The Influence of Low-Dose Radiotherapy on Paraoxonase-1 and Inflammatory Biomarkers in COVID-19 Pneumonia Patients
Main Article Content
Abstract
The COVID-19 pandemic will be remembered for its significant health and economic impact worldwide. Severe pneumonia could often progress to acute respiratory distress syndrome (ARDS), this being a critical complication characterised by an exaggerated inflammatory response, known as cytokine-release syndrome (CRS). Amid debates regarding the efficacy of conventional treatments, low-dose Radiotherapy (LDRT) has emerged as a potential therapy due to its anti-inflammatory effects. LDRT modulates immune responses by polarizing macrophages towards an anti-inflammatory phenotype and reducing oxidative stress. While studies investigating LDRT for COVID-19 pneumonia have shown promising results, conflicting data has been published and challenges persist in patient selection and treatment timing. Biomarkers such as paraoxonase-1 activity hold promise for predicting treatment outcomes. LDRT presents an alternative approach to modulating the immune response in COVID-19 pneumonia, offering hope for improved clinical outcomes. Further research is warranted to validate its efficacy and elucidate underlying mechanisms.
This article provides summary of the radioimmunological mechanisms and the results of biomarkers research in this context.
Article Details
How to Cite
ROYO, Laura et al.
The Influence of Low-Dose Radiotherapy on Paraoxonase-1 and Inflammatory Biomarkers in COVID-19 Pneumonia Patients.
Medical Research Archives, [S.l.], v. 12, n. 5, may 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5283>. Date accessed: 27 june 2024.
doi: https://doi.org/10.18103/mra.v12i5.5283.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Frey B, Gaipl US, Sarter K, Zaiss MM, Stillkrieg W, Rödel F, et al. Whole body low dose irradiation improves the course of beginning polyarthritis in human TNF-transgenic mice. Autoimmunity. 2009; 42(4):346-8. Doi: 10.1080/08916930902831738
2. Arenas M, Gil F, Gironella M, Hernández V, Biete A, Piqué JM, Panés J. Time course of anti-inflammatory effect of low-dose radiotherapy: correlation with TGF-beta(1) expression. 2008; Radiother Oncol 86(3):399-406. Doi: 10.1016/j.radonc.2007.10.03
3. Yufang S, Ying W, Changshun S, Jianan H, Jianhe G, et al. COVID-19 infection: the perspectives on immune responses. Cell Death Differ. 2020; 27(5):1451-1454, no. Doi: 10.1038/s41418-020-0530-3
4. Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020; 130:2620–9. Doi: 10.1172/JCI137244
5. Coperchini F, Chiovato L, Ricci G,Croce L, Magri F, Rotondi M. The cytokine storm in COVID-19: Further advances in our understanding the role of specific chemokines involved. Cytokine Growth Factor Rev. 2021; 58: 82–91. Doi: 10.1016/j.cytogfr.2020.12.005
6. Battaglini D, Lopes-Pacheco M, Castro-Faria-Neto H, Pelosi P, Rocco PRM. Laboratory Biomarkers for Diagnosis and Prognosis in COVID-19. Front Immunol. 2022; 13: 857573. Doi: 10.3389/fimmu.2022.857573
7. Matthew ZT, Check MP, Laurent R, Paul AM, Lisa FPN. The trinity of COVID-19: immunity, inflammation and intervention. Nature Reviews Immunology. 2020; 20, pages363–374. Doi: 10.1038/s41577-020-0311-8
8. Hällgren, Samuelsson T, Laurent TC , Modig J. Accumulation of hyaluronan (hyaluronic acid) in the lung in adult respiratory distress syndrome. Am Rev Respir Dis. 1989; 139(3):682-7. Doi: 10.1164/ajrccm/139.3.682
9. Musser JH, Edsall DL. A study of metabolism in leukaemia, under the influence of the X-ray. Tr A Am Physicians. 1905; 20: 294–323
10. Edward J. Calabrese, Gaurav Dhawan. How Radiotherapy Was Historically Used To Treat Pneumonia: Could It Be Useful Today? Yale J Biol Med. 2013; 86(4): 555–570. PMCID: PMC3848110
