CD63-GPC1-Positive Exosomes Coupled with CA19-9 Offer Good Diagnostic Potential for Resectable Pancreatic Ductal Adenocarcinoma

Tumor-released extracellular vesicles (EVs) contain tumor-specific cargo distinguishing them from healthy EVs, and making them eligible as circulating biomarkers. Glypican 1 (GPC1)-positive exosome relevance as liquid biopsy elements is still debated. We carried out a prospective study to quantify GPC1-positive exosomes in sera from pancreatic ductal adenocarcinoma (PDAC) patients undergoing up-front surgery, as compared to controls including patients without cancer history and patients displaying pancreatic preneoplasic lesions. Sera were enriched in EVs, and exosomes were pulled down with anti-CD63 coupled magnetic beads. GPC1-positive bead percentages determined by flow cytometry were significantly higher in PDAC than in the control group. Diagnosis accuracy reached 78% (sensitivity 64% and specificity 90%), when results from peripheral and portal blood were combined. In association with echo-guided-ultrasound-fine-needle-aspiration (EUS-FNA) negative predictive value was 80% as compared to 33% for EUS-FNA only. This approach is clinically relevant as a companion test to the already available diagnostic tools, since patients with GPC1-positive exosomes in peripheral blood showed decreased tumor free survival

Pharmacological targeting of the protein synthesis mTOR/4E-BP1 pathway in cancer-associated fibroblasts abrogates pancreatic tumourchemoresistance

International audiencePancreatic ductal adenocarcinoma (PDAC) is extremely stroma-rich. Cancer-associated fibroblasts (CAFs) secrete proteins that activate survival and promote chemoresistance of cancer cells. Our results demonstrate that CAF secretome-triggered chemoresistance is abolished upon inhibition of the protein synthesis mTOR/4E-BP1 regulatory pathway which we found highly activated in primary cultures of -SMA-positive CAFs, isolated from human PDAC resections. CAFs selectively express the sst1 somatostatin receptor. The SOM230 analogue (Pasireotide) activates the sst1 receptor and inhibits the mTOR/4E-BP1 pathway and the resultant synthesis of secreted proteins including IL-6. Consequently, tumour growth and chemoresistance in nude mice xenografted with pancreatic cancer cells and CAFs, or with pieces of resected human PDACs, are reduced when chemotherapy (gemcitabine) is combined with SOM230 treatment. While gemcitabine alone has marginal effects, SOM230 is permissive to gemcitabine-induced cancer cell apoptosis and acts as an antifibrotic agent. We propose that selective inhibition of CAF protein synthesis with sst1-directed pharmacological compounds represents an anti-stromal-targeted therapy with promising chemosensitization potential

Etudes d'interventions nutritionnelles en populations défavorisées réalisées en Seine-Saint-Denis

