{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T01:29:11Z","timestamp":1792114151278,"version":"4.4.0"},"reference-count":62,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,4,30]],"date-time":"2022-04-30T00:00:00Z","timestamp":1651276800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Checkpoint inhibitors (CPI) represent a novel therapeutical strategy with a high efficacy both in solid and hematological cancers. They act by reactivating the immune system against neoplastic cells but may, in turn, cause immune-related adverse events (IRAEs) involving several organs with variable frequency and severity. Up to 10% of CPI-treated patients experience hematological IRAEs, mainly cytopenias. The differential diagnosis is challenging due to underlying disease, previous treatments and the variable liability of available tests (i.e., the direct antiglobulin test, anti-platelet antibodies, etc.). Among extra-hematological IRAEs, cutaneous and endocrine ones are the most frequent (up to 30\u201350%), ranging from mild (pruritus, eczema and thyroid dysfunctions) to severe forms (bullous disorders, hypophysitis and diabetes), mostly requiring topic or replacement therapy. Gastroenteric and kidney toxicities occur in about 5% of patients, biopsies may support the diagnosis, and immunosuppressive treatment is required in severe cases. Finally, neurologic and cardiologic IRAEs, although rare, may be life-threatening and require prompt intervention. By reviewing the most recent literature on post-CPI IRAEs, it emerged that clinical suspicion and monitoring of laboratory markers of organ damage is pivotal to a prompt diagnosis. In severe cases, CPI should be discontinued and immunosuppressive therapy started, whilst rechallenge is anecdotal and should be carefully evaluated.<\/jats:p>","DOI":"10.3390\/ph15050557","type":"journal-article","created":{"date-parts":[[2022,5,2]],"date-time":"2022-05-02T07:08:58Z","timestamp":1651475338000},"page":"557","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Hematological and Extra-Hematological Autoimmune Complications after Checkpoint Inhibitors"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0857-8379","authenticated-orcid":false,"given":"Bruno","family":"Fattizzo","sequence":"first","affiliation":[{"name":"Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicol\u00f2","family":"Rampi","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilma","family":"Barcellini","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1056\/NEJMoa1003466","article-title":"Improved Survival with Ipilimumab in Patients with Metastatic Melanoma","volume":"363","author":"Hodi","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1056\/NEJMoa1504030","article-title":"Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma","volume":"373","author":"Larkin","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1056\/NEJMoa1507643","article-title":"Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer","volume":"373","author":"Borghaei","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1016\/S0140-6736(18)32409-7","article-title":"Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): A randomised, open-label, controlled, phase 3 trial","volume":"393","author":"Mok","year":"2019","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1056\/NEJMoa1510665","article-title":"Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma","volume":"373","author":"Motzer","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1200\/JCO.2016.72.1316","article-title":"Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed\/Refractory Classic Hodgkin Lymphoma","volume":"35","author":"Chen","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1016\/S1470-2045(16)30167-X","article-title":"Nivolumab for classical Hodgkin\u2019s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: A multicentre, multicohort, single-arm phase 2 trial","volume":"17","author":"Younes","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1056\/NEJMra1703481","article-title":"Immune-Related Adverse Events Associated with Immune Checkpoint Blockade","volume":"378","author":"Postow","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.ejca.2018.07.129","article-title":"Haematological toxicities with immunotherapy in patients with cancer: A systematic review and meta-analysis","volume":"103","author":"Petrelli","year":"2018","journal-title":"Eur. J. Cancer"},{"key":"ref_10","first-page":"100648","article-title":"Diagnosis and treatment of autoimmune hemolytic anemia in adults: Recommendations from the First International Consensus Meeting","volume":"41","author":"Barcellini","year":"2019","journal-title":"Blood Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"946","DOI":"10.3389\/fimmu.2020.00946","article-title":"The