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Résumé Fabien Arcelin, médecin lyonnais, fut le thésard de Destot, l’un des pères de la radiologie française et le propre élève de son père, Adrien Arcelin, l’un des archéologues préhistoriens majeurs de notre pays, co-inventeur du site de la Roche-de-Solutré. Ainsi, radiologue à Lyon en semaine et archéologue en Bourgogne le week-end, Fabien Arcelin fit avancer ces deux disciplines avec le même brio. En archéologie, il découvrit les premières sépultures aurignaciennes. En radiologie, il examina près de 2000 cœurs avec l’orthodiagraphe de Destot pour déterminer le rapport cardiothoracique et laissa un ouvrage de référence sur l’utilisation des rayons X dans la détection des calculs rénaux. En radiothérapie, il marqua l’histoire de la discipline en réalisant le premier sondage adressé à ses collègues sur les effets secondaires de l’irradiation, base documentaire à l’origine de la mise en évidence de la radiosensibilité individuelle. En parallèle des essais de Regaud à l’institut Curie, il réalisa à Lyon les premières séries de radiothérapies. Fabien Arcelin, physician working in Lyon, pioneer of radiology and radiotherapy, was both mentored by Destot (one of the fathers of the French radiology for his thesis of medicine) and by his own father Adrien Arcelin (one of the two codiscoverers of the prehistorical site of the Roche-de-Solutré in Burgundy) for archeological works. Hence, radiologist in Lyon during the week and archeologist during the weekend, Fabien Arcelin made significant advances in both radiation research and archeology. He was notably the discoverer of the first tombs of Aurignacian men. In radiology, he examined about 2000 radiographic heart views with the Destot's orthodiagraph to assess the cardiothoracic ratio and wrote a reference book about the use of X-rays to detect kidney stones. He made the first survey about the secondary effects of radiotherapy, important database for pointing out individual radiosensitivity. In parallel to the radiotherapy trials of Regaud at Curie institute (Paris), he performed the first series of anticancer treatments in Lyon. [ABSTRACT FROM AUTHOR]

Résumé Étienne Destot est un médecin d’origine bourguignonne qui bénéficia à Lyon, lors de ses études, de la qualité de l’enseignement et de la recherche des plus grands spécialistes du moment : Augagneur pour l’hygiène, Testut pour l’anatomie, Ollier pour la chirurgie, Lépine pour l’utilisation de l’électricité en médecine et les frères Lumière pour le développement technologique. Lors de ses expériences, il côtoya Despeignes, premier radiothérapeute de l’histoire, Regaud, pionnier de la radiobiologie, et Bouchacourt, chantre de la radiosensibilité individuelle. Moins de deux mois après la découverte des rayons X par Roentgen, il réalisa des clichés radiographiques qui furent à l’origine de nos connaissances actuelles en anatomie ostéoarticulaire et en traumatologie. Il créa également le premier service de radiologie en France dans la boutique désaffectée d’un bouquiniste où il laissa libre cours à son esprit de création. Si on compare son action avec celle de Béclère, il paraît évident qu’alors ce dernier a été le grand organisateur de la radiologie française, Destot en a été le grand « défricheur » : il est à l’origine de plusieurs innovations technologiques qui aboutirent à la stéréoscopie, à l’imagerie des corps internes ou à la mesure du rapport cardiothoracique. En revanche, il ne fut jamais convaincu des vertus thérapeutiques des rayons X, même s’il contribua largement au développement de tubes à rayons X. Martyr des radiations, mort en décembre 1918, en plein dévouement pour les blessés de la Grande Guerre, son nom est inscrit au monument aux morts d’Arc-et-Senans. Étienne Destot is a French physician from Burgundy who benefited, during his studies in Lyon, from the quality of teaching of the best specialists of the time: Augagneur for hygiene, Testut for anatomy, Ollier for surgery, Lépine for the medical applications of electricity and the Lumière brothers for the technological development. During its experiments, he met Despeignes, the first radiation oncologist, Regaud pioneer of radiobiology and Bouchacourt who pointed out individual radiosensitivity. Less than two months after the X-rays discovery by Roentgen, he produced one of the first French radiographic views that were at the origin of our current knowledge in bone and cartilage anatomy and traumatology. He funded the first department of radiology in France in a former library of the major hospital of Lyon, where he made a number of original advances. It appears obvious that, while Antoine Beclère was the great organizer of the French radiology, Destot was its pathfinder. Destot was at the origin of several technological advances that gave stereoscopy, internal organs imaging and quantification of the heart-thorax ratio. By contrast, he was not convinced of the therapeutic properties of X-rays even if he contributed to the technological development of X-ray tubes. Victim of radiations, exhausted, Destot died on December 1918, by helping the Great War victims. His name is written in a war tribute monument in Arc-et-Senans (Burgundy). [ABSTRACT FROM AUTHOR]