Nutrition (including food and physical activity) is one of the leading protective factors against non-communicable diseases. And it is also subject to social health inequalities. Overall, disadvantaged populations have been shown to have less healthy nutritional habits. One of the main aims of the French Nutritional and Health Program (PNNS) is to tackle nutritional social health inequalities. In this frame, two quasi-experimental interventional trials, aiming to assess the efficiency of nutritional promotion actions have been developed in Saint-Denis city (Paris suburb, Ile-de-France County, France). The first one focused on physical activity, and the other one on fruits and vegetables consumption.The first trial entitled “For the health, I move in my neighbourhood!” took place in a Saint-Denis’ area from May 2013 to May 2015. The aim was to increase the proportion of adults practicing daily moderate physical activity in accordance with the WHO recommendations (i.e. at least 30 minutes of moderate physical activity per day). Two assessments of the physical activity level of the population were performed: in 2013 (before) and in 2015 (after) the intervention. Subjects were selected through a stratified cluster sampling. The proportion of adults practicing moderate physical activity level in accordance with the recommendations was significantly increased by about 30%. This raise was mainly due to an increase of leisure physical activity in women, and an increase of daily walk.The other trial entitled “Fruits and vegetables at home” (FLAM), aimed to assess the impact of fruits and vegetables vouchers on the consumption of fruits and vegetables among children from low-income families. Families were recruited in the north neighbourhoods of Saint-Denis, from May 2015 to May 2016, and each family was followed over a one year period. At inclusion, families were randomly allocated either in the intervention group (i.e. the one that received fruits and vegetables vouchers over one year) or in the control group. Finally, 92 parent-child pairs were included in the study. After one year follow-up, fruits and vegetables consumption was higher in children from the intervention group, compared to those from the control group.These two trials underlie the important role played by the interventional research as a decision support tool for the development of public health policies. Though the results are modest, they are still promising and could serve as a base for discussion for the implementation of actions struggling nutritional social health inequalities.La nutrition (qui regroupe l’alimentation et l’activité physique), facteur clé modifiable de la prévention des maladies chroniques, est l’objet d’importantes inégalités sociales. Les populations vulnérables présentant globalement des comportements nutritionnels moins favorables à la santé. L’un des principaux objectifs du Programme National Nutrition Santé (PNNS) est de réduire les inégalités sociales de santé dans le champ de la nutrition. Dans ce contexte, deux études d’intervention quasi-expérimentales, visant à tester l’efficacité d’actions de promotion nutritionnelle ont été mises en place dans la ville de Saint-Denis (département de la Seine-Saint-Denis, région Ile-de-France). L’une portait sur l’activité physique et l’autre sur la consommation de fruits et légumes. La première étude intitulée « Pour la santé je bouge dans mon quartier ! » s’est déroulée de mai 2013 à mai 2015 dans un quartier en politique de la ville. L’objectif était d’augmenter la proportion d’adultes pratiquant une activité physique régulière modérée conforme aux recommandations de l’OMS (soit au moins 30 minutes d’activité physique modérée par jour). Deux évaluations du niveau d’activité physique avant (2013) et après (2015) mise en place du programme ont été réalisées. Les participants ont été sélectionnés par un tirage au sort selon un sondage stratifié par grappes. La proportion d’adultes pratiquant une activité physique de niveau au moins modéré a augmenté significativement d’environ 30%. Cette augmentation était le fait presque exclusif d’une augmentation de l’activité physique de loisir chez les femmes, et d’une augmentation de la marche. La seconde étude intitulée « Fruits et légumes à la Maison » (FLAM), avait pour objectif d’évaluer l’impact de bons d’achat pour les fruits et légumes sur la consommation de ces derniers chez des enfants issus de familles en situation de précarité. Elle s’est déroulée dans les quartiers nord de Saint-Denis de mai 2015 à juin 2017. A leur inclusion, les familles étaient randomisées soit dans le groupe intervention qui recevait des bons d’achat échangeables contre des fruits et légumes pendant 1 an soit dans le groupe contrôle. Au total, 92 couples parent-enfant ont été inclus. Après un an de suivi, la consommation de fruits et légumes était significativement plus importante chez les enfants du groupe intervention. Ces deux études illustrent le rôle central de la recherche interventionnelle dans l’aide à la décision et la mise en place de politiques de santé publique. Les résultats bien que modestes, sont encourageants et peuvent servir de base de réflexion pour la mise en place de mesures visant à diminuer les inégalités sociales de santé dans le champ de la nutrition

Etudes d'interventions nutritionnelles en populations défavorisées réalisées en Seine-Saint-Denis

