Examining Arginase-1 Trimerization Uncovers a Promising Allosteric Site for Inhibition

Arginase-1 (ARG-1) is a promising target for cancer immunotherapy, but the small size and the highly polar nature of its catalytic site present significant challenges for inhibitor development. An alternative strategy to induce enzyme inhibition by targeting protein oligomerization has been developed recently, offering several advantages such as increased selectivity, promotion of protein degradation, and potential substoichiometric inhibition. In this study, we demonstrated that only trimeric ARG-1 is active, which was confirmed by producing monomeric arginase-1. Through in silico-driven site-directed mutagenesis, we identified an allosteric site involving five key amino acids responsible for ARG-1 trimerization. We further demonstrated the covalent modification of a key arginine residue within this pocket using phenylglyoxal disrupted ARG-1 oligomerization. Although phenylglyoxal has limited potency, it effectively supports the concept of ARG-1 inhibition via homomeric disruption, validating this allosteric targeting approach

Statistical Inference for Hicks–Moorsteen Productivity Indices

The statistical framework for the Malmquist productivity index (MPI) is now well-developed and emphasizes the importance of developing such a framework for its alternatives. In this paper, we try to fill this gap in the literature for another popular measure, known as the Hicks–Moorsteen productivity index (HMPI). Unlike MPI, the HMPI has a total factor productivity interpretation in the sense of measuring productivity as the ratio of aggregated outputs to aggregated inputs and has other useful advantages over MPI. In this work, we develop a novel framework for statistical inference for HMPI in various contexts: when its components are known or when they are replaced with non-parametric envelopment estimators. This will be done for a particular firm’s HMPI as well as for the simple mean (unweighted) HMPI and the aggregate (weighted) HMPI. Our results further enrich the recent theoretical developments of nonparametric envelopment estimators for the various efficiency and productivity measures. We also examine the performance of these theoretical results for both the unweighted and weighted mean of HMPI for a finite sample, using Monte-Carlo simulations and also provide an empirical illustration along with the computation code

Imaginer les soins primaires de demain

Le livre Imaginer les soins primaires de demain est basé sur les preuves scientifiques actuelles et coécrit par des chercheur·euses et professionnel·les de santé en association avec le Groupe francophone de soins primaires (www.gfisp.org). Par leur position centrale d’accès au système de santé, leur rôle naturel dans la coordination des soins et s’inscrivant dans un partenariat à long terme avec les individus au sein de leur communauté, les soins primaires devraient être le pivot de tout système de santé. Pourtant, alors qu’ils constituent effectivement un premier niveau de soins pour la population sur un territoire donné afin de répondre à une majorité des besoins individuels, nous observons dans les pays occidentaux un déficit encore important du déploiement des soins primaires. Les causes sont multiples : prépondérance dans nos sociétés d’une médecine technologique centrée sur l’hôpital et les soins aigus, manque de culture de santé publique des professionnel·les, déficits structuraux et de gouvernance des systèmes de santé ou encore manque de volonté politique. Le livre Imaginer les soins primaires de demain est basé sur les preuves scientifiques actuelles et coécrit par des chercheur·euses et professionnel·les de santé en association avec le Groupe francophone de soins primaires (www.gfisp.org). Il propose une réflexion sur les défis contemporains que doivent affronter les soins primaires ainsi que sur les possibles voies d’action pour y faire face. Rédigé par plus d’une quarantaine d’expert·es, il s’agit de faire le bilan de cinquante ans « d’histoire du futur des soins primaires » et de proposer une réflexion sur la manière de stimuler le changement et la créativité dans leur organisation. Il s’agit également et surtout de propo-ser de nouvelles voies, à la fois pour la recherche sur les services de santé et pour les pratiques professionnelles. Le coeur de l’ouvrage est articulé autour des six enjeux majeurs pour les soins primaires que sont les dimensions sociale, environnementale et politique de la santé, la santé mentale, la résilience et l’intégration des services de santé. La dernière partie du livre présente de façon pragmatique, et souvent basée sur des expériences concrètes de terrain, comment mieux organiser et développer les structures de soins primaires de demain