Résumé Le 4 juillet 1896, dans son cabinet médical des Échelles (Savoie), Victor Despeignes réalisa la toute première radiothérapie contre un cancer, étayée par des preuves indiscutables. Pourtant, la démarche intellectuelle et pratique qui a abouti à ce premier traitement peut apparaître aujourd’hui comme inattendue. En effet, il est très probable que la radiothérapie que Victor Despeignes appliqua sur son voisin, qui ne souffrait probablement pas d’un cancer de l’estomac, soit née avec le soutien indirect des frères Lumière, sur la base d’une théorie biologique (la théorie parasitaire du cancer) abandonnée aujourd’hui, avec un protocole issu d’expériences sur la tuberculose et sur un mode bifractionné imposé par les contraintes liées à l’état de médecin de canton qu’était devenu Victor Despeignes. On the 4th July, 1896, in his medical office of Les Échelles (Savoie, France), Victor Despeignes performed the very first radiotherapy against cancer, documented by indisputable proofs. However, the intellectual and practical approach that leads to this first radiotherapy may appear unexpected to date. Indeed, it is likely that the treatment that Despeignes applied to his neighbour, who did not suffer from stomach cancer, was born with the indirect support of the Lumière brothers, on the basis of a biological theory (the parasitory theory of cancer) that is irrelevant today, with an experimental protocol based on experiments performed on tuberculosis et in a bifractionated model linked by the constraints of a district medical doctor. [ABSTRACT FROM AUTHOR]

Résumé Léon Bouchacourt (1865–1949) fut un pionnier de la radiologie et de la radiothérapie d’origine lyonnaise bien trop méconnu. Interne en obstétrique des hôpitaux de Paris en 1894, période pendant laquelle il rencontra Charcot, le futur explorateur polaire, il réalisa la première thèse de médecine concernant les rayons X. Il inventa une technique de radiographie des organes cavitaires comme le vagin, le rectum et la bouche, l’ endodiascopie , qui lui permit de réaliser les toutes premières pelvimétries et radiographies dentaires en France. Alors qu’il effectuait déjà les premiers essais de contact-radiothérapie, il dut faire face aux réactions tissulaires radio-induites. En 1911, il publia le tout premier article sur la notion de radiosensibilité individuelle. Pendant la Première guerre mondiale, commandant de l’une des voitures radiologiques, il côtoya Irène Curie et développa la « bonnette » qui portera son nom et deviendra indispensable à la radiologie interventionnelle. Après-guerre, aux côtés de Béclère et de dix autres pionniers, Léon Bouchacourt fonda la Société française de radiologie. Il termina sa carrière en se passionnant pour la santé publique, les divers aspects de son métier et les devoirs du radiologue. Léon Bouchacourt (1865–1949) was a misknown pioneer of radiology and radiotherapy from Lyon, France. While he was resident in obstetrics in Hôpitaux de Paris from 1892 to 1898, he met Charcot, the future polar explorer, and wrote the first thesis dissertation about X-rays. He invented a new radiology technique for cavitary organs such as vagina, rectum and mouth, the endodiascopy, which permitted him to perform the first pelvimetry and dental radiographies in France. While he undertook the first trials of contact-radiotherapy, he was confronted with radiation-induced reactions. In 1911, he wrote the first paper about individual radiosensitivity. During the First World War, he commanded one of the radiology vehicles, he met Irène Curie and developed his « radiological helmet », which will hold his name and became essential for interventional radiology. After the war, with Béclère and ten others, Léon Bouchacourt funded the French Radiology Society. He ended his career by thinking about public health and the different aspects of the duties of radiologists. [ABSTRACT FROM AUTHOR]

Immunofluorescence that permits the detection of nuclear targets specific to DNA damage signalling and repair have completely renewed the approach of individual radiosensitivity. It is a concern in radiotherapy in which radiosensitivity is responsible for the development of adverse side-effects in normal tissues in absence of any mistake in the dose delivery. Furthermore, individual radiosensitivity at low-dose has been recently demonstrated in human mammary epithelium exposed ex vivo in the conditions of mammographic screening. Although these results do not demonstrate directly the existence of mutagenesis, they indicate a possible link between cancer proneness and radiosensitivity. Hence, individual radiosensitivity is a real concern for public health since 5-15% of the population may be concerned and radiosensitive individuals generally show higher cancer risk than the rest of the population. Thus, individual radiosensitivity is a key issue to be addressed in future recommendations of the radioprotection system. [ABSTRACT FROM AUTHOR]