Nutrition (including food and physical activity) is one of the leading protective factors against non-communicable diseases. And it is also subject to social health inequalities. Overall, disadvantaged populations have been shown to have less healthy nutritional habits. One of the main aims of the French Nutritional and Health Program (PNNS) is to tackle nutritional social health inequalities. In this frame, two quasi-experimental interventional trials, aiming to assess the efficiency of nutritional promotion actions have been developed in Saint-Denis city (Paris suburb, Ile-de-France County, France). The first one focused on physical activity, and the other one on fruits and vegetables consumption.The first trial entitled “For the health, I move in my neighbourhood!” took place in a Saint-Denis’ area from May 2013 to May 2015. The aim was to increase the proportion of adults practicing daily moderate physical activity in accordance with the WHO recommendations (i.e. at least 30 minutes of moderate physical activity per day). Two assessments of the physical activity level of the population were performed: in 2013 (before) and in 2015 (after) the intervention. Subjects were selected through a stratified cluster sampling. The proportion of adults practicing moderate physical activity level in accordance with the recommendations was significantly increased by about 30%. This raise was mainly due to an increase of leisure physical activity in women, and an increase of daily walk.The other trial entitled “Fruits and vegetables at home” (FLAM), aimed to assess the impact of fruits and vegetables vouchers on the consumption of fruits and vegetables among children from low-income families. Families were recruited in the north neighbourhoods of Saint-Denis, from May 2015 to May 2016, and each family was followed over a one year period. At inclusion, families were randomly allocated either in the intervention group (i.e. the one that received fruits and vegetables vouchers over one year) or in the control group. Finally, 92 parent-child pairs were included in the study. After one year follow-up, fruits and vegetables consumption was higher in children from the intervention group, compared to those from the control group.These two trials underlie the important role played by the interventional research as a decision support tool for the development of public health policies. Though the results are modest, they are still promising and could serve as a base for discussion for the implementation of actions struggling nutritional social health inequalities.La nutrition (qui regroupe l’alimentation et l’activité physique), facteur clé modifiable de la prévention des maladies chroniques, est l’objet d’importantes inégalités sociales. Les populations vulnérables présentant globalement des comportements nutritionnels moins favorables à la santé. L’un des principaux objectifs du Programme National Nutrition Santé (PNNS) est de réduire les inégalités sociales de santé dans le champ de la nutrition. Dans ce contexte, deux études d’intervention quasi-expérimentales, visant à tester l’efficacité d’actions de promotion nutritionnelle ont été mises en place dans la ville de Saint-Denis (département de la Seine-Saint-Denis, région Ile-de-France). L’une portait sur l’activité physique et l’autre sur la consommation de fruits et légumes. La première étude intitulée « Pour la santé je bouge dans mon quartier ! » s’est déroulée de mai 2013 à mai 2015 dans un quartier en politique de la ville. L’objectif était d’augmenter la proportion d’adultes pratiquant une activité physique régulière modérée conforme aux recommandations de l’OMS (soit au moins 30 minutes d’activité physique modérée par jour). Deux évaluations du niveau d’activité physique avant (2013) et après (2015) mise en place du programme ont été réalisées. Les participants ont été sélectionnés par un tirage au sort selon un sondage stratifié par grappes. La proportion d’adultes pratiquant une activité physique de niveau au moins modéré a augmenté significativement d’environ 30%. Cette augmentation était le fait presque exclusif d’une augmentation de l’activité physique de loisir chez les femmes, et d’une augmentation de la marche. La seconde étude intitulée « Fruits et légumes à la Maison » (FLAM), avait pour objectif d’évaluer l’impact de bons d’achat pour les fruits et légumes sur la consommation de ces derniers chez des enfants issus de familles en situation de précarité. Elle s’est déroulée dans les quartiers nord de Saint-Denis de mai 2015 à juin 2017. A leur inclusion, les familles étaient randomisées soit dans le groupe intervention qui recevait des bons d’achat échangeables contre des fruits et légumes pendant 1 an soit dans le groupe contrôle. Au total, 92 couples parent-enfant ont été inclus. Après un an de suivi, la consommation de fruits et légumes était significativement plus importante chez les enfants du groupe intervention. Ces deux études illustrent le rôle central de la recherche interventionnelle dans l’aide à la décision et la mise en place de politiques de santé publique. Les résultats bien que modestes, sont encourageants et peuvent servir de base de réflexion pour la mise en place de mesures visant à diminuer les inégalités sociales de santé dans le champ de la nutrition

