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51. PREMISE: A database of 20Macaca FascicularisPET/MRI brain imaging available for research

Author

Chalet, Lucie, primary, Debatisse, Justine, additional, Wateau, Oceane, additional, Boutelier, Timothe, additional, Wiart, Marlène, additional, Costes, Nicolas, additional, Merida, Ines, additional, Redouté, Jérôme, additional, Langlois, Jean-Baptiste, additional, Lancelot, Sophie, additional, Léon, Christelle, additional, Cho, Tae-Hee, additional, Mechtouff, Laura, additional, Eker, Omer Faruk, additional, Nighoghossian, Norbert, additional, Canet-Soulas, Emmanuelle, additional, and Becker, Guillaume, additional

Published
2023
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52. TIPIN depletion leads to apoptosis in breast cancer cells

Author

Baldeyron, Céline, Brisson, Amélie, Tesson, Bruno, Némati, Fariba, Koundrioukoff, Stéphane, Saliba, Elie, De Koning, Leanne, Martel, Elise, Ye, Mengliang, Rigaill, Guillem, Meseure, Didier, Nicolas, André, Gentien, David, Decaudin, Didier, Debatisse, Michelle, Depil, Stéphane, Cruzalegui, Francisco, Pierré, Alain, Roman-Roman, Sergio, Tucker, Gordon C., and Dubois, Thierry

Published
2015
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53. USP37 deubiquitinates Cdt1 and contributes to regulate DNA replication

Author

Santiago Hernández-Pérez, Elisa Cabrera, Hugo Amoedo, Sara Rodríguez-Acebes, Stephane Koundrioukoff, Michelle Debatisse, Juan Méndez, and Raimundo Freire

Subjects
Initiation of DNA replication, DNA damage response, Ubiquitin hydrolase, DNA damage, Protein degradation, Proteasome, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

DNA replication control is a key process in maintaining genomic integrity. Monitoring DNA replication initiation is particularly important as it needs to be coordinated with other cellular events and should occur only once per cell cycle. Crucial players in the initiation of DNA replication are the ORC protein complex, marking the origin of replication, and the Cdt1 and Cdc6 proteins, that license these origins to replicate by recruiting the MCM2‐7 helicase. To accurately achieve its functions, Cdt1 is tightly regulated. Cdt1 levels are high from metaphase and during G1 and low in S/G2 phases of the cell cycle. This control is achieved, among other processes, by ubiquitination and proteasomal degradation. In an overexpression screen for Cdt1 deubiquitinating enzymes, we isolated USP37, to date the first ubiquitin hydrolase controlling Cdt1. USP37 overexpression stabilizes Cdt1, most likely a phosphorylated form of the protein. In contrast, USP37 knock down destabilizes Cdt1, predominantly during G1 and G1/S phases of the cell cycle. USP37 interacts with Cdt1 and is able to de‐ubiquitinate Cdt1 in vivo and, USP37 is able to regulate the loading of MCM complexes onto the chromatin. In addition, downregulation of USP37 reduces DNA replication fork speed. Taken together, here we show that the deubiquitinase USP37 plays an important role in the regulation of DNA replication. Whether this is achieved via Cdt1, a central protein in this process, which we have shown to be stabilized by USP37, or via additional factors, remains to be tested.

Published
2016
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54. Signaling from Mus81-Eme2-Dependent DNA Damage Elicited by Chk1 Deficiency Modulates Replication Fork Speed and Origin Usage

Author

Hervé Técher, Stéphane Koundrioukoff, Sandra Carignon, Therese Wilhelm, Gaël A. Millot, Bernard S. Lopez, Olivier Brison, and Michelle Debatisse

Subjects
Biology (General), QH301-705.5
Abstract

Summary: Mammalian cells deficient in ATR or Chk1 display moderate replication fork slowing and increased initiation density, but the underlying mechanisms have remained unclear. We show that exogenous deoxyribonucleosides suppress both replication phenotypes in Chk1-deficient, but not ATR-deficient, cells. Thus, in the absence of exogenous stress, depletion of either protein impacts the replication dynamics through different mechanisms. In addition, Chk1 deficiency, but not ATR deficiency, triggers nuclease-dependent DNA damage. Avoiding damage formation through invalidation of Mus81-Eme2 and Mre11, or preventing damage signaling by turning off the ATM pathway, suppresses the replication phenotypes of Chk1-deficient cells. Damage and resulting DDR activation are therefore the cause, not the consequence, of replication dynamics modulation in these cells. Together, we identify moderate reduction of precursors available for replication as an additional outcome of DDR activation. We propose that resulting fork slowing, and subsequent firing of backup origins, helps replication to proceed along damaged templates. : Técher et al. show that modulation of DNA replication dynamics in Chk1-deficient mammalian cells is the consequence of DNA damage arising through unscheduled Mus81-Eme2 and Mre11 activation. Signaling of this damage by the ATM pathway impedes fork progression through dNTP shortage.

