VEGF Spliced Variants: Possible Role of Anti-Angiogenesis Therapy

Angiogenesis has been targeted in retinopathies, psoriasis, and a variety of cancers (colon, breast, lung, and kidney). Among these tumour types, clear cell renal cell carcinomas (RCCs) are the most vascularized tumours due to mutations of the von Hippel Lindau gene resulting in HIF-1 alpha stabilisation and overexpression of Vascular Endothelial Growth Factor (VEGF). Surgical nephrectomy remains the most efficient curative treatment for patients with noninvasive disease, while VEGF targeting has resulted in varying degrees of success for treating metastatic disease. VEGF pre-mRNA undergoes alternative splicing generating pro-angiogenic isoforms. However, the recent identification of novel splice variants of VEGF with anti-angiogenic properties has provided some insight for the lack of current treatment efficacy. Here we discuss an explanation for the relapse to anti-angiogenesis treatment as being due to either an initial or acquired resistance to the therapy. We also discuss targeting angiogenesis via SR (serine/arginine-rich) proteins implicated in VEGF splicing

Nutri-Score and NutrInform Battery: Effects on Performance and Preference in Italian Consumers

In May 2020, the European Commission announced a proposal for a mandatory front-of-pack label (FoPL) for all European Union (EU) countries. Indeed, FoPLs have been recognized by several public institutions as a cost-effective measure to guide consumers toward nutritionally favorable food products. The aim of this study was to compare the performance and consumer preference of two FoPLs currently proposed or implemented in EU countries, the interpretive format Nutri-Score and the non-interpretive format NutrInform Battery, among Italian consumers. The experimental study was conducted in 2021 on a representative sample of 1064 Italian adults (mean age = 46.5 +/- 14.1 years; 48% men). Participants were randomized to either Nutri-Score or NutrInform and had to fill out an online questionnaire testing their objective understanding of the FoPL on three food categories (breakfast products, breakfast cereals and added fats) as well as purchase intention, subjective understanding and perception. Multivariable logistic regressions and t-tests were used to analyze the answers. In terms of the capacity of participants to identify the most nutritionally favorable products, Nutri-Score outperformed NutrInform in all food categories, with the highest odds ratio being observed for added fats (OR = 21.7 [15.3-31.1], p < 0.0001). Overall, with Nutri-Score, Italian participants were more likely to intend to purchase nutritionally favorable products than with NutrInform (OR = 5.29 [4.02-6.97], p < 0.0001). Focusing on olive oil, participants of the Nutri-Score group had higher purchase intention of olive oil compared to those in the NutrInform group (OR = 1.92 [1.42-2.60], p < 0.0001) after manipulating the label. The interpretive format Nutri-Score appears to be a more efficient tool than NutrInform for orienting Italian consumers towards more nutritionally favorable food choices

The Yin-Yang of the Green Fluorescent Protein:Impact on Saccharomyces cerevisiae stress resistance

International audienceAlthough fluorescent proteins are widely used as biomarkers (Yin), no study focuses on their influence on the microbial stress response. Here, the Green Fluorescent Protein (GFP) was fused to two proteins of interest in Saccharomyces cerevisiae. Pab1p and Sur7p, respectively involved in stress granules structure and in Can1 membrane domains. These were chosen since questions remain regarding the understanding of the behavior of S. cerevisiae facing different heat kinetics or oxidative stresses. The main results showed that Pab1p-GFP fluorescent mutant displayed a higher resistance than that of the wild type under a heat shock. Moreover, fluorescent mutants exposed to oxidative stresses displayed changes in the cultivability compared to the wild type strain. In silico approaches showed that the presence of the GFP did not influence the structure and so the functionality of the tagged proteins meaning that changes in yeast resistance were certainly related to GFP ROS-scavenging ability (Yang)

Consumption of dairy products and cardiovascular disease risk: results from the French prospective cohort NutriNet-Santé

