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5 pages, 214 KiB

Open AccessEditorial

Cancer and Non-Cancer Effects Following Ionizing Irradiation

by Nobuyuki Hamada

Cancers 2024, 16(6), 1141; https://doi.org/10.3390/cancers16061141 - 13 Mar 2024

Viewed by 569

Abstract

On the one hand, ionizing radiation has been used to treat not only cancer, but also non-cancer diseases. On the other hand, associations with radiation exposure have increasingly been reported not only for cancer, but also non-cancer diseases, both at doses or dose [...] Read more.

On the one hand, ionizing radiation has been used to treat not only cancer, but also non-cancer diseases. On the other hand, associations with radiation exposure have increasingly been reported not only for cancer, but also non-cancer diseases, both at doses or dose rates much lower than previously suggested or considered. This underscores the need for considering both cancer and non-cancer effects of medical (diagnostic or therapeutic), occupational or environmental exposure to radiation. As such, this Special Issue aims to serve as a forum to gather the latest developments and discuss future prospects in the field of normal tissue responses to radiation exposure. The Special Issue is composed of 18 articles outlining the radiation effects arising in various tissues (e.g., those in the circulatory, sensory, nervous, respiratory, and reproductive systems). Full article

(This article belongs to the Special Issue Cancer and Non-cancer Effects following Ionizing Irradiation)

Research

Jump to: Editorial, Review

21 pages, 4036 KiB

Open AccessArticle

Late Effects of Chronic Low Dose Rate Total Body Irradiation on the Heart Proteome of ApoE^−/− Mice Resemble Premature Cardiac Ageing

by Omid Azimzadeh, Juliane Merl-Pham, Vikram Subramanian, Kateryna Oleksenko, Franziska Krumm, Mariateresa Mancuso, Emanuela Pasquali, Ignacia B. Tanaka III, Satoshi Tanaka, Michael J. Atkinson, Soile Tapio and Simone Moertl

Cancers 2023, 15(13), 3417; https://doi.org/10.3390/cancers15133417 - 29 Jun 2023

Cited by 1 | Viewed by 1247

Abstract

Recent epidemiologic studies support an association between chronic low-dose radiation exposure and the development of cardiovascular disease (CVD). The molecular mechanisms underlying the adverse effect of chronic low dose exposure are not fully understood. To address this issue, we have investigated changes in [...] Read more.

Recent epidemiologic studies support an association between chronic low-dose radiation exposure and the development of cardiovascular disease (CVD). The molecular mechanisms underlying the adverse effect of chronic low dose exposure are not fully understood. To address this issue, we have investigated changes in the heart proteome of ApoE deficient (ApoE^−/−) C57Bl/6 female mice chronically irradiated for 300 days at a very low dose rate (1 mGy/day) or at a low dose rate (20 mGy/day), resulting in cumulative whole-body doses of 0.3 Gy or 6.0 Gy, respectively. The heart proteomes were compared to those of age-matched sham-irradiated ApoE^−/− mice using label-free quantitative proteomics. Radiation-induced proteome changes were further validated using immunoblotting, enzyme activity assays, immunohistochemistry or targeted transcriptomics. The analyses showed persistent alterations in the cardiac proteome at both dose rates; however, the effect was more pronounced following higher dose rates. The altered proteins were involved in cardiac energy metabolism, ECM remodelling, oxidative stress, and ageing signalling pathways. The changes in PPARα, SIRT, AMPK, and mTOR signalling pathways were found at both dose rates and in a dose-dependent manner, whereas more changes in glycolysis and ECM remodelling were detected at the lower dose rate. These data provide strong evidence for the possible risk of cardiac injury following chronic low dose irradiation and show that several affected pathways following chronic irradiation overlap with those of ageing-associated heart pathology. Full article

(This article belongs to the Special Issue Cancer and Non-cancer Effects following Ionizing Irradiation)

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10 pages, 815 KiB

Open AccessArticle

Effects of Whole and Partial Heart Irradiation on Collagen, Mast Cells, and Toll-like Receptor 4 in the Mouse Heart

by Vijayalakshmi Sridharan, Kimberly J. Krager, Snehalata A. Pawar, Shivani Bansal, Yaoxiang Li, Amrita K. Cheema and Marjan Boerma

Cancers 2023, 15(2), 406; https://doi.org/10.3390/cancers15020406 - 07 Jan 2023

Cited by 2 | Viewed by 1700

Abstract

In radiation therapy of tumors in the chest, such as in lung or esophageal cancer, part of the heart may be situated in the radiation field. This can lead to the development of radiation-induced heart disease. The mechanisms by which radiation causes long-term [...] Read more.

