The identification of reliable biomarkers for amyotrophic lateral sclerosis (ALS) is an unmet medical need for the development of diagnostic and therapeutic strategies. Brain-derived extracellular vesicles (EVs) have been described in peripheral blood serum and used as a direct readout of the status of the central nervous system. Here, we aimed to explore exosome-enriched EVs (referred to simply as EVs) from ALS patients via omics analysis at an early disease stage. Serum EVs were obtained from 9 healthy controls and 9 ALS patients. After EV purification, proteomic (LC‒MS/MS followed by TimsTOF Pro Mass Spectrometry) and metabolomic (Q Exactive mass spectrometer) analyses were performed. No differences in the size or concentration of EVs were observed between the controls and ALS patients. Proteomic analysis revealed 45 proteins differentially expressed in the EVs of ALS patients compared with those of controls. Metabolomic analysis revealed several distinctly represented metabolites involved in the citrate cycle and complex lipid metabolism between patients and controls. Interomics correlation analysis revealed 2 modules that were strongly associated with ALS and included several lipid metabolism-related proteins and metabolites. This study is the first to evaluate EVs by integrated proteomics and metabolomics in early-stage ALS patients, highlighting the technological progress in global inter-omics explorations of small biological samples. The differences observed in the levels of several exosomal proteins and metabolites, including phospholipids, could be used to identify serum biomarkers and novel players involved in ALS pathogenesis.

Very few quantitative data exist on tramadol metabolites, which hampers our understanding of their role in efficacy and safety of tramadol. We aimed to provide quantitative data on tramadol and its 5 main metabolites in a patient cohort and to determine whether metabolite ratios can be predictive of a CYP2D6 metabolism phenotype. We also aimed to investigate the influence of co-medications and patient profile (BMI, glycemia, lipid levels) on tramadol metabolite ratios. Overall, 37 patient samples from the CONSTANCES cohort contained tramadol and its 5 metabolites. Mean concentrations found tramadol at 343.2 +/- 223.2 mu g/L, M1 at 62.4 +/- 41.4 mu g/L, M2 at 210.0 +/- 272.3, M3 at 1.76 +/- 3.0 mu g/L, M4 at 1.8 +/- 2.8 mu g/L and M5 at 31.8 +/- 28.4 mu g/L. The most frequent CYP2D6 phenotype was extensive metabolizers (51.3%), followed by intermediate metabolizers (24.3%) and poor metabolizers (10.8%). CYP2D6-inhibiting co-medications impacted tramadol metabolism independently of CYP2D6 metabolism phenotype. Lipid parameters and glycemia were significantly associated with changes in tramadol metabolic ratios. Metabolic ratios are not sufficient to determine the CYP2D6 metabolic phenotype in patients. CYP2D6 inhibitors and obesity/NAFLD/diabetes impact tramadol metabolism. These factors are likely to impact the analgesic efficacy and safety profile of tramadol, justifying the need for further studies in this area.

Human hepatocellular carcinomas (HCCs) with cancer stem cell (CSC) features are a subclass of therapeutically challenging cancers. We recently showed that retrodifferentiation of hepatic cancer cells into CSC-like cells leads to metabolic reprogramming and chemoresistance. The molecular mechanisms whereby differentiated cancer cells switch towards a CSC phenotype are poorly understood. By studying metabolic reprogramming associated with HCC cell plasticity, we identified an unsuspected role of peroxisome proliferator-activated receptor (PPAR)γ in hepatic CSC phenotype acquisition. Gene expression and metabolic analyses performed throughout the cell differentiation/retrodifferentiation process of human HepaRG and HBG-BC2 HCC cells show that metabolic reprogramming in hepatic CSCs is associated with a fragmented mitochondrial network, decreased respiration, de novo lipogenesis, and fatty acid oxidation, but increased glycolysis and lipid storage. Mitochondrial genes downregulated in HepaRG-CSCs are also downregulated in the STEM HCC subclass. While PPARα is the main isoform in differentiated hepatic cells, we find high PPARγ expression in hepatic CSCs. Accordingly, nuclear localization of PPARγ is detected in human HCC tumors, and PPARγhigh/PPARαlow expression is associated with the STEM HCC subclass and a poor outcome in human HCC cohorts. PPARγ silencing or/and inhibition of its target gene pyruvate dehydrogenase kinase 4 reactivates cell respiration, increases reactive oxygen species production and sensitizes hepatic CSCs to chemotherapy. Conversely, PPARα activation synergizes with chemotherapy to induce cell death. Targeting PPARγ, a key regulator of metabolic reprogramming and stemness in hepatic CSCs, or modulating the PPARγ/PPARα balance that finely tunes the differentiation/retrodifferentiation process in HCC deserves further investigation for anti-tumor therapy.

