{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T11:01:11Z","timestamp":1777806071055,"version":"3.51.4"},"reference-count":50,"publisher":"Walter de Gruyter GmbH","issue":"8","license":[{"start":{"date-parts":[[2023,2,28]],"date-time":"2023-02-28T00:00:00Z","timestamp":1677542400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,7,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec id=\"j_cclm-2023-0093_abs_001\">\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>Extracellular histone levels are associated with the severity of many human pathologies, including sepsis and COVID-19. This study aimed to investigate the role of extracellular histones on monocyte distribution width (MDW), and their effect on the release of cytokines by blood cells.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec id=\"j_cclm-2023-0093_abs_002\">\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Peripheral venous blood was collected from healthy subjects and treated with different doses of a histone mixture (range 0\u2013200\u00a0\u03bcg\/mL) to analyze MDW modifications up-to 3\u00a0h and digital microscopy of blood smears. Plasma obtained after 3\u00a0h of histone treatment were assayed to evaluate a panel of 24 inflammatory cytokines.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec id=\"j_cclm-2023-0093_abs_003\">\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>MDW values significantly increased in a time- and dose-dependent manner. These findings are associated with the histone-induced modifications of cell volume, cytoplasmic granularity, vacuolization, and nuclear structure of monocytes, promoting their heterogeneity without affecting their count. After 3\u00a0h of treatment almost all cytokines significantly increased in a dose-dependent manner. The most relevant response was shown by the significantly increased G-CSF levels, and by the increase of IL-1\u03b2, IL-6, MIP-1\u03b2, and IL-8 at the histone doses of 50, 100, and 200\u00a0\u00b5g\/mL. VEGF, IP-10, GM-CSF, TNF-\u03b1, Eotaxin, and IL-2 were also up-regulated, and a lower but significant increase was observed for IL-15, IL-5, IL-17, bFGF, IL-10, IFN-\u03b3, MCP-1, and IL-9.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec id=\"j_cclm-2023-0093_abs_004\">\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Circulating histones critically induce functional alterations of monocytes mirrored by MDW, monocyte anisocytosis, and hyperinflammation\/cytokine storm in sepsis and COVID-19. MDW and circulating histones may be useful tools to predict higher risks of worst outcomes.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1515\/cclm-2023-0093","type":"journal-article","created":{"date-parts":[[2023,2,27]],"date-time":"2023-02-27T14:29:31Z","timestamp":1677508171000},"page":"1525-1535","source":"Crossref","is-referenced-by-count":18,"title":["Monocyte distribution width alterations and cytokine storm are modulated by circulating histones"],"prefix":"10.1515","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5546-8765","authenticated-orcid":false,"given":"Daniela","family":"Ligi","sequence":"first","affiliation":[{"name":"Unit of Clinical Biochemistry, Section of Biochemistry and Biotechnology, Department of Biomolecular Sciences-DISB , University of Urbino Carlo Bo , Urbino , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruna","family":"Lo Sasso","sequence":"additional","affiliation":[{"name":"Institute of Clinical Biochemistry, Clinical Molecular Medicine and Clinical Laboratory Medicine, Department of Biomedicine, Neurosciences and Advanced Diagnostics, BiND , University of Palermo , Palermo , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Della Franca","sequence":"additional","affiliation":[{"name":"Unit of Clinical Biochemistry, Section of Biochemistry and Biotechnology, Department of Biomolecular Sciences-DISB , University of Urbino Carlo Bo , Urbino , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosaria Vincenza","family":"Giglio","sequence":"additional","affiliation":[{"name":"Institute of Clinical Biochemistry, Clinical Molecular Medicine and Clinical Laboratory Medicine, Department of