Predicting Cell Death and Mutation Frequency for a Wide Spectrum of LET by Assuming DNA Break Clustering Inside Repair Domains

Cosmic radiation, which is composed of high charged and energy (HZE) particles, is responsible for cell death and mutation, which may be involved in cancer induction. Mutations are consequences of mis-repaired DNA breaks especially double-strand breaks (DSBs) that induce inter- and intra-chromosomal rearrangements (translocations, deletions, inversion). In this study, a computer simulation model is used to investigate the clustering of DSBs in repair domains, previously evidenced by our group in human breast cells [1]. This model is calibrated with experimental data measuring persistent 53BP1 radiation-induced foci (RIF) and is used to explain the high relative biological effectiveness (RBE) of HZE for both cell death and DNA mutation frequencies. We first validate our DSB cluster model using a new track structure model deployed on a simple geometrical configuration for repair domains in the nucleus; then we extend the scope from cell death to mutation induction. This work suggests that mechanism based on DSB repair process can explain several biological effects induced by HZE particles on different type of living cell

Du jeu des identités à la transformation de réalités partagées : un programme d’ateliers d’expression théâtrale pour adolescents immigrants et réfugiés

La migration à l’adolescence est particulièrement délicate à cause du fardeau conjugué que représente à ce stade de la vie l’intégration des multiples pertes associées à la migration et l’adaptation au statut de jeune adulte. Le programme d’ateliers d’expression théâtrale vise à faciliter l’adaptation des adolescents immigrants et réfugiés à leur nouvel environnement à partir d’un travail créatif autour des enjeux identitaires liés à la migration et à un statut de minorité. Ces ateliers conjuguent une approche inspirée du théâtre playback qui permet une mise en scène du vécu personnel et le théâtre forum de Boal qui met l’accent sur la transformation collective de l’expérience. Les résultats d’une évaluation qualitative des ateliers d’expression théâtrale suggèrent que ceux-ci constituent un lieu d’expression ou les participants se sentent en sécurité et soutenus par l’équipe ainsi que par le caractère rituel du jeu théâtral. Les ateliers permettent de représenter la multiplicité des valeurs et des références internes et externes de l’adolescent et de les renégocier sans dichotomiser le « eux » et le « nous », en s’adressant aux questions de justice sociale qui se posent à la collectivité. Ils favorisent aussi l’élaboration des transitions de l’adolescence en permettant l’évocation des pertes de la migration et le passage vers une identité hybride.Migration during adolescence represents a challenge for the youth who need to simultaneously work through the multiple losses associated with the migratory journey and adapt to a young adult status. The drama workshop program described here was designed to facilitate the adjustment of newly arrived immigrant teens. The aim of the program is to make it easier for adolescents to adjust to their new environment through creative group work around identity issues. The program also seeks to improve intergroup relations in multiethnic schools. The workshops are inspired both from playback theater and from Boal’s form theater which emphasizes the collective transformation of the singular experience. The qualitative assessment of the program effects on the adolescents suggests that the workshops constitute a safe space of expression, in which the team and the ritual nature of the play hold the participants. The workshops facilitate the representation of the multiplicity of values in the adolescent world and invite them to reconsider the way in which they interact, with their environment, without splitting between “us” and “them,” but rather creating solidarities around issues of social justice. The workshops also address the life transformation associated both with adolescence and migration and help the elaboration of the losses linked to the migratory journey and the construction of a hybrid identity.La migración en la adolescencia es particularmente delicada a causa de la carga conjunta que representa en esta etapa de la vida la integración de las múltiples pérdidas asociadas a la migración y la adaptación a un estatus de joven adulto. El programa de talleres de expresión teatral busca facilitar la adaptación de los adolescentes inmigrantes y refugiados a su nuevo entorno, a partir de un trabajo creativo relacionado con las cuestiones de identidad ligadas a la migración y a un estatus de minoría. Estos talleres conjugan un enfoque inspirado del teatro playback, que permite una puesta en escena de una experiencia personal, y el teatro forum de Boal, que pone el acento en la transformación colectiva de la experiencia. Los resultados de una evaluación cualitativa de los talleres de expresión teatral sugieren que éstos constituyen un lugar de expresión en el que los participantes se sienten seguros y apoyados por el equipo, así como por el carácter ritual de la representación teatral. Los talleres permiten representar la multiplicidad de los valores y referencias internas y externas del adolescente, y renegociarlos sin crear una dicotomía entre el “ellos” y “nosotros” al tratar cuestiones de justicia social que se plantean a la colectividad. Favorecen también la elaboración de las transiciones de la adolescencia al permitir la evocación de las pérdidas de la migración y el paso hacia una identidad híbrida.A imigração na adolescência é especialmente delicada, por causa do fardo conjugado que representa, neste ponto da vida, a integração das múltiplas perdas associadas à imigração e à adaptação ao estatuto de jovem adulto. O programa de ateliês de expressão teatral visa facilitar a adaptação dos adolescentes imigrantes e refugiados ao seu novo ambiente, a partir de um trabalho criativo a respeito das preocupações identitárias relacionadas à imigração e a um estatuto de minoria. Estes ateliês conjugam uma abordagem inspirada no teatro playback, que permite uma representação da vivência pessoal, e no teatro fórum de Boal, que ressalta a transformação coletiva da experiência. Os resultados de uma avaliação qualitativa dos ateliês de expressão teatral sugerem que estes continuam sendo um lugar de expressão onde os participantes sentem-se em segurança e apoiados pela equipe e pelo caráter ritual da representação teatral. Os ateliês permitem representar a multiplicidade dos valores e das referências internas e externas do adolescente e renegociá-los sem dicotomizar o “eles” e o “nós”, falando sobre questões de justiça social que são colocadas à coletividade. Os ateliês favorecem também a elaboração das transições da adolescência permitindo a evocação das perdas da imigração e a passagem para uma identidade híbrida

