Cold-Atmospheric Plasma Induces Tumor Cell Death in Preclinical In Vivo and In Vitro Models of Human Cholangiocarcinoma

Through the last decade, cold atmospheric plasma (CAP) has emerged as an innovative therapeutic option for cancer treatment. Recently, we have set up a potentially safe atmospheric pressure plasma jet device that displays antitumoral properties in a preclinical model of cholangiocarcinoma (CCA), a rare and very aggressive cancer emerging from the biliary tree with few efficient treatments. In the present study, we aimed at deciphering the molecular mechanisms underlying the antitumor effects of CAP towards CCA in both an in vivo and in vitro context. In vivo, using subcutaneous xenografts into immunocompromised mice, CAP treatment of CCA induced DNA lesions and tumor cell apoptosis, as evaluated by 8-oxoguanine and cleaved caspase-3 immunohistochemistry, respectively. The analysis of the tumor microenvironment showed changes in markers related to macrophage polarization. In vitro, the incubation of CCA cells with CAP-treated culture media (i.e., plasma-activated media, PAM) led to a dose response decrease in cell survival. At molecular level, CAP treatment induced double-strand DNA breaks, followed by an increased phosphorylation and activation of the cell cycle master regulators CHK1 and p53, leading to cell cycle arrest and cell death by apoptosis. In conclusion, CAP is a novel therapeutic option to consider for CCA in the future

On the evolution of the size of Lyman alpha halos across cosmic time: no change in the circumgalactic gas distribution when probed by line emission

Lyman $\alpha$ (Ly$\alpha$) is now routinely used as a tool for studying high-redshift galaxies and its resonant nature means it can trace neutral hydrogen around star-forming galaxies. Integral field spectrograph measurements of high-redshift Ly$\alpha$ emitters indicate that significant extended Ly$\alpha$ halo emission is ubiquitous around such objects. We present a sample of redshift 0.23 to 0.31 galaxies observed with the Hubble Space Telescope selected to match the star formation properties of high-$z$ samples while optimizing the observations for detection of low surface brightness Ly$\alpha$ emission. The Ly$\alpha$ escape fractions range between 0.7\% and 37\%, and we detect extended Ly$\alpha$ emission around six out of seven targets. We find Ly$\alpha$ halo to UV scale length ratios around 6:1 which is marginally lower than high-redshift observations, and halo flux fractions between 60\% and 85\% -- consistent with high-redshift observations -- when using comparable methods. However, our targets show additional extended stellar UV emission: we parametrize this with a new double exponential model. We find that this parametrization does not strongly affect the observed Ly$\alpha$ halo fractions. We find that deeper H$\alpha$ data would be required to firmly determine the origin of Ly$\alpha$ halo emission, however, there are indications that H$\alpha$ is more extended than the central FUV profile, potentially indicating conditions favorable for the escape of ionizing radiation. We discuss our results in the context of high-redshift galaxies, cosmological simulations, evolutionary studies of the circumgalactic medium in emission, and the emission of ionizing radiation.Comment: 20 page, 14 figures, 6 tables. Accepted for publication in MNRA

Caractérisation du microenvironnement tumoral immunitaire des carcinomes hépatocellulaires réséqués

