Assessing the impact of exposome on the course of chronic obstructive pulmonary disease and cystc fibrosis:The REMEDIA European Project Approach

International audienceBecause of the direct interaction of lungs with the environment, respiratory diseases are among the leading causes of environment-related deaths in the world. Chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) are two highly debilitating diseases that are of particular interest in the context of environmental studies; they both are characterized by a similar progressive loss of lung function with small bronchi alterations, and a high phenotypic variability of unknown origin, which prevents a good therapeutic efficacy. In the last years, there has been an evolution in the apprehension of the study of diseases going from a restricted "one exposure, one disease" approach to a broader concept with other associating factors, the exposome. The overall objective of the REMEDIA project is to extend the understanding of the contribution of the exposome to COPD and CF diseases. To achieve our aim, we will (1) exploit data from existing cohorts and population registries to create a unified global database gathering phenotype and exposome information; (2) develop a flexible individual sensor device combining environmental and biomarker toolkits; (3) use a versatile atmospheric simulation chamber to simulate the health effects of complex exposomes; (4) use machine learning supervised analyses and causal inference models to identify relevant risk factors; and (5) develop econometric and cost-effectiveness models to assess the costs, performance, and cost-effectiveness of a selection of prevention strategies. The results will be used to develop guidelines to better predict disease risks and constitute the elements of the REMEDIA toolbox. The multidisciplinary approach carried out by the REMEDIA European project should represent a major breakthrough in reducing the morbidity and mortality associated with COPD and CF diseases

Etude de l’impact du radiomarquage de cellules avec des émetteurs β+ pour l'imagerie TEP : développement dosimétrique à l'échelle multi-cellulaire, analyse des paramètres d'influence et application au cas du ¹⁸F-FDG

In vitro labelling of cells with β+-emitting radionuclides combined with nuclear medicine imaging is a potential method for in vivo cell trafficking analysis with PET imaging. The labeling-associated exposition of cells to high levels of activity still raises some concerns since it may result in cell death and therefore a loss of image quality. In addition, the administration of potentially damaged cells rises essential questions regarding the safety of such procedure. This research work was conducted with a view of better understand the issues underlying the radiolabelling procedure in order to optimize the current clinical practice. More precisely, this thesis focused on the calculation of the absorbed doses to cells during in vitro ¹⁸F-FDG radiolabelling and the correlation to the biological observed effects. As a first step, computing tools at the multi-cellular scale were developed and optimized. Based on a generic approach, we explored and compared several hybrid methods mixing Monte Carlo simulations, analytic approaches or molecular dynamics. Then, JURKAT and adipose mesenchymal stem cells (adMSCs) were radiolabelled with ¹⁸F-FDG and tested for clonogenic survival assay, cell cycle analysis and ᵧ-H2AX phosphorylation quantification. A multi-cellular dosimetry model describing the full experiment, from the incubation of cells with ¹⁸F-FDG, washing steps, to culture of cells for functional assays was developed. Dynamic changes in cell density, as well as experimentally determined activity uptake and retention with time were thus considered. Lastly, the mean cell absorbed dose was correlated with the three biological endpoints and results were compared with X-ray irradiation. The results helped to better understand the irradiation features associated to ¹⁸F-FDG labelling and the observed biological effects, thus providing a knowledge base in favour of harmonizing the labelling methods.En médecine nucléaire, suite au marquage de cellules in vitro avec des radionucléides, l’évaluation des doses reçues à la cellule est essentielle pour comprendre les effets biologiques associés et comparer différentes expériences entre elles. Réalisée notamment avec des émetteurs β+ pour le suivi de cellules par imagerie TEP, la procédure implique l’utilisation de fortes activités dans un volume restreint pouvant alors induire des doses élevées et entrainer une mortalité cellulaire et par la même une perte de la qualité de l’image. Ce travail de recherche s’inscrit dans la perspective de mieux appréhender les enjeux qui sous-tendent cette procédure et d’éclairer les pratiques actuelles. Dans ce cadre, l’étude a porté plus précisément sur l’évaluation réaliste des doses reçues aux cellules lors d’un radiomarquage de cellules au ¹⁸F-FDG pour l’imagerie TEP et leur corrélation aux effets observés. Une première partie du travail de thèse a reposé sur le développement et l’optimisation d’outils de calculs de dose à l’échelle cellulaire. Une analyse comparée de plusieurs méthodes de calculs hybrides a été réalisée en s’appuyant sur des approches analytiques, Monte Carlo ou de la dynamique moléculaire. L’impact de différents facteurs comme la densité cellulaire et l'efficacité de marquage sur les doses aux cellules a pu être ainsi étudié et discuté. Dans un second temps, des expériences de radiomarquage de cellules mésenchymateuses et lymphoblastoïdes au ¹⁸F-FDG ont été réalisées suivies d’une évaluation de la survie clonogénique, du cycle cellulaire et de la cinétique d’apparition et réparation de cassures double brins. Pour relier les effets observés à des doses précises, un modèle dosimétrique multi-cellulaire a été développé, prenant en compte l’ensemble des étapes de l’expérience. Les résultats obtenus permettent de mieux comprendre l’exposition des cellules au cours des étapes de marquage et des conséquences fonctionnelles sur les cellules marquées, apportant ainsi une base de connaissances pour une future standardisation des méthodes de marquage