Nutritional intervention trials performed amongst disadvantaged populations in the Paris suburb

La nutrition (qui regroupe l’alimentation et l’activité physique), facteur clé modifiable de la prévention des maladies chroniques, est l’objet d’importantes inégalités sociales. Les populations vulnérables présentant globalement des comportements nutritionnels moins favorables à la santé. L’un des principaux objectifs du Programme National Nutrition Santé (PNNS) est de réduire les inégalités sociales de santé dans le champ de la nutrition. Dans ce contexte, deux études d’intervention quasi-expérimentales, visant à tester l’efficacité d’actions de promotion nutritionnelle ont été mises en place dans la ville de Saint-Denis (département de la Seine-Saint-Denis, région Ile-de-France). L’une portait sur l’activité physique et l’autre sur la consommation de fruits et légumes. La première étude intitulée « Pour la santé je bouge dans mon quartier ! » s’est déroulée de mai 2013 à mai 2015 dans un quartier en politique de la ville. L’objectif était d’augmenter la proportion d’adultes pratiquant une activité physique régulière modérée conforme aux recommandations de l’OMS (soit au moins 30 minutes d’activité physique modérée par jour). Deux évaluations du niveau d’activité physique avant (2013) et après (2015) mise en place du programme ont été réalisées. Les participants ont été sélectionnés par un tirage au sort selon un sondage stratifié par grappes. La proportion d’adultes pratiquant une activité physique de niveau au moins modéré a augmenté significativement d’environ 30%. Cette augmentation était le fait presque exclusif d’une augmentation de l’activité physique de loisir chez les femmes, et d’une augmentation de la marche. La seconde étude intitulée « Fruits et légumes à la Maison » (FLAM), avait pour objectif d’évaluer l’impact de bons d’achat pour les fruits et légumes sur la consommation de ces derniers chez des enfants issus de familles en situation de précarité. Elle s’est déroulée dans les quartiers nord de Saint-Denis de mai 2015 à juin 2017. A leur inclusion, les familles étaient randomisées soit dans le groupe intervention qui recevait des bons d’achat échangeables contre des fruits et légumes pendant 1 an soit dans le groupe contrôle. Au total, 92 couples parent-enfant ont été inclus. Après un an de suivi, la consommation de fruits et légumes était significativement plus importante chez les enfants du groupe intervention. Ces deux études illustrent le rôle central de la recherche interventionnelle dans l’aide à la décision et la mise en place de politiques de santé publique. Les résultats bien que modestes, sont encourageants et peuvent servir de base de réflexion pour la mise en place de mesures visant à diminuer les inégalités sociales de santé dans le champ de la nutrition.Nutrition (including food and physical activity) is one of the leading protective factors against non-communicable diseases. And it is also subject to social health inequalities. Overall, disadvantaged populations have been shown to have less healthy nutritional habits. One of the main aims of the French Nutritional and Health Program (PNNS) is to tackle nutritional social health inequalities. In this frame, two quasi-experimental interventional trials, aiming to assess the efficiency of nutritional promotion actions have been developed in Saint-Denis city (Paris suburb, Ile-de-France County, France). The first one focused on physical activity, and the other one on fruits and vegetables consumption.The first trial entitled “For the health, I move in my neighbourhood!” took place in a Saint-Denis’ area from May 2013 to May 2015. The aim was to increase the proportion of adults practicing daily moderate physical activity in accordance with the WHO recommendations (i.e. at least 30 minutes of moderate physical activity per day). Two assessments of the physical activity level of the population were performed: in 2013 (before) and in 2015 (after) the intervention. Subjects were selected through a stratified cluster sampling. The proportion of adults practicing moderate physical activity level in accordance with the recommendations was significantly increased by about 30%. This raise was mainly due to an increase of leisure physical activity in women, and an increase of daily walk.The other trial entitled “Fruits and vegetables at home” (FLAM), aimed to assess the impact of fruits and vegetables vouchers on the consumption of fruits and vegetables among children from low-income families. Families were recruited in the north neighbourhoods of Saint-Denis, from May 2015 to May 2016, and each family was followed over a one year period. At inclusion, families were randomly allocated either in the intervention group (i.e. the one that received fruits and vegetables vouchers over one year) or in the control group. Finally, 92 parent-child pairs were included in the study. After one year follow-up, fruits and vegetables consumption was higher in children from the intervention group, compared to those from the control group.These two trials underlie the important role played by the interventional research as a decision support tool for the development of public health policies. Though the results are modest, they are still promising and could serve as a base for discussion for the implementation of actions struggling nutritional social health inequalities