In radiation therapy of tumors in the chest, such as in lung or esophageal cancer, part of the heart may be situated in the radiation field. This can lead to the development of radiation-induced heart disease. The mechanisms by which radiation causes long-term injury to the heart are not fully understood, but investigations in pre-clinical research models can contribute to mechanistic insights. Recent developments in X-ray technology have enabled partial heart irradiation in mouse models. In this study, adult male and female C57BL/6J mice were exposed to whole heart (a single dose of 8 or 16 Gy) and partial heart irradiation (16 Gy to 40% of the heart). Plasma samples were collected at 5 days and 2 weeks after the irradiation for metabolomics analysis, and the cardiac collagen deposition, mast cell numbers, and left ventricular expression of Toll-like receptor 4 (TLR4) were examined in the irradiated and unirradiated parts of the heart at 6 months after the irradiation. Small differences were found in the plasma metabolite profiles between the groups. However, the collagen deposition did not differ between the irradiated and unirradiated parts of the heart, and radiation did not upregulate the mast cell numbers in either part of the heart. Lastly, an increase in the expression of TLR4 was seen only after a single dose of 8 Gy to the whole heart. These results suggest that adverse tissue remodeling was not different between the irradiated and unirradiated portions of the mouse heart. While there were no clear differences between male and female animals, additional work in larger cohorts may be required to confirm this result, and to test the inhibition of TLR4 as an intervention strategy in radiation-induced heart disease. Full article

(This article belongs to the Special Issue Cancer and Non-cancer Effects following Ionizing Irradiation)

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18 pages, 798 KiB

Open AccessArticle

Updated Mortality Analysis of SELTINE, the French Cohort of Nuclear Workers, 1968–2014

by Olivier Laurent, Eric Samson, Sylvaine Caër-Lorho, Lucie Fournier, Dominique Laurier and Klervi Leuraud

Cancers 2023, 15(1), 79; https://doi.org/10.3390/cancers15010079 - 23 Dec 2022

Cited by 8 | Viewed by 1464

Abstract

Cohorts of nuclear workers are particularly relevant to study the health effects of protracted exposures to low doses at low dose-rates of ionizing radiation (IR). In France, a cohort of nuclear workers badge-monitored for external IR exposure has been followed-up for several decades. [...] Read more.

Cohorts of nuclear workers are particularly relevant to study the health effects of protracted exposures to low doses at low dose-rates of ionizing radiation (IR). In France, a cohort of nuclear workers badge-monitored for external IR exposure has been followed-up for several decades. Its size and follow-up period have recently been extended. The present paper focuses on mortality from both cancer and non-cancer diseases in this cohort. The SELTINE cohort of nuclear workers employed by CEA, Orano, and EDF companies was followed-up for mortality from 1968 to 2014. Mortality in the cohort was compared to that in the French general population. Poisson regression methods were used to estimate excess relative rates of mortality per unit of cumulative dose of IR, adjusted for calendar year, age, company, duration of employment, and socioeconomic status. The cohort included 80,348 workers. At the end of the follow-up, the mean attained age was 63 years, and 15,695 deaths were observed. A strong healthy worker effect was observed overall. A significant excess of pleural cancer mortality was observed but not associated with IR dose. Death from solid cancers was positively but non-significantly associated with radiation. Death from leukaemia (excluding chronic lymphocytic leukaemia), dementia, and Alzheimer’s disease were positively and significantly associated with IR dose. Estimated dose–risk relationships were consistent with those from other nuclear worker studies for all solid cancers and leukaemia but remained associated with large uncertainty. The association between IR dose and dementia mortality risk should be interpreted with caution and requires further investigation by other studies. Full article

(This article belongs to the Special Issue Cancer and Non-cancer Effects following Ionizing Irradiation)

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15 pages, 769 KiB

Open AccessArticle

Early Coronary Artery Calcification Progression over Two Years in Breast Cancer Patients Treated with Radiation Therapy: Association with Cardiac Exposure (BACCARAT Study)

by Manoj Kumar Honaryar, Rodrigue Allodji, Jean Ferrières, Loïc Panh, Médéa Locquet, Gaelle Jimenez, Matthieu Lapeyre, Jérémy Camilleri, David Broggio, Florent de Vathaire and Sophie Jacob

Cancers 2022, 14(23), 5724; https://doi.org/10.3390/cancers14235724 - 22 Nov 2022

Cited by 5 | Viewed by 1669

Abstract

Background: Radiotherapy (RT) for breast cancer (BC) can induce coronary artery disease many years after RT. At an earlier stage, during the first two years after RT, we aimed to evaluate the occurrence of increased coronary artery calcium (CAC) and its association with [...] Read more.

Background: Radiotherapy (RT) for breast cancer (BC) can induce coronary artery disease many years after RT. At an earlier stage, during the first two years after RT, we aimed to evaluate the occurrence of increased coronary artery calcium (CAC) and its association with cardiac exposure. Methods: This prospective study included 101 BC patients treated with RT without chemotherapy. Based on CAC CT scans performed before and two years after RT, the event ‘CAC progression’ was defined by an increase in overall CAC score (CAC RT+ two years—CAC before RT > 0). Dosimetry was evaluated for whole heart, left ventricle (LV), and coronary arteries. Multivariable logistic regression models were used to assess association with doses. Results: Two years after RT, 28 patients presented the event ‘CAC progression’, explained in 93% of cases by a higher CAC score in the left anterior descending coronary (LAD). A dose–response relationship was observed with LV exposure (for Dmean LV: OR = 1.15, p = 0.04). LAD exposure marginally explained increased CAC in the LAD (for D2 LV: OR =1.03, p = 0.07). Conclusion: The risk of early CAC progression may be associated with LV exposure. This progression might primarily be a consequence of CAC increase in the LAD and its exposure. Full article

(This article belongs to the Special Issue Cancer and Non-cancer Effects following Ionizing Irradiation)

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20 pages, 5263 KiB

Open AccessArticle

TRPM4 Participates in Irradiation-Induced Aortic Valve Remodeling in Mice

by Harlyne Mpweme Bangando, Christophe Simard, Margaux Aize, Alexandre Lebrun, Alain Manrique, Romain Guinamard and on behalf of the STOP-AS Investigators

Cancers 2022, 14(18), 4477; https://doi.org/10.3390/cancers14184477 - 15 Sep 2022

Cited by 3 | Viewed by 1630

Abstract

Thoracic radiotherapy can lead to cardiac remodeling including valvular stenosis due to fibrosis and calcification. The monovalent non-selective cation channel TRPM4 is known to be involved in calcium handling and to participate in fibroblast transition to myofibroblasts, a phenomenon observed during aortic valve [...] Read more.

