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      Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

      1 , 2 , 3 , * , 1 , 2 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 6 , 35 , 36 , 37 , 38 , 37 , 38 , 39 , 5 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 2 , 4 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 58 , 93 , 94 , 30 , 46 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 69 , 106 , 100 , 107 , 108 , 109 , 55 , 110 , 111 , 112 , 15 , 16 , 15 , 16 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 28 , 64 , 2 , 3 , 4 , 61 , 125 , *

      Cell Death and Differentiation

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          Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.

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          Most cited references 328

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          Autophagy fights disease through cellular self-digestion.

          Autophagy, or cellular self-digestion, is a cellular pathway involved in protein and organelle degradation, with an astonishing number of connections to human disease and physiology. For example, autophagic dysfunction is associated with cancer, neurodegeneration, microbial infection and ageing. Paradoxically, although autophagy is primarily a protective process for the cell, it can also play a role in cell death. Understanding autophagy may ultimately allow scientists and clinicians to harness this process for the purpose of improving human health.
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            • Abstract: found
            • Article: not found

            Apoptosis: A Basic Biological Phenomenon with Wide-ranging Implications in Tissue Kinetics

            The term apoptosis is proposed for a hitherto little recognized mechanism of controlled cell deletion, which appears to play a complementary but opposite role to mitosis in the regulation of animal cell populations. Its morphological features suggest that it is an active, inherently programmed phenomenon, and it has been shown that it can be initiated or inhibited by a variety of environmental stimuli, both physiological and pathological. The structural changes take place in two discrete stages. The first comprises nuclear and cytoplasmic condensation and breaking up of the cell into a number of membrane-bound, ultrastructurally well-preserved fragments. In the second stage these apoptotic bodies are shed from epithelial-lined surfaces or are taken up by other cells, where they undergo a series of changes resembling in vitro autolysis within phagosomes, and are rapidly degraded by lysosomal enzymes derived from the ingesting cells. Apoptosis seems to be involved in cell turnover in many healthy adult tissues and is responsible for focal elimination of cells during normal embryonic development. It occurs spontaneously in untreated malignant neoplasms, and participates in at least some types of therapeutically induced tumour regression. It is implicated in both physiological involution and atrophy of various tissues and organs. It can also be triggered by noxious agents, both in the embryo and adult animal. Images Fig. 8-10 Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 6 Fig. 7 Fig. 11-14 Fig. 15-18 Fig. 19 Fig. 20-22 Fig. 23 and 24
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              Guidelines for the use and interpretation of assays for monitoring autophagy.

