{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T10:40:25Z","timestamp":1793529625523,"version":"4.5.0"},"reference-count":50,"publisher":"American Society of Hematology","issue":"8","license":[{"start":{"date-parts":[[2021,9,16]],"date-time":"2021-09-16T00:00:00Z","timestamp":1631750400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/legalcode"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,2,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>There is a critical need for cerebro-protective interventions to improve the suboptimal outcomes of patients with ischemic stroke who have been treated with reperfusion strategies. We found that nuclear pyruvate kinase muscle 2 (PKM2), a modulator of systemic inflammation, was upregulated in neutrophils after the onset of ischemic stroke in both humans and mice. Therefore, we determined the role of PKM2 in stroke pathogenesis by using murine models with preexisting comorbidities. We generated novel myeloid cell\u2013specific PKM2\u2212\/\u2212 mice on wild-type (PKM2fl\/flLysMCre+) and hyperlipidemic background (PKM2fl\/flLysMCre+Apoe\u2212\/\u2212). Controls were littermate PKM2fl\/flLysMCre\u2013 or PKM2fl\/flLysMCre\u2013Apoe\u2212\/\u2212 mice. Genetic deletion of PKM2 in myeloid cells limited inflammatory response in peripheral neutrophils and reduced neutrophil extracellular traps after cerebral ischemia and reperfusion, suggesting that PKM2 promotes neutrophil hyperactivation in the setting of stroke. In the filament and autologous clot and recombinant tissue plasminogen activator stroke models, irrespective of sex, deletion of PKM2 in myeloid cells in either wild-type or hyperlipidemic mice reduced infarcts and enhanced long-term sensorimotor recovery. Laser speckle imaging revealed improved regional cerebral blood flow in myeloid cell\u2013specific PKM2-deficient mice that was concomitant with reduced post-ischemic cerebral thrombo-inflammation (intracerebral fibrinogen, platelet [CD41+] deposition, neutrophil infiltration, and inflammatory cytokines). Mechanistically, PKM2 regulates post-ischemic inflammation in peripheral neutrophils by promoting STAT3 phosphorylation. To enhance the translational significance, we inhibited PKM2 nuclear translocation using a small molecule and found significantly reduced neutrophil hyperactivation and improved short-term and long-term functional outcomes after stroke. Collectively, these findings identify PKM2 as a novel therapeutic target to improve brain salvage and recovery after reperfusion.<\/jats:p>","DOI":"10.1182\/blood.2021012322","type":"journal-article","created":{"date-parts":[[2021,9,16]],"date-time":"2021-09-16T15:19:19Z","timestamp":1631805559000},"page":"1234-1245","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":177,"title":["PKM2 promotes neutrophil activation and cerebral thromboinflammation: therapeutic implications for ischemic stroke"],"prefix":"10.1182","volume":"139","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9268-4363","authenticated-orcid":false,"given":"Nirav","family":"Dhanesha","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Hematology\/Oncology, University of Iowa, Iowa City, IA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9727-9738","authenticated-orcid":false,"given":"Rakesh B.","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Hematology\/Oncology, University of Iowa, Iowa City, IA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4219-5240","authenticated-orcid":false,"given":"Prakash","family":"Doddapattar","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Hematology\/Oncology, University of Iowa, Iowa City, IA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madankumar","family":"Ghatge","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Hematology\/Oncology, University of Iowa, Iowa City, IA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gagan D.","family":"Flora","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Hematology\/Oncology, University of Iowa, Iowa City, IA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manish","family":"Jain","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Hematology\/Oncology, University of Iowa, Iowa City, IA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4704-3185","authenticated-orcid":false,"given":"Daniel","family":"Thedens","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of