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  1. Article ; Online: β-hydroxybutyrate accumulates in the rat heart during low-flow ischaemia with implications for functional recovery.

    Lindsay, Ross T / Dieckmann, Sophie / Krzyzanska, Dominika / Manetta-Jones, Dominic / West, James A / Castro, Cecilia / Griffin, Julian L / Murray, Andrew J

    eLife

    2021  Volume 10

    Abstract: Extrahepatic tissues which oxidise ketone bodies also have the capacity to accumulate them under particular conditions. We hypothesised that acetyl-coenzyme A (acetyl-CoA) accumulation and altered redox status during low-flow ischaemia would support ... ...

    Abstract Extrahepatic tissues which oxidise ketone bodies also have the capacity to accumulate them under particular conditions. We hypothesised that acetyl-coenzyme A (acetyl-CoA) accumulation and altered redox status during low-flow ischaemia would support ketone body production in the heart. Combining a Langendorff heart model of low-flow ischaemia/reperfusion with liquid chromatography coupled tandem mass spectrometry (LC-MS/MS), we show that β-hydroxybutyrate (β-OHB) accumulated in the ischaemic heart to 23.9 nmol/gww and was secreted into the coronary effluent. Sodium oxamate, a lactate dehydrogenase (LDH) inhibitor, increased ischaemic β-OHB levels 5.3-fold and slowed contractile recovery. Inhibition of β-hydroxy-β-methylglutaryl (HMG)-CoA synthase (HMGCS2) with hymeglusin lowered ischaemic β-OHB accumulation by 40%, despite increased flux through succinyl-CoA-3-oxaloacid CoA transferase (SCOT), resulting in greater contractile recovery. Hymeglusin also protected cardiac mitochondrial respiratory capacity during ischaemia/reperfusion. In conclusion, net ketone generation occurs in the heart under conditions of low-flow ischaemia. The process is driven by flux through both HMGCS2 and SCOT, and impacts on cardiac functional recovery from ischaemia/reperfusion.
    MeSH term(s) 3-Hydroxybutyric Acid/metabolism ; Animals ; Chromatography, Liquid ; Citric Acid Cycle ; Heart/physiology ; Hydroxymethylglutaryl-CoA Synthase ; Ischemia/metabolism ; Ketone Bodies ; Male ; Mitochondria ; Myocardial Ischemia ; Myocytes, Cardiac ; Oxidation-Reduction ; Rats ; Rats, Wistar ; Tandem Mass Spectrometry
    Chemical Substances Ketone Bodies ; Hydroxymethylglutaryl-CoA Synthase (EC 2.3.3.10) ; 3-Hydroxybutyric Acid (TZP1275679)
    Language English
    Publishing date 2021-09-07
    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.71270
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Tumor-targeted therapy with BRAF-inhibitor recruits activated dendritic cells to promote tumor immunity in melanoma.

    Hornsteiner, Florian / Vierthaler, Janine / Strandt, Helen / Resag, Antonia / Fu, Zhe / Ausserhofer, Markus / Tripp, Christoph H / Dieckmann, Sophie / Kanduth, Markus / Farrand, Kathryn / Bregar, Sarah / Nemati, Niloofar / Hermann-Kleiter, Natascha / Seretis, Athanasios / Morla, Sudhir / Mullins, David / Finotello, Francesca / Trajanoski, Zlatko / Wollmann, Guido /
    Ronchese, Franca / Schmitz, Marc / Hermans, Ian F / Stoitzner, Patrizia

    Journal for immunotherapy of cancer

    2024  Volume 12, Issue 4

    Abstract: Background: Tumor-targeted therapy causes impressive tumor regression, but the emergence of resistance limits long-term survival benefits in patients. Little information is available on the role of the myeloid cell network, especially dendritic cells ( ... ...

