Advances in anti-cancer immunotherapy: car-T cell, checkpoint inhibitors, dendritic cell vaccines, and oncolytic viruses, and emerging cellular and molecular targets

Unlike traditional cancer therapies, such as surgery, radiation and chemotherapy that are typically non-specific, cancer immunotherapy harnesses the high specificity of a patient’s own immune system to selectively kill cancer cells. The immune system is the body’s main cancer surveillance system, but cancers may evade destruction thanks to various immune-suppressing mechanisms. We therefore need to deploy various immunotherapy-based strategies to help bolster the anti-tumour immune responses. These include engineering T cells to express chimeric antigen receptors (CARs) to specifically recognise tumour neoantigens, inactivating immune checkpoints, oncolytic viruses and dendritic cell (DC) vaccines, which have all shown clinical benefit in certain cancers. However, treatment efficacy remains poor due to drug-induced adverse events and immunosuppressive tendencies of the tumour microenvironment. Recent preclinical studies have unveiled novel therapies such as anti-cathepsin antibodies, galectin-1 blockade and anti-OX40 agonistic antibodies, which may be utilised as adjuvant therapies to modulate the tumour microenvironment and permit more ferocious anti-tumour immune response

An ERK1/2-driven RNA-binding switch in nucleolin drives ribosome biogenesis and pancreatic tumorigenesis downstream of RAS oncogene

Oncogenic RAS signaling reprograms gene expression through both transcriptional and post-transcriptional mechanisms. While transcriptional regulation downstream of RAS is relatively well characterized, how RAS post-transcriptionally modulates gene expression to promote malignancy remains largely unclear. Using quantitative RNA interactome capture analysis, we here reveal that oncogenic RAS signaling reshapes the RNA-bound proteomic landscape of pancreatic cancer cells, with a network of nuclear proteins centered around nucleolin displaying enhanced RNA-binding activity. We show that nucleolin is phosphorylated downstream of RAS, which increases its binding to pre-ribosomal RNA (rRNA), boosts rRNA production, and promotes ribosome biogenesis. This nucleolin-dependent enhancement of ribosome biogenesis is crucial for RAS-induced pancreatic cancer cell proliferation and can be targeted therapeutically to inhibit tumor growth. Our results reveal that oncogenic RAS signaling drives ribosome biogenesis by regulating the RNA-binding activity of nucleolin and highlight a crucial role for this mechanism in RAS-mediated tumorigenesis

Recommendations and guidelines from the ISMRM Diffusion Study Group for preclinical diffusion MRI: Part 1 -- In vivo small-animal imaging

The value of in vivo preclinical diffusion MRI (dMRI) is substantial. Small-animal dMRI has been used for methodological development and validation, characterizing the biological basis of diffusion phenomena, and comparative anatomy. Many of the influential works in this field were first performed in small animals or ex vivo samples. The steps from animal setup and monitoring, to acquisition, analysis, and interpretation are complex, with many decisions that may ultimately affect what questions can be answered using the data. This work aims to serve as a reference, presenting selected recommendations and guidelines from the diffusion community, on best practices for preclinical dMRI of in vivo animals. In each section, we also highlight areas for which no guidelines exist (and why), and where future work should focus. We first describe the value that small animal imaging adds to the field of dMRI, followed by general considerations and foundational knowledge that must be considered when designing experiments. We briefly describe differences in animal species and disease models and discuss how they are appropriate for different studies. We then give guidelines for in vivo acquisition protocols, including decisions on hardware, animal preparation, imaging sequences and data processing, including pre-processing, model-fitting, and tractography. Finally, we provide an online resource which lists publicly available preclinical dMRI datasets and software packages, to promote responsible and reproducible research. An overarching goal herein is to enhance the rigor and reproducibility of small animal dMRI acquisitions and analyses, and thereby advance biomedical knowledge.Comment: 69 pages, 6 figures, 1 tabl

Functional film by trigger-free self-assembly of adhesive soft microgels at skin temperature