Published
2016
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55. Spatio-Temporal Characterization of Brain Inflammation in a Non-human Primate Stroke Model Mimicking Endovascular Thrombectomy

Author

Guillaume Becker, Justine Debatisse, Margaux Rivière, Claire Crola Da Silva, Maude Beaudoin-Gobert, Omer Eker, Océane Wateau, Tae Hee Cho, Marlène Wiart, Léon Tremblay, Nicolas Costes, Inès Mérida, Jérôme Redouté, Christelle Léon, Jean-Baptiste Langlois, Didier Le Bars, Sophie Lancelot, Norbert Nighoghossian, Laura Mechtouff, and Emmanuelle Canet-Soulas

Subjects
Pharmacology, Pharmacology (medical), Neurology (clinical)
Abstract

Reperfusion therapies in acute ischemic stroke have demonstrated their efficacy in promoting clinical recovery. However, ischemia/reperfusion injury and related inflammation remain a major challenge in patient clinical management. We evaluated the spatio-temporal evolution of inflammation using sequential clinical [11C]PK11195 PET-MRI in a non-human primate (NHP) stroke model mimicking endovascular thrombectomy (EVT) with a neuroprotective cyclosporine A (CsA) treatment. The NHP underwent a 110-min transient endovascular middle cerebral artery occlusion. We acquired [11C]PK11195 dynamic PET-MR imaging at baseline, 7 and 30 days after intervention. Individual voxel-wise analysis was performed thanks to a baseline scan database. We quantified [11C]PK11195 in anatomical regions and in lesioned areas defined on per-occlusion MR diffusion-weighted imaging and perfusion [15O2]H2OPET imaging. [11C]PK11195 parametric maps showed a clear uptake overlapping the lesion core at D7, which further increased at D30. Voxel-wise analysis identified individuals with significant inflammation at D30, with voxels located within the most severe diffusion reduction area during occlusion, mainly in the putamen. The quantitative analysis revealed that thalamic inflammation lasted until D30 and was significantly reduced in the CsA-treated group compared to the placebo. In conclusion, we showed that chronic inflammation matched ADC decrease at occlusion time, a region exposed to an initial burst of damage-associated molecular patterns, in an NHP stroke model mimicking EVT. We described secondary thalamic inflammation and the protective effect of CsA in this region. We propose that major ADC drop in the putamen during occlusion may identify individuals who could benefit from early personalized treatment targeting inflammation.

Published
2023
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56. PREMISE: A database of 20Macaca FascicularisPET/MRI brain imaging available for research

Author

Lucie Chalet, Justine Debatisse, Oceane Wateau, Timothe Boutelier, Marlène Wiart, Nicolas Costes, Ines Merida, Jérôme Redouté, Jean-Baptiste Langlois, Sophie Lancelot, Christelle Léon, Tae-Hee Cho, Laura Mechtouff, Omer Faruk Eker, Norbert Nighoghossian, Emmanuelle Canet-Soulas, and Guillaume Becker

Abstract

Non-human primate (NHP) studies are unique in translational research, especially in neurosciences and neuroimaging approaches are a preferred method for scaling cross-species comparative neurosciences. In this regard, neuroimaging database development and sharing are encouraged to increase the number of subjects available to the community while limiting the number of animals used in research. We present here a simultaneous PET/MR dataset of 20 Macaca Fascicularis structured according to the Brain Imaging Data Structure (BIDS) standards. This database contains multiple MRI sequences (anatomical, diffusion and perfusion imaging notably), as well as PET perfusion and inflammation using respectively [15O]H2O and [11C]PK11195 radiotracers. We describe the pipeline method to assemble baseline data from various cohorts and qualitatively assessed all the data using signal-to-noise and contrast-to-noise ratios as well as the median of intensity. The database is stored and available through the PRIME-DE consortium repository.

Published
2023
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57. Contributors

Author

Maha R.A. Abdollah, Mir Hilal Ahmad, Berta Alcover-Sanchez, Alfonso Alfaro Rodríguez, Marwa A. Ali, Karim A. Alkadhi, Georg Auburger, Meheli Banerjee, Christoph G. Baums, Daria V. Belan, Tom Bleeser, Larisa Bobrovskaya, Hayrunnisa Bolay, Joline E. Brandenburg, Josiane Budni, Jennifer Burnsed, Antonio Cadiz, Katherine Carlin, Raul Chavez-Valdez, Win Ning Chen, Jacques-Olivier Coq, Stephen J. Crocker, Beatriz Cubelos, I.S. Darshini, Nicole de Buhr, Justine Debatisse, Isaac Deng, Jan Deprest, Sarah Devroe, Maria Laura Cecconi dos Santos, Olga Doszyn, Tomasz Dulski, Omer Faruk Eker, Irina V. Ekimova, Barbara Falquetto, Ana Fernández, Matthew J. Fogarty, Abdelrahman Y. Fouda, Luis Gandía, Antonio G. García, Angélica González Maciel, Denis Grandgirard, Bernadette E. Grayson, David A. Greenberg, Natalia Gulyaeva, Sangeetha Gupta, Bora Gürer, Omar Guzmán-Quevedo, Daniel Gyamfi, Sarah Hamimi, Junqiu He, Sung-Ha Hong, Hiroyuki Ida, Salinee Jantrapirom, Lauren L. Jantzie, Mykola Kadzhaya, Jyotshna Kanungo, Ginpreet Kaur, Gabriela Serafim Keller, Sally Kelliny, Olga N. Kokiko-Cochran, Ilia Komoltsev, P. Pramod Kumar, Diego Cabral Lacerda, Geoffrey A. Lambert, Ksenia V. Lapshina, Tally M. Largent-Milnes, Ngoc Dung Le, Stephen L. Leib, Aidan A. Levine, Lulin Li, Erika Liktor-Busa, Fang Liu, Sufang Liu, Jian Luo, Raul Manhães-de-Castro, Devin W. McBride, Eduarda Behenck Medeiros, Marita Meurer, Brandon A. Miller, Amal Chandra Mondal, Thiago S. Moreira, S. Priya Narayanan, Andy Nguyen, Andrii Panteleichuk, Nuria Paricio, Yuri F. Pastukhov, Vinood B. Patel, Eugene Pedachenko, Misha Perouansky, Taras Petriv, Luca Lo Piccolo, K.V. Harish Prashanth, Victor R. Preedy, Cristina Puig, Rajkumar Rajendram, Ramalakshmi Ramasamy, Santhamani Ramasamy, Manuel Alejandro Ramirez-Lee, Trenton J. Ray, Lisienny Campoli Tono Rempel, Miriam Renz, Steffen Rex, Rafael Reynoso Robles, Susanna Ricci, Sandra Rieger, Shenandoah Robinson, Rosa María Romero Velázquez, Robert Rümmler, Francisco José Sanz, Serhii Savosko, Nada K. Sedky, Nesli-Ece Sen, Mohd. Farooq Shaikh, Shengshuai Shan, Uma Sharma, Anna Shmeleva, Gary C. Sieck, Pascal Siegert, Allie M. Smith, Phillip P. Smith, Cristina Solana-Manrique, Emmanuelle Canet Soulas, Rhea Subba, Selvakumar Subbian, Ana C. Takakura, John C. Talpos, Kin Yip Tam, Feng Tao, Zoe Tapp, Baban S Thawkar, Mai F. Tolba, Ana Elisa Toscano, Masahiro Tsuji, Ignacio Valenzuela, Marc Van de Velde, Lennart Van der Veeken, Libor Velíšek, Jana Velíšková, Diego Bulcão Visco, Sydney M. Vita, Maren von Köckritz-Blickwede, Doga Vuralli, Jennifer L. Walters, David A. Wassarman, Océane Wateau, Masamitsu Yamaguchi, Hideki Yoshida, Xin-Fu Zhou, and Justyna Zmorzynska

