Centre d'Investigation Clinique de Besançon

Type III epithelial-mesenchymal transition (EMT) has been previously associated with increased cell migration, invasion, metastasis, and therefore cancer aggressiveness. This reversible process is associated with an important gene expression reprogramming mainly due to epigenetic plasticity. Nevertheless, most of the studies describing the central role of epigenetic modifications during EMT were performed in a single-cell model and using only one mode of EMT induction. In our study, we studied the overall modulations of gene expression and epigenetic modifications in four different EMT-induced cell models issued from different tissues and using different inducers of EMT. Pangenomic analysis (transcriptome and ChIP-sequencing) validated our hypothesis that gene expression reprogramming during EMT is largely regulated by epigenetic modifications of a wide range of genes. Indeed, our results confirmed that each EMT model is unique and can be associated with a specific transcriptome profile and epigenetic program. However, we could select some genes or pathways that are similarly regulated in the different models and that could therefore be used as a common signature of all EMT models and become new biomarkers of the EMT phenotype. As an example, we can cite the regulation of gene-coding proteins involved in the degradation of the extracellular matrix (ECM), which are highly induced in all EMT models. Based on our investigations and results, we identified ADAM19 as a new biomarker of in vitro and in vivo EMT and we validated this biological new marker in a cohort of non-small lung carcinomas.

Background Altered body composition may impact on the clinical course of Crohn's disease (CD) but is not detected by the simple body mass index (BMI) assessment. Aim To assess the prevalence of sarcopenia and visceral obesity by a single computed tomography (CT) slice, and its association with adverse events in an adult hospitalized CD cohort. Methods 88 CD patients who had abdominal CT scans during hospitalization were retrospectively enrolled. The skeletal muscle index (SMI) at the third lumbar vertebra level was used to assess sarcopenia. Sarcopenia was defined as a SMI <38.5 cm 2 /m 2 in women, <52.4 cm 2 /m 2 in men and visceral obesity as a visceral fat area ≥130 cm 2 . Clinical malnutrition was defined by a BMI <18.5 kg/m 2 . Univariate analysis was performed, and predictors for surgery in the follow-up were entered in a stepwise logistic regression model for multivariate analysis. Results The prevalence of sarcopenia was 58%, malnutrition 21.6%, and visceral obesity 19.3%. Among sarcopenic patients, 49% had a normal BMI, 13.7% were overweight, and 1(2%) was obese. Sarcopenic CD patients had significantly more abscesses (51% vs 16.7%, p = 0.001), hospitalizations (61.2% vs 36.1%, p = 0.022) and digestive surgery (63.3% vs 27.8%, p = 0.001) than non-sarcopenic patients during the follow-up, whereas usual malnutrition assessment was not correlated with disease outcomes. In multivariate analysis, both sarcopenia and visceral obesity were associated with further occurrence of digestive surgery. Conclusion Both sarcopenia and visceral obesity were associated with adverse outcomes in severe CD patients whereas usual nutritional assessment was not.

Bipolar disorder (BD) has been associated with premature cellular aging with shortened telomere length (TL) as compared to the general population. We recently identified a subgroup of young individuals with prematurely shortened TL. The aims of the present study were to replicate this observation in a larger sample and analyze the expression levels of genes associated with age or TL in a subsample of these individuals. TL was measured on peripheral blood DNA using quantitative polymerase chain reaction in a sample of 542 individuals with BD and clustering analyses were performed. Gene expression level of 29 genes, associated with aging or with telomere maintenance, was analyzed in RNA samples from a subsample of 129 individuals. Clustering analyses identified a group of young individuals (mean age 29.64 years), with shorter TL. None of the tested clinical variables were significantly associated with this subgroup. Gene expression level analyses showed significant downregulation of MYC, POT1, and CD27 in the prematurely aged young individuals compared to the young individuals with longer TL. After adjustment only POT1 remained significantly differentially expressed between the two groups of young individuals. This study confirms the existence of a subgroup of young individuals with BD with shortened TL. The observed decrease of POT1 expression level suggests a newly described cellular mechanism in individuals with BD, that may contribute to telomere shortening.

