{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:19:50Z","timestamp":1790702390907,"version":"4.1.0"},"reference-count":41,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T00:00:00Z","timestamp":1683504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Euratom research and training program","award":["847707"],"award-info":[{"award-number":["847707"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The Health Effects of Cardiac Fluoroscopy and Modern Radiotherapy (photon and proton) in Pediatrics (HARMONIC) is a five-year project funded by the European Commission that aimed to improve the understanding of the long-term ionizing radiation (IR) risks for pediatric patients. In this paper, we provide a detailed overview of the rationale, design, and methods for the biological aspect of the project with objectives to provide a mechanistic understanding of the molecular pathways involved in the IR response and to identify potential predictive biomarkers of individual response involved in long-term health risks. Biological samples will be collected at three time points: before the first exposure, at the end of the exposure, and one year after the exposure. The average whole-body dose, the dose to the target organ, and the dose to some important out-of-field organs will be estimated. State-of-the-art analytical methods will be used to assess the levels of a set of known biomarkers and also explore high-resolution approaches of proteomics and miRNA transcriptomes to provide an integrated assessment. By using bioinformatics and systems biology, biological pathways and novel pathways involved in the response to IR exposure will be deciphered.<\/jats:p>","DOI":"10.3390\/ijms24098416","type":"journal-article","created":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T03:34:53Z","timestamp":1683516893000},"page":"8416","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A Longitudinal Study of Individual Radiation Responses in Pediatric Patients Treated with Proton and Photon Radiotherapy, and Interventional Cardiology: Rationale and Research Protocol of the HARMONIC Project"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2163-0816","authenticated-orcid":false,"given":"Maria Grazia","family":"Andreassi","sequence":"first","affiliation":[{"name":"CNR National Research Council Institute of Clinical Physiology, 56125 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Haddy","sequence":"additional","affiliation":[{"name":"Radiation Epidemiology Team, Center for Research in Epidemiology and Population Health, INSERM U1018, Gustave Roussy, Universit\u00e9 Paris-Saclay, 94805 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mats","family":"Harms-Ringdahl","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 10691 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1711-6216","authenticated-orcid":false,"given":"Jonica","family":"Campolo","sequence":"additional","affiliation":[{"name":"CNR National Research Council Institute of Clinical Physiology, ASST Grande Ospedale Metropolitano Niguarda, 20162 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1061-8309","authenticated-orcid":false,"given":"Andrea","family":"Borghini","sequence":"additional","affiliation":[{"name":"CNR National Research Council Institute of Clinical Physiology, 56125 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8488-2324","authenticated-orcid":false,"given":"Fran\u00e7ois","family":"Chevalier","sequence":"additional","affiliation":[{"name":"UMR6252 CIMAP, CEA-CNRS-ENSICAEN-University of Caen Normandy, 14000 Caen, France"},{"name":"Advanced Resource Center for HADrontherapy in Europe (ARCHADE), 14000 Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8141-8449","authenticated-orcid":false,"given":"Jochen M.","family":"Schwenk","sequence":"additional","affiliation":[{"name":"Affinity Proteomics, SciLifeLab, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH\u2014Royal Institute of Technology, 10044 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7603-7828","authenticated-orcid":false,"given":"Brice","family":"Fresneau","sequence":"additional","affiliation":[{"name":"Department of Children and Adolescents Oncology, Gustave Roussy, Universit\u00e9 Paris-Saclay, 94805 Villejuif, France"},{"name":"Cancer and Radiation Team, Center for Research in Epidemiology and Population Health, INSERM U1018, Gustave Roussy, Universit\u00e9 Paris-Saclay, 94805 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Bolle","sequence":"additional","affiliation":[{"name":"Department of Radiation Therapy, Gustave Roussy, Universit\u00e9 Paris-Saclay, 94805 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7305-3766","authenticated-orcid":false,"given":"Manuel","family":"Fuentes","sequence":"additional","affiliation":[{"name":"Deparment of Medicine and General Service of Cytometry, Proteomics Unit, Cancer Research Centre-IBMCC, CSIC-USAL, IBSAL, Campus Miguel de Unamuno s\/n, University of Salamanca-CSIC, 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2867-4774","authenticated-orcid":false,"given":"Siamak","family":"Haghdoost","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 10691 Stockholm, Sweden"},{"name":"UMR6252 CIMAP, CEA-CNRS-ENSICAEN-University of Caen Normandy, 14000 Caen, France"},{"name":"Advanced Resource Center for HADrontherapy in Europe (ARCHADE), 14000 Caen, 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J. Radiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/j.jcmg.2017.04.003","article-title":"Radiation