Published
2023
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61. Cortical diffusivity associates with early neuronal damage

Author

Joseph Nowell, Justine Debatisse, Grazia Daniela Femminella, Sanara Raza, and Paul Edison

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2022
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64. In vivo inactivation of RAD51-mediated homologous recombination leads to premature aging, but not to tumorigenesis

Author

Gabriel Matos-Rodrigues, Vilma Barroca, Ali-Akbar Muhammad, Awatef Allouch, Stephane Koundrioukoff, Daniel Lewandowski, Emmanuelle Despras, Josée Guirouilh-Barbat, Lucien Frappart, Patricia Kannouche, Pauline Dupaigne, Eric Le Cam, Jean-Luc Perfettini, Paul-Henri Romeo, Michelle Debatisse, Maria Jasin, Gabriel Livera, Emmanuelle Martini, Bernard S. Lopez, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire de Développement des Gonades, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Radiobiologie Cellulaire et Moléculaire (IRCM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Signalisation, noyaux et innovations en cancérologie (UMR8126), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Radiothérapie Moléculaire et Innovation Thérapeutique (RaMo-IT), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Stabilité Génétique et Oncogenèse (UMR 8200), Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Leibniz Association, Radiothérapie moléculaire (UMR 1030), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Memorial Sloan Kettering Cancer Center (MSKCC), Stabilité génétique, cellules souches et radiations (SGCSR (U_1274 / UMR_E_008)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), Intégrité du génome et cancers (IGC), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), and Memorial Sloane Kettering Cancer Center [New York]

Subjects
Genetics Homologous recombination, tumorigenesis, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, mouse model, [SDV]Life Sciences [q-bio], aging, RAD51, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biological Sciences
Abstract

Genetic instability is a hallmark of both cancer and aging. Homologous recombination (HR) is a prominent DNA repair pathway maintaining genomic integrity. Mutations in many HR genes lead to cancer predisposition. Paradoxically, the consequences of mutations in the pivotal HR player, RAD51, on cancer development remain puzzling. Moreover, in contrast with other HR genes, RAD51 mouse models are not available to experimentally address the role of RAD51 on aging and carcinogenesis, in vivo. Here, we engineered a mouse model with an inducible dominant negative form of RAD51 (SMRad51) that suppresses RAD51-mediated HR without stimulating alternative non-conservative repair pathways. We found that, in vivo expression of SMRad51 did not trigger tumorigenesis, but instead induced premature aging. We propose that these in vivo phenotypes result from the exhaustion of proliferating progenitors submitted to chronic endogenous replication stress resulting from RAD51-mediated HR suppression. Our data underline the importance of the RAD51 activity for progenitors homeostasis, preventing aging, and more generally for the balance between cancer and aging.

Published
2022

73. Sixteen-Year Monitoring of Particulate Matter Exposure in the Parisian Subway: Data Inventory and Compilation in a Database

Author

Ben Rayana, Tesnim, Debatisse, Amélie, Jouannique, Valérie, Sakthithasan, Kirushanthi, Besançon, Sophie, Molle, Romain, Wild, Pascal, Guinhouya, Benjamin C., and Guseva Canu, Irina

Subjects
Atmospheric Science, Environmental Science (miscellaneous)
Abstract

The regularly reported associations between particulate matter (PM) exposure, and morbidity and mortality due to respiratory, cardiovascular, cancer, and metabolic diseases have led to the reduction in recommended outdoor PM10 and PM2.5 exposure limits. However, indoor PM10 and PM2.5 concentrations in subway systems in many cities are often higher than outdoor concentrations. The effects of these exposures on subway workers and passengers are not well known, mainly because of the challenges in exposure assessment and the lack of longitudinal studies combining comprehensive exposure and health surveillance. To fulfill this gap, we made an inventory of the PM measurement campaigns conducted in the Parisian subway since 2004. We identified 5856 PM2.5 and 18,148 PM10 results from both personal and stationary air sample measurements that we centralized in a database along with contextual information of each measurement. This database has extensive coverage of the subway network and will enable descriptive and analytical studies of indoor PM exposure in the Parisian subway and its potential effects on human health.