DNA Repair Domain Modeling Can Predict Cell Death and Mutation Frequency for Wide Range Spectrum of Radiation

Exploration missions to Mars and other destinations raise many questions about the health of astronauts. The continuous exposure of astronauts to galactic cosmic rays is one of the main concerns for long-term missions. Cosmic ionizing radiations are composed of different ions of various charges and energies notably, highly charged energy (HZE) particles. The HZE particles have been shown to be more carcinogenic than low-LET radiation, suggesting the severity of chromosomal aberrations induced by HZE particles is one possible explanation. However, most mathematical models predicting cell death and mutation frequency are based on directly fitting various HZE dose response and are in essence empirical approaches. In this work, we assume a simple biological mechanism to model DNA repair and use it to simultaneously explain the low- and high-LET response using the exact same fitting parameters. Our work shows that the geometrical position of DNA repair along tracks of heavy ions are sufficient to explain why high-LET particles can induce more death and mutations. Our model is based on assuming DNA double strand breaks (DSBs) are repaired within repair domain, and that any DSBs located within the same repair domain cluster into one repair unit, facilitating chromosomal rearrangements and increasing the probability of cell death. We introduced this model in 2014 using simplified microdosimetry profiles to predict cell death. In this work, we collaborated with NASA Johnson Space Center to generate more accurate microdosimetry profiles derived by Monte Carlo techniques, taking into account track structure of HZE particles and simulating DSBs in realistic cell geometry. We simulated 224 data points (D, A, Z, E) with the BDSTRACKS model, leading to a large coverage of LET from ~10 to 2,400 keV/m. This model was used to generate theoretical RBE for various particles and energies for both cell death and mutation frequencies. The RBE LET dependence is in agreement with experimental data known in human and murine cells. It suggests that cell shape and its orientation with respect to the HZE particle beam can modify the biological response to radiation. Such discovery will be tested experimentally and, if proven accurate, will be another strong supporting evidence for DNA repair domains and their critical role in interpreting cosmic radiation sensitivity