Thoracic radiotherapy can lead to cardiac remodeling including valvular stenosis due to fibrosis and calcification. The monovalent non-selective cation channel TRPM4 is known to be involved in calcium handling and to participate in fibroblast transition to myofibroblasts, a phenomenon observed during aortic valve stenosis. The goal of this study was to evaluate if TRPM4 is involved in irradiation-induced aortic valve damage. Four-month-old Trpm4^+/+ and Trpm4^−/− mice received 10 Gy irradiation at the aortic valve. Cardiac parameters were evaluated by echography until 5 months post-irradiation, then hearts were collected for morphological and histological assessments. At the onset of the protocol, Trpm4^+/+ and Trpm4^−/− mice exhibited similar maximal aortic valve jet velocity and mean pressure gradient. Five months after irradiation, Trpm4^+/+ mice exhibited a significant increase in those parameters, compared to the untreated animals while no variation was detected in Trpm4^−/− mice. Morphological analysis revealed that irradiated Trpm4^+/+ mice exhibited a 53% significant increase in the aortic valve cusp surface while no significant variation was observed in Trpm4^−/− animals. Collagen staining revealed aortic valve fibrosis in irradiated Trpm4^+/+ mice but not in irradiated Trpm4^−/− animals. It indicates that TRPM4 influences irradiation-induced valvular remodeling. Full article

(This article belongs to the Special Issue Cancer and Non-cancer Effects following Ionizing Irradiation)

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10 pages, 1607 KiB

Open AccessArticle

The Kinetics of FMS-Related Tyrosine Kinase 3 Ligand (Flt-3L) during Chemoradiotherapy Suggests a Potential Gain from the Earlier Initiation of Immunotherapy

by Łukasz Kuncman, Magdalena Orzechowska, Konrad Stawiski, Michał Masłowski, Magdalena Ciążyńska, Leszek Gottwald, Tomasz Milecki and Jacek Fijuth

Cancers 2022, 14(16), 3844; https://doi.org/10.3390/cancers14163844 - 09 Aug 2022

Cited by 4 | Viewed by 1632

Abstract

The optimal sequence of chemoradiotherapy with immunotherapy is still not established. The patient’s immune status may play a role in determining this order. We aim to determine the kinetics of a multi-potential haemopoietic factor FMS-related tyrosine kinase 3 ligand (Flt-3L) during chemoradiotherapy. Our [...] Read more.

The optimal sequence of chemoradiotherapy with immunotherapy is still not established. The patient’s immune status may play a role in determining this order. We aim to determine the kinetics of a multi-potential haemopoietic factor FMS-related tyrosine kinase 3 ligand (Flt-3L) during chemoradiotherapy. Our pilot, a single arm prospective study, enrolled patients with rectal cancer who qualified for neoadjuvant chemoradiotherapy. Blood samples for Flt-3L were collected before and every second week of chemoradiotherapy for a complete blood count every week. The kinetics of Flt-3L were assessed using Friedman’s ANOVA. A multiple factor analysis (MFA) was performed to find relevant factors affecting levels of serum Flt-3L during chemoradiotherapy. FactoMineR and factoextra R packages were used for analysis. In the 33 patients enrolled, the level of Flt-3L increased from the second week and remained elevated until the end of treatment (p < 0.01). All patients experienced Grade ≥2 lymphopenia with a nadir detected mostly in the 5/6th week. MFA revealed the spatial partitioning of patients among the first and second dimensions (explained by 38.49% and 23.14% variance). The distribution along these dimensions represents the magnitude of early changes of Flt-3L. Patients with the lowest values of Flt-3L change showed the highest lymphocyte nadirs and lowest dose/volume parameters of active bone marrow. Our hypothesis-generating study supports the concept of early initiation of immuno-therapy when the concentration of Flt-3L is high and no lymphopenia has yet occurred. Full article

(This article belongs to the Special Issue Cancer and Non-cancer Effects following Ionizing Irradiation)

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21 pages, 2416 KiB

Open AccessArticle

Revealing the Increased Stress Response Behavior through Transcriptomic Analysis of Adult Zebrafish Brain after Chronic Low to Moderate Dose Rates of Ionizing Radiation

by Elsa Cantabella, Virginie Camilleri, Isabelle Cavalie, Nicolas Dubourg, Béatrice Gagnaire, Thierry D. Charlier, Christelle Adam-Guillermin, Xavier Cousin and Oliver Armant

Cancers 2022, 14(15), 3793; https://doi.org/10.3390/cancers14153793 - 04 Aug 2022

Cited by 3 | Viewed by 1973

Abstract

High levels of ionizing radiation (IR) are known to induce neurogenesis defects with harmful consequences on brain morphogenesis and cognitive functions, but the effects of chronic low to moderate dose rates of IR remain largely unknown. In this study, we aim at defining [...] Read more.

