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1. In vitro hyperspectral biomarkers of human chondrosarcoma cells in nanoparticle-mediated radiosensitization using carbon ions

Author

Mihaela Tudor, Roxana Cristina Popescu, Raluca D. Negoita, Antoine Gilbert, Mihaela A. Ilisanu, Mihaela Temelie, Anca Dinischiotu, François Chevalier, Mona Mihailescu, and Diana Iulia Savu

Subjects
Medicine, Science
Abstract

Abstract New therapeutic approaches are needed for the management of the highly chemo- and radioresistant chondrosarcoma (CHS). In this work, we used polyethylene glycol-encapsulated iron oxide nanoparticles for the intracellular delivery of the chemotherapeutic doxorubicin (IONPDOX) to augment the cytotoxic effects of carbon ions in comparison to photon radiation therapy. The in vitro biological effects were investigated in SW1353 chondrosarcoma cells focusing on the following parameters: cell survival using clonogenic test, detection of micronuclei (MN) by cytokinesis blocked micronucleus assay and morphology together with spectral fingerprints of nuclei using enhanced dark-field microscopy (EDFM) assembled with a hyperspectral imaging (HI) module. The combination of IONPDOX with ion carbon or photon irradiation increased the lethal effects of irradiation alone in correlation with the induction of MN. Alterations in the hyperspectral images and spectral profiles of nuclei reflected the CHS cell biological modifications following the treatments, highlighting possible new spectroscopic markers of cancer therapy effects. These outcomes showed that the proposed combined treatment is promising in improving CHS radiotherapy.

Published
2023
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2. Radiosensitizing Effect of PARP Inhibition on Chondrosarcoma and Chondrocyte Cells Is Dependent on Radiation LET

Author

Antoine Gilbert, Mihaela Tudor, Amandine Delaunay, Raphaël Leman, Julien Levilly, Alexandre Atkinson, Laurent Castéra, Anca Dinischiotu, Diana Iulia Savu, Samuel Valable, and François Chevalier

Subjects
carbon ion irradiation, chondrosarcoma, PARP inhibitor, DNA damages, Microbiology, QR1-502
Abstract

Chondrosarcoma is a rare malignant tumor that forms in bone and cartilage. The primary treatment involves surgical removal of the tumor with a margin of healthy tissue. Especially if complete surgical removal is not possible, radiation therapy and chemotherapy are used in conjunction with surgery, but with a generally low efficiency. Ongoing researches are focused on understanding the genetic and molecular basis of chondrosarcoma following high linear energy transfer (LET) irradiation, which may lead to treatments that are more effective. The goal of this study is to evaluate the differential effects of DNA damage repair inhibitors and high LET irradiation on chondrosarcoma versus chondrocyte cells and the LET-dependency of the effects. Two chondrosarcoma cell lines with different IDH mutation status and one chondrocyte cell line were exposed to low LET (X-ray) and high LET (carbon ion) irradiation in combination with an Olaparib PARP inhibitor. Cell survival and DNA repair mechanisms were investigated. High LET irradiation drastically reduced cell survival, with a biological efficiency three times that of low LET. Olaparib significantly inhibited PARylation in all the tested cells. A significant reduction in cell survival of both chondrosarcoma and chondrocyte cells was observed following the treatment combining Olaparib and X-ray. PARP inhibition induced an increase in PARP-1 expression and a reduced effect on the cell survival of WT IDH chondrosarcoma cells. No radiosensitizing effect was observed in cells exposed to Olaparib paired with high LET irradiation. NHEJ was activated in response to high LET irradiation, neutralizing the PARP inhibition effect in both chondrosarcoma cell lines. When high LET irradiation is not available, PARP inhibition could be used in combination with low LET irradiation, with significant radiosensitizing effects on chondrosarcoma cells. Chondrocytes may be affected by the treatment combination too, showing the need to preserve normal tissues from radiation fields when this kind of treatment is suggested.

Published
2024
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3. Potential Benefits of Combining Proton or Carbon Ion Therapy with DNA Damage Repair Inhibitors

Author

Gro Elise Rødland, Mihaela Temelie, Adrian Eek Mariampillai, Sissel Hauge, Antoine Gilbert, François Chevalier, Diana I. Savu, and Randi G. Syljuåsen

Subjects
high-LET irradiation, DNA repair, DNA damage response inhibitors, antitumor immune response, radiosensitivity, Cytology, QH573-671
Abstract

The use of charged particle radiotherapy is currently increasing, but combination therapy with DNA repair inhibitors remains to be exploited in the clinic. The high-linear energy transfer (LET) radiation delivered by charged particles causes clustered DNA damage, which is particularly effective in destroying cancer cells. Whether the DNA damage response to this type of damage is different from that elicited in response to low-LET radiation, and if and how it can be targeted to increase treatment efficacy, is not fully understood. Although several preclinical studies have reported radiosensitizing effects when proton or carbon ion irradiation is combined with inhibitors of, e.g., PARP, ATR, ATM, or DNA-PKcs, further exploration is required to determine the most effective treatments. Here, we examine what is known about repair pathway choice in response to high- versus low-LET irradiation, and we discuss the effects of inhibitors of these pathways when combined with protons and carbon ions. Additionally, we explore the potential effects of DNA repair inhibitors on antitumor immune signaling upon proton and carbon ion irradiation. Due to the reduced effect on healthy tissue and better immune preservation, particle therapy may be particularly well suited for combination with DNA repair inhibitors.

Published
2024
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4. Label-Free Direct Mass Spectrometry Analysis of the Bystander Effects Induced in Chondrocytes by Chondrosarcoma Cells Irradiated with X-rays and Carbon Ions

Author

Antoine Gilbert, Valentin Payet, Benoît Bernay, Elisabeth Chartier-Garcia, Isabelle Testard, Serge M. Candéias, and François Chevalier

Subjects
bystander effect, carbon irradiation, chondrosarcoma, proteomic analysis, stress granules, il12, Biochemistry, QD415-436, Biology (General), QH301-705.5
Abstract

Background: Radiation-induced bystander effects are induced changes in cells that were not themselves directly irradiated but were in the vicinity of a radiation path. Such effects, which occur in the microenvironment of an irradiated tumor, remain poorly understood and depend on the cell type and irradiation quality. This study aimed to evaluate bystander effects in non-irradiated chondrocytes that received conditioned medium from irradiated chondrosarcoma cells. Methods: SW1353 chondrosarcoma cells were irradiated with X-rays and carbon ions, each at 0.1 Gy and 2 Gy, and the conditioned media of the irradiated cells were transferred to T/C-28A2 chondrocytes and Human Umbilical Venous Endothelial Cells (HUVECs). The whole proteome of bystander chondrocytes was analyzed by label-free mass spectrometry, and a comparative study was performed by dose and irradiation quality. HUVECs were evaluated for inflammatory cytokine secretion. Results: The bystander response of chondrocytes to X-ray irradiation primarily affected the protein translation pathway (DHX36, EIF3B, EIF3D, EIF3M, EIF5, RPL6, RPLP0, RPS24, SYNCRIP), IL-12 (AIP, BOLA2, MIF, GAS6, MIF, PDGFRB) and the oxidative stress pathway (MGST3, PRDX2, PXDN, SOD2, TXN, TXNL1). Following carbon-ion irradiation, the G1/S pathway (PCBP4, PSMD12, PSME, XIAP) and mitotic G2 DNA damage checkpoint pathway (MRE11, TAOK1, UIMC1) were engaged. Changes in the regulation of chromosome separation (BCL7C, BUB3, CENPF, DYNC1LI1, SMARCA4, SMC4) were associated with only low-dose X-ray and carbon-ion irradiation. Modification of the protein translation pathway represented at least 30% of bystander effects and could play a role, possibly along with stress granules, in reduction in cellular metabolism to protect proteins. Stress granules were significantly enriched according to an interaction map. Conclusions: All these accessions corresponded to a window of the proteins modulated in response to the bystander effect. Our chondrosarcoma model clarified the nature of the bystander response of chondrocytes and may suggest several interesting new mechanisms that are specific to particular irradiation doses and qualities.

Published
2022
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5. Sensitization of chondrosarcoma cells with PARP inhibitor and high-LET radiation

Author

Mathieu Césaire, Utpal Ghosh, Jean-Baptiste Austry, Etienne Muller, Francesco Paolo Cammarata, Marilyne Guillamin, Massimo Caruso, Laurent Castéra, Giada Petringa, Giuseppe Antonio Pablo Cirrone, and François Chevalier

Subjects
Diseases of the musculoskeletal system, RC925-935, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Chondrosarcoma is a malignant tumor that arises from cartilaginous tissue and is radioresistant and chemoresistant to conventional treatments. The preferred treatment consists of surgical resection, which might cause severe disabilities for the patient; in addition, this procedure might be impossible for inoperable locations, such as the skull base. Carbon ion irradiation (hadron therapy) has been proposed as an alternative treatment, primarily due to its greater biological effectiveness and improved ballistic properties compared with conventional radiotherapy with X-rays. The goal of this study was to characterize the genetic mutations of a grade III chondrosarcoma cell line (CH2879) and examine the cellular responses to conventional radiotherapy (X-rays) and hadron therapy (proton and carbon ions) in the presence of the PARP inhibitor Olaparib. To better understand PARP inhibition, we first analyzed the formation of poly-ADP ribose chains by western blot; we observed an increase in its signal after irradiation, which disappeared on addition of the PARP inhibitor. PARPi enhanced ratio of approximately 1.3, 1.8, and 1.5 following irradiation of cells with X-rays, protons, and C-ions, respectively, as detected by clonogenic assay. The decrease in cell survival was confirmed by proliferation assay. The radiosensitivity of CH2879 cells was associated with mutations in homologous recombination repair genes, such as RAD50, SMARCA2 and NBN. This study demonstrates the capacity of the PARP inhibitor Olaparib to radiosensitize mutated chondrosarcoma cells to conventional photon irradiation, proton and carbon ion irradiation. Keywords: PARP inhibitor, Olaparib, Chondrosarcoma, Carbon ions irradiation, Mutation status

Published
2019
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7. El Marquesado del Valle

Author

François Chevalier

Subjects
Marquesado del Valle, encomienda, merced real, terratenientes, conquista, siglo XVI, History America, E-F, Latin America. Spanish America, F1201-3799
Published
1951

13. A Longitudinal Study of Individual Radiation Responses in Pediatric Patients Treated with Proton and Photon Radiotherapy, and Interventional Cardiology: Rationale and Research Protocol of the HARMONIC Project

Author

Maria Grazia Andreassi, Nadia Haddy, Mats Harms-Ringdahl, Jonica Campolo, Andrea Borghini, François Chevalier, Jochen M. Schwenk, Brice Fresneau, Stephanie Bolle, Manuel Fuentes, Siamak Haghdoost, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR), The Wenner-Gren Institute, Stockholm University, Accueil et Recherche en Radiobiologie des Ions Accélérés (ARIA), Centre de recherche sur les Ions, les MAtériaux et la Photonique (CIMAP - UMR 6252), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche sur les Matériaux Avancés (IRMA), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), ARCHADE (Advanced Resource Centre for HADrontherapy in Europe), Royal Institute of Technology [Stockholm] (KTH ), Université Paris-Saclay, Département de radiothérapie [Gustave Roussy], and Universidad de Salamanca

Subjects
cardiac catheterization, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Organic Chemistry, [SDV.CAN]Life Sciences [q-bio]/Cancer, General Medicine, pediatric oncology, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, congenital heart disease, Catalysis, Computer Science Applications, Inorganic Chemistry, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, proton radiotherapy, HARMONIC project, radiation biomarkers, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Physical and Theoretical Chemistry, ionizing radiation, Molecular Biology, Spectroscopy, radiotherapy
Abstract

International audience; The Health Effects of Cardiac Fluoroscopy and Modern Radiotherapy (photon and proton) in Pediatrics (HARMONIC) is a five-year project funded by the European Commission that aimed to improve the understanding of the long-term ionizing radiation (IR) risks for pediatric patients. In this paper, we provide a detailed overview of the rationale, design, and methods for the biological aspect of the project with objectives to provide a mechanistic understanding of the molecular pathways involved in the IR response and to identify potential predictive biomarkers of individual response involved in long-term health risks. Biological samples will be collected at three time points: before the first exposure, at the end of the exposure, and one year after the exposure. The average whole-body dose, the dose to the target organ, and the dose to some important out-of-field organs will be estimated. State-of-the-art analytical methods will be used to assess the levels of a set of known biomarkers and also explore high-resolution approaches of proteomics and miRNA transcriptomes to provide an integrated assessment. By using bioinformatics and systems biology, biological pathways and novel pathways involved in the response to IR exposure will be deciphered.

