Low-Dose Hypersensitivity and Bystander Effect are Not Mutually Exclusive in A549 Lung Carcinoma Cells after Irradiation with Charged Particles

The purpose of this study was to measure survival fraction of A549 lung carcinoma cells irradiated with charged particles of various LET and to determine mechanisms responsible for enhanced cell killing in the low-dose region. A549 cells were irradiated with a broadbeam of either 10 and 25 keV/μm protons or 100 keV/μm alpha particles and then processed for clonogenic assays and phospho-histone H3 staining. The survival fraction of unirradiated A549 cells co-cultured with irradiated cells was also evaluated. A549 cells were shown to exhibit low-dose hypersensitivity (HRS) for both protons and alpha particles. The dose threshold at which HRS occurs decreased with increasing linear energy transfer (LET), whereas αs, the initial survival curve slope, increased with increasing LET. In addition, the enhanced cell killing observed after irradiation with alpha particles was partly attributed to the bystander effect, due to the low proportion of hit cells at very low doses. Co-culture experiments suggest a gap junction-mediated bystander signal. Our results indicate that HRS is likely to be dependent on LET, and that a bystander effect and low-dose hypersensitivity may co-exist within a given cell line

Low-LET proton irradiation of A549 non-small cell lung adenocarcinoma cells: dose response and RBE determination

Since 1957, broad proton beam radiotherapy with a spread out Bragg peak has been used for cancer treatment. More recently, studies on the use of proton therapy in the treatment of non-small cell lung cancer (NSCLC) were performed and although the benefit of using protons for the treatment of NSCLC is recognized, more work is needed to gather additional data for the understanding of cell response. Human A549 cell survival was evaluated by colony forming assay 11 days after 10 keV/μm proton beam irradiation at 0.1 and 1 Gy/min. The residual energy of the proton beam at the location of the irradiated cells was 3.9 MeV. In parallel, early effects on the cell viability and DNA damage were assessed and DNA synthesis was measured. The survival curve obtained was fitted with both the linear and the induced-repair models, as a hyper-radiosensitivity was evidenced at very low doses. Above 0.5 Gy, a linear shape was observed with the α parameter equal to 0.824 ± 0.029 Gy(-1). In addition, early cell death and cell proliferation arrest were enhanced. Moreover, a clear correlation between DNA damage and surviving fraction was observed. Finally, comparisons with X and γ ray results indicate that proton irradiation at 10 keV/μm enhanced the tumor radiosensitivity with a significant dose-dependent decrease in the survival fraction. The RBE value of 1.9 ± 0.4 obtained for a 10% survival support this observation

Effects of alpha particle and proton beam irradiation as putative cross-talk between A549 cancer cells and the endothelial cells in a co-culture system

High-LET ion irradiation is being more and more often used to control tumors in patients. Given that tumors are now considered as complex organs composed of multiple cell types that can influence radiosensitivity, we investigated the effects of proton and alpha particle irradiation on the possible radioprotective cross-talk between cancer and endothelial cells

Étude des effets de radiations par rayons X ou par particules alpha sur les interactions entre cellules tumorales et cellules endothéliales