High levels of ionizing radiation (IR) are known to induce neurogenesis defects with harmful consequences on brain morphogenesis and cognitive functions, but the effects of chronic low to moderate dose rates of IR remain largely unknown. In this study, we aim at defining the main molecular pathways impacted by IR and how these effects can translate to higher organizational levels such as behavior. Adult zebrafish were exposed to gamma radiation for 36 days at 0.05 mGy/h, 0.5 mGy/h and 5 mGy/h. RNA sequencing was performed on the telencephalon and completed by RNA in situ hybridization that confirmed the upregulation of oxytocin and cone rod homeobox in the parvocellular preoptic nucleus. A dose rate-dependent increase in differentially expressed genes (DEG) was observed with 27 DEG at 0.05 mGy/h, 200 DEG at 0.5 mGy/h and 530 DEG at 5 mGy/h. Genes involved in neurotransmission, neurohormones and hypothalamic-pituitary-interrenal axis functions were specifically affected, strongly suggesting their involvement in the stress response behavior observed after exposure to dose rates superior or equal to 0.5 mGy/h. At the individual scale, hypolocomotion, increased freezing and social stress were detected. Together, these data highlight the intricate interaction between neurohormones (and particularly oxytocin), neurotransmission and neurogenesis in response to chronic exposure to IR and the establishment of anxiety-like behavior. Full article

(This article belongs to the Special Issue Cancer and Non-cancer Effects following Ionizing Irradiation)

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16 pages, 3636 KiB

Open AccessArticle

MiRNA-Mediated Fibrosis in the Out-of-Target Heart following Partial-Body Irradiation

by Barbara Tanno, Flavia Novelli, Simona Leonardi, Caterina Merla, Gabriele Babini, Paola Giardullo, Munira Kadhim, Damien Traynor, Dinesh K. R. Medipally, Aidan D. Meade, Fiona M. Lyng, Soile Tapio, Luca Marchetti, Anna Saran, Simonetta Pazzaglia and Mariateresa Mancuso

Cancers 2022, 14(14), 3463; https://doi.org/10.3390/cancers14143463 - 16 Jul 2022

Cited by 5 | Viewed by 2023

Abstract

Recent reports have shown a link between radiation exposure and non-cancer diseases such as radiation-induced heart disease (RIHD). Radiation exposures are often inhomogeneous, and out-of-target effects have been studied in terms of cancer risk, but very few studies have been carried out for [...] Read more.

Recent reports have shown a link between radiation exposure and non-cancer diseases such as radiation-induced heart disease (RIHD). Radiation exposures are often inhomogeneous, and out-of-target effects have been studied in terms of cancer risk, but very few studies have been carried out for non-cancer diseases. Here, the role of miRNAs in the pathogenesis of RIHD was investigated. C57Bl/6J female mice were whole- (WBI) or partial-body-irradiated (PBI) with 2 Gy of X-rays or sham-irradiated (SI). In PBI exposure, the lower third of the mouse body was irradiated, while the upper two-thirds were shielded. From all groups, hearts were collected 15 days or 6 months post-irradiation. The MiRNome analysis at 15 days post-irradiation showed that miRNAs, belonging to the myomiR family, were highly differentially expressed in WBI and PBI mouse hearts compared with SI hearts. Raman spectral data collected 15 days and 6 months post-irradiation showed biochemical differences among SI, WBI and PBI mouse hearts. Fibrosis in WBI and PBI mouse hearts, indicated by the increased deposition of collagen and the overexpression of genes involved in myofibroblast activation, was found 6 months post-irradiation. Using an in vitro co-culture system, involving directly irradiated skeletal muscle and unirradiated ventricular cardiac human cells, we propose the role of miR-1/133a as mediators of the abscopal response, suggesting that miRNA-based strategies could be relevant for limiting tissue-dependent reactions in non-directly irradiated tissues. Full article

(This article belongs to the Special Issue Cancer and Non-cancer Effects following Ionizing Irradiation)

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14 pages, 626 KiB

Open AccessArticle

Definition of an Normal Tissue Complication Probability Model for the Inner Ear in Definitive Radiochemotherapy of Nasopharynx Carcinoma

by Leonie Peuker, Daniel Rolf, Michael Oertel, Alexander Peuker, Sergiu Scobioala, Dominik Hering, Claudia Rudack, Uwe Haverkamp and Hans Theodor Eich

Cancers 2022, 14(14), 3422; https://doi.org/10.3390/cancers14143422 - 14 Jul 2022

Cited by 2 | Viewed by 1462

Abstract

Background: Definitive radiochemotherapy is the treatment of choice for locally advanced nasopharyngeal carcinoma. Due to the vicinity of the nasopharynx to the inner ear and the use of ototoxic platinum-based chemotherapy, there is a risk for irreversible damage to the auditory system. To [...] Read more.

