{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T12:06:02Z","timestamp":1792670762774,"version":"4.5.0"},"reference-count":34,"publisher":"American Chemical Society (ACS)","issue":"9","license":[{"start":{"date-parts":[[2019,5,7]],"date-time":"2019-05-07T00:00:00Z","timestamp":1557187200000},"content-version":"vor","delay-in-days":18,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["01951"],"award-info":[{"award-number":["01951"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2822"],"award-info":[{"award-number":["2822"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,5,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Apoptosis is a controlled form of cell death that can be induced by various diseases and exogenous toxicants. Common apoptosis-detection methods rely on fluorescent markers, which necessitate the use of costly reagents and time-consuming labeling procedures. Label-free methods avoid these problems, but often require specialized instruments instead. Here, we utilize apoptotic-cell disintegration to develop a novel label-free detection method based on the quantification of subcellular debris particles in bright-field-microscopy images. Debris counts show strong correlations with fluorescence-based annexin V staining and can be used to study concentration-dependent and temporal apoptosis activation. The method is rapid, low-cost, and easy to apply, as the only experimental step comprises bright-field imaging of culture-media samples followed by automated image processing. The late-stage nature of the debris measurement means that the method can complement other, established apoptosis assays, and its accessibility will allow a wider community of researchers to study apoptotic cell death.<\/jats:p>","DOI":"10.1021\/acs.analchem.9b01243","type":"journal-article","created":{"date-parts":[[2019,4,19]],"date-time":"2019-04-19T05:25:12Z","timestamp":1555651512000},"page":"5548-5552","source":"Crossref","is-referenced-by-count":28,"title":["Image-Based Quantification of Cell Debris as a Measure\nof Apoptosis"],"prefix":"10.1021","volume":"91","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4502-8184","authenticated-orcid":true,"given":"Magnus","family":"O\u0308lander","sequence":"first","affiliation":[{"name":"Uppsala University , , ,","place":["Uppsala, Sweden, SE-75123"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niklas","family":"Handin","sequence":"additional","affiliation":[{"name":"Uppsala University , , ,","place":["Uppsala, Sweden, SE-75123"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Per","family":"Artursson","sequence":"additional","affiliation":[{"name":"Uppsala University , , ,","place":["Uppsala, Sweden, SE-75123"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2019,4,19]]},"reference":[{"key":"2026090201481794000_cit1","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1080\/01926230701320337","article-title":"Apoptosis:\na review of programmed cell death","volume":"35","author":"Elmore","year":"2007","journal-title":"Toxicol.\nPathol."},{"key":"2026090201481794000_cit2","doi-asserted-by":"publisher","first-page":"1456","DOI":"10.1126\/science.7878464","article-title":"Apoptosis\nin the pathogenesis and treatment of disease","volume":"267","author":"Thompson","year":"1995","journal-title":"Science"},{"key":"2026090201481794000_cit3","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1038\/nrd1720","article-title":"Elucidating mechanisms of drug-induced toxicity","volume":"4","author":"Liebler","year":"2005","journal-title":"Nat. Rev. Drug Discovery"},{"key":"2026090201481794000_cit4","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1039\/c0ay00247j","article-title":"Detection of apoptosis: A review\nof conventional and novel techniques","volume":"2","author":"Martinez","year":"2010","journal-title":"Anal.\nMethods"},{"key":"2026090201481794000_cit5","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1083\/jcb.119.3.493","article-title":"Identification\nof programmed cell\ndeath in situ via specific labeling of nuclear DNA fragmentation","volume":"119","author":"Gavrieli","year":"1992","journal-title":"J. Cell Biol."},{"key":"2026090201481794000_cit6","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1182\/blood.V84.5.1415.bloodjournal8451415","article-title":"Annexin V for flow cytometric detection of phosphatidylserine\nexpression on B cells undergoing apoptosis","volume":"84","author":"Koopman","year":"1994","journal-title":"Blood"},{"key":"2026090201481794000_cit7","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1006\/abio.1997.2220","article-title":"Fluorometric\nand colorimetric detection\nof caspase activity associated with apoptosis","volume":"251","author":"Gurtu","year":"1997","journal-title":"Anal. Biochem."