{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nS100A9—a calcium‐binding protein that predominantly functions as part of the S100A8/S100A9 heterodimer (calprotectin)—plays a central role in innate immune responses and inflammation. At attomolar to nanomolar concentrations, S100A9 contributes to neutrophil chemotaxis and adhesion, modulating leukocyte trafficking and cytokine release in inflamed tissues. Through interactions with pattern‐recognition receptors such as the receptor for advanced glycation end‐products (RAGE) and Toll‐like receptors (TLRs), it initiates NF‐κB–dependent signaling cascades that lead to the production of proinflammatory mediators. The protein is highly expressed in neutrophils, monocytes and activated endothelial cells, and its extracellular release has been implicated in both local tissue inflammation (e.g. in rheumatoid arthritis and inflammatory bowel disease) and even in the pathophysiology of epithelial cancers where it contributes to proinflammatory tumor–stroma interactions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nOn a biochemical level, S100A9 is intricately regulated by divalent cations and undergoes calcium‐ and zinc‐dependent oligomerization that is essential for its biological activity. Moreover, S100A9 (and its heterocomplex with S100A8) binds key nutrients such as manganese and zinc, thereby mediating “nutritional immunity” by restricting access of these metals to invading pathogens. In addition, by binding fatty acids like arachidonic acid, it facilitates activation of NADPH oxidase and the production of reactive oxygen species, further contributing to antimicrobial defense. Its expression in various body fluids (e.g. fecal calprotectin in inflammatory bowel disease and amniotic fluid antimicrobial peptides) and on specific myeloid cell subsets (including myeloid‐derived suppressor cells and activated macrophages in juvenile idiopathic arthritis) underscores its utility as a biomarker of disease activity and tissue damage in disorders ranging from atherosclerosis and osteoarthritis to ulcerative colitis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "30"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its roles in inflammation and host defense, S100A9 exerts multifaceted functions in tumor biology and related pathologies. In the tumor microenvironment, S100A9 produced both by myeloid cells and by tumor cells—with its engagement of receptors such as EMMPRIN and TLR4—promotes cell migration, invasion, and metastasis by activating p38 MAPK and NF‐κB signaling pathways. Paradoxically, S100A9 can also induce apoptotic and autophagy‐like cell death in neoplastic cells, underscoring its context‐dependent functions. Its presence in tumor‐associated immune suppressor cells and its overexpression in aggressive cancers such as breast and gastric carcinomas, as well as its involvement in platelet‐dependent thrombus formation, indicate that S100A9 is a critical mediator of both tumor progression and the thrombo‐inflammatory response."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "31", "end_ref": "41"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Carle Ryckman, Karen Vandal, Pascal Rouleau, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "S100A9/S100A8: Myeloid representatives of the S100 protein family as prominent players in innate immunity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Microsc Res Tech (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jemt.10299"}], "href": "https://doi.org/10.1002/jemt.10299"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12645005"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12645005"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Aileen M Healy, Michael D Pickard, Aruna D Pradhan, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "The S100A8/A9 heterodimer amplifies proinflammatory cytokine production by macrophages via activation of nuclear factor kappa B and p38 mitogen-activated protein kinase in rheumatoid arthritis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arthritis Res Ther (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/ar1939"}], "href": "https://doi.org/10.1186/ar1939"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16613612"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16613612"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Emily K Wright, Michael A Kamm, Peter De Cruz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Measurement of fecal calprotectin improves monitoring and detection of recurrence of Crohn's disease after surgery."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/j.gastro.2015.01.026"}], "href": "https://doi.org/10.1053/j.gastro.2015.01.026"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25620670"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25620670"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Alexander Hermani, Jochen Hess, Barbara De Servi, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "S100A8/A9 induces autophagy and apoptosis via ROS-mediated cross-talk between mitochondria and lysosomes that involves BNIP3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Res (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/cr.2009.129"}], "href": "https://doi.org/10.1038/cr.2009.129"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19935772"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19935772"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Linda Wang, Esther W Y Chang, Siew Cheng Wong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Increased myeloid-derived suppressor cells in gastric cancer correlate with cancer stage and plasma S100A8/A9 proinflammatory proteins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.1202088"}], "href": "https://doi.org/10.4049/jimmunol.1202088"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23248262"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23248262"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Matteo Bianchi, Maria J Niemiec, Ulrich Siler, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Restoration of anti-Aspergillus defense by neutrophil extracellular traps in human chronic granulomatous disease after gene therapy is calprotectin-dependent."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Allergy Clin Immunol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jaci.2011.01.021"}], "href": "https://doi.org/10.1016/j.jaci.2011.01.021"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21376380"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21376380"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Joseph P Zackular, Jessica L Moore, Ashley T Jordan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Dietary zinc alters the microbiota and decreases resistance to Clostridium difficile infection."