    Abstract Background: Tumor-targeted therapy causes impressive tumor regression, but the emergence of resistance limits long-term survival benefits in patients. Little information is available on the role of the myeloid cell network, especially dendritic cells (DC) during tumor-targeted therapy.
    Methods: Here, we investigated therapy-mediated immunological alterations in the tumor microenvironment (TME) and tumor-draining lymph nodes (LN) in the D4M.3A preclinical melanoma mouse model (harboring the V-Raf murine sarcoma viral oncogene homolog B (BRAF)
    Results: Our findings reveal that BRAF-inhibitor therapy increased tumor immunogenicity, reflected by an upregulation of genes associated with immune activation. The T cell-inflamed TME contained higher numbers of activated cDC1 and cDC2 but also inflammatory CCR2-expressing monocytes. At the same time, tumor-targeted therapy enhanced the frequency of migratory, activated DC subsets in tumor-draining LN. Even more, we identified a cDC2 population expressing the Fc gamma receptor I (FcγRI)/CD64 in tumors and LN that displayed high levels of CD40 and CCR7 indicating involvement in T cell-mediated tumor immunity. The importance of cDC2 is underlined by just a partial loss of therapy response in a cDC1-deficient mouse model. Both CD4
    Conclusion: Our results give novel insights into the remodeling of the myeloid landscape by tumor-targeted therapy. We demonstrate that the transient immunogenic tumor milieu contains more activated DC. This knowledge has important implications for the development of future combinatorial therapies.
    MeSH term(s) Humans ; Animals ; Mice ; Melanoma/metabolism ; CD8-Positive T-Lymphocytes ; Proto-Oncogene Proteins B-raf/genetics ; Dendritic Cells ; Antigens, Neoplasm ; Tumor Microenvironment
    Chemical Substances Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; Antigens, Neoplasm ; BRAF protein, human (EC 2.7.11.1)
    Language English
    Publishing date 2024-04-17
    Publishing country England
    Document type Journal Article
    ZDB-ID 2719863-7
    ISSN 2051-1426 ; 2051-1426
    ISSN (online) 2051-1426
    ISSN 2051-1426
    DOI 10.1136/jitc-2023-008606
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Guidelines for DC preparation and flow cytometry analysis of mouse nonlymphoid tissues.

    Probst, Hans Christian / Stoitzner, Patrizia / Amon, Lukas / Backer, Ronald A / Brand, Anna / Chen, Jianzhou / Clausen, Björn E / Dieckmann, Sophie / Dudziak, Diana / Heger, Lukas / Hodapp, Katrin / Hornsteiner, Florian / Hovav, Avi-Hai / Jacobi, Lukas / Ji, Xingqi / Kamenjarin, Nadine / Lahl, Katharina / Lahmar, Imran / Lakus, Jelena /
    Lehmann, Christian H K / Ortner, Daniela / Picard, Marion / Roberti, Maria Paula / Rossnagel, Lukas / Saba, Yasmin / Schalla, Carmen / Schlitzer, Andreas / Schraml, Barbara U / Schütze, Kristian / Seichter, Anna / Seré, Kristin / Seretis, Athanasios / Sopper, Sieghart / Strandt, Helen / Sykora, Martina M / Theobald, Hannah / Tripp, Christoph H / Zitvogel, Laurence

    European journal of immunology

    2022  Volume 53, Issue 11, Page(s) e2249819

    Abstract: This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy and functional characterization ...

    Abstract This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy and functional characterization of mouse and human dendritic cells (DC) from lymphoid organs and various nonlymphoid tissues. DC are sentinels of the immune system present in almost every mammalian organ. Since they represent a rare cell population, DC need to be extracted from organs with protocols that are specifically developed for each tissue. This article provides detailed protocols for the preparation of single-cell suspensions from various mouse nonlymphoid tissues, including skin, intestine, lung, kidney, mammary glands, oral mucosa and transplantable tumors. Furthermore, our guidelines include comprehensive protocols for multiplex flow cytometry analysis of DC subsets and feature top tricks for their proper discrimination from other myeloid cells. With this collection, we provide guidelines for in-depth analysis of DC subsets that will advance our understanding of their respective roles in healthy and diseased tissues. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all coauthors, making it an essential resource for basic and clinical DC immunologists.
    MeSH term(s) Animals ; Humans ; Flow Cytometry ; Dendritic Cells ; Skin ; Myeloid Cells ; Kidney ; Mammals
    Language English
    Publishing date 2022-12-13
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 120108-6
    ISSN 1521-4141 ; 0014-2980
    ISSN (online) 1521-4141
    ISSN 0014-2980
    DOI 10.1002/eji.202249819
    Database MEDical Literature Analysis and Retrieval System OnLINE

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