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Nivolumab in Metastatic Clear-cell Renal Cell Carcinoma: An Integrative Biomarker Analysis from the NIVOREN GETUG-AFU 26 Phase 2 Study
No full textInternational audienceNivolumab improved survival in patients with refractory metastatic clear-cell renal cell carcinoma (ccRCC), but no reliable biomarker of activity has been identified. We conducted a real-world phase 2 trial of nivolumab in patients progressing after one or more vascular endothelial growth factor (VEGF) receptor-directed therapies, which included an integrated translational programme. Candidate tissue and circulating biomarkers were assessed using immunoassays and gene expression profiling. Overall, 720 patients were treated, with activity and safety in line with pivotal trial data. Exploration of tissue architecture showed that the presence of tertiary lymphoid structures, CD8+ lymphocytes, and CD163+ macrophage infiltration at the invasive margin were all marginally associated with longer progression-free survival, similarly to PD-1 expression on immune cells. Expression of hypoxia-related marker VEGF on tumour cells was however strongly associated with shorter progression-free and overall survival. Recapitulation of microenvironment composition based on gene expression signatures showed that patients harbouring a high tumour lymphocyte infiltration, concomitantly to low infiltration of neutrophil and non-immune stromal cells, had improved response to nivolumab. Conversely, circulating cytokines related to protumoral inflammation interleukin (IL)-6 and IL-8 were independently associated with shorter progression-free and overall survival. Overall, immune and angiogenic features helped inform outcomes to nivolumab. Circulating factors were best potential predictors for immunotherapy activity in ccRCC
Dire ou ne pas dire son nom en ligne : l'anonymat des journalistes à l'ère numérique
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Une histoire des élites d’Italie centrale (Xᵉ-XIIIᵉ siècle). Dominer et se distinguer
No full textInternational audienceBetween the end of the tenth century and the mid-thirteenth century, central Italy underwent major upheavals: the fading of Carolingian structures, the rise of lordships, and the emergence of communes reshaped the social and political order. How did elites take part in these transformations and adapt their behaviours? At the crossroads of social history and anthropology, this study—focused on Umbria and Roman Tuscia—explores everyday power relations, which ultimately either gained legal recognition or drove political change. It shows how these relations reconfigured structures of power and social hierarchies, contributing to the evolution of both lordships and communes.Entre la fin du Xᵉ et le milieu du XIIIᵉ siècle, l’Italie centrale connaît des bouleversements majeurs : l’effacement des structures carolingiennes, l’essor des seigneuries et l’émergence des communes redéfinissent l’organisation sociale et politique. Comment les élites ont-elles participé à ces transformations et adapté leurs comportements ? À la croisée de l’histoire sociale et de l’anthropologie, cette étude centrée sur l’Ombrie et la Tuscie romaine explore les relations de pouvoir au quotidien, lesquelles finissent par obtenir une reconnaissance légale ou par entraîner des évolutions politiques. Elle montre comment ces relations ont redéfini les structures de pouvoir et les hiérarchies sociales, participant aux évolutions des seigneuries et des communes
Psychosocial outcomes among adults with type 1 diabetes using a tubeless automated insulin delivery system compared with sensor augmented pump therapy: A randomised, parallel‐group clinical trial sub‐study
No full textInternational audienceAims: Beyond their glycaemic benefits, automated insulin delivery (AID) systems can provide psychosocial benefits for people with type 1 diabetes (T1D) and improve quality of life. In this study, we evaluated psychosocial outcomes in adults with T1D using the tubeless Omnipod® 5 AID System compared with sensor augmented pump (SAP) therapy.Materials and methods: As part of a 13-week multicentre, parallel-group, randomised controlled trial comparing intervention (tubeless AID) and control (SAP) groups (2:1), adults aged 18-70 years with T1D completed validated psychosocial questionnaires assessing health-related quality of life (European Quality of Life 5 Dimensions 3 Level Version [EQ-5D-3L] index score and visual analogue scale [VAS]), the impact of diabetes on quality of life (DAWN2 Impact of Diabetes Profile [DIDP]), sleep quality (Pittsburgh Sleep Quality Index [PSQI]), system usability (System Usability Scale [SUS]) and perceptions before and experiences after using AID systems (INsulin Dosing Systems: Perceptions, Ideas, Reflections and Expectations [INSPIRE]).Results: The intervention group saw greater score improvements than the control group for all measures evaluated, including health-related quality of life (EQ-5D-3L VAS, p = 0.01; EQ-5D-3L index score, p = 0.002), impact of diabetes on quality of life (DIDP, p = 0.004), perceived system usability (SUS, p < 0.0001) and sleep quality (PSQI, p = 0.03). INSPIRE scores, determined only for the intervention group, were high at baseline and follow-up, suggesting positive perceptions of tubeless AID.Conclusions: This randomised controlled trial demonstrated that the use of a tubeless AID system improved psychosocial measures to a greater extent than SAP therapy. These results contribute to the growing body of evidence demonstrating that AID may improve quality of life and alleviate some of the burden associated with diabetes self-management in adults with T1D