We are proposing a reform of the French research system with the aim of simplifying, encouraging interdisciplinarity and optimizing the use of resources to stimulate research and innovation. Recent studies on the international standing of French research show that France is falling further and further behind, particularly in biology and health. The Academie nationale de medecine proposes a reform scenario to overcome this challenge, based on the example of the United Kingdom, where UK Research and Innovation (UKRI) has been created. This is a holding that brings together the initially independent Research Councils, the ministerial structure for contractualizing research in universities, and another structure for innovation that extends to business start-ups. According to a recent audit, this global integration and transver-sal, longitudinal approach to research has proved effective. In France, a comparable national holding acting as a strategic pivot, encompassing research organizations and agencies, would simplify procedures, eliminate sterile competition between institutions, promote multidiscipli-nary research and help empower universities. The implementation of such a reform must win the support of the stakeholders, demonstrating that such organizational change is necessary to reduce bureaucracy, increase staff mobility and give priority to research and innovation in the field.(c) 2023 l'Academie nationale de medecine. Published by Elsevier Masson SAS. All rights reserved.

We present the principles and methodology of a project to reform research funding by the French Ministry of Health. The aim is to bring the allocation of these funds, known as MERRI, into line with international practice by basing it on objective criteria of scientific quality and medical need. A minority of these funds would be allocated to hospitals on a competitive basis and the remainder on a multi-year contractual basis, using secure and transparent distribution channels. A substantial overhead would be allocated to the host hospitals. This reform, which aims to improve the efficiency of hospital research funding in France, is eagerly awaited (c) 2024 l'Academie nationale de medecine. Published by Elsevier Masson SAS. All rights reserved.

Nous présentons les principes et la méthodologie d’un projet de réforme du financement de la recherche par le ministère chargé de la Santé. L’objectif est d’aligner l’attribution de ces fonds, appelés MERRI, sur les pratiques internationales en la fondant sur des critères objectifs de qualité scientifique et de besoin médical. Une minorité de ces fonds serait attribuée aux hôpitaux sur une base concurrentielle et le reste sur une base contractuelle pluriannuelle, en utilisant des canaux de distribution sûrs et transparents. Un préciput substantiel serait alloué aux établissements. Cette réforme, qui vise à améliorer l’efficacité du financement de la recherche hospitalière en France, est très attendue par l’ensemble des chercheurs et des cliniciens.

L’évaluation est un processus indispensable et indissociable de l’activité de recherche. Elle permet de mesurer la qualité, l’impact et la pertinence des travaux, en tenant compte à la fois des aspects quantitatifs et qualitatifs de la recherche. L’évaluation intervient à de multiples étapes de la démarche scientifique : elle concerne la formation et l’activité des personnels de la recherche, leur production scientifique et leurs projets, les équipes et organismes de recherche, les centres hospitalo-universitaires, les infrastructures. L’Académie nationale de médecine a organisé un colloque le 19 septembre 2023 pour faire le point sur les critères et modalités de l’évaluation de la recherche en France. Après une introduction du Président de l’Office parlementaire d’évaluation des choix scientifiques et technologiques, les présidents de l’ANR, du HCERES et de l’Inserm ont exposé la mission de leur institution et leur utilisation respective des indicateurs pour l’attribution des moyens à la recherche en biologie et santé.

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. The immunosuppressive functions of regulatory T lymphocytes (Tregs) are impaired in ALS, and correlate to disease progression. The phase 2a IMODALS trial reported an increase in Treg number in ALS patients following the administration of low-dose (ld) interleukin-2 (IL-2). We propose a pharmacometabolomics approach to decipher metabolic modifications occurring in patients treated with ld-IL-2 and its relationship with Treg response. Blood metabolomic profiles were determined on days D1, D64, and D85 from patients receiving 2 MIU of IL-2 (n = 12) and patients receiving a placebo (n = 12). We discriminated the three time points for the treatment group (average error rate of 42%). Among the important metabolites, kynurenine increased between D1 and D64, followed by a reduction at D85. The percentage increase of Treg number from D1 to D64, as predicted by the metabolome at D1, was highly correlated with the observed value. This study provided a proof of concept for metabolic characterization of the effect of ld-IL-2 in ALS. These data could present advances toward a personalized medicine approach and present pharmacometabolomics as a key tool to complement genomic and transcriptional data for drug characterization, leading to systems pharmacology.

