Papers by Marc Benderitter
Radiation Research, Sep 23, 2021
Treatment of accidental radiation-induced myelosuppression is primarily based on supportive care ... more Treatment of accidental radiation-induced myelosuppression is primarily based on supportive care and requires specific treatment based on hematopoietic growth factors injection or hematopoietic cell transplantation for the most severe cases. The cytokines used consisted of pegylated erythropoietin (darbepoetin alfa) 500 IU once per week, pegylated G-CSF (pegfilgrastim) 6 mg × 2 once, stem cell factor 20 μg.kg–1 for five days, and romiplostim (TPO analog) 10 μg.kg−1 once per week, with different combinations depending on the accidents. As the stem cell factor did not have regulatory approval for clinical use in France, the French regulatory authorities (ANSM, formerly, AFSSAPS) approved their compassionate use as an investigational drug “on a case-by-case basis”. According to the evolution and clinical characteristics, each patient's treatment was adopted on an individual basis. Daily blood count allows initiating G-CSF and SCF delivery when granulocyte <1,000/mm3, TPO delivery when platelets <50,000/mm3, and EPO when Hb<80 g/L. The length of each treatment was based on blood cell recovery criteria. The concept of “stimulation strategy” is linked to each patient's residual hematopoiesis, which varies among them, depending on the radiation exposure's characteristics and heterogeneity. This paper reports the medical management of 8 overexposed patients to ionizing radiation. The recovery of bone marrow function after myelosuppression was accelerated using growth factors, optimized by multiple-line combinations. Particularly in the event of prolonged exposure to ionizing radiation in dose ranges inducing severe myelosuppression (in the order of 5 to 8 Gy), with no indication of hematopoietic stem cell…
Environnement Risques & Sante, 2015
Un modele experimental animal, mimant la contamination chronique des populations vivant sur des t... more Un modele experimental animal, mimant la contamination chronique des populations vivant sur des territoires contamines a ete utilise dans le cadre du programme de recherche ENVIRHOM-Sante de l’Institut de radioprotection et de surete nucleaire (IRSN). Il a revele que l’ingestion chronique de radionucleides a faibles doses entrainait des atteintes biologiques multiples de faibles amplitudes caracterisees par des ruptures subtiles d’equilibres metaboliques consecutives a l’exposition interne. En effet, il a ete montre qu’une contamination interne de radionucleides etait capable d’affecter in vivo un certain nombre de metabolismes majeurs de l’organisme, tels que le metabolisme du cholesterol, de la vitamine D, du fer, des hormones steroidiennes et des xenobiotiques sans effet toxique ou apparition de pathologie. Pour completer et affiner ces connaissances, des etudes associant pour la premiere fois une approche metabolomique a la radiotoxicologie des faibles doses ont ete initiees en ...
Radioprotection, 2011
Le traitement par radiothérapie des cancers des sphères thoracique, médiastinale et ORL est assoc... more Le traitement par radiothérapie des cancers des sphères thoracique, médiastinale et ORL est associé à un risque de complications cardiovasculaires. Les patients traités et guéris de leur cancer sont de plus en plus nombreux, vivent de plus en plus longtemps, et leur devenir à long terme doit être pris en considération. Les complications cardiovasculaires associées principalement au traitement des cancers du sein, du lymphome de Hodgkin et des tumeurs de la tête et du cou se manifestent de manière insidieuse et chronique. Leur survenue est liée à de nombreux facteurs comme l'âge du patient au moment du traitement, le nombre d'années suivant la radiothérapie, la dose et le volume au coeur et aux gros vaisseaux (artères coronaires et carotides) ou encore l'association avec les autres facteurs de risque cardiovasculaire traditionnels. Les mécanismes physiopathologiques sont mal connus. Même si des similitudes avec l'athérosclérose liée à l'âge sont établies, les spécificités et les particularités de l'athérosclérose radio-induite pour des fortes doses d'irradiation restent à établir. Pour des faibles niveaux d'exposition aux rayonnements ionisants, des études épidémiologiques récentes suggèrent aussi un risque accru de développer des pathologies cardiovasculaires. L'amélioration