Iowa, Iowa City, IA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heena","family":"Olalde","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Iowa, Iowa City, IA;"},{"name":"Department of Neurosurgery, University of Iowa, Iowa City, IA; and"},{"name":"Department of Epidemiology, University of Iowa, Iowa City, IA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariia","family":"Kumskova","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Hematology\/Oncology, University of Iowa, Iowa City, IA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrique C.","family":"Leira","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Iowa, Iowa City, IA;"},{"name":"Department of Neurosurgery, University of Iowa, Iowa City, IA; and"},{"name":"Department of Epidemiology, University of Iowa, Iowa City, IA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8554-0898","authenticated-orcid":false,"given":"Anil K.","family":"Chauhan","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Hematology\/Oncology, University of Iowa, Iowa City, IA;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"6","key":"2022050218123557700_B1","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1212\/WNL.59.6.862","article-title":"Arterial reocclusion in stroke patients treated with intravenous tissue plasminogen activator","volume":"59","author":"Alexandrov","year":"2002","journal-title":"Neurology."},{"issue":"7","key":"2022050218123557700_B2","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1161\/01.STR.0000170711.43405.81","article-title":"Predictors of early arterial reocclusion after tissue plasminogen activator-induced recanalization in acute ischemic stroke","volume":"36","author":"Rubiera","year":"2005","journal-title":"Stroke."},{"issue":"10029","key":"2022050218123557700_B3","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1016\/S0140-6736(16)00163-X","article-title":"Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials","volume":"387","author":"Goyal","year":"2016","journal-title":"Lancet."},{"issue":"8","key":"2022050218123557700_B4","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/s41582-019-0221-1","article-title":"Thrombo-inflammation in acute ischaemic stroke - implications for treatment","volume":"15","author":"Stoll","year":"2019","journal-title":"Nat Rev Neurol."},{"issue":"4","key":"2022050218123557700_B5","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1161\/STROKEAHA.115.011238","article-title":"Thromboinflammation in stroke brain damage","volume":"47","author":"De Meyer","year":"2016","journal-title":"Stroke."},{"issue":"10","key":"2022050218123557700_B6","doi-asserted-by":"crossref","first-page":"e20190613","DOI":"10.1084\/jem.20190613","article-title":"PKM2 promotes Th17 cell differentiation and autoimmune inflammation by fine-tuning STAT3 activation","volume":"217","author":"Damasceno","year":"2020","journal-title":"J Exp Med."},{"issue":"4","key":"2022050218123557700_B7","doi-asserted-by":"crossref","first-page":"763","DOI":"10.4049\/jimmunol.1901086","article-title":"Pyruvate kinase M2 promotes expression of proinflammatory mediators in house dust mite-induced allergic airways disease","volume":"204","author":"van de Wetering","year":"2020","journal-title":"J Immunol."},{"issue":"7","key":"2022050218123557700_B8","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1016\/j.cellsig.2015.02.032","article-title":"Pyruvate kinase M2 accelerates pro-inflammatory cytokine secretion and cell proliferation induced by lipopolysaccharide in colorectal cancer","volume":"27","author":"Yang","year":"2015","journal-title":"Cell Signal."},{"issue":"3","key":"2022050218123557700_B9","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1016\/S0021-9258(19)68155-X","article-title":"The M1 and M2 subunits of rat pyruvate kinase are encoded by different messenger RNAs","volume":"257","author":"Noguchi","year":"1982","journal-title":"J Biol Chem."},{"issue":"5","key":"2022050218123557700_B10","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.1161\/ATVBAHA.121.316021","article-title":"Smooth muscle cell-specific PKM (pyruvate kinase M) 2 promotes smooth muscle cell phenotypic switching and neointimal hyperplasia","volume":"41","author":"Jain","year":"2021","journal-title":"Arterioscler Thromb Vasc Biol."