},{"key":"2026090201481794000_cit8","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1007\/s004410000193","article-title":"The morphology\nof apoptosis","volume":"301","author":"Ha\u0308cker","year":"2000","journal-title":"Cell Tissue Res."},{"key":"2026090201481794000_cit9","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.tcb.2016.08.011","article-title":"Disassembly of the\ndying: mechanisms and functions","volume":"27","author":"Atkin-Smith","year":"2017","journal-title":"Trends Cell\nBiol."},{"key":"2026090201481794000_cit10","doi-asserted-by":"publisher","first-page":"1411","DOI":"10.1007\/s10495-014-1009-9","article-title":"Label free high throughput screening\nfor apoptosis inducing chemicals using time-lapse microscopy signal\nprocessing","volume":"19","author":"Aftab","year":"2014","journal-title":"Apoptosis"},{"key":"2026090201481794000_cit11","doi-asserted-by":"publisher","first-page":"064002","DOI":"10.1117\/1.2804926","article-title":"Noninvasive time-dependent\ncytometry monitoring by\ndigital holography","volume":"12","author":"Kemmler","year":"2007","journal-title":"J. Biomed. Opt."},{"key":"2026090201481794000_cit12","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1016\/j.jsb.2012.03.008","article-title":"Cell volume changes\nduring apoptosis monitored in real\ntime using digital holographic microscopy","volume":"178","author":"Khmaladze","year":"2012","journal-title":"J.\nStruct. Biol."},{"key":"2026090201481794000_cit13","doi-asserted-by":"publisher","first-page":"916","DOI":"10.1007\/s10495-012-0737-y","article-title":"Label-free\nmonitoring of apoptosis by surface plasmon resonance detection of\nmorphological changes","volume":"17","author":"Maltais","year":"2012","journal-title":"Apoptosis"},{"key":"2026090201481794000_cit14","doi-asserted-by":"publisher","first-page":"6408","DOI":"10.1039\/C6AN01596D","article-title":"Accurate\nquantification of apoptosis\nprogression and toxicity using a dielectrophoretic approach","volume":"141","author":"Henslee","year":"2016","journal-title":"Analyst"},{"key":"2026090201481794000_cit15","doi-asserted-by":"publisher","first-page":"4723","DOI":"10.1021\/ac403394z","article-title":"Electrochemical approach for the development of a simple\nmethod for detecting cell apoptosis based on caspase-3 activity","volume":"86","author":"Takano","year":"2014","journal-title":"Anal. Chem."},{"key":"2026090201481794000_cit16","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1007\/978-1-60761-688-7_3","article-title":"Isolation and\nCulture of Primary Hepatocytes from Resected Human Liver Tissue","volume-title":"Hepatocytes: Methods and Protocols","author":"LeCluyse","year":"2010"},{"key":"2026090201481794000_cit17","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of\nimage analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. Methods"},{"key":"2026090201481794000_cit18","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: an open-source platform for biological-image\nanalysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. 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Toxicol."},{"key":"2026090201481794000_cit20","doi-asserted-by":"publisher","first-page":"1907","DOI":"10.1128\/IAI.73.4.1907-1916.2005","article-title":"Apoptosis, pyroptosis,\nand necrosis: mechanistic description\nof dead and dying eukaryotic cells","volume":"73","author":"Fink","year":"2005","journal-title":"Infect.\nImmun."},{"key":"2026090201481794000_cit21","doi-asserted-by":"publisher","first-page":"1295","DOI":"10.1007\/s10495-011-0651-8","article-title":"A rapid detection\nmethod for apoptosis and necrosis measurement using the Cellometer\nimaging cytometry","volume":"16","author":"Chan","year":"2011","journal-title":"Apoptosis"},{"key":"2026090201481794000_cit22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/(SICI)1097-0320(19980101)31:1&lt;1::AID-CYTO1&gt;3.0.CO;2-R","article-title":"Annexin V-affinity assay: a review\non an apoptosis detection system based on phosphatidylserine exposure","volume":"31","author":"van Engeland","year":"1998","journal-title":"Cytometry"},{"key":"2026090201481794000_cit23","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1016\/j.cell.2010.02.014","article-title":"Autoimmunity\nand the clearance of\ndead cells","volume":"140","author":"Nagata","year":"2010","journal-title":"Cell"},{"key":"2026090201481794000_cit24","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1007\/s00204-018-2375-9","article-title":"A simple approach\nfor restoration of differentiation\nand function in cryopreserved human hepatocytes","volume":"93","author":"O\u0308lander","year":"2019","journal-title":"Arch. Toxicol."