Genetic Correlation with the DNA Repair Assay in Mice Exposed to High-LET

We hypothesize that DNA damage induced by high local energy deposition, occurring when cells are traversed by high-LET (Linear Energy Transfer) particles, can be experimentally modeled by exposing cells to high doses of low-LET. In this work, we validate such hypothesis by characterizing and correlating the time dependence of 53BP1 radiation-induced foci (RIF) for various doses and LET across 72 primary skin fibroblast from mice. This genetically diverse population allows us to understand how genetic may modulate the dose and LET relationship. The cohort was made on average from 3 males and 3 females belonging to 15 different strains of mice with various genetic backgrounds, including the collaborative cross (CC) genetic model (10 strains) and 5 reference mice strains. Cells were exposed to two fluences of three HZE (High Atomic Energy) particles (Si 350 megaelectronvolts per nucleon, Ar 350 megaelectronvolts per nucleon and Fe 600 megaelectronvolts per nucleon) and to 0.1, 1 and 4 grays from a 160 kilovolt X-ray. Individual radiation sensitivity was investigated by high throughput measurements of DNA repair kinetics for different doses of each radiation type. The 53BP1 RIF dose response to high-LET particles showed a linear dependency that matched the expected number of tracks per cell, clearly illustrating the fact that close-by DNA double strand breaks along tracks cluster within one single RIF. By comparing the slope of the high-LET dose curve to the expected number of tracks per cell we computed the number of remaining unrepaired tracks as a function of time post-irradiation. Results show that the percentage of unrepaired track over a 48 hours follow-up is higher as the LET increases across all strains. We also observe a strong correlation between the high dose repair kinetics following exposure to 160 kilovolts X-ray and the repair kinetics of high-LET tracks, with higher correlation with higher LET. At the in-vivo level for the 10-CC strains, we observe that drops in the number of T-cells and B-cells found in the blood of mice 24 hours after exposure to 0.1 gray of 320 kilovolts X-ray correlate well with slower DNA repair kinetics in skin cells exposed to X-ray. Overall, our results suggest that repair kinetics found in skin is a surrogate marker for in-vivo radiation sensitivity in other tissue, such as blood cells, and that such response is modulated by genetic variability

A cancer model for the angiogenic switch

International audienceThe occurrence of metastasis is an important feature in cancer development. In order to have a one-site model taking into account the interactions between host, effector immune and tumor cells which is not only valid for the early stages of tumor growth, we developed in this paper a new model where are incorporated interactions of these three cell populations with endothelial cells. These latter cells are responsible for the neo-vascularization of the tumor site which allows the migration of tumor cells to distant sites. It is then shown that, for some parameter values, the resulting model for the four cell populations reproduces the angiogenic switch, that is, the transition from avascular to vascular tumor

Approche déteministe des dynamiques de cancer : vers une individualisation des pronostics d'évolution des cancers

Currently, most research in oncology involve genetic mutations potentially responsible for cancer initiation. Since the identification of a large number of genes involved in carcinogenesis is not correlated to an increase in number of patients in remission, investigating a cancer as a pure genetic process was not effecient as initially expected. Although genetic mutations have a key role in tumorigenesis, some other factors such as the micro-environment should be also considered. In daily practice, the oncologist must address the question of his ability to predict (or not) the evolution of the cancer his patient has. He is thus challenged by too often unpredictable outcomes, which can be explained by the too large number of parameters influencing the cancer evolution and the technology available to evaluate them. The nonlinear dynamical systems theory could be helpful to better understand this disease.Thus, the aim of this thesis is to investigate tumor dynamics, thanks to chaos theory, by taking into account the role of the micro-environment. After a description of the biology involved in carcinogenesis, a model having the advantage of involving the host cells, the tumor micro-environment, in addition to effector immune and tumor cells, was analyzed. We found that an action on host cells is more efficient than an action on the tumor mass. In order to reproduce the tumor neo-angiogenesis, a fourth equation was added to describe the evolution of endothelial cells. This new model was able to reproduce the angiogenic switch occurring between the avascular and vascular stages of tumorigenesis. This four-dimensional model (limited to a single tumor site) was then extended to a regular grid to simulate the spatial growth of tumors. Avascular phase simulations of tumor growth were performed and the obtained dynamic was analyzed.Actuellement, la majorité des recherches en oncologie portent sur les mutations génétiques potentiellement à l’origine de l’initiation du cancer. Mais l’identification d’un grand nombre de gènes impliqués dans la cancérogenèse n’est pas corrélée à une augmentation du nombre de patients en rémission. Ainsi, limiter le cancer à un processus purement génétique, donc stochastique, ne se révèle pas aussi efficace que cela était espéré. Bien que les mutations génétiques aient un rôle clé dans la tumorigenèse, d’autres facteurs tels que le micro-environnement doivent être pris en compte.Dans sa pratique quotidienne, l’oncologue est amené à se poser des questions relatives à l’évolution d’un cancer chez un patient spécifique. Il est interpelé par les évolutions souvent imprédictibles à long terme, ce qui s’explique par le nombre de paramètres influençant cette évolution qui ne peuvent être actuellement évalués par les techniques à sa disposition. La théorie des systèmes dynamiques non linéaires pourraient permettre de mieux appréhender cette pathologie.Ainsi, l’objectif de cette thèse est d’étudier la dynamique tumorale grâce à la théorie du chaos dans une perspective prenant en compte le micro-environnement. Après une étude de la biologie impliquée dans la cancérogenèse, un modèle présentant l’avantage d’impliquer les cellules hôtes, c’est-à-dire le micro-environnement tumoral, en plus des cellules immunitaires effectrices et tumorales, a été analysé. Il est apparu qu’une action sur les cellules hôtes est préférable à une action sur la masse tumorale. Afin de reproduire la néo-angiogenèse tumorale, nous avons ajouté une équation reflétant l’évolution des cellules endothéliales. Ce modèle a permis de retrouver la bascule angiogénique apparaissant entre les phases avasculaire et vasculaire de la tumorigenèse. Le modèle (limité à un site tumoral) a ensuite été étendu sur réseau de manière à simuler la croissance spatiale de tumeurs. Des simulations de la phase avasculaire de la croissance tumorale ont été réalisées et les dynamiques ainsi obtenues analysées