Study of the impact of cell radiolabelling with β+ emitters for PET imaging : dosimetric development on a multi-cellular scale, analysis of influencing parameters and application for ¹⁸F-FDG labelling

En médecine nucléaire, suite au marquage de cellules in vitro avec des radionucléides, l’évaluation des doses reçues à la cellule est essentielle pour comprendre les effets biologiques associés et comparer différentes expériences entre elles. Réalisée notamment avec des émetteurs β+ pour le suivi de cellules par imagerie TEP, la procédure implique l’utilisation de fortes activités dans un volume restreint pouvant alors induire des doses élevées et entrainer une mortalité cellulaire et par la même une perte de la qualité de l’image. Ce travail de recherche s’inscrit dans la perspective de mieux appréhender les enjeux qui sous-tendent cette procédure et d’éclairer les pratiques actuelles. Dans ce cadre, l’étude a porté plus précisément sur l’évaluation réaliste des doses reçues aux cellules lors d’un radiomarquage de cellules au ¹⁸F-FDG pour l’imagerie TEP et leur corrélation aux effets observés. Une première partie du travail de thèse a reposé sur le développement et l’optimisation d’outils de calculs de dose à l’échelle cellulaire. Une analyse comparée de plusieurs méthodes de calculs hybrides a été réalisée en s’appuyant sur des approches analytiques, Monte Carlo ou de la dynamique moléculaire. L’impact de différents facteurs comme la densité cellulaire et l'efficacité de marquage sur les doses aux cellules a pu être ainsi étudié et discuté. Dans un second temps, des expériences de radiomarquage de cellules mésenchymateuses et lymphoblastoïdes au ¹⁸F-FDG ont été réalisées suivies d’une évaluation de la survie clonogénique, du cycle cellulaire et de la cinétique d’apparition et réparation de cassures double brins. Pour relier les effets observés à des doses précises, un modèle dosimétrique multi-cellulaire a été développé, prenant en compte l’ensemble des étapes de l’expérience. Les résultats obtenus permettent de mieux comprendre l’exposition des cellules au cours des étapes de marquage et des conséquences fonctionnelles sur les cellules marquées, apportant ainsi une base de connaissances pour une future standardisation des méthodes de marquage.In vitro labelling of cells with β+-emitting radionuclides combined with nuclear medicine imaging is a potential method for in vivo cell trafficking analysis with PET imaging. The labeling-associated exposition of cells to high levels of activity still raises some concerns since it may result in cell death and therefore a loss of image quality. In addition, the administration of potentially damaged cells rises essential questions regarding the safety of such procedure. This research work was conducted with a view of better understand the issues underlying the radiolabelling procedure in order to optimize the current clinical practice. More precisely, this thesis focused on the calculation of the absorbed doses to cells during in vitro ¹⁸F-FDG radiolabelling and the correlation to the biological observed effects. As a first step, computing tools at the multi-cellular scale were developed and optimized. Based on a generic approach, we explored and compared several hybrid methods mixing Monte Carlo simulations, analytic approaches or molecular dynamics. Then, JURKAT and adipose mesenchymal stem cells (adMSCs) were radiolabelled with ¹⁸F-FDG and tested for clonogenic survival assay, cell cycle analysis and ᵧ-H2AX phosphorylation quantification. A multi-cellular dosimetry model describing the full experiment, from the incubation of cells with ¹⁸F-FDG, washing steps, to culture of cells for functional assays was developed. Dynamic changes in cell density, as well as experimentally determined activity uptake and retention with time were thus considered. Lastly, the mean cell absorbed dose was correlated with the three biological endpoints and results were compared with X-ray irradiation. The results helped to better understand the irradiation features associated to ¹⁸F-FDG labelling and the observed biological effects, thus providing a knowledge base in favour of harmonizing the labelling methods