The regeneration index, an agronomic tool to scale up agroecology
No full textInternational audienceAgroecology lays on well-established agronomic principles that are universal: endogenous soil fertility, plant nutrition in water and mineral nutrients, and crop protection against plant bio-aggressors, all ensured as much as possible by the biological activity in the cultivated ecosystem. However, their implementation must be adapted to the pedo-climatic and socio-economic contexts of each farm. A variety of tools exist to evaluate a farm's agroecological level and monitor its progression, often with a main objective of pedagogy. In parallel, downstream corporations engaged in the agroecological transition impose on their suppliers' specifications or certification labels often based on means, ill-adapted to the context of farms, and sometimes at odds with the agronomic principles underlying agroecology.To bridge this major gap between agronomic evaluation and economical valorization, and thus allow for a massive scale-up of agroecology in the field, there is a need for a tool that i) relies on a solid agronomic basis and integrates the key principles of agroecology; ii) does not impose means but sets goals that can be achieved in different technical ways; and iii) allows for direct economical valorization in the supply chain.We present here a new agronomic tool that has been developed to meet these three objectives: the Regeneration Index. After presenting the Regeneration Index's co-construction process, the details of its indicators and their scientific foundation, we enlighten with a case study the relevance of the Regeneration Index to reconcile actors of supply chains around a robust agronomic core in complementarity with environmental certifications
The black-chinned tilapia Sarotherodon melanotheron, a model for environmental genomics and aquaculture resilience in the Western African's context of climate change
No full textInternational audienceThe euryhaline black-chinned tilapia (Sarotherodon melanotheron, Rüppell, 1852) has long been recognised as a valuable local resource in West African aquaculture and artisanal fisheries. Its production contributes to food security, the local economy and farmer’s incomes. Initial research on this species focused on understanding its biology and ecology in the field and in controlled conditions, and then on evaluating and improving practices to increase local production. More recently, the scope of this research has expanded to include investigations integrating molecular approaches in wild populations, such as population genetics and genomics studies, as well as ecophysiological and functional transcriptomics. Additionally, issues related to climate change have been incorporated. In the range of the black-chinned tilapia, the increase in salinity observed in so-called ‘inverse estuaries’ in Senegal, where hypersaline conditions of up to 130 psu may prevail throughout the year, has attracted significant attention. Even for a euryhaline species such as S. melanotheron, such conditions impose substantial energetic costs, resulting in observed phenotypic and adaptive changes to the fish’s biological and life-history traits. Salinity is a major issue in tilapia aquaculture. Improved production could be achieved by selecting strains from populations that are tolerant to salinity, or by hybridising with less tolerant tilapia species that demonstrate better growth performance. This study reviews and summarises knowledge acquired on S. melanotheron over several decades, paying particular attention to the northern subspecies, S. m. heudelotii. Current research limitations consist of: (i) the status of the species itself, comprising subspecies that are still too poorly characterized; (ii) the interaction between salinity and other parameters, particularly hypoxia; (iii) the impact of climate change on the entire species range, involving multiple environmental parameters in Western Africa; and (iv) limited access to resources in Africa, hindering local and regional development
Tet2 deficiency promotes IgG1+ B‐cell expansion and differentiation blockade through deregulation of the Nfkbia –c‐Rel axis