In France, dairy products contribute to dietary saturated fat intake, of which reduced consumption is often recommended for cardiovascular disease (CVD) prevention. Epidemiological evidence on the association between dairy consumption and CVD risk remains unclear, suggesting either null or inverse associations. This study aimed to investigate the associations between dairy consumption (overall and specific foods) and CVD risk in a large cohort of French adults. This prospective analysis included participants aged ≥ 18 years from the NutriNet-Santé cohort (2009–2019). Daily dietary intakes were collected using 24h-dietary records. Total dairy, milk, cheese, yogurts, fermented and reduced-fat dairy intakes were investigated. CVD cases (n=1,952) included cerebrovascular (n=878 cases) and coronary heart diseases (CHD, n=1,219 cases). Multivariable Cox models were performed to investigate associations. This analysis included n=104,805 French adults (mean age at baseline 42.8 years (SD 14.6), mean follow-up 5.5 years (SD 3.0, i.e. 579,155 persons years). There were no significant associations between dairy intakes and total CVD or CHD risks. However, the consumption of at least 160 g/d of fermented dairy (e.g. cheese and yogurts) was associated with a reduced risk of cerebrovascular diseases compared to intakes below 57 g/d (HR=0.81 [0.66-0.98], p-trend=0.01). Despite being a major dietary source of saturated fats, dairy consumption was not associated with CVD or CHD risks in this study. However, fermented dairy was associated with a lower cerebrovascular disease risk. Robust randomized controlled trials are needed to further assess the impact of consuming different dairy foods on CVD risk and potential underlying mechanisms

Association between nutritional profiles of foods underlying Nutri-Score front-of-pack labels and mortality: EPIC cohort study in 10 European countries.

OBJECTIVE: To determine if the Food Standards Agency nutrient profiling system (FSAm-NPS), which grades the nutritional quality of food products and is used to derive the Nutri-Score front-of-packet label to guide consumers towards healthier food choices, is associated with mortality. DESIGN: Population based cohort study. SETTING: European Prospective Investigation into Cancer and Nutrition (EPIC) cohort from 23 centres in 10 European countries. PARTICIPANTS: 521 324 adults; at recruitment, country specific and validated dietary questionnaires were used to assess their usual dietary intakes. A FSAm-NPS score was calculated for each food item per 100 g content of energy, sugars, saturated fatty acids, sodium, fibre, and protein, and of fruit, vegetables, legumes, and nuts. The FSAm-NPS dietary index was calculated for each participant as an energy weighted mean of the FSAm-NPS score of all foods consumed. The higher the score the lower the overall nutritional quality of the diet. MAIN OUTCOME MEASURE: Associations between the FSAm-NPS dietary index score and mortality, assessed using multivariable adjusted Cox proportional hazards regression models. RESULTS: After exclusions, 501 594 adults (median follow-up 17.2 years, 8 162 730 person years) were included in the analyses. Those with a higher FSAm-NPS dietary index score (highest versus lowest fifth) showed an increased risk of all cause mortality (n=53 112 events from non-external causes; hazard ratio 1.07, 95% confidence interval 1.03 to 1.10, P<0.001 for trend) and mortality from cancer (1.08, 1.03 to 1.13, P<0.001 for trend) and diseases of the circulatory (1.04, 0.98 to 1.11, P=0.06 for trend), respiratory (1.39, 1.22 to 1.59, P<0.001), and digestive (1.22, 1.02 to 1.45, P=0.03 for trend) systems. The age standardised absolute rates for all cause mortality per 10 000 persons over 10 years were 760 (men=1237; women=563) for those in the highest fifth of the FSAm-NPS dietary index score and 661 (men=1008; women=518) for those in the lowest fifth. CONCLUSIONS: In this large multinational European cohort, consuming foods with a higher FSAm-NPS score (lower nutritional quality) was associated with a higher mortality for all causes and for cancer and diseases of the circulatory, respiratory, and digestive systems, supporting the relevance of FSAm-NPS to characterise healthier food choices in the context of public health policies (eg, the Nutri-Score) for European populations. This is important considering ongoing discussions about the potential implementation of a unique nutrition labelling system at the European Union level

Les thérapies anti-angiogéniques : entre espoir et réalité. Vers l'identification de marqueurs prédictifs et de nouvelles cibles thérapeutiques dans le traitement du cancer du rein

