Spectral and spatial shaping of a laser-produced ion beam for radiation-biology experiments

International audience; The study of radiation biology on laser-based accelerators is most interesting due to the unique irradiation conditions they can produce, in terms of peak current and duration of the irradiation. In this paper we present the implementation of a beam transport system to transport and shape the proton beam generated by laser-target interaction for in vitro irradiation of biological samples. A set of four permanent magnet quadrupoles is used to transport and focus the beam, efficiently shaping the spectrum and providing a large and relatively uniform irradiation surface. Real time, absolutely calibrated, dosimetry is installed on the beam line, to enable shot-to-shot control of dose deposition in the irradiated volume. Preliminary results of cell sample irradiation are presented to validate the robustness of the full system

Combinatorial, additive and dose-dependent drug–microbiome associations

Data availability: The source data for the figures are provided at Zenodo (https://doi.org/10.5281/zenodo.4728981). Raw shotgun sequencing data that support the findings of this study have been deposited at the ENA under accession codes PRJEB41311, PRJEB38742 and PRJEB37249 with public access. Raw spectra for metabolomics have been deposited in the MassIVE database under the accession codes MSV000088043 (UPLC–MS/MS) and MSV000088042 (GC–MS). The metadata on disease groups and drug intake are provided in Supplementary Tables 1–3. The demographic, clinical and phenotype metadata, and processed microbiome and metabolome data for French, German and Danish participants are available at Zenodo (https://doi.org/10.5281/zenodo.4674360).Code availability: The new drug-aware univariate biomarker testing pipeline is available as an R package (metadeconfoundR; Birkner et al., manuscript in preparation) at Github (https://github.com/TillBirkner/metadeconfoundR) and at Zenodo (https://doi.org/10.5281/zenodo.4721078). The latest version (0.1.8) of this package was used to generate the data shown in this publication. The code used for multivariate analysis based on the VpThemAll package is available at Zenodo (https://doi.org/10.5281/zenodo.4719526). The phenotype and drug intake metadata, processed microbiome, and metabolome data and code resources are available for download at Zenodo (https://doi.org/10.5281/zenodo.4674360). The code for reproducing the figures is provided at Zenodo (https://doi.org/10.5281/zenodo.4728981).During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery1,2,3,4,5. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the explanatory power of drugs for the variability in both host and gut microbiome features exceeds that of disease. We quantify inferred effects of single medications, their combinations as well as additive effects, and show that the latter shift the metabolome and microbiome towards a healthier state, exemplified in synergistic reduction in serum atherogenic lipoproteins by statins combined with aspirin, or enrichment of intestinal Roseburia by diuretic agents combined with beta-blockers. Several antibiotics exhibit a quantitative relationship between the number of courses prescribed and progression towards a microbiome state that is associated with the severity of cardiometabolic disease. We also report a relationship between cardiometabolic drug dosage, improvement in clinical markers and microbiome composition, supporting direct drug effects. Taken together, our computational framework and resulting resources enable the disentanglement of the effects of drugs and disease on host and microbiome features in multimedicated individuals. Furthermore, the robust signatures identified using our framework provide new hypotheses for drug–host–microbiome interactions in cardiometabolic disease.This work was supported by the European Union’s Seventh Framework Program for research, technological development and demonstration under grant agreement HEALTH-F4-2012-305312 (METACARDIS). Part of this work was also supported by the EMBL, by the Metagenopolis grant ANR-11-DPBS-0001, by the H2020 European Research Council (ERC-AdG-669830) (to P.B.), and by grants from the Deutsche Forschungsgemeinschaft (SFB1365 to S.K.F. and L.M.; and SFB1052/3 A1 MS to M.S. (209933838)). Assistance Publique-Hôpitaux de Paris is the promoter of the clinical investigation (MetaCardis). M.-E.D. is supported by the NIHR Imperial Biomedical Research Centre and by grants from the French National Research Agency (ANR-10-LABX-46 (European Genomics Institute for Diabetes)), from the National Center for Precision Diabetic Medicine – PreciDIAB, which is jointly supported by the French National Agency for Research (ANR-18-IBHU-0001), by the European Union (FEDER), by the Hauts-de-France Regional Council (Agreement 20001891/NP0025517) and by the European Metropolis of Lille (MEL, Agreement 2019_ESR_11) and by Isite ULNE (R-002-20-TALENT-DUMAS), also jointly funded by ANR (ANR-16-IDEX-0004-ULNE), the Hauts-de-France Regional Council (20002845) and by the European Metropolis of Lille (MEL). R.J.A. is a member of the Collaboration for joint PhD degree between EMBL and Heidelberg University, Faculty of Bioscience. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research institution at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation

Combinatorial, additive and dose-dependent drug–microbiome associations

During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the explanatory power of drugs for the variability in both host and gut microbiome features exceeds that of disease. We quantify inferred effects of single medications, their combinations as well as additive effects, and show that the latter shift the metabolome and microbiome towards a healthier state, exemplified in synergistic reduction in serum atherogenic lipoproteins by statins combined with aspirin, or enrichment of intestinal Roseburia by diuretic agents combined with beta-blockers. Several antibiotics exhibit a quantitative relationship between the number of courses prescribed and progression towards a microbiome state that is associated with the severity of cardiometabolic disease. We also report a relationship between cardiometabolic drug dosage, improvement in clinical markers and microbiome composition, supporting direct drug effects. Taken together, our computational framework and resulting resources enable the disentanglement of the effects of drugs and disease on host and microbiome features in multimedicated individuals. Furthermore, the robust signatures identified using our framework provide new hypotheses for drug–host–microbiome interactions in cardiometabolic disease

Modulation of the Rho/ROCK pathway in heart and lung after thorax irradiation reveals targets to improve normal tissue toxicity