Western Dietary Pattern Is Associated with Irritable Bowel Syndrome in the French NutriNet Cohort

Background: Diet appears to play a key role in the pathogenesis of the irritable bowel syndrome (IBS). Some dietary patterns (DP) could increase the risk of triggering or worsening IBS symptoms. This cross-sectional study aimed to assess the association between a posteriori derived DP and IBS in a large French population, the web-based NutriNet-Santé cohort. Methods: Study population included participants of the NutriNet-Santé study who completed a questionnaire based on Rome III criteria assessing IBS. A principal component analysis (PCA) was performed to identify major DPs based on 29 food groups’ consumption. Associations between DP quintiles and IBS were investigated with multivariable logistic regressions. Results: 44,350 participants were included, with 2423 (5.5%) presenting IBS. Three major DP were extracted using PCA, “healthy,” “western,” and “traditional.” After adjustments on confounders, the “western” DP was positively associated with IBS (OR Q5 vs. Q1 = 1.38, 95% CI 1.19–1.61, p trend < 0.0001) and the “traditional” DP was positively associated with IBS in women (OR Q5 vs. Q1 = 1.29 95% CI 1.08–1.54, p trend = 0.001). Conclusions: In this study, a “western” DP—highly correlated with the consumption of fatty and sugary products and snacks—was associated with a moderate increased risk of IBS

Cartographie du risque sanitaire lié à la canicule pour le développement d'actions locales de santé publique

Face à un réchauffement climatique inévitable, des mesures d'adaptation aux canicules doivent être élaborées. Le but de ce travail était de développer une méthode permettant de cartographier le risque sanitaire lié à la canicule dans les grandes villes. L'étude a porté sur la ville de Rennes. Une image du satellite Landsat ETM+ prise en juin 2001 lors d'une canicule localisée a permis d'estimer la température de surface (TS) et de créer un indice de danger. Un modèle de régression spatialisée a été élaboré pour prédire la TS. Des données populationnelles ont permis de créer un indice de vulnérabilité qui, combiné au danger a permis d'obtenir un indice de risque final. Le modèle de régression spatialisée était très prédictif de la TS (R =0,87) avec trois éléments de couverture du sol négativement lié à celle-ci. La température était très élevée au centre ville et la vulnérabilité dans 3 zones périphériques. Le risque final était prépondérant sur une bande centrale nord-sud.Climate change poses many challenges ranging from global and local policy challenges to personal and social action. We aimed at demonstrating a simple conceptual framework in order to map high risk areas at the community level. The study area encompasses a medium-size French city (Rennes). A Landsat ETM+ image acquired during a localized heatwave (June 2001) was used to estimate land surface temperature (LST), and derive a hazard index. A land-use regression mode was performed to predict LST. Vulnerability was assessed through census data and was combined to hazard to deliver a heatwave health risk index. A spatial error regression model revealed highly predictive of the spatial variation in LST (R =0.87). Elevated temperatures were mainly observed in the city centre, while 3 pockets of high vulnerability were observed in outskirts of the city. The heatwave health risk map showed evidence of infra-city spatial clustering, with the highest risks observed in a North-South central band.RENNES1-BU Santé (352382103) / SudocSudocFranceF

