{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T12:35:07Z","timestamp":1740141307054,"version":"3.37.3"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,3,30]],"date-time":"2020-03-30T00:00:00Z","timestamp":1585526400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,3,30]],"date-time":"2020-03-30T00:00:00Z","timestamp":1585526400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010665","name":"H2020 Marie Sk\u0142odowska-Curie Actions","doi-asserted-by":"publisher","award":["675132","675132","675132","675132"],"award-info":[{"award-number":["675132","675132","675132","675132"]}],"id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Inflamm"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Chronic inflammation is involved in the initiation and progression of various cancers, including liver cancer. The current study focuses on the characterization of the peripheral immune response in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) patients, before and after surgical procedure, in order to assess the effect of tumor resection in the immune system homeostasis and to determine possible prognostic factors associated with high-grade tumors. We developed a whole-blood assay to monitor immune alterations and functional competence of peripheral monocytes in a group of 10 healthy individuals (HG), in 20 HCC patients and 8 CCA patients, by multi-color flow cytometry, qRT-PCR, and ELISA techniques.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>The qRT-PCR analysis showed an upregulation of TNF\u03b1 expression by classical and intermediate monocytes purified from HCC patients presenting tumors in grade G3-G4 as compared to G1-G2 HCC patients. Moreover, ELISA assay confirmed elevated serum levels of TNF\u03b1 in G3-G4 compared to G1-G2 HCC patients. A significant decrease of circulating non-classical monocytes was detected in both CCA and HCC patients before and after surgical procedure. In addition, a functional defect in circulating classical and intermediate monocytes was observed in both groups of cancer patients when compared to the HG, with partial recovery after the surgical intervention.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>This integrated analysis permitted the identification of altered functional competence of monocyte subsets in CCA and HCC patients. In addition, our results point to a potential role of TNF\u03b1 as a prognostic peripheral biomarker in HCC patients, indicating the presence of high-grade tumors that should be further validated.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12950-020-00243-7","type":"journal-article","created":{"date-parts":[[2020,3,30]],"date-time":"2020-03-30T16:04:09Z","timestamp":1585584249000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Elevated soluble TNF\u03b1 levels and upregulated TNF\u03b1 mRNA expression in purified peripheral blood monocyte subsets associated with high-grade hepatocellular carcinoma"],"prefix":"10.1186","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5120-1054","authenticated-orcid":false,"given":"C.","family":"Mart\u00edn-Sierra","sequence":"first","affiliation":[]},{"given":"R.","family":"Martins","sequence":"additional","affiliation":[]},{"given":"M.","family":"Coucelo","sequence":"additional","affiliation":[]},{"given":"A. M.","family":"Abrantes","sequence":"additional","affiliation":[]},{"given":"R. C.","family":"Oliveira","sequence":"additional","affiliation":[]},{"given":"J. G.","family":"Tralh\u00e3o","sequence":"additional","affiliation":[]},{"given":"M. F.","family":"Botelho","sequence":"additional","affiliation":[]},{"given":"E.","family":"Furtado","sequence":"additional","affiliation":[]},{"given":"M. R.","family":"Domingues","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6562-5859","authenticated-orcid":false,"given":"A.","family":"Paiva","sequence":"additional","affiliation":[]},{"given":"P.","family":"Laranjeira","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2020,3,30]]},"reference":[{"key":"243_CR1","doi-asserted-by":"publisher","unstructured":"Llovet JM, Zucman-Rossi J, Pikarsky E, Sangro B, Schwartz M, Sherman M, Gores G. Hepatocellular carcinoma. Nat Rev Dis Prim. 2016. https:\/\/doi.org\/10.1038\/nrdp.2016.18.","DOI":"10.1038\/nrdp.2016.18"},{"key":"243_CR2","doi-asserted-by":"publisher","unstructured":"Sia D, Villanueva A, Friedman SL, Llovet JM. Liver Cancer cell of origin, molecular class, and effects on patient prognosis. Gastroenterology. 2017. https:\/\/doi.org\/10.1053\/J.GASTRO.2016.11.048.","DOI":"10.1053\/J.GASTRO.2016.11.048"},{"key":"243_CR3","doi-asserted-by":"publisher","unstructured":"Pardee AD, Butterfield LH. Immunotherapy of hepatocellular carcinoma. Oncoimmunology. 2012. https:\/\/doi.org\/10.4161\/onci.1.1.18344.","DOI":"10.4161\/onci.1.1.18344"},{"key":"243_CR4","doi-asserted-by":"publisher","unstructured":"Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting Cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014. https:\/\/doi.org\/10.1158\/0008-5472.CAN-14-0155.","DOI":"10.1158\/0008-5472.CAN-14-0155"},{"key":"243_CR5","doi-asserted-by":"publisher","unstructured":"Ghouri YA, Mian I, Blechacz B. Cancer review: Cholangiocarcinoma. J Carcinog. 2015. https:\/\/doi.org\/10.4103\/1477-3163.151940.","DOI":"10.4103\/1477-3163.151940"},{"key":"243_CR6","doi-asserted-by":"publisher","unstructured":"Blechacz B, Komuta M, Roskams T, Gores GJ. Clinical diagnosis and staging of cholangiocarcinoma. Nat Rev Gastroenterol Hepatol. 2011. https:\/\/doi.org\/10.1038\/nrgastro.2011.131.","DOI":"10.1038\/nrgastro.2011.131"},{"key":"243_CR7","doi-asserted-by":"publisher","unstructured":"El-Serag HB. Hepatocellular Carcinoma. N Engl J Med. 2011. https:\/\/doi.org\/10.1056\/NEJMra1001683.","DOI":"10.1056\/NEJMra1001683"},{"key":"243_CR8","doi-asserted-by":"publisher","unstructured":"Lubezky N, Facciuto M, Harimoto N, Schwartz ME, Florman SS. Surgical treatment of intrahepatic cholangiocarcinoma in the USA. J Hepatobiliary Pancreat Sci. 2015. https:\/\/doi.org\/10.1002\/jhbp.157.","DOI":"10.1002\/jhbp.157"},{"key":"243_CR9","doi-asserted-by":"publisher","unstructured":"Zhang X, Li J, Shen F, Lau WY. Significance of presence of microvascular invasion in specimens obtained after surgical treatment of hepatocellular carcinoma. J Gastroenterol Hepatol. 2018. https:\/\/doi.org\/10.1111\/jgh.13843.","DOI":"10.1111\/jgh.13843"},{"key":"243_CR10","doi-asserted-by":"publisher","unstructured":"Showe MK, Kossenkov AV, Showe LC. The peripheral immune response and lung cancer prognosis. Oncoimmunology. 2012. https:\/\/doi.org\/10.4161\/onci.21096.","DOI":"10.4161\/onci.21096"},{"key":"243_CR11","doi-asserted-by":"publisher","unstructured":"Gustafson MP, Lin Y, LaPlant B, Liwski CJ, Maas ML, League SC, Bauer PR, Abraham RS, Tollefson MK, Kwon ED, Gastineau DA, Dietz AB. Immune monitoring using the predictive power of immune profiles. J Immunother Cancer. 