11. Gyuleva, I, Djounova J, Rupova I. Impact of Low-Dose Occupational Exposure to Ionizing Radiation on T-Cell Populations and Subpopulations and Humoral Factors Included in the Immune Response. Dose Response. 2018; 16(3). Doi: 10.1177/1559325818785564
12. Awais N, Deepsha Al, Jayashree P, Iakovos T. Low-dose X-ray therapy for COVID-19: lessons from the past. Br J Radiol. 2021; 94(1117): 20200581. Doi: 10.1259/bjr.20200581
13. Rödel F, Arenas M, Ott OJ, Fournier C, Georgakilas AG, et al. Low-dose radiation therapy for COVID-19 pneumopathy: what is the evidence? Strahlenther Onkol. 2020; 196(8):679-682, no. Doi: 10.1007/s00066-020-01635-7
14. Kirkby C, Mackenzie M. Is low dose radiation therapy a potential treatment for COVID-19 pneumonia? Radiother Oncol. 2020; 147:221. Doi: 10.1016/j.radonc.2020.04.004
15. Dhawan G, Kapoor R, Dhawan R, Singh R, Monga B, et al. Low dose radiation therapy as a potential life saving treatment for COVID-19-induced acute respiratory distress syndrome (ARDS). Radiother Oncol. 2020; 147:212-216. Doi: 10.1016/j.radonc.2020.05.002
16. Schaue D, McBride WH. Flying by the seat of our pants: is low dose radiation therapy for COVID-19 an option? Int J Radiat Biol. 2020; 96(10):1219-1223. Doi: 10.1080/09553002.2020.1767314
17. Papachristofilou A, Finazzi T, Blum A, Zehnder T, Zellweger N, et al. Low-Dose Radiation Therapy for Severe COVID-19 Pneumonia: A Randomized Double-Blind Study. Int J Radiat Oncol Biol Phys. 2021; 110(5):1274-1282. Doi: 10.1016/j.ijrobp.2021.02.054
18. Kolahdouzan K, Chavoshi M, Bayani R, i Darzikolaee NM. Low-Dose Whole Lung Irradiation for Treatment of COVID-19 Pneumonia: A Systematic Review and Meta-Analysis. Int J Radiat Oncol Biol Phys. 2022; 1;113(5):946-959. Doi: 10.1016/j.ijrobp.2022.04.043
19. Mortazavi SMJ, Shams SF, Mohammadi S, Mortazavi SAR, Sihver L. Low-Dose Radiation Therapy for COVID-19: A Systematic Review. Radiation. 2021; 196, 1086–1093, no. Doi: 10.3390/radiation1030020
20. Arenas M, Piqué B, Torres-Royo L, et al. Treatment of COVID-19 pneumonia with low-dose radiotherapy plus standard of care versus standard of care alone in frail patients: The SEOR-GICOR IPACOVID comparative cohort trial. Strahlenther Onkol. 2023; 199(9):847-856. Doi: 10.1007/s00066-023-02067-9
21. Sharma DN, Guleria R, Wig N, Mohan A, Rath G, et al. Low-dose radiation therapy for COVID-19 pneumonia: a pilot study. Br J Radiol. 2021; 94(1126):20210187, no. Doi: 10.1259/bjr.20210187 .
22. Hess CB, Buchwald ZS, Stokes W, Nasti TH, Switchenko JM, et al. Immunomodulatory low-dose whole-lung radiation for COVID-19 pneumonia. Int. J. Radiat. Oncol. Biol. Phys. 2020; 108, 1401. Doi: 10.1016/j.ijrobp.2020.09.025
23. Hess CB, Buchwald ZS, Stokes W, Nasti TH, Switchenko JM. Low-dose whole-lung radiation for COVID-19 pneumonia: Planned day 7 interim analysis of a registered clinical trial. Cancer. 2020; 126, 5109–5113. Doi: 10.1002/cncr.33130
24. Ameri A, Rahnama N, Bozorgmehr R, Mokhtari M, Farahbakhsh M, et al. Low-Dose Whole-Lung Irradiation for COVID-19 Pneumonia: Short Course Results. Int J Radiat Oncol Biol Phys. 2020; 108(5):1134-1139, no. Doi: 10.1016/j.ijrobp.2020.07.026
25. Ameri A, Ameri P, Rahnama N, Mokhtari M, Sedaghat M. Low-Dose Whole-Lung Irradiation for COVID-19 Pneumonia: Final Results of a Pilot Study. Int J Radiat Oncol Biol Phys. 2021; 109(4):859-866. Doi: 10.1016/j.ijrobp.2020.11.065
26. Moreno-Olmedo E, Suárez-Gironzini V, Pérez M, Filigheddu T, Mínguez C, et al. COVID-19 pneumonia treated with ultra-low doses of radiotherapy (ULTRA-COVID study): a single institution report of two cases. Strahlenther Onkol. 2021; 197(5): 429–437. Doi: 10.1007/s00066-020-01743-4
27. Sanmamed N, Alcantara P, Cerezo E, Gaztañaga M, Cabello N, et al. Low-Dose Radiation Therapy in the Management of Coronavirus Disease 2019 (COVID-19) Pneumonia (LOWRAD-Cov19): Preliminary Report. Int J Radiat Oncol Biol Phys. 2020; 109(4):880-885. Doi: 10.1016/j.ijrobp.2020.11.049.