The aim of my work is to study resistance mechanisms to anti-angiogenic treatments of Clear Cell Renal Carcinoma (ccRCC). We observed that bevacizumab (BVZ) -a humanized monoclonal antibody targeting VEGF and currently used in the clinic- promotes the growth of human ccRCC xenografts in nude mice. This model mimics the “escape phase” widely observed in patients. BVZ treatment induces lymphangiogenesis and over-expression of VEGF-C. Tumor cells exposed to the treatment acquire an increased spreading capacity. Hence, BVZ might promote tumor progression and metastasis formation of ccRCC. Furthermore, this treatment decreases the expression of the receptor phosphor tyrosine phosphatase kappa (PTRP). This phosphatase is involved in the regulation of tyrosine kinase receptors controlling growth and migration, among others EGF, PDGF and HGF receptors. Thus, BVZ might promote tumor growth independently of VEGF. Moreover, the treatment increases secretion of redundant cytokines like CXCL7 and CXCL8. By their ability to exert similar effect as VEGF, these cytokines promote tumor development under BVZ treatment. In particular, CXCL7 and its receptors CXCR1 and CXCR2, play a central role in the development of ccRCC. Targeting this pathway efficiently reduces tumor growth. Target receptors of PTRP for which inhibitors are currently used for other cancers, VEGF-C and CXCL7 could therefore be regarded as new predictive markers for BVZ efficiency and may be considered as potential therapeutic targets. Resistance to BVZ could also be explained by the presence of "beneficial" forms of anti-angiogenic VEGF recognized by the BVZ with the same affinity as the pro-angiogenic forms. We have demonstrated that prophylactic immunization with a pro-angiogenic VEGF-specific peptide limits tumor growth of murine syngeneic ccRCC. Similarly, in curative therapy, antibodies specific for pro-angiogenic VEGF block growth of ccRCC in nude mice without inducing the escape mechanisms observed with BVZ. These results highlight the relevance of targeting such pro-angiogenic forms of VEGF for the treatment of ccRCC.L’ensemble de ce travail vise à étudier les mécanismes de résistance aux thérapies anti-angiogéniques dans le traitement du cancer du rein à cellules claires (ccRCC). Nous avons mis en évidence que le bévacizumab (BVZ), un anticorps monoclonal humanisé anti-VEGF utilisé en clinique, accélère la croissance de ccRCC humain chez la souris nude. Ce modèle mime la phase d’échappement souvent observée chez les patients. Le traitement BVZ induit de la lymphangiogenèse associée à une surexpression du VEGF-C. Les cellules tumorales après traitement possèdent également des capacités d’invasion accrues. Ainsi, le traitement BVZ pourrait faciliter la progression tumorale et la formation de métastases dans les ccRCC. Le traitement entraine également une diminution de l’expression d’une phosphatase membranaire, la phospho-tyrosine phosphatase récepteur kappa (PTPR)impliquée dans le contrôle de l’activité de récepteurs à activité tyrosine kinase, comme le récepteur de l’EGF, du PDGF et de l’HGF. Ces récepteurs régulent la prolifération et la migration cellulaire. Le traitement BVZ faciliterait donc la croissance tumorale indépendante du VEGF. Enfin, le traitement induit une augmentation de la sécrétion de cytokines angiogéniques redondantes qui prennent le relais du VEGF, comme les cytokines CXCL7 et CXCL8, et facilitent le développement tumoral sous traitement BVZ. En particuliers, la cytokine CXCL7 et ses récepteurs CXCR1-2 ont un rôle central dans le développement des ccRCC. Cibler l’axe CXCL7/CXCR1-2 réduit efficacement la croissance tumorale. Les récepteurs cibles de PTPR, pour lesquels des inhibiteurs sont actuellement utilisés pour le traitement d’autres cancers, le VEGF-C et la cytokine CXCL7, pourraient donc constituer de nouveaux marqueurs prédictifs d’efficacité du BVZ et de nouvelles cibles thérapeutiques dans le traitement des ccRCC. La résistance au BVZ pourrait également s’expliquer par l’existence de formes "bénéfiques" anti-angiogéniques du VEGF qui sont reconnues par le BVZ avec la même affinité que les formes pro-angiogéniques. Nous avons mis en évidence qu’une immunisation prophylactique à l’aide d’un peptide spécifique du VEGF pro-angiogénique limite la croissance tumorale de ccRCC syngéniques de souris. De la même façon, en traitement curatif, l’utilisation d’anticorps spécifiques du VEGF pro-angiogénique bloque la croissance de ccRCC chez la souris nude sans induire les différents mécanismes d’échappement observés avec le BVZ. Ces résultats suggèrent la pertinence du ciblage spécifique des formes pro-angiogéniques de VEGF dans le traitement des ccRCC

The anti-angiogenic therapy : between hope and reality. Toward the identification of predictive markers and new therapeutic targets in renal cancer