Changing Landscape of Autoimmune Hemolytic Anemia","volume":"11","author":"Barcellini","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1002\/ajh.25448","article-title":"Clinical and laboratory features of autoimmune hemolytic anemia associated with immune checkpoint inhibitors","volume":"94","author":"Leaf","year":"2019","journal-title":"Am. J. Hematol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Barcellini, W., Giannotta, J.A., and Fattizzo, B. (2021). Autoimmune Complications in Hematologic Neoplasms. Cancers, 13.","DOI":"10.3390\/cancers13071532"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1159\/000452296","article-title":"Autoimmune Hemolytic Anemia as a Complication of Nivolumab Therapy","volume":"9","author":"Palla","year":"2016","journal-title":"Case Rep. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"622","DOI":"10.3324\/haematol.2020.250522","article-title":"Efficacy of recombinant erythropoietin in autoimmune haemolytic anaemia: A multicentre international study","volume":"106","author":"Fattizzo","year":"2020","journal-title":"Haematologica"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.ejca.2021.01.013","article-title":"Re: Hematological immune related adverse events after treatment with immune checkpoint inhibitors","volume":"147","author":"Grewal","year":"2021","journal-title":"Eur. J. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e48","DOI":"10.1016\/S2352-3026(18)30175-3","article-title":"Haematological immune-related adverse events induced by anti-PD-1 or anti-PD-L1 immunotherapy: A descriptive observational study","volume":"6","author":"Delanoy","year":"2019","journal-title":"Lancet Haematol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"765608","DOI":"10.3389\/fonc.2021.765608","article-title":"Grade 4 Neutropenia Secondary to Immune Checkpoint Inhibition\u2014A Descriptive Observational Retrospective Multicenter Analysis","volume":"11","author":"Zaremba","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.ejca.2019.07.014","article-title":"Haematological immune-related adverse events with immune checkpoint inhibitors, how to manage?","volume":"122","author":"Michot","year":"2019","journal-title":"Eur. J. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1634\/theoncologist.2018-0574","article-title":"Hematologic Complications of Immune Checkpoint Inhibitors","volume":"24","author":"Davis","year":"2019","journal-title":"Oncologist"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s41199-020-0050-3","article-title":"Pembrolizumab-induced Hemophagocytic Lymphohistiocytosis: An immunotherapeutic challenge","volume":"5","author":"Kalmuk","year":"2020","journal-title":"Cancers Head Neck"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1007\/s12020-021-02750-w","article-title":"Endocrine-related adverse events in a large series of cancer patients treated with anti-PD1 therapy","volume":"74","author":"Rubino","year":"2021","journal-title":"Endocrine"},{"key":"ref_23","first-page":"173","article-title":"Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens a systematic review and meta-analysis","volume":"4","author":"Barry","year":"2018","journal-title":"JAMA Oncol. Am. Med. Assoc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4078","DOI":"10.1210\/jc.2014-2306","article-title":"Ipilimumab-Induced Hypophysitis: A Detailed Longitudinal Analysis in a Large Cohort of Patients With Metastatic Melanoma","volume":"99","author":"Faje","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1530\/EJE-19-0238","article-title":"Hypophysitis secondary to nivolumab and pembrolizumab is a clinical entity distinct from ipilimumab-associated hypophysitis","volume":"181","author":"Faje","year":"2019","journal-title":"Eur. J. Endocrinol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"19419","DOI":"10.1038\/s41598-019-56026-5","article-title":"Immune check point inhibitors-induced hypophysitis: A retrospective analysis of the French Pharmacovigilance database","volume":"9","author":"Petitpain","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1111\/cen.13297","article-title":"Thyroid abnormalities following the use of cytotoxic T-lymphocyte antigen-4 and programmed death receptor protein-1 inhibitors in the treatment of melanoma","volume":"86","author":"Morganstein","year":"2017","journal-title":"Clin. Endocrinol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/s40618-019-01112-8","article-title":"Endocrine toxicity in cancer patients treated with nivolumab or pembrolizumab: Results of a large multicentre study","volume":"43","author":"Presotto","year":"2019","journal-title":"J. Endocrinol. Investig."