Biomedicine, Neurosciences and Advanced Diagnostics, BiND , University of Palermo , Palermo , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luisa","family":"Agnello","sequence":"additional","affiliation":[{"name":"Institute of Clinical Biochemistry, Clinical Molecular Medicine and Clinical Laboratory Medicine, Department of Biomedicine, Neurosciences and Advanced Diagnostics, BiND , University of Palermo , Palermo , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcello","family":"Ciaccio","sequence":"additional","affiliation":[{"name":"Institute of Clinical Biochemistry, Clinical Molecular Medicine and Clinical Laboratory Medicine, Department of Biomedicine, Neurosciences and Advanced Diagnostics, BiND , University of Palermo , Palermo , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8112-6139","authenticated-orcid":false,"given":"Ferdinando","family":"Mannello","sequence":"additional","affiliation":[{"name":"Unit of Clinical Biochemistry, Section of Biochemistry and Biotechnology, Department of Biomolecular Sciences-DISB , University of Urbino Carlo Bo , Urbino , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"374","published-online":{"date-parts":[[2023,2,28]]},"reference":[{"key":"2023063017541071827_j_cclm-2023-0093_ref_001","doi-asserted-by":"crossref","unstructured":"Chen, R, Kang, R, Fan, XG, Tang, D. Release and activity of histone in diseases. Cell Death Dis 2014;5:e1370. https:\/\/doi.org\/10.1038\/cddis.2014.337.","DOI":"10.1038\/cddis.2014.337"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_002","doi-asserted-by":"crossref","unstructured":"Szatmary, P, Huang, W, Criddle, D, Tepikin, A, Sutton, R. Biology, role and therapeutic potential of circulating histones in acute inflammatory disorders. J Cell Mol Med 2018;22:4617\u201329. https:\/\/doi.org\/10.1111\/jcmm.13797.","DOI":"10.1111\/jcmm.13797"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_003","doi-asserted-by":"crossref","unstructured":"Silk, E, Zhao, H, Weng, H, Ma, D. The role of extracellular histone in organ injury. Cell Death Dis 2017;8:e2812. https:\/\/doi.org\/10.1038\/cddis.2017.52.","DOI":"10.1038\/cddis.2017.52"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_004","doi-asserted-by":"crossref","unstructured":"Zhang, X, Li, X. The role of histones and heparin in sepsis: a review. J\u00a0Intensive Care Med 2022;37:319\u201326. https:\/\/doi.org\/10.1177\/0885066621992320.","DOI":"10.1177\/0885066621992320"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_005","doi-asserted-by":"crossref","unstructured":"Ligi, D, Giglio, RV, Henry, BM, Lippi, G, Ciaccio, M, Plebani, M, et al.. What is the impact of circulating histones in COVID-19: a systematic review. Clin Chem Lab Med 2022;60:1506\u201317. https:\/\/doi.org\/10.1515\/cclm-2022-0574.","DOI":"10.1515\/cclm-2022-0574"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_006","doi-asserted-by":"crossref","unstructured":"Ligi, D, Maniscalco, R, Plebani, M, Lippi, G, Mannello, F. Do circulating histones represent the missing link among COVID-19 infection and multiorgan injuries, microvascular coagulopathy and systemic hyperinflammation? J Clin Med 2022;11:1800. https:\/\/doi.org\/10.3390\/jcm11071800.","DOI":"10.3390\/jcm11071800"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_007","doi-asserted-by":"crossref","unstructured":"Ekaney, ML, Otto, GP, Sossdorf, M, Sponholz, C, Boehringer, M, Loesche, W, et al.. Impact of plasma histones in human sepsis and their contribution to cellular injury and inflammation. Crit Care 2014;18:543. https:\/\/doi.org\/10.1186\/s13054-014-0543-8.","DOI":"10.1186\/s13054-014-0543-8"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_008","doi-asserted-by":"crossref","unstructured":"Shaw, RJ, Abrams, ST, Austin, J, Taylor, JM, Lane, S, Dutt, T, et al.. Circulating histones play a central role in COVID-19-associated coagulopathy and mortality. Haematologica 2021;106:2493\u20138. https:\/\/doi.org\/10.3324\/haematol.2021.278492.","DOI":"10.3324\/haematol.2021.278492"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_009","doi-asserted-by":"crossref","unstructured":"Cani, E, Dwivedi, DJ, Liaw, KL, Fraser, DD, Yeh, CH, Martin, C, et