des connaissances sur les mécanismes lésionnels à l'origine des pathologies cardiovasculaires radio-induites et l'identification plus précise des populations à risque devraient permettre dans le futur une prise en charge plus efficace de ces patients à risque vasculaire. ABSTRACT Effect of ionizing radiation on cardiovascular system Radiotherapy treatment for cancer of the chest, mediastinal area or the neck area is associated with increased risk of cardiovascular disease. With the increasing number of cancer patients and the increased treatment efficiency, the number of cancer survivors is increasing exponentially. The cancer survivors live longer and their long-term follow-up must be considered. The cardiovascular toxicity is mainly associated with the treatment of breast cancer, Hodgkin's lymphoma and head and neck cancer. Radiation-induced cardiovascular effects are insidious and chronic. Their occurrence is linked to numerous factors including the age of the patient at the beginning of the radiotherapy schedule, the number of years following radiotherapy, the doses (and volume) to the heart and the large vessels (coronary and carotid arteries), and the association with the traditional cardiovascular risk factors. Pathophysiological mechanisms remain unclear and, even if similarities with agerelated atherosclerosis were established, the specificities of the radiation-induced atherosclerosis for high doses remain to be discovered. For low/moderate doses of ionising radiation, recent epidemiological studies provide evidence of increased risk of cardiovascular pathologies. A better knowledge of the mechanisms associated Article publié par EDP Sciences F. MILLIAT et al. 494 RADIOPROTECTION-VOL. 46-N°4 (2011) with the radiation-induced cardiovascular pathologies and the more precise identification of the populations at risk in the future should allow a more effective care of these patients with cardiovascular risk.
Caffeic acid phenethyl ester modifi es the Th1/Th2 balance in ileal mucosa after γ-irradiation in... more Caffeic acid phenethyl ester modifi es the Th1/Th2 balance in ileal mucosa after γ-irradiation in the rat by modulating the cytokine pattern
Despite advances in radiation delivery protocols, exposure of normal tissues during the course of... more Despite advances in radiation delivery protocols, exposure of normal tissues during the course of radiation therapy remains a limiting factor of cancer treatment. If the canonical TGF-b/Smad pathway has been extensively studied and implicated in the development of radiation damage in various organs, the precise modalities of its activation following radiation exposure remain elusive. In the present study, we hypothesized that TGF-b1 signaling and target genes expression may depend on radiation-induced modifications in Smad transcriptional co-repressors/inhibitors expressions (TGIF1, SnoN, Ski and Smad7). In endothelial cells (HUVECs) and in a model of experimental radiation enteropathy in mice, radiation exposure increases expression of TGF-b/Smad pathway and of its target gene PAI-1, together with the overexpression of Smad co-repressor TGIF1. In mice, TGIF1 deficiency is not associated with changes in the expression of radiation-induced TGF-b pathwayrelated transcripts following l...
Stem Cell Research & Therapy, 2021
Background The intestine is particularly sensitive to moderate-high radiation dose and the develo... more Background The intestine is particularly sensitive to moderate-high radiation dose and the development of gastrointestinal syndrome (GIS) leads to the rapid loss of intestinal mucosal integrity, resulting in bacterial infiltration, sepsis that comprise patient survival. There is an urgent need for effective and rapid therapeutic countermeasures. The stromal vascular fraction (SVF) derived from adipose tissue is an easily accessible source of cells with angiogenic, anti-inflammatory and regenerative properties. We studied the therapeutic impact of SVF and its action on the intestinal stem cell compartment. Methods Mice exposed to the abdominal radiation (18 Gy) received a single intravenous injection of stromal vascular fraction (SVF) (2.5 × 106 cells), obtained by enzymatic digestion of inguinal fat tissue, on the day of irradiation. Mortality was evaluated as well as intestinal regeneration by histological analyses and absorption function. Results The SVF treatment limited the weig...