2013. https:\/\/doi.org\/10.1186\/2051-1426-1-7.","DOI":"10.1186\/2051-1426-1-7"},{"key":"243_CR12","doi-asserted-by":"publisher","unstructured":"Buonaguro L, Mauriello A, Cavalluzzo B, Petrizzo A, Tagliamonte M. Immunotherapy in hepatocellular carcinoma. Ann Hepatol. 2019. https:\/\/doi.org\/10.1016\/J.AOHEP.2019.04.003.","DOI":"10.1016\/J.AOHEP.2019.04.003"},{"key":"243_CR13","doi-asserted-by":"publisher","unstructured":"Connaughton EP, Naicker S, Hanley SA, Slevin SM, Eykelenboom JK, Lowndes NF, O\u2019Brien T, Ceredig R, Griffin MD, Dennedy MC. Phenotypic and functional heterogeneity of human intermediate monocytes based on HLA-DR expression. Immunol Cell Biol. 2018. https:\/\/doi.org\/10.1111\/imcb.12032.","DOI":"10.1111\/imcb.12032"},{"key":"243_CR14","doi-asserted-by":"publisher","unstructured":"Yu M, Zhou X, Niu L, Lin G, Huang J, Zhou W, Gan H, Wang J, Jiang X, Yin B, Li Z. Targeting transmembrane TNF-\u03b1 suppresses breast cancer growth. Cancer Res. 2013. https:\/\/doi.org\/10.1158\/0008-5472.CAN-12-3946.","DOI":"10.1158\/0008-5472.CAN-12-3946"},{"key":"243_CR15","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1007\/BF00199290","volume":"29","author":"T Moritz","year":"1989","unstructured":"Moritz T, Niederle N, Baumann J, May D, Kurschel E, Osieka R, Kempeni J, Schlick E, Schmidt CG. Phase I study of recombinant human tumor necrosis factor alpha in advanced malignant disease. Cancer Immunol Immunother. 1989;29:144\u201350.","journal-title":"Cancer Immunol Immunother"},{"key":"243_CR16","doi-asserted-by":"publisher","unstructured":"Jing Y, Sun K, Liu W, Sheng D, Zhao S, Gao L, Wei L. Tumor necrosis factor-\u03b1 promotes hepatocellular carcinogenesis through the activation of hepatic progenitor cells. Cancer Lett. 2018. https:\/\/doi.org\/10.1016\/j.canlet.2018.07.001.","DOI":"10.1016\/j.canlet.2018.07.001"},{"key":"243_CR17","doi-asserted-by":"publisher","unstructured":"Gomez D, Farid S, Malik HZ, Young AL, Toogood GJ, Lodge JPA, Prasad KR. Preoperative Neutrophil-to-Lymphocyte Ratio as a Prognostic Predictor after Curative Resection for Hepatocellular Carcinoma. World J Surg. 2008. https:\/\/doi.org\/10.1007\/s00268-008-9552-6.","DOI":"10.1007\/s00268-008-9552-6"},{"key":"243_CR18","doi-asserted-by":"publisher","unstructured":"Dan J, Zhang Y, Peng Z, Huang J, Gao H, Xu L, Chen M. Postoperative Neutrophil-to-Lymphocyte Ratio Change Predicts Survival of Patients with Small Hepatocellular Carcinoma Undergoing Radiofrequency Ablation. PLoS ONE. 2013. https:\/\/doi.org\/10.1371\/journal.pone.0058184.","DOI":"10.1371\/journal.pone.0058184"},{"key":"243_CR19","doi-asserted-by":"publisher","unstructured":"Limaye AR, Clark V, Soldevila-Pico C, Morelli G, Suman A, Firpi R, Nelson DR, Cabrera R. Neutrophil-lymphocyte ratio predicts overall and recurrence-free survival after liver transplantation for hepatocellular carcinoma. Hepatol Res. 2013. https:\/\/doi.org\/10.1111\/hepr.12019.","DOI":"10.1111\/hepr.12019"},{"key":"243_CR20","doi-asserted-by":"publisher","unstructured":"Karlmark KR, Weiskirchen R, Zimmermann HW, Gassler N, Ginhoux F, Weber C, Merad M, Luedde T, Trautwein C, Tacke F. Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology. 2009. https:\/\/doi.org\/10.1002\/hep.22950.","DOI":"10.1002\/hep.22950"},{"key":"243_CR21","doi-asserted-by":"publisher","unstructured":"Mart\u00edn-Sierra C, Martins R, Laranjeira P, Abrantes AM, Oliveira RC, Tralh\u00e3o JG, Botelho MF, Furtado E, Domingues R, Paiva A. Functional impairment of circulating Fc\u03b5RI + monocytes and myeloid dendritic cells in hepatocellular carcinoma and Cholangiocarcinoma patients. Cytom Part B Clin Cytom. 