L’ensemble de ce travail vise à étudier les mécanismes de résistance aux thérapies anti-angiogéniques dans le traitement du cancer du rein à cellules claires (ccRCC). Nous avons mis en évidence que le bévacizumab (BVZ), un anticorps monoclonal humanisé anti-VEGF utilisé en clinique, accélère la croissance de ccRCC humain chez la souris nude. Ce modèle mime la phase d’échappement souvent observée chez les patients. Le traitement BVZ induit de la lymphangiogenèse associée à une surexpression du VEGF-C. Les cellules tumorales après traitement possèdent également des capacités d’invasion accrues. Ainsi, le traitement BVZ pourrait faciliter la progression tumorale et la formation de métastases dans les ccRCC. Le traitement entraine également une diminution de l’expression d’une phosphatase membranaire, la phospho-tyrosine phosphatase récepteur kappa (PTPR)impliquée dans le contrôle de l’activité de récepteurs à activité tyrosine kinase, comme le récepteur de l’EGF, du PDGF et de l’HGF. Ces récepteurs régulent la prolifération et la migration cellulaire. Le traitement BVZ faciliterait donc la croissance tumorale indépendante du VEGF. Enfin, le traitement induit une augmentation de la sécrétion de cytokines angiogéniques redondantes qui prennent le relais du VEGF, comme les cytokines CXCL7 et CXCL8, et facilitent le développement tumoral sous traitement BVZ. En particuliers, la cytokine CXCL7 et ses récepteurs CXCR1-2 ont un rôle central dans le développement des ccRCC. Cibler l’axe CXCL7/CXCR1-2 réduit efficacement la croissance tumorale. Les récepteurs cibles de PTPR, pour lesquels des inhibiteurs sont actuellement utilisés pour le traitement d’autres cancers, le VEGF-C et la cytokine CXCL7, pourraient donc constituer de nouveaux marqueurs prédictifs d’efficacité du BVZ et de nouvelles cibles thérapeutiques dans le traitement des ccRCC. La résistance au BVZ pourrait également s’expliquer par l’existence de formes "bénéfiques" anti-angiogéniques du VEGF qui sont reconnues par le BVZ avec la même affinité que les formes pro-angiogéniques. Nous avons mis en évidence qu’une immunisation prophylactique à l’aide d’un peptide spécifique du VEGF pro-angiogénique limite la croissance tumorale de ccRCC syngéniques de souris. De la même façon, en traitement curatif, l’utilisation d’anticorps spécifiques du VEGF pro-angiogénique bloque la croissance de ccRCC chez la souris nude sans induire les différents mécanismes d’échappement observés avec le BVZ. Ces résultats suggèrent la pertinence du ciblage spécifique des formes pro-angiogéniques de VEGF dans le traitement des ccRCC.The aim of my work is to study resistance mechanisms to anti-angiogenic treatments of Clear Cell Renal Carcinoma (ccRCC). We observed that bevacizumab (BVZ) -a humanized monoclonal antibody targeting VEGF and currently used in the clinic- promotes the growth of human ccRCC xenografts in nude mice. This model mimics the “escape phase” widely observed in patients. BVZ treatment induces lymphangiogenesis and over-expression of VEGF-C. Tumor cells exposed to the treatment acquire an increased spreading capacity. Hence, BVZ might promote tumor progression and metastasis formation of ccRCC. Furthermore, this treatment decreases the expression of the receptor phosphor tyrosine phosphatase kappa (PTRP). This phosphatase is involved in the regulation of tyrosine kinase receptors controlling growth and migration, among others EGF, PDGF and HGF receptors. Thus, BVZ might promote tumor growth independently of VEGF. Moreover, the treatment increases secretion of redundant cytokines like CXCL7 and CXCL8. By their ability to exert similar effect as VEGF, these cytokines promote tumor development under BVZ treatment. In particular, CXCL7 and its receptors CXCR1 and CXCR2, play a central role in the development of ccRCC. Targeting this pathway efficiently reduces tumor growth. Target receptors of PTRP for which inhibitors are currently used for other cancers, VEGF-C and CXCL7 could therefore be regarded as new predictive markers for BVZ efficiency and may be considered as potential therapeutic targets. Resistance to BVZ could also be explained by the presence of "beneficial" forms of anti-angiogenic VEGF recognized by the BVZ with the same affinity as the pro-angiogenic forms. We have demonstrated that prophylactic immunization with a pro-angiogenic VEGF-specific peptide limits tumor growth of murine syngeneic ccRCC. Similarly, in curative therapy, antibodies specific for pro-angiogenic VEGF block growth of ccRCC in nude mice without inducing the escape mechanisms observed with BVZ. These results highlight the relevance of targeting such pro-angiogenic forms of VEGF for the treatment of ccRCC

Survie et/ou réactivation de microorganismes du sol sous hautes pressions gazeuses

