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  1. Article: A 3D organoid platform that supports liver-stage

    Rao, Shringar / Romal, Shahla / Torenvliet, Bram / Slotman, Johan A / Huijs, Tonnie / Mahmoudi, Tokameh

    Heliyon

    2024  Volume 10, Issue 10, Page(s) e30740

    Abstract: Malaria, a major public health burden, is caused ... ...

    Abstract Malaria, a major public health burden, is caused by
    Language English
    Publishing date 2024-05-08
    Publishing country England
    Document type Journal Article
    ZDB-ID 2835763-2
    ISSN 2405-8440
    ISSN 2405-8440
    DOI 10.1016/j.heliyon.2024.e30740
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Production of Recombinant Hepatitis B virus (HBV) and Detection of HBV in Infected Human Liver Organoids.

    Hossain, Tanvir / Romal, Shahla / Mahmoudi, Tokameh

    Bio-protocol

    2022  Volume 12, Issue 8, Page(s) e4392

    Abstract: The absence of long term, primary ... ...

    Abstract The absence of long term, primary untransformed
    Language English
    Publishing date 2022-04-20
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2833269-6
    ISSN 2331-8325 ; 2331-8325
    ISSN (online) 2331-8325
    ISSN 2331-8325
    DOI 10.21769/BioProtoc.4392
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Generation, Maintenance and HBV Infection of Human Liver Organoids.

    Romal, Shahla / Hossain, Tanvir / Mahmoudi, Tokameh

    Bio-protocol

    2022  Volume 12, Issue 6, Page(s) e4358

    Abstract: Hepatitis B virus (HBV) infection represents a major public health problem infecting approximately 400 million people worldwide. Despite the availability of a preventive vaccine and anti-viral therapies, chronic HBV infection remains a major health issue ...

    Abstract Hepatitis B virus (HBV) infection represents a major public health problem infecting approximately 400 million people worldwide. Despite the availability of a preventive vaccine and anti-viral therapies, chronic HBV infection remains a major health issue because it increases the risk of developing liver cirrhosis and hepatocellular carcinoma (HCC). The lack of a relevant
    Language English
    Publishing date 2022-03-20
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2833269-6
    ISSN 2331-8325 ; 2331-8325
    ISSN (online) 2331-8325
    ISSN 2331-8325
    DOI 10.21769/BioProtoc.4358
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: NPEPPS Is a Druggable Driver of Platinum Resistance.

    Jones, Robert T / Scholtes, Mathijs / Goodspeed, Andrew / Akbarzadeh, Maryam / Mohapatra, Saswat / Feldman, Lily Elizabeth / Vekony, Hedvig / Jean, Annie / Tilton, Charlene B / Orman, Michael V / Romal, Shahla / Deiter, Cailin / Kan, Tsung Wai / Xander, Nathaniel / Araki, Stephanie P / Joshi, Molishree / Javaid, Mahmood / Clambey, Eric T / Layer, Ryan /
    Laajala, Teemu D / Parker, Sarah J / Mahmoudi, Tokameh / Zuiverloon, Tahlita C M / Theodorescu, Dan / Costello, James C

    Cancer research

    2024  Volume 84, Issue 10, Page(s) 1699–1718

    Abstract: There is an unmet need to improve the efficacy of platinum-based cancer chemotherapy, which is used in primary and metastatic settings in many cancer types. In bladder cancer, platinum-based chemotherapy leads to better outcomes in a subset of patients ... ...