},{"key":"2026090201481794000_cit25","doi-asserted-by":"publisher","first-page":"32608","DOI":"10.1074\/jbc.273.49.32608","article-title":"Inhibition of human caspases by peptide-based\nand macromolecular\ninhibitors","volume":"273","author":"Garcia-Calvo","year":"1998","journal-title":"J. Biol. Chem."},{"key":"2026090201481794000_cit26","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1083\/jcb.124.4.619","article-title":"Disruption of epithelial\ncell-matrix interactions induces\napoptosis","volume":"124","author":"Frisch","year":"1994","journal-title":"J. Cell Biol."},{"key":"2026090201481794000_cit27","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1016\/S1096-7192(02)00004-5","article-title":"Loss of cell anchorage\ntriggers apoptosis (anoikis) in primary mouse hepatocytes","volume":"75","author":"Smets","year":"2002","journal-title":"Mol. Genet. Metab."},{"key":"2026090201481794000_cit28","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1289\/ehp.98106559","article-title":"Nephrotoxicity testing in vitro--what\nwe know and what\nwe need to know","volume":"106","author":"Pfaller","year":"1998","journal-title":"Environ. Health Perspect."},{"key":"2026090201481794000_cit29","doi-asserted-by":"publisher","first-page":"7059","DOI":"10.1158\/0008-5472.CAN-06-0325","article-title":"Cyclooxygenase-2 inhibition induces apoptosis signaling via death\nreceptors and mitochondria in hepatocellular carcinoma","volume":"66","author":"Kern","year":"2006","journal-title":"Cancer Res."},{"key":"2026090201481794000_cit30","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1124\/dmd.116.074369","article-title":"Transcriptional,\nfunctional and mechanistic\ncomparisons of stem cell-derived hepatocytes, HepaRG cells and 3D\nhuman hepatocyte spheroids as predictive in vitro systems for drug-induced\nliver injury","volume":"45","author":"Bell","year":"2017","journal-title":"Drug Metab. Dispos."},{"key":"2026090201481794000_cit31","doi-asserted-by":"publisher","first-page":"2155","DOI":"10.1016\/j.bcp.2003.08.003","article-title":"Diclofenac\ninduces apoptosis in hepatocytes by alteration of mitochondrial\nfunction and generation of ROS","volume":"66","author":"Go\u0301mez-Lecho\u0301n","year":"2003","journal-title":"Biochem. Pharmacol."},{"key":"2026090201481794000_cit32","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/S0925-4439(02)00144-8","article-title":"Mitochondrial\ndysfunction is an early indicator of\ndoxorubicin-induced apoptosis","volume":"1588","author":"Green","year":"2002","journal-title":"Biochim. Biophys.\nActa, Mol. Basis Dis."},{"key":"2026090201481794000_cit33","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1111\/j.2042-7158.2012.01567.x","article-title":"Doxorubicin: an\nupdate on anticancer\nmolecular action, toxicity and novel drug delivery systems","volume":"65","author":"Tacar","year":"2013","journal-title":"J. Pharm. Pharmacol."},{"key":"2026090201481794000_cit34","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1038\/nchembio.1270","article-title":"Identification of\nsmall molecules\nfor human hepatocyte expansion and iPS differentiation","volume":"9","author":"Shan","year":"2013","journal-title":"Nat. Chem. Biol."}],"container-title":["Analytical Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.analchem.9b01243","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/ancham\/article-pdf\/91\/9\/5548\/67632106\/acs.analchem.9b01243.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/ancham\/article-pdf\/91\/9\/5548\/67632106\/acs.analchem.9b01243.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T05:48:24Z","timestamp":1788328104000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/ancham\/article\/91\/9\/5548\/823573\/Image-Based-Quantification-of-Cell-Debris-as-a"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,19]]},"references-count":34,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2019,4,19]]},"published-print":{"date-parts":[[2019,5,7]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.analchem.9b01243","relation":{},"ISSN":["0003-2700","1520-6882"],"issn-type":[{"value":"0003-2700","type":"print"},{"value":"1520-6882","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4,19]]}}}