk, Susanne H / Tran, Xue-Ting / Englinger, Bernhard / Hauswirth, Patrick / Grünig, David / van Schoonhoven, Sushilla / Krähenbühl, Stephan / Terracciano, Luigi M / Berger, Walter / Piscuoglio, Salvatore / Quagliata, Luca / Rommelaere, Jean / Nüesch, Jürg P F / Huwyler, Jörg

    Journal of controlled release : official journal of the Controlled Release Society

    2021  Volume 334, Page(s) 138–152

    Abstract: Hepatocellular carcinoma (HCC) is related to increasing incidence rates and poor clinical outcomes due to lack of efficient treatment options and emerging resistance mechanisms. The aim of the present study is to exploit a non-viral gene therapy enabling ...

    Abstract Hepatocellular carcinoma (HCC) is related to increasing incidence rates and poor clinical outcomes due to lack of efficient treatment options and emerging resistance mechanisms. The aim of the present study is to exploit a non-viral gene therapy enabling the expression of the parvovirus-derived oncotoxic protein NS1 in HCC. This anticancer protein interacts with different cellular kinases mediating a multimodal host-cell death. Lipoplexes (LPX) designed to deliver a DNA expression plasmid encoding NS1 are characterized using a comprehensive set of in vitro assays. The mechanisms of cell death induction are assessed and phosphoinositide-dependent kinase 1 (PDK1) is identified as a potential predictive biomarker for a NS1-LPX-based gene therapy. In an HCC xenograft mouse model, NS1-LPX therapeutic approach results in a significant reduction in tumor growth and extended survival. Data provide convincing evidence for future studies using a targeted NS1 gene therapy for PDK1 overexpressing HCC.
    MeSH term(s) Animals ; Carcinoma, Hepatocellular/therapy ; Genetic Therapy ; Liver Neoplasms/therapy ; Mice ; Plasmids ; Proteins
    Chemical Substances Proteins
    Language English
    Publishing date 2021-04-22
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 632533-6
    ISSN 1873-4995 ; 0168-3659
    ISSN (online) 1873-4995
    ISSN 0168-3659
    DOI 10.1016/j.jconrel.2021.04.023
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2055: Show issues Location:
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  7. Article: Non-viral gene delivery of the oncotoxic protein NS1 for treatment of hepatocellular carcinoma

    Witzigmann, Dominik / Grossen, Philip / Quintavalle, Cristina / Lanzafame, Manuela / Schenk, Susanne H / Tran, Xue-Ting / Englinger, Bernhard / Hauswirth, Patrick / Grünig, David / van Schoonhoven, Sushilla / Krähenbühl, Stephan / Terracciano, Luigi M / Berger, Walter / Piscuoglio, Salvatore / Quagliata, Luca / Rommelaere, Jean / Nüesch, Jürg P.F / Huwyler, Jörg

    Journal of controlled release. 2021 June 10, v. 334

    2021  

    Abstract: Hepatocellular carcinoma (HCC) is related to increasing incidence rates and poor clinical outcomes due to lack of efficient treatment options and emerging resistance mechanisms. The aim of the present study is to exploit a non-viral gene therapy enabling ...

    Abstract Hepatocellular carcinoma (HCC) is related to increasing incidence rates and poor clinical outcomes due to lack of efficient treatment options and emerging resistance mechanisms. The aim of the present study is to exploit a non-viral gene therapy enabling the expression of the parvovirus-derived oncotoxic protein NS1 in HCC. This anticancer protein interacts with different cellular kinases mediating a multimodal host-cell death. Lipoplexes (LPX) designed to deliver a DNA expression plasmid encoding NS1 are characterized using a comprehensive set of in vitro assays. The mechanisms of cell death induction are assessed and phosphoinositide-dependent kinase 1 (PDK1) is identified as a potential predictive biomarker for a NS1-LPX-based gene therapy. In an HCC xenograft mouse model, NS1-LPX therapeutic approach results in a significant reduction in tumor growth and extended survival. Data provide convincing evidence for future studies using a targeted NS1 gene therapy for PDK1 overexpressing HCC.
    Keywords biomarkers ; cell death ; death ; gene therapy ; gene transfer ; hepatoma ; mice ; phosphotransferases (kinases) ; plasmids ; xenotransplantation
    Language English
    Dates of publication 2021-0610
    Size p. 138-152.
    Publishing place Elsevier B.V.
    Document type Article
    Note NAL-AP-2-clean
    ZDB-ID 632533-6
    ISSN 1873-4995 ; 0168-3659
    ISSN (online) 1873-4995
    ISSN 0168-3659
    DOI 10.1016/j.jconrel.2021.04.023
    Database NAL-Catalogue (AGRICOLA)

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2055: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (1.OG)
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