Targeting KRAS for diagnosis, prognosis, and treatment of pancreatic cancer: Hopes and realities

International audienceMutation of the KRAS oncogene in pancreatic cancer is responsible for permanent activation of the P21 RAS protein and the cascade of signalling pathways. Consequently, multiple cellular processes, such as transformation, proliferation, invasion, and survival are activated. The aim of this review was to present all potential clinical applications of targeting KRAS in terms of diagnosis and management of pancreatic adenocarcinoma. Quantitative polymerase chain reaction technology provides reliable assessment of KRAS mutations, both in tissues and from fine-needle aspiration biopsies. Numerous studies report that the combination of endoscopic ultrasound-guided cytopathology and a KRAS mutation assay can improve the positive and differential diagnosis of pancreatic cancer, differentiating between benign versus malignant solid pancreatic cancer, and reducing false-negative results compared to cytopathology alone. In addition, the presence of a KRAS mutation is frequently associated with a worse prognosis, both in cases of advanced and resected tumours. However, the KRAS mutation assay is not as efficient at predicting a response to both anti-epidermal growth factor receptor treatments and/or chemotherapy. Targeting of KRAS to treat pancreatic adenocarcinoma has been applied at different stages of RAS molecular intracellular processes: at the transcription level with antisense or interference RNA, at the posttranslational level with inhibitors of farnesyl transferase or anti-RAS vaccination peptides, and to target multiple signalling pathways using inhibitors of mitogen-activated protein kinase, phosphoinositide 3-kinase, AKT, mammalian target of rapamycin, RAF. Despite some encouraging results at pre-clinical and phase I stages, no significant clinical benefits have been observed. Combinatory approaches with standard chemotherapy will be welcom

Mapping heatwave health risk at the community level for public health action

<p>Abstract</p> <p>Background</p> <p>Climate change poses unprecedented challenges, ranging from global and local policy challenges to personal and social action. Heat-related deaths are largely preventable, but interventions for the most vulnerable populations need improvement. Therefore, the prior identification of high risk areas at the community level is required to better inform planning and prevention. We aimed to demonstrate a simple and flexible conceptual framework relying upon satellite thermal data and other digital data with the goal of easily reproducing this framework in a variety of urban configurations.</p> <p>Results</p> <p>The study area encompasses Rennes, a medium-sized French city. A Landsat ETM + image (60 m resolution) acquired during a localized heatwave (June 2001) was used to estimate land surface temperature (LST) and derive a hazard index. A land-use regression model was performed to predict the LST. Vulnerability was assessed through census data describing four dimensions (socio-economic status, extreme age, population density and building obsolescence). Then, hazard and vulnerability indices were combined to deliver a heatwave health risk index. The LST patterns were quite heterogeneous, reflecting the land cover mosaic inside the city boundary, with hotspots of elevated temperature mainly observed in the city center. A spatial error regression model was highly predictive of the spatial variation in the LST (<it>R</it>^<it>2</it> = 0.87) and was parsimonious. Three land cover descriptors (NDVI, vegetation and water fractions) were negatively linked with the LST. A sensitivity analysis (based on an image acquired on July 2000) yielded similar results. Southern areas exhibited the most vulnerability, although some pockets of higher vulnerability were observed northeast and west of the city. The heatwave health risk map showed evidence of infra-city spatial clustering, with the highest risks observed in a north–south central band. Another sensitivity analysis gave a very high correlation between 2000 and 2001 risk indices (<it>r</it> = 0.98, <it>p</it> < 10^-12).</p> <p>Conclusions</p> <p>Building on previous work, we developed a reproducible method that can provide guidance for local planners in developing more efficient climate impact adaptations. We recommend, however, using the health risk index together with hazard and vulnerability indices to implement tailored programs because exposure to heat and vulnerability do not require the same prevention strategies.</p