Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen–specific CD8+ T cell dysfunction in melanoma patients

The paradoxical coexistence of spontaneous tumor antigen–specific immune responses with progressive disease in cancer patients furthers the need to dissect the molecular pathways involved in tumor-induced T cell dysfunction. In patients with advanced melanoma, we have previously shown that the cancer-germline antigen NY-ESO-1 stimulates spontaneous NY-ESO-1–specific CD8+ T cells that up-regulate PD-1 expression. We also observed that PD-1 regulates NY-ESO-1–specific CD8+ T cell expansion upon chronic antigen stimulation. In the present study, we show that a fraction of PD-1+ NY-ESO-1–specific CD8+ T cells in patients with advanced melanoma up-regulates Tim-3 expression and that Tim-3+PD-1+ NY-ESO-1–specific CD8+ T cells are more dysfunctional than Tim-3−PD-1+ and Tim-3−PD-1− NY-ESO-1–specific CD8+ T cells, producing less IFN-γ, TNF, and IL-2. Tim-3–Tim-3L blockade enhanced cytokine production by NY-ESO-1–specific CD8+ T cells upon short ex vivo stimulation with cognate peptide, thus enhancing their functional capacity. In addition, Tim-3–Tim-3L blockade enhanced cytokine production and proliferation of NY-ESO-1–specific CD8+ T cells upon prolonged antigen stimulation and acted in synergy with PD-1–PD-L1 blockade. Collectively, our findings support the use of Tim-3–Tim-3L blockade together with PD-1–PD-L1 blockade to reverse tumor-induced T cell exhaustion/dysfunction in patients with advanced melanoma

Signalisation du stress mécanique dans les cellules de disque intervertébral (l'hème-oxygénase-1, un facteur de rétro-contrôle anti-inflammatoire)

L altération des protéines matricielles et le processus inflammatoire conduisent à la dégénérescence du cartilage ou du disque intervertébral avec perte de fonction biomécanique. Ceci peut être contrecarré par une inhibition de la signalisation du stress et/ou par la stimulation de facteurs endogènes tels que HO-1. Nous avons comparé la signalisation du stress mécanique et cytokinique dans des chondrocytes in vitro. Les 2 diminuent la production des protéines matricielles, mais le stress mécanique agit via NO plutôt que par l induction des métalloprotéases. NOS I et III sont impliquées. IL-10 et un stress mécanique doux atténuent les effets de IL-1beta en diminuant la production de NO et PGE2. Comme le stress mécanique et IL-10 induisent HO-1, nous avons étudié les effets de l induction de HO-1 dans un modèle in vivo d arthrite inductible. HO-1 diminue l ensemble des symptômes ces derniers sont supprimés par un co-traitement avec un siARN anti HO-1.PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Comportements alimentaires des personnes atteintes du syndrome de Lynch présentant un risque élevé de cancer colorectal : Résultats de l'étude AAS-lynch