Unrepaired and misrepaired DNA Double-Strand Breaks (DSBs) were shown to be the key events of radiation-induced toxicity (radiosensitivity) and genomic instability (cancer proneness), respectively. We have previously shown that immunofluorescence with ?-H2AX and MRE11 biomarkers may account for unrepaired and misrepaired DSBs for doses higher than 1 Gy. Three radiosensitivity groups had been defined (group I: radioresistance; group II: moderate radiosensitivity and cancer proneness; group III: hyper-radiosensitivity). Here, we investigated X-ray doses ranging from 9 mGy to 2 Gy in three cell lines representative of these radiosensitivity groups. We observed a non-linear dose-dependent increase of the severity of DSB, suggesting a correlation with the phenomenon of hyper-radiosensitivity to low dose; a non-linear dose-dependent increase of MRE11 foci, revealing a dose-threshold for the radiation-induced genomic instability. Altogether, these data document the evidence of a threshold in low-dose response and strongly suggest the impact of individual factor. [ABSTRACT FROM AUTHOR]

Bleomycin is a cytotoxic antibiotic that generates DNA double-strand breaks (DSB) and DNA single-strand breaks (SSB). It is possible to introduce known quantities of bleomycin molecules into cells. Low amounts kill the cells by a slow process termed mitotic cell death, while high amounts produce a fast process that has been termed pseudoapoptosis. We previously showed that these types of cell death are a direct consequence of the DSB generated by bleomycin. Here, we use deglyco-bleomycin, a bleomycin derivative lacking the carbohydrate moiety. Although this molecule performs the same nucleophilic attacks on DNA as bleomycin, we show that deglyco-bleomycin is at least 100 times less toxic to Chinese hamster fibroblasts than bleomycin. In fact, deglyco-bleomycin treatment results in apoptosis induction. In contrast, however, deglyco-bleomycin was found to generate almost exclusively SSB. Our results suggest that more than 150 000 SSB per cell are required to trigger apoptosis in Chinese hamster fibroblasts and that SSB are 300 times less toxic than DSB. Taken together with previous studies on bleomycin, our data demonstrates that cells can die by apoptosis, mitotic cell death, or pseudoapoptosis, depending on the number of DNA breaks and on the ratio of SSB to DSB. [ABSTRACT FROM AUTHOR]

Purpose: To overcome the underestimation of the small residual damage when measuring DNA double-strand breaks (DSB) as fraction of activity released (FAR) by pulsed-field gel electrophoresis. Materials and methods: The techniques used to assess DNA damage (e.g. pulsed-field gel electrophoresis, neutral elution, comet assay) do not directly measure the number of DSB. The Blocher model can be used to express data as DSB after irradiation at 4° C by calculating the distribution of all radiation-induced DNA fragments as a function of their size. We have used this model to measure the residual DSB (irradiation at 4° C followed by incubation at 37° C) in untransformed human fibroblasts. Results: The DSB induction rate after irradiation at 4° C was 39.1 +/- 2.0Gy [sup -1] . The DSB repair rate obtained after doses of 10 to 80Gy followed by repair times of 0 to 24h was expressed as unrepaired DSB calculated from the Blocher formula. All the damage appeared to be repaired at 24h when the data were expressed as FAR, whereas 15% of DSB remained unrepaired. The DSB repair rate and the chromosome break repair rate assessed by premature condensation chromosome (PCC) techniques were similar. Conclusion: The expression of repair data in terms of FAR dramatically underestimates the amount of unrepaired DNA damage. The Blocher model that takes into account the size distribution of radiation-induced DNA fragments should therefore be used to avoid this bias. Applied to a normal human fibroblast cell line, this model shows that DSB repair is never complete. [ABSTRACT FROM AUTHOR]

Purpose: To propose a novel interpretation of DNA double-strand break (dsb) repair based on the distribution of energy microdeposition. Materials and methods: Double-strand break repair curves were studied either after irradiation at 4degreeC or at 37degreeC (low dose rate). Two human fibroblast cell lines were used: a control line, HF19, and an ataxia telangiectasia repair-deficient line, AT5BI. Irradiations were made with gamma -rays or alpha -particles ( 241Am). Repair data were fitted by the variable repair half-time (VRHT) model. Assuming that each dsb has its own inherent repair half-time (IRHT) and that the VRHT is the average of the IRHT at any time during repair, the distribution of the IRHT was calculated. Results: At the end of the irradiation, the distribution was a continuous asymmetric curve with a maximum of dsb having a short IRHT. After 1 h of repair, the curve became bell-shaped. There is a striking similarity between the distribution of dsb repair half-times and that of energy micro-deposition described by Goodhead et al . (1993). Conclusion: This similarity suggests a possible causal relationship between the energy density deposition and the repair rate or the probability of dsb repair. [ABSTRACT FROM AUTHOR]