2019. https:\/\/doi.org\/10.1002\/cyto.b.21777.","DOI":"10.1002\/cyto.b.21777"},{"key":"243_CR22","doi-asserted-by":"publisher","unstructured":"Carlin LM, Stamatiades EG, Auffray C, Hanna RN, Glover G, Vizcay-Barrena G, Hedrick CC, Cook HT, Diebold S, Geissmann F. Nr4a1-dependent Ly6Clow monocytes monitor endothelial cells and orchestrate their disposal. Cell. 2013. https:\/\/doi.org\/10.1016\/j.cell.2013.03.010.","DOI":"10.1016\/j.cell.2013.03.010"},{"key":"243_CR23","doi-asserted-by":"publisher","unstructured":"Hanna RN, Cekic C, Sag D, Tacke R, Thomas GD, Nowyhed H, Herrley E, Rasquinha N, McArdle S, Wu R, Peluso E, Metzger D, Ichinose H, Shaked I, Chodaczek G, Biswas SK, Hedrick CC. Patrolling monocytes control tumor metastasis to the lung. Science. 2015. https:\/\/doi.org\/10.1126\/science.aac9407.","DOI":"10.1126\/science.aac9407"},{"key":"243_CR24","doi-asserted-by":"publisher","unstructured":"Zimmermann HW, Seidler S, Nattermann J, Gassler N, Hellerbrand C, Zernecke A, Tischendorf JJW, Luedde T, Weiskirchen R, Trautwein C, Tacke F. Functional contribution of elevated circulating and hepatic non-classical CD14CD16 monocytes to inflammation and human liver fibrosis. PLoS One. 2010. https:\/\/doi.org\/10.1371\/journal.pone.0011049.","DOI":"10.1371\/journal.pone.0011049"},{"key":"243_CR25","doi-asserted-by":"publisher","unstructured":"Lopez-Gonzalez JS, Avila-Moreno F, Prado-Garcia H, Aguilar-Cazares D, Mandoki JJ, Meneses-Flores M. Lung carcinomas decrease the number of monocytes\/macrophages (CD14+ cells) that produce TNF-\u03b1. Clin Immunol. 2007. https:\/\/doi.org\/10.1016\/j.clim.2006.11.003.","DOI":"10.1016\/j.clim.2006.11.003"},{"key":"243_CR26","doi-asserted-by":"publisher","unstructured":"Verron\u00e8se E, Delgado A, Valladeau-Guilemond J, Garin G, Guillemaut S, Tredan O, Ray-Coquard I, Bachelot T, N\u2019Kodia A, Bardin-Dit-Courageot C, Rigal C, P\u00e9rol D, Caux C, M\u00e9n\u00e9trier-Caux C. Immune cell dysfunctions in breast cancer patients detected through whole blood multi-parametric flow cytometry assay. Oncoimmunology. 2016. https:\/\/doi.org\/10.1080\/2162402X.2015.1100791.","DOI":"10.1080\/2162402X.2015.1100791"},{"key":"243_CR27","doi-asserted-by":"publisher","unstructured":"Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K. Development of monocytes, macrophages, and dendritic cells. Science. 2010. https:\/\/doi.org\/10.1126\/science.1178331.","DOI":"10.1126\/science.1178331"},{"key":"243_CR28","doi-asserted-by":"publisher","unstructured":"Panek CA, Ramos MV, Mejias MP, Abrey-Recalde MJ, Fernandez-Brando RJ, Gori MS, Salamone GV, Palermo MS. Differential expression of the fractalkine chemokine receptor (CX3CR1) in human monocytes during differentiation. Cell Mol Immunol. 2015. https:\/\/doi.org\/10.1038\/cmi.2014.116.","DOI":"10.1038\/cmi.2014.116"},{"key":"243_CR29","doi-asserted-by":"publisher","unstructured":"Groom JR, Luster AD. CXCR3 ligands: redundant, collaborative and antagonistic functions. Immunol Cell Biol. 2011. https:\/\/doi.org\/10.1038\/ICB.2010.158.","DOI":"10.1038\/ICB.2010.158"},{"key":"243_CR30","doi-asserted-by":"publisher","unstructured":"Liu M, Guo S, Stiles JK. The emerging role of CXCL10 in cancer (review). Oncol Lett. 2011. https:\/\/doi.org\/10.3892\/ol.2011.300.","DOI":"10.3892\/ol.2011.300"},{"key":"243_CR31","doi-asserted-by":"publisher","unstructured":"Schutyser E, Struyf S, Van Damme J. The CC chemokine CCL20 and its receptor CCR6. Cytokine Growth Factor Rev. 