Chlordecone (CLD) is a pesticide persisting in soils and contaminating food webs. CLD is sequestered in the liver and poorly metabolized into chlordecol (CLDOH). In vitro liver cell models were used to investigate the fate and mechanistic effects of CLD and CLDOH using multiomics. A 3D-cell model was used to investigate whether CLD and CLDOH can affect susceptibility to the metabolic dysfunction-associated steatotic liver disease (MASLD). Hepatocytes were more sensitive to CLD than CLDOH. CLDOH was intensively metabolized into a glucuronide conjugate, whereas CLD was sequestered. CLD but not CLDOH induced a depletion of Septin-2,- 7,- 9,- 10,- 11 due to proteasomal degradation. Septin binding with CLD and CLDOH was confirmed by surface plasmon resonance. CLD disrupted lipid droplet size and increased saturated long-chain dicarboxylic acid production by inhibiting stearoyl-CoA desaturase (SCD) abundance. Neither CLD nor CLDOH induced steatosis, but CLD induced fibrosis in the 3D model of MASLD. To conclude, CLD hepatoxicity is specifically driven by the degradation of septins. CLDOH, was too rapidly metabolized to induce septin degradation. We show that the conversion of CLD to CLDOH reduced hepatotoxicity and fibrosis in liver organoids. This suggests that protective strategies could be explored to reduce the hepatotoxicity of CLD.

. - Like innovation in general, innovation in healthcare meets the criteria of novelty with a leap of inventiveness that cannot be predicted by the state of the art. Its specific nature relies on the strict constraints inherent in its application, in particular the compliance with bioethics principles and the specific regulations governing research and innovation in humans. Public support for innovation has been steadily strengthened over the past twenty years, through the "Programmes d'investissements d'avenir" (PIA) from 2010. However, the proliferation of agencies, calls for proposals, and technology transfer offices has led to a disorganization of the system, detrimental to efficiency. In addition, the increase in funding via the PIA is not consistent with the steady decline in resources allocated to basic research in biology and health, which is at the root of innovation. If innovation is to reach the patient's bedside, and should contribute to France's healthcare sovereignty, it is essential (i) to strengthen and coordinate the continuum of funding from basic research to seed capital for innovation projects, and then to the development capital; (ii) to simplify by reducing the number of national and local technology transfer bodies; (iii) to encourage private investment in biology and health, notably through tax incentives; (iv) to shorter contractual terms; and (v) to support for research infrastructures open to start-ups and high -risk projects. (c) 2024 l'Acad & eacute;mie nationale de m & eacute;decine. Published by Elsevier Masson SAS. All rights reserved.

Comme l’innovation en général, l’innovation en santé répond à des critères de nouveauté associée à un saut d’inventivité qui ne pouvait pas être prévu par l’état de l’art. Sa spécificité repose sur les fortes contraintes propres à son application, notamment le respect des principes de la bioéthique et la réglementation spécifique à la recherche et à l’innovation sur la personne humaine. Le soutien public à l’innovation s’est renforcé de manière continue au cours des vingt dernières années, notamment via les Programmes d’investissements d’avenir (PIA) à partir de 2010. Cependant, la multiplication des agences, des organismes de valorisation et des appels à proposition a induit une désorganisation du système, au détriment de son efficience. De plus, l’augmentation des financements via les PIA est incohérente avec l’affaiblissement constant des moyens alloués à la recherche fondamentale en biologie-santé qui est à l’origine de l’innovation. Pour que l’innovation arrive au lit du malade et concoure à la souveraineté de la France en matière de santé, il est indispensable de (i) coordonner le continuum du financement de la recherche fondamentale vers l’amorçage de projets d’innovation, et jusqu’au capital développement, tout en renforçant l’évaluation ; (ii) de simplifier, notamment en réduisant le nombre d’organismes nationaux et locaux de transfert de technologie ; (iii) d’encourager l’investissement privé en biologie-santé, notamment via des incitations fiscales ; (iv) de réduire les délais de contractualisation ; et (v) de soutenir les infrastructures de recherche ouvertes au start-ups et aux projets à risque.