Ketonization of Valeric Acid to 5-Nonanone Over Metal Oxides Catalysts

Valeric acid (VA), readily obtainable in the biorefinery from sugary biomass streams, can be upgraded to 5-nonanone, a versatile chemical building block with numerous applications. This study investigates the performance of nine metal oxide catalysts (SnO2, SiO2, Y2O3, CeO2, ZrO2, TiO2, La2O3, Cr2O3, and Al2O3) in the gas-phase ketonization of VA to 5-nonanone in the 350–450 °C range. The screening reveals a correlation between the metal oxides lattice energy and their catalytic activity for valeric acid ketonization. ZrO2, TiO2, and La2O3, characterized by high lattice energy, demonstrate the highest catalytic activity, whereas Y2O3, SnO2, and SiO2, showing low lattice energy, are barely active. However, exceptions to this trend were observed: Cr2O3 and Al2O3 displayed poor catalytic performance despite their elevated lattice energy. The comprehensive characterization of the catalysts, encompassing XRD, N2-physisorption, NH3-TPD, and CO2-TPD analyses, has unveiled the crucial role of important parameters including acid–base properties in addition to lattice energy. Only oxides showing amphoteric properties can catalyze the reaction effectively. Interestingly, low-lattice energy and amphoteric oxides such as SnO2 (showing poor performance) become significantly active at higher temperature (500 °C). Analysis of by-products by online GCMS and spent catalyst characterization indicated that in this case the ketonization mechanism changed from the so-called surface mechanism to the so-called bulk mechanism

Management of Patients with Advanced Prostate Cancer. Report from the 2024 Advanced Prostate Cancer Consensus Conference (APCCC).

BACKGROUND AND OBJECTIVE: Innovations have improved outcomes in advanced prostate cancer (PC). Nonetheless, we continue to lack high-level evidence on a variety of topics that greatly impact daily practice. The 2024 Advanced Prostate Cancer Consensus Conference (APCCC) surveyed experts on key questions in clinical management in order to supplement evidence-based guidelines. Here we present voting results for questions from APCCC 2024. METHODS: Before the conference, a panel of 120 international PC experts used a modified Delphi process to develop 183 multiple-choice consensus questions on eight different topics. Before the conference, these questions were administered via a web-based survey to the voting panel members ("panellists"). KEY FINDINGS AND LIMITATIONS: Consensus was a priori defined as ≥75% agreement, with strong consensus defined as ≥90% agreement. The voting results show varying degrees of consensus, as discussed in this article and detailed in the Supplementary material. These findings do not include a formal literature review or meta-analysis. CONCLUSIONS AND CLINICAL IMPLICATIONS: The voting results can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers in prioritising areas for future research. Diagnostic and treatment decisions should always be individualised on the basis of patient and cancer characteristics, and should incorporate current and emerging clinical evidence, guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2024 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials

Françoise Collin, le féminisme radical d'une intellectuelle belge internationale

Françoise Collin (1928-2012) est la penseuse du féminisme intellectuel et militant des années 1970 aux années 2000, point de référence du mouvement féministe de la deuxième vague dans les pays francophones. Cet article présente ses contributions majeures tout en les situant dans les mouvements féministes belges et internationaux

Advantages of a genomic DNA-based next-generation sequencing assay for detection of mutant NPM1 measurable residual disease in AML.

Mutations in the nucleophosmin-1 (NPM1) gene are among the most common molecular aberrations in acute myeloid leukemia (AML). Various studies have established mutant NPM1 (mNPM1) as a faithful molecular measurable residual disease (MRD) marker with prognostic significance. Assessment of prognostic mNPM1 is included in the European LeukemiaNet recommendations on MRD detection in AML. Because of recent advancements of promising drugs targeting mNPM1 AML, monitoring of mNPM1 MRD has gained interest, and is generally done by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). However, these RT-qPCR assays use complementary DNA (cDNA) as input, are based on gene expression levels of mNPM1, and are generally limited to specific mNPM1 gene variants. The main advantages of next-generation sequencing (NGS) using genomic DNA as input are stability, independence of gene expression levels, and the ability to detect any NPM1 variant in a single assay. Here, we comprehensively investigated the applicability of NGS on DNA to detect mNPM1 MRD in a cohort of 119 (cDNA) and 310 (DNA) patients with mNPM1 AML in complete remission after 2 cycles of induction chemotherapy. We demonstrate high correlations in levels and prognostic value between RT-qPCR/cDNA and NGS/DNA approaches, postulating NGS/DNA as an attractive alternative to RT-qPCR. We report that the 2% mNPM1/ABL1 threshold by RT-qPCR/cDNA corresponds to an NGS/DNA variant allele frequency of 0.01%. The NGS/DNA threshold of >0.01% after 2 cycles of induction chemotherapy identifies significantly more patients with AML with an increased relapse risk than current RT-qPCR/cDNA assays. The prognostic significance of mNPM1 MRD appears greatest in patients with AML with FLT3-internal tandem duplications