Published
2022

74. Sixteen-Year Monitoring of Particulate Matter Exposure in the Parisian Subway: Data Inventory and Compilation in a Database

Author

Canu, Tesnim Ben Rayana, Amélie Debatisse, Valérie Jouannique, Kirushanthi Sakthithasan, Sophie Besançon, Romain Molle, Pascal Wild, Benjamin C. Guinhouya, and Irina Guseva

Subjects
particles, occupational exposure, mass concentration, environmental exposure, personal measurement, subway users’ exposure
Abstract

The regularly reported associations between particulate matter (PM) exposure, and morbidity and mortality due to respiratory, cardiovascular, cancer, and metabolic diseases have led to the reduction in recommended outdoor PM10 and PM2.5 exposure limits. However, indoor PM10 and PM2.5 concentrations in subway systems in many cities are often higher than outdoor concentrations. The effects of these exposures on subway workers and passengers are not well known, mainly because of the challenges in exposure assessment and the lack of longitudinal studies combining comprehensive exposure and health surveillance. To fulfill this gap, we made an inventory of the PM measurement campaigns conducted in the Parisian subway since 2004. We identified 5856 PM2.5 and 18,148 PM10 results from both personal and stationary air sample measurements that we centralized in a database along with contextual information of each measurement. This database has extensive coverage of the subway network and will enable descriptive and analytical studies of indoor PM exposure in the Parisian subway and its potential effects on human health.

Published
2022
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75. Gene Amplification Mechanisms

Author

Debatisse, Michelle, Malfoy, Bernard, Back, Nathan, editor, Cohen, Irun R., editor, Kritchevsky, David, editor, Lajtha, Abel, editor, Paoletti, Rodolfo, editor, and Nigg, Erich A., editor

Published
2005
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76. The RBBP6/ZBTB38/MCM10 Axis Regulates DNA Replication and Common Fragile Site Stability

Author

Benoit Miotto, Moredreck Chibi, Ping Xie, Stéphane Koundrioukoff, Hanlie Moolman-Smook, David Pugh, Michelle Debatisse, Fuchu He, Lingqiang Zhang, and Pierre-Antoine Defossez

Subjects
Biology (General), QH301-705.5
Abstract

Summary: Faithful DNA replication is essential for the maintenance of genome integrity. Incomplete genome replication leads to DNA breaks and chromosomal rearrangements, which are causal factors in cancer and other human diseases. Despite their importance, the molecular mechanisms that control human genome stability are incompletely understood. Here, we report a pathway that is required for human genome replication and stability. This pathway has three components: an E3 ubiquitin ligase, a transcriptional repressor, and a replication protein. The E3 ubiquitin ligase RBBP6 ubiquitinates and destabilizes the transcriptional repressor ZBTB38. This repressor negatively regulates transcription and levels of the MCM10 replication factor on chromatin. Cells lacking RBBP6 experience reduced replication fork progression and increased damage at common fragile sites due to ZBTB38 accumulation and MCM10 downregulation. Our results uncover a pathway that ensures genome-wide DNA replication and chromosomal stability. : DNA replication duplicates the genome at every cell cycle. Miotto et al. have now identified a molecular pathway that ensures proper replication of the mammalian genome. Common fragile sites are regions in the mammalian genome that are prone to loss when DNA replication is suboptimal. The new data show that common fragile sites are exquisitely sensitive to the activity of this RBBP6/ZBTB38/MCM10 axis, suggesting that deregulation of these factors may underlie genome instability and human disease.

Published
2014
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79. COVID-19 : concilier prévention et activités essentielles

Author

Sakthithasan, Kirushanthi, primary, Allanic, Christophe, additional, Tang-Tardieux, Sandrine, additional, Bard, Laurence, additional, Bonga Bouna, Kéti, additional, Debatisse, Amélie, additional, Merat, Florence, additional, Philippon, Jean Jacques, additional, and Jouannique, Valérie, additional

Published
2022
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82. Analyse exploratoire des mesures de particules ultrafines en temps réel dans des enceintes ferroviaires souterraines de transport public [Exploratory analysis of real-time ultrafine particles measurements in a public transport underground railway]

Author

Ben Rayana, T., Hemmendinger, M., Crézé, C., Wild, P., Sauvain, J.-J., Suarez, G., Besançon, S., Méthy, N., Sakthithasan, K., Carillo, G., Debatisse, A., Jouannique, V., Guinhouya, B.C., and Guseva Canu, I.

Subjects
Public Health, Environmental and Occupational Health
Published
2022

83. Common Fragile Site Profiling in Epithelial and Erythroid Cells Reveals that Most Recurrent Cancer Deletions Lie in Fragile Sites Hosting Large Genes

Author

Benoît Le Tallec, Gaël Armel Millot, Marion Esther Blin, Olivier Brison, Bernard Dutrillaux, and Michelle Debatisse

Subjects
Biology (General), QH301-705.5
Abstract

Cancer genomes exhibit numerous deletions, some of which inactivate tumor suppressor genes and/or correspond to unstable genomic regions, notably common fragile sites (CFSs). However, 70%–80% of recurrent deletions cataloged in tumors remain unexplained. Recent findings that CFS setting is cell-type dependent prompted us to reevaluate the contribution of CFS to cancer deletions. By combining extensive CFS molecular mapping and a comprehensive analysis of CFS features, we show that the pool of CFSs for all human cell types consists of chromosome regions with genes over 300 kb long, and different subsets of these loci are committed to fragility in different cell types. Interestingly, we find that transcription of large genes does not dictate CFS fragility. We further demonstrate that, like CFSs, cancer deletions are significantly enriched in genes over 300 kb long. We now provide evidence that over 50% of recurrent cancer deletions originate from CFSs associated with large genes.

