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      Innovations, challenges, and minimal information for standardization of humanized mice

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          Abstract

          Mice xenotransplanted with human cells and/or expressing human gene products (also known as “humanized mice”) recapitulate the human evolutionary specialization and diversity of genotypic and phenotypic traits. These models can provide a relevant in vivo context for understanding of human‐specific physiology and pathologies. Humanized mice have advanced toward mainstream preclinical models and are now at the forefront of biomedical research. Here, we considered innovations and challenges regarding the reconstitution of human immunity and human tissues, modeling of human infections and cancer, and the use of humanized mice for testing drugs or regenerative therapy products. As the number of publications exploring different facets of humanized mouse models has steadily increased in past years, it is becoming evident that standardized reporting is needed in the field. Therefore, an international community‐driven resource called “Minimal Information for Standardization of Humanized Mice” ( MISHUM) has been created for the purpose of enhancing rigor and reproducibility of studies in the field. Within MISHUM, we propose comprehensive guidelines for reporting critical information generated using humanized mice.

          Abstract

          Humanized mice are at the forefront of biomedical research and becoming more mainstream preclinical models. This comprehensive review talks about innovations and challenges regarding the reconstitution of human immunity and introduces “Minimal Information for Standardization of Humanized Mice” ( MISHUM).

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          Most cited references81

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          The blockade of immune checkpoints in cancer immunotherapy.

          Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
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            Human Primary Liver Cancer -derived Organoid Cultures for disease modelling and drug screening

            Human liver cancer research currently lacks in vitro models that faithfully recapitulate the pathophysiology of the original tumour. We recently described a novel, near-physiological organoid culture system, where primary human healthy liver cells form long-term expanding organoids that retain liver tissue function and genetic stability. Here, we extend this culture system to the propagation of primary liver cancer (PLC) organoids from three of the most common PLC subtypes: hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and combined HCC/CC (CHC) tumours. PLC-derived organoid cultures preserve the histological architecture, gene expression and genomic landscape of the original tumour, allowing discrimination between different tumour tissues and subtypes, even after long term expansion in culture in the same medium conditions. Xenograft studies demonstrate that the tumourogenic potential, histological features and metastatic properties of PLC-derived organoids are preserved in vivo. PLC-derived organoids are amenable for biomarker identification and drug screening testing and lead to the identification of the ERK inhibitor SCH772984 as a potential therapeutic agent for primary liver cancer. We thus demonstrate the wide-ranging biomedical utilities of PLC-derived organoid models in furthering the understanding of liver cancer biology and in developing personalized medicine approaches for the disease.
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              Decisions about dendritic cells: past, present, and future.

              A properly functioning adaptive immune system signifies the best features of life. It is diverse beyond compare, tolerant without fail, and capable of behaving appropriately with a myriad of infections and other challenges. Dendritic cells are required to explain how this remarkable system is energized and directed. I frame this article in terms of the major decisions that my colleagues and I have made in dendritic cell science and some of the guiding themes at the time the decisions were made. As a result of progress worldwide, there is now evidence of a central role for dendritic cells in initiating antigen-specific immunity and tolerance. The in vivo distribution and development of a previously unrecognized white cell lineage is better understood, as is the importance of dendritic cell maturation to link innate and adaptive immunity in response to many stimuli. Our current focus is on antigen uptake receptors on dendritic cells. These receptors enable experiments involving selective targeting of antigens in situ and new approaches to vaccine design in preclinical and clinical systems.
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                Author and article information