},{"issue":"12","key":"2022050218123557700_B11","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1182\/blood.2020007140","article-title":"The metabolic enzyme pyruvate kinase M2 regulates platelet function and arterial thrombosis","volume":"137","author":"Nayak","year":"2021","journal-title":"Blood."},{"issue":"1","key":"2022050218123557700_B12","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.cmet.2014.12.005","article-title":"Pyruvate kinase M2 regulates Hif-1\u03b1 activity and IL-1\u03b2 induction and is a critical determinant of the warburg effect in LPS-activated macrophages","volume":"21","author":"Palsson-McDermott","year":"2015","journal-title":"Cell Metab."},{"issue":"1","key":"2022050218123557700_B13","doi-asserted-by":"crossref","first-page":"13280","DOI":"10.1038\/ncomms13280","article-title":"PKM2-dependent glycolysis promotes NLRP3 and AIM2 inflammasome activation","volume":"7","author":"Xie","year":"2016","journal-title":"Nat Commun."},{"key":"2022050218123557700_B14","doi-asserted-by":"crossref","first-page":"145","DOI":"10.3389\/fimmu.2016.00145","article-title":"Pyruvate kinase M2: a potential target for regulating inflammation","volume":"7","author":"Alves-Filho","year":"2016","journal-title":"Front Immunol."},{"issue":"5","key":"2022050218123557700_B15","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/j.molcel.2012.01.001","article-title":"Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase","volume":"45","author":"Gao","year":"2012","journal-title":"Mol Cell."},{"issue":"7375","key":"2022050218123557700_B16","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1038\/nature10598","article-title":"Nuclear PKM2 regulates \u03b2-catenin transactivation upon EGFR activation","volume":"480","author":"Yang","year":"2011","journal-title":"Nature."},{"issue":"5","key":"2022050218123557700_B17","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1016\/j.cell.2011.03.054","article-title":"Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1","volume":"145","author":"Luo","year":"2011","journal-title":"Cell."},{"issue":"5","key":"2022050218123557700_B18","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1016\/j.biocel.2007.11.009","article-title":"Pyruvate kinase isozyme type M2 (PKM2) interacts and cooperates with Oct-4 in regulating transcription","volume":"40","author":"Lee","year":"2008","journal-title":"Int J Biochem Cell Biol."},{"issue":"3","key":"2022050218123557700_B19","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1084\/jem.20150900","article-title":"The glycolytic enzyme PKM2 bridges metabolic and inflammatory dysfunction in coronary artery disease","volume":"213","author":"Shirai","year":"2016","journal-title":"J Exp Med."},{"issue":"2","key":"2022050218123557700_B20","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.cmet.2019.10.015","article-title":"Pharmacological activation of pyruvate kinase M2 inhibits CD4+ T cell pathogenicity and suppresses autoimmunity","volume":"31","author":"Angiari","year":"2020","journal-title":"Cell Metab."},{"issue":"12","key":"2022050218123557700_B21","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1161\/CIRCRESAHA.120.316659","article-title":"Targeting myeloid-specific integrin \u03b19\u03b21 improves short- and long-term stroke outcomes in murine models with preexisting comorbidities by limiting thrombosis and inflammation","volume":"126","author":"Dhanesha","year":"2020","journal-title":"Circ Res."},{"issue":"3","key":"2022050218123557700_B22","doi-asserted-by":"crossref","first-page":"e40","DOI":"10.1161\/STROKEAHA.118.021564","article-title":"Polymorphonuclear neutrophils play a decisive role for brain injury and neurological recovery poststroke","volume":"50","author":"Hermann","year":"2019","journal-title":"Stroke."},{"issue":"10","key":"2022050218123557700_B23","doi-asserted-by":"crossref","first-page":"2916","DOI":"10.1161\/STROKEAHA.115.010620","article-title":"Role of neutrophils in exacerbation of brain injury after focal cerebral ischemia in hyperlipidemic mice","volume":"46","author":"Herz","year":"2015","journal-title":"Stroke."},{"issue":"6","key":"2022050218123557700_B24","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1038\/jcbfm.2015.45","article-title":"Targeting neutrophils in ischemic stroke: translational insights from experimental studies","volume":"35","author":"Jickling","year":"2015","journal-title":"J Cereb Blood Flow Metab."