Multiple risk factors are associated with adverse pregnancy outcomes (APO), but how all these different factors combine and accumulate remains unknown. The objective of this observational retrospective study was to describe the accumulation of multiple vulnerability markers in pregnant women living in an urban area. Women living in Besançon (France) who delivered between 2005 and 2009 were included. Individual data were collected from the obstetrical records while environmental exposures were collected using environmental prediction models. The accumulation of 15 vulnerability markers, grouped into six dimensions (maternal age, smoking, body mass index (BMI), socio-economic, medico-obstetrical and environmental vulnerabilities) was described and analyzed in comparison with four APO. Among the 3686 included women, 20.8% were aged under 20 or over 34 and 21.9% had an extreme pre-pregnancy BMI. 18.8% declared smoking during pregnancy. Women exposed to socio-economic, medico-obstetrical or environmental vulnerability were 14.2%, 31.6% and 42.4% respectively. While 20.6% were not exposed to any marker, 18.8% accumulated three or more dimensions. The risk of APO increased significantly with the cumulative number of vulnerabilities. Define and validate a vulnerability score could be useful to identify vulnerable women, adapt their pregnancy monitoring and help policy makers to implement appropriate education or health promotion programs.

En donnant la parole à une minorité fortement discriminée, les détenus en fin de vie, l’ouvrage interroge l’expérience de la maladie grave et le sens de la punition. Le thème de la maladie en prison est un sujet sensible qui intéresse divers champs des sciences humaines et de la politique, du droit, de la médecine. Plusieurs histoires ont récemment traversé notre actualité, celle de Patrick Henry ou celle du prix Nobel chinois Liu Xiaobo. La question de la mort en prison reste controversée quel que soit le système carcéral et politique parce qu'elle touche profondément à ce qui fonde notre humanité. Dans cette « double épreuve », les détenus gravement malades nous révèlent en filigrane ce qui semble acceptable ou inacceptable, juste et injuste à notre société.

Human toxocariasis is a widespread, zoonotic, parasitic disease caused by the presence of larvae from Toxocara canis or Toxocara cati in human tissues. Toxocara spp infections are highly pleomorphic, depending on the number and location of encysted larvae in the body and the immune sensitivity of

INTRODUCTION: Over the past 50 years, the prevalence of allergic respiratory diseases has been increasing. The Hygiene hypothesis explains this progression by the decrease in the bio-diversity of early microbial exposure. This study aims to evaluate the effect of early-life farm exposure on airway hyperresponsiveness and cough hypersensitivity in an allergic airway inflammation rabbit model. METHOD: A specific environment was applied to pregnant rabbits and their offspring until six weeks after birth. Rabbits were housed in a pathogen-free zone for the control group and a calf barn for the farm group. At the end of the specific environmental exposure, both groups were then housed in a conventional zone and then sensitized to ovalbumin. Ten days after sensitization, the rabbit pups received ovalbumin aerosols to provoke airway inflammation. Sensitization to ovalbumin was assessed by specific IgE assay. Cough sensitivity was assessed by mechanical stimulation of the trachea, and bronchial reactivity was assessed by methacholine challenge. The farm environment was characterized by endotoxin measurement. RESULTS: A total of 38 rabbit pups were included (18 in the farm group). Endotoxin levels in the farm environment varied from 30 to 1854 EU.m-3. There was no significant difference in specific IgE values to ovalbumin (p = 0.826) between the two groups. The mechanical threshold to elicit a cough did not differ between the two groups (p = 0.492). There was no difference in the number of cough (p = 0.270) or the intensity of ventilatory responses (p = 0.735). After adjusting for age and weight, there was no difference in respiratory resistance before and after methacholine challenge. CONCLUSION: Early exposure to the calf barn did not affect cough sensitivity or bronchial reactivity in ovalbumin-sensitized rabbits. These results suggest that not all farm environments protect against asthma and atopy. Continuous exposure to several sources of microbial diversity is probably needed.