National audienceLe sol constitue une réserve considérable de microorganismes représentatifs de nombreuses communautés cellulaires. Les recherches reposent sur l’hypothèse qu’il existe, dans les échantillons de sol, des communautés microbiennes adaptées à des conditions physiques (pression, température) très différentes de celles rencontrées dans nos laboratoires : soit parce que les conditions de milieu ont changé (sol), soit parce que les conditions de prélèvement sont très différentes des conditions de culture (grands fonds marins). Dans cette optique, l’utilisation des hautes pressions gazeuses (200-1000 bars dans un premier temps) est envisagée afin d’essayer de réactiver des microorganismes dormants que l’on ne sait pas cultiver. La découverte et la culture de ces microorganismes pourrait permettre de découvrir des formes microbiennes avec des adaptations qu’il serait possible d’utiliser à des fins de connaissance sur la plasticité cellulaire ou d’exploiter industriellement certains éléments spécifiques du métabolisme (enzymes, produits). L’objectif de la présente étude est de valider l’utilisation de procédés originaux de culture sous Hautes Pressions. La maîtrise de ces procédés devrait permettre d’approcher les conditions optimales de culture par l’utilisation d’enceintes Hautes Pressions spécifiques : (1) Enceintes « aveugles » : elles permettent de placer des échantillons sous pression et de maintenir cette pression constante au cours de l’incubation mais ne permettent pas de visualiser la croissance des microorganismes lors du traitement hyperbare. Elles possèdent un volume utile d’environ 100 cm3 permettant l’introduction de 3 petites boîtes de Petri (4 cm de diamètre) et résistent à des pressions allant de 250 à 2000 bars selon le modèle de l’enceinte. (2) Enceintes « optiques » ou cellules de visualisation : elles permettent de visualiser les échantillons et de suivre, en temps réel, la croissance microbienne au cours du traitement hyperbare. Elles peuvent être utilisées pour réaliser des cultures sous pression gazeuse isostatique en milieu solide ou sous pression hydrostatique en milieu liquide. La présence d’une double enveloppe permet de réguler la température d’incubation. Cette cellule de visualisation peut résister à des pressions allant jusqu’à 4000 bars. Dans un premier temps, la levure Saccharomyces cerevisiae a été utilisée comme microorganisme modèle. Son taux de croissance a été mesuré entre 1 et 500 bars dans ces deux types d’enceintes. Une étude comparative a été menée afin de retenir l’enceinte la plus adaptée au suivi de la croissance microbienne. Dans un second temps, des échantillons de différents sols (terrestre et marin) ont été récupérés afin d’identifier les populations microbiennes piézotolérantes et/ou piézophiles éventuelles. Les échantillons de sol terrestre proviennent du domaine de Bretenières (I.N.R.A., Dijon) et les échantillons de sol marin ont été prélevés dans deux carottes profondes du Bassin Indien Central (Océan Indien) à plus de 5000 m de profondeur et ont été gracieusement fournis par la carothèque océanique du Muséum National d’Histoire Naturelle

High gas pressure survival/reactivation of soil microorganisms

International audienceDeep sea sediments constitute a considerable reserve of microorganisms belonging to different microbial communities. Our researches aimed to better understand cellular mechanisms related to cellular plasticity involved in resistance of such microbial communities to extreme conditions and more particularly to high level of pressure (> 50 MPa). Obviously, the first step is to isolate microorganisms present in deep sea sediments and then cultivate. The comparison of the cultivation of such microorganisms under atmospheric conditions and under pressure conditions will afford a possible reactivation of specific piezotolerants and/or piezophiles organisms from dormancy. The aim of the present study is to validate the use of original processes of culture under high gaseous pressures (50 MPa). (1) « Blind » chambers, of about 100 cm3, are designed to maintain microorganisms spread on solid medium contained in 3 small Petri Dishes (4 cm diameter) at 25-200 MPa. Observation in real time of colonies is not possible. (2) « Optical » or microscopic chambers are designed to resist up to 400 MPa and to visualize the microbial growth during hyperbaric treatment in real time. They can be used to cultivate and visualize microorganisms under gaseous isostatic pressure on solid medium or under hydrostatic pressure in liquid medium. The yeast Saccharomyces cerevisiae was used as a model of microorganism. Results show that its growth rate, measured between 1 and 50 MPa, decreased when the pressure level increased. The “optical” chamber is more adapted to the follow-up of the microbial growth because the growth rate can be calculated without decompression of the chamber and cells can be followed-up individually. The “blind” chamber is more adapted to cultivate samples in order to isolate piezotolerants and/or piezophiles microorganisms. Thus, they will be used to cultivate and isolate microorganisms present in deep sea sediments (-5000 m under Indian Ocean surface)

Oxidised polyphenols are involved in haze formation in apple-based beverages

International audienc