Published
2013
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85. Slow Replication Fork Velocity of Homologous Recombination-Defective Cells Results from Endogenous Oxidative Stress.

Author

Therese Wilhelm, Sandrine Ragu, Indiana Magdalou, Christelle Machon, Elodie Dardillac, Hervé Técher, Jérôme Guitton, Michelle Debatisse, and Bernard S Lopez

Subjects
Genetics, QH426-470
Abstract

Replications forks are routinely hindered by different endogenous stresses. Because homologous recombination plays a pivotal role in the reactivation of arrested replication forks, defects in homologous recombination reveal the initial endogenous stress(es). Homologous recombination-defective cells consistently exhibit a spontaneously reduced replication speed, leading to mitotic extra centrosomes. Here, we identify oxidative stress as a major endogenous source of replication speed deceleration in homologous recombination-defective cells. The treatment of homologous recombination-defective cells with the antioxidant N-acetyl-cysteine or the maintenance of the cells at low O2 levels (3%) rescues both the replication fork speed, as monitored by single-molecule analysis (molecular combing), and the associated mitotic extra centrosome frequency. Reciprocally, the exposure of wild-type cells to H2O2 reduces the replication fork speed and generates mitotic extra centrosomes. Supplying deoxynucleotide precursors to H2O2-exposed cells rescued the replication speed. Remarkably, treatment with N-acetyl-cysteine strongly expanded the nucleotide pool, accounting for the replication speed rescue. Remarkably, homologous recombination-defective cells exhibit a high level of endogenous reactive oxygen species. Consistently, homologous recombination-defective cells accumulate spontaneous γH2AX or XRCC1 foci that are abolished by treatment with N-acetyl-cysteine or maintenance at 3% O2. Finally, oxidative stress stimulated homologous recombination, which is suppressed by supplying deoxynucleotide precursors. Therefore, the cellular redox status strongly impacts genome duplication and transmission. Oxidative stress should generate replication stress through different mechanisms, including DNA damage and nucleotide pool imbalance. These data highlight the intricacy of endogenous replication and oxidative stresses, which are both evoked during tumorigenesis and senescence initiation, and emphasize the importance of homologous recombination as a barrier against spontaneous genetic instability triggered by the endogenous oxidative/replication stress axis.

Published
2016
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86. A non-human primate model of stroke reproducing endovascular thrombectomy and allowing long-term imaging and neurological read-outs

Author

F. Taborik, Karine Portier, Norbert Nighoghossian, Adrien Oudotte, Michaël Verset, Thomas Troalen, Omer Eker, Denis Vivien, Inés Mérida, Christelle Leon, Christian Tourvieille, Didier Le Bars, Emmanuelle Canet-Soulas, Michel Ovize, Hugues Contamin, Nicolas Costes, Nikolaos Makris, Véronique Agin, Joachim Confais, Tae-Hee Cho, Mohamed Aggour, Sophie Lancelot, Justine Debatisse, Jean-Baptiste Langlois, Océane Wateau, Marjorie Villien, Imagerie Tomographique et Radiothérapie, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche et d'Application en Traitement de l'Image et du Signal (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École Supérieure Chimie Physique Électronique de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Etude et de Recherche Multimodal Et Pluridisciplinaire en imagerie du vivant (CERMEP - imagerie du vivant), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Laboratoire d'Ecologie des Hydrosystèmes Naturels et Anthropisés (LEHNA), Université de Lyon-Université de Lyon-École Nationale des Travaux Publics de l'État (ENTPE)-Centre National de la Recherche Scientifique (CNRS), Cynbiose, CYNBIOSE, Institut Claude Bourgelat (ICLB), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Siemens Healthcare [France], Siemens AG [Munich], Institute of Electronic Structure and Laser (FORTH-IESL), Foundation for Research and Technology - Hellas (FORTH), Radiopharmaceutical and Neurochemical Biomarkers Team (BioRaN), Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Cardiology, Hospices Civils de Lyon (HCL), Laboratoire de Chimie de la Matière Condensée de Paris (site ENSCP) (LCMCP (site ENSCP)), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF (institution))-Institut de Chimie du CNRS (INC), French Ministry of Higher Education and Research (ANRT), ANR-15-CE17-0020,CYCLOPS,CYCLOsporine A : effet neuroprotecteur dans un modèle Primate de Stroke en imagerie(2015), ANR-16-RHUS-0009,MARVELOUS,MARVELOUS(2016), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-École Supérieure de Chimie Physique Électronique de Lyon (CPE)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF (institution))-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, [SDV]Life Sciences [q-bio], Executive Function, 0302 clinical medicine, Occlusion, Stroke, Thrombectomy, 0303 health sciences, Behavior, Animal, Endovascular Procedures, Infarction, Middle Cerebral Artery, Magnetic Resonance Imaging, 3. Good health, Treatment Outcome, Neurology, Blood-Brain Barrier, Motor Skills, Reperfusion Injury, Middle cerebral artery, Cardiology, medicine.symptom, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, Ischemia, Context (language use), ischemia–reperfusion, Asymptomatic, Lesion, 03 medical and health sciences, medicine.artery, Internal medicine, medicine, Animals, cardiovascular diseases, Thrombus, Ischemic Stroke, 030304 developmental biology, business.industry, Original Articles, medicine.disease, Disease Models, Animal, Macaca fascicularis, Endovascular non-human primate stroke model, PET-MRI imaging, Positron-Emission Tomography, neurofunctional tests, Neurology (clinical), Tomography, X-Ray Computed, business, 030217 neurology & neurosurgery
Abstract