Stem Cell Research & Therapy, 2020
Background Human exposure to high doses of radiation resulting in acute radiation syndrome and de... more Background Human exposure to high doses of radiation resulting in acute radiation syndrome and death can rapidly escalate to a mass casualty catastrophe in the event of nuclear accidents or terrorism. The primary reason is that there is presently no effective treatment option, especially for radiation-induced gastrointestinal syndrome. This syndrome results from disruption of mucosal barrier integrity leading to severe dehydration, blood loss, and sepsis. In this study, we tested whether extracellular vesicles derived from mesenchymal stromal cells (MSC) could reduce radiation-related mucosal barrier damage and reduce radiation-induced animal mortality. Methods Human MSC-derived extracellular vesicles were intravenously administered to NUDE mice, 3, 24, and 48 h after lethal whole-body irradiation (10 Gy). Integrity of the small intestine epithelial barrier was assessed by morphologic analysis, immunostaining for tight junction protein (claudin-3), and in vivo permeability to 4 kDa ...
International Journal of Molecular Sciences, 2021
Fibrosis is a leading cause of death in occidental states. The increasing number of patients with... more Fibrosis is a leading cause of death in occidental states. The increasing number of patients with fibrosis requires innovative approaches. Despite the proven beneficial effects of mesenchymal stem cell (MSC) therapy on fibrosis, there is little evidence of their anti-fibrotic effects in colorectal fibrosis. The ability of MSCs to reduce radiation-induced colorectal fibrosis has been studied in vivo in Sprague–Dawley rats. After local radiation exposure, rats were injected with MSCs before an initiation of fibrosis. MSCs mediated a downregulation of fibrogenesis by a control of extra cellular matrix (ECM) turnover. For a better understanding of the mechanisms, we used an in vitro model of irradiated cocultured colorectal fibrosis in the presence of human MSCs. Pro-fibrotic cells in the colon are mainly intestinal fibroblasts and smooth muscle cells. Intestinal fibroblasts and smooth muscle cells were irradiated and cocultured in the presence of unirradiated MSCs. MSCs mediated a decr...
Archives of Toxicology, 2020
It is widely thought that Atemporalism-the view that, because God is "outside" of time, he does n... more It is widely thought that Atemporalism-the view that, because God is "outside" of time, he does not foreknow anything (rather, his knowledge is timeless)-constitutes a unique solution to the problem of freedom and foreknowledge. However, as I argue here, in order for Atemporalism to escape certain worries (raised independently by Alvin Plantinga and Linda Zagzebski), the view must appeal to the dependence of God's timeless knowledge on our actions. I then argue that, because it must appeal to such dependence, Atemporalism is crucially similar to the recent sempiternalist accounts proposed by Trenton Merricks, Philip Swenson, and Jonathan Westphal, and I conclude by briefly sketching some implications of this result.
Radiation Protection Dosimetry, 2018
Single dose of potassium iodide (KI) is recommended to prevent the risk of thyroid cancer during ... more Single dose of potassium iodide (KI) is recommended to prevent the risk of thyroid cancer during nuclear accidents. However in the case of repeated/protracted radioiodine release, a unique dose of KI may not protect efficiently the thyroid against the risk of further developing a radiation-induced cancer. The new WHO guidelines for the use in planning for and responding to radiological and nuclear emergencies identify the need of more data on this subject as one of the four research priorities. The aims of the PRIODAC project are (1) to assess the associated side effects of repeated intakes of KI, (2) to better understand the molecular mechanisms regulating the metabolism of iodine, (3) to revise the regulatory French marketing authorization of 65-mg KI tablets and (4) to develop new recommendations related to the administration of KI toward a better international harmonization. A review of the literature and the preliminary data are presented here.
Radiation Research, 2019
BioOne Complete (complete.BioOne.org) is a full-text database of 200 subscribed and open-access t... more BioOne Complete (complete.BioOne.org) is a full-text database of 200 subscribed and open-access titles in the biological, ecological, and environmental sciences published by nonprofit societies, associations, museums, institutions, and presses.