AIM: The purpose of this study was to examine the effects of a cycle competition on the large arteries stiffness, 24-hours after the end of the effort. METHODS: Two males elite cyclists were studied before and after performing a stage-race. Their heart rate (HR) was measured continuously during the two competition days. The impact of the competition on their vascular system was determined using the measure of pulse wave velocity (PWV), an index of regional arterial stiffness. HR and blood pressure were also measured before and 24-hours postexercise. RESULTS: During the race, mean cyclists HR were relatively similar. Changes in PWV and HR were found after competition: these measures increased for the offensive subject and decreased for the other. CONCLUSIONS: Despite their involvement in the same cycling competition, we suggest that the long-term effects induced by effort on arterial stiffness were inverted according to the subject's comportment during the race. This study should be completed by others measures in order to precise our results and to precise the possible link between arteries stiffness and the recovery kinetic process, both depending on the cardiovascular autonomic nervous system control.

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Abstract In this study we propose a novel agent-based model to reproduce and propose new hypotheses on the biological mechanisms of cell-cell interactions and cell migration from data obtained during scratch assay with healthy and keloid fibroblasts. The advantage of the agent-based model we propose in this paper lies in its simplicity: only three governing parameters. We conducted a parametric sensitivity analysis and we incorporated the evaluation of contact inhibition of locomotion, aligning with the observed loss during malignant invasion. To study invasion modalities, we conducted in vitro wound healing assays using healthy and pseudo-tumoral (keloid) fibroblasts under diverse conditions: control, macrophage type 1 secretome, and macrophage type 2 secretome. Mitomycin inhibition of proliferation isolated the contribution of migration to wound filling. Our agent-based mathematical model describes configurations based on our microscopy imaging and statistical data, which enables quantitative comparisons between our experimental and numerical results. Calibration and evaluation were performed on the same experiments, enriched by external datasets. With only three governing parameters, our model not only demonstrated good agreement (8.78% to 18.75% error) with external evaluation datasets for all experimental configurations but also provided us with a nuanced understanding of keloid fibroblast behavior during wound healing, especially regarding contact inhibition dynamics.

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WOS:000368021800069

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Entre les années 2009 et 2015, plusieurs rivières du département du Doubs ont été le théâtre d’épisodes de mortalité piscicole. Résumant les incertitudes et les inquiétudes à l’égard de la pérennité des pratiques de pêche et de potentiels risques sanitaires, ce phénomène a été le plus souvent expliqué par « la pollution des rivières ». Or, il semble qu’une telle qualification jette un voile sur les tentatives de solutions mises en place par les acteurs. En revenant sur les différentes enquêtes à travers lesquelles les acteurs concernés par cette situation mobilisent des ressources différentes pour comprendre les causes des épisodes de mortalité piscicole et les maîtriser, ce travail montre que la complexité du phénomène, la diversité des enjeux qu’il recouvre ainsi que sa taille géographique dépassent la capacité de résolution singulière propre à chaque groupe (associations de défense de l’environnement, structures représentatives du monde agricole, autorités publiques...) et nécessitent d’engager une activité collective mais toujours incertaine de définition du problème et de ses solutions. Il apparaît également que ces investigations portent le risque de la dénonciation réciproque et de l’imputation de responsabilités. Aussi, alors que les défenseurs des rivières s’engagent dans une dénonciation des activités agricoles et de la gestion de l’assainissement débouchant sur l’ouverture d’une situation conflictuelle, les experts mandatés par les représentants des pouvoirs publics concluent au caractère multifactoriel du phénomène et conduisent à une dilution des responsabilités. La situation reste alors en partie indéterminée et l’explication par « la pollution des rivières » devient une solution politique, voire un « outil diplomatique » pour un problème collectif qui peine à prendre sens.

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