Abstract. We have studied the intrinsic radiosensitivity, repair of potentially lethal damage (PLD) and the repair rate of radiation-induced DNA double-strand breaks (DSB) in 11 nontransformed human fibroblast cell lines, four of which were homozygous for the A-T mutation and two that were heterozygous (A-TH). All the experiments were done on cells in plateau phase of growth (97-99% of cells in G0/G1). With a dose of 30 Gy delivered at 4 C, the A-T cell lines had faster repair rates of up to 6 h, after which the repair curve crossed that of the control so that the residual damage at 24 h was higher in the A-T cells. Irradiation at 37 C at low dose rate (1 cGy.min -1) produced even more marked differences between the A-T cells and controls: the residual DSB level was always higher in A-T cells than controls at doses of 5-40 Gy, due to defective repair of a small fraction of DSB in A-T cells. The two protocols showed DSB repair rates for the A-TH cell lines that were intermediate between those of the A-T and control cells. There was a quantitative relationship between the residual DSB after irradiation at 37 C and the intrinsic radiosensitivity, and with the extent of PLD repair. There were very few apoptotic cells in the non-transformed control and A-T cell lines, both before and after irradiation. In combination, these results support the contention that the defective repair of DSB is a mechanism of the hypersensitivity linked to the A-T mutation. [ABSTRACT FROM AUTHOR]

Abstract: Radiobiologists have pointed out a novel radiobiological phenomenon observed in many tumor and normal cell lines: hyper-radiosensitivity to very low-dose (HRS) followed by induced radioresistance (IRR) after a threshold dose of 0.1–0.3 Gy that depends on the cell line. Radioresistance at high dose (i.e. higher than 0.5 Gy) and metastatic potential of tumor cells are likely major factors of failure in radiotherapy. A careful review of literature suggests that: 1) radiotherapy does not increase the metastatic potential of tumor cells; 2) radioresistance at high dose and metastatic potential are not related. However, inside a given tumor cell line, highly metastatic clones may elicit more cells showing HRS or are more radiosensitive at high dose than poorly metastatic ones. Recent data obtained from molecular techniques (comet and immunofluorescence assays) applied to single cells irradiated at very low radiation doses (1–100 mGy) suggest that DNA single-strand breaks (SSB) and double-strand breaks (DSB) may be the key-lesions responsible for the HRS phenomenon. These data suggest that the HRS phenomenon may find application in radiotherapy for micrometastasis. These early disseminated and probably unvascularised cells may escape the influence of high-dose chemotherapy after excision of the primary tumor. Considering the link between metastatic potential and HRS, we have previously proposed to apply very low-dose total body irradiation (TBI) at M0 stage that may prevent the development of micrometastases. Literature data suggest that the smallest radiation dose that can produce HRS without increasing the risk of cancer may be in the milliGrays range. [Copyright &y& Elsevier]

Résumé La bronchiolite oblitérante avec organisation pneumonique est une réaction inflammatoire pouvant survenir dans les suites de diverses agressions pulmonaires. L’imputabilité de la radiothérapie dans la survenue d’une pneumopathie survenant en cours ou au décours d’une irradiation n’est pas systématique. La bronchiolite oblitérante avec organisation pneumonique ne doit pas être confondue avec la fibrose pulmonaire post-radique dose-dépendante, qui est inflammatoire, non immunologique, et localisée dans la zone d’irradiation. Le rôle de l’immunité, de l’inflammation locale et de la radiosensibilité individuelle, doit probablement être mieux défini dans cet effet secondaire qui représente 1 % des patientes irradiées pour un cancer du sein, soit près de 400 patientes par an en France. Elle se traduit par une fièvre (syndrome pseudogrippal), une toux plutôt sèche et une dyspnée. En contexte post-radique, une bronchiolite oblitérante avec organisation pneumonique peut être diagnostiquée plusieurs mois, voire jusqu’à un an, après la fin d’une irradiation mammaire. Le traitement est une corticothérapie de longue durée ou des immunosuppresseurs, qui n’éviteraient pas le passage à la chronicité pour 15 % des patients et le décès dans 5 % des observations dans certaines séries, les 80 % des patients restants guérissant sans séquelle. Bronchiolitis obliterans with organizing pneumonia is an inflammatory reaction that can occur as a consequence of various pulmonary affections. Radiotherapy is not the sole and systematic cause of bronchiolitis obliterans with organizing pneumonia. Radiation-induced should not be confused with post-radiation, dose-dependent, inflammatory pulmonary fibrosis, which is non-immunological and located within the irradiation field. The role of immunity, local inflammation and individual radiosensitivity in bronchiolitis obliterans with organizing pneumonia is not well defined. Bronchiolitis obliterans with organizing pneumonia represents 1% of irradiated patients with breast cancer. It results in fever (flu-like symptoms), a rather dry cough and dyspnea. In the post-radiation context, bronchiolitis obliterans with organizing pneumonia may be diagnosed several months and up to a year after breast irradiation. The treatment consists of prolonged steroids or immunosuppressants, which do not prevent chronicity in 15% of patients and death in up to 5% of cases, the remaining 80% of patients healing without sequelae. [ABSTRACT FROM AUTHOR]

