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      Paving the way for precision medicine v2.0 in intensive care by profiling necroinflammation in biofluids

      research-article
      1 , 2 , , 3 , 4
      Cell Death and Differentiation
      Nature Publishing Group UK

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          Abstract

          Current clinical diagnosis is typically based on a combination of approaches including clinical examination of the patient, clinical experience, physiologic and/or genetic parameters, high-tech diagnostic medical imaging, and an extended list of laboratory values mostly determined in biofluids such as blood and urine. One could consider this as precision medicine v1.0. However, recent advances in technology and better understanding of molecular mechanisms underlying disease will allow us to better characterize patients in the future. These improvements will enable us to distinguish patients who have similar clinical presentations but different cellular and molecular responses. Treatments will be able to be chosen more “precisely”, resulting in more appropriate therapy, precision medicine v2.0. In this review, we will reflect on the potential added value of recent advances in technology and a better molecular understanding of necrosis and inflammation for improving diagnosis and treatment of critically ill patients. We give a brief overview on the mutual interplay between necrosis and inflammation, which are two crucial detrimental factors in organ and/or systemic dysfunction. One of the challenges for the future will thus be the cellular and molecular profiling of necroinflammation in biofluids. The huge amount of data generated by profiling biomolecules and single cells through, for example, different omic-approaches is needed for data mining methods to allow patient-clustering and identify novel biomarkers. The real-time monitoring of biomarkers will allow continuous (re)evaluation of treatment strategies using machine learning models. Ultimately, we may be able to offer precision therapies specifically designed to target the molecular set-up of an individual patient, as has begun to be done in cancer therapeutics.

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          Most cited references141

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          Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a Gasdermin

          Pyroptosis is a form of cell death that is critical for immunity. It can be induced by the canonical caspase-1 inflammasomes or by activation of caspase-4, -5 and -11 by cytosolic lipopolysaccharide. The caspases cleave gasdermin D (GSDMD) in its middle linker to release autoinhibition on its gasdermin-N domain, which executes pyroptosis via its pore-forming activity. GSDMD belongs to a gasdermin family that shares the pore-forming domain. The functions and mechanisms of activation of other gasdermins are unknown. Here we show that GSDME, which was originally identified as DFNA5 (deafness, autosomal dominant 5), can switch caspase-3-mediated apoptosis induced by TNF or chemotherapy drugs to pyroptosis. GSDME was specifically cleaved by caspase-3 in its linker, generating a GSDME-N fragment that perforates membranes and thereby induces pyroptosis. After chemotherapy, cleavage of GSDME by caspase-3 induced pyroptosis in certain GSDME-expressing cancer cells. GSDME was silenced in most cancer cells but expressed in many normal tissues. Human primary cells exhibited GSDME-dependent pyroptosis upon activation of caspase-3 by chemotherapy drugs. Gsdme-/- (also known as Dfna5-/-) mice were protected from chemotherapy-induced tissue damage and weight loss. These findings suggest that caspase-3 activation can trigger necrosis by cleaving GSDME and offer new insights into cancer chemotherapy.
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            Neutrophil extracellular traps in immunity and disease

            Neutrophils are innate immune phagocytes that have a central role in immune defence. Our understanding of the role of neutrophils in pathogen clearance, immune regulation and disease pathology has advanced dramatically in recent years. Web-like chromatin structures known as neutrophil extracellular traps (NETs) have been at the forefront of this renewed interest in neutrophil biology. The identification of molecules that modulate the release of NETs has helped to refine our view of the role of NETs in immune protection, inflammatory and autoimmune diseases and cancer. Here, I discuss the key findings and concepts that have thus far shaped the field of NET biology.
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              The danger model: a renewed sense of self.

              For over 50 years immunologists have based their thoughts, experiments, and clinical treatments on the idea that the immune system functions by making a distinction between self and nonself. Although this paradigm has often served us well, years of detailed examination have revealed a number of inherent problems. This Viewpoint outlines a model of immunity based on the idea that the immune system is more concerned with entities that do damage than with those that are foreign.

                Author and article information

                Contributors
                +3293313721 , Tom.VandenBerghe@irc.vib-ugent.be
                Journal
                Cell Death Differ
                Cell Death Differ
                Cell Death and Differentiation
                Nature Publishing Group UK (London )
                1350-9047
                1476-5403
                10 September 2018
                10 September 2018
                January 2019
                : 26
                : 1
                : 83-98
                Affiliations
                [1 ]ISNI 0000000104788040, GRID grid.11486.3a, VIB Center for Inflammation Research, ; Ghent, Belgium
                [2 ]ISNI 0000 0001 2069 7798, GRID grid.5342.0, Department of Biomedical Molecular Biology, , Ghent University, ; Ghent, Belgium
                [3 ]Division of Intensive Care, Department of Internal Medicine, Ghent University Hospital, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
                [4 ]ISNI 0000 0000 8597 7208, GRID grid.434261.6, Research Foundation Flanders, ; Brussels, Belgium
                Author information
                http://orcid.org/0000-0002-1633-0974
                Article
                196
                10.1038/s41418-018-0196-2
                6294775
                30201975
                34baf7e6-8f62-4964-ae5f-4cd0a3d15a85
                © ADMC Associazione Differenziamento e Morte Cellulare 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
                : 26 April 2018
                : 16 July 2018
                : 10 August 2018
                Categories
                Review Article
                Custom metadata
                © ADMC Associazione Differenziamento e Morte Cellulare 2019

                Cell biology
                Cell biology

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