Published
2023
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14. A multimodal treatment of carbon ions irradiation, miRNA-34 and mTOR inhibitor specifically control high-grade chondrosarcoma cancer stem cells

Author

Vares, Guillaume, Ahire, Vidhula, Sunada, Shigeaki, Ho Kim, Eun, Sai, Sei, François, Chevalier, Paul-Henri, Romeo, Yamamoto, Tadashi, Nakajima, Tetsuo, and Saintigny, Yannick

Abstract

(Background and purpose) High-grade chondrosarcomas are chemo-and radio-resistant cartilage-forming tumors of bone that often relapse and metastases. Thus, new therapeutic strategies are urgently needed. (Material and methods) Chondrosarcoma cells (CH-2879) were exposed to carbon-ion irradiation, combined with miR-34 mimic and/or rapamycin administration. The effects of treatment on cancer stem cells, stemness-associated phenotype, radioresistance and tumor-initiating properties were evaluated. (Results) We show that high-grade chondrosarcoma cells contain a population of radioresistant cancer stem cells that can be targeted by a combination of carbon-ion therapy, miR-34 mimic administration and/or rapamycin treatment that triggers FOXO3 and miR-34 over-expression. mTOR inhibition by rapamycin triggered FOXO3 and miR-34, leading to KLF4 repression. (Conclusion) Our results show that particle therapy combined with molecular treatments effectively controls cancer stem cells and may overcome treatment resistance of high-grade chondrosarcoma.

Published
2020

15. Radioresistance of Non-Small Cell Lung Cancers and Therapeutic Perspectives

Author

Mathieu Césaire, Juliette Montanari, Hubert Curcio, Delphine Lerouge, Radj Gervais, Pierre Demontrond, Jacques Balosso, François Chevalier, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Accueil et Recherche en Radiobiologie des Ions Accélérés (ARIA), Centre de recherche sur les Ions, les MAtériaux et la Photonique (CIMAP - UMR 6252), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche sur les Matériaux Avancés (IRMA), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), and Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cancer Research, cancer stem cell, Oncology, non-small-cell lung cancer, proton irradiation, cancer mutation, [SDV.CAN]Life Sciences [q-bio]/Cancer, immunotherapy, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, radiotherapy
Abstract

International audience; Survival in unresectable locally advanced stage non-small cell lung cancer (NSCLC) patients remains poor despite chemoradiotherapy. Recently, adjuvant immunotherapy improved survival for these patients but we are still far from curing most of the patients with only a 57% survival remaining at 3 years. This poor survival is due to the resistance to chemoradiotherapy, local relapses, and distant relapses. Several biological mechanisms have been found to be involved in the chemoradioresistance such as cancer stem cells, cancer mutation status, or the immune system. New drugs to overcome this radioresistance in NSCLCs have been investigated such as radiosensitizer treatments or immunotherapies. Different modalities of radiotherapy have also been investigated to improve efficacity such as dose escalation or proton irradiations. In this review, we focused on biological mechanisms such as the cancer stem cells, the cancer mutations, the antitumor immune response in the first part, then we explored some strategies to overcome this radioresistance in stage III NSCLCs with new drugs or radiotherapy modalities.

Published
2022
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16. Chondrosarcoma Resistance to Radiation Therapy: Origins and Potential Therapeutic Solutions

Author

Antoine Gilbert, Mihaela Tudor, Juliette Montanari, Kevin Commenchail, Diana Iulia Savu, Paul Lesueur, François Chevalier, Accueil et Recherche en Radiobiologie des Ions Accélérés (ARIA), Centre de recherche sur les Ions, les MAtériaux et la Photonique (CIMAP - UMR 6252), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche sur les Matériaux Avancés (IRMA), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Horia Hulubei National Institute of Physics and Nuclear Engineering (NIPNE), IFIN-HH, University of Bucharest (UniBuc), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Imagerie et Stratégies Thérapeutiques pour les Cancers et Tissus cérébraux (ISTCT), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), and Region Normandy: RIN CHOXTRACC (2021–2022) 'Recherche de combinaisons thérapeutiques hadronthérapie—thérapies ciblant la radiorésistance biologique liée à l’hypoxie et au stress oxydant tumoral'

Subjects
carbon ions therapy, cancer stem cells, chondrosarcoma, radiation resistance, Cancer Research, Oncology, hypoxia, hadrontherapy, [SDV.CAN]Life Sciences [q-bio]/Cancer
Abstract

International audience; Chondrosarcoma is a malignant cartilaginous tumor that is particularly chemoresistant and radioresistant to X-rays. The first line of treatment is surgery, though this is almost impossible in some specific locations. Such resistances can be explained by the particular composition of the tumor, which develops within a dense cartilaginous matrix, producing a resistant area where the oxygen tension is very low. This microenvironment forces the cells to adapt and dedifferentiate into cancer stem cells, which are described to be more resistant to conventional treatments. One of the main avenues considered to treat this type of tumor is hadrontherapy, in particular for its ballistic properties but also its greater biological effectiveness against tumor cells. In this review, we describe the different forms of chondrosarcoma resistance and how hadrontherapy, combined with other treatments involving targeted inhibitors, could help to better treat high-grade chondrosarcoma.

Published
2023
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17. Avoidance or adaptation of radiotherapy in patients with cancer with Li-Fraumeni and heritable TP53-related cancer syndromes

Author

Gaëlle Bougeard, Pierre-Yves Marcy, François Chevalier, Nadège Corradini, Nicolas Foray, Luc Ollivier, Daniel Orbach, Juliette Thariat, A. Beddok, Laboratoire de physique corpusculaire de Caen (LPCC), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Accueil et Recherche en Radiobiologie des Ions Accélérés (ARIA), Centre de recherche sur les Ions, les MAtériaux et la Photonique (CIMAP - UMR 6252), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche sur les Matériaux Avancés (IRMA), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Service de pédiatrie, adolescents, jeunes adultes [Institut Curie], Institut Curie [Paris], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Centre Léon Bérard [Lyon], Unité Ad Hoc INSERM 000008 'Radiations : Défense, Santé, Environnement' [Lyon] (Inserm U1296), Centre Léon Bérard [Lyon]-Service de Santé des Armées-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU), Radiations : Défense, Santé, Environnement [Lyon] (Inserm UA8), and Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Oncology, medicine.medical_specialty, Neoplasms, Radiation-Induced, medicine.medical_treatment, [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Germline, Li-Fraumeni Syndrome, 03 medical and health sciences, 0302 clinical medicine, Neoplastic Syndromes, Hereditary, Internal medicine, Radioresistance, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Humans, Genetic Predisposition to Disease, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Radiosensitivity, education, Proton therapy, Germ-Line Mutation, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, education.field_of_study, Particle therapy, Radiotherapy, business.industry, Cancer, medicine.disease, Prognosis, 3. Good health, Radiation therapy, 030220 oncology & carcinogenesis, Tumor Suppressor Protein p53, business
Abstract

International audience; The management of patients with cancer and Li-Fraumeni or heritable TP53-related cancer syndromes is complex because of their increased risk of developing second malignant neoplasms after genotoxic stresses such as systemic treatments or radiotherapy (radiosusceptibility). Clinical decision making also integrates the risks of normal tissue toxicity and sequelae (radiosensitivity) and tumour response to radiotherapy (radioresistance and radiocurability). Radiotherapy should be avoided in patients with cancer and Li-Fraumeni or heritable TP53 cancer-related syndromes, but overall prognosis might be poor without radiotherapy: radioresistance in these patients seems similar to or worse than that of the general population. Radiosensitivity in germline TP53 variant carriers seems similar to that in the general population. The risk of second malignant neoplasms according to germline TP53 variant and the patient's overall oncological prognosis should be assessed during specialised multidisciplinary staff meetings. Radiotherapy should be avoided whenever other similarly curative treatment options are available. In other cases, it should be adapted to minimise the risk of second malignant neoplasms in patients who still require radiotherapy despite its genotoxicity, in view of its potential benefit. Adaptations might be achieved through the reduction of irradiated volumes using proton therapy, non-ionising diagnostic procedures, image guidance, and minimal stray radiation. Non-ionising imaging should become more systematic. Radiotherapy approaches that might result in a lower probability of misrepaired DNA damage (eg, particle therapy biology and tumour targeting) are an area of investigation.

Published
2021
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18. A Proteomic Study Suggests Stress Granules as New Potential Actors in Radiation-Induced Bystander Effects

Author

François Chevalier, Jean Armengaud, Sonia Hem, Mihaela Tudor, Charlotte Lepleux, Diana Savu, Antoine Gilbert, Siamak Haghdoost, Emilie Brotin, Mihaela Temelie, Horia Hulubei National Institute of Physics and Nuclear Engineering (NIPNE), IFIN-HH, University of Bucharest (UniBuc), Accueil et Recherche en Radiobiologie des Ions Accélérés (ARIA), Centre de recherche sur les Ions, les MAtériaux et la Photonique (CIMAP - UMR 6252), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU), Biochimie et Physiologie Moléculaire des Plantes (BPMP), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche sur les Matériaux Avancés (IRMA), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), and Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Proteomics, 0301 basic medicine, stress granules, DNA damage, QH301-705.5, Bone Neoplasms, Radiation induced, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Cytoplasmic Granules, medicine.disease_cause, Article, Catalysis, Inorganic Chemistry, 03 medical and health sciences, Chondrocytes, 0302 clinical medicine, Stress granule, Western blot, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], bystander signaling, Conditioned medium, Bystander effect, medicine, Humans, Physical and Theoretical Chemistry, Biology (General), Molecular Biology, QD1-999, Spectroscopy, chondrosarcoma, medicine.diagnostic_test, Chemistry, X-Rays, Organic Chemistry, Bystander Effect, General Medicine, proteomic analysis, Microvesicles, Computer Science Applications, Cell biology, secretome, 030104 developmental biology, 030220 oncology & carcinogenesis, [PHYS.PHYS.PHYS-MED-PH]Physics [physics]/Physics [physics]/Medical Physics [physics.med-ph], Oxidative stress
Abstract

Besides the direct effects of radiations, indirect effects are observed within the surrounding non-irradiated area, irradiated cells relay stress signals in this close proximity, inducing the so-called radiation-induced bystander effect. These signals received by neighboring unirradiated cells induce specific responses similar with those of direct irradiated cells. To understand the cellular response of bystander cells, we performed a 2D gel-based proteomic study of the chondrocytes receiving the conditioned medium of low-dose irradiated chondrosarcoma cells. The conditioned medium was directly analyzed by mass spectrometry in order to identify candidate bystander factors involved in the signal transmission. The proteomic analysis of the bystander chondrocytes highlighted 20 proteins spots that were significantly modified at low dose, implicating several cellular mechanisms, such as oxidative stress responses, cellular motility, and exosomes pathways. In addition, the secretomic analysis revealed that the abundance of 40 proteins in the conditioned medium of 0.1 Gy irradiated chondrosarcoma cells was significantly modified, as compared with the conditioned medium of non-irradiated cells. A large cluster of proteins involved in stress granules and several proteins involved in the cellular response to DNA damage stimuli were increased in the 0.1 Gy condition. Several of these candidates and cellular mechanisms were confirmed by functional analysis, such as 8-oxodG quantification, western blot, and wound-healing migration tests. Taken together, these results shed new lights on the complexity of the radiation-induced bystander effects and the large variety of the cellular and molecular mechanisms involved, including the identification of a new potential actor, namely the stress granules.