Résumé Le modèle linéaire-quadratique (LQ) est aujourd’hui la seule relation mathématique liant la survie cellulaire et la dose de radiation qui soit suffisamment consensuelle pour que radiothérapeutes et radiobiologistes l’utilisent régulièrement dans leurs interprétations des phénomènes radioinduits. Pourtant, cette formule proposée dans les années 1970 et les paramètres α et β sur lesquels elle est basée sont restés sans signification biologique cohérente. À partir d’une collection de fibroblastes cutanés de radiosensibilité différente constituée pendant 12 ans par plus de 50 radiothérapeutes français, nous avons mis récemment en évidence que la protéine ATM, acteur majeur de la réponse aux radiations ionisantes, diffuse du cytoplasme au noyau après irradiation. La mise en évidence de ce transit cytonucléaire de la protéine ATM nous a permis de fournir une interprétation biologique cohérente du modèle linéaire-quadratique dans ses aspects les plus mathématiques, validée par une centaine de cas. Une explication mécanistique de la radiosensibilité des syndromes causés par des mutations de protéines cytoplasmiques et du phénomène d’hypersensibilité aux faibles doses a pu être aussi avancée. Dans cette revue, nous avons abordé la résolution de ce modèle linéaire-quadratique de façon didactique, en se limitant strictement aux aspects mathématiques les plus essentiels. The linear-quadratic (LQ) model is the only mathematical formula linking cellular survival and radiation dose that is sufficiently consensual to help radiation oncologists and radiobiologists in describing the radiation-induced events. However, this formula proposed in the 1970s and α and β parameters on which it is based remained without relevant biological meaning. From a collection of cutaneous fibroblasts with different radiosensitivity, built over 12 years by more than 50 French radiation oncologists, we recently pointed out that the ATM protein, major actor of the radiation response, diffuses from the cytoplasm to the nucleus after irradiation. The evidence of this nuclear shuttling of ATM allowed us to provide a biological interpretation of the LQ model in its mathematical features, validated by a hundred of radiosensitive cases. A mechanistic explanation of the radiosensitivity of syndromes caused by the mutation of cytoplasmic proteins and of the hypersensitivity to low-dose phenomenon has been proposed, as well. In this review, we present our resolution of the LQ model in the most didactic way. [ABSTRACT FROM AUTHOR]

Résumé L’effet du fractionnement de la dose d’irradiation est une question récurrente qui reste globalement irrésolue car aucun modèle ne permet aujourd’hui de déduire l’effet clinique par la seule donnée de la dose cumulée et des caractéristiques radiobiologiques des tissus irradiés. Cette question importante est abordée différemment en radioprotection, radiothérapie, radiologie ou épidémiologie. Une meilleure compréhension de la réponse moléculaire aux radiations rend aujourd’hui possible une approche nouvelle pour identifier les paramètres qui conditionnent l’effet du fractionnement. En particulier, l’intervalle de temps entre les doses apparaît comme un facteur essentiel puisqu’il permettra, ou non, la réparation de certains dommages radio-induits de l’ADN comme les dommages de bases, les cassures simple-brin ou les cassures double-brin dont les rythmes de réparation sont respectivement de l’ordre de la seconde, de la minute ou de l’heure : l’effet de fractionnement variera alors suivant les statuts fonctionnels de ces voies de réparation, que ce soit pour les tissus sains comme pour les tumeurs. The dose fractionation effect is a recurrent question of radiation biology research that remains unsolved since no model predicts the clinical effect only with the cumulated dose and the radiobiology of irradiated tissues. Such an important question is differentially answered in radioprotection, radiotherapy, radiology or epidemiology. A better understanding of the molecular response to radiation makes possible today a novel approach to identify the parameters that condition the fractionation effect. Particularly, the time between doses appears to be a key factor since it will permit, or not, the repair of certain radiation-induced DNA damages whose repair rates are of the order of seconds, minutes or hours: the fractionation effect will therefore vary according to the functionality of the different repair pathways, whatever for tumor or normal tissues. [ABSTRACT FROM AUTHOR]