28. Del Castillo R, Martinez D, J Sarria GJ, Pinillos L, Garcia B, et al. Low-dose radiotherapy for COVID-19 pneumonia treatment: case report, procedure, and literature review. Strahlenther Onkol. 2020; 196(12):1086-1093. Doi: 10.1007/s00066-020-01675-z
29. Caterino M, Costanzo M, Fedele R, Cevenini A, Gelzo M, et al. The Serum Metabolome of Moderate and Severe COVID-19 Patients Reflects Possible Liver Alterations Involving Carbon and Nitrogen Metabolism. Int J Mol Sci. 2021; 22:9548. Doi: 10.3390/ijms22179548
30. Rodríguez-Tomàs E, Acosta JC, Torres-Royo L, De Febrer G, Baiges-Gaya G, et al. Effect of Low-Dose Radiotherapy on the Circulating Levels of Paraoxonase-1-Related Variables and Markers of Inflammation in Patients with COVID-19 Pneumonia. Antioxidants (Basel). 2022; 16;11(6):1184. Doi: 10.3390/antiox11061184
31. Marsillach J, Mackness B, Mackness M, Riu F, Beltrán R, et al. Immunohistochemical analysis of paraoxonases-1, 2, and 3 expression in normal mouse tissues. Free Radic Biol Med . 2008; 15;45(2):146-57. Doi: 10.1016/j.freeradbiomed.2008.03.023
32. Deakin SP, Bioletto S, Bochaton-Piallat ML, James RW. HDL-associated paraoxonase-1 can redistribute to cell membranes and influence sensitivity to oxidative stress. Free Radic Biol Med. 2010; 50(1):102-9. Doi: 10.1016/j.freeradbiomed.2010.09.002
33. Camps J, Marsillach J, Joven J. The paraoxonases: role in human diseases and methodological difficulties in measurement. Crit Rev Clin Lab Sci. 2009; 46(2):83-106. Doi: 10.1080/10408360802610878
34. Rodríguez-Tomàs E, Iftimie S, Castañé H, Baiges-Gaya G, et al. Clinical Performance of Paraoxonase-1-Related Variables and Novel Markers of Inflammation in Coronavirus Disease-19. A Machine Learning Approach. Antioxidants (Basel). 2021; 10(6):991. Doi: 10.3390/antiox10060991
35. Cho KH, Kim JR, Lee IC, Kwon HJ. Native High-Density Lipoproteins (HDL) with Higher Paraoxonase Exerts a Potent Antiviral Effect against SARS-CoV-2 (COVID-19), While Glycated HDL Lost the Antiviral Activity. Antioxidants (Basel). 2021; 10(2):209. Doi: 10.3390/antiox10020209
36. Lalosevic M, Kotur-Stevuljevic J, Vekic J, Rizzo M, Kosanovic T, et al. Alteration in Redox Status and Lipoprotein Profile in COVID-19 Patients with Mild, Moderate, and Severe Pneumonia. Oxid Med Cell Longev. 2022; 14:2022:8067857. Doi: 10.1155/2022/8067857
37. Ghoreshi ZAS, Abbasi-Jorjandi M, Asadikaram G, Sharif-Zak M, Seyedi F, et al. Paraoxonase 1 rs662 polymorphism, its related variables, and COVID-19 intensity: Considering gender and post-COVID complications. Exp Biol Med (Maywood). 2023; 248(23):2351-2362, no. Doi: 10.1177/15353702221128563
38. Kefayat A, Ghahremani F. Low dose radiation therapy for COVID-19 pneumonia: A double-edged sword. Radiother Oncol. 2020; 147: 224–225. Doi: 10.1016/j.radonc.2020.04.026
39. Brenner DJ, Sachs RK. Estimating radiation-induced cancer risks at very low doses: rationale for using a linear no-threshold approach. Radiat Environ Biophys. 2006; 44(4):253-6. Doi: 10.1007/s00411-006-0029-4