              In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

                Author and article information

                [1 ]Gustave Roussy Cancer Center , Villejuif, France
                [2 ]Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers , Paris, France
                [3 ]Université Paris Descartes/Paris V, Sorbonne Paris Cité , Paris, France
                [4 ]INSERM, U1138, Gustave Roussy , Paris, France
                [5 ]Regina Elena National Cancer Institute , Rome, Italy
                [6 ]Department of Oncological Sciences, The Tisch Cancer Institute, Ichan School of Medicine at Mount Sinai , New York, NY, USA
                [7 ]Department of Cell Biology, UT Southwestern Medical Center , Dallas, TX, USA
                [8 ]Institute of Immunology, Christian-Albrechts University , Kiel, Germany
                [9 ]Department of Biochemistry and Molecular Biology, Thomas Jefferson University , Philadelphia, PA, USA
                [10 ]Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università degli Studi di Napoli , Napoli, Italy
                [11 ]Department of Biochemistry and Medical Biophysics, University of Toronto , Toronto, ON, Canada
                [12 ]Biochemistry Laboratory, Istituto Dermopatico dell'Immacolata – Istituto Ricovero Cura Carattere Scientifico (IDI-IRCCS) , Rome, Italy
                [13 ]Department of Cancer Biology, University of Massachusetts Medical School , Worcester, MA, USA
                [14 ]Neuroscience Center of Excellence, School of Medicine , New Orleans, LA, USA
                [15 ]VIB Inflammation Research Center , Ghent, Belgium
                [16 ]Department of Biomedical Molecular Biology, Ghent University , Ghent, Belgium
                [17 ]Barts Cancer Institute, Cancer Research UK Centre of Excellence , London, UK
                [18 ]Queen Mary University of London, John Vane Science Centre , London, UK
                [19 ]Department of Cell Stress Biology, Roswell Park Cancer Institute , Buffalo, NY, USA
                [20 ]Karolinska University Hospital, Karolinska Institute , Stockholm, Sweden
                [21 ]Institute of Molecular Medicine and Spemann Graduate School of Biology and Medicine, Albert-Ludwigs University , Freiburg, Germany
                [22 ]Buck Institute for Research on Aging , Novato, CA, USA
                [23 ]Department of Neurology, University of California, San Francisco (UCSF) , San Francisco, CA, USA
                [24 ]INSERM, UMRS769 , Châtenay Malabry, France
                [25 ]LabEx LERMIT , Châtenay Malabry, France
                [26 ]Université Paris Sud/Paris XI , Orsay, France
                [27 ]Department of Comparative Biomedical Sciences and Consortium for Mitochondrial Research, University College London (UCL) , London, UK
                [28 ]Department of Experimental Medicine and Surgery, University of Rome Tor Vergata , Rome, Italy
                [29 ]Laboratory of Molecular Neuroembryology, IRCCS Fondazione Santa Lucia , Rome, Italy
                [30 ]Department of Biology, University of Rome Tor Vergata ; Rome, Italy
                [31 ]Unit of Cell Stress and Survival, Danish Cancer Society Research Center , Copenhagen, Denmark
                [32 ]Department of Pathology, University of Massachusetts Medical School , Worcester, MA, USA
                [33 ]Department of Medicine, Feinberg School of Medicine, Northwestern University , Chicago, IL, USA
                [34 ]Human Oncology and Pathogenesis Program and Department of Pathology, Memorial Sloan Kettering Cancer Center (MSKCC) , New York, NY, USA
                [35 ]Laboratory of Signal Transduction, National Institute of Environmental Health Sciences (NIEHS), National Institute of Health (NIH) , North Carolina, NC, USA
                [36 ]Tumor and Vascular Biology Research Center, The Rappaport Faculty of Medicine and Research Institute, Technion Israel Institute of Technology , Haifa, Israel
                [37 ]Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering (ICE), Departments of Neurology, Pharmacology and Molecular Sciences, Solomon H Snyder Department of Neuroscience, Johns Hopkins University School of Medicine , Baltimore, MD, USA
                [38 ]Adrienne Helis Malvin Medical Research Foundation , New Orleans, LA, USA
                [39 ]Department of Experimental and Clinical Sciences, Gabriele d'Annunzio University , Chieti, Italy
                [40 ]Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center , Ulm, Germany
                [41 ]Department of Systems Medicine, University of Rome Tor Vergata , Rome, Italy
                [42 ]Department of Physiological Chemistry, Genentech , South San Francisco, CA, USA
                [43 ]Department of Pathology and Cancer Institute, Smilow Research Center, New York University School of Medicine , New York, NY, USA