Marfan syndrome (MFS) is an autosomal dominant connective-tissue disorder affecting multiple systems, such as skeletal, cardiovascular, and ocular systems. MFS is predominantly caused by mutations in the FBN1 gene, which encodes the fibrillin-1 protein, crucial for connective-tissue integrity. FBN1 mutations lead to defective fibrillin, resulting in structurally compromised connective tissues. Additionally, these mutations cause aberrant TGF-β expression, contributing to vascular issues and increased susceptibility to radiation-induced fibrosis. Studies about the potential radiosensitivity of MFS are rare and generally limited to case reports. Here, we aimed to investigate the radiation-induced ATM nucleo-shuttling (RIANS) model to explore the molecular and cellular radiation response in fibroblasts from MFS patients. The results showed that the MFS fibroblast cell lines tested are associated with moderate but significant radiosensitivity, high yield of micronuclei, and impaired recognition of DNA double-strand breaks (DSBs) caused by a diminished RIANS. The diminished RIANS is supported by the sequestration of ATM protein in the cytoplasm not only by mutated FBN1 protein but also by overexpressed TGF-β. This report is the first molecular and cellular characterization of the radiation response of MFS fibroblasts and highlights the importance of the FBN1-TGF-β complex after irradiation.

Purpose: Fibrosis is a common late complication of radiation therapy. Molecular dysregulations leading to fibrosis have been characterized for the coding part of the genome, notably those involving the TGFB1 gene network. However, because a large part of the human genome encodes RNA transcripts that are not translated into proteins, exploring the involvement of the noncoding part of the genome in fibrosis susceptibility and development was the aim of this work., Methods and Materials: Breast cancer patients having or not having developed severe breast fibrosis after radiation therapy were retrospectively selected from the COPERNIC collection. Exome sequencing and RNA-seq transcriptomic profiling were performed on 19 primary dermal fibroblast strains isolated from the patients' nonirradiated skin. Functional experiments were based on fibrogenic induction by transforming growth factor-Beta1 (TGFB1) and gene knockdown in healthy donor fibroblasts., Results: Coding and noncoding transcriptomes discriminated fibrosis from nonfibrosis conditions, and a signature of breast fibrosis susceptibility comprising 15 long noncoding RNAs (lncRNAs) was identified. A hazard ratio validation showed that the lncRNA vimentin antisense long noncoding RNA 1 (VIM-AS1) was the best biomarker associated with fibrosis risk. This lncRNA has not been previously associated with any fibrotic disorder, but we found it upregulated in data sets from cardiac fibrosis and scleroderma, suggesting a general role in tissue fibrosis. Functional experiments demonstrated a profibrotic action of VIM-AS1 because its knockdown reduced myofibroblast activation, collagen matrix production, and dermal organoid contraction. RNA-seq data analysis after VIM-AS1 silencing also pointed out the regulation of replication, cell cycle, and DNA repair. Mechanistically, because VIM-AS1 was found coregulated with the vimentin gene, these data support a profibrotic function of the TGFB1/VIM-AS1/vimentin axis, targeting the dynamics of fibroblast-myofibroblast transition., Conclusions: Noncoding RNA analysis can provide specific biomarkers relevant to the prediction of normal tissue responses after radiation therapy, which opens perspectives of next-generation approaches for treatment, in the frame of the recent developments of RNA-based technologies., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Radiation impacting astronauts in their spacecraft come from a "bath" of high-energy rays (0.1-0.5 mGy per mission day) that reaches deep tissues like the heart and bones and a "stochastic rain" of low-energy particles from the shielding and impacting surface tissues like skin and lenses. However, these two components cannot be reproduced on Earth together. The MarsSimulator facility (Toulouse University, France) emits, thanks to a bag containing thorium salts, a continuous exposure of 120 mSv/y, corresponding to that prevailing in the International Space Station (ISS). By using immunofluorescence, we assessed DNA double-strand breaks (DSB) induced by 1-5 weeks exposure in ISS of human tissues evoked above, identified at risk for space exploration. All the tissues tested elicited DSBs that accumulated proportionally to the dose at a tissue-dependent rate (about 40 DSB/Gy for skin, 3 times more for lens). For the lens, bones, and radiosensitive skin cells tested, perinuclear localization of phosphorylated forms of ataxia telangiectasia mutated protein (pATM) was observed during the 1st to 3rd week of exposure. Since pATM crowns were shown to reflect accelerated aging, these findings suggest that a low dose rate of 120 mSv/y may accelerate the senescence process of the tested tissues. A mathematical model of pATM crown formation and disappearance has been proposed. Further investigations are needed to document these results in order to better evaluate the risks related to space exploration.