International audienceTrigger-free self-assembly of oligo(ethylene glycol) OEG-based responsive microgels is for the first time describedvia simple solvent evaporation process at skin temperature and ambient pressure. This unique behaviouris attributed to the intrensic OEG microgel structure and properties due to a negative glass transition temperature,a high adhesion energy, an elastic mechanical property and a high interpenetration of microgels, combinedin an all-in-one building block. Furthermore, the encapsulation of magnetic nanoparticles (NPs) into the OEGbasedmicrogels introduced interferential photonic and magnetic properties to the films. These microgelsexhibiting simultaneously spontaneous film-forming and colored photonic properties open up the developmentof a unique easy-to-handlematerial for cosmetic applications, but also smart patches for healthcare ormedicine

Dating post-Archean lithospheric mantle: Insights from Re-Os and Lu-Hf isotopic systematics of the Cameroon Volcanic Line peridotites

International audienceHighly depleted Archean peridotites have proven very amenable to Re-Os model age dating. In contrast, due to the increasing heterogeneity of mantle Os isotope compositions with time, the Re-Os system has not been as effective in dating post-Archean peridotites. The timing of depletion and accretion of post-Archean lithospheric mantle around cratons is important to understand within the context of the evolution of the continents. In an attempt to precisely date post-Archean peridotite xenoliths, we present a study of the petrology, mineralogy and geochemistry, including whole-rock Re-Os isotopes, highly siderophile elements and clinopyroxene-orthopyroxene Sr-Nd-Hf isotopes of peridotite xenoliths from Lake Nyos in the Cameroon Volcanic Line (CVL). Eight Nyos peridotite xenoliths, all fresh spinel lherzolites, are characterized by low to moderate olivine Fo contents (88.9–91.2) and low spinel Cr# (8.4–19.3), together with moderate to high whole-rock Al2O3 contents (2.0–3.7%). These chemical characteristics indicate that they are mantle residues of a few percent to <20% partial melting. However, trace element patterns of both clinopyroxene and orthopyroxene are not a pristine reflection of melt depletion but instead show various extents of evidence of metasomatic enrichment. Some of the samples contain orthopyroxene with 143Nd/144Nd lower than its coexisting clinopyroxene, which is best explained by recent short-timescale alteration, most likely by infiltration of the host basalt. Because of these metasomatic effects, the Sr-Nd isotope systematics in pyroxenes cannot sufficiently reflect melt depletion signatures. Unlike Sr-Nd isotopes, the Lu-Hf isotope system is less sensitive to recent metasomatic overprinting. Given that orthopyroxene hosts up to 33% of the Lu and 14% of the Hf in the whole rock budget of these rocks and has 176Hf/177Hf similar to, or higher than, coexisting clinopyroxene, it is necessary to reconstruct a whole-rock Lu-Hf isochron in order to constrain the melt depletion age of peridotites. The reconstructed Nyos Lu-Hf isochron from ortho- and clinopyroxenes gives an age of 2.01 ± 0.18 Ga (1σ), and when olivine and spinel are considered, is 1.82 ± 0.14 Ga (1σ). Both ages are identical within error, and they are within error of the alumina-187Os/188Os pseudo-isochron ages (1.2–2.4 Ga) produced on the peridotites from Lake Nyos, consistent with their oldest rhenium depletion Os model ages (2.0 Ga). We conclude that the Nyos peridotites, and the lithospheric mantle that they represent, were formed at ∼2.0 Ga, indicating that the reconstructed whole-rock Lu-Hf isotope system can be a powerful radiometric dating tool that is complementary to and in some instances, more precise than the Re-Os isotope system in dating well-preserved post-Archean peridotites. The recognition of ∼2.0 Ga subcontinental lithospheric mantle (SCLM) in the Nyos area suggests that the Nyos region was assembled as a Paleoproterozoic block, or that it represents fragments of the SCLM from the nearby Paleoproterozoic domain juxtaposed through collisional emplacement during the Pan African Orogeny. With regards to the origin of the CVL, our data reveal that the Hf isotopic compositions of the Nyos peridotites are too radiogenic to be the main source of the CVL basalts