Approche déteministe des dynamiques de cancer : vers une individualisation des pronostics d'évolution des cancers

Currently, most research in oncology involve genetic mutations potentially responsible for cancer initiation. Since the identification of a large number of genes involved in carcinogenesis is not correlated to an increase in number of patients in remission, investigating a cancer as a pure genetic process was not effecient as initially expected. Although genetic mutations have a key role in tumorigenesis, some other factors such as the micro-environment should be also considered. In daily practice, the oncologist must address the question of his ability to predict (or not) the evolution of the cancer his patient has. He is thus challenged by too often unpredictable outcomes, which can be explained by the too large number of parameters influencing the cancer evolution and the technology available to evaluate them. The nonlinear dynamical systems theory could be helpful to better understand this disease.Thus, the aim of this thesis is to investigate tumor dynamics, thanks to chaos theory, by taking into account the role of the micro-environment. After a description of the biology involved in carcinogenesis, a model having the advantage of involving the host cells, the tumor micro-environment, in addition to effector immune and tumor cells, was analyzed. We found that an action on host cells is more efficient than an action on the tumor mass. In order to reproduce the tumor neo-angiogenesis, a fourth equation was added to describe the evolution of endothelial cells. This new model was able to reproduce the angiogenic switch occurring between the avascular and vascular stages of tumorigenesis. This four-dimensional model (limited to a single tumor site) was then extended to a regular grid to simulate the spatial growth of tumors. Avascular phase simulations of tumor growth were performed and the obtained dynamic was analyzed.Actuellement, la majorité des recherches en oncologie portent sur les mutations génétiques potentiellement à l’origine de l’initiation du cancer. Mais l’identification d’un grand nombre de gènes impliqués dans la cancérogenèse n’est pas corrélée à une augmentation du nombre de patients en rémission. Ainsi, limiter le cancer à un processus purement génétique, donc stochastique, ne se révèle pas aussi efficace que cela était espéré. Bien que les mutations génétiques aient un rôle clé dans la tumorigenèse, d’autres facteurs tels que le micro-environnement doivent être pris en compte.Dans sa pratique quotidienne, l’oncologue est amené à se poser des questions relatives à l’évolution d’un cancer chez un patient spécifique. Il est interpelé par les évolutions souvent imprédictibles à long terme, ce qui s’explique par le nombre de paramètres influençant cette évolution qui ne peuvent être actuellement évalués par les techniques à sa disposition. La théorie des systèmes dynamiques non linéaires pourraient permettre de mieux appréhender cette pathologie.Ainsi, l’objectif de cette thèse est d’étudier la dynamique tumorale grâce à la théorie du chaos dans une perspective prenant en compte le micro-environnement. Après une étude de la biologie impliquée dans la cancérogenèse, un modèle présentant l’avantage d’impliquer les cellules hôtes, c’est-à-dire le micro-environnement tumoral, en plus des cellules immunitaires effectrices et tumorales, a été analysé. Il est apparu qu’une action sur les cellules hôtes est préférable à une action sur la masse tumorale. Afin de reproduire la néo-angiogenèse tumorale, nous avons ajouté une équation reflétant l’évolution des cellules endothéliales. Ce modèle a permis de retrouver la bascule angiogénique apparaissant entre les phases avasculaire et vasculaire de la tumorigenèse. Le modèle (limité à un site tumoral) a ensuite été étendu sur réseau de manière à simuler la croissance spatiale de tumeurs. Des simulations de la phase avasculaire de la croissance tumorale ont été réalisées et les dynamiques ainsi obtenues analysées