Background: Definitive radiochemotherapy is the treatment of choice for locally advanced nasopharyngeal carcinoma. Due to the vicinity of the nasopharynx to the inner ear and the use of ototoxic platinum-based chemotherapy, there is a risk for irreversible damage to the auditory system. To avoid or minimize these critical side effects, radiation exposure to each inner ear must be balanced between target volume coverage and toxicity. However, normal tissue complication probability (NTCP) models of the inner ear validated by clinical data are rare. Patients and Methods: This retrospective study investigates the inner ear toxicity of 46 patients who received radio(chemo-)therapy for nasopharyngeal carcinoma at our institution from 2004 to 2021 according to CTCAE

5.0

criteria. For each inner ear, the mean

(D m e a n)

and maximum

(D m a x)

dose in Gray

(G y)

was evaluated and correlated with clinical toxicity data. Based on the data, an NTCP model and a cutoff dose logistic regression model (CDLR) were created. Results: In 11 patients (

23.9 %

) hearing impairment and/or tinnitus was observed as a possible therapy-associated toxicity.

D m e a n

was between 15–

60

Gy, whereas

D m a x

was between 30–

75

Gy. There was a dose-dependent, sigmoidal relation between inner ear dose and toxicity. A

D m e a n

of

44

Gy and

65

Gy was associated with inner ear damage in

25 %

and

50 %

of patients, respectively. The maximum curve slope (m) was found at

50 %

and is

m = 0.013

. The Dmax values showed a

25 %

and

50 %

complication probability at

58

Gy and

69

Gy, respectively, and a maximum slope of the sigmoid curve at

50 %

with

m = 0.025

. Conclusion: There is a sigmoidal relation between radiation dose and incidence of inner ear toxicities. Dose constraints for the inner ear of

< 44

Gy

(D m e a n)

or

< 58

Gy

(D m a x)

are suggested to limit the probability of inner ear toxicity

< 25 %

. Full article

(This article belongs to the Special Issue Cancer and Non-cancer Effects following Ionizing Irradiation)

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14 pages, 5069 KiB

Open AccessArticle

Temporal Changes in Sparing and Enhancing Dose Protraction Effects of Ionizing Irradiation for Aortic Damage in Wild-Type Mice

by Nobuyuki Hamada, Ki-ichiro Kawano, Takaharu Nomura, Kyoji Furukawa, Farina Mohamad Yusoff, Tatsuya Maruhashi, Makoto Maeda, Ayumu Nakashima and Yukihito Higashi

Cancers 2022, 14(14), 3319; https://doi.org/10.3390/cancers14143319 - 07 Jul 2022

Cited by 6 | Viewed by 1253

Abstract

In medical and occupational settings, ionizing irradiation of the circulatory system occurs at various dose rates. We previously found sparing and enhancing dose protraction effects for aortic changes in wild-type mice at 6 months after starting irradiation with 5 Gy of photons. Here, [...] Read more.

In medical and occupational settings, ionizing irradiation of the circulatory system occurs at various dose rates. We previously found sparing and enhancing dose protraction effects for aortic changes in wild-type mice at 6 months after starting irradiation with 5 Gy of photons. Here, we further analyzed changes at 12 months after stating irradiation. Irrespective of irradiation regimens, irradiation little affected left ventricular function, heart weight, and kidney weight. Irradiation caused structural disorganizations and intima-media thickening in the aorta, along with concurrent elevations of markers for proinflammation, macrophage, profibrosis, and fibrosis, and reductions in markers for vascular functionality and cell adhesion in the aortic endothelium. These changes were qualitatively similar but quantitatively less at 12 months than at 6 months. The magnitude of such changes at 12 months was not smaller in 25 fractions (Frs) but was smaller in 100 Frs and chronic exposure than acute exposure. The magnitude at 6 and 12 months was greater in 25 Frs, smaller in 100 Frs, and much smaller in chronic exposure than acute exposure. These findings suggest that dose protraction changes aortic damage, in a fashion that depends on post-irradiation time and is not a simple function of dose rate. Full article

(This article belongs to the Special Issue Cancer and Non-cancer Effects following Ionizing Irradiation)

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18 pages, 1686 KiB

Open AccessArticle

Transcriptional Dynamics of DNA Damage Responsive Genes in Circulating Leukocytes during Radiotherapy

by Lourdes Cruz-Garcia, Farah Nasser, Grainne O’Brien, Jakub Grepl, Volodymyr Vinnikov, Viktor Starenkiy, Sergiy Artiukh, Svetlana Gramatiuk and Christophe Badie

Cancers 2022, 14(11), 2649; https://doi.org/10.3390/cancers14112649 - 26 May 2022

Cited by 8 | Viewed by 2292

Abstract

External beam radiation therapy leads to cellular activation of the DNA damage response (DDR). DNA double-strand breaks (DSBs) activate the ATM/CHEK2/p53 pathway, inducing the transcription of stress genes. The dynamic nature of this transcriptional response has not been directly observed in vivo in [...] Read more.