al.. Immunothrombosis biomarkers for distinguishing coronavirus disease 2019 patients from noncoronavirus disease septic patients with pneumonia and for predicting ICU mortality. Crit Care Explor 2021;3:e0588. https:\/\/doi.org\/10.1097\/cce.0000000000000588.","DOI":"10.1097\/CCE.0000000000000588"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_010","doi-asserted-by":"crossref","unstructured":"Gallo, CG, Fiorino, S, Posabella, G, Antonacci, D, Tropeano, A, Pausini, E, et al.. COVID-19, what could sepsis, severe acute pancreatitis, gender differences, and aging teach us? Cytokine 2021;148:155628. https:\/\/doi.org\/10.1016\/j.cyto.2021.155628.","DOI":"10.1016\/j.cyto.2021.155628"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_011","doi-asserted-by":"crossref","unstructured":"Riva, G, Castellano, S, Nasillo, V, Ottomano, AM, Bergonzini, G, Paolini, A, et al.. Monocyte Distribution Width (MDW) as novel inflammatory marker with prognostic significance in COVID-19 patients. Sci Rep 2021;11:12716. https:\/\/doi.org\/10.1038\/s41598-021-92236-6.","DOI":"10.1038\/s41598-021-92236-6"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_012","doi-asserted-by":"crossref","unstructured":"Agnello, L, Vidali, M, Lo Sasso, B, Giglio, RV, Gambino, CM, Scazzone, C, et al.. Monocyte distribution width (MDW) as a screening tool for early detecting sepsis: a systematic review and meta-analysis. Clin Chem Lab Med 2022;60:786\u201392. https:\/\/doi.org\/10.1515\/cclm-2021-1331.","DOI":"10.1515\/cclm-2021-1331"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_013","doi-asserted-by":"crossref","unstructured":"Alsuwaidi, L, Al Heialy, S, Shaikh, N, Al Najjar, F, Seliem, R, Han, A, et al.. Monocyte distribution width as a novel sepsis indicator in COVID-19 patients. BMC Infect Dis 2022;22:27. https:\/\/doi.org\/10.1186\/s12879-021-07016-4.","DOI":"10.1186\/s12879-021-07016-4"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_014","doi-asserted-by":"crossref","unstructured":"Lorubbio, M, Tacconi, D, Iannelli, G, Feri, M, Scala, R, Montemerani, S, et al.. The role of monocyte distribution width (MDW) in the prognosis and monitoring of COVID-19 patients. Clin Biochem 2022;103:29\u201331. https:\/\/doi.org\/10.1016\/j.clinbiochem.2022.02.007.","DOI":"10.1016\/j.clinbiochem.2022.02.007"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_015","doi-asserted-by":"crossref","unstructured":"Ognibene, A, Lorubbio, M, Magliocca, P, Tripodo, E, Vaggelli, G, Iannelli, G, et al.. Elevated monocyte distribution width in COVID-19 patients: the contribution of the novel sepsis indicator. Clin Chim Acta 2020;509:22\u20134. https:\/\/doi.org\/10.1016\/j.cca.2020.06.002.","DOI":"10.1016\/j.cca.2020.06.002"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_016","doi-asserted-by":"crossref","unstructured":"Polilli, E, Sozio, F, Frattari, A, Persichitti, L, Sensi, M, Posata, R, et al.. Comparison of monocyte distribution width (MDW) and procalcitonin for early recognition of sepsis. PLoS One 2020;15:e0227300. https:\/\/doi.org\/10.1371\/journal.pone.0227300.","DOI":"10.1371\/journal.pone.0227300"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_017","doi-asserted-by":"crossref","unstructured":"Hossain, R, Ayub, S, Tarabichi, Y. Monocyte distribution width adds prognostic value in detection of COVID-19 respiratory failure. Int J Lit Humanit 2022;44:e64\u2013e6. https:\/\/doi.org\/10.1111\/ijlh.13712.","DOI":"10.1111\/ijlh.13712"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_018","doi-asserted-by":"crossref","unstructured":"Lippi, G, Sanchis-Gomar, F, Henry, BM. Pooled analysis of monocyte distribution width in subjects with SARS-CoV-2 infection. Int J Lit Humanit 2021;43:O161\u2013O3. https:\/\/doi.org\/10.1111\/ijlh.13482.","DOI":"10.1111\/ijlh.13482"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_019","doi-asserted-by":"crossref","unstructured":"Zeng, F, Huang, Y, Guo, Y, Yin, M, Chen, X, Xiao, L, et al.. Association of inflammatory markers with the severity of COVID-19: a meta-analysis. Int J Infect Dis 