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Med (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nm.4174"}], "href": "https://doi.org/10.1038/nm.4174"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27668938"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27668938"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Fei Zhao, Bastian Hoechst, Austin Duffy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "S100A9 a new marker for monocytic human myeloid-derived suppressor cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Immunology (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1365-2567.2012.03566.x"}], "href": "https://doi.org/10.1111/j.1365-2567.2012.03566.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22304731"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22304731"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Martine De Vos, Edouard J Louis, Jørgen Jahnsen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Consecutive fecal calprotectin measurements to predict relapse in patients with ulcerative colitis receiving infliximab maintenance therapy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Inflamm Bowel Dis (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/MIB.0b013e31829b2a37"}], "href": "https://doi.org/10.1097/MIB.0b013e31829b2a37"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23883959"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23883959"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Michelle M McCormick, Farid Rahimi, Yuri V Bobryshev, et al. "}, {"type": "b", "children": [{"type": "t", "text": "S100A8 and S100A9 in human arterial wall. Implications for atherogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M509442200"}], "href": "https://doi.org/10.1074/jbc.M509442200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16216873"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16216873"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Philipp Ehlermann, Kai Eggers, Angelika Bierhaus, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Increased proinflammatory endothelial response to S100A8/A9 after preactivation through advanced glycation end products."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cardiovasc Diabetol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1475-2840-5-6"}], "href": "https://doi.org/10.1186/1475-2840-5-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16573830"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16573830"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Rik F P Schelbergen, Arjen B Blom, Martijn H J van den Bosch, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Alarmins S100A8 and S100A9 elicit a catabolic effect in human osteoarthritic chondrocytes that is dependent on Toll-like receptor 4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arthritis Rheum (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/art.33495"}], "href": "https://doi.org/10.1002/art.33495"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22127564"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22127564"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Steven T Leach, Zheng Yang, Isabella Messina, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Serum and mucosal S100 proteins, calprotectin (S100A8/S100A9) and S100A12, are elevated at diagnosis in children with inflammatory bowel disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Scand J Gastroenterol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/00365520701416709"}], "href": "https://doi.org/10.1080/00365520701416709"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17852869"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17852869"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Nadja Leukert, Thomas Vogl, Kerstin Strupat, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Calcium-dependent tetramer formation of S100A8 and S100A9 is essential for biological activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Biol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jmb.2006.04.009"}], "href": "https://doi.org/10.1016/j.jmb.2006.04.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16690079"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16690079"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Thomas Vogl, Nadja Leukert, Katarzyna Barczyk, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Biophysical characterization of S100A8 and S100A9 in the absence and presence of bivalent cations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbamcr.2006.08.028"}], "href": "https://doi.org/10.1016/j.bbamcr.2006.08.028"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17050004"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17050004"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "J Espinoza, T Chaiworapongsa, R Romero, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Antimicrobial peptides in amniotic fluid: defensins, calprotectin and bacterial/permeability-increasing protein in patients with microbial invasion of the amniotic cavity, intra-amniotic inflammation, preterm labor and premature rupture of membranes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Matern Fetal Neonatal Med (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/jmf.13.1.2.21"}], "href": "https://doi.org/10.1080/jmf.13.1.2.21"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12710851"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12710851"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "C Kerkhoff, M Klempt, V Kaever, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The two calcium-binding proteins, S100A8 and S100A9, are involved in the metabolism of arachidonic acid in human neutrophils."