    Abstract There is an unmet need to improve the efficacy of platinum-based cancer chemotherapy, which is used in primary and metastatic settings in many cancer types. In bladder cancer, platinum-based chemotherapy leads to better outcomes in a subset of patients when used in the neoadjuvant setting or in combination with immunotherapy for advanced disease. Despite such promising results, extending the benefits of platinum drugs to a greater number of patients is highly desirable. Using the multiomic assessment of cisplatin-responsive and -resistant human bladder cancer cell lines and whole-genome CRISPR screens, we identified puromycin-sensitive aminopeptidase (NPEPPS) as a driver of cisplatin resistance. NPEPPS depletion sensitized resistant bladder cancer cells to cisplatin in vitro and in vivo. Conversely, overexpression of NPEPPS in sensitive cells increased cisplatin resistance. NPEPPS affected treatment response by regulating intracellular cisplatin concentrations. Patient-derived organoids (PDO) generated from bladder cancer samples before and after cisplatin-based treatment, and from patients who did not receive cisplatin, were evaluated for sensitivity to cisplatin, which was concordant with clinical response. In the PDOs, depletion or pharmacologic inhibition of NPEPPS increased cisplatin sensitivity, while NPEPPS overexpression conferred resistance. Our data present NPEPPS as a druggable driver of cisplatin resistance by regulating intracellular cisplatin concentrations.
    Significance: Targeting NPEPPS, which induces cisplatin resistance by controlling intracellular drug concentrations, is a potential strategy to improve patient responses to platinum-based therapies and lower treatment-associated toxicities.
    MeSH term(s) Humans ; Drug Resistance, Neoplasm ; Cisplatin/pharmacology ; Urinary Bladder Neoplasms/drug therapy ; Urinary Bladder Neoplasms/genetics ; Urinary Bladder Neoplasms/pathology ; Urinary Bladder Neoplasms/metabolism ; Animals ; Mice ; Cell Line, Tumor ; Aminopeptidases/genetics ; Aminopeptidases/metabolism ; Xenograft Model Antitumor Assays ; Antineoplastic Agents/pharmacology ; Organoids/drug effects ; Organoids/metabolism
    Language English
    Publishing date 2024-03-27
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-23-1976
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uh III Zs.135/5: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  5. Article ; Online: Application of human liver organoids as a patient-derived primary model for HBV infection and related hepatocellular carcinoma.

    De Crignis, Elisa / Hossain, Tanvir / Romal, Shahla / Carofiglio, Fabrizia / Moulos, Panagiotis / Khalid, Mir Mubashir / Rao, Shringar / Bazrafshan, Ameneh / Verstegen, Monique Ma / Pourfarzad, Farzin / Koutsothanassis, Christina / Gehart, Helmuth / Kan, Tsung Wai / Palstra, Robert-Jan / Boucher, Charles / IJzermans, Jan Nm / Huch, Meritxell / Boj, Sylvia F / Vries, Robert /
    Clevers, Hans / van der Laan, Luc Jw / Hatzis, Pantelis / Mahmoudi, Tokameh

    eLife

    2021  Volume 10

    Abstract: The molecular events that drive hepatitis B virus (HBV)-mediated transformation and tumorigenesis have remained largely unclear, due to the absence of a relevant primary model system. Here we propose the use of human liver organoids as a platform for ... ...

    Abstract The molecular events that drive hepatitis B virus (HBV)-mediated transformation and tumorigenesis have remained largely unclear, due to the absence of a relevant primary model system. Here we propose the use of human liver organoids as a platform for modeling HBV infection and related tumorigenesis. We first describe a primary ex vivo HBV-infection model derived from healthy donor liver organoids after challenge with recombinant virus or HBV-infected patient serum. HBV-infected organoids produced covalently closed circular DNA (cccDNA) and HBV early antigen (HBeAg), expressed intracellular HBV RNA and proteins, and produced infectious HBV. This ex vivo HBV-infected primary differentiated hepatocyte organoid platform was amenable to drug screening for both anti-HBV activity and drug-induced toxicity. We also studied HBV replication in transgenically modified organoids; liver organoids exogenously overexpressing the HBV receptor sodium taurocholate co-transporting polypeptide (NTCP) after lentiviral transduction were not more susceptible to HBV, suggesting the necessity for additional host factors for efficient infection. We also generated transgenic organoids harboring integrated HBV, representing a long-term culture system also suitable for viral production and the study of HBV transcription. Finally, we generated HBV-infected patient-derived liver organoids from non-tumor cirrhotic tissue of explants from liver transplant patients. Interestingly, transcriptomic analysis of patient-derived liver organoids indicated the presence of an aberrant early cancer gene signature, which clustered with the hepatocellular carcinoma (HCC) cohort on The Cancer Genome Atlas Liver Hepatocellular Carcinoma dataset and away from healthy liver tissue, and may provide invaluable novel biomarkers for the development of HCC and surveillance in HBV-infected patients.
    MeSH term(s) Carcinoma, Hepatocellular/virology ; Hep G2 Cells ; Hepatitis B/complications ; Hepatitis B/virology ; Hepatitis B virus/pathogenicity ; Humans ; Liver/pathology ; Liver/virology ; Liver Neoplasms/virology ; Living Donors ; Models, Biological ; Organoids/virology ; Virus Replication
    Language English
    Publishing date 2021-07-30
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.60747
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Clinical stage drugs targeting inhibitor of apoptosis proteins purge episomal Hepatitis B viral genome in preclinical models.