Impact de la structure des lisières bois / parcelles agricoles sur les plantes et les pollinisateurs (apoïdes et papillons)

Les lisières, entre milieux forestiers et milieux ouverts agricoles, sont très fréquentes dans les paysages ruraux caractérisés par de petits fragments forestiers. Elles constituent un enjeu pour la gestion des territoires et rendent des services écosystémiques à l’agriculture et à la foresterie. L’objectif de ce travail est d’étudier l’effet de la structure des lisières entre bois et parcelles agricoles sur la biodiversité des plantes et des pollinisateurs (apoïdes et papillons) et de tester l’hypothèse selon laquelle les communautés végétales et animales seront d’autant plus différentes entre la lisière et la parcelle adjacente que la parcelle adjacente est fortement perturbée et que la lisière est abrupte. Notre étude porte sur la flore vasculaire et des insectes pollinisateurs : apoïdes, rhopalocères présents sur une vingtaine de segments de lisières étudiés simultanément sur 3 sites de forêts de plaine (Régions : Centre, Aquitaine et Midi-Pyrénées). Les lisières étudiées présentaient des faciès différents en termes de perturbations de la parcelle adjacente (prairies versus cultures annuelles) et du type de lisière (abrupt ou douce). Les relevés floristiques et les captures de rhopalocères ont été réalisés sur les 3 sites, alors que lescaptures d'apoïdes n'ont été réalisées que dans les régions Centre et Midi-Pyrénées. Les observations conduites montrent des patrons de réponse diversifiés des communautés végétales aux effets de lisière, en fonctions de la région d’étude et du régime de perturbation des habitats ouverts. La similarité de composition des communautés végétales entre la parcelle la lisière ne varie pas en fonction de l'intensité de perturbation de la parcelle adjacente mais entre sites d'études, les communautés les plus similaires présentant la flore la plus pauvre. L’intérêt des lisères forestières en milieu tempéré pour les apoïdes est confirmé dans deux cultures àpollinisation entomophile (colza et vergers). Elles abritent des sites de nidification et d’accouplement desabeilles terricoles, dominantes dans les assemblages observés. Concernant les apoïdes, seule la région Midi-Pyrénées présente une différence entre lisières et parcelles, avec un indice de diversité assez faible pour lesparcelles de milieu ouvert. Les papillons sont plus abondants dans les lisières de milieu ouvert que dans les milieux ouverts. Les communautés de Rhoaplocères présentent des diversités de Shannon sensiblement identiques entre lisières et parcelles en Aquitaine et en Midi-Pyrénées. Seule la région Centre montre une différence plus sensible entre lisières et parcelles. Compte tenu de leur importance et de leur omniprésence dans les paysages ruraux tempérés ; il semble nécessaire de mieux prendre en compte les caractéristiques des lisières, dans leur variabilité, dans les stratégies de gestion de la biodiversité. Cette biodiversité est susceptible de rendre des services écosystémiques, notamment de régulation des bioagresseurs

Impact de la structure des lisières bois / parcelles agricoles sur les plantes et les pollinisateurs (apoïdes et papillons)