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1093\/annonc\/mdw640","article-title":"Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer","volume":"28","author":"Osorio","year":"2017","journal-title":"Ann. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1089\/thy.2019.0250","article-title":"PD-L1 Inhibitor-Induced Thyroiditis Is Associated with Better Overall Survival in Cancer Patients","volume":"30","author":"Kotwal","year":"2020","journal-title":"Thyroid"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1111\/cei.13424","article-title":"Immune checkpoint inhibitor diabetes mellitus: A novel form of autoimmune diabetes","volume":"200","author":"Quandt","year":"2020","journal-title":"Clin. Exp. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Muniz, T.P., Araujo, D.V., Savage, K.J., Cheng, T., Saha, M., Song, X., Gill, S., Monzon, J.G., Grenier, D., and Genta, S. (2021). CANDIED: A Pan-Canadian Cohort of Immune Checkpoint Inhibitor-Induced Insulin-Dependent Diabetes Mellitus. Cancers, 14.","DOI":"10.3390\/cancers14010089"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/j.jaad.2015.10.029","article-title":"Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: A single-institution cohort","volume":"74","author":"Hwang","year":"2016","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1016\/j.jaad.2020.03.132","article-title":"Immune checkpoint inhibitor\u2013related dermatologic adverse events","volume":"83","author":"Geisler","year":"2020","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1016\/j.jaad.2018.10.062","article-title":"Inflammatory eruptions associated with immune checkpoint inhibitor therapy: A single-institution retrospective analysis with stratification of reactions by toxicity and implications for management","volume":"80","author":"Coleman","year":"2019","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1016\/j.jaad.2018.07.008","article-title":"Bullous disorders associated with anti\u2013PD-1 and anti\u2013PD-L1 therapy: A retrospective analysis evaluating the clinical and histopathologic features, frequency, and impact on cancer therapy","volume":"79","author":"Siegel","year":"2018","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e186","DOI":"10.3346\/jkms.2019.34.e186","article-title":"Characterization and Prognostic Significance of Cutaneous Adverse Events to Anti-Programmed Cell Death-1 Therapy","volume":"34","author":"Lee","year":"2019","journal-title":"J. Korean Med. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1158\/2326-6066.CIR-15-0123","article-title":"Autoimmune Bullous Skin Disorders with Immune Checkpoint Inhibitors Targeting PD-1 and PD-L1","volume":"4","author":"Naidoo","year":"2016","journal-title":"Cancer Immunol. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1111\/1346-8138.15345","article-title":"Vitiligo expansion and extent correlate with durable response in anti-programmed death 1 antibody treatment for advanced melanoma: A multi-institutional retrospective study","volume":"47","author":"Matsuya","year":"2020","journal-title":"J. Dermatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.jaad.2019.06.035","article-title":"Survival and prognosis of individuals receiving programmed cell death 1 inhibitor with and without immunologic cutaneous adverse events","volume":"82","author":"Chan","year":"2020","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"202","DOI":"10.14309\/ajg.0000000000000497","article-title":"Checkpoint Inhibitor\u2013Induced Colitis","volume":"115","author":"Bellaguarda","year":"2020","journal-title":"Am. J. Gastroenterol."},{"key":"ref_42","first-page":"e000278","article-title":"Immune checkpoint inhibition-related colitis: Symptoms, endoscopic features, histology and response to management. ESMO Open","volume":"3","author":"Rozeman","year":"2018","journal-title":"BMJ Publ. Group"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1186\/s40425-018-0411-1","article-title":"Importance of endoscopic and histological evaluation in the management of immune checkpoint inhibitor-induced colitis","volume":"6","author":"Ali","year":"2018","journal-title":"J. Immunother. Cancer"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1186\/s40425-019-0577-1","article-title":"Early introduction of selective immunosuppressive therapy associated with favorable clinical outcomes in patients with immune checkpoint inhibitor\u2013induced colitis","volume":"7","author":"Ali","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/s41416-020-0882-y","article-title":"Immune checkpoint inhibitor-related colitis assessment and prognosis: Can IBD scoring point the way?","volume":"123","author":"Cheung","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1111\/liv.14489","article-title":"Immune-related hepatitis related to checkpoint inhibitors: Clinical and prognostic factors","volume":"40","author":"Viladomiu","year":"2020","journal-title":"Liver Int."