Nous proposons une réforme du système de recherche en France avec l’objectif de simplifier, d’encourager l’interdisciplinarité et d’optimiser l’utilisation des ressources pour stimuler la recherche et l’innovation. Les études récentes sur la place internationale de la recherche française montrent en effet un décrochage qui ne cesse d’empirer, en particulier en biologie-santé. L’Académie nationale de médecine propose un scénario de réforme pour surmonter ce défi, en s’appuyant sur l’exemple du Royaume-Uni où a été créé UK Research and Innovation (UKRI). Il s’agit d’une holding regroupant les Research Councils initialement indépendantes ainsi que la structure ministérielle de contractualisation de la recherche dans les universités et une autre structure pour l’innovation qui va jusqu’à la création d’entreprises. Cette intégration globale et approche transversale et longitudinale de la recherche a fait preuve d’efficacité selon un récent audit. En France, une holding nationale comparable qui agirait comme pivot stratégique, englobant les organismes de recherche et les agences permettrait de simplifier les procédures, d’éliminer la compétition stérile entre institutions, de favoriser la recherche pluridisciplinaire et de contribuer à l’autonomisation des universités. La mise en œuvre d’une telle réforme doit susciter l’adhésion des acteurs impliqués en montrant qu’un tel changement organisationnel est nécessaire pour la réduction de la bureaucratie, une mobilité accrue des personnels et la priorité à accorder à la recherche et à l’innovation sur le terrain.

Evaluation is an essential process and inseparable part of the research activity. It enables to assess the quality, impact and relevance of work carried out in this field, considering both the quantitative and qualitative aspects of research. Evaluation takes place at many stages of the scientific process, including the training and activities of researchers, their scientific output and projects, research teams and organizations, university hospitals and infrastructures. The French National Academy of Medicine organized a symposium on September 19, 2023, to discuss the French research environment and the criteria and methods used to evaluate it. Following an introduction by the President of the Parliamentary Office for the Evaluation of Scientific and Technological Choices, the Presidents of the ANR, HCERES and Inserm presented the missions of their institutions and their respective use of indicators to allocate resources to research in biology and health. (c) 2024 l'Acad & eacute;mie nationale de m & eacute;decine. Published by Elsevier Masson SAS. All rights reserved.

Description of the core human HCC signature.

Exhaustive data mining of up- and down-regulated genes of the core human HCC signature using Enrichr algorithm.

Connectivity map results of the core human HCC signature.

Pour enrayer le déclin de la recherche dont celle en biologie et santé, l’Académie nationale de médecine a proposé plusieurs scénarii s’appuyant sur une politique de site renforcée et une refonte structurelle des organismes nationaux de recherche et des agences de financement. Cependant, il serait illusoire de croire qu’une réforme basée uniquement sur une réorganisation des structures administratives puisse résoudre le problème de l’efficience de la recherche et de son attractivité. Toute réforme de simplification de l’organisation de la recherche doit remettre en priorité le chercheur et son équipe au cœur du dispositif, faciliter la mise en œuvre des projets et alléger son environnement administratif. Cet article reprend plusieurs recommandations antérieures de l’Académie nationale de médecine pour une réforme de la recherche en biologie et santé.

Les Centres hospitaliers universitaires (CHU) ont une triple mission de soins, d’enseignement et de recherche. Cette dernière a une place prépondérante car elle permet d’offrir aux malades des soins de pointe adaptés à toutes les pathologies, et elle est la garantie d’une formation de haut niveau pour les futurs médecins et personnels soignants. L’évolution des bases scientifiques, technologiques, sociales, culturelles de la médecine justifient une refondation de la médecine universitaire dont la crise de la Covid-19 a révélé le besoin. Force est de constater que l’évolution des CHU s’est progressivement éloignée des principes fondateurs qui avaient montré leur efficacité en offrant aux malades une médecine de haut niveau. Face à ce constat, un colloque a réuni plus de cent personnalités du monde scientifique, économique et politique, des représentants des ministères, des parlementaires, avec pour objectifs de : faire un état des lieux de la recherche et de l’innovation en santé ; produire des recommandations sur la nécessaire refondation des CHU et leur place dans une organisation simplifiée de la recherche en biologie-santé ; et identifier les points qui devront faire l’objet d’une réflexion approfondie.

Models that postulate the existence of hidden sectors address contemporary questions, such as the source of baryogenesis and the nature of dark matter. Neutron-to-hidden-neutron oscillations are among the possible mixing processes and have been tested with ultracold neutron storage and passing-through-wall experiments to set constraints on the oscillation period τ_{nn^{'}}. These searches probe the oscillations as a function of the mass splitting due to the neutron-hidden-neutron energy degeneracy. In this work, we present a new limit derived from neutron disappearance in ultracold neutron beam experiments. The overall limit, given by τ_{nn^{'}}>1  s  for |δm|∈[2,69]  peV(95.45%  C.L.), covers the yet unexplored intermediate mass-splitting range and contributes to the ongoing research on hidden sectors.

Characteristics of the 28 liver-oriented HCC microarray datasets (MDS).