Hepatocellular carcinoma (HCC) shows globally low response to immunotherapy and HCC immune microenvironment is not well characterized. Our objective was to connect immune, viral and morphologic aspects of HCC and understand how they intervene in sensitivity to immune checkpoint blockade. In this study, we performed a transcriptomic analysis of onco-immune genes to characterize the tumor microenvironment of 170 HCC: 23% hepatitis B (HBV), 29% hepatitis C (HCV), 16% metabolic syndrome, 17% alcohol consumption related, and 14% of undetermined etiology. We correlated gene expression profiles with clinical, morphological and viral features. We did not observe difference of immune microenvironment at a global scale, between etiologies. But within HBV group, we identified 3 Clusters. None of of these clusters expressed ϒ-interferon (compared to 25% of HCC of all etiologies combined). Cluster 1 showed an ambivalent « hot » and exhausted profile with higher expression of exhaustion markers but lower densities of T lymphocytes by immunostaining. This Cluster was associated with HBV transcription and patients from this Cluster showed higher recurrence. Cluster 2 was enriched with macrotrabecular massive subtype and was immunologically “cold” and was also associated with higher recurrence. At last, Cluster 3 was developed much more on cirrhotic liver and showed an intermediate level of immune cells infiltration, with no marker of exhaustion. It was associated with lower recurrence. In conclusion we highlight viral related specificities within HBV HCC, associated with prognostic significance.Les carcinomes hépatocellulaires (CHC) répondent mal à l’immunothérapie et leur environnement immun n’est pas bien caractérisé. Notre objectif était de faire le pont entre les aspects morphologiques, viraux et immuns et analyser leur impact sur la sensibilité à l’immunothérapie. Nous avons réalisé une analyse transcriptomique de l’environnement immun de 170 CHC: 23% d’étiologie virale B (VHB), 29% d’étiologie virale C (VHC), 16% d’étiologie métabolique, 17% d’étiologie alcoolique, 14% d’étiologie indéterminée. Nous avons corrélé les profils transcriptomiques aux données cliniques, morphologiques et virales (ARN prégénomique du VHB). Nous n’avons pas observé de différence globale dans l’environnement immun des CHC en fonction des étiologies, mais avons identifié 3 clusters du VHB donc aucun n’exprimait d’interféron-γ (contre 25% des CHC toutes étiologies confondues). Le Cluster 1, associé à une récurrence élevée, avait un profil immun ambivalent et chaud, surexprimait des marqueurs d’épuisement mais montrait morphologiquement une faible densité de lymphocytes T et était associé à la présence d’une transcription du VHB. Le Cluster 2, aussi associé à une récurrence élevée, était enrichi en sous-type macrotrabéculaire et avait profil immun froid. Le Cluster 3, de meilleur pronostic, était plus développé sur foie cirrhotique et montrait un niveau intermédiaire d’infiltration de cellules immunes, sans expression de marqueurs d’épuisement. En conclusion, nous montrons des spécificités immunes au sein des CHC liés à l’HBV, en relation avec des facteurs viraux transcriptionnels, et avec une portée pronostique

Openwind: a software to simulate wind instruments, as a tool for acoustic teachers

International audienceOpenwind is a python library, (free and open source) dedicated to the simulation of wind instruments. It provides the computation of the acoustic response in the frequency domain (impedance or admittance) or in the time domain (impulse response), from the geometry of the instrument (main bore, side holes, valves). Several models are implemented and gives the possibility to take into account thermo-viscous losses, several radiation conditions etc. It is also possible to perform a sound simulation of brass and reed instruments. A graphical interface freely available online (https://demo-openwind. inria.fr) gives the possibility to perform frequency domain simulations without coding. After having presenting the main features of the python library and the associated documentation, we will focus on the graphical interface through the presentation of a pedagogical activity. During this course proposed by the ITEMM (school for instrument makers), the students in musical instrument making were asked to study several problems common in wind instruments, and especially the optimization of the main bore or the position of the side holes. From geometry design to impedance curves and resonances analysis, we will present how students learn to implement a general methodology for solving problems in wind instruments using this virtual prototyping tool

Using machine learning surrogate modeling for faster QSP VP cohort generation

Abstract Virtual patients (VPs) are widely used within quantitative systems pharmacology (QSP) modeling to explore the impact of variability and uncertainty on clinical responses. In one method of generating VPs, parameters are sampled randomly from a distribution, and possible VPs are accepted or rejected based on constraints on model output behavior. This approach works but can be inefficient (i.e., the vast majority of model runs typically do not result in valid VPs). Machine learning surrogate models offer an opportunity to improve the efficiency of VP creation significantly. In this approach, surrogate models are trained using the full QSP model and subsequently used to rapidly pre‐screen for parameter combinations that result in feasible VPs. The overwhelming majority of parameter combinations pre‐vetted using the surrogate models result in valid VPs when tested in the original QSP model. This tutorial presents this novel workflow and demonstrates how a surrogate model software application can be used to select and optimize the surrogate models in a case study. We then discuss the relative efficiency of the methods and scalability of the proposed method

Creation of an experimental database, for the validation of resonator models, comparison of geometries and materials, and quantification of measurement errors