Journal of Toxicology and Environmental Health, Part A, 2019
ABSTRACT Preparedness for nuclear accident responsiveness includes interventions to protect pregn... more ABSTRACT Preparedness for nuclear accident responsiveness includes interventions to protect pregnancies against prolonged exposure to radioactive iodine. The aim of this study was to investigate a new design consisting of repeated administration of potassium iodide (KI, 1 mg/kg) for 8 days in late pregnancy gestational day 9–16 (GD9–GD16) in rats. The later-life effects of this early-life iodine thyroid blocking (ITB) strategy were assessed in offspring two months afterbirth. Functional behavioral tests including forced swimming test (FST) and rotarod test (RRT) in rats of both genders showed lower FST performance in KI-treated females and lower RRT performance in KI-treated male pups. This performance decline was associated with metabolic disruptions in cortex involving amino acid metabolism, tyrosine metabolism, as well as docosahexaenoic acid (DHA) lipids and signaling lipids in males and females. Beyond these behavior-associated metabolic changes, a portion of the captured metabolome (17–25%) and lipidome (3.7–7.35%) remained sensitive to in utero KI prophylactic treatment in both cortex and plasma of post-weaning rats, with some gender-related variance. Only part of these disruptions was attributed to lower levels of TSH and T4 (males only). The KI-induced metabolic shifts involved a broad spectrum of functions encompassing metabolic and cell homeostasis and cell signaling functions. Irrespective Regardless of gender and tissues, the predominant effects of KI affected neurotransmitters, amino acid metabolism, and omega-3 DHA metabolism. Taken together, data demonstrated that repeated daily KI administration at 1 mg/kg/day for 8 days during late pregnancy failed to protect the mother-fetus against nuclear accident radiation. Abbreviations: CV-ANOVA: Cross-validation analysis of variance; DHA: Docosahexaenoic acid; FST: Forced swimming test; FT3: plasma free triiodothyronine; FT4: plasma free thyroxine; GD: Gestational day; ITB: Iodine thyroid blocking; KI: potassium iodide; LC/MS: Liquid chromatography coupled with mass spectrometry; MTBE: Methyl tert-butyl ether; m/z: mass-to-charge ratio; PLS-DA: Partial least squares–discriminant analysis; PRIODAC: Repeated stable iodide prophylaxis in accidental radioactive releases; RRT: Rotarod test; TSH: Thyroid-stimulating hormone; VIP: Variable importance in projection.
Neuroscience, 2019
Protracted radioiodine release, may requires repeated intake of potassium iodide (KI) to protect ... more Protracted radioiodine release, may requires repeated intake of potassium iodide (KI) to protect thyroid gland. It is well established that iodine excess inhibits transiently the thyroid function. As developing foetus depends on maternal thyroid hormones (TH) supply, more knowledge are needed about the plausible effects that repeated KI intake can cause in this sensitive population, especially that even subtle variation of maternal thyroid function may have persistent consequences on progeny brain processing. The aim of this study is to assess 1 ACCEPTED MANUSCRIPT the conséquences of repeated intake of KI during pregnancy on the progeny's thyroid function and brain development. To do so pregnant Wistar rats received KI over eight days, and then thirty days after the weaning, male progeny was subjected to behaviour test. Pituitary and thyroid hormones level, anti-thyroid antibodies level, organs morphology, genes expression and global DNA methylation were assessed. Thirty days after the weaning, KI-exposed male progeny showed an uncommon hormonal status, characterized by a decrease of both TSH (-28%) and FT4 (-7%) levels. Motor coordination was altered in KI-exposed male progeny, at the cerebellar level we observed a decrease of mRNA expression of DCX (-42%) and RC3 (-85%), on the other hand at the cortical level mRNA expression of MBP (+71%), MOBP (+90%) and Kcna1 (+42%) was increased. To conclude, repeated KI prophylaxis is not adequate during pregnancy since it led to long-term irreversible neurotoxicity in the male progeny.