Les lisières, entre milieux forestiers et milieux ouverts agricoles, sont très fréquentes dans les paysages ruraux caractérisés par de petits fragments forestiers. Elles constituent un enjeu pour la gestion des territoires et rendent des services écosystémiques à l’agriculture et à la foresterie. L’objectif de ce travail est d’étudier l’effet de la structure des lisières entre bois et parcelles agricoles sur la biodiversité des plantes et des pollinisateurs (apoïdes et papillons) et de tester l’hypothèse selon laquelle les communautés végétales et animales seront d’autant plus différentes entre la lisière et la parcelle adjacente que la parcelle adjacente est fortement perturbée et que la lisière est abrupte. Notre étude porte sur la flore vasculaire et des insectes pollinisateurs : apoïdes, rhopalocères présents sur une vingtaine de segments de lisières étudiés simultanément sur 3 sites de forêts de plaine (Régions : Centre, Aquitaine et Midi-Pyrénées). Les lisières étudiées présentaient des faciès différents en termes de perturbations de la parcelle adjacente (prairies versus cultures annuelles) et du type de lisière (abrupt ou douce). Les relevés floristiques et les captures de rhopalocères ont été réalisés sur les 3 sites, alors que lescaptures d'apoïdes n'ont été réalisées que dans les régions Centre et Midi-Pyrénées. Les observations conduites montrent des patrons de réponse diversifiés des communautés végétales aux effets de lisière, en fonctions de la région d’étude et du régime de perturbation des habitats ouverts. La similarité de composition des communautés végétales entre la parcelle la lisière ne varie pas en fonction de l'intensité de perturbation de la parcelle adjacente mais entre sites d'études, les communautés les plus similaires présentant la flore la plus pauvre. L’intérêt des lisères forestières en milieu tempéré pour les apoïdes est confirmé dans deux cultures àpollinisation entomophile (colza et vergers). Elles abritent des sites de nidification et d’accouplement desabeilles terricoles, dominantes dans les assemblages observés. Concernant les apoïdes, seule la région Midi-Pyrénées présente une différence entre lisières et parcelles, avec un indice de diversité assez faible pour lesparcelles de milieu ouvert. Les papillons sont plus abondants dans les lisières de milieu ouvert que dans les milieux ouverts. Les communautés de Rhoaplocères présentent des diversités de Shannon sensiblement identiques entre lisières et parcelles en Aquitaine et en Midi-Pyrénées. Seule la région Centre montre une différence plus sensible entre lisières et parcelles. Compte tenu de leur importance et de leur omniprésence dans les paysages ruraux tempérés ; il semble nécessaire de mieux prendre en compte les caractéristiques des lisières, dans leur variabilité, dans les stratégies de gestion de la biodiversité. Cette biodiversité est susceptible de rendre des services écosystémiques, notamment de régulation des bioagresseurs

Modelling the Impact of Chronic Cigarette Smoke Exposure in Obese Mice: Metabolic, Pulmonary, Intestinal, and Cardiac Issues

International audienceUnhealthy lifestyle choices, such as bad eating behaviors and cigarette smoking, have major detrimental impacts on health. However, the interrelations between obesity and smoking are still not fully understood. We thus developed an experimental model of high-fat diet-fed obese C57BL/6 male mice chronically exposed to cigarette smoke. Our study evaluated for the first time the resulting effects of the combined exposure to unhealthy diet and cigarette smoke on several metabolic, pulmonary, intestinal, and cardiac parameters. We showed that the chronic exposure to cigarette smoke modified the pattern of body fat distribution in favor of the visceral depots in obese mice, impaired the respiratory function, triggered pulmonary inflammation and emphysema, and was associated with gut microbiota dysbiosis, cardiac hypertrophy and myocardial fibrosis

FAK activity in cancer-associated fibroblasts is a prognostic marker and a druggable key metastatic player in pancreatic cancer

International audienceCancer-associated fibroblasts (CAFs) are considered the most abundant type of stromal cells in pancreatic ductal adenocarcinoma (PDAC), playing a critical role in tumour progression and chemoresistance; however, a druggable target on CAFs has not yet been identified. Here we report that focal adhesion kinase (FAK) activity (evaluated based on 397 tyrosine phosphorylation level) in CAFs is highly increased compared to its activity in fibroblasts from healthy pancreas. Fibroblastic FAK activity is an independent prognostic marker for disease-free and overall survival of PDAC patients (cohort of 120 PDAC samples). Genetic inactivation of FAK within fibroblasts (FAK kinase-dead, KD) reduces fibrosis and immunosuppressive cell number within primary tumours and dramatically decreases tumour spread. FAK pharmacologic or genetic inactivation reduces fibroblast migration/invasion, decreases extracellular matrix (ECM) expression and deposition by CAFs, modifies ECM track generation and negatively impacts M2 macrophage polarization and migration. Thus, FAK activity within CAFs appears as an independent PDAC prognostic marker and a druggable driver of tumour cell invasion