},{"issue":"1","key":"2022050218123557700_B25","doi-asserted-by":"crossref","first-page":"2488","DOI":"10.1038\/s41467-020-16191-y","article-title":"Neutrophil extracellular traps released by neutrophils impair revascularization and vascular remodeling after stroke","volume":"11","author":"Kang","year":"2020","journal-title":"Nat Commun."},{"issue":"2","key":"2022050218123557700_B26","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/s00401-014-1355-2","article-title":"Very-late-antigen-4 (VLA-4)-mediated brain invasion by neutrophils leads to interactions with microglia, increased ischemic injury and impaired behavior in experimental stroke","volume":"129","author":"Neumann","year":"2015","journal-title":"Acta Neuropathol."},{"issue":"2","key":"2022050218123557700_B27","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1002\/ana.24993","article-title":"Neutrophil extracellular traps in ischemic stroke thrombi","volume":"82","author":"Laridan","year":"2017","journal-title":"Ann Neurol."},{"issue":"2","key":"2022050218123557700_B28","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.cell.2013.09.025","article-title":"PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells","volume":"155","author":"Israelsen","year":"2013","journal-title":"Cell."},{"issue":"9","key":"2022050218123557700_B29","doi-asserted-by":"crossref","first-page":"2632","DOI":"10.1161\/STROKEAHA.117.017112","article-title":"Translational stroke research: vision and opportunities","volume":"48","author":"Bosetti","year":"2017","journal-title":"Stroke."},{"issue":"6","key":"2022050218123557700_B30","doi-asserted-by":"crossref","first-page":"2244","DOI":"10.1161\/STROKEAHA.108.541128","article-title":"Update of the stroke therapy academic industry roundtable preclinical recommendations","volume":"40","author":"Fisher","year":"2009","journal-title":"Stroke."},{"issue":"6","key":"2022050218123557700_B31","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1038\/jcbfm.2013.38","article-title":"Hyperlipidemia disrupts cerebrovascular reflexes and worsens ischemic perfusion defect","volume":"33","author":"Ayata","year":"2013","journal-title":"J Cereb Blood Flow Metab."},{"issue":"7399","key":"2022050218123557700_B32","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1038\/nature11087","article-title":"Apolipoprotein E controls cerebrovascular integrity via cyclophilin A","volume":"485","author":"Bell","year":"2012","journal-title":"Nature."},{"issue":"4","key":"2022050218123557700_B33","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.ccr.2009.02.015","article-title":"Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors","volume":"15","author":"Lee","year":"2009","journal-title":"Cancer Cell."},{"key":"2022050218123557700_B34","volume-title":"Probe Reports from the NIH Molecular Libraries Program","author":"Jiang","year":"2010"},{"issue":"3","key":"2022050218123557700_B35","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1002\/ana.20741","article-title":"1,026 experimental treatments in acute stroke","volume":"59","author":"O\u2019Collins","year":"2006","journal-title":"Ann Neurol."},{"issue":"5","key":"2022050218123557700_B36","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1002\/ana.21127","article-title":"Future of neuroprotection for acute stroke: in the aftermath of the SAINT trials","volume":"61","author":"Savitz","year":"2007","journal-title":"Ann Neurol."},{"issue":"10227","key":"2022050218123557700_B37","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1016\/S0140-6736(20)30258-0","article-title":"Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial","volume":"395","author":"Hill","year":"2020","journal-title":"Lancet."},{"issue":"12","key":"2022050218123557700_B38","doi-asserted-by":"crossref","first-page":"3413","DOI":"10.1161\/STROKEAHA.117.017283","article-title":"Reconsidering neuroprotection in the reperfusion era","volume":"48","author":"Savitz","year":"2017","journal-title":"Stroke."},{"issue":"8","key":"2022050218123557700_B39","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1038\/sj.jcbfm.9600264","article-title":"Gene expression in blood changes rapidly in neutrophils and monocytes after ischemic stroke in humans: a microarray study","volume":"26","author":"Tang","year":"2006","journal-title":"J Cereb Blood Flow Metab."