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      Neutralization of CD95 ligand protects the liver against ischemia-reperfusion injury and prevents acute liver failure

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          Abstract

          Ischemia-reperfusion injury is a common pathological process in liver surgery and transplantation, and has considerable impact on the patient outcome and survival. Death receptors are important mediators of ischemia-reperfusion injury, notably the signaling pathways of the death receptor CD95 (Apo-1/Fas) and its corresponding ligand CD95L. This study investigates, for the first time, whether the inhibition of CD95L protects the liver against ischemia-reperfusion injury. Warm ischemia was induced in the median and left liver lobes of C57BL/6 mice for 45 min. CD95Fc, a specific inhibitor of CD95L, was applied prior to ischemia. Hepatic injury was assessed via consecutive measurements of liver serum enzymes, histopathological assessment of apoptosis and necrosis and caspase assays at 3, 6, 12, 18 and 24 h after reperfusion. Serum levels of liver enzymes, as well as characteristic histopathological changes and caspase assays indicated pronounced features of apoptotic and necrotic liver damage 12 and 24 h after ischemia-reperfusion injury. Animals treated with the CD95L-blocker CD95Fc, exhibited a significant reduction in the level of serum liver enzymes and showed both decreased histopathological signs of parenchymal damage and decreased caspase activation. This study demonstrates that inhibition of CD95L with the CD95L-blocker CD95Fc, is effective in protecting mice from liver failure due to ischemia-reperfusion injury of the liver. CD95Fc could therefore emerge as a new pharmacological therapy for liver resection, transplantation surgery and acute liver failure.

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          CD95's deadly mission in the immune system.

          Apoptosis in the immune system is a fundamental process regulating lymphocyte maturation, receptor repertoire selection and homeostasis. Thus, death by apoptosis is as essential for the function of lymphocytes as growth and differentiation. This article focuses on death receptor-associated apoptosis and the role of CD95 (Apo-1/Fas)-mediated signalling in T-cell and B-cell development and during the course of an immune response. Gaining an insight into these processes improves our understanding of the pathogenesis of diseases such as cancer, autoimmunity and AIDS, and opens new approaches to rational treatment strategies.
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            The CD95(APO-1/Fas) DISC and beyond.

            CD95 (APO-1/Fas) is a prototype death receptor characterized by the presence of an 80 amino acid death domain in its cytoplasmic tail. This domain is essential for the recruitment of a number of signaling components upon activation by either agonistic anti-CD95 antibodies or cognate CD95 ligand that initiate apoptosis. The complex of proteins that forms upon triggering of CD95 is called the death-inducting signaling complex (DISC). The DISC consists of an adaptor protein and initiator caspases and is essential for induction of apoptosis. A number of proteins have been reported to regulate formation or activity of the DISC. This review discusses recent developments in this area of death receptor research.
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              Localization and density of immune cells in the invasive margin of human colorectal cancer liver metastases are prognostic for response to chemotherapy.

              Analysis of tumor-infiltrating lymphocytes (TIL) in primary human colorectal cancer (CRC) by in situ immunohistochemical staining supports the hypothesis that the adaptive immune response influences the course of human CRC. Specifically, high densities of TILs in the primary tumor are associated with good prognosis independent of other prognostic markers. However, the prognostic role of TILs in metastatic CRC lesions is unknown, as is their role in response or resistance to conventional chemotherapy. We analyzed the association of TIL densities at the invasive margin of CRC liver metastases with response to chemotherapy and progression-free survival in a set of 101 large section samples. High-resolution automated microscopy on complete tissue sections was used to objectively generate cell densities for CD3, CD8, granzyme B, or FOXP3 positive immune cells. A predictive scoring system using TIL densities was developed in a training set and tested successfully in an independent validation set. TIL densities at the invasive margin of liver metastases allowed the prediction of response to chemotherapy with a sensitivity of 79% and specificity of 100%. The association of high density values with longer progression-free survival under chemotherapy was statistically significant. Overall, these findings extend the impact of the local immune response on the clinical course from the primary tumor also to metastatic lesions. Because detailed quantification of TILs in metastatic lesions revealed a strong association with chemotherapy efficacy and prognosis, we suggest that the developed scoring system may be used as a predictive tool for response to chemotherapy in metastatic CRC. ©2011 AACR.
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                Author and article information

                Contributors
                +43 316 385 14094 , Peter.Schemmer@medunigraz.at
                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group UK (London )
                2041-4889
                26 January 2018
                26 January 2018
                February 2018
                : 9
                : 2
                : 132
                Affiliations
                [1 ]ISNI 0000 0001 0328 4908, GRID grid.5253.1, Department of General, Visceral, and Transplant Surgery, , Heidelberg University Hospital, ; Heidelberg, Germany
                [2 ]ISNI 0000 0001 0328 4908, GRID grid.5253.1, Department of Gastroenterology, Intoxications, and Infectious Diseases, , Heidelberg University Hospital, ; Heidelberg, Germany
                [3 ]ISNI 0000 0001 2190 4373, GRID grid.7700.0, Medical Oncology, National Center for Tumor Diseases, , University of Heidelberg, ; Heidelberg, Germany
                [4 ]ISNI 0000 0001 0328 4908, GRID grid.5253.1, Department of Pathology, , Heidelberg University Hospital, ; Heidelberg, Germany
                [5 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, Division of Immunogenetics, , German Cancer Research Center, ; Heidelberg, Germany
                [6 ]ISNI 0000 0000 8988 2476, GRID grid.11598.34, Department of Surgery, Division of Transplant Surgery, , Medical University of Graz, ; Graz, Austria
                [7 ]ISNI 0000 0000 9194 7179, GRID grid.411941.8, Department of Internal Medicine I, Gastroenterology, Endocrinology, Rheumatology, and Infectious Diseases, , Regensburg University Hospital, ; Regensburg, Germany
                Article
                150
                10.1038/s41419-017-0150-0
                5833836
                29374146
                dbdeaa79-66ca-4248-b56d-0c5a6272a2a8
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 18 June 2017
                : 3 November 2017
                : 6 November 2017
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                © The Author(s) 2018

                Cell biology
                Cell biology

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