Published
2021
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20. A multimodal treatment of carbon ions irradiation, miRNA-34 and mTOR inhibitor specifically control high-grade chondrosarcoma cancer stem cells

Author

Guillaume Vares, Shigeaki Sunada, Yannick Saintigny, Eun Ho Kim, Tetsuo Nakajima, Tadashi Yamamoto, Vidhula Ahire, Sei Sai, Paul-Henri Romeo, François Chevalier, National Institute of Radiobiological Sciences, Accueil et Recherche en Radiobiologie des Ions Accélérés (ARIA), Centre de recherche sur les Ions, les MAtériaux et la Photonique (CIMAP - UMR 6252), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Recherche sur la Réparation et la Transcription dans les Cellules Souches (LRTS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche sur les Matériaux Avancés (IRMA), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)

Subjects
mTOR inhibitor, [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Population, Chondrosarcoma, Particle therapy, Bone Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 030218 nuclear medicine & medical imaging, Kruppel-Like Factor 4, 03 medical and health sciences, 0302 clinical medicine, Cancer stem cell, Cell Line, Tumor, Radioresistance, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], microRNA, medicine, Humans, Radiology, Nuclear Medicine and imaging, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, education, PI3K/AKT/mTOR pathway, Ions, education.field_of_study, miR-34, business.industry, TOR Serine-Threonine Kinases, Hematology, medicine.disease, Combined Modality Therapy, Carbon, 3. Good health, MicroRNAs, Oncology, KLF4, 030220 oncology & carcinogenesis, Neoplastic Stem Cells, Cancer research, FOXO3, Neoplasm Recurrence, Local, business
Abstract

International audience; AbstractBackground and purposeHigh-grade chondrosarcomas are chemo- and radio-resistant cartilage-forming tumors of bone that often relapse and metastase. Thus, new therapeutic strategies are urgently needed.Material and methodsChondrosarcoma cells (CH-2879) were exposed to carbon-ion irradiation, combined with miR-34 mimic and/or rapamycin administration. The effects of treatment on cancer stem cells, stemness-associated phenotype, radioresistance and tumor-initiating properties were evaluated.ResultsWe show that high-grade chondrosarcoma cells contain a population of radioresistant cancer stem cells that can be targeted by a combination of carbon-ion therapy, miR-34 mimic administration and/or rapamycin treatment that triggers FOXO3 and miR-34 over-expression. mTOR inhibition by rapamycin triggered FOXO3 and miR-34, leading to KLF4 repression.ConclusionOur results show that particle therapy combined with molecular treatments effectively controls cancer stem cells and may overcome treatment resistance of high-grade chondrosarcoma.

Published
2020
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21. Hadrontherapy Interactions in Molecular and Cellular Biology

Author

Elodie A. Pérès, Siamak Haghdoost, Sebastien Thureau, Jean-Louis Habrand, Aurélie Ferré, Michael Gérard, Carine Laurent, Sven Skog, Juliette Thariat, François Chevalier, Paul Lesueur, Jacques Balosso, Myriam Bernaudin, Mihaela Tudor, Yannick Saintigny, Samuel Valable, Mathieu Césaire, Edwige Petit, François Sichel, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), ARCHADE (Advanced Resource Centre for HADrontherapy in Europe), Laboratoire de physique corpusculaire de Caen (LPCC), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Aliments Bioprocédés Toxicologie Environnements (ABTE), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Laboratoire d'Accueil et de Recherche avec les Ions Accélérés (LARIA), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de recherche sur les Ions, les MAtériaux et la Photonique (CIMAP - UMR 6252), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche sur les Matériaux Avancés (IRMA), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Sino-Swed Molecular Bio-Medicine Research Institute (SSTK), Horia Hulubei National Institute of Physics and Nuclear Engineering (NIPNE), IFIN-HH, University of Bucharest (UniBuc), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3), and Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Carbon therapy, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Review, [PHYS.NEXP]Physics [physics]/Nuclear Experiment [nucl-ex], Catalysis, Inorganic Chemistry, lcsh:Chemistry, 03 medical and health sciences, 0302 clinical medicine, Radioresistance, Neoplasms, hadrontherapy, medicine, Proton Therapy, Humans, cancer, Radiosensitivity, Physical and Theoretical Chemistry, Molecular Biology, Proton therapy, lcsh:QH301-705.5, Spectroscopy, 030304 developmental biology, 0303 health sciences, Particle therapy, Radiotherapy, business.industry, hypoxia, Organic Chemistry, Cancer, General Medicine, medicine.disease, 3. Good health, Computer Science Applications, Radiation therapy, radioresistance, lcsh:Biology (General), lcsh:QD1-999, particle therapy, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, [PHYS.PHYS.PHYS-MED-PH]Physics [physics]/Physics [physics]/Medical Physics [physics.med-ph], business
Abstract

CERVOXY COLL; International audience; The resistance of cancer cells to radiotherapy is a major issue in the curative treatment of cancer patients. This resistance can be intrinsic or acquired after irradiation and has various definitions, depending on the endpoint that is chosen in assessing the response to radiation. This phenomenon might be strengthened by the radiosensitivity of surrounding healthy tissues. Sensitive organs near the tumor that is to be treated can be affected by direct irradiation or experience nontargeted reactions, leading to early or late effects that disrupt the quality of life of patients. For several decades, new modalities of irradiation that involve accelerated particles have been available, such as proton therapy and carbon therapy, raising the possibility of specifically targeting the tumor volume. The goal of this review is to examine the up-to-date radiobiological and clinical aspects of hadrontherapy, a discipline that is maturing, with promising applications. We first describe the physical and biological advantages of particles and their application in cancer treatment. The contribution of the microenvironment and surrounding healthy tissues to tumor radioresistance is then discussed, in relation to imaging and accurate visualization of potentially resistant hypoxic areas using dedicated markers, to identify patients and tumors that could benefit from hadrontherapy over conventional irradiation. Finally, we consider combined treatment strategies to improve the particle therapy of radioresistant cancers.

Published
2019
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22. A multimodal treatment of carbon ions irradiation, miRNA-34 and mTOR inhibitor specifically control high-grade chondrosarcoma cancer stem cells

Author

Guillaume, Vares, Vidhula, Ahire, Shigeaki, Sunada, Eun, Ho Kim, Sei, Sai, François, Chevalier, Paul-Henri, Romeo, Tadashi, Yamamoto, Tetsuo, Nakajima, Yannick, Saintigny, Guillaume, Vares, Vidhula, Ahire, Shigeaki, Sunada, Eun, Ho Kim, Sei, Sai, François, Chevalier, Paul-Henri, Romeo, Tadashi, Yamamoto, Tetsuo, Nakajima, and Yannick, Saintigny

Abstract

Background and purposeHigh-grade chondrosarcomas are chemo- and radio-resistant cartilage-forming tumors of bone that often relapse and metastase. Thus, new therapeutic strategies are urgently needed.Material and methodsChondrosarcoma cells (CH-2879) were exposed to carbon-ion irradiation, combined with miR-34 mimic and/or rapamycin administration. The effects of treatment on cancer stem cells, stemness-associated phenotype, radioresistance and tumor-initiating properties were evaluated.ResultsWe show that high-grade chondrosarcoma cells contain a population of radioresistant cancer stem cells that can be targeted by a combination of carbon-ion therapy, miR-34 mimic administration and/or rapamycin treatment that triggers FOXO3 and miR-34 over-expression. mTOR inhibition by rapamycin triggered FOXO3 and miR-34, leading to KLF4 repression.ConclusionOur results show that particle therapy combined with molecular treatments effectively controls cancer stem cells and may overcome treatment resistance of high-grade chondrosarcoma., source:https://doi.org/10.1016/j.radonc.2020.07.034

Published
2020

23. Bystander effectors of chondrosarcoma cells irradiated at different LET impair proliferation of chondrocytes

Author

Yannick Saintigny, Mihaela Temelie, Guillaume Vares, François Chevalier, Marion Boulanger, Diana Savu, Christophe Hirtz, Emilie Brotin, Charlotte Lepleux, Tetsuo Nakajima, Aurélie Marie-Brasset, Mary B. Goldring, Laboratoire d'Accueil et de Recherche avec les Ions Accélérés (LARIA), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de recherche sur les Ions, les MAtériaux et la Photonique (CIMAP - UMR 6252), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Horia Hulubei National Institute of Physics and Nuclear Engineering (NIPNE), IFIN-HH, ImpedanCELL, Interactions Cellules Organismes Environnement (ICORE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Axe BioTICLA, Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Caen Normandie (UNICAEN), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Weill Medical College of Cornell University [New York], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Okinawa Institute of Science and Technology Graduate University (OIST), Chiba University, This work was also supported by 'Agence Nationale de la Recherche', in the frame of the 'Investments for the Future' under the references France HADRON (ANR-11-INBS-0007) and Equipex Rec-Hadron (ANR-10-EQPX-1401), French Institute of Romania, French Ministry of Foreign Affairs – Partenariat Hubert Curien Sakura (35973SB)., ANR-10-EQPX-0014,REC-HADRON,RECherche fondamentale en HADRONthérapie(2010), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche sur les Matériaux Avancés (IRMA), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Bodescot, Myriam, and Equipements d'excellence - RECherche fondamentale en HADRONthérapie - - REC-HADRON2010 - ANR-10-EQPX-0014 - EQPX - VALID

Subjects
0301 basic medicine, Cell type, Chondrosarcoma, Linear energy transfer, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, Biochemistry, Chondrocyte, [SDV.IB.MN] Life Sciences [q-bio]/Bioengineering/Nuclear medicine, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Bystander effect, Clonogenic assay, Molecular Biology, Effector, Chemistry, Low-dose irradiation, Cell Biology, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Micronucleus test, Radiation-induced bystander effect, Cancer research, Research Article, High-LET
Abstract

While the dose-response relationship of radiation-induced bystander effect (RIBE) is controversial at low and high linear energy transfer (LET), mechanisms and effectors of cell-to-cell communication stay unclear and highly dependent of cell type. In the present study, we investigated the capacity of chondrocytes in responding to bystander factors released by chondrosarcoma cells irradiated at different doses (0.05 to 8 Gy) with X-rays and C-ions. Following a medium transfer protocol, cell survival, proliferation and DNA damages were quantified in bystander chondrocytes. The bystander factors secreted by chondrosarcoma cells were characterized. A significant and major RIBE response was observed in chondrocyte cells (T/C-28a2) receiving conditioned medium from chondrosarcoma cells (SW1353) irradiated with 0.1 Gy of X-rays and 0.05 Gy of C-ions, resulting in cell survivals of 36% and 62%, respectively. Micronuclei induction in bystander cells was observed from the same low doses. The cell survival results obtained by clonogenic assays were confirmed using impedancemetry. The bystander activity was vanished after a heat treatment or a dilution of the conditioned media. The cytokines which are well known as bystander factors, TNF-α and IL-6, were increased as a function of doses and LET according to an ELISA multiplex analysis. Together, the results demonstrate that irradiated chondrosarcoma cells can communicate stress factors to non-irradiated chondrocytes, inducing a wide and specific bystander response related to both doses and LET. Electronic supplementary material The online version of this article (10.1007/s12079-019-00515-9) contains supplementary material, which is available to authorized users.