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (1999)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.274.46.32672"}], "href": "https://doi.org/10.1074/jbc.274.46.32672"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "10551823"}], "href": "https://pubmed.ncbi.nlm.nih.gov/10551823"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Michael Frosch, Martina Ahlmann, Thomas Vogl, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The myeloid-related proteins 8 and 14 complex, a novel ligand of toll-like receptor 4, and interleukin-1beta form a positive feedback mechanism in systemic-onset juvenile idiopathic arthritis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arthritis Rheum (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/art.24349"}], "href": "https://doi.org/10.1002/art.24349"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19248102"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19248102"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Klaus Theede, Susanne Holck, Per Ibsen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Fecal Calprotectin Predicts Relapse and Histological Mucosal Healing in Ulcerative Colitis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Inflamm Bowel Dis (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/MIB.0000000000000736"}], "href": "https://doi.org/10.1097/MIB.0000000000000736"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26919460"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26919460"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "S Y Lim, A E Yuzhalin, A N Gordon-Weeks, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tumor-infiltrating monocytes/macrophages promote tumor invasion and migration by upregulating S100A8 and S100A9 expression in cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2016.107"}], "href": "https://doi.org/10.1038/onc.2016.107"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27086923"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27086923"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Toshihiko Hibino, Masakiyo Sakaguchi, Shoko Miyamoto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "S100A9 is a novel ligand of EMMPRIN that promotes melanoma metastasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-11-3843"}], "href": "https://doi.org/10.1158/0008-5472.CAN-11-3843"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23135911"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23135911"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Saeid Ghavami, Claus Kerkhoff, Marek Los, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mechanism of apoptosis induced by S100A8/A9 in colon cancer cell lines: the role of ROS and the effect of metal ions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Leukoc Biol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1189/jlb.0903435"}], "href": "https://doi.org/10.1189/jlb.0903435"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15075348"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15075348"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "Saeid Ghavami, Claus Kerkhoff, Walter J Chazin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "S100A8/9 induces cell death via a novel, RAGE-independent pathway that involves selective release of Smac/DIABLO and Omi/HtrA2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbamcr.2007.10.015"}], "href": "https://doi.org/10.1016/j.bbamcr.2007.10.015"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18060880"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18060880"}]}, {"type": "r", "ref": 35, "children": [{"type": "t", "text": "Chae Hwa Kwon, Hyun Jung Moon, Hye Ji Park, et al. "}, {"type": "b", "children": [{"type": "t", "text": "S100A8 and S100A9 promotes invasion and migration through p38 mitogen-activated protein kinase-dependent NF-κB activation in gastric cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cells (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10059-013-2269-x"}], "href": "https://doi.org/10.1007/s10059-013-2269-x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23456298"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23456298"}]}, {"type": "r", "ref": 36, "children": [{"type": "t", "text": "Taekyoung Kwak, Fang Wang, Hui Deng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Distinct Populations of Immune-Suppressive Macrophages Differentiate from Monocytic Myeloid-Derived Suppressor Cells in Cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2020.108571"}], "href": "https://doi.org/10.1016/j.celrep.2020.108571"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33378668"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33378668"}]}, {"type": "r", "ref": 37, "children": [{"type": "t", "text": "Hui Shi, Yu Zuo, Srilakshmi Yalavarthi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Neutrophil calprotectin identifies severe pulmonary disease in COVID-19."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Leukoc Biol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/JLB.3COVCRA0720-359R"}], "href": "https://doi.org/10.1002/JLB.3COVCRA0720-359R"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32869342"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32869342"}]}, {"type": "r", "ref": 38, "children": [{"type": "t", "text": "Thomas Ulas, Sabine Pirr, Beate Fehlhaber, et al. "}, {"type": "b", "children": [{"type": "t", "text": "S100-alarmin-induced innate immune programming protects newborn infants from sepsis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Immunol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ni.3745"}], "href": "https://doi.org/10.1038/ni.3745"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28459433"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28459433"}]}, {"type": "r", "ref": 39, "children": [{"type": "t", "text": "Kazumori Arai, Sachiko Takano, Takumi Teratani, et al. "}, {"type": "b", "children": [{"type": "t", "text": "S100A8 and S100A9 overexpression is associated with poor pathological parameters in invasive ductal carcinoma of the breast."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Curr Cancer Drug Targets (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2174/156800908784533445"}], "href": "https://doi.org/10.2174/156800908784533445"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18537548"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18537548"}]}, {"type": "r", "ref": 40, "children": [{"type": "t", "text": "Marieke A D van Zoelen, Thomas Vogl, Dirk Foell, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression and role of myeloid-related protein-14 in clinical and experimental sepsis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Respir Crit Care Med (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1164/rccm.200810-1552OC"}], "href": "https://doi.org/10.1164/rccm.200810-1552OC"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19762566"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19762566"}]}, {"type": "r", "ref": 41, "children": [{"type": "t", "text": "Yunmei Wang, Chao Fang, Huiyun Gao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Platelet-derived S100 family member myeloid-related protein-14 regulates thrombosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI70966"}], "href": "https://doi.org/10.1172/JCI70966"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24691441"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24691441"}]}]}]}