    Clark, Michelle P / Huynh, Thao / Rao, Shringar / Mackiewicz, Liana / Mason, Hugh / Romal, Shahla / Stutz, Michael D / Ahn, Sang H / Earnest, Linda / Sozzi, Vitina / Littlejohn, Margaret / Tran, Bang M / Wiedemann, Norbert / Vincan, Elizabeth / Torresi, Joseph / Netter, Hans J / Mahmoudi, Tokameh / Revill, Peter / Pellegrini, Marc /
    Ebert, Gregor

    Cell death & disease

    2021  Volume 12, Issue 7, Page(s) 641

    Abstract: A major unmet clinical need is a therapeutic capable of removing hepatitis B virus (HBV) genome from the liver of infected individuals to reduce their risk of developing liver cancer. A strategy to deliver such a therapy could utilize the ability to ... ...

    Abstract A major unmet clinical need is a therapeutic capable of removing hepatitis B virus (HBV) genome from the liver of infected individuals to reduce their risk of developing liver cancer. A strategy to deliver such a therapy could utilize the ability to target and promote apoptosis of infected hepatocytes. Presently there is no clinically relevant strategy that has been shown to effectively remove persistent episomal covalently closed circular HBV DNA (cccDNA) from the nucleus of hepatocytes. We used linearized single genome length HBV DNA of various genotypes to establish a cccDNA-like reservoir in immunocompetent mice and showed that clinical-stage orally administered drugs that antagonize the function of cellular inhibitor of apoptosis proteins can eliminate HBV replication and episomal HBV genome in the liver. Primary human liver organoid models were used to confirm the clinical relevance of these results. This study underscores a clinically tenable strategy for the potential elimination of chronic HBV reservoirs in patients.
    MeSH term(s) Animals ; Antiviral Agents/pharmacology ; Azocines/pharmacology ; Benzhydryl Compounds/pharmacology ; Disease Models, Animal ; Genome, Viral ; Hep G2 Cells ; Hepatitis B/drug therapy ; Hepatitis B/metabolism ; Hepatitis B/pathology ; Hepatitis B/virology ; Hepatitis B virus/drug effects ; Hepatitis B virus/genetics ; Hepatocytes/drug effects ; Hepatocytes/metabolism ; Hepatocytes/pathology ; Hepatocytes/virology ; Host-Pathogen Interactions ; Humans ; Inhibitor of Apoptosis Proteins/antagonists & inhibitors ; Inhibitor of Apoptosis Proteins/metabolism ; Liver/drug effects ; Liver/metabolism ; Liver/pathology ; Liver/virology ; Mice, Inbred C57BL ; Mice, Knockout ; Molecular Targeted Therapy ; Organoids ; Thiazoles/pharmacology ; Tumor Necrosis Factor-alpha/genetics ; Tumor Necrosis Factor-alpha/metabolism ; Virus Replication/drug effects ; Mice
    Chemical Substances Antiviral Agents ; Azocines ; Benzhydryl Compounds ; Inhibitor of Apoptosis Proteins ; LCL161 ; N-benzhydryl-5-(2-(methylamino)propanamido)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo(1,2-a)(1,5)diazocine-8-carboxamide ; Thiazoles ; Tnf protein, mouse ; Tumor Necrosis Factor-alpha
    Language English
    Publishing date 2021-06-23
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2541626-1
    ISSN 2041-4889 ; 2041-4889
    ISSN (online) 2041-4889
    ISSN 2041-4889
    DOI 10.1038/s41419-021-03924-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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