40. A, Sagan L. What is hormesis and why haven't we heard about it before?. Health Phys. 1987; 52(5):521-5. PMID: 3570794
41. Nikitaki Z, Nikolov V, Mavragani IV, Mladenov E, Mangelis A, et al. Measurement of complex DNA damage induction and repair in human cellular systems after exposure to ionizing radiations of varying linear energy transfer (LET). Free Radic Res. 2016; 50(sup1):S64-S78. Doi: 10.1080/10715762.2016.1232484
2. Arenas M, Gil F, Gironella M, Hernández V, Biete A, Piqué JM, Panés J. Time course of anti-inflammatory effect of low-dose radiotherapy: correlation with TGF-beta(1) expression. 2008; Radiother Oncol 86(3):399-406. Doi: 10.1016/j.radonc.2007.10.03
3. Yufang S, Ying W, Changshun S, Jianan H, Jianhe G, et al. COVID-19 infection: the perspectives on immune responses. Cell Death Differ. 2020; 27(5):1451-1454, no. Doi: 10.1038/s41418-020-0530-3
4. Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020; 130:2620–9. Doi: 10.1172/JCI137244
5. Coperchini F, Chiovato L, Ricci G,Croce L, Magri F, Rotondi M. The cytokine storm in COVID-19: Further advances in our understanding the role of specific chemokines involved. Cytokine Growth Factor Rev. 2021; 58: 82–91. Doi: 10.1016/j.cytogfr.2020.12.005
6. Battaglini D, Lopes-Pacheco M, Castro-Faria-Neto H, Pelosi P, Rocco PRM. Laboratory Biomarkers for Diagnosis and Prognosis in COVID-19. Front Immunol. 2022; 13: 857573. Doi: 10.3389/fimmu.2022.857573
7. Matthew ZT, Check MP, Laurent R, Paul AM, Lisa FPN. The trinity of COVID-19: immunity, inflammation and intervention. Nature Reviews Immunology. 2020; 20, pages363–374. Doi: 10.1038/s41577-020-0311-8
8. Hällgren, Samuelsson T, Laurent TC , Modig J. Accumulation of hyaluronan (hyaluronic acid) in the lung in adult respiratory distress syndrome. Am Rev Respir Dis. 1989; 139(3):682-7. Doi: 10.1164/ajrccm/139.3.682
9. Musser JH, Edsall DL. A study of metabolism in leukaemia, under the influence of the X-ray. Tr A Am Physicians. 1905; 20: 294–323
10. Edward J. Calabrese, Gaurav Dhawan. How Radiotherapy Was Historically Used To Treat Pneumonia: Could It Be Useful Today? Yale J Biol Med. 2013; 86(4): 555–570. PMCID: PMC3848110
11. Gyuleva, I, Djounova J, Rupova I. Impact of Low-Dose Occupational Exposure to Ionizing Radiation on T-Cell Populations and Subpopulations and Humoral Factors Included in the Immune Response. Dose Response. 2018; 16(3). Doi: 10.1177/1559325818785564
12. Awais N, Deepsha Al, Jayashree P, Iakovos T. Low-dose X-ray therapy for COVID-19: lessons from the past. Br J Radiol. 2021; 94(1117): 20200581. Doi: 10.1259/bjr.20200581
13. Rödel F, Arenas M, Ott OJ, Fournier C, Georgakilas AG, et al. Low-dose radiation therapy for COVID-19 pneumopathy: what is the evidence? Strahlenther Onkol. 2020; 196(8):679-682, no. Doi: 10.1007/s00066-020-01635-7
14. Kirkby C, Mackenzie M. Is low dose radiation therapy a potential treatment for COVID-19 pneumonia? Radiother Oncol. 2020; 147:221. Doi: 10.1016/j.radonc.2020.04.004