International audienceBackground & Aims: Individuals with Lynch syndrome (LS) have a high lifetime risk of developing colorectal cancer (CRC) due to genetic alterations. Nutrition is one of the main modifiable risk factors for sporadic CRC, however this has not been established in LS patients. The present study aimed to give a detailed overview of dietary intakes in individuals with LS, and associated individual characteristics. Methods: Dietary behaviours of individuals with LS from the AAS-Lynch clinical trial (2017-2022) were obtained using a food frequency questionnaire. Dietary intakes, food group consumption and overall diet quality (dietary patterns, adherence to the Mediterranean diet) were described according to sociodemographic, anthropometric and clinical characteristics, and compared to participants without LS from the NutriNet-Santé study (matched on sex, age, BMI and region). Results: 280 individuals with LS were included in this analysis and matched with 547 controls. Compared to controls, LS patients consumed less fibre, legumes, fruit and vegetables and more red and processed meat (all p<0.01). They also had a lower Mediterranean diet score (p=0.002). Among LS patients, men, younger patients, or those with disadvantaged situation had a diet of poorer nutritional quality with lower adherence to a "Healthy" diet (all p≤0.01). LS Patients with prevalent CRC had a higher consumption of dairy products than recommended, while those with prevalent adenoma consumed more vegetables, and less sugar and sweets (all p≤0.01). Conclusions: Although patients with LS were aware of their high lifetime risk of developing cancer, their diets were not optimal and included nutritional risk factors associated to CRC. The study is registered with # NCT04791644 at ClinicalTrials.gov.Contexte et objectifs : Les personnes atteintes du syndrome de Lynch (LS) présentent un risque élevé de développer un cancer colorectal au cours de leur vie en raison d'altérations génétiques. L'alimentation est l'un des principaux facteurs de risque modifiables pour le CCR sporadique, mais cela n'a pas été établi chez les patients atteints du syndrome de Lynch. Cette étude visait à donner un aperçu détaillé des apports alimentaires chez les personnes atteintes de LS et des caractéristiques individuelles associées. Méthodes : Les comportements alimentaires des personnes atteintes de LS de l'essai clinique AAS-Lynch (2017-2022) ont été obtenus à l'aide d'un questionnaire de fréquence alimentaire. Les apports alimentaires, la consommation de groupes d'aliments et la qualité globale de l'alimentation (modèles alimentaires, adhésion au régime méditerranéen) ont été décrits en fonction des caractéristiques sociodémographiques, anthropométriques et cliniques, et comparés à des participants sans LS de l'étude NutriNet-Santé (appariés sur le sexe, l'âge, l'IMC et la région). Résultats : 280 personnes atteintes de LS ont été incluses dans cette analyse et appariées à 547 témoins. Par rapport aux témoins, les patients atteints de LS consommaient moins de fibres, de légumineuses, de fruits et de légumes et plus de viande rouge et de viande transformée (tous p<0,01). Ils avaient également un score de régime méditerranéen plus faible (p=0,002). Parmi les patients LS, les hommes, les jeunes patients ou les patients défavorisés avaient une alimentation de moins bonne qualité nutritionnelle avec une plus faible adhésion à un régime "sain" (tous les p≤0,01). Les patients LS atteints de CCR prévalent avaient une consommation de produits laitiers supérieure aux recommandations, tandis que ceux atteints d'adénome prévalent consommaient plus de légumes et moins de sucre et de sucreries (tous p≤0,01). Conclusions : Bien que les patients atteints de LS soient conscients de leur risque élevé de développer un cancer au cours de leur vie, leur régime alimentaire n'était pas optimal et incluait des facteurs de risque nutritionnels associés au CCR. L'étude est enregistrée sous le numéro NCT04791644 sur ClinicalTrials.gov

Modulation of proteoglycan production by cyclic tensile stretch in intervertebral disc cells through a post-translational mechanism

Proteoglycan production is one of the major extracellular matrix components implicated in the dynamic process of intervertebral disc degeneration. Mechanical stress is an important modulator of the degeneration, but the underlying molecular mechanism at the proteoglycan level remains unclear. The aim of this work was to study the regulation of proteoglycan production by cyclic tensile stretch applied to intervertebral disc annulus fibrosus cells. Matrix metalloproteinases do not seem to be implicated in the regulation of proteoglycan production. By contrast, nitrite oxide production is induced by cyclic tensile stretch, in a time, intensity, and frequency dependant manner. Using a non-specific nitric oxide synthases inhibitor [NG-methyl-L-arginine (L-NMA)], we suppress totally the inhibition of proteoglycan production induced by cyclic tensile stretch suggesting the implication of nitric oxide synthases in the observed phenomenon. Introducing the transcriptional inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole or a more specific inhibitor of nitric oxide synthases II [N-iminoethyl-L-lysine (L-NIL)] did not affect the decreased proteoglycan production, which suggests a post-translational regulation. In contrast, N-omega nitro-L-arginine (L-NNA) a more specific inhibitor of NOS I and III abrogated the cyclic tensile stretch-dependant inhibition of proteoglycan production. These results suggest that cyclic tensile stretch regulates proteoglycan production through a post-translational mechanism involving nitrite oxide. This result could be of interest in the development of local therapeutic strategies aimed at controlling intervertebral disc degeneration

Glycemic response, satiety, gastric secretions and emptying after bread consumption with water, tea or lemon juice: a randomized crossover intervention using MRI