External beam radiation therapy leads to cellular activation of the DNA damage response (DDR). DNA double-strand breaks (DSBs) activate the ATM/CHEK2/p53 pathway, inducing the transcription of stress genes. The dynamic nature of this transcriptional response has not been directly observed in vivo in humans. In this study we monitored the messenger RNA transcript abundances of nine DNA damage-responsive genes (CDKN1A, GADD45, CCNG1, FDXR, DDB2, MDM2, PHPT1, SESN1, and PUMA), eight of them regulated by p53 in circulating blood leukocytes at different time points (2, 6–8, 16–18, and 24 h) in cancer patients (lung, neck, brain, and pelvis) undergoing radiotherapy. We discovered that, although the calculated mean physical dose to the blood was very low (0.038–0.169 Gy), an upregulation of Ferredoxin reductase (FDXR) gene transcription was detectable 2 h after exposure and was dose dependent from the lowest irradiated percentage of the body (3.5% whole brain) to the highest, (up to 19.4%, pelvic zone) reaching a peak at 6–8 h. The radiation response of the other genes was not strong enough after such low doses to provide meaningful information. Following multiple fractions, the expression level increased further and was still significantly up-regulated by the end of the treatment. Moreover, we compared FDXR transcriptional responses to ionizing radiation (IR) in vivo with healthy donors’ blood cells exposed ex vivo and found a good correlation in the kinetics of expression from the 8-hours time-point onward, suggesting that a molecular transcriptional regulation mechanism yet to be identified is involved. To conclude, we provided the first in vivo human report of IR-induced gene transcription temporal response of a panel of p53-dependant genes. FDXR was demonstrated to be the most responsive gene, able to reliably inform on the low doses following partial body irradiation of the patients, and providing an expression pattern corresponding to the % of body exposed. An extended study would provide individual biological dosimetry information and may reveal inter-individual variability to predict radiotherapy-associated adverse health outcomes. Full article

(This article belongs to the Special Issue Cancer and Non-cancer Effects following Ionizing Irradiation)

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Graphical abstract

13 pages, 2505 KiB

Open AccessArticle

The Influence of Radiotherapy on the Function of the Left and Right Ventricles in Relation to the Radiation Dose Administered to the Left Anterior Descending Coronary Artery—From a Cardiologist’s Point of View

by Izabela Nabialek-Trojanowska, Marcin Sinacki, Hanna Jankowska, Zuzanna Lewicka-Potocka, Rafał Dziadziuszko and Ewa Lewicka

Cancers 2022, 14(10), 2420; https://doi.org/10.3390/cancers14102420 - 13 May 2022

Cited by 4 | Viewed by 1624

Abstract

The aim of this study was to assess the effects of radiotherapy involving the heart on LV and RV function using modern speckle-tracking echocardiography (STE), and in relation to the radiation dose applied to the LAD. This retrospective, single-centre study included 12 patients [...] Read more.

The aim of this study was to assess the effects of radiotherapy involving the heart on LV and RV function using modern speckle-tracking echocardiography (STE), and in relation to the radiation dose applied to the LAD. This retrospective, single-centre study included 12 patients after a median of 51 months after irradiation for mediastinal lymphoma, in whom we were able to delineate the LAD. Correlations between doses of ionising radiation and echocardiographic parameters reflecting the systolic function of the LV and RV were analysed. The median irradiation dose delivered to the whole heart was 16.4 Gy (0.5–36.2 Gy), and to the LAD it was 15.1 Gy (0.3–35.3 Gy). LV longitudinal strain (LS) was impaired in the anteroseptal and anterior walls. Parameters reflecting RV function were normal, with the exception of RV myocardial performance index (RIMP). Significant correlations were found between the median dose to the LAD and LV global LS (rho = 0.6468, p = 0.034), the maximum dose to the LAD and LV anterior LS (rho = 0.6046, p = 0.049), the median and the mean dose to the whole heart and LV anterior LS (R = 0.772, p = 0.009 and rho = 0.7676, p = 0.01, respectively), and the total irradiation dose and RIMP (rho = 0.5981, p = 0.04). The calculation of irradiation doses allows the identification of patients at risk of cardiac dysfunction detected by modern STE. Full article

(This article belongs to the Special Issue Cancer and Non-cancer Effects following Ionizing Irradiation)

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15 pages, 3308 KiB

Open AccessArticle

Inflammatory Signaling and DNA Damage Responses after Local Exposure to an Insoluble Radioactive Microparticle

by Yusuke Matsuya, Nobuyuki Hamada, Yoshie Yachi, Yukihiko Satou, Masayori Ishikawa, Hiroyuki Date and Tatsuhiko Sato

Cancers 2022, 14(4), 1045; https://doi.org/10.3390/cancers14041045 - 18 Feb 2022

Cited by 9 | Viewed by 2161

Abstract

Cesium-bearing microparticles (Cs-BMPs) can reach the human respiratory system after inhalation, resulting in chronic local internal exposure. We previously investigated the spatial distribution of DNA damage induced in areas around a Cs-BMP; however, the biological impacts have not been fully clarified due to [...] Read more.