Safety in Children with Congenital and Acquired Heart Disease: A Scientific Position Statement on Multimodality Dose Optimization from the Image Gently Alliance","volume":"10","author":"Hill","year":"2017","journal-title":"JACC Cardiovasc. Imaging"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1161\/CIRCULATIONAHA.114.010699","article-title":"Reduction of radiation to children: Our responsibility to change","volume":"130","author":"Andreassi","year":"2014","journal-title":"Circulation"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1093\/jncimonographs\/lgaa010","article-title":"Epidemiological Studies of Low-Dose Ionizing Radiation and Cancer: Summary Bias Assessment and Meta-Analysis","volume":"2020","author":"Hauptmann","year":"2020","journal-title":"J. Natl. Cancer Inst. Monogr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1007\/s00381-008-0631-7","article-title":"Radiation-induced brain tumours after central nervous system irradiation in childhood: A review","volume":"24","author":"Pettorini","year":"2008","journal-title":"Childs Nerv. Syst."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Zahnreich, S., and Schmidberger, H. (2021). Childhood Cancer: Occurrence, Treatment and Risk of Second Primary Malignancies. Cancers, 13.","DOI":"10.3390\/cancers13112607"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"106286","DOI":"10.1016\/j.envint.2020.106286","article-title":"Guest editorial: Non-cancer effects of ionizing radiation\u2014Clinical implications, epidemiological and mechanistic evidence and research gaps","volume":"149","author":"Kreuzer","year":"2021","journal-title":"Environ. Int."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.ijrobp.2016.10.015","article-title":"Cerebrovascular Diseases in Childhood Cancer Survivors: Role of the Radiation Dose to Willis Circle Arteries","volume":"97","author":"Haddy","year":"2017","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1093\/brain\/awr071","article-title":"Relationship between the brain radiation dose for the treatment of childhood cancer and the risk of long-term cerebrovascular mortality","volume":"134","author":"Haddy","year":"2011","journal-title":"Brain"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1056\/NEJMoa1209825","article-title":"Risk of ischemic heart disease in women after radiotherapy for breast cancer","volume":"368","author":"Darby","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1161\/CIRCULATIONAHA.115.016686","article-title":"Cardiac Diseases Following Childhood Cancer Treatment: Cohort Study","volume":"133","author":"Haddy","year":"2016","journal-title":"Circulation"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1161\/CIRCULATIONAHA.117.029138","article-title":"Exposure to Low-Dose Ionizing Radiation from Cardiac Procedures and Malignancy Risk in Adults with Congenital Heart Disease","volume":"137","author":"Cohen","year":"2018","journal-title":"Circulation"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e048576","DOI":"10.1136\/bmjopen-2020-048576","article-title":"Exposure to low-dose ionising radiation from cardiac catheterisation and risk of cancer: The COCCINELLE study cohort profile","volume":"11","author":"Abalo","year":"2021","journal-title":"BMJ. Open"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1161\/CIRCULATIONAHA.117.032815","article-title":"Adult Congenital Heart Disease and Radiation Exposure: The Malignant Price of Cardiac Care","volume":"137","author":"Lang","year":"2018","journal-title":"Circulation"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1882","DOI":"10.3390\/ijerph6061882","article-title":"Health risk and biological effects of cardiac ionising imaging: From epidemiology to genes","volume":"6","author":"Foffa","year":"2009","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.mrrev.2012.05.003","article-title":"Ionizing radiation biomarkers for potential use in epidemiological studies","volume":"751","author":"Pernot","year":"2012","journal-title":"Mutat. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1080\/09553002.2019.1704908","article-title":"Establishing mechanisms affecting the individual response to ionizing radiation","volume":"96","author":"Averbeck","year":"2020","journal-title":"Int. J. Radiat. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1080\/10715760500043132","article-title":"Extracellular 8-oxo-dG as a sensitive parameter for oxidative stress in vivo and in vitro","volume":"39","author":"Haghdoost","year":"2005","journal-title":"Free Radic. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/S0360-3016(00)01580-7","article-title":"Can 8-oxo-dG be used as a predictor for individual radiosensitivity?","volume":"50","author":"Haghdoost","year":"2001","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1080\/10590500902885684","article-title":"8-hydroxy-2\u2032-deoxyguanosine (8-OHdG): A critical biomarker of oxidative stress and carcinogenesis","volume":"27","author":"Valavanidis","year":"2009","journal-title":"J. Environ. Sci. Health C Environ. Carcinog. Ecotoxicol. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1667\/RR13732.1","article-title":"Chronic Gamma-Irradiation Induces a Dose-Rate-Dependent Pro-inflammatory Response and Associated Loss of Function in Human Umbilical Vein Endothelial Cells","volume":"183","author":"Ebrahimian","year":"2015","journal-title":"Radiat. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1016\/j.jacc.2009.10.047","article-title":"Sustained inflammation due to nuclear factor-kappa B activation in irradiated human arteries","volume":"55","author":"Halle","year":"2010","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Ma, H., Zhou, Z., Wei, S., Liu, Z., Pooley, K.A., Dunning, A.M., Svenson, U., Roos, G., Hosgood, H.D., and Shen, M. (2011). Shortened telomere length is associated with increased risk of cancer: A meta-analysis. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0020466"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.ijcard.2015.11.133","article-title":"Leukocyte telomere shortening in grown-up patients with congenital heart disease","volume":"204","author":"Vecoli","year":"2016","journal-title":"Int. J. Cardiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1177\/2047487319831495","article-title":"Increased mitochondrial DNA4977-bp deletion in catheterization laboratory workers with long-term low-dose exposure to ionizing radiation","volume":"26","author":"Borghini","year":"2019","journal-title":"Eur. J. Prev. Cardiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"35859","DOI":"10.1038\/srep35859","article-title":"Altered mitochondrial DNA copy number contributes to human cancer risk: Evidence from an updated meta-analysis","volume":"6","author":"Hu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.freeradbiomed.2013.07.024","article-title":"Effects of ionizing radiation on mitochondria","volume":"65","author":"Kam","year":"2013","journal-title":"Free Radic. Biol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s13058-018-0955-5","article-title":"Mitochondrial DNA copy number variation, leukocyte telomere length, and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study","volume":"20","author":"Campa","year":"2018","journal-title":"Breast Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Assarsson, E., Lundberg, M., Holmquist, G., Bj\u00f6rkesten, J., Thorsen, S.B., Ekman, D., Eriksson, A., Rennel Dickens, E., Ohlsson, S., and Edfeldt, G. (2014). Homogenous 96-plex pea immunoassay exhibiting high sensitivity, specificity, and excellent scalability. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0095192"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Troncale, S., Barbet, A., Coulibaly, L., Henry, E., He, B., Barillot, E., Dubois, T., Hup\u00e9, P., and de Koning, L. (2012). NormaCurve: A SuperCurve-based method that simultaneously quantifies and normalizes reverse phase protein array data. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0038686"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2516","DOI":"10.1161\/CIRCULATIONAHA.117.031251","article-title":"Low-Dose Exposure to Ionizing Radiation Deregulates the Brain-Specific MicroRNA-134 in Interventional Cardiologists","volume":"136","author":"Borghini","year":"2017","journal-title":"Circulation"},{"key":"ref_33","first-page":"1074","article-title":"The HARMONIC project: Study design for the assessment of radiation doses and associated cancer risks following cardiac fluoroscopy in childhood","volume":"40","author":"Harbron","year":"2020","journal-title":"J. Radiol. Prot."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"882489","DOI":"10.3389\/fonc.2022.882489","article-title":"Validation of a Monte Carlo Framework for Out-of-Field Dose Calculations in Proton Therapy","volume":"12","author":"Verbeek","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"882506","DOI":"10.3389\/fonc.2022.882506","article-title":"Experimental Validation of an Analytical Program and a Monte Carlo Simulation for the Computation of the Far Out-of-Field Dose in External Beam Photon Therapy Applied to Pediatric Patients","volume":"12","author":"Suesselbeck","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e84","DOI":"10.1002\/mp.12824","article-title":"Image guidance doses delivered during radiotherapy: Quantification, management, and reduction: Report of the AAPM Therapy Physics Committee Task Group 180","volume":"45","author":"Ding","year":"2018","journal-title":"Med. Phys."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1088\/0952-4746\/33\/2\/433","article-title":"An analysis of radiation dose reduction in paediatric interventional cardiology by altering frame rate and use of the anti-scatter grid","volume":"33","author":"McFadden","year":"2013","journal-title":"J. Radiol. Prot."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1089\/ars.2013.5489","article-title":"Effects of ionizing radiation on biological molecules-mechanisms of damage and emerging methods of detection","volume":"21","author":"Reisz","year":"2014","journal-title":"Antioxid. Redox. Signal."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.mrrev.2017.01.001","article-title":"Ionizing radiation biomarkers in epidemiological studies\u2014An update","volume":"771","author":"Hall","year":"2017","journal-title":"Mutat. Res. Rev. Mutat. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1373\/clinchem.2010.153767","article-title":"Diagnostic potential of saliva: Current state and future applications","volume":"57","author":"Pfaffe","year":"2011","journal-title":"Clin. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00420-014-0938-5","article-title":"Saliva as a matrix for human biomonitoring in occupational and environmental medicine","volume":"88","author":"Michalke","year":"2015","journal-title":"Int. Arch. Occup. Environ. 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