Cancer is a leading cause of death worldwide and the number of deaths due to this disease is increasing from year to year. Unfortunately, lung cancer has the highest mortality rate among all types of cancers, in Belgium or worldwide. Thus, it is essential to improve treatments already in use and to develop new modalities to fight cancer. Radiotherapy plays an important role in cancer treatment since about 50% of all cancer patients will undergo at least one radiotherapeutic session during their illness. Any improvement in radiotherapy may therefore be of benefit for a large number of patients. One way to improve radiotherapy is to maximize the dose delivered to the tumour while minimizing damages to healthy tissues. Hadrontherapy has the advantage to spare normal tissues surrounding the tumour because of the particular ballistic of charged particles, which is characterized by the Bragg peak. Indeed, charged particles release most of their energy at the end of their track in the matter whereas the energy deposition of photons (X-rays) is intense at the entrance in the tissues and decreases exponentially with depth. Another way to improve radiotherapy is to limit tumour radioresistance by increasing our knowledge of the radioresistance mechanisms in order to disrupt them. It has been demonstrated that tumour cells are able to protect tumour associated endothelial cells by secreting growth factors which inhibit endothelial cell apoptosis and promote angiogenesis. A reciprocal dialogue seems also to occur. Consequently, the therapeutic effect of ionizing radiations is limited. In the first part of this work, we compared the effects of X-ray and alpha particle irradiations on tumour cells, derived from a lung cancer, and endothelial cells. We demonstrated that alpha particles were more effective that X-rays and that mitotic catastrophe was the main type of cell death induced by both types of irradiation. We also demonstrated that X-ray and alpha particle irradiations induced the overexpression of genes implicated in cell death, angiogenesis and inflammation. In the second part of this work, we set up a co-culture system in order to study the interplay between tumour cells and endothelial cells after alpha particle irradiation. Lastly, we performed a gene expression study of proteins, cytokines and growth factors that could play a role in tumour radioresistance. We also observed gene expression changes for proteins that could be implicated in a crosstalk between the two cell types that could activate radioresistant or radiosensitive pathways. The study of the interplay between tumour cells and endothelial cells suggests the existence of an active communication between both cell types after irradiation that could be implicated in radioresistance mechanisms. The identification of molecules involved in these radioresistance processes could lead, in a near future, to the development of new targeted drugs which will block these radioprotective signals in order to improve radiotherapy effectiveness.La radiothérapie occupe une place importante dans le traitement contre le cancer. Un grand nombre de patients pourrait donc profiter de l’amélioration des traitements radiothérapeutiques. L’hadronthérapie possède l’avantage de mieux épargner les tissus sains environnants par rapport à la radiothérapie conventionnelle qui utilise des rayons X, grâce à la balistique particulière des particules chargées. Ainsi, l’essentiel de l’énergie de la particule est déposé à la fin du parcours de celle-ci contrairement aux photons (rayons X) qui perdent leur énergie tout au long de leur trajet. Une autre piste pour améliorer la radiothérapie serait de limiter la résistance des tumeurs aux radiations ionisantes en étudiant plus avant les mécanismes responsables de cette radiorésistance. En effet, un dialogue réciproque entre cellules tumorales et cellules endothéliales, via la sécrétion de facteurs de croissance et de cytokines, peut limiter les effets thérapeutiques des radiations ionisantes. Le premier objectif de cette thèse était donc de comparer les effets des rayons X et des particules alpha sur des cellules tumorales et des cellules endothéliales. Nous avons montré que les particules alpha sont plus efficaces que les rayons X et que la mitose catastrophique est le principal type de mort induit par ces deux types de radiation. Nous avons également montré que les irradiations par particules alpha et par rayons X induisent la surexpression de gènes impliqués dans la mort cellulaire, l’angiogenèse et l’inflammation. La seconde partie de ce travail consistait à mettre au point un système de co-culture permettant d’étudier le dialogue entre les cellules tumorales et les cellules endothéliales après irradiation au moyen de particules alpha. Nous avons à nouveau mis en évidence des changements d’expression de gènes codant pour des protéines pouvant être impliquées dans un dialogue entre les deux types cellulaires et pouvant conduire à des phénomènes de radiorésistance ou inversement de radio-sensibilisation.(DOCSC03) -- FUNDP, 201

The interplay of flow processes shapes aquatic invertebrate successions in floodplain channels - A modelling applied to restoration scenarios