2003. https:\/\/doi.org\/10.1016\/S1359-6101(03)00049-2.","DOI":"10.1016\/S1359-6101(03)00049-2"},{"key":"243_CR32","doi-asserted-by":"publisher","unstructured":"Chen K-J, Lin S-Z, Zhou L, Xie H-Y, Zhou W-H, Taki-Eldin A, Zheng S-S. Selective recruitment of regulatory T cell through CCR6-CCL20 in hepatocellular carcinoma fosters tumor progression and predicts poor prognosis. PLoS One. 2011. https:\/\/doi.org\/10.1371\/journal.pone.0024671.","DOI":"10.1371\/journal.pone.0024671"},{"key":"243_CR33","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1016\/0092-8674(91)90124-H","volume":"66","author":"J Liu","year":"1991","unstructured":"Liu J, Farmer JD, Lane WS, Friedman J, Weissman I, Schreiber SL. Calcineurin is a common target of cyclophilin-cyclosporin a and FKBP-FK506 complexes. Cell. 1991;66:807\u201315.","journal-title":"Cell."},{"key":"243_CR34","doi-asserted-by":"publisher","unstructured":"Pallet N, Fern\u00e1ndez-Ramos AA, Loriot M-A. Impact of immunosuppressive drugs on the metabolism of T cells. Int Rev Cell Mol Biol. 2018. https:\/\/doi.org\/10.1016\/bs.ircmb.2018.05.009.","DOI":"10.1016\/bs.ircmb.2018.05.009"},{"key":"243_CR35","doi-asserted-by":"publisher","unstructured":"Kannegieter NM, Hesselink DA, Dieterich M, Kraaijeveld R, Rowshani AT, Leenen PJM, Baan CC. The effect of Tacrolimus and Mycophenolic acid on CD14+ monocyte activation and function. PLoS One. 2017. https:\/\/doi.org\/10.1371\/journal.pone.0170806.","DOI":"10.1371\/journal.pone.0170806"},{"key":"243_CR36","doi-asserted-by":"publisher","unstructured":"Mart\u00edn-Sierra C, Martins R, Laranjeira P, Coucelo M, Abrantes AM, Tralh\u00e3o JG, Botelho MF, Furtado E, Domingues R, Paiva A. Functional and Phenotypic Characterization of Tumor-Infiltrating Leukocyte Subsets and Their Contribution to the Pathogenesis of Hepatocellular Carcinoma and Cholangiocarcinoma. Transl Oncol. 2019. https:\/\/doi.org\/10.1016\/j.tranon.2019.07.019.","DOI":"10.1016\/j.tranon.2019.07.019"}],"container-title":["Journal of Inflammation"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12950-020-00243-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s12950-020-00243-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12950-020-00243-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T23:38:02Z","timestamp":1617061082000},"score":1,"resource":{"primary":{"URL":"https:\/\/journal-inflammation.biomedcentral.com\/articles\/10.1186\/s12950-020-00243-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,30]]},"references-count":36,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["243"],"URL":"https:\/\/doi.org\/10.1186\/s12950-020-00243-7","relation":{},"ISSN":["1476-9255"],"issn-type":[{"type":"electronic","value":"1476-9255"}],"subject":[],"published":{"date-parts":[[2020,3,30]]},"assertion":[{"value":"13 December 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 March 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 March 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The experimental protocols were approved by the Ethical Committee of the Faculty of Medicine, University of Coimbra, Coimbra, Portugal (CE-136\/2016). All procedures performed involving human participants were in accordance with the ethical standards of Ethical Committee of the Faculty of Medicine, University of Coimbra, Coimbra, Portugal (CE-136\/2016), and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All participants gave their signed informed consent before entering in the study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"14"}}