International audience; Stroke is a devastating disease. Endovascular mechanical thrombectomy is dramatically changing the management of acute ischemic stroke, raising new challenges regarding brain outcome and opening up new avenues for brain protection. In this context, relevant experiment models are required for testing new therapies and addressing important questions about infarct progression despite successful recanalization, reversibility of ischemic lesions, blood-brain barrier disruption and reperfusion damage. Here, we developed a minimally invasive non-human primate model of cerebral ischemia (Macaca fascicularis) based on an endovascular transient occlusion and recanalization of the middle cerebral artery (MCA). We evaluated per-occlusion and post-recanalization impairment on PET-MRI, in addition to acute and chronic neuro-functional assessment. Voxel-based analyses between per-occlusion PET-MRI and day-7 MRI showed two different patterns of lesion evolution: "symptomatic salvaged tissue" (SST) and "asymptomatic infarcted tissue" (AIT). Extended SST was present in all cases. AIT, remote from the area at risk, represented 45% of the final lesion. This model also expresses both worsening of fine motor skills and dysexecutive behavior over the chronic post-stroke period, a result in agreement with cortical-subcortical lesions. We thus fully characterized an original translational model of ischemia-reperfusion damage after stroke, with consistent ischemia time, and thrombus retrieval for effective recanalization.

Published
2020
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87. Additional file 1 of Malondialdehyde and anion patterns in exhaled breath condensate among subway workers

Author

Sauvain, Jean-Jacques, Hemmendinger, Maud, Suárez, Guillaume, Creze, Camille, Hopf, Nancy B., Jouannique, Valérie, Debatisse, Amélie, Pralong, Jacques A., Wild, Pascal, and Canu, Irina Guseva

Subjects
respiratory tract diseases
Abstract

Additional file 1: Supplemental Table S1. Average exposure level of the three different professional groups. Supplemental Table S2. Geomtric concentration of the selected variables in EBC samples collected during the two working weeks for the three professional categories. Supplemental Figure S1. Effect of the professional activity on the predicted EBC levels of MDA. Supplemental Table S3. Averaged EBC concentration of selected anions in pre- and post-shift for all volunteers.

Published
2022
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88. Gene Amplification Mechanisms: The Role of Fragile Sites

Author

Debatisse, M., Coquelle, A., Toledo, F., Buttin, G., Schlag, P. M., editor, Senn, H.-J., editor, Diehl, V., editor, Parkin, D. M., editor, Rajewsky, M. F., editor, Rubens, R., editor, Wannenmacher, M., editor, Schwab, Manfred, editor, Rabes, Hartmut M., editor, Munk, Klaus, editor, and Hofschneider, Hans Peter, editor

Published
1998
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89. Clinical Imaging of the Penumbra in Ischemic Stroke: From the Concept to the Era of Mechanical Thrombectomy

Author

Chalet, Lucie, primary, Boutelier, Timothé, additional, Christen, Thomas, additional, Raguenes, Dorian, additional, Debatisse, Justine, additional, Eker, Omer Faruk, additional, Becker, Guillaume, additional, Nighoghossian, Norbert, additional, Cho, Tae-Hee, additional, Canet-Soulas, Emmanuelle, additional, and Mechtouff, Laura, additional

Published
2022
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90. In vivo inactivation of RAD51-mediated homologous recombination leads to premature aging, but not to tumorigenesis

Author

Matos-Rodrigues, Gabriel, primary, Barroca, Vilma, additional, Muhammad, Ali-Akbar, additional, Allouch, Awatef, additional, Koundrioukoff, Stephane, additional, Lewandowski, Daniel, additional, Despras, Emmanuelle, additional, Guirouilh-Barbat, Josée, additional, Frappart, Lucien, additional, Kannouche, Patricia, additional, Dupaigne, Pauline, additional, Cam, Eric Le, additional, Perfettini, Jean-Luc, additional, Romeo, Paul-Henri, additional, Debatisse, Michelle, additional, Jasin, Maria, additional, Livera, Gabriel, additional, Martini, Emmanuelle, additional, and Lopez, Bernard S., additional

Published
2022
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91. Malondialdehyde and anion patterns in exhaled breath condensate among subway workers

Author

Sauvain, J.J., Hemmendinger, M., Suárez, G., Creze, C., Hopf, N.B., Jouannique, V., Debatisse, A., Pralong, J.A., Wild, P., and Guseva Canu, I.

Subjects
Anions, Nitrates, Anion, Exhaled breath condensate, Exposure, Metabolism, Particulate matter, Underground, Dust, Acetates, Breath Tests, Malondialdehyde, Humans, Nitrogen Oxides, Particulate Matter, Lactic Acid, Railroads, Biomarkers, Nitrites
Abstract