Published
2019
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24. QCM d'entrée dans la fonction publique

Author

Michel Philbert, Thierry Marquetty, François Chevalier, and Anne Ducastel

Abstract

Un ouvrage d'entrainement ultra riche en QCM pour faire le point avant de passer les concours de la Fonction publique 730 QCM pour faire le point sur ses acquis dans les 4 disciplines que l'on rencontre aux epreuves des concours de categories A, B et C de la fonction publique. Connaissances generales Aptitude verbale Aptitude logique Aptitude numerique L'ouvrage ideal pour s’entrainer et reviser !

Published
2018
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25. Radiosensitization Effect of Talazoparib, a Parp Inhibitor, on Glioblastoma Stem Cells Exposed to Low and High Linear Energy Transfer Radiation

Author

Yannick Saintigny, François Chevalier, Etienne Muller, Paul Lesueur, Laurent Castera, Elias A. El-Habr, Hervé Chneiweiss, Marie-Pierre Junier, Dinu Stefan, Laboratoire d'Accueil et de Recherche avec les Ions Accélérés (LARIA), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de recherche sur les Ions, les MAtériaux et la Photonique (CIMAP - UMR 6252), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Plasticité gliale et neuro-oncologie = Glial Plasticity (NPS-04), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-10-EQPX-0014,REC-HADRON,RECherche fondamentale en HADRONthérapie(2010), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche sur les Matériaux Avancés (IRMA), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), HAL UPMC, Gestionnaire, Equipements d'excellence - RECherche fondamentale en HADRONthérapie - - REC-HADRON2010 - ANR-10-EQPX-0014 - EQPX - VALID, Centre Régional de Lutte contre le Cancer François Baclesse (CRLC François Baclesse ), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), and ANR-10-EQPX-0014/10-EQPX-0014,REC-HADRON,RECherche fondamentale en HADRONthérapie(2010)

Subjects
0301 basic medicine, Radiation-Sensitizing Agents, Cell cycle checkpoint, DNA repair, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, lcsh:Medicine, [SDV.CAN]Life Sciences [q-bio]/Cancer, Poly(ADP-ribose) Polymerase Inhibitors, Article, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cancer stem cell, Cell Line, Tumor, Radioresistance, medicine, Humans, Linear Energy Transfer, lcsh:Science, Cell Proliferation, Multidisciplinary, Temozolomide, Cell growth, Chemistry, lcsh:R, Cell Cycle, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, 3. Good health, 030104 developmental biology, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, 030220 oncology & carcinogenesis, PARP inhibitor, Neoplastic Stem Cells, Cancer research, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Phthalazines, lcsh:Q, Stem cell, Glioblastoma, Signal Transduction, medicine.drug
Abstract

Despite continuous improvements in treatment of glioblastoma, tumor recurrence and therapy resistance still occur in a high proportion of patients. One underlying reason for this radioresistance might be the presence of glioblastoma cancer stem cells (GSCs), which feature high DNA repair capability. PARP protein plays an important cellular role by detecting the presence of damaged DNA and then activating signaling pathways that promote appropriate cellular responses. Thus, PARP inhibitors (PARPi) have recently emerged as potential radiosensitizing agents. In this study, we investigated the preclinical efficacy of talazoparib, a new PARPi, in association with low and high linear energy transfer (LET) irradiation in two GSC cell lines. Reduction of GSC fraction, impact on cell proliferation, and cell cycle arrest were evaluated for each condition. All combinations were compared with a reference schedule: photonic irradiation combined with temozolomide. The use of PARPi combined with photon beam and even more carbon beam irradiation drastically reduced the GSC frequency of GBM cell lines in vitro. Furthermore, talazoparib combined with irradiation induced a marked and prolonged G2/M block, and decreased proliferation. These results show that talazoparib is a new candidate that effects radiosensitization in radioresistant GSCs, and its combination with high LET irradiation, is promising.

Published
2018
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26. Poly-(ADP-ribose)-polymerase inhibitors as radiosensitizers: a systematic review of pre-clinical and clinical human studies

Author

Georges Noël, Yannick Saintigny, Jean-Louis Habrand, Waisse Waissi, Paul Lesueur, Florence Joly, Hélène Burckel, Jean-Baptiste Austry, François Chevalier, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Laboratoire d'Accueil et de Recherche avec les Ions Accélérés (LARIA), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Progression tumorale et microenvironnement. Approches translationnelles et épidémiologie, Université de Strasbourg (UNISTRA)-CHU Strasbourg-Les Hôpitaux Universitaires de Strasbourg (HUS)-Institut Régional du Cancer-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC), Service d'Oncologie médicale [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Institut Régional du Cancer-Université de Strasbourg (UNISTRA)-CHU Strasbourg-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC), Centre Régional de Lutte contre le Cancer François Baclesse (CRLC François Baclesse ), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Paul Strauss, CRLCC Paul Strauss, University of Washington [Seattle], Cancers et préventions, Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Chevalier, Francois

Subjects
0301 basic medicine, DNA repair, Poly ADP ribose polymerase, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, Synthetic lethality, Poly (ADP-Ribose) Polymerase Inhibitor, poly(ADP-ribose)-polymerase inhibitors, Chromatin remodeling, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Medicine, ComputingMilieux_MISCELLANEOUS, radiotherapy, business.industry, BRCA mutation, Cancer, medicine.disease, 3. Good health, 030104 developmental biology, Oncology, radiobiology, 030220 oncology & carcinogenesis, PARP inhibitor, Cancer research, radiosensitization, business
Abstract

International audience; Background: Poly-(ADP-Ribose)-Polymerase (PARP) inhibitors are becoming important actors of anti-neoplasic agents landscape, with recent but narrow FDA's approvals for ovarian BRCA mutated cancers and prostatic cancer. Nevertheless, PARP inhibitors are also promising drugs for combined treatments particularly with radiotherapy. More than seven PARP inhibitors have been currently developed. Central Role of PARP in DNA repair, makes consider PARP inhibitor as potential radiosensitizers, especially for tumors with DNA repair defects, such as BRCA mutation, because of synthetic lethality. Furthermore the replication-dependent activity of PARP inhibitor helps to maintain the differential effect between tumoral and healthy tissues. Inhibition of chromatin remodeling, G2/M arrest, vasodilatory effect induced by PARP inhibitor, also participate to their radio-sensitization effect. Materials and Methods: Here, after highlighting mechanisms of PARP inhibitors radiosensitization we methodically searched PubMed, Google Scholar, Cochrane Databases and meeting proceedings for human pre-clinical and clinical studies that evaluated PARP inhibitor radiosensitizing effect. Enhancement ratio, when available, was systematically reported. Results: Sixty four studies finally met our selection criteria and were included in the analysis. Only three pre-clinical studies didn't find any radiosensitizing effect. Median enhancement ratio vary from 1,3 for prostate tumors to 1,5 for lung cancers. Nine phase I or II trials assessed safety data. Conclusion: PARP inhibitors are promising radiosensitizers, but need more clinical investigation. The next ten years will be determining for judging their real potential.

Published
2017
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27. Counteracting Radio-Resistance Using the Optimization of Radiotherapy

Author

François Chevalier, Laboratoire d'Accueil et de Recherche avec les Ions Accélérés (LARIA), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de recherche sur les Ions, les MAtériaux et la Photonique (CIMAP - UMR 6252), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche sur les Matériaux Avancés (IRMA), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), and Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, medicine.medical_treatment, Radio resistance, Cancer therapy, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, Radiation Tolerance, Catalysis, lcsh:Chemistry, Inorganic Chemistry, 03 medical and health sciences, 0302 clinical medicine, Radiation tolerance, Neoplasms, Internal medicine, Component (UML), medicine, Humans, Effective treatment, Physical and Theoretical Chemistry, lcsh:QH301-705.5, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Spectroscopy, Radiotherapy, business.industry, Organic Chemistry, General Medicine, 3. Good health, Computer Science Applications, Radiation therapy, n/a, Editorial, 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, 030220 oncology & carcinogenesis, business
Abstract

Radiotherapy is an essential component of cancer therapy and remains one of the most (cost-) effective treatment options available [...]

Published
2020
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29. Review of the Mechanisms Involved in the Abscopal Effect and Future Directions with a Focus on Thymic Carcinoma

Author

Jean-Louis Habrand, Paul Lesueur, François Chevalier, Radj Gervais, Dinu Stefan, Delphine Lerouge, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Laboratoire d'Accueil et de Recherche avec les Ions Accélérés (LARIA), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)

Subjects
0301 basic medicine, Oncology, Male, Cancer Research, medicine.medical_specialty, Pathology, Thymoma, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, Radiosurgery, Stereotactic radiotherapy, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Tumor regression, Humans, Neoplasm Metastasis, Thymic carcinoma, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, business.industry, Abscopal effect, General Medicine, Bystander Effect, medicine.disease, 3. Good health, Carcinoma, Neuroendocrine, Radiation therapy, 030104 developmental biology, 030220 oncology & carcinogenesis, Immunotherapy, business
Abstract

The abscopal effect is a rare phenomenon in radiotherapy, leading to impressive tumor regression outside the radiotherapy field. In this article we describe the occurrence of a postradiotherapy abscopal effect in an 89-year-old patient suffering from a metastatic neuroendocrine large-cell thymic carcinoma, the first case of the abscopal effect related to a thymic carcinoma reported in the literature. Along with the description of this case, we discuss and review the main potential mechanisms of bystander and abscopal effects in solid tumors so as to enable clinicians to identify and control these effects more resourcefully in the age of immunotherapy and stereotactic radiotherapy.

Published
2017
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30. Translational research in radiobiology in the framework of France HADRON national collaboration

Author

Agnès François, Michael Beuve, Frédérique Mégnin-Chanet, Yolanda Prezado, Carine Laurent, Olivier Guipaud, Frederic Pouzoulet, François Chevalier, Claire Rodriguez-Lafrasse, Jacques Balosso, Myriam Bernaudin, Yannick Saintigny, Rayet, Béatrice, Institut de Physique Nucléaire de Lyon (IPNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Ciblage thérapeutique en Oncologie (EA3738), Université de Lyon-Université de Lyon, Laboratoire d'Accueil et de Recherche avec les Ions Accélérés (LARIA), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), SAPHYN (SAnté et PHYsique Nucléaire), Aliments Bioprocédés Toxicologie Environnements (ABTE), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Institut Curie [Paris], Imagerie et Modélisation en Neurobiologie et Cancérologie (IMNC (UMR_8165)), Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Chimie, Modélisation et Imagerie pour la Biologie [Orsay], Université Paris-Sud - Paris 11 (UP11)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Département de cancérologie et radiothérapie, CHU Grenoble, Departement de Recherche Translationelle, Curie Institute, Université Paris-Sud - Paris 11 (UP11)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Radiobiology, medicine.medical_treatment, Cellular differentiation, Translational research, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, Bioinformatics, [SDV.IB.MN] Life Sciences [q-bio]/Bioengineering/Nuclear medicine, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Radioresistance, Internal medicine, Hadrontherapy, medicine, Radiology, Nuclear Medicine and imaging, modelization, [PHYS.PHYS.PHYS-MED-PH] Physics [physics]/Physics [physics]/Medical Physics [physics.med-ph], protons, business.industry, medicine.disease, Head and neck squamous-cell carcinoma, [INFO.INFO-MO]Computer Science [cs]/Modeling and Simulation, 3. Good health, Radiation therapy, Clinical trial, carbon ions, 030104 developmental biology, radiobiology, [PHYS.PHYS.PHYS-MED-PH]Physics [physics]/Physics [physics]/Medical Physics [physics.med-ph], [INFO.INFO-MO] Computer Science [cs]/Modeling and Simulation, Stem cell, business
Abstract