The high biotic diversity supported byfloodplains is ruled by the interplay of geomorphic and hydrological pro-cesses at various time scales, from dailyfluctuations to decennial successions. Because understanding such pro-cesses is a key question in river restoration, we attempted to model changes in taxonomic richness in anassemblage of 58 macroinvertebrate taxa (21 gastropoda and 37 ephemeroptera, plecoptera and trichoptera,EPT) along two successional sequences typical for former braided channels. Individual models relating the occur-rence of taxa to overflow and backflow durations were developed fromfield measurements in 19floodplainchannels of the Rhônefloodplain (France) monitored over 10 years. The models were combined to simulate di-versity changes along a progressive alluviation and disconnection sequence after the reconnection with the mainriver of a previously isolated channel. Two scenarios were considered: (i) an upstream + downstream reconnec-tion creating a lotic channel, (ii) a downstream reconnection creating a semi-lotic channel. Reconnection led to adirect increase in invertebrate richness (on average x2.5). However, taxonomical richness showed a constant de-crease asisolationprogressedand reachedanaverage of 2 for EPTand 7 for gastropodsatthe end of the scenarios.With more than 80% of the taxonomic models with an AUC equal or higher than 0.7 and slopes of linear relationsbetween observed and predicted richness of 0.75 (gastropods) and 1 (EPT), the Boosted Regression Trees (BRT)provided a goodbasis for prediction ofspeciesassemblages. These models canbeusedto quantify a priorithe sus-tainability and ecological efficiency of restoration actions and helpfloodplain restoration planning andmanagement

La valeur de l'argent

International audienceMoney's value is undermined by inequalities, speculative bubbles affected by mimetism phenonena, and the environmental crisis. It is therefore a relation, which is socially constructed, in particular by accounting standards. It is displayed on the art market, and carries the religious symbolism of debt.La valeur de l'argent est mise à mal par les inégalités, les bulles spéculatives affectées par des phénomènes de mimétisme et la crise écologique. Elle est donc une relation socialement construite, notamment par les normes comptables, mise en spectacle sur le marché de l'art et inscrite dans une symbolique religieuse de la dette

Thermal regime, together with lateral connectivity, control aquatic invertebrate composition in river floodplains

International audience1. Large river floodplains are dynamic environments, where alternating low and high flows are key ecological processes shaping aquatic biota. As a result of fluctuations in flow in floodplain channels, the diversity of benthic assemblages is assumed to result from the balance between surface flow connections, which are dominant during high flows, and groundwater inputs, which are dominant during low flows. However, the relative importance of these inputs in explaining aquatic invertebrate diversity has never been tested. 2. The response of aquatic invertebrates to hydrological changes of a river flood-plain was investigated in seven braided and six braided-anastomosed flood-plain channels of the French upper Rhône River that are fed by three different processes: groundwater supply (which controls the thermal inertia of the water bodies), surface slow flow connections (i.e. diffuse overbank flows; passive overflow), and surface shear stress-related connections (i.e. condensed flows; active overflow) during high flows. 3. Generalised dissimilarity models indicated that floodplain invertebrate composition had complex relationships with the three processes considered. The relative importance of the latter appeared dependent upon the morphology of the floodplain channels. In the braided channels, the effects of shear stress-related connections were more prominent than in the anastomosed ones, for which the effects of the three processes were more similar. 4. Overall, the diversity of flow connections, that is, lateral surface water connections (both shear stress-related and slow, as defined above) and vertical connection with groundwater (inferred through thermal inertia) enhanced the species turnover at the reach scale. Thermal inertia influenced invertebrate composition when, during low flow periods, surface flow connections had limited effect. 5. Our results highlighted that the role of hydrologic connectivity upon flood-plain diversity cannot be reduced to a single process. They also indicate the importance of vertical connectivity for maintaining biodiversity in floodplain habitats where surface flow connectivity is neither frequent nor constant

Comparison of X-ray and alpha particle effects on a human cancer and endothelial cells: survival curves and gene expression profiles.

Alpha particle irradiations are more effective than X-rays. The gene expression changes observed in both cell types after alpha particle or X-ray exposure showed possible crosstalk between both cell types that may induce the development of radioresistance

Six-minute stepper test: a valid clinical exercise tolerance test for COPD patients

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