Underground transportation systems can contribute to the daily particulates and metal exposures for both commuter and subway workers. The redox and metabolic changes in workers exposed to such metal-rich particles have yet to be characterized. We hypothesize that the distribution of nitrosative/oxidative stress and related metabolic biomarkers in exhaled breath condensate (EBC) are modified depending on exposures. Particulate number and size as well as mass concentration and airborne metal content were measured in three groups of nine subway workers (station agents, locomotive operators and security guards). In parallel, pre- and post-shift EBC was collected daily during two consecutive working weeks. In this biological matrix, malondialdehyde, lactate, acetate, propionate, butyrate, formate, pyruvate, the sum of nitrite and nitrate (ΣNO x ) and the ratio nitrite/nitrate as well as metals and nanoparticle concentrations was determined. Weekly evolution of the log-transformed selected biomarkers as well as their association with exposure variables was investigated using linear mixed effects models with the participant ID as random effect. The professional activity had a strong influence on the pattern of anions and malondialdehyde in EBC. The daily number concentration and the lung deposited surface area of ultrafine particles was consistently and mainly associated with nitrogen oxides variations during the work-shift, with an inhibitory effect on the ΣNO x . We observed that the particulate matter (PM) mass was associated with a decreasing level of acetate, lactate and ΣNO x during the work-shift, suggestive of a build-up of these anions during the previous night in response to exposures from the previous day. Lactate was moderately and positively associated with some metals and with the sub-micrometer particle concentration in EBC. These results are exploratory but suggest that exposure to subway PM could affect concentrations of nitrogen oxides as well as acetate and lactate in EBC of subway workers. The effect is modulated by the particle size and can correspond to the body's cellular responses under oxidative stress to maintain the redox and/or metabolic homeostasis.

Published
2021

92. Unscheduled origin building in S-phase upon tight CDK1 inhibition suppresses CFS instability

Author

Michelle Debatisse, El-Hilali S, Azar D, A.-M. Lachages, Yan Jaszczyszyn, Chun-Long Chen, Mélanie Schmidt, Stefano Gnan, Claude Thermes, Koundrioukoff S, Olivier Brison, Stabilité Génétique et Oncogenèse (UMR 8200), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Sorbonne Université (SU), 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), Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Intégrité du génome et cancers (IGC), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE), and CHEN, Chunlong

Subjects
[SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Instability, Chromosome segregation, DNA replication factor CDT1, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Transcription (biology), [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Mitosis, 030304 developmental biology, 0303 health sciences, Cyclin-dependent kinase 1, Chromosomal fragile site, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030220 oncology & carcinogenesis, biology.protein, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Chromosome breakage
Abstract

SummaryGenome integrity requires replication to be completed before chromosome segregation. This coordination essentially relies on replication-dependent activation of a dedicated checkpoint that inhibits CDK1, delaying mitotic onset. Under-replication of Common Fragile Sites (CFSs) however escapes surveillance, which triggers chromosome breakage. Using human cells, we asked here whether such leakage results from insufficient CDK1 inhibition under modest stresses used to destabilize CFSs. We found that tight CDK1 inhibition suppresses CFS instability. Repli-Seq and molecular combing analyses consistently showed a burst of replication initiations in mid S phase across large origin-poor domains shaped by transcription, including CFSs. Strikingly, CDC6 or CDT1 depletion or CDC7-DBF4 inhibition during the S phase prevented both extra-initiations and CFS rescue, showing that CDK1 inhibition promotes targeted and mistimed building of functional extra-origins. In addition to delay mitotic onset, checkpoint activation therefore advances replication completion of chromosome domains at risk of under-replication, two complementary roles preserving genome stability.

Published
2021

95. Relationship between particle and metal concentrations in subway workers’ personal breath zone (PBZ), exhaled breath condensate (EBC), and urine

Author

Véronique Jouannique, Camille Crézé, Irina Guseva Canu, Sophie Besançon, Nancy B. Hopf, Pascal Wild, Tesnim Ben Rayana, Guillaume Suarez, M. Hemmendinger, J.-J. Sauvain, and Amélie Debatisse

Subjects
Chromatography, Chemistry, General Earth and Planetary Sciences, Particle, Exhaled breath condensate, Urine, General Environmental Science
Published
2021
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96. Particle and metal exposure in Parisian subway: Relationship between exposure biomarkers in air, exhaled breath condensate, and urine

Author

Camille Crézé, Nancy B. Hopf, T. Ben Rayana, J.-J. Sauvain, Pascal Wild, Valérie Jouannique, Guillaume Suarez, M. Hemmendinger, Sophie Besançon, I. Guseva Canu, and Amélie Debatisse

Subjects
Population, Urine, 010501 environmental sciences, 01 natural sciences, Metal, 03 medical and health sciences, 0302 clinical medicine, Ultrafine particle, Biomonitoring, Humans, Exhaled breath condensate, Particle Size, education, Railroads, 0105 earth and related environmental sciences, Gravimetric method, Indoor air pollution, Occupational exposure, Particle number concentration, Particle size, Air Pollutants, education.field_of_study, Inhalation, Chemistry, Public Health, Environmental and Occupational Health, Particulates, respiratory tract diseases, 030228 respiratory system, visual_art, Environmental chemistry, visual_art.visual_art_medium, Particulate Matter, Biomarkers, Environmental Monitoring
Abstract