2020;96:467\u201374. https:\/\/doi.org\/10.1016\/j.ijid.2020.05.055.","DOI":"10.1016\/j.ijid.2020.05.055"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_020","doi-asserted-by":"crossref","unstructured":"Ligi, D, Lo Sasso, B, Giglio, RV, Maniscalco, R, DellaFranca, C, Agnello, L, et al.. Circulating histones contribute to monocyte and MDW alterations as common mediators in classical and COVID-19 sepsis. Crit Care 2022;26:260. https:\/\/doi.org\/10.1186\/s13054-022-04138-2.","DOI":"10.1186\/s13054-022-04138-2"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_021","doi-asserted-by":"crossref","unstructured":"Crouser, ED, Parrillo, JE, Seymour, C, Angus, DC, Bicking, K, Tejidor, L, et al.. Improved early detection of sepsis in the ED with a novel monocyte distribution width biomarker. Chest 2017;152:518\u201326. https:\/\/doi.org\/10.1016\/j.chest.2017.05.039.","DOI":"10.1016\/j.chest.2017.05.039"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_022","doi-asserted-by":"crossref","unstructured":"Radzyukevich, YV, Kosyakova, NI, Prokhorenko, IR. Participation of monocyte subpopulations in progression of experimental endotoxemia (EE) and systemic inflammation. J Immunol Res 2021;2021:1762584. https:\/\/doi.org\/10.1155\/2021\/1762584.","DOI":"10.1155\/2021\/1762584"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_023","doi-asserted-by":"crossref","unstructured":"Ahmadi, E, Bagherpour, Z, Zarei, E, Omidkhoda, A. Pathological effects of SARS-CoV-2 on hematological and immunological cells: alterations in count, morphology, and function. Pathol Res Pract 2022;231:153782. https:\/\/doi.org\/10.1016\/j.prp.2022.153782.","DOI":"10.1016\/j.prp.2022.153782"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_024","doi-asserted-by":"crossref","unstructured":"Merad, M, Martin, JC. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol 2020;20:355\u201362. https:\/\/doi.org\/10.1038\/s41577-020-0331-4.","DOI":"10.1038\/s41577-020-0331-4"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_025","doi-asserted-by":"crossref","unstructured":"Zini, G, Bellesi, S, Ramundo, F, d\u2019Onofrio, G. Morphological anomalies of circulating blood cells in COVID-19. Am J Hematol 2020;95:870\u20132. https:\/\/doi.org\/10.1002\/ajh.25824.","DOI":"10.1002\/ajh.25824"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_026","doi-asserted-by":"crossref","unstructured":"Ligi, D, Sasso, BL, Henry, BM, Ciaccio, M, Lippi, G, Plebani, M, et al.. Deciphering the role of monocyte and monocyte distribution width (MDW) in COVID-19: an updated systematic review and meta-analysis. Clin Chem Lab Med 2023;61:960\u201373. https:\/\/doi.org\/10.1515\/cclm-2022-0936.","DOI":"10.1515\/cclm-2022-0936"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_027","doi-asserted-by":"crossref","unstructured":"Agnello, L, Bivona, G, Vidali, M, Scazzone, C, Giglio, RV, Iacolino, G, et al.. Monocyte distribution width (MDW) as a screening tool for sepsis in the Emergency Department. Clin Chem Lab Med 2020;58:1951\u20137. https:\/\/doi.org\/10.1515\/cclm-2020-0417.","DOI":"10.1515\/cclm-2020-0417"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_028","doi-asserted-by":"crossref","unstructured":"Agnello, L, Lo Sasso, B, Bivona, G, Gambino, CM, Giglio, RV, Iacolino, G, et al.. Reference interval of monocyte distribution width (MDW) in healthy blood donors. Clin Chim Acta 2020;510:272\u20137. https:\/\/doi.org\/10.1016\/j.cca.2020.07.036.","DOI":"10.1016\/j.cca.2020.07.036"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_029","doi-asserted-by":"crossref","unstructured":"Singh, A, Verma, S, Modak, SB, Chaturvedi, MM, Purohit, JS. Extra-nuclear histones: origin, significance and perspectives. Mol Cell Biochem 2022;477:507\u201324. https:\/\/doi.org\/10.1007\/s11010-021-04300-4.","DOI":"10.1007\/s11010-021-04300-4"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_030","doi-asserted-by":"crossref","unstructured":"Damsgaard, CT, Lauritzen, L, Calder, PC, Kjaer, TM, Fr\u00f8kiaer, H. Whole-blood culture is a valid low-cost method to measure monocytic cytokines - a comparison of cytokine production in cultures of human whole-blood, mononuclear cells and monocytes. J Immunol Methods 2009;340:95\u2013101. https:\/\/doi.org\/10.1016\/j.jim.2008.10.005.","DOI":"10.1016\/j.jim.2008.10.005"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_031","doi-asserted-by":"crossref","unstructured":"Chousterman, BG, Swirski, FK, Weber, GF. Cytokine storm and sepsis disease pathogenesis. Semin Immunopathol 2017;39:517\u201328. https:\/\/doi.org\/10.1007\/s00281-017-0639-8.","DOI":"10.1007\/s00281-017-0639-8"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_032","doi-asserted-by":"crossref","unstructured":"Liao, M, Liu, Y, Yuan, J, Wen, Y, Xu, G, Zhao, J, et al.. Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19. Nat Med 2020;26:842\u20134. https:\/\/doi.org\/10.1038\/s41591-020-0901-9.","DOI":"10.1038\/s41591-020-0901-9"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_033","doi-asserted-by":"crossref","unstructured":"Zhang, Q, Bastard, P, Liu, Z, Le Pen, J, Moncada-Velez, M, Chen, J, et al.. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science 2020;370:eabd4570. https:\/\/doi.org\/10.1126\/science.abd4570.","DOI":"10.1126\/science.abd4570"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_034","doi-asserted-by":"crossref","unstructured":"Zhou, Z, Ren, L, Zhang, L, Zhong, J, Xiao, Y, Jia, Z, et al.. Heightened innate immune responses in the respiratory tract of COVID-19 patients. Cell Host Microbe 2020;27:883\u201390.e2. https:\/\/doi.org\/10.1016\/j.chom.2020.04.017.","DOI":"10.1016\/j.chom.2020.04.017"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_035","doi-asserted-by":"crossref","unstructured":"Eichhorn, T, Linsberger, I, Laukov\u00e1, L, Tripisciano, C, Fendl, B, Weiss, R, et al.. Analysis of inflammatory mediator profiles in sepsis patients reveals that extracellular histones are strongly elevated in nonsurvivors. Mediat Inflamm 2021;2021:8395048. https:\/\/doi.org\/10.1155\/2021\/8395048.","DOI":"10.1155\/2021\/8395048"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_036","doi-asserted-by":"crossref","unstructured":"Mera, S, Tatulescu, D, Cismaru, C, Bondor, C, Slavcovici, A, Zanc, V, et al.. Multiplex cytokine profiling in patients with sepsis. Apmis 2011;119:155\u201363. https:\/\/doi.org\/10.1111\/j.1600-0463.2010.02705.x.","DOI":"10.1111\/j.1600-0463.2010.02705.x"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_037","doi-asserted-by":"crossref","unstructured":"Gouel-Ch\u00e9ron, A, Allaouchiche, B, Guignant, C, Davin, F, Floccard, B, Monneret, G. Early interleukin-6 and slope of monocyte human leukocyte antigen-DR: a powerful association to predict the development of sepsis after major trauma. PLoS One 2012;7:e33095. https:\/\/doi.org\/10.1371\/journal.pone.0033095.","DOI":"10.1371\/journal.pone.0033095"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_038","doi-asserted-by":"crossref","unstructured":"Wu, HP, Chen, CK, Chung, K, Tseng, JC, Hua, CC, Liu, YC, et al.. Serial cytokine levels in patients with severe sepsis. Inflamm Res 2009;58:385\u201393. https:\/\/doi.org\/10.1007\/s00011-009-0003-0.","DOI":"10.1007\/s00011-009-0003-0"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_039","doi-asserted-by":"crossref","unstructured":"Kellum, JA, Kong, L, Fink, MP, Weissfeld, LA, Yealy, DM, Pinsky, MR, et al.. Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the genetic and inflammatory markers of sepsis (GenIMS) study. Arch Intern Med 2007;167:1655\u201363. https:\/\/doi.org\/10.1001\/archinte.167.15.1655.","DOI":"10.1001\/archinte.167.15.1655"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_040","doi-asserted-by":"crossref","unstructured":"Hirano, T, Murakami, M. COVID-19: a new virus, but a familiar receptor and cytokine release syndrome. Immunity 2020;52:731\u20133. https:\/\/doi.org\/10.1016\/j.immuni.2020.04.003.","DOI":"10.1016\/j.immuni.2020.04.003"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_041","doi-asserted-by":"crossref","unstructured":"Liu, Y, Zhang, C, Huang, F, Yang, Y, Wang, F, Yuan, J, et al.. Elevated plasma levels of selective cytokines in COVID-19 patients reflect viral load and lung injury. Natl Sci Rev 2020;7:1003\u201311. https:\/\/doi.org\/10.1093\/nsr\/nwaa037.","DOI":"10.1093\/nsr\/nwaa037"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_042","doi-asserted-by":"crossref","unstructured":"Liu, J, Li, S, Liu, J, Liang, B, Wang, X, Wang, H, et al.. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients. EBioMedicine 2020;55:102763. https:\/\/doi.org\/10.1016\/j.ebiom.2020.102763.","DOI":"10.1016\/j.ebiom.2020.102763"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_043","doi-asserted-by":"crossref","unstructured":"Mohammad, RA. Use of granulocyte colony-stimulating factor in patients with severe sepsis or septic shock. Am J Health Syst Pharm 2010;67:1238\u201345. https:\/\/doi.org\/10.2146\/ajhp090325.","DOI":"10.2146\/ajhp090325"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_044","doi-asserted-by":"crossref","unstructured":"Xu, J, Zhang, X, Monestier, M, Esmon, NL, Esmon, CT. Extracellular histones are mediators of death through TLR2 and TLR4 in mouse fatal liver injury. J Immunol 2011;187:2626\u201331. https:\/\/doi.org\/10.4049\/jimmunol.1003930.","DOI":"10.4049\/jimmunol.1003930"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_045","doi-asserted-by":"crossref","unstructured":"Allam, R, Kumar, SV, Darisipudi, MN, Anders, HJ. Extracellular histones in tissue injury and inflammation. J Mol Med 2014;92:465\u201372. https:\/\/doi.org\/10.1007\/s00109-014-1148-z.","DOI":"10.1007\/s00109-014-1148-z"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_046","doi-asserted-by":"crossref","unstructured":"Hogwood, J, Pitchford, S, Mulloy, B, Page, C, Gray, E. Heparin and non-anticoagulant heparin attenuate histone-induced inflammatory responses in whole blood. PLoS One 2020;15:e0233644. https:\/\/doi.org\/10.1371\/journal.pone.0233644.","DOI":"10.1371\/journal.pone.0233644"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_047","doi-asserted-by":"crossref","unstructured":"Kawai, C, Kotani, H, Miyao, M, Ishida, T, Jemail, L, Abiru, H, et al.. Circulating extracellular histones are clinically relevant mediators of multiple organ injury. Am J Pathol 2016;186:829\u201343. https:\/\/doi.org\/10.1016\/j.ajpath.2015.11.025.","DOI":"10.1016\/j.ajpath.2015.11.025"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_048","doi-asserted-by":"crossref","unstructured":"Moiana, M, Aranda, F, de Larranaga, G. A focus on the roles of histones in health and diseases. Clin Biochem 2021;94:12\u20139. https:\/\/doi.org\/10.1016\/j.clinbiochem.2021.04.019.","DOI":"10.1016\/j.clinbiochem.2021.04.019"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_049","doi-asserted-by":"crossref","unstructured":"Westman, J, Papareddy, P, Dahlgren, MW, Chakrakodi, B, Norrby-Teglund, A, Smeds, E, et al.. Extracellular histones induce chemokine production in whole blood ex\u00a0vivo and leukocyte recruitment in\u00a0vivo. PLoS Pathog 2015;11:e1005319. https:\/\/doi.org\/10.1371\/journal.ppat.1005319.","DOI":"10.1371\/journal.ppat.1005319"},{"key":"2023063017541071827_j_cclm-2023-0093_ref_050","doi-asserted-by":"crossref","unstructured":"Sharma, N, Haggstrom, L, Sohrabipour, S, Dwivedi, DJ, Liaw, PC. Investigations of the effectiveness of heparin variants as inhibitors of histones. J Thromb Haemostasis 2022;20:1485\u201395. https:\/\/doi.org\/10.1111\/jth.15706.","DOI":"10.1111\/jth.15706"}],"container-title":["Clinical Chemistry and Laboratory Medicine (CCLM)"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.degruyter.com\/document\/doi\/10.1515\/cclm-2023-0093\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.degruyter.com\/document\/doi\/10.1515\/cclm-2023-0093\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,30]],"date-time":"2023-06-30T17:54:55Z","timestamp":1688147695000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.degruyter.com\/document\/doi\/10.1515\/cclm-2023-0093\/html"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,28]]},"references-count":50,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,1,5]]},"published-print":{"date-parts":[[2023,7,26]]}},"alternative-id":["10.1515\/cclm-2023-0093"],"URL":"https:\/\/doi.org\/10.1515\/cclm-2023-0093","relation":{},"ISSN":["1434-6621","1437-4331"],"issn-type":[{"value":"1434-6621","type":"print"},{"value":"1437-4331","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,28]]}}}