CERVOXY COLL; International audience; France HADRON is a French national collaboration that brings together 26 teams in nine different French cities (Lyon, Caen, Clermont-Ferrand, Paris-Orsay, Nice, Toulouse, Marseille, Strasbourg and Grenoble). This infrastructure was created in 2013 and follows the ETOILE and ARCHADE projects; it is presently funded by public money. Ten teams, from different scientific background, using a wide range of approaches, participate in radiobiology researches upon protons and carbon ion therapy in comparison with photons used in classical radiation oncology. These approaches combine the use of multiple biological models of radioresistant tumors and healthy tissue critical for treatment tolerance. Thus, the determinants of the radioresistance of head and neck squamous cell carcinoma (HNSSC), high-grade gliomas, sarcomas including chondrosarcomas and the ubiquitous endothelial cells and fibroblasts are studied. Multiple methodological approaches are implemented. In particular, these include: the extraction of tumor stem cell populations and their radiobiological comparison with the differentiated tumor cells; the studies in hypoxic and normoxic conditions; the development and the use of models of 3D cell cultures that highlight important differences in cell behaviors; the cell biology with the analysis of typical neoplastic mechanisms such as invasive and cell migration processes, as well as late recovery of irradiated tumor cells that reenter proliferation; the molecular biochemistry with analysis of resistance signaling pathways, telomerase regulation and genomic analysis of predictors of radioresistance in retrospective and prospective series of patients (gliomas, HNSSC, sarcomas) and finally the oxidative stress, genotoxicity and inflammatory measurements in normal human cells at early and late times after irradiation. This work allows a better understanding of the mechanisms of cellular and tumor radioresistance, normal tissue toxicity, but they also enable pre-clinical and clinical approaches. Thus, experimental approaches of combinations of pharmacological treatments acting on the identified resistance or toxicity mechanisms with the different types of radiation studied are developed. The comparison between stem cells and differentiated cells is very interesting in this respect. This information, combined with phenomenological data on survival and relative biological effectiveness (RBE), contributes to the adjustment and parameterization of bio-mathematical predictive models of the cellular response such as the Nanox ® model. This work enables, on the one hand, to suggest hypotheses of clinical trials aimed at acting on tumor radioresistance; and, on the other hand, to integrate into studies associated with prospective transnational clinical research protocols, comparing carbontherapy vs. photon or proton radiotherapy, in collaboration with the European carbontherapy centers, in particular the Heidelberg Ion Therapy (HIT) in Germany and Centro Nazionale di Adroterapia Oncologica (CNAO) in Italy. The potential of France HADRON in radiobiology is important and can make a useful contribution to this field of research, in particular by pursuing a convergence approach of the methods, the models and the topics investigated

Published
2017
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31. A threshold of endogenous stress is required to engage cellular response to protect against mutagenesis

Author

David Laurent, Elodie Dardillac, François Chevalier, Jordane Depagne, Anne Bravard, Bernard S. Lopez, Yannick Saintigny, J. Pablo Radicella, Sonia Hem, Institute of Cellular and Molecular Radiobiology, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Université Paris-Saclay, Institut Gustave Roussy (IGR), Centre National de la Recherche Scientifique (CNRS), Stabilité Génétique et Oncogenèse (UMR 8200), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Biochimie et Physiologie Moléculaire des Plantes (BPMP), Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Plateforme de Spectrométrie de Masse Protéomique - Mass Spectrometry Proteomics Platform (MSPP), Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Saintigny, Yannick, Stabilité génétique, Cellules Souches et Radiations (SCSR (U_967)), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), ANR14-CE10-0010-02, Université de Montpellier (UM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Cellules Souches et Radiations (SCSR (U967 / UMR-E_008)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris-Sud - Paris 11 (UP11), ProdInra, Archive Ouverte, Lopez, Bernard S, and Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)

Subjects
0301 basic medicine, Genome instability, Proteomics, irradiation aux rayons gamma, DNA repair, DNA damage, Cellular detoxification, mammalian-cells, Endogeny, cellule mammaire, CHO Cells, Biology, tumor cell, medicine.disease_cause, Article, Genomic Instability, 03 medical and health sciences, Cricetulus, gamma-irradiation, medicine, dna-bas damage, [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, Animals, [SDV.BV] Life Sciences [q-bio]/Vegetal Biology, tumorigénèse, protéomique, cellule cancereuse, Genetics, Mutation, Vegetal Biology, Multidisciplinary, 030102 biochemistry & molecular biology, tumorigenesis, proteomics, Mutagenesis, Base excision repair, Cell biology, [SDV.TOX] Life Sciences [q-bio]/Toxicology, Oxidative Stress, 030104 developmental biology, [SDV.TOX]Life Sciences [q-bio]/Toxicology, activation, Biologie végétale, DNA Damage, Thymidine
Abstract

Endogenous stress represents a major source of genome instability, but is in essence difficult to apprehend. Incorporation of labeled radionuclides into DNA constitutes a tractable model to analyze cellular responses to endogenous attacks. Here we show that incorporation of [3H]thymidine into CHO cells generates oxidative-induced mutagenesis, but, with a peak at low doses. Proteomic analysis showed that the cellular response differs between low and high levels of endogenous stress. In particular, these results confirmed the involvement of proteins implicated in redox homeostasis and DNA damage signaling pathways. Induced-mutagenesis was abolished by the anti-oxidant N-acetyl cysteine and plateaued, at high doses, upon exposure to L-buthionine sulfoximine, which represses cellular detoxification. The [3H]thymidine-induced mutation spectrum revealed mostly base substitutions, exhibiting a signature specific for low doses (GC > CG and AT > CG). Consistently, the enzymatic activity of the base excision repair protein APE-1 is induced at only medium or high doses. Collectively, the data reveal that a threshold of endogenous stress must be reached to trigger cellular detoxification and DNA repair programs; below this threshold, the consequences of endogenous stress escape cellular surveillance, leading to high levels of mutagenesis. Therefore, low doses of endogenous local stress can jeopardize genome integrity more efficiently than higher doses.

Published
2016
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32. Comparable Senescence Induction in Three-dimensional Human Cartilage Model by Exposure to Therapeutic Doses of X-rays or C-ions

Author

Carl Mann, François Chevalier, Jean-Yves Thuret, Florent Durantel, Dounia Houria Hamdi, Yannick Saintigny, J.-E. Groetz, Laboratoire d'Accueil et de Recherche avec les Ions Accélérés (LARIA), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire Chrono-environnement (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre de recherche sur les Ions, les MAtériaux et la Photonique (CIMAP - UMR 6252), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche sur les Matériaux Avancés (IRMA), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Génétique moléculaire et destin cellulaire (FRE 3377), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Sénescence et stabilité génomique (SEN), Département Biologie des Génomes (DBG), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), and Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11)

Subjects
0301 basic medicine, Senescence, Pathology, medicine.medical_specialty, Cancer Research, Cell Survival, medicine.medical_treatment, Cell Culture Techniques, Chondrosarcoma, Linear energy transfer, Bone Neoplasms, Heavy Ion Radiotherapy, [SDV.CAN]Life Sciences [q-bio]/Cancer, Ion, 03 medical and health sciences, 0302 clinical medicine, Chondrocytes, Relative biological effectiveness, Medicine, Humans, Radiology, Nuclear Medicine and imaging, Linear Energy Transfer, Irradiation, Radiation Injuries, Cells, Cultured, Cellular Senescence, Particle therapy, Radiation, Cell Death, business.industry, Cartilage, X-Rays, Carbon, 3. Good health, Radiation therapy, 030104 developmental biology, medicine.anatomical_structure, Oncology, Radiology Nuclear Medicine and imaging, 030220 oncology & carcinogenesis, Biophysics, [PHYS.PHYS.PHYS-MED-PH]Physics [physics]/Physics [physics]/Medical Physics [physics.med-ph], business, Relative Biological Effectiveness
Abstract

PurposeParticle therapy using carbon ions (C-ions) has been successfully used in the treatment of tumors resistant to conventional radiation therapy. However, the potential side effects to healthy cartilage exposed to lower linear energy transfer (LET) ions in the beam track before the tumor have not been evaluated. The aim of the present study was to assess the extent of damage after C-ion irradiation in a 3-dimensional (3D) cartilage model close to human homeostasis.Methods and MaterialsPrimary human articular chondrocytes from a healthy donor were cultured in a collagen scaffold to construct a physioxic 3D cartilage model. A 2-dimensional (2D) culture was used as a reference. The cells were irradiated with a single dose of a monoenergetic C-ion beam with a LET of approximatively 30 keV/μm. This LET corresponds to the entrance channel of C-ions in the shallow healthy tissues before the spread-out Bragg peak (∼100 keV/μm) during hadron therapy protocols. The same dose of X-rays was used as a reference. Survival, cell death, and senescence assays were performed.ResultsAs expected, in the 2D culture, C-ions were more efficient than X-rays in reducing cell survival with a relative biological effectiveness of 2.6. This correlated with stronger radiation-induced senescence (two-fold) but not with higher cell death induction. This differential effect was not reflected in the 3D culture. Both ionizing radiation types induced a comparable rate of senescence induction in the 3D model.ConclusionsThe greater biological effectiveness of C-ions compared with low LET radiation when evaluated in treatment planning systems might be misevaluated using 2D culture experiments. Radiation-induced senescence is an important factor of potential cartilage attrition. The present data should encourage the scientific community to use relevant models and beams to improve the use of charged particles with better safety for patients.

Published
2016
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33. Dosimetry for radiobiology experiments at GANIL

Author

F. Ropars, Amine Cassimi, François Chevalier, Yannick Saintigny, Jean-Christophe Poully, Toiammou Madi, Jean-Marc Ramillon, Florent Durantel, Emmanuel Balanzat, Hermann Rothard, Lucas Schwob, Isabelle Testard, Y. Ngono-Ravache, Centre de recherche sur les Ions, les MAtériaux et la Photonique (CIMAP - UMR 6252), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche sur les Matériaux Avancés (IRMA), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Accueil et de Recherche avec les Ions Accélérés (LARIA), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
0301 basic medicine, X-ray detector, Nuclear and High Energy Physics, medicine.medical_specialty, Radiobiology, Nuclear engineering, Fluence, [SPI.MAT]Engineering Sciences [physics]/Materials, 03 medical and health sciences, 0302 clinical medicine, medicine, Dosimetry, Medical physics, Irradiation, [PHYS.PHYS.PHYS-INS-DET]Physics [physics]/Physics [physics]/Instrumentation and Detectors [physics.ins-det], Instrumentation, Physics, Detector, High energy heavy ions, Carbon hadrontherapy, 3. Good health, CR39, 030104 developmental biology, Beamline, 030220 oncology & carcinogenesis, [PHYS.PHYS.PHYS-MED-PH]Physics [physics]/Physics [physics]/Medical Physics [physics.med-ph], Beam (structure)
Abstract

International audience; Mainly encouraged by the increasing application of ion beams for cancer treatment (hadron-therapy) including carbon beams, the use of heavy ion facilities for radiobiology is expanding rapidly today. As an alternative to dedicated centers for treatment and medical research, accelerators like GANIL offer the possibility to undertake such experiments. Since 20 years, CIMAP, reinforced 15 years ago by the biological host laboratory LARIA, has been receiving researchers in radiobiology and assisted them in performing experiments in different fields such as hadron-therapy, space radioprotection and fundamental biological and physico-chemical mechanisms. We present here a short description of the beam line and the on-line equipments that allow the automatic irradiation of up to 24 biological samples at once. We also developed an original on-line beam monitoring procedure for low ion flux (low dose rates) based on the measurement of the K-shell X-rays emitted from a thin iron foil. This detector is calibrated on an absolute scale before each experiment by counting etched tracks on an irradiated CR39 polymer plate. We present the performances and limits of this method and finally give typical fluence (dose) uncertainties for a standard irradiation in radiobiology.