                [44 ]Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medicine (Hematology/Oncology), Penn State Hershey Cancer Institute, Penn State College of Medicine , Hershey, PA, USA
                [45 ]Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento , Lecce, Italy
                [46 ]Department of Epidemiology and Preclinical Research, National Institute for Infectious Diseases Lazzaro Spallanzani, Istituto Ricovero Cura Carattere Scientifico (IRCCS) , Rome, Italy
                [47 ]Department of Immunobiology, Yale School of Medicine , New Haven, CT, USA
                [48 ]Institute for Experimental Cancer Research in Pediatrics, Goethe University , Frankfurt, Germany
                [49 ]INSERM, U866 , Dijon, France
                [50 ]Faculty of Medicine, University of Burgundy , Dijon, France
                [51 ]Antiviral Immunity, Biotherapy and Vaccine Unit, Infection and Epidemiology Department, Institut Pasteur , Paris, France
                [52 ]Department of Immunology, St Jude's Children's Research Hospital , Memphis, TN, USA
                [53 ]Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) , Illkirch, France
                [54 ]Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University , Philadelphia, PA, USA
                [55 ]W Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University , Baltimore, MD, USA
                [56 ]Institute of Molecular Life Sciences, University of Zurich , Zurich, Switzerland
                [57 ]Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo , Tokyo, Japan
                [58 ]Department of Oncology-Pathology, Cancer Centrum Karolinska (CCK), Karolinska Institute , Stockholm, Sweden
                [59 ]Medical Department for Hematology, Technical University of Munich , Munich, Germany
                [60 ]Institute of Pharmacology, Medical Faculty, University of Bern , Bern, Switzerland
                [61 ]Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center , Villejuif, France
                [62 ]Life Sciences Institute, University of Michigan , Ann Arbor, MI, USA
                [63 ]Medical Molecular Biology Unit, Institute of Child Health, University College London (UCL) , London, UK
                [64 ]Medical Research Council Toxicology Unit , Leicester, UK
                [65 ]Centre for Cancer Biology, University of South Australia , Adelaide, SA, Australia
                [66 ]School of Medicine and School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA, Australia
                [67 ]Departments of Drug Discovery and Biomedical Sciences and Biochemistry and Molecular Biology, Medical University of South Carolina , Charleston, SC, USA
                [68 ]Center for Autophagy Research, University of Texas, Southwestern Medical Center , Dallas, TX, USA
                [69 ]Howard Hughes Medical Institute (HHMI) , Chevy Chase, MD, USA
                [70 ]Division of Nephrology and Hypertension, Christian-Albrechts University , Kiel, Germany
                [71 ]The Scripps Research Institute , La Jolla, CA, USA
                [72 ]Sanford-Burnham Center for Neuroscience, Aging, and Stem Cell Research , La Jolla, CA, USA
                [73 ]Salk Institute for Biological Studies , La Jolla, CA, USA
                [74 ]University of California, San Diego (UCSD) , San Diego, CA, USA
                [75 ]Department of Biological Sciences, St. John's University , Queens, NY, USA
                [76 ]Department of Biochemistry and Molecular Biology, Faculty of Medecine, Instituto Universitario de Oncología (IUOPA), University of Oviedo , Oviedo, Spain
                [77 ]Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center , Milan, Italy
                [78 ]Institute of Molecular Biosciences, University of Graz , Graz, Austria
                [79 ]Department of Therapeutic Research and Medicine Evaluation, Istituto Superiore di Sanita (ISS) , Roma, Italy
                [80 ]San Raffaele Institute , Sulmona, Italy
                [81 ]Laboratory for Molecular Cancer Biology, Center for the Biology of Disease , Leuven, Belgium
                [82 ]Laboratory for Molecular Cancer Biology, Center of Human Genetics , Leuven, Belgium
                [83 ]Department of Genetics, The Smurfit Institute, Trinity College , Dublin, Ireland
                [84 ]Department of Cell Biology, University of Geneva , Geneva, Switzerland
                [85 ]Laboratory for Experiments Oncology and Radiobiology (LEXOR), Academic Medical Center (AMC) , Amsterdam, The Netherlands
                [86 ]Institute of Cancer Research, The Breakthrough Toby Robins Breast Cancer Research Centre , London, UK
                [87 ]Department of Chemical Sciences and Technologies, University of Rome Tor Vergata , Rome, Italy
                [88 ]Graduate School and Faculty of Medicine, University of Tokyo , Tokyo, Japan