Cell Transplantation, 2018
Skin lesions caused by accidental exposure to radiation or by radiotherapy are a major clinical c... more Skin lesions caused by accidental exposure to radiation or by radiotherapy are a major clinical challenge. We evaluated the effect of bone marrow mononuclear cells (BMMNC) on collagen remodeling and vascular function in radiation-induced skin lesions in the acute and late phases in mice. We studied the effect of BMMNC transplantation in a mouse model of cutaneous radiation injury combining local skin gamma-irradiation and biopsy punch wound. Mice were first irradiated, punched and then BMMNC were intramuscularly administered. Seven days after injury, BMMNC promoted wound healing by (i) increasing reepithelialization, tissue collagen density and mRNA levels of collagens 1A1, 1A2, and 3A1, and (ii) inhibiting the radiationinduced vascular activation and limiting interactions between leukocytes and the vascular endothelium compared with control. Importantly, BMMNC did not amplify the inflammatory response despite the infiltration of neutrophils and macrophages associated with the expression of IL-6 and MCP-1 mRNAs in the tissue. Remarkably, the beneficial effects of BMMNC therapy on matrix remodeling were maintained for 2 months. Furthermore, BMMNC injection restored vascular function in skin tissue by increasing vascular density and vascular permeability. This therapeutic strategy based on BMMNC injection protects against radiation-induced skin lesions by preventing vascular dysfunction and unfavorable remodeling in the acute and late phases.
Stem Cell Research & Therapy, 2018
Background: Medical management of the severe musculocutaneous radiation syndrome involves surgica... more Background: Medical management of the severe musculocutaneous radiation syndrome involves surgical intervention with debridement of necrotic tissue. Even when skin excision is replaced by specific plastic surgery, treatment of the muscle radiation injury nonetheless remains difficult, for it involves a massive muscle defect in an unpredictable environment, subject to inflammatory waves weeks to months after irradiation, which delay healing and predispose the patient to the development of fibrous scar tissue. In this study, we investigated the long-term effect of local injections of bone marrow-derived mesenchymal stromal cells (BM-MSCs), combined with plastic surgery, to treat muscle necrosis in a large animal model. Methods: Three months after irradiation to the rump, minipigs were treated by excision of necrotic muscle tissue, vascularized flap surgery, and four injections with or without local autologous BM-MSCs, performed weekly. The quality of the muscle wound healing was examined 1 year post-surgery. Results: The skeletal muscle surgery without MSC treatment led to permanent deposition of collagen 1 and 3, decreased myofiber diameter, failed muscle fiber regeneration, a reduced number of capillaries, and the accumulation of high calcium and fat. In animals treated by surgery and MSC injections, these indicators were substantially better and demonstrated established regeneration. MSC therapy acts at several levels by stimulating growth factors such as VEGF, which is involved in angiogenesis and satellite cell pool maintenance, and creating a macrophage M1/ M2 balance. Conclusion: Thus, cell therapy using BM-MSCs is an effective and safe way to improve recovery of irradiationinduced skeletal muscle damage without signs of long-term degeneration.
Scientific reports, Jan 11, 2018
A correction to this article has been published and is linked from the HTML and PDF versions of t... more A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Cell transplantation, 2017
Cancer patients treated with radiotherapy (RT) could develop severe late side effects that affect... more Cancer patients treated with radiotherapy (RT) could develop severe late side effects that affect their quality of life. Long-term bowel complications after RT are mainly characterized by a transmural fibrosis that could lead to intestinal obstruction. Today, surgical resection is the only effective treatment. However, preoperative RT increases the risk of anastomotic leakage. In this study, we attempted to use mesenchymal stromal cells from adipose tissue (Ad-MSCs) to improve colonic anastomosis after high-dose irradiation. MSCs were isolated from the subcutaneous fat of rats, amplified in vitro, and characterized by flow cytometry. An animal model of late radiation side effects was induced by local irradiation of the colon. Colonic anastomosis was performed 4 wk after irradiation. It was analyzed another 4 wk later (i.e., 8 wk after irradiation). The Ad-MSC-treated group received injections several times before and after the surgical procedure. The therapeutic benefit of the Ad-MS...