15. Dhawan G, Kapoor R, Dhawan R, Singh R, Monga B, et al. Low dose radiation therapy as a potential life saving treatment for COVID-19-induced acute respiratory distress syndrome (ARDS). Radiother Oncol. 2020; 147:212-216. Doi: 10.1016/j.radonc.2020.05.002
16. Schaue D, McBride WH. Flying by the seat of our pants: is low dose radiation therapy for COVID-19 an option? Int J Radiat Biol. 2020; 96(10):1219-1223. Doi: 10.1080/09553002.2020.1767314
17. Papachristofilou A, Finazzi T, Blum A, Zehnder T, Zellweger N, et al. Low-Dose Radiation Therapy for Severe COVID-19 Pneumonia: A Randomized Double-Blind Study. Int J Radiat Oncol Biol Phys. 2021; 110(5):1274-1282. Doi: 10.1016/j.ijrobp.2021.02.054
18. Kolahdouzan K, Chavoshi M, Bayani R, i Darzikolaee NM. Low-Dose Whole Lung Irradiation for Treatment of COVID-19 Pneumonia: A Systematic Review and Meta-Analysis. Int J Radiat Oncol Biol Phys. 2022; 1;113(5):946-959. Doi: 10.1016/j.ijrobp.2022.04.043
19. Mortazavi SMJ, Shams SF, Mohammadi S, Mortazavi SAR, Sihver L. Low-Dose Radiation Therapy for COVID-19: A Systematic Review. Radiation. 2021; 196, 1086–1093, no. Doi: 10.3390/radiation1030020
20. Arenas M, Piqué B, Torres-Royo L, et al. Treatment of COVID-19 pneumonia with low-dose radiotherapy plus standard of care versus standard of care alone in frail patients: The SEOR-GICOR IPACOVID comparative cohort trial. Strahlenther Onkol. 2023; 199(9):847-856. Doi: 10.1007/s00066-023-02067-9
21. Sharma DN, Guleria R, Wig N, Mohan A, Rath G, et al. Low-dose radiation therapy for COVID-19 pneumonia: a pilot study. Br J Radiol. 2021; 94(1126):20210187, no. Doi: 10.1259/bjr.20210187 .
22. Hess CB, Buchwald ZS, Stokes W, Nasti TH, Switchenko JM, et al. Immunomodulatory low-dose whole-lung radiation for COVID-19 pneumonia. Int. J. Radiat. Oncol. Biol. Phys. 2020; 108, 1401. Doi: 10.1016/j.ijrobp.2020.09.025
23. Hess CB, Buchwald ZS, Stokes W, Nasti TH, Switchenko JM. Low-dose whole-lung radiation for COVID-19 pneumonia: Planned day 7 interim analysis of a registered clinical trial. Cancer. 2020; 126, 5109–5113. Doi: 10.1002/cncr.33130
24. Ameri A, Rahnama N, Bozorgmehr R, Mokhtari M, Farahbakhsh M, et al. Low-Dose Whole-Lung Irradiation for COVID-19 Pneumonia: Short Course Results. Int J Radiat Oncol Biol Phys. 2020; 108(5):1134-1139, no. Doi: 10.1016/j.ijrobp.2020.07.026
25. Ameri A, Ameri P, Rahnama N, Mokhtari M, Sedaghat M. Low-Dose Whole-Lung Irradiation for COVID-19 Pneumonia: Final Results of a Pilot Study. Int J Radiat Oncol Biol Phys. 2021; 109(4):859-866. Doi: 10.1016/j.ijrobp.2020.11.065
26. Moreno-Olmedo E, Suárez-Gironzini V, Pérez M, Filigheddu T, Mínguez C, et al. COVID-19 pneumonia treated with ultra-low doses of radiotherapy (ULTRA-COVID study): a single institution report of two cases. Strahlenther Onkol. 2021; 197(5): 429–437. Doi: 10.1007/s00066-020-01743-4
27. Sanmamed N, Alcantara P, Cerezo E, Gaztañaga M, Cabello N, et al. Low-Dose Radiation Therapy in the Management of Coronavirus Disease 2019 (COVID-19) Pneumonia (LOWRAD-Cov19): Preliminary Report. Int J Radiat Oncol Biol Phys. 2020; 109(4):880-885. Doi: 10.1016/j.ijrobp.2020.11.049.