International audiencePurpose Numerous studies, including our previous work with lemon juice, have reported that low-pH meals reduce the glycemic response to starchy foods. However, the underlying mechanism is not yet understood. Tea, for its polyphenol content, has also been investigated. The main objective of this research was to concurrently study gastric emptying, appetite perceptions and glycemic responses to bread consumed with water, tea, or lemon juice. Methods In this randomized, crossover intervention, ten participants consumed equal portions of bread (100 g) with 250 mL of water, water-diluted lemon juice, or black tea at breakfast. Gastric volumes, blood glucose concentrations and appetite perceptions were alternately assessed over 180 min using magnetic resonance imaging, the finger-prick method and visual analogue scales, respectively. Results Compared to water, lemon juice led to a 1.5 fold increase of the volume of gastric contents, 30 min after the meal (454.0 ± 18.6 vs. 298.4 ± 19.5 mL, x ± SEM P < 0.00001). Gastric emptying was also 1.5 times faster (P < 0.01). Conversely, lemon juice elicited a lower glycemic response than water (blood glucose concentrations at t = 55 min were 35% lower, P = 0.039). Tea had no effect. Changes in appetite perceptions and gastric volumes correlated well, but with no significant differences between the meals. Conclusions Lemon juice lowered the glycemic response and increased both gastric secretions and emptying rate. The results are compatible with the hypothesis that the reduction of the glycemic response is mainly due to the interruption of starch hydrolysis via the acid-inhibition of salivary α-amylase

Efficacy and safety of pasireotide-LAR for the treatment of refractory bleeding due to gastrointestinal angiodysplasias: results of the ANGIOPAS multicenter phase II noncomparative prospective double-blinded randomized study

Background: Gastrointestinal angiodysplasias (GIADs) could be responsible for recurrent bleeding and severe anemia. Somatostatin analogs could reduce transfusion requirements in these patients but no randomized controlled study is available. The main objective of the ANGIOPAS phase II double-blinded randomized, noncomparative study was to assess the effectiveness of pasireotide-LAR in reducing transfusion requirements in patients with refractory GIADs bleeding. Methods: A total of 22 patients with transfusion requirements ⩾6 units of packed red blood cells (pRBCs) during the 6 months prior to inclusion were randomized to receive pasireotide-LAR 60 mg ( n = 10) or placebo ( n = 12) every 28 days for 6 months. Patients were then followed for an additional 6 months after stopping treatment. Results: The pasireotide-LAR and placebo groups were equivalent for age, sex, comorbidities and transfusion requirement during the reference period (median 13 and 9.5 pRBCs). A 50 and 83% success rate (success defined as a decrease of at least 30% of transfused pRBCs) was observed in the pasireotide-LAR arm in the Intent to Treat (ITT) and per protocol (PP) analysis respectively. The need for transfusion during the intervention period was 3 pRBC units in the pasireotide-LAR group (range 0–26) and 11.5 pRBC units in the placebo group (range 0–23). Overall, three cases with glycemic control impairment were observed in the pasireotide-LAR group including one de novo diabetes. Conclusion: This double-blinded noncomparative randomized phase II study suggests, for the first time, the effectiveness of pasireotide-LAR 60 mg every 28 days to decrease the transfusion requirement in patients with recurrent bleeding due to GIADs

Efficacy and safety of pasireotide-LAR for the treatment of refractory bleeding due to gastrointestinal angiodysplasias: results of the ANGIOPAS multicenter phase II noncomparative prospective double-blinded randomized study

Background: Gastrointestinal angiodysplasias (GIADs) could be responsible for recurrent bleeding and severe anemia. Somatostatin analogs could reduce transfusion requirements in these patients but no randomized controlled study is available. The main objective of the ANGIOPAS phase II double-blinded randomized, noncomparative study was to assess the effectiveness of pasireotide-LAR in reducing transfusion requirements in patients with refractory GIADs bleeding. Methods: A total of 22 patients with transfusion requirements ⩾6 units of packed red blood cells (pRBCs) during the 6 months prior to inclusion were randomized to receive pasireotide-LAR 60 mg ( n = 10) or placebo ( n = 12) every 28 days for 6 months. Patients were then followed for an additional 6 months after stopping treatment. Results: The pasireotide-LAR and placebo groups were equivalent for age, sex, comorbidities and transfusion requirement during the reference period (median 13 and 9.5 pRBCs). A 50 and 83% success rate (success defined as a decrease of at least 30% of transfused pRBCs) was observed in the pasireotide-LAR arm in the Intent to Treat (ITT) and per protocol (PP) analysis respectively. The need for transfusion during the intervention period was 3 pRBC units in the pasireotide-LAR group (range 0–26) and 11.5 pRBC units in the placebo group (range 0–23). Overall, three cases with glycemic control impairment were observed in the pasireotide-LAR group including one de novo diabetes. Conclusion: This double-blinded noncomparative randomized phase II study suggests, for the first time, the effectiveness of pasireotide-LAR 60 mg every 28 days to decrease the transfusion requirement in patients with recurrent bleeding due to GIADs