                [89 ]Department of Pathology, Stony Brook University , Stony Brook, NY, USA
                [90 ]Cell Death Regulation Group, Bellvitge Biomedical Research Institute (IDIBELL) , Barcelona, Spain
                [91 ]Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School , Ann Arbor, MI, USA
                [92 ]Department of Immunology, University of Washington , Seattle, WA, USA
                [93 ]Institute of Molecular Biotechnology of the Austrian Academy of Sciences , Vienna, Austria
                [94 ]Department of Hematology/Oncology, Feinberg School of Medicine, Northwestern University , Chicago, IL, USA
                [95 ]Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology and LTTA Center, University of Ferrara , Ferrara, Italy
                [96 ]Department of Physiology and Medical Physics, Royal College of Surgeons , Dublin, Ireland
                [97 ]Department of Biochemistry, La Trobe Institute of Molecular Science, La Trobe University , Melbourne, Australia
                [98 ]Laboratory of Immunopathology, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) , Buenos Aires, Argentina
                [99 ]Department of Microbiology, Immunology and Cancer Biology, University of Virginia , Charlottesville, VA, USA
                [100 ]Department Biomedical Sciences, University of Padova , Padova, Italy
                [101 ]Research Institute for Medicines, Faculty of Pharmacy, University of Lisbon , Lisbon, Portugal
                [102 ]Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine , Cambridge, UK
                [103 ]Department of Microbiology, University of Würzburg ; Würzburg, Germany
                [104 ]Soochow Institute for Translational Medicine, Soochow University , Suzhou, China
                [105 ]Institute of Pharmacology, University of Bern , Bern, Switzerland
                [106 ]Departments of Biological Sciences and Chemistry, Columbia University , New York, NY, USA
                [107 ]Department of Cell and Developmental Biology and Consortium for Mitochondrial Research, University College London (UCL) , London, UK
                [108 ]Cancer Research UK Beatson Institute , Glasgow, UK
                [109 ]Institute of Cancer Sciences, University of Glasgow , Glasgow, UK
                [110 ]Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas , Heraklion, Crete, Greece
                [111 ]Department of Basic Sciences, Faculty of Medicine, University of Crete , Heraklion, Crete, Greece
                [112 ]Osaka Medical Center for Cancer and Cardiovascular Diseases , Osaka, Japan
                [113 ]Methusalem Program, Ghent University , Ghent, Belgium
                [114 ]Division of Developmental Immunology, Biocenter, Medical University Innsbruck , Innsbruck, Austria
                [115 ]Cancer Cell Biology Program, Spanish National Cancer Research Centre (CNIO) , Madrid, Spain
                [116 ]Centre for Cell Death, Cancer and Inflammation (CCCI), UCL Cancer Institute, University College London (UCL) , London, UK
                [117 ]Rutgers Cancer Institute of New Jersey , New Brunswick, NJ, USA
                [118 ]Department of Pharmacology, University of Minnesota School of Medicine , Minneapolis, MN, USA
                [119 ]Geriatric Research, Education and Clinical Center, VA Medical Center , Minneapolis, MN, USA
                [120 ]Department of Cell Biology, Harvard Medical School , Boston, MA, USA
                [121 ]Department of Biology, Queens College , Queens, NY, USA
                [122 ]Graduate Center, City University of New York (CUNY) , Queens, NY, USA
                [123 ]Division of Toxicology, Institute of Environmental Medicine, Karolinska Institute , Stockholm, Sweden
                [124 ]Faculty of Fundamental Medicine, Lomonosov Moscow State University , Moscow, Russia
                [125 ]Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP , Paris, France.
                Author notes
                [* ]Equipe 11 - ‘Apoptose, cancer et immunité', Centre de Recherche des Cordeliers, 15 rue de l'École de Médecine , 75006 Paris, France. Tel: +33 1 4427 7661 or +33 1 4427 7667; Fax: +33 1 4427 7674; E-mail: deadoc@ or kroemer@

                Share senior co-authorship.

                Cell Death Differ
                Cell Death Differ
                Cell Death and Differentiation
                Nature Publishing Group
                January 2015
                19 September 2014
                1 January 2015
                : 22
                : 1
                : 58-73
                25236395 4262782 cdd2014137 10.1038/cdd.2014.137
                Copyright © 2014 Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 3.0 Unported License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit


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