Search

Inflammation and tissue damage associated with pancreatitis can precede or occur concurrently with pancreatic ductal adenocarcinoma (PDAC). We demonstrate that in PDAC coupled with pancreatitis (ptPDAC), antigen-presenting type-I conventional dendritic cells (cDC1s) are specifically activated. Immune checkpoint blockade therapy (iCBT) leads to cytotoxic CD8+T cell activation and eradication of ptPDAC with restoration of lifespan even upon PDAC re-challenge. Such eradication of ptPDAC was reversed following specific depletion of dendritic cells. Employing PDAC antigen-loaded cDC1s as a vaccine, immunotherapy-resistant PDAC was rendered sensitive to iCBT with a curative outcome. Analysis of the T-cell receptor (TCR) sequences in the tumor infiltrating CD8+T cells following cDC1 vaccination coupled with iCBT identified unique CDR3 sequences with potential therapeutic significance. Our findings identify a fundamental difference in the immune microenvironment and adaptive immune response in PDAC concurrent with, or without pancreatitis, and provides a rationale for combining cDC1 vaccination with iCBT as a potential treatment option.

Pancreatic ductal adenocarcinoma (PDAC) is associated with mutations in Kras, a known oncogenic driver of PDAC; and theKRASG12Dmutation is present in nearly half of PDAC patients. Recently, a non-covalent small molecule inhibitor (MRTX1133) was identified with specificity to the KrasG12Dmutant protein. Here we explore the impact of KrasG12Dinhibition by MRTX1133 on advanced PDAC and its influence on the tumor microenvironment. Employing different orthotopic xenograft and syngeneic tumor models, eight different PDXs, and two different autochthonous genetic models, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8+effector T cells, decreases myeloid infiltration, and reprograms cancer associated fibroblasts. Autochthonous genetic mouse models treated with MRTX1133 leads to regression of both established PanINs and advanced PDAC. Regression of advanced PDAC requires CD8+T cells and immune checkpoint blockade therapy (iCBT) synergizes with MRTX1133 to eradicate PDAC and prolong overall survival. Mechanistically, inhibition of mutant Kras in advanced PDAC and human patient derived organoids (PDOs) induces Fas expression in cancer cells and facilitates CD8+T cell mediated death. These results demonstrate the efficacy of MRTX1133 in different mouse models of PDAC associated with reprogramming of stromal fibroblasts and a dependency on CD8+T cell mediated tumor clearance. Collectively, this study provides a rationale for a synergistic combination of MRTX1133 with iCBT in clinical trials.

Background A balanced anaesthetic protocol is a common concept in modern veterinary anaesthesia and aims to maintain good intraoperative cardiopulmonary function. In horses, alpha-2-agonists produce sedation and analgesia and have been shown to reduce inhalational anaesthetic requirements when administered intravenously. Furthermore, these drugs can improve recovery quality. Preliminary investigations of subcutaneous dexmedetomidine administration in humans demonstrated a reduced haemodynamic impact if compared with the intravenous route suggesting that dexmedetomidine is adequately absorbed with both administration routes. The aim of the study was to compare two different dexmedetomidine (DEX) administration routes: intravenous constant rate infusion (CRI) versus repeated subcutaneous (SC) injections on cardiopulmonary function and recovery in anaesthetized horses. Results No significant differences between groups in heart rate and systolic arterial pressure were detected. A significantly higher mean and diastolic arterial pressure were detected in the SC group at T25 (p = 0.04; p = 0.02), T75 (p = 0.02; p = 0.009), and T85 (p = 0.001; p = 0.005). In SC group there was a significantly lower dobutamine infusion rate (p = 0.03) and a significantly higher urinary output (p = 0.02). Moreover, recovery quality was higher (p = 0.01). Conclusions Cardiopulmonary effects in both groups were comparable and within clinical ranges with less dobutamine requirement in the subcutaneous group. Recovery was of better quality with fewer attempts in horses receiving subcutaneous dexmedetomidine. The present study suggests that intravenous constant rate infusion and subcutaneous repeated administration of dexmedetomidine at indicated dosage can be useful in balanced anaesthesia without any systemic or local adverse effects; moreover, in healthy horses undergoing general anaesthesia, repeated subcutaneous dexmedetomidine administration may be a suitable alternative if constant rate infusion is not feasible.

The objective of this work is the synthesis and complexation of heterocycles under simple reaction conditions. We performed an effective synthesis of substituted quinoxalinones followed by a complexation with transition metals in 1/1 ratio in ethanol. The products obtained were characterized by 1H NMR, 13C NMR, mass spectrometry and IR.

This work reports the synthesis and characterization of new benzimidazole-cyclohexanone derivatives 3a-d, 4a-d and 5a-d under different reaction conditions. The intermediates and final compounds were purified and their chemical structures were elucidated using 1H-NMR, 13C-NMR and mass spectral data.Keywords: Benzimidazole, Cyclohexanone, NMR, Reaction intermediates

International audience

International audience; In a driving car, passengers are submitted to complex sound and vibration stimuli. These stimuli are integrated in a complex way and contribute to the comfort for passengers. This talk will summarize some work related to that field, during which a noise and vibration simulator was used to evaluate the relative contributions of noise and vibration to comfort in a driving car. A first step showed that this evaluation was only slightly modified by vision (of a video showing the road on which the car was driven on). Then a complete experimental plan was used : sound and vibration levels were independently varied and the subjects were asked to evaluate the comfort of the overall situation. The results were in concordance with the existing literature, i.e. the interaction between both stimuli is very small. But the relative contributions of sound and vibration to comfort were different from the existing models; this was certainly due to the range of levels used in that experiment, which represented usual levels measured in cars.

International audience