28. Del Castillo R, Martinez D, J Sarria GJ, Pinillos L, Garcia B, et al. Low-dose radiotherapy for COVID-19 pneumonia treatment: case report, procedure, and literature review. Strahlenther Onkol. 2020; 196(12):1086-1093. Doi: 10.1007/s00066-020-01675-z
29. Caterino M, Costanzo M, Fedele R, Cevenini A, Gelzo M, et al. The Serum Metabolome of Moderate and Severe COVID-19 Patients Reflects Possible Liver Alterations Involving Carbon and Nitrogen Metabolism. Int J Mol Sci. 2021; 22:9548. Doi: 10.3390/ijms22179548
30. Rodríguez-Tomàs E, Acosta JC, Torres-Royo L, De Febrer G, Baiges-Gaya G, et al. Effect of Low-Dose Radiotherapy on the Circulating Levels of Paraoxonase-1-Related Variables and Markers of Inflammation in Patients with COVID-19 Pneumonia. Antioxidants (Basel). 2022; 16;11(6):1184. Doi: 10.3390/antiox11061184
31. Marsillach J, Mackness B, Mackness M, Riu F, Beltrán R, et al. Immunohistochemical analysis of paraoxonases-1, 2, and 3 expression in normal mouse tissues. Free Radic Biol Med . 2008; 15;45(2):146-57. Doi: 10.1016/j.freeradbiomed.2008.03.023
32. Deakin SP, Bioletto S, Bochaton-Piallat ML, James RW. HDL-associated paraoxonase-1 can redistribute to cell membranes and influence sensitivity to oxidative stress. Free Radic Biol Med. 2010; 50(1):102-9. Doi: 10.1016/j.freeradbiomed.2010.09.002
33. Camps J, Marsillach J, Joven J. The paraoxonases: role in human diseases and methodological difficulties in measurement. Crit Rev Clin Lab Sci. 2009; 46(2):83-106. Doi: 10.1080/10408360802610878
34. Rodríguez-Tomàs E, Iftimie S, Castañé H, Baiges-Gaya G, et al. Clinical Performance of Paraoxonase-1-Related Variables and Novel Markers of Inflammation in Coronavirus Disease-19. A Machine Learning Approach. Antioxidants (Basel). 2021; 10(6):991. Doi: 10.3390/antiox10060991
35. Cho KH, Kim JR, Lee IC, Kwon HJ. Native High-Density Lipoproteins (HDL) with Higher Paraoxonase Exerts a Potent Antiviral Effect against SARS-CoV-2 (COVID-19), While Glycated HDL Lost the Antiviral Activity. Antioxidants (Basel). 2021; 10(2):209. Doi: 10.3390/antiox10020209
36. Lalosevic M, Kotur-Stevuljevic J, Vekic J, Rizzo M, Kosanovic T, et al. Alteration in Redox Status and Lipoprotein Profile in COVID-19 Patients with Mild, Moderate, and Severe Pneumonia. Oxid Med Cell Longev. 2022; 14:2022:8067857. Doi: 10.1155/2022/8067857
37. Ghoreshi ZAS, Abbasi-Jorjandi M, Asadikaram G, Sharif-Zak M, Seyedi F, et al. Paraoxonase 1 rs662 polymorphism, its related variables, and COVID-19 intensity: Considering gender and post-COVID complications. Exp Biol Med (Maywood). 2023; 248(23):2351-2362, no. Doi: 10.1177/15353702221128563
38. Kefayat A, Ghahremani F. Low dose radiation therapy for COVID-19 pneumonia: A double-edged sword. Radiother Oncol. 2020; 147: 224–225. Doi: 10.1016/j.radonc.2020.04.026
39. Brenner DJ, Sachs RK. Estimating radiation-induced cancer risks at very low doses: rationale for using a linear no-threshold approach. Radiat Environ Biophys. 2006; 44(4):253-6. Doi: 10.1007/s00411-006-0029-4
40. A, Sagan L. What is hormesis and why haven't we heard about it before?. Health Phys. 1987; 52(5):521-5. PMID: 3570794
41. Nikitaki Z, Nikolov V, Mavragani IV, Mladenov E, Mangelis A, et al. Measurement of complex DNA damage induction and repair in human cellular systems after exposure to ionizing radiations of varying linear energy transfer (LET). Free Radic Res. 2016; 50(sup1):S64-S78. Doi: 10.1080/10715762.2016.1232484