                Contributors
                stripecke.renata@mh-hannover.de
                Journal
                EMBO Mol Med
                EMBO Mol Med
                10.1002/(ISSN)1757-4684
                EMMM
                embomm
                EMBO Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1757-4676
                1757-4684
                24 June 2020
                07 July 2020
                : 12
                : 7 ( doiID: 10.1002/emmm.v12.7 )
                : e8662
                Affiliations
                [ 1 ] Regenerative Immune Therapies Applied Hannover Medical School Hannover Germany
                [ 2 ] German Center for Infection Research (DZIF) Hannover Region Germany
                [ 3 ] Viral Immunobiology Institute of Experimental Immunology University of Zurich Zurich Switzerland
                [ 4 ] Department of Hematology University Medical Center Groningen University of Groningen Groningen The Netherlands
                [ 5 ] Department of Pediatrics Duke University Medical Center Durham NC USA
                [ 6 ] The Jackson Laboratory Bar Harbor ME USA
                [ 7 ] Kymab Biotechnology Cambridge UK
                [ 8 ] The Jackson Laboratory Sacramento CA USA
                [ 9 ] Institut Pasteur INSERM U1223 Paris France
                [ 10 ] University of Massachusetts Medical School Worcester MA USA
                [ 11 ] Virology Dept. Bernhard Nocht Institute for Tropical Medicine Hamburg Germany
                [ 12 ] Department of Gynecology and Obstetrics University Cancer Center Regensburg Regensburg Germany
                [ 13 ] The Francis Crick Institute London UK
                [ 14 ] Guionaud Nonclinical Consulting Canterbury UK
                [ 15 ] U.S. Food & Drug Administration Silver Spring MD USA
                [ 16 ] University of California, Los Angeles Los Angeles CA USA
                [ 17 ] University of Cologne Cologne Germany
                [ 18 ] University of Cambridge Cambridge UK
                [ 19 ] Roche Innovation Center Zurich Zurich Switzerland
                [ 20 ] Division of Stem Cells and Cancer German Cancer Research Center (DKFZ) Heidelberg Germany
                [ 21 ] Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI‐STEM gGmbH) Heidelberg Germany
                [ 22 ] Department of Oncology University of Torino Medical School Turin Italy
                [ 23 ] Candiolo Cancer Institute FPO IRCCS Candiolo Italy
                Author notes
                [*] [* ]Corresponding author. Tel: +49 (511) 532‐6999; Fax: +49 (511) 532‐6975; E‐mail: stripecke.renata@ 123456mh-hannover.de
                [†]

                These authors contributed equally to this work

                Author information
                https://orcid.org/0000-0001-7756-8460
                https://orcid.org/0000-0001-6419-1940
                https://orcid.org/0000-0001-8452-8555
                https://orcid.org/0000-0002-6212-3466
                Article
                EMMM201708662
                10.15252/emmm.201708662
                7338801
                32578942
                850fe4a8-9fac-4d95-b85f-5ea324ac193a
                © 2020 The Authors. Published under the terms of the CC BY 4.0 license

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 14 December 2019
                : 29 April 2020
                : 14 May 2020
                Page count
                Figures: 1, Tables: 1, Pages: 17, Words: 14365
                Funding
                Funded by: Deutsches Zentrum für Infektionsforschung (DZIF) , open-funder-registry 10.13039/100009139;
                Award ID: TTU 07.815
                Funded by: Else Kroener Fresenius Stiftung
                Award ID: 2017 T04
                Funded by: HHS | NIH | NIH Office of the Director (OD) , open-funder-registry 10.13039/100000052;
                Award ID: R24 ODO26440
                Funded by: HHS | NIH | National Cancer Institute (NCI) , open-funder-registry 10.13039/100000054;
                Award ID: CA031496
                Award ID: U01 CA224013
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases , open-funder-registry 10.13039/100000062;
                Award ID: DK104218
                Funded by: National Institute of Allergy and Infectious Diseases (NIAID)
                Award ID: AI32963
                Categories
                Review
                Review
                Custom metadata
                2.0
                07 July 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.5 mode:remove_FC converted:07.07.2020

                Molecular medicine
                humanized mice,infections,pdx,immuno‐oncology,regenerative medicine,chromatin, epigenetics, genomics & functional genomics,immunology

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