Cesium-bearing microparticles (Cs-BMPs) can reach the human respiratory system after inhalation, resulting in chronic local internal exposure. We previously investigated the spatial distribution of DNA damage induced in areas around a Cs-BMP; however, the biological impacts have not been fully clarified due to the limited amount of data. Here, we investigated the inflammatory signaling and DNA damage responses after local exposure to a Cs-BMP in vitro. We used two normal human lung cell lines, i.e., lung fibroblast cells (WI-38) and bronchial epithelial cells (HBEC3-KT). After 24 h exposure to a Cs-BMP, inflammation was evaluated by immunofluorescent staining for nuclear factor κB (NF-κB) p65 and cyclooxygenase 2 (COX-2). The number of DNA double-strand breaks (DSBs) was also detected by means of phospholylated histone H2AX (γ-H2AX) focus formation assay. Cs-BMP exposure significantly increased NF-κB p65 and COX-2 expressions, which were related to the number of γ-H2AX foci in the cell nuclei. Compared to the uniform (external) exposure to ¹³⁷Cs γ-rays, NF-κB tended to be more activated in the cells proximal to the Cs-BMP, while both NF-κB p65 and COX-2 were significantly activated in the distal cells. Experiments with chemical inhibitors for NF-κB p65 and COX-2 suggested the involvement of such inflammatory responses both in the reduced radiosensitivity of the cells proximal to Cs-BMP and the enhanced radiosensitivity of the cells distal from Cs-BMP. The data show that local exposure to Cs-BMP leads to biological effects modified by the NF-κB pathway, suggesting that the radiation risk for Cs-BMP exposure can differ from that estimated based on conventional uniform exposure to normal tissues. Full article

(This article belongs to the Special Issue Cancer and Non-cancer Effects following Ionizing Irradiation)

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13 pages, 861 KiB

Open AccessArticle

The Incidence Risk for Primary Glaucoma and Its Subtypes following Chronic Exposure to Ionizing Radiation in the Russian Cohort of Mayak Nuclear Workers

by Tamara V. Azizova, Evgeny V. Bragin, Maria V. Bannikova, Nobuyuki Hamada and Evgeniya S. Grigoryeva

Cancers 2022, 14(3), 602; https://doi.org/10.3390/cancers14030602 - 25 Jan 2022

Cited by 7 | Viewed by 1931

Abstract

Secondary glaucoma is a typical normal tissue complication following radiation therapy involving ocular radiation exposure at high fractionated dose (several tens of Gy). In contrast, recent studies in acutely exposed Japanese atomic bomb survivors showed a significantly increased risk for normal-tension glaucoma (NTG, [...] Read more.

Secondary glaucoma is a typical normal tissue complication following radiation therapy involving ocular radiation exposure at high fractionated dose (several tens of Gy). In contrast, recent studies in acutely exposed Japanese atomic bomb survivors showed a significantly increased risk for normal-tension glaucoma (NTG, a subtype of primary open-angle glaucoma) at much lower dose, but such information is not available in any other cohorts. We therefore set out to evaluate the incidence of risk for primary glaucoma and its subtypes in a Russian cohort of Mayak Production Association nuclear workers who received chronic radiation exposure over many years. Of these, we found a significantly increased relative risk (RR) of NTG incidence (RR = 1.88 95% confidence intervals (CI): 1.01, 3.51; p = 0.047) in workers exposed to gamma rays at cumulative brain absorbed dose above >1 Gy. We observed the linear relationship between NTG incidence and brain absorbed gamma dose with an excess relative risk per unit brain absorbed dose of 0.53 (95% CI: 0.01, 1.68; p < 0.05), but not for any other subtypes nor for total primary glaucoma. Such elevated risk of radiogenic NTG incidence, if confirmed in other cohorts, has significant implications for normal tissue complications in radiotherapy patients receiving ocular radiation exposure, and for ocular radiation protection in radiation workers. Full article

(This article belongs to the Special Issue Cancer and Non-cancer Effects following Ionizing Irradiation)

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16 pages, 7313 KiB

Open AccessArticle

IGF-I and Hyaluronic Acid Mitigate the Negative Effect of Irradiation on Human Skin Keratinocytes

by Celena A. Sörgel, Rafael Schmid, Nina Stadelmann, Volker Weisbach, Luitpold Distel, Raymund E. Horch and Annika Kengelbach-Weigand

Cancers 2022, 14(3), 588; https://doi.org/10.3390/cancers14030588 - 24 Jan 2022

Cited by 9 | Viewed by 3318

Abstract

Ionizing radiation has become an integral part of modern cancer therapy regimens. Various side effects, such as radiation dermatitis, affect patients in acute and chronic forms and decrease therapy compliance significantly. In this study, primary keratinocytes were irradiated in a 2-dimensional (2D) culture [...] Read more.

Ionizing radiation has become an integral part of modern cancer therapy regimens. Various side effects, such as radiation dermatitis, affect patients in acute and chronic forms and decrease therapy compliance significantly. In this study, primary keratinocytes were irradiated in a 2-dimensional (2D) culture as well as on a 3-dimensional (3D) collagen-elastin matrix with doses of 2 and 5 Gy. The effect of different concentrations of IGF-I, KGF, platelet lysate (PL), high and low molecular weight hyaluronic acid (H-HA, L-HA), and adipose-derived stem cell (ADSC) conditioned medium was analyzed in respect to cell viability (WST-8), wound closure (migration), and the gene expression (quantitative real-time PCR) of 2D cultures. The 3D culture was evaluated by WST-8. A mixture of H-HA and L-HA, as well as IGF-I, could significantly stimulate the keratinocyte viability and migration which were severely reduced by irradiation. The MKI67and IL6 gene expression of irradiated keratinocytes was significantly higher after H-HA/L-HA treatment. The stimulating effects of H-HA/L-HA and IGF-I were able to be confirmed in 3D culture. A positive influence on cell viability, migration, and gene expression was achieved after the treatment with H-L-HA and IGF-I. These results open the possibility of a novel therapeutic method for both the prevention and the treatment of radiation dermatitis. Full article