Published
2016
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34. Accumulation of cyclophilin A isoforms in conditioned medium of irradiated breast cancer cells

Author

Jordane Depagne, Jérôme Lebeau, Julie Bensimon, Sylvie Chevillard, François Chevalier, Sonia Hem, Pascale Bertrand, Plateforme de protéomique, Institut de radiobiologie cellulaire et moléculaire (iRCM), Laboratoire de Protéomique Fonctionnelle (LPF), Institut National de la Recherche Agronomique (INRA), Laboratoire de Cancérologie Expérimentale (LCE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire d'étude des Mécanismes de la recombinaison (LMR), Centre National de la Recherche Scientifique (CNRS), Unité de Recherche Protéomique (PROTEOMIQUE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institute of Cellular and Molecular Radiobiology (DSV, CEA), and Proteomic Platform of Montpellier-LR Genopole

Subjects
Proteomics, TUMOR-CELLS, Cell, Biochemistry, Breast cancer, 0302 clinical medicine, Tandem Mass Spectrometry, Radiation, Ionizing, Protein Isoforms, Receptor, Protein maturation, IN-VIVO, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, IMMUNOSUPPRESSION, Cell Death, Acetylation, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Female, Cyclophilin A, Signal Transduction, Gene isoform, Cell biology, Programmed cell death, PROTEINS, INSTABILITY, BIOMARKERS, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Methylation, Radiosensitivity, 03 medical and health sciences, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Humans, Secretion, Molecular Biology, 030304 developmental biology, IDENTIFICATION, Molecular biology, Culture Media, Conditioned, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Irradiation, SECRETOME, IONIZING-RADIATION, Protein Processing, Post-Translational
Abstract

International audience; Secreted proteins play a key role in cell signaling and communication. We recently showed that ionizing radiations induced a delayed cell death of breast cancer cells, mediated by the death receptor pathways through the expression of soluble forms of death ligands. Using the same cell model, the objective of our work was the identification of diffusible factors, secreted following cell irradiation, potentially involved in cell death signaling. Differential proteomic analysis of conditioned media using 2DE resulted in detection of numerous spots that were significantly modulated following cell irradiation. The corresponding proteins were identified using MALDI-TOF MS and LC-MS/MS approaches. Interestingly, five isoforms of cyclophilin A were observed as increased in conditioned medium of irradiated cells. These isoforms differed in isoelectric points and in accumulation levels. An increase of cyclophilin A secretion was confirmed by Western blotting of conditioned media of irradiated or radiosentive mammary cells. These isoforms displayed an interesting pattern of protein maturation and post-translational modifications, including an alternating removal of N-terminal methionine, associated with a combination of acetylations and methylations. The role of the protein is discussed in relation with its potential involvement in the mechanisms of intercells relationships and radiosensitivity.

Published
2012
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35. Proteomic analysis of Arabidopsis thaliana ecotypes with contrasted root architecture in response to phosphate deficiency

Author

Michel Rossignol, François Chevalier, Unité de Recherche Protéomique (PROTEOMIQUE), and Institut National de la Recherche Agronomique (INRA)

Subjects
Proteomics, 0106 biological sciences, Ecotypes, Proteome, Physiology, Arabidopsis, Malic enzyme, Plant Science, Plant Roots, 01 natural sciences, Aconitase, Phosphates, 03 medical and health sciences, Gene Expression Regulation, Plant, Stress, Physiological, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Arabidopsis thaliana, Electrophoresis, Gel, Two-Dimensional, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Aconitate Hydratase, Ecotype, 2. Zero hunger, Gel electrophoresis, Genetics, 0303 health sciences, biology, Arabidopsis Proteins, Phosphate deficiency, biology.organism_classification, Adaptation, Physiological, Oxidative Stress, [SDV.BV.AP]Life Sciences [q-bio]/Vegetal Biology/Plant breeding, Biochemistry, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Carbohydrate Metabolism, Agronomy and Crop Science, 010606 plant biology & botany
Abstract

International audience; Owing to a weak availability in soil, plants have developed numerous morphological, physiological and biochemical adaptations to acquire phosphate (Pi). Identification and characterisation of key genes involved in the initial steps of Pi-signalling might provide clues about the regulation of the complex Pi deficiency adaptation mechanism. A two-dimensional gel electrophoresis approach was performed to investigate proteome responses to Pi starvation in Arabidopsis. Two ecotypes were selected according to contrasting responses of their root system architecture to low availability of Pi. Thirty protein spots were shown to be affected by Pi deficiency. Fourteen proteins appeared to be up-regulated and ten down-regulated with ecotype Be-0, wheras only thirteen proteins were observed as down-regulated for ecotype Ll-0. Furthermore, systematic and opposite responses to Pi deficiency were observed between the two ecotypes. The sequences of these 30 differentially expressed protein spots were identified using mass spectrometry, and most of the proteins were involved in oxidative stress, carbohydrate and proteins metabolism. The results suggested that the modulation of alcohol dehydrogenase, malic enzyme and aconitate hydratase may contribute to the contrasted adaptation strategy to Pi deficiency of Be-0 and Ll-0 ecotypes. A focus on aconitate hydratase highlighted a complex reverse response of the pattern of corresponding spots between the two ecotypes. This protein, also potentially involved in iron homeostasis, was speculated to contribute, at least indirectly, to the root architecture response of these ecotypes. (C) 2011 Elsevier GmbH. All rights reserved.

Published
2011
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36. Bcl-2 Inhibits Nuclear Homologous Recombination by Localizing BRCA1 to the Endomembranes

Author

Catherine Le Chalony, Pascale Bertrand, Aurelia Barascu, Corentin Laulier, Gaëlle Palierne, Jean-Marc Verbavatz, Josée Guirouilh-Barbat, Bernard S. Lopez, François Chevalier, Gaëlle Pennarun, Radiobiologie moléculaire et cellulaire (RMC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut de Radiobiologie Cellulaire et Moléculaire (IRCM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Plateforme de protéomique, Institut de radiobiologie cellulaire et moléculaire (iRCM), Système membranaires, photobiologie, stress et détoxication (SMPSD), Institut de Biologie et de Technologies de Saclay (IBITECS), and Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
Cytoplasm, Cancer Research, Tumor suppressor gene, DNA repair, Genes, BRCA1, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Proximity ligation assay, Mitochondrion, Endoplasmic Reticulum, HeLa, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, Humans, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], skin and connective tissue diseases, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Recombination, Genetic, 0303 health sciences, Microscopy, Confocal, Models, Genetic, biology, Endoplasmic reticulum, Cell Membrane, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, biology.organism_classification, Mitochondria, Cell biology, Gene Expression Regulation, Neoplastic, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Microscopy, Fluorescence, Proto-Oncogene Proteins c-bcl-2, Oncology, 030220 oncology & carcinogenesis, Meganuclease, Cancer research, Homologous recombination, HeLa Cells, Subcellular Fractions
Abstract

Genetic stability requires coordination of a network of pathways including DNA repair/recombination and apoptosis. In addition to its canonical anti-apoptotic role, Bcl-2 negatively impacts genome stability. In this study, we identified the breast cancer tumor suppressor BRCA1, which plays an essential role in homologous recombination (HR), as a target for Bcl-2 in the repression of HR. Indeed, ionizing radiation–induced BRCA1 foci assembly was repressed when Bcl-2 was expressed ectopically, in human SV40 fibroblasts, or spontaneously, in lymphoma t(14:18) cells and in HeLa and H460 cancer cell lines. Moreover, we showed that the transmembrane (TM) domain of Bcl-2 was required for both inhibition of BRCA1 foci assembly and the inhibition of HR induced by a double-strand break targeted into an intrachromosomal HR substrate by the meganuclease I-SceI. Fluorescence confocal microscopy, proximity ligation assay, and electron microscopy analyses as well as Western blot analysis of subcellular fractions showed that Bcl-2 and BRCA1 colocalized to mitochondria and endoplasmic reticulum in a process requiring the TM domain of Bcl-2. Targeting BRCA1 to the endomembranes depletes BRCA1 from the nucleus and, thus, accounts for the inhibition of HR. Furthermore, our findings support an apoptosis-stimulatory role for the cytosolic form of BRCA1, suggesting a new tumor suppressor function of BRCA1. Together, our results reveal a new mode of BRCA1 regulation and for HR in the maintenance of genome stability. Cancer Res; 71(10); 3590–602. ©2011 AACR.

Published
2011
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37. Effect of high-pressure treatment on microbiology, proteolysis, lipolysis and levels of flavour compounds in mature blue-veined cheese

Author

Daniela D. Voigt, François Chevalier, Alan L. Kelly, Michael C. Qian, Department of Food and Nutritional Sciences, University College Cork (UCC), Plateforme de protéomique, Institut de radiobiologie cellulaire et moléculaire (iRCM), and Oregon State University (OSU)

Subjects
Aerobic bacteria, Blue cheese, Flavour, Cheese ripening, Industrial and Manufacturing Engineering, Microbiology, chemistry.chemical_compound, 0404 agricultural biotechnology, Cheese spread, food, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Cheesemaking, Food science, food.cheese, ComputingMilieux_MISCELLANEOUS, 2. Zero hunger, Chemistry, 0402 animal and dairy science, Ripening, 04 agricultural and veterinary sciences, General Chemistry, 040401 food science, 040201 dairy & animal science, Lactic acid, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Food Science
Abstract

The effect of high-pressure (HP) treatment (400 MPa, 600 MPa) on ripening of mature 42-day-old Irish blue-veined cheese was studied. Counts of non-starter lactic acid bacteria, lactococci, yeasts, moulds, enterococci and total aerobic bacteria significantly decreased due to HP, with moulds being most sensitive and 600 MPa the most effective treatment. The levels of pH 4.6-soluble nitrogen and (12%) trichloroacetic acid-soluble nitrogen increased immediately after both HP treatments; however, after 28 days of storage, values were lower in HP-treated cheeses than in the control cheese. Urea-polyacrylamide gel electrophoresis showed increased breakdown of β-casein due to HP treatment at both 400 MPa and 600 MPa. Levels of free fatty acids were lower in HP-treated cheese than in the control, but not significantly so, and no significant changes could be observed in the level of flavour compounds of blue-veined cheese. Overall, HP treatment of blue-veined cheese reduced microbiological activity and decelerated proteolysis, with no statistically significant effects on development of flavour compounds. Industrial relevance High-pressure treatment has been studied for the past 100 years; nevertheless, it was not applied in dairy industry, until recently, for a cheese spread. In this study, HP-induced inactivation of microbes and enzymes, which could arrest the ripening of high-quality mature (i.e., ripened) Irish farmhouse blue-veined cheese and thus extend shelf-life at optimal quality, was examined.