No full textInternational audienceThe germinal center (GC) reaction is essential for orchestrating humoral immunity by producing plasma cells (PCs) and memory B cells (MBCs). TET2, an α‐ketoglutarate‐dependent dioxygenase, plays a critical role in B‐cell exit from the GC and in plasma cell differentiation. Moreover, TET2 functions as a tumor suppressor in diffuse large B‐cell lymphoma (DLBCL), with mutations frequently observed in the ST2 DLBCL subgroup, which is marked by elevated NF‐κB and PI3K signaling and predominant expression of IgG B‐cell receptors (BCRs). We used a combination of in vivo mouse models and in vitro differentiation systems to investigate the effects of Tet2 deficiency on IgG1+ GC B‐cells. We performed flow cytometry, gene expression, and DNA methylation analysis to assess differentiation, proliferation, and molecular alterations. Tet2 ‐deficient IgG1+ GC B‐cells displayed impaired differentiation into both PCs and MBCs, accompanied by enhanced proliferation. These cells exhibited hypermethylation and repression of the Nfkbia locus, increased activation of the NF‐κB subunit c‐Rel, and sustained high levels of surface IgG1. Upon recall immunization, Tet2 ‐deficient IgG1+ MBCs failed to efficiently differentiate into PCs, resulting in their accumulation and further GC expansion. These findings demonstrate that Tet2 is essential for balancing proliferation and terminal differentiation of IgG1+ GC B‐cells during the humoral response. The impaired regulation of this balance due to Tet2 loss provides mechanistic insight into a contributory pathway that may facilitate DLBCL transformation in TET2 ‐mutated cases
Exploring the environmental distribution of the oyster parasite Haplosporidium costale
No full textInternational audienceThe protozoan parasite Haplosporidium costale is known to occur in the USA where it has been associated with sharp seasonal mortality of the Eastern oyster Crassostrea virginica since the 1960’s. In 2019, the parasite was detected for the first time in the Pacific oyster Magallana gigas in France in the context of light mortality and was subsequently detected in archived material collected since 2008. This detection raised several questions regarding the ability of the parasite to maintain in the ecosystem and the potential involvement of other species in its life cycle. To answer these questions, an integrated sampling approach was deployed seasonally in three oyster farming areas where the parasite was already known to occur. Parasite presence was evaluated after checking the presence of PCR inhibitors and using a previously developed and validated Real Time PCR assay, optimized in this study to detect parasite DNA in various environmental compartments. Parasite DNA was almost only detected in cupped oysters. Considering the high number of oysters found positive with low infection intensity, a complementary experiment was undertaken to better characterize sub-clinical infections in oysters. The presence of the parasite was tested twice a week in water and sediment from aquaria hosting cupped oysters from a known infected site. After one month, oysters were sacrificed and tested regarding the presence of the parasite at the tissular level. Altogether, field and experimental results indicate that the parasite is stably established in oyster, particularly in gills, which may act as a reservoir all along the year. The detection of parasite DNA in nanoplankton and sediment suggests that H. costale is released from the oysters outside mortality event. Our results do not support the involvement of other species than cupped oyster in the parasite life cycle except periwinkles, whose role would deserve to be further investigate
Non-local aspects of cognition
No full textInternational audienceThis article explores the non-local aspects of cognition in two main directions, respectively contradicting the idea that 1) it exclusively refers to the cognitive subject's intrinsic mental aptitudes and that 2) it is exclusively centred on the subject’s spatial and temporal localisation. Following 4E cognition, the first direction mentions quite reasonable externalist and multiscale aspects of cognition by successively referring to Clark’s and Chalmers’ concept of extended mind, to social cognition, to Hutchins’ concept of distributed cognition and to Laurent’s multiscale enaction model. The second direction the concept of non-local cognition will be explored puts into question the spatio-temporal locality of cognition since it refers to the possibility of extra-sensory perception. The reality of extra-sensory perception is suggested by the non-reductive solutions to the problem of consciousness, and it is supported by very significant experimental results. The millenary interest in extra-sensory perception will be mentioned, with a special focus on Hinduism for its explicit reference in Pantanjali’s Yoga Sutra. Some of the significant experimental tests aimed to show its existence and some hints for building a theoretical modelling of it will then be presented. The reasons why the reality of extra-sensory perception is generally rejected by the scientific community despite numerous significant experimental results, as well as philosophical justifications and theoretical advances, will be discussed. This article pays particular attention to the second sense of ‘non-local’, based on the possibility of extra-sensory perception, insofar as this disturbing but rigorous scientific field of research is almost not at all considered by the current studies in cognitive science