Multi-cellular dosimetry of cells labelled with B+-emitting radionuclides for PET imaging

International audienceAim: In vitro labeling of cells with β+-emitting radionuclides combined with nuclear medicineimaging is a potential method for in vivo cell traffi cking analysis with PET imaging. Thelabeling-associated exposition of cells to high levels of activity still raises some concerns.Although there are some studies on the subsequent cellular effects, they are often carried outwithout dose assessment. This work aimed to develop a realistic multi-cellular dosimetry andto apply the model to labeling experiments with 18F-FDG.Materials and Methods: A 3D cellular model taking into account the realistic conditions oflabeling was developed to calculate the mean absorbed dose to cells. The cells were assumedto be packed in a cubic lattice or uniformly distributed within the studied volume, whilethe cell density and the proportion of activity incorporated by the cells were varied. Withthe aim of achieving as accurate as possible results while managing a very large number ofcells, a hybrid method was developed, combining Monte-Carlo (MNCP6 code) and an analyticalapproach implemented in Python. This approach was based on the use of radial distributionfunction g(r) derived from the molecular dynamic software LAMMPS. Comparison with thestandard approach, based on the explicit summation of cell-to-cell dose contributions, wasdone. Then, calculations were done for 18F-FDG-labeled cells assuming parameters used in 8different publications, i.e, cell density, added activity concentration, incubation time andlabeling effi ciency.Results: The cell absorbed doses calculated with the two methods agreed well. LAMMPS-basedindirect approach was showed to be more effective and less time consuming than the standardapproach. Results also showed that the absorbed dose was not signifi cantly impacted by thetype of cell distribution considered, but strongly dependent of the cell density and labelingeffi ciency. Application of the model to 18F-FDG labeling to different experimental conditionsshowed that a same activity per cell can result in signifi cantly different absorbed doses,reinforcing the crucial role of the absorbed dose, as the reference, for studying the cellulareffects rather than the added activity.Conclusions: Through the development of a new calculation approach, our multi-cellulardosimetry provided a generic and robust method to estimate the cell absorbed dose and betterunderstand the infl uence of key labeling parameter

Photoluminescent properties of the carbon-dimer defect in hexagonal boron-nitride: A many-body finite-size cluster approach

International audienc

Modelling the Fluorescence Quantum Yields of Aromatic Compounds: Benchmarking the Machinery to Compute Intersystem Crossing Rates