Published
2010
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38. MS characterization of multiple forms of alpha-amylase in human saliva

Author

Jean-Christophe Egea, Nicolas Sommerer, Dominique Deville de Périère, François Chevalier, Christophe Hirtz, Valérie Rofidal, Michel Rossignol, Delphine Centeno, Laboratoire de physiologie, UFR d'Odontologie, Université Montpellier 1, Université Montpellier 1 (UM1), Unité de Recherche Protéomique (PROTEOMIQUE), and Institut National de la Recherche Agronomique (INRA)

Subjects
Gene isoform, Saliva, Glycosylation, Molecular Sequence Data, Proteomics, 01 natural sciences, Biochemistry, Mass Spectrometry, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Humans, Electrophoresis, Gel, Two-Dimensional, Amino Acid Sequence, Amylase, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Gel electrophoresis, 0303 health sciences, biology, Spots, Chemistry, 010401 analytical chemistry, Peptide Fragments, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], 0104 chemical sciences, Isoenzymes, Electrophoresis, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, biology.protein, alpha-Amylases, Alpha-amylase, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

Alpha-amylase is a major and well-characterized component of human saliva. Recent proteomic studies suggested that this protein could be observed in more than twenty spots on 2-D gels of salivary proteins. The aim of this work was to investigate this unexpected redundancy. 2-D gel electrophoresis was combined with systematic MALDI-TOF MS analysis. More than 140 protein spots identifying the alpha-amylase were shown to constitute a stable but very complex pattern. Careful analysis of mass spectra and simultaneous hierarchical clustering of the observed peptides and of the electrophoretic features of spots allowed one to define three major groups. A main class grouping 90 spots was shown to correspond to full length alpha-amylases that can be assumed to include isoforms and post-translationally modified forms, a subset of this class being demonstrated to be N-glycosylated. A second group included short alpha-amylases that are differently truncated in a non-random manner, very likely in the oral cavity. The last class grouped alpha-amylase forms showing both the N- and C-terminal sequences of the enzyme but displaying a molecular weight that was up to 50% lower than that of the native protein. It is speculated that the last group of alpha-amylase spots could correspond to proteins submitted to internal deletions prior to the secretion.

Published
2005
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39. Le président du conseil d’arbitrage et l’arbitre unique dans le règlement des conflits de travail

Author

François Chevalier

Subjects
Organizational Behavior and Human Resource Management, Management of Technology and Innovation, Strategy and Management
Abstract

Dans cet article, l’auteur décrit les attitudes des présidents et des arbitres en essayant de les classifier selon les tendances qu'il qualifie de juridique, sociologique, médiationniste, compromissionniste.

Published
2005
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40. Effects of phosphate availability on the root system architecture: large-scale analysis of the natural variation between Arabidopsis accessions

Author

François Chevalier, Philippe Nacry, Patrick Doumas, Michel Rossignol, and Mickael O. Pata

Subjects
0106 biological sciences, Physiology, Range (biology), Plant Science, Root system, medicine.disease_cause, 01 natural sciences, 03 medical and health sciences, chemistry.chemical_compound, Nutrient, Arabidopsis, Botany, medicine, Arabidopsis thaliana, Genetic variability, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, biology, Environmental factor, 15. Life on land, biology.organism_classification, Phosphate, Horticulture, chemistry, 010606 plant biology & botany
Abstract

Developmental plasticity is one main adaptative response of plants to the availability of nutrients. In the present study, the naturally occurring variation existing in Arabidopsis for the growth responses to phosphate availability was investigated. Initially details of the effects of phosphate starvation for the four currently used accessions Cvi, Col, Ler and Ws were compared. A set of 10 growth parameters, concerning the aerial part and the root system, was measured in both single-point and time-course experiments. The length of the primary root and the number of laterals were found to be consistently reduced by phosphate starvation in all four accessions. These two robust parameters were selected to further screen a set of 73 accessions originating from a wide range of habitats. One-half of the accessions showed also a reduced primary root and less lateral roots when phosphate-starved, and 25% were not responsive to phosphate availability. For the last quarter of accessions, phosphate starvation was found to affect only one of the two growth parameters, indicating the occurrence of different adaptative strategies. These accessions appear to offer new tools to investigate the molecular basis of the corresponding growth responses to phosphate availability.

Published
2003
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41. Proteomic overview and perspectives of the radiation-induced bystander effects

Author

Jean-Louis Lefaix, Yannick Saintigny, Dounia Houria Hamdi, François Chevalier, Laboratoire d'Accueil et de Recherche avec les Ions Accélérés (LARIA), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
Proteomics, Cell type, Radiobiology, Health, Toxicology and Mutagenesis, medicine.medical_treatment, Context (language use), [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, In Vitro Techniques, Biology, 03 medical and health sciences, 0302 clinical medicine, Radiation, Ionizing, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Biomarkers, Tumor, Genetics, Bystander effect, medicine, Animals, Humans, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Bystander Effect, 3. Good health, Review article, Radiation therapy, Gene Expression Regulation, 030220 oncology & carcinogenesis, Immunology, Signal transduction, Neuroscience
Abstract

Radiation proteomics is a recent, promising and powerful tool to identify protein markers of direct and indirect consequences of ionizing radiation. The main challenges of modern radiobiology is to predict radio-sensitivity of patients and radio-resistance of tumor to be treated, but considerable evidences are now available regarding the significance of a bystander effect at low and high doses. This “radiation-induced bystander effect” (RIBE) is defined as the biological responses of non-irradiated cells that received signals from neighboring irradiated cells. Such intercellular signal is no more considered as a minor side-effect of radiotherapy in surrounding healthy tissue and its occurrence should be considered in adapting radiotherapy protocols, to limit the risk for radiation-induced secondary cancer. There is no consensus on a precise designation of RIBE, which involves a number of distinct signal-mediated effects within or outside the irradiated volume. Indeed, several cellular mechanisms were proposed, including the secretion of soluble factors by irradiated cells in the extracellular matrix, or the direct communication between irradiated and neighboring non-irradiated cells via gap junctions. This phenomenon is observed in a context of major local inflammation, linked with a global imbalance of oxidative metabolism which makes its analysis challenging using in vitro model systems. In this review article, the authors first define the radiation-induced bystander effect as a function of radiation type, in vitro analysis protocols, and cell type. In a second time, the authors present the current status of protein biomarkers and proteomic-based findings and discuss the capacities, limits and perspectives of such global approaches to explore these complex intercellular mechanisms.

Published
2015
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42. Determination of expression and activity of genes involved in starch metabolism in Lactobacillus plantarum A6 during fermentation of a cereal-based gruel

Author

François Chevalier, Christian Picq, Jean-Pierre Guyot, Isabelle Rochette, Williams Turpin, and Christèle Humblot

Subjects
Pennisetum, Starch, mRNA, Microbiology, Maltose phosphorylase, Pearl millet, chemistry.chemical_compound, Lactobacillus, Lactic Acid, Amylase, biology, Hydrolysis, food and beverages, Gene Expression Regulation, Bacterial, General Medicine, Lactobacillus manihotivorans, biology.organism_classification, Enzymes, Real time PCR, Kinetics, Biochemistry, chemistry, Amylopectin, Fermentation, Food Microbiology, biology.protein, Alpha-amylase, Food Analysis, Lactobacillus plantarum, Food Science
Abstract

Traditional fermented gruels prepared from cereals are widely used for complementary feeding of young children in Africa and usually have a low energy density. The amylase activity of some lactic acid bacteria (LAB) helps increase the energy content of gruels through partial hydrolysis of starch, thus enabling the incorporation of more starchy material while conserving the desired semi-liquid consistency for young children. Even if this ability is mainly related to the production of alpha-amylase (E.C. 3.2.1.1), in a recent molecular screening, genes coding for enzymes involved in starch metabolism were detected in the efficient amylolytic LAB Lactobacillus plantarum A6: alpha-glucosidase (E.C. 3.2.1.20), neopullulanase (E.C. 3.2.1.135), amylopectin phosphorylase (E.C. 2.4.1.1) and maltose phosphorylase (E.C. 2.4.1.8). The objective of this study was to investigate the expression of these genes in a model of starchy fermented food made from pearl millet (Pennisetum glaucum). Transcriptional and enzymatic analyses were performed during the 18-h fermentation period. Liquefaction was mainly caused by an extracellular alpha amylase encoded by the amyA gene specific to the A6 strain among L. plantarum species and found in both Lactobacillus amylovorus and Lactobacillus manihotivorans. The second most active enzyme was neopullulanase. Other starch metabolizing enzymes were less often detected. The dynamic detection of transcripts of gene during starch fermentation in pearl millet porridge suggests that the set of genes we investigated was not expressed continuously but transiently.

Published
2014

43. Proteomic Comparison of Equine and Bovine Milks on Renneting

Author

Patrick F. Fox, Sonia Hem, Daniel M. Mulvihill, T. Uniacke-Lowe, François Chevalier, Univ Coll Cork, Sch Food & Nutr Sci, National University of Ireland (NUI), Plateforme de protéomique, Institut de radiobiologie cellulaire et moléculaire (iRCM), Unité de Recherche Protéomique (PROTEOMIQUE), Institut National de la Recherche Agronomique (INRA), Laboratoire d'Accueil et de Recherche avec les Ions Accélérés (LARIA), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Plateforme de Spectrométrie de Masse Protéomique - Mass Spectrometry Proteomics Platform (MSPP), Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), iRCM, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Biochimie et Physiologie Moléculaire des Plantes (BPMP), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Université de Montpellier (UM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA), and Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)

Subjects
Proteomics, PROTEIN-FRACTION, [SDV]Life Sciences [q-bio], BETA-CASEIN, 01 natural sciences, Casein, SKIM MILK, Electrophoresis, Gel, Two-Dimensional, Chymosin, CAMEL MILK, Chromatography, High Pressure Liquid, proteomic, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Chemistry, Caseins, food and beverages, COWS MILK, Milk Proteins, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Milk, MARES MILK, Biochemistry, KAPPA-CASEIN, General Agricultural and Biological Sciences, Gene isoform, Bovine milk, equine milk, food.ingredient, bovine milk, 2-DIMENSIONAL ELECTROPHORESIS, 03 medical and health sciences, food, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Skimmed milk, rennet coagulation, Camel milk, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Horses, 030304 developmental biology, Chromatography, 010401 analytical chemistry, CHYMOSIN, General Chemistry, 0104 chemical sciences, Electrophoresis, Biocatalysis, Cattle, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, DESORPTION/IONISATION MASS-SPECTROMETRY
Abstract

Rennet-induced coagulation of bovine milk is a complex mechanism in which chymosin specifically hydrolyzes kappa-casein, the protein responsible for the stability of the casein micelle. In equine milk, this mechanism is still unclear, and the protein targets of chymosin are unknown. To reveal the proteins involved, the rennetability of equine milk by calf chymosin was examined using gel free and gel based proteomic analysis and compared to bovine milk RP-HPLC analysis of bovine and equine milks showed the release of several peptides following chymosin incubation. The hydrolyses of equine and bovine casein by chymosin were different, and the major peptides produced from equine milk were identified by mass spectrometry as fragments of beta-casein. Using two-dimensional electrophoresis, equine beta-casein was confirmed as the main target of calf chymosin over 24 h at 30 degrees C and pH 6.5. The gel based analysis of equine milk discriminated between the different individual proteins and provided information on the range of isoforms of each protein as a result of post translational modifications, as well as positively identified for the first time several isoforms of kappa-casein. In comparison to bovine milk, kappa-casein isoforms in equine milk were not involved in chymosin-induced coagulation. The intensity of equine beta-casein spots decreased following chymosin addition, but at a slower rate than bovine kappa-casein.