International audienceWith an objective of providing wind instrument makers with design and simulation tools, many methods for both characterization and simulation of the behavior of acoustic properties have been developed. Some of these tools are made available to makers via softwares and devices. In parallel with a benchmark of numerical approaches for their verification detailed in a companion paper, an experimental campaign is presented here in order to create a reference database for the validation of models, and to estimate the uncertainties associated with the input impedance measurements. In particular, the random inter / intra sample uncertainty is quantified. The experimental campaign is based on batches of five specimens each of tubes and cones. The experimental plan allows to obtain consolidated experimental results concerning materials and making processes. The specimens produced are tested in different laboratories with varying characterization methods. The campaigns that took place defined a measurement protocol and evaluated biases and irreducible uncertainties. These measurements give first estimates of the variability of the results and provide precision thresholds of modifications to be significantly measured. Generally, for a batch of five specimens made with the same process, the orders of magnitude for the coefficient of variation is equal to 5 cents and 5 dB

Controlling the spatio-temporal dynamics of tsetse flies in a cattle breeding region of senegal

The tsetse fly complex (Glossina spp.) transmits the parasite responsible for African Animal Trypanosomiasis (AAT), or nagana, which is the most economically important livestock disease in Africa. The challenge of the last decades was to design programs that could sustainably control fly populations in different regions of the continent. Given the contrasted outcomes of these programs, there is still a need for a better understanding of the spatio-temporal dynamics of this vector.Mathematical models and computer-based simulations are relevant to assess which control measures should be used and when, accounting for the ecological complexity of the target pest and territorial specificities of the controlled area. They provide a useful tool, complementary to field observations and experiments, to suggest efficient vector management strategies.We developed a deterministic and mechanistic spatio-temporal model of the population dynamics of tsetse flies, structured by sex and age (pupae, teneral and non teneral adults). Temperature and fly density influenced the life-cycle, while spatial diffusion depended on density and relative quality of neighbouring locations. We applied the model on populations of Glossina palpalis gambiensis in the Niayes area of Senegal, for which biological and landscape data were available. The landscape was divided into 250m x 250m cells of heterogeneous carrying capacity, estimated by habitat suitability models. We transformed observed temperatures into “perceived” ones, to account for micro-environments where flies live. Dispersal, mortality, and development rates were calibrated on laboratory data, experts’ opinions and literature.The sensitivity analysis of the model identified the biological and environmental parameters influencing the most population dynamics. We showed that the mortality and development of adult females, along with temperature, were the key drivers of population persistence. Our predictions suggested that combining techniques to both increase mortality and decrease fecundity would be optimal to eradicate tsetse flies in targeted zones. Sequential aerosol technique (SAT), traps and targets (TT) and insecticide-treated livestock (ITL) increase daily mortality rates, whereas the sterile insect technique (SIT), by preventing egg-laying, slows down the development rate of the population. Furthermore, our results highlighted the need for more biological insights to achieve accurate model predictions. Additional field work and experiments are necessary to better infer the relationship between adult mortality and temperature, as well as differences between temperatures from weather stations and temperatures in tsetse fly resting places

Étude de la prévalence du papillomavirus (HPV) dans les cancers des voies aéro-digestives sur une cohorte unicentrique française de 372 patients

International audienceIntroduction: French data about HPV role in head and neck carcinomas are sparse, although French patients are mostly heavy smokers. In this series of oropharyngeal et non-oropharyngeal tumors, we aimed to determine what were the clinicopathological features associated with HPV and evaluate survival of patients according to HPV status.Methods: Three hundred and seventy-two cases of head and neck squamous cell carcinomas were reviewed and clinicopathological data were detailed. For each case, we performed a HPV PCR and an immunostaining against p16 protein (paraffin embedded tissues).Results: The series contained 90% of heavy smokers and 36% of tumors were located in oropharynx. HPV DNA was detected in 46% of oropharyngeal carcinomas and 16% of non-oropharyngeal carcinomas. Genotype 16 was the most frequently detected (84%). Clinicopathological features significantly associated with HPV DNA were: oropharyngeal location; absence of tobacco smoking; nodal involvement; poorly-differentiated non-keratinizing histology; positive p16 immunostaining. HPV infection was significantly associated with a longer survival for oropharyngeal carcinomas. It was not the case for non-oropharyngeal carcinomas.Conclusion: In this French series with lot of heavy smokers, under half of carcinomas are HPV induced. Clinicopathological features and survival data associated with HPV infection are the same as those classically described in literature