Subway particulate toxicity results from in vitro and in vivo studies diverge and call for applied human research on outcomes from chronic exposures and potential exposure biomarkers. We aimed to (1) quantify airborne particulate matter (PM) concentrations (mass and number) and metal concentrations in exhaled breath condensate (EBC), urine, and PM; (2) investigate their associations (EBC vs. PM vs. urine); and (3) assess the relevance of EBC in biomonitoring. Nine subway workers in three jobs: station agents, locomotive operators and security guards were monitored during their 6-h shifts over two consecutive weeks. Six-hour weighed average mass concentrations expressed as PM10, PM2.5 and their metal concentrations were determined. Urine and EBC samples were collected pre- and post-shift. Ultrafine particle (UFP) number concentrations were quantified in PM and EBC samples. Metal concentrations in urine and EBC were standardized by creatinine and EBC volume, respectively, and log-transformed. Associations were investigated using Pearson correlation and linear mixed regression models, with participant's ID as random effect. PM concentrations were below occupational exposure limits (OEL) and varied significantly between jobs. Locomotive operators had the highest exposure (189 and 137 μg/m 3 for PM10 and PM2.5, respectively), while station agents had the highest UFP exposure (1.97 × 10 4 particles/cm 3 ). Five metals (Al, Fe, Zn, Cu, and Mn) in PM2.5 and three (Al, Fe, and Zn) in PM10 were above the limit of quantification (LOQ). Fe, Cu, Al and Zn were the most abundant by mass fraction in PM. In EBC, the metal concentrations in decreasing order were: Zn > Cu > Ni > Ba > Mn. Security guards had the highest EBC metal concentrations, and in particular Zn and Cu. Urinary metal concentrations in decreasing order were: Si > Zn > Mo > Ti > Cu > Ba ≈ Ni > Co. All urinary metal concentrations from the subway workers were similar to concentrations found in the general population. A statistically significant relationship was found for ultrafine particle number concentrations in PM and in EBC. Zn and Cu concentrations in post-shift EBC were associated with Zn and Cu concentrations in PM10 and with post-shift urinary Zn and Cu concentrations. Therefore, EBC appears a relevant matrix for assessing exposure to UFP in human biomonitoring when inhalation is a primary route of exposure. We found different temporal variation patterns between particle and metal exposures in three matrices (PM, urine, EBC) quantified daily over two full weeks in subway workers. These patterns might be related to metal oxidation, particulates' solubility and size as well as their lung absorption capabilities, which need to be further explored in toxicological research. Further research should also focus on understanding possible influences of low chronic exposures to subway particulates on health in larger cohorts.

Published
2021

99. Cortical inflammation and brain signs of high-risk atherosclerosis in a non-human primate model

Author

Cataldo, Vanessa, Debatisse, Justine, Piraquive, Joao, Géloën, Alain, Grandin, Clément, Verset, Michaël, Taborik, Fabrice, Labaronne, Emmanuel, Loizon, Emmanuelle, Millon, Antoine, Mury, Pauline, Pialoux, Vincent, Serusclat, André, Lamberton, Franck, Ibarrola, Danielle, Lavenne, Franck, Le Bars, Didier, Troalen, Thomas, Confais, Joachim, CROLA DA SILVA, Claire, Mechtouff, Laura, Contamin, Hugues, Fayad, Zahi, Canet-Soulas, Emmanuelle, Canet-Soulas, Emmanuelle, MARVELOUS - - MARVELOUS2016 - ANR-16-RHUS-0009 - RHUS - VALID, Equipements d'excellence - Lyon - Imagerie Intégrée du Vivant : IRM-TEP hybride - - LILI2011 - ANR-11-EQPX-0026 - EQPX - VALID, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Siemens Healthcare, CYNBIOSE SA, Laboratoire Interuniversitaire de Biologie de la Motricité (LIBM ), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Hospices Civils de Lyon (HCL), CERMEP - Imagerie du vivant, Hospices Civils de Lyon, Departement de Neurologie (HCL), Icahn School of Medicine at Mount Sinai [New York] (MSSM), ANR-16-RHUS-0009,MARVELOUS,MARVELOUS(2016), ANR-11-EQPX-0026,LILI,Lyon - Imagerie Intégrée du Vivant : IRM-TEP hybride(2011), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)

Subjects
choroid plexus, AcademicSubjects/SCI01870, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, aging, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Original Article, AcademicSubjects/MED00310, atherosclerosis, stroke, neuroinflammation
Abstract

Atherosclerosis is a chronic systemic inflammatory disease, inducing cardiovascular and cerebrovascular acute events. A role of neuroinflammation is suspected, but not yet investigated in the gyrencephalic brain and the related activity at blood−brain interfaces is unknown. A non-human primate model of advanced atherosclerosis was first established using longitudinal blood samples, multimodal imaging and gene analysis in aged animals. Non-human primate carotid lesions were compared with human carotid endarterectomy samples. During the whole-body imaging session, imaging of neuroinflammation and choroid plexus function was performed. Advanced plaques were present in multiple sites, premature deaths occurred and downstream lesions (myocardial fibrosis, lacunar stroke) were present in this model. Vascular lesions were similar to in humans: high plaque activity on PET and MRI imaging and systemic inflammation (high plasma C-reactive protein levels: 42 ± 14 µg/ml). We also found the same gene association (metabolic, inflammatory and anti-inflammatory markers) as in patients with similar histological features. Metabolic imaging localized abnormal brain glucose metabolism in the frontal cortex. It corresponded to cortical neuro-inflammation (PET imaging) that correlated with C-reactive protein level. Multimodal imaging also revealed pronounced choroid plexus function impairment in aging atherosclerotic non-human primates. In conclusion, multimodal whole-body inflammation exploration at the vascular level and blood−brain interfaces identified high-risk aging atherosclerosis. These results open the way for systemic and central inflammation targeting in atherosclerosis in the new era of immunotherapy., Elevated cortical inflammation and defective choroid plexus activity associate with high-risk atherosclerosis in cynomolgus monkeys. Using diet-induced atherosclerosis, in-vivo imaging and gene analysis, Di Cataldo et al. showed (i) monkeys exhibit similar atherosclerosis features and vulnerable plaques-associated genes as patients, (ii) brain imaging demonstrated frontal cortex neuroinflammation and neurovascular signs., Graphical Abstract Graphical Abstract

Published
2021
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