},{"issue":"3","key":"2022050218123557700_B40","doi-asserted-by":"crossref","first-page":"e42","DOI":"10.1161\/STROKEAHA.118.021563","article-title":"Neutrophils, the felons of the brain","volume":"50","author":"Aronowski","year":"2019","journal-title":"Stroke."},{"issue":"10","key":"2022050218123557700_B41","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1161\/01.STR.22.10.1276","article-title":"Poly morphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons","volume":"22","author":"del Zoppo","year":"1991","journal-title":"Stroke."},{"key":"2022050218123557700_B42","doi-asserted-by":"crossref","first-page":"83","DOI":"10.3389\/fneur.2019.00083","article-title":"IL-6 plasma levels correlate with cerebral perfusion deficits and infarct sizes in stroke patients without associated infections","volume":"10","author":"Hotter","year":"2019","journal-title":"Front Neurol."},{"issue":"9","key":"2022050218123557700_B43","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1038\/jcbfm.2012.88","article-title":"Inflammatory cytokines in experimental and human stroke","volume":"32","author":"Lambertsen","year":"2012","journal-title":"J Cereb Blood Flow Metab."},{"issue":"1","key":"2022050218123557700_B44","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/1750-1326-6-11","article-title":"Pathophysiology, treatment, and animal and cellular models of human ischemic stroke","volume":"6","author":"Woodruff","year":"2011","journal-title":"Mol Neurodegener."},{"issue":"8","key":"2022050218123557700_B45","doi-asserted-by":"crossref","first-page":"1884","DOI":"10.1161\/ATVBAHA.112.250993","article-title":"Extracellular chromatin is an important mediator of ischemic stroke in mice","volume":"32","author":"De Meyer","year":"2012","journal-title":"Arterioscler Thromb Vasc Biol."},{"issue":"16","key":"2022050218123557700_B46","doi-asserted-by":"crossref","first-page":"3354","DOI":"10.1182\/blood-2009-08-240317","article-title":"STAT3 controls the neutrophil migratory response to CXCR2 ligands by direct activation of G-CSF-induced CXCR2 expression and via modulation of CXCR2 signal transduction","volume":"115","author":"Nguyen-Jackson","year":"2010","journal-title":"Blood."},{"issue":"12","key":"2022050218123557700_B47","doi-asserted-by":"crossref","first-page":"3682","DOI":"10.1182\/blood-2006-02-003012","article-title":"STAT3 governs distinct pathways in emergency granulopoiesis and mature neutrophils","volume":"108","author":"Panopoulos","year":"2006","journal-title":"Blood."},{"issue":"5834","key":"2022050218123557700_B48","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1126\/science.1140485","article-title":"Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production","volume":"317","author":"Naugler","year":"2007","journal-title":"Science."},{"issue":"15","key":"2022050218123557700_B49","doi-asserted-by":"crossref","first-page":"4182","DOI":"10.1523\/JNEUROSCI.4317-15.2016","article-title":"Monocyte-derived macrophages contribute to spontaneous long-term functional recovery after stroke in mice","volume":"36","author":"Wattananit","year":"2016","journal-title":"J Neurosci."},{"key":"2022050218123557700_B50","doi-asserted-by":"crossref","first-page":"707972","DOI":"10.3389\/fimmu.2021.707972","article-title":"T cell response in ischemic stroke: from mechanisms to translational insights","volume":"12","author":"Zhang","year":"2021","journal-title":"Front Immunol."}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/139\/8\/1234\/1888957\/bloodbld2021012322.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/139\/8\/1234\/1888957\/bloodbld2021012322.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,2]],"date-time":"2022-05-02T14:13:37Z","timestamp":1651500817000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/139\/8\/1234\/476940\/PKM2-promotes-neutrophil-activation-and-cerebral"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,24]]},"references-count":50,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2022,2,24]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.2021012322","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.740828243.793593701","asserted-by":"object"}]},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,24]]}}}