International audienceThe medical options available to prevent or treat radiation-induced injury are scarce and developing effective countermeasures is still an open research field. In addition, more than half of cancer patients are treated with radiation therapy, which displays a high antitumor efficacy but can cause, albeit rarely, disabling long-term toxicities including radiation fibrosis. Progress has been made in the definition of molecular pathways associated with normal tissue toxicity that suggest potentially effective therapeutic targets. Targeting the Rho/ROCK pathway seems a promising anti-fibrotic approach, at least in the gut; the current study was performed to assess whether this target was relevant to the prevention and/or treatment of injury to the main thoracic organs, namely heart and lungs. First, we showed activation of two important fibrogenic pathways (Smad and Rho/ROCK) in response to radiationexposure to adult cardiomyocytes; we extended these observations in vivo to the heart and lungs of mice, 15 and 30 weeks post-irradiation. We correlated this fibrogenic molecular imprint with alteration of heart physiology and long-term remodelling of pulmonary and cardiac histological structures. Lastly, cardiac and pulmonary radiation injury and bleomycin-induced pulmonary fibrosis were successfully modulated using Rho/ROCK inhibitors (statins and Y-27632) and this was associated with a normalization of fibrogenic markers. In conclusion, the present paper shows for the first time, activation of Rho/ROCK and Smad pathways in pulmonary and cardiac radiation-induced delayed injury. Our findings thereby reveal a safe and efficient therapeutic opportunity for the abrogation of late thoracic radiation injury, potentially usable either before or after radiation exposure; this approach is especially attractive in (i) the radiation oncology setting, as it does not interfere with prior anti-cancer treatment and in (ii) radioprotection, as applicable to the treatment of established radiation injury, for example in the case of radiation accidents or acts of terrorism. © 2010 Bentham Science Publishers Ltd

Chin wing: Technical note

International audienc

Automatic detection of dicentrics chromosomes in biodosimetry

In case of large scale accidental overexposure to ionizing radiation, a rapid triage of the population exposed is needed first, followed by an accurate dose estimation for each individual. Currently, these two steps are performed by scoring unstable chromosomal aberrations (dicentrics, rings and fragments) in peripheral blood lymphocytes after Giemsa staining. For the triage step, only 50 metaphases are currently manually analysed. This is rapid but not accurate and may introduce false negative dose classification. For the second step, 500 metaphases are currently manually analysed. This is very accurate but very long. To improve the method, we have studied the automatic dicentrics detection by Metafer 4 software (MetaSystems) on accidental overexposure victims of the Dakar accident (Africa). The study has been performed firstly by the manual scoring of dicentrics on 50 metaphases (50 MS) used for a population triage, secondly by the manual scoring of dicentrics on 500 metaphases (standard approach; 500 MS) and thirdly by the automatic scoring of dicentrics (ADS). The comparison between dose classification obtained by 50MS and obtained by 500MS methods shows 54.2% (32 on 59 individuals) correlation however there is 45.8% (27 on 59 individuals) of underestimation. Moreover, comparisons of dose classification between the results obtained by ADS and 500MS show 95.7% (44 on 46 individuals) of correlation and 4.3% (2 on 46 individuals) of underestimation. In addition, the mean doses obtained by ADS method are near to the mean doses obtained by 500MS. To conclude, ADS method is faster and more accurate than the manual scoring of 50 cells and could be used in case of triage. In addition, ADS method could also be used instead of 500MS in case of individual dose estimation as it is as accurate and much faster

Strategy for population triage based on dicentric analysis

After large-scale accidental overexposure to ionizing radiation, a rapid triage of the exposed population can be performed by scoring dicentrics and ring chromosomes among 50 metaphases. This is rapid but is not accurate because the sensitivity is around 0.5 Gy. After the triage step, dose can be estimated by scoring 500 metaphases. This is lengthy but very accurate because the sensitivity is between 0.1 and 0.2 Gy. To improve the methodology, we propose the use of software for automatic dicentric scoring that was tested on victims of an accident in Dakar. Manual scoring of 50 metaphases was carried out, then manual scoring of 500 metaphases, and automatic scoring. Comparison between the dose classifications obtained with manual scoring on 50 metaphases and 500 metaphases showed 50 misclassification with the manual scoring on 50 metaphases. Comparison between the dose classifications obtained with the automatic scoring and manual scoring on 500 metaphases showed only 4.35 misclassification with the automatic scoring. The automatic scoring method is more accurate than the manual scoring on 50 metaphases and can therefore be used for triage, and in place of the manual scoring on 500 metaphases method for individual dose estimation, because it is as accurate and much faster. © 2009 The Radiation Research Society

Monitoring translocations by M-FISH and three-color FISH painting techniques: A study of two radiotherapy patients

Purpose: To compare translocation rate using either M-FISH or FISH-3 in two patients treated for head and neck cancer, with a view to retrospective dosimetry. Materials and methods: Translocation analysis was performed on peripheral blood lymphocyte cultures from blood samples taken at different times during the radiotherapy (0 Gy, 12 Gy and 50 Gy) and a few months after the end of the treatment (follow-up). Results: Estimated translocation yield varied according to the FISH technique used. At 50 Gy and follow-up points, the translocation yields were higher with FISH-3 than with M-FISH. This difference can be attributed to three events. First, an increase in complex aberrations was observed for 50 Gy and follow-up points compared with 0 Gy and 12 Gy points. Second, at the end of treatment for patient A, involvement of chromosomes 2, 4, 12 in translocations was less than expected according to the Lucas formula. Third, a clone bearing a translocation involving a FISH-3 painted chromosome was detected. Conclusions: More translocations were detected with M-FISH than with FISH-3, and so M-FISH is expected to improve the accuracy of chromosome aberration analyses in some situations