Purpose: Since 2004, in the frame of the care pathway, our Research Unit has replied to the demand of expertise of radiation oncologists about the individual radiosensitivity of some of their patients. This procedure, called COPERNIC, is based on a skin biopsy and the radiation-induced nucleoshuttling of the ATM protein (the RIANS model), a major actor of DNA break repair and signaling. In 2016, with the first 117COPERNIC fibroblast lines, we obtained a significant correlation between the maximum number of the nuclear ATM foci, pATM max , and the CTCAE severity grade of the post-radiotherapy tissue reactions. In this study, we propose to verify the validity of our previous findings with a new COPERNIC data subset obtained in the 2014-2024 period., Materials and Methods: We applied a standard immunofluorescence technique to quiescent COPERNIC fibroblasts to assess, after 2Gy, the level of micronuclei, γH2AX and pATM foci. The 117 COPERNIC data published in 2016 were considered as the reference data subset. A new COPERNIC data subset composed of 133fibroblast cell lines was considered as the validating data subset., Results: Our data showed that spontaneous or residual micronuclei levels, and residual γH2AX foci levels cannot predict CTCAE grades. Conversely, the linear formula linking the maximal number of pATM foci and the corresponding CTCAE grade and obtained in 2016 from the reference data subset fitted well the validating data., Conclusions: The maximal number of pATM foci appears to be one of the most reliable biomarkers for predicting post-radiotherapy radiotoxicity., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Context: Although carcinogenesis is a multi-factorial process, the mutability and the capacity of cells to proliferate are among the major features of the cells that contribute together to the initiation and promotion steps of cancer formation. Particularly, mutability can be quantified by hyper-recombination rate assessed with specific plasmid assay, hypoxanthine-guanine phosphoribosyltransferase (HPRT) mutations frequency rate, or MRE11 nuclease activities. Cell proliferation can be assessed by flow cytometry by quantifying G2/M, G1 arrests, or global cellular evasion., Methods: All these assays were applied to skin untransformed fibroblasts derived from eight major cancer syndromes characterized by their excess of relative cancer risk (ERR)., Results: Significant correlations with ERR were found between hyper-recombination assessed by the plasmid assay and G2/M arrest and described a third-degree polynomial ERR function and a sigmoidal ERR function, respectively. The product of the hyper-recombination rate and capacity of proliferation described a linear ERR function that permits one to better discriminate each cancer syndrome., Conclusions: Hyper-recombination and cell proliferation were found to obey differential equations that better highlight the intrinsic bases of cancer formation. Further investigations to verify their relevance for cancer proneness induced by exogenous agents are in progress.

Radiobiological data, whether obtained at the clinical, biological or molecular level has significantly contributed to a better description and prediction of the individual dose-response to ionizing radiation and a better estimation of the radiation-induced risks. Particularly, over the last seventy years, the amount of radiobiological data has considerably increased, and permitted the mathematical formulas describing dose-response to become less empirical. A better understanding of the basic radiobiological mechanisms has also contributed to establish quantitative inter-correlations between clinical, biological and molecular biomarkers, refining again the mathematical models of description. Today, big data approaches and, more recently, artificial intelligence may finally complete and secure this long process of thinking from the multi-scale description of radiation-induced events to their prediction. Here, we reviewed the major dose-response models applied in radiobiology for quantifying molecular and cellular radiosensitivity and aimed to explain their evolution: Specifically, we highlighted the advances concerning the target theory with the cell survival models and the progressive introduction of the DNA repair process in the mathematical models. Furthermore, we described how the technological advances have changed the description of DNA double-strand break (DSB) repair kinetics by introducing the important notion of DSB recognition, independent of that of DSB repair. Initially developed separately, target theory on one hand and, DSB recognition and repair, on the other hand may be now fused into a unified model involving the cascade of phosphorylations mediated by the ATM kinase in response to any genotoxic stress., (© 2024 by Radiation Research Society. All rights of reproduction in any form reserved.)