Published
2013
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44. Impairing the microRNA biogenesis pathway induces proteome modifications characterized by size bias and enrichment in antioxidant proteins

Author

Jean Labarre, François Chevalier, Delphine Peric, Germain Rousselet, Laboratoire de Génétique de la Radiosensibilité (LGR), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire de Biologie Intégrative (LBI), Plateforme de protéomique, Institut de radiobiologie cellulaire et moléculaire (iRCM), Laboratoire de Recherche sur la Réparation et la Transcription dans les Cellules Souches (LRTS), Université Paris Diderot - Paris 7 (UPD7)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Ribonuclease III, Proteome, Saccharomyces cerevisiae, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, medicine.disease_cause, Biochemistry, Antioxidants, 03 medical and health sciences, 0302 clinical medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], microRNA, medicine, Homeostasis, Humans, Electrophoresis, Gel, Two-Dimensional, RNA, Small Interfering, Molecular Biology, Drosha, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Proteins, Cell Cycle Checkpoints, Hydrogen Peroxide, HCT116 Cells, biology.organism_classification, Cell biology, MicroRNAs, Oxidative Stress, Proteostasis, 030220 oncology & carcinogenesis, Cancer cell, MCF-7 Cells, Carcinogenesis, Oxidative stress, Signal Transduction
Abstract

Perturbation of individual microRNAs, or of the microRNA pathway, plays a role in carcinogenesis. In certain cancer cells, inhibition of the microRNA biogenesis pathway leads to a growth arrest state (CoGAM for Colony Growth Arrest induced by Microprocessor inhibition), which can be rescued by re-expression of individual microRNAs such as miR-20a. We now report that inhibition of the microRNA biogenesis pathway induced proteome changes characterized by a size bias in differentially expressed proteins, with induction of small proteins and inhibition of large ones. This size bias was observed in cells undergoing CoGAM, as well as in CoGAM-resistant cells, and in CoGAM-sensitive cells rescued by miR-20a. In this case, GO analysis of induced proteins identified by mass spectrometry revealed a significant enrichment in proteins involved in resistance to oxidative stress. In addition, H(2) O(2) treatment of Saccharomyces cerevisiae or mammalian cells led to similarly size-biased proteome modifications. Our results point to size bias as a relevant readout of proteome modifications, in particular in conditions of stress such as inhibition of the microRNA biogenesis pathway or oxidative stress. They also suggest research avenues to study the role of the microRNA pathway in proteostasis.

Published
2012
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45. Identification of Factors Involved in Neurogenesis Recovery After Irradiation of the Adult Mouse Subventricular Zone: A Preliminary Study

Author

François D. Boussin, Marc-André Mouthon, Jordane Depagne, Alexandra Chicheportiche, Mathieu Daynac, François Chevalier, and Pascale Bertrand

Subjects
0303 health sciences, Neurogenesis, Subventricular zone, Biology, Molecular biology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, nervous system, medicine, reproductive and urinary physiology, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

Francois Chevalier1*, Alexandra Chicheportiche2,3,4,5*, Mathieu Daynac2,3,4,5, Jordane Depagne1, Pascale Bertrand1, Francois D. Boussin2,3,4,5 and Marc-Andre Mouthon2,3,4,5 1CEA DSV iRCM, Plateforme de Proteomique, F-92265 Fontenay-aux-Roses 2CEA DSV iRCM SCSR, Laboratoire de Radiopathologie, F-92265 Fontenay-aux-Roses 3INSERM, U967, F-92265 Fontenay-aux-Roses 4Universite Paris Diderot, Sorbonne Paris Cite, UMR 967, F-92265 Fontenay-aux-Roses 5Universite Paris Sud, UMR 967, F-92265 Fontenay-aux-Roses, Institut de Radiobiologie Cellulaire et Moleculaire, Fontenay-aux-Roses France

Published
2012
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46. Technical updates to basic proteins focalization using IPG strips

Author

Jordane Depagne, François Chevalier, Plateforme de protéomique, and Institut de radiobiologie cellulaire et moléculaire (iRCM)

Subjects
Bovine milk, Materials science, STRIPS, Standard solution, computer.software_genre, 01 natural sciences, Biochemistry, law.invention, Paper bridge loading, 03 medical and health sciences, Basic proteins, Two dimensional electrophoresis, law, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Protein purification, lcsh:QH573-671, Cup-loading, Molecular Biology, 030304 developmental biology, 0303 health sciences, Reproducibility, Chromatography, lcsh:Cytology, 010401 analytical chemistry, Methodology, 0104 chemical sciences, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Two-dimensional electrophoresis, IPG, Data mining, Proteomic methods, computer, Protein loading, MCF7 Cells, Isoelectric focusing
Abstract

Background Gel-based proteomic is a popular and versatile method of global protein separation and quantification. However, separation of basic protein still represents technical challenges with recurrent problems of resolution and reproducibility. Results Three different protocols of protein loading were compared using MCF7 cells proteins. In-gel rehydration, cup-loading and paper-bridge loading were first compared using 6–11 IPG strips, as attempted, in-gel rehydration gave large horizontal steaking; paper-bridge loading displayed an interesting spot resolution, but with a predominant loss of material; cup-loading was selected as the most relevant method, but still needing improvement. Twelve cup-loading protocols were compared with various strip rehydration, and cathodic wick solutions. Destreak appeared as better than DTT for strip rehydration; the use of isopropanol gave no improvement. The best 2DE separation was observed with cathodic wicks filled with rehydration solution complemented with DTT. Paper-bridge loading was finally analyzed using non-limited samples, such as bovine milk. In this case, new spots of basic milk proteins were observed, with or without paper wicks. Conclusion According to this technical study of basic protein focalization with IPG strips, the cup-loading protocol clearly displayed the best resolution and reproducibility: strips were first rehydrated with standard solution, then proteins were cup-loaded with destreak reagent, and focalisation was performed with cathodic wicks filled with rehydration solution and DTT. Paper-bridge loading could be as well used, but preferentially with non-limited samples.

Published
2012
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47. Effect of high-pressure treatment of milk for cheese manufacture on proteolysis, lipolysis, texture and functionality of Cheddar cheese during ripening

Author

Margaret F. Patterson, Alan L. Kelly, Daniela D. Voigt, Michael C. Qian, François Chevalier, John A. Donaghy, Department of Food and Nutritional Sciences, University College Cork (UCC), Plateforme de protéomique, Institut de radiobiologie cellulaire et moléculaire (iRCM), Food Safety Microbiology Group, Nestlé Suisse, and Oregon State University (OSU)

Subjects
Proteolysis, Flavour, Microbial contamination, Industrial and Manufacturing Engineering, chemistry.chemical_compound, 0404 agricultural biotechnology, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Lipolysis, Food science, ComputingMilieux_MISCELLANEOUS, 2. Zero hunger, medicine.diagnostic_test, 0402 animal and dairy science, food and beverages, Ripening, 04 agricultural and veterinary sciences, General Chemistry, Raw milk, 040401 food science, 040201 dairy & animal science, Lactic acid, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, chemistry, High pressure, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Food Science
Abstract

Ripening of Cheddar cheese manufactured from raw milk (control) and milk HP-treated at 400 MPa or 600 MPa for 10 min at 20 °C was studied. Counts of non-starter lactic acid bacteria (NSLAB) were significantly reduced after HP-treatment of milk at 600 MPa; however, NSLAB recovered after 60 days of ripening. Overall, increased proteolysis and levels of free fatty acids were found in cheese manufactured from milk HP-treated at 600 MPa. In addition, cheese manufactured from HP-treated milk was less hard, gummy and chewy compared to the control cheese; however, melting ability was significantly decreased in the former. Colour measurements indicated an increase in whiteness in cheese manufactured from HP-treated milk compared to the control cheese. Overall, HP treatment of milk at 600 MPa prior to manufacture of Cheddar cheese decreased initial microbial counts and increased proteolysis during ripening. Industrial relevance Raw milk cheese is in high demand by the consumer due to its unique traits; however, the cheese is prone to microbial contamination and flavour defects. The possibility of treating the milk with high-pressure prior to cheese manufacture helps to eliminate a number of risk factors, yet results in cheese with similar characteristics to cheese made from untreated raw milk. This could help to develop new innovative safe cheese, which could give a competitive advantage.

Published
2012
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48. Milk Proteins | Proteomics

Author

François Chevalier

Subjects
Gel electrophoresis, Isoelectric point, Chromatography, Two-dimensional gel electrophoresis, Isoelectric focusing, Chemistry, Quantitative proteomics, Bottom-up proteomics, Benjamin Cravatt III, Polyacrylamide gel electrophoresis
Abstract

Gel-based proteomics is the most popular and versatile method for the separation and quantification of global proteins. Based on two independent biochemical characteristics of proteins, two-dimensional electrophoresis (2DE) combines isoelectric focusing, which separates proteins according to their isoelectric point (related to the characteristics of amino acids, i.e., acid/basic/neutral), and sodium dodecyl sulfate polyacrylamide gel electrophoresis, which separates proteins further according to their molecular mass (related to the amount of amino acids). At present, 2DE allows up to a thousand protein spots in the same gel to be detected and quantified simultaneously. This article provides instructions for the application of a standardized 2DE protocol to a milk sample and the possibilities for gel staining and protein identification using mass spectrometry, with an example of a 2D map of bovine milk. This method can be adapted easily to any type of milk or dairy product sample. The protocol provides detailed information on how to apply samples to an immobilized dry strip gel, make acrylamide gels, run the gels, and perform staining, according to the specific scientific question and the financial capacity.

Published
2011
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49. Analytical Methods | Electrophoresis

Author

François Chevalier

Subjects
Free-flow electrophoresis, Gel electrophoresis, Two-dimensional gel electrophoresis, Chromatography, Capillary electrophoresis, Chemistry, Pulsed-field gel electrophoresis, Affinity electrophoresis, Gel electrophoresis of proteins, Polyacrylamide gel electrophoresis
Abstract

Gel electrophoresis is a widely used technique in research and development laboratories. It provides information about the molecular weights and charges of macromolecules, their subunit structures, and the purity of a particular preparation. It is relatively simple to use and is highly reproducible. The most common use of gel electrophoresis is the qualitative analysis of complex mixtures of proteins or nucleic acids. Image analysis systems make gel electrophoresis popular for quantitative and preparative purposes. The first part of the article describes gel-based electrophoresis capacities for protein analysis under denaturing or nondenaturing conditions. Native electrophoresis is realized when proteins are separated because of their native charges. Denaturing electrophoresis is realized when using SDS, an anionic detergent. The second part of the article describes gel-free electrophoresis and multidimensional electrophoresis, involving at least two different electrophoretic separations of proteins.

Published
2011
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50. Après dix années de gestion, déroulement et enseignements issus de la révision d'un plan d'aménagement forestier en République Centrafricaine

Author

Alexandra Pasquier and Jean-François Chevalier

Subjects
Production forestière, Aménagement forestier, Conduite de la culture, Political science, Forêt tropicale humide, Crop management, Permis, Ecology, Evolution, Behavior and Systematics, Ecology, secteur privé, Forestry, Exploitation forestière, K10 - Production forestière, Tropical rain forest, Gestion des ressources, Développement durable, P01 - Conservation de la nature et ressources foncières, Humanities
Abstract

La concession forestière de Ngotto, permis d'exploitation et d'aménagement (Pea 169), en République centrafricaine a fait l'objet d'un des premiers plans d'aménagement de forêt dense humide africaine, en 1997. Il s'agissait alors de mettre en application les premiers résultats de la recherche sur ces écosystèmes complexes, tout en s'appuyant sur de nouveaux outils tels que la cartographie numérique. Ce plan d'aménagement a été mis en ¿uvre dans ses grandes lignes pendant dix années ; des désaccords récurrents sont apparus entre le gestionnaire de la forêt (une composante du projet Ecofac) et l'entreprise Ifb, titulaire exploitant le permis, conduisant progressivement à la remise en cause du scénario d'aménagement par cette dernière. La révision du plan a démarré en 2006, en vue de remettre en adéquation " production durable " et " rentabilité ". La révision en profondeur du scénario d'aménagement a exigé plus d'un an et demi d'étude. Cet exercice nouveau en République centrafricaine s'est appuyé sur un processus aux nombreuses étapes mettant en oeuvre des outils modernes de traitement de l'information, adaptés au cadre institutionnel. L'accent a été mis sur les avancées techniques obtenues depuis 2000 ainsi que sur la concertation avec la société d'exploitation afin d'obtenir une adhésion complète à ce processus. Cette étude riche d'enseignements méthodologiques a été l'occasion de mener une analyse constructive sur les divers motifs de révision se multipliant probablement dans l'avenir. (Résumé d'auteur)

Published
2011

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