Scientific Reports, 2017
Chronic skin ulcers and burns require advanced treatments. Mesenchymal Stromal Cells (MSCs) are e... more Chronic skin ulcers and burns require advanced treatments. Mesenchymal Stromal Cells (MSCs) are effective in treating these pathologies. Bone Morphogenic Protein-2 (BMP-2) is known to enhance angiogenesis. We investigated whether recombinant human hBMP-2 potentiates the effect of MSCs on wound healing. Severe ulceration was induced in rats by irradiation and treated by co-infusion of MSCs with hBMP-2 into the ulcerated area which accelerated wound healing. Potentiation of the effect of MSCs by hBMP-2 on endothelial repair improved skin healing. HBMP-2 and MSCs synergistically, in a supra additive or enhanced manner, renewed tissue structures, resulting in normalization of the epidermis, hair follicles, sebaceous glands, collagen fibre density, and blood vessels. Co-localization of MSCs with CD31 + cells suggests recruitment of endothelial cells at the site of injection. HBMP-2 and MSCs enhanced angiogenesis and induced micro-vessel formation in the dermis where hair follicles were regenerated. HBMP-2 acts by causing hypoxia-inducible factor-1 α (HIF-1α) expression which impacts endothelial tube formation and skin repair. This effect is abolished by siRNA. These results propose that new strategies adding cytokines to MSCs should be evaluated for treating radiationinduced dermatitis, burns, and chronic ulcers in humans. Chronic wounds significantly impair the quality of life of millions of people and remain a major challenge in modern medicine. The treatment of burns and chronic skin ulcers still requires more effective therapy 1-4 . Cutaneous irradiation may cause chronic, torpid long lasting ulcerations . Microvascular lesions with endothelium dysfunction play a key role in their pathogenesis . In the last two decades, extensive laboratory, preclinical and clinical studies of stem cells have provided new perspectives for the management of chronic non-healing wounds 10 . Local and/or systemic administration of progenitor/stem cells, mesenchymal stromal cells (MSCs), in particular harvested from bone marrow (BM) or adipose tissue, have been tested in patients suffering from many chronic diseases . MSCs have the potential to improve limb ischemia, systemic scleroderma, ulcerative wounds in diabetes, severe skin damage, and thermal and radiation burns . They have also been used for aesthetic and reconstructive surgery . Recent case reports have highlighted the favourable therapeutic results in victims of radiation accidents with severe cutaneous ulcerations, by the combination of local MSC administration and surgery, drawing attention to the angiogenic effect of MSC infusion . MSCs have been used in the field but the results have remained somewhat uncertain. The scientific question we are addressing is whether we can improve the efficacy of stem cell therapy for ulcerative damage, with
Biomaterials, 2017
Healthy tissues surrounding abdomino-pelvic tumours can be impaired by radiotherapy, leading to c... more Healthy tissues surrounding abdomino-pelvic tumours can be impaired by radiotherapy, leading to chronic gastrointestinal complications with substantial mortality. Adipose-derived Mesenchymal Stromal Cells (Ad-MSCs) represent a promising strategy to reduce intestinal lesions. However, systemic administration of Ad-MSCs results in low cell engraftment within the injured tissue. Biomaterials, able to encapsulate and withstand Ad-MSCs, can overcome these limitations. A silanized hydroxypropylmethyl cellulose (Si-HPMC) hydrogel has been designed and characterized for injectable cell delivery using the operative catheter of a colonoscope. We demonstrated that hydrogel loaded-Ad-MSCs were viable, able to secrete trophic factors and responsive to the inflammatory environment. In a rat model of radiationinduced severe colonic damage, Ad-MSC þ Si-HPMC improve colonic epithelial structure and hyperpermeability compared with Ad-MSCs injected intravenously or locally. This therapeutic benefit is associated with greater engraftment of Si-HPMC-embedded Ad-MSCs in the irradiated colonic mucosa. Moreover, macrophage infiltration near the injection site was less pronounced when Ad-MSCs were embedded in the hydrogel. Si-HPMC induces modulation of chemoattractant secretion by Ad-MSCs that could contribute to the decrease in macrophage infiltrate. Si-HPMC is suitable for cell delivery by colonoscopy and induces protection of Ad-MSCs in the tissue potentiating their therapeutic effect and could be proposed to patients suffering from colon diseases.
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Papers by Marc Benderitter