(This article belongs to the Special Issue Cancer and Non-cancer Effects following Ionizing Irradiation)

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Review

Jump to: Editorial, Research

18 pages, 326 KiB

Open AccessReview

Radiation-Induced Brain Injury: Age Dependency of Neurocognitive Dysfunction Following Radiotherapy

by Claudia E. Rübe, Silvia Raid, Jan Palm and Christian Rübe

Cancers 2023, 15(11), 2999; https://doi.org/10.3390/cancers15112999 - 31 May 2023

Cited by 6 | Viewed by 2428

Abstract

Cranial radiotherapy is a known risk factor for neurocognitive impairment in cancer survivors. Although radiation-induced cognitive dysfunction is observed in patients of all ages, children seem to be more vulnerable than adults to suffering age-related deficits in neurocognitive skills. So far, the underlying [...] Read more.

Cranial radiotherapy is a known risk factor for neurocognitive impairment in cancer survivors. Although radiation-induced cognitive dysfunction is observed in patients of all ages, children seem to be more vulnerable than adults to suffering age-related deficits in neurocognitive skills. So far, the underlying mechanisms by which IR negatively influences brain functions as well as the reasons for the profound age dependency are still insufficiently known. We performed a comprehensive Pubmed-based literature search to identify original research articles that reported on age dependency of neurocognitive dysfunction following cranial IR exposure. Numerous clinical trials in childhood cancer survivors indicate that the severity of radiation-induced cognitive dysfunction is clearly dependent on age at IR exposure. These clinical findings were related to the current state of experimental research providing important insights into the age dependency of radiation-induced brain injury and the development of neurocognitive impairment. Research in pre-clinical rodent models demonstrates age-dependent effects of IR exposure on hippocampal neurogenesis, radiation-induced neurovascular damage and neuroinflammation. Full article

(This article belongs to the Special Issue Cancer and Non-cancer Effects following Ionizing Irradiation)

21 pages, 2591 KiB

Open AccessReview

Non-Cancer Effects following Ionizing Irradiation Involving the Eye and Orbit

by Juliette Thariat, Arnaud Martel, Alexandre Matet, Olivier Loria, Laurent Kodjikian, Anh-Minh Nguyen, Laurence Rosier, Joël Herault, Sacha Nahon-Estève and Thibaud Mathis

Cancers 2022, 14(5), 1194; https://doi.org/10.3390/cancers14051194 - 25 Feb 2022

Cited by 7 | Viewed by 2868

Abstract

The eye is an exemplarily challenging organ to treat when considering ocular tumors. It is at the crossroads of several major aims in oncology: tumor control, organ preservation, and functional outcomes including vision and quality of life. The proximity between the tumor and [...] Read more.

The eye is an exemplarily challenging organ to treat when considering ocular tumors. It is at the crossroads of several major aims in oncology: tumor control, organ preservation, and functional outcomes including vision and quality of life. The proximity between the tumor and organs that are susceptible to radiation damage explain these challenges. Given a high enough dose of radiation, virtually any cancer will be destroyed with radiotherapy. Yet, the doses inevitably absorbed by normal tissues may lead to complications, the likelihood of which increases with the radiation dose and volume of normal tissues irradiated. Precision radiotherapy allows personalized decision-making algorithms based on patient and tumor characteristics by exploiting the full knowledge of the physics, radiobiology, and the modifications made to the radiotherapy equipment to adapt to the various ocular tumors. Anticipation of the spectrum and severity of radiation-induced complications is crucial to the decision of which technique to use for a given tumor. Radiation can damage the lacrimal gland, eyelashes/eyelids, cornea, lens, macula/retina, optic nerves and chiasma, each having specific dose–response characteristics. The present review is a report of non-cancer effects that may occur following ionizing irradiation involving the eye and orbit and their specific patterns of toxicity for a given radiotherapy modality. Full article

(This article belongs to the Special Issue Cancer and Non-cancer Effects following Ionizing Irradiation)

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13 pages, 628 KiB

Open AccessReview

A Brief Overview of Radiation-Induced Effects on Spermatogenesis and Oncofertility

by Hisanori Fukunaga, Akinari Yokoya and Kevin M. Prise

Cancers 2022, 14(3), 805; https://doi.org/10.3390/cancers14030805 - 04 Feb 2022

Cited by 7 | Viewed by 3909

Abstract

The genotoxicity of radiation on germ cells may be passed on to the next generation, thus its elucidation is not only a scientific issue but also an ethical, legal, and social issue in modern society. In this article, we briefly overview the effects [...] Read more.

The genotoxicity of radiation on germ cells may be passed on to the next generation, thus its elucidation is not only a scientific issue but also an ethical, legal, and social issue in modern society. In this article, we briefly overview the effects of radiation on spermatogenesis and its associated genotoxicity, including the latest findings in the field of radiobiology. The potential role of transgenerational effects is still poorly understood, and further research in this area is desirable. Furthermore, from the perspective of oncofertility, we discuss the historical background and clinical importance of preserving male fertility during radiation treatment and the potential of microbeam radiotherapy. We hope that this review will contribute to stimulating further discussions and investigations for therapies for pediatric and adolescent/young adult patients. Full article

(This article belongs to the Special Issue Cancer and Non-cancer Effects following Ionizing Irradiation)

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