Immunofluorescence with antibodies against phosphorylated forms of H2AX (γH2AX) is revolutionizing our understanding of repair and signaling of DNA double-strand breaks (DSBs). Unfortunately, the pattern of γH2AX foci depends upon a number of parameters (nature of stress, number of foci, radiation dose, repair time, cell cycle phase, gene mutations, etc…) whose one of the common points is chromatin condensation/decondensation. Here, we endeavored to demonstrate how chromatin conformation affects γH2AX foci pattern and influences immunofluorescence signal. DSBs induced in non-transformed human fibroblasts were analyzed by γH2AX immunofluorescence with sodium butyrate treatment of chromatin applied after the irradiation that decondenses chromatin but does not induce DNA breaks. Our data showed that the pattern of γH2AX foci may drastically change with the experimental protocols in terms of size and brightness. Notably, some γH2AX minifoci resulting from the dispersion of the main signal due to chromatin decondensation may bias the quantification of the number of DSBs. We proposed a model called "Christmas light models" to tentatively explain this diversity of γH2AX foci pattern that may also be considered for any DNA damage marker that relocalizes as nuclear foci.

While cancer is one of the most documented diseases, how normal cells become cancerous is still debated. To address this question, in the first part of this review, we investigated the long succession of theories of carcinogenesis since antiquity. Initiated by Hippocrates, Aristotle, and Galen, the humoral theory interpreted cancer as an excess of acid, the black bile. The discovery of the circulation of blood by Harvey in 1628 destroyed the basis of the humoral theory but revived the spontaneous generation hypothesis which was also promoted by Aristotle. In 1859, the theory of microbes promoted by Pasteur demonstrated the irrelevance of this last theory and contributed to the emergence of the germ cancer theory, opposed to the cellular theory of cancer, in which cancer was supposed to be caused by microbes or transformed cells, respectively. These theories were progressively refined by the notions of initiation, promotion, and progression thanks to advances in mutagenesis and cellular proliferation. In the second part of this review, recent discoveries and paradigms in carcinogenesis, notably the role of the protein ATM, a major actor of the stress response involved in both mutagenesis and cellular proliferation, were discussed to better understand the current state of the art of carcinogenesis.

Pulmonary cryptococcosis is becoming increasingly common in immunocompetent hosts, manifesting with variable clinical presentations ranging from asymptomatic colonization to severe pneumonia. Radiological findings are non-specific, such as nodular infiltrates, mass-like lesions, and mediastinal lymphadenopathy. We present a case of a 61-year-old woman with Cryptococcus neoformans pneumonia coinfected with  Exophiala dermatitidis , an unusual occurrence in an immunocompetent host and the first of its kind. This coinfection posed significant diagnostic challenges due to the rare occurrence of each individual organism in immunocompetent patients as well as the difficulty of their laboratory diagnosis. Treatment regimens, particularly in coinfections, warrant careful consideration to mitigate mortality risk. This case underscores the importance of comprehensive diagnostic strategies and optimized treatment regimens for rare fungal coinfections in immunocompetent hosts., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Kohli et al.)

Introduction: Residential exposure is estimated to be responsible for nearly 10% of lung cancers in 2015 in France, making it the second leading cause, after tobacco. The Auvergne-Rhône-Alpes region, in the southwest of France, is particularly affected by this exposure as 30% of the population lives in areas with medium or high radon potential. This study aimed to investigate the impact of radon exposure on the survival of lung cancer patients., Methods: In this single-center study, patients with a histologically confirmed diagnosis of lung cancer, and newly managed, were prospectively included between 2014 and 2020. Univariate and multivariate survival analyses were carried out using a non-proportional risk survival model to consider variations in risk over time., Results: A total of 1,477 patients were included in the analysis. In the multivariate analysis and after adjustment for covariates, radon exposure was not statistically associated with survival of bronchopulmonary cancers (HR = 0.82 [0.54-1.23], HR = 0.92 [0.72-1.18], HR = 0.95 [0.76-1.19] at 1, 3, and 5 years, respectively, for patients residing in category 2 municipalities; HR = 0.87 [0.66-1.16], HR = 0.92 [0.76-1.10], and HR = 0.89 [0.75-1.06] at 1, 3, and 5 years, respectively, for patients residing in category 3 municipalities)., Discussion: Although radon exposure is known to increase the risk of lung cancer, in the present study, no significant association was found between radon exposure and survival of bronchopulmonary cancers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Dessemon, Perol, Chauvel, Noelle, Coudon, Grassot, Foray, Belladame, Fayette, Fournie, Swalduz, Neidhart, Saintigny, Tabutin, Boussageon, Gomez, Avrillon, Perol, Charbotel and Fervers.)