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1212\/WNL.0000000000007235","article-title":"Neuromuscular adverse events associated with anti-PD-1 monoclonal antibodies","volume":"92","author":"Johansen","year":"2019","journal-title":"Neurology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.ejca.2018.09.033","article-title":"Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors","volume":"106","author":"Moreira","year":"2019","journal-title":"Eur. J. Cancer"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1097\/CJI.0000000000000196","article-title":"PD-1 Inhibitor-associated Myopathies: Emerging Immune-mediated Myopathies","volume":"41","author":"Liewluck","year":"2018","journal-title":"J. Immunother."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"M\u00f6hn, N., Beutel, G., Gutzmer, R., Ivanyi, P., Satzger, I., and Skripuletz, T. (2019). Neurological Immune Related Adverse Events Associated with Nivolumab, Ipilimumab, and Pembrolizumab Therapy\u2014Review of the Literature and Future Outlook. J. Clin. Med., 8.","DOI":"10.3390\/jcm8111777"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e438","DOI":"10.1111\/jdv.15809","article-title":"Donovanosis in migrants: A clinical case series in an Italian dermatological hospital","volume":"33","author":"Morrone","year":"2019","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.ejca.2016.02.024","article-title":"Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy","volume":"60","author":"Zimmer","year":"2016","journal-title":"Eur. J. Cancer"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1681\/ASN.2019070676","article-title":"Clinical Features and Outcomes of Immune Checkpoint Inhibitor\u2013Associated AKI: A Multicenter Study","volume":"31","author":"Cortazar","year":"2020","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e003467","DOI":"10.1136\/jitc-2021-003467","article-title":"Acute kidney injury in patients treated with immune checkpoint inhibitors","volume":"9","author":"Gupta","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.ekir.2020.10.002","article-title":"A Systematic Review of Immune Checkpoint Inhibitor\u2013Associated Glomerular Disease","volume":"6","author":"Kitchlu","year":"2021","journal-title":"Kidney Int. Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1053\/j.ajkd.2019.04.016","article-title":"Renal Vasculitis and Pauci-immune Glomerulonephritis Associated With Immune Checkpoint Inhibitors","volume":"74","author":"Gallan","year":"2019","journal-title":"Am. J. Kidney Dis."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s40425-018-0478-8","article-title":"Nephrotoxicity of immune checkpoint inhibitors beyond tubulointerstitial nephritis: Single-center experience","volume":"7","author":"Mamlouk","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1053\/j.ajkd.2016.02.057","article-title":"Association of Acute Interstitial Nephritis With Programmed Cell Death 1 Inhibitor Therapy in Lung Cancer Patients","volume":"68","author":"Shirali","year":"2016","journal-title":"Am. J. Kidney Dis."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1093\/cvr\/cvz026","article-title":"Cardiovascular toxicities associated with immune checkpoint inhibitors","volume":"115","author":"Hu","year":"2019","journal-title":"Cardiovasc. Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1016\/S1470-2045(18)30608-9","article-title":"Cardiovascular toxicities associated with immune checkpoint inhibitors: An observational, retrospective, pharmacovigilance study","volume":"19","author":"Salem","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.1016\/j.jacc.2018.02.037","article-title":"Myocarditis in Patients Treated With Immune Checkpoint Inhibitors","volume":"71","author":"Mahmood","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.jacc.2019.11.049","article-title":"Global Longitudinal Strain and Cardiac Events in Patients With Immune Checkpoint Inhibitor-Related Myocarditis","volume":"75","author":"Awadalla","year":"2020","journal-title":"J. Am. Coll. Cardiol."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/5\/557\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:04:43Z","timestamp":1760137483000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/15\/5\/557"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,30]]},"references-count":62,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["ph15050557"],"URL":"https:\/\/doi.org\/10.3390\/ph15050557","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,30]]}}}