The from-first-principles calculation of fluorescence quantum yields (FQYs) and lifetimes of organic dyes remains very challenging. In this manuscript we extensively test the static machinery to calculate FQYs. Specifically, we perform an extensive analysis on the parameters influencing the intersystem crossing (ISC), internal conversion (IC), and fluorescence rates calculations. The impact of i) the electronic structure (chosen exchange-correlation functional and spin-orbit Hamiltonian), ii) the vibronic parameters (coordinate system, broadening function, and dipole expansion), and iii) the excited-state kinetic models, are systematically assessed for a series of seven rigid aromatic molecules. Our studies provide more insights into the choice of parameters and the expected accuracy for the computational protocols aiming to deliver FQYs values. Some challenges are highlighted, such as, on the one hand, the difficulty to benchmark against the experimental non-radiative rates, for which the separation between the IC and ISC contributions is often not provided in the literature and, on the other hand, the need to go beyond the harmonic approximation for the calculation of the IC rates

Using radial distribution functions to calculate cellular crossabsorbed dose for β emitters: comparison with reference methodsand application for 18F-FDG cell labeling

International audienceTo further improve the understanding of in vitro biological effects of incorporated radionuclides, it is essential to accurately determine cellular absorbed doses. In the case of β emitters, the cross-dose is a major contribution, and can involve up to millions of cells. Realistic and efficient computational models are needed for that purpose. Conventionally, distances between each cell are calculated and the related dose contributions are cumulated to get the total cross-dose (standard method). In this work, we developed a novel approach for the calculation of the cross-absorbed dose, based on the use of the radial distribution function (rdf)) that describes the spatial properties of the cellular model considered. The dynamic molecular tool LAMMPS was used to create 3D cellular models and compute rdfs for various conditions of cell density, volume size, and configuration type (lattice and randomized geometry). The novel method is suitable for any radionuclide of nuclear medicine. Here, the model was applied for the labeling of cells with 18F-FDG used for PET imaging, and first validated by comparison with other reference methods. Mean Scross values calculated with the novel approach versus the standard method agreed very well (relative differences less that 0.1%). Implementation of the rdf -based approach with LAMMPS allowed to achieved results considerably faster than with the standard method, the computing time decreasing from hours to seconds for 106 cells. The rdf -based approach was also faster and easier to accommodate more complex cellular models than the standard and other published methods. Finally, a comparative study of the mean Scross for different types of configuration was carried out, as a function of the cell density and the volume size, allowing to better understand the impact of the configuration on the cross-absorbed dos

18F-FDG Labelling in Cell-Tracking PET Studies: Calculation of the Precise Absorbed Dose Deposited to Cell Nucleus and Correlation to in Vitro Biological Effects

International audiencePurpose: To investigate the biological impact of in vitro ¹8F-FDG cell labelling with respect to the absorbed dose.Methods: JURKAT and adipose mesenchymal stem cells (adMSCs) were radiolabelled with 18F-FDG and then tested for clonogenic survival assay, cell cycle analysis and ?-H2AX phosphorylation quantification. The cell density and incubation time were fixed while the ¹8F-FDG added activity was changed, such as the total absorbed dose to cells resulted in the ranges 0-4 Gy for JURKAT and 0-10 Gy for adMSCs. To this end, we developed a multi-cellular dosimetry model describing the full experiment, from the incubation of cells with ¹8F-FDG, washing steps, to culture of cells for functional assays. Dynamic changes in cell density, as well as experimentally determined activity uptake and retention with time were thus considered. Calculation of the self, cross and culture medium absorbed doses to the cell nucleus were done using MCNP6 simulations and analytical approaches. Lastly, the mean cell absorbed dose was correlated with the three biological endpoints and results were compared with X-ray irradiation (2.5 Gy/min).Results: The dose rate calculated over time was found to vary considerably along the labelling procedure. The centrifugation step required for cell washing induced an increase of the dose rate by a factor of 8 (reaching 0.12 Gy/min) and was mostly due to cross-irradiation.We observed that the survival percentage of cells dropped below 1% from 4.3 Gy and 8.3 Gy for JURKAT and adMSCs, respectively. The range of doses found in the literature for ¹8F-FDG labelling (0.5 Gy up to beyond 20 Gy) suggests that most of administered cells could eventually die, for some cases probably in the course of imaging.Conclusion: Our dosimetric model allowed to accurately determine the cell dose deposited throughout the ¹8F-FDG labelling. This will help to better understand the observed biological effects