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Only young age and genetics retain prognostic value for 2-year relapse-free survival in AML
No full textInternational audienceBackground: Intensive chemotherapy (IC) regimen is the standard of care and the only curative treatment for acute myeloid leukemia (AML) since 1970's (Döhner and al, NEJM 2015) that allows a five-year survival of less than 50% (Kantarjian and al, Cancer 2021). While most patients are eligible for allogeneic transplantation (ASCT), some do not receive it due to donor unavailability, comorbidities, or other limiting factors. Factors associated with prolonged 2-year progression-free survival (PFS) in AML patients—especially those with an indication for ASCT in first complete remission (CR1)—remain poorly understood (Bennett and al, Cancer 1997; Bloomfield and al, Cancer 1997; Heering and al, Eur J Haematol 2022). We focused on AML patients alive at 2 years, not transplanted in CR1, with or without an initial transplant indication. Methods: Between 2008 and 2018, among more than two thousand patients included in the AML Hauts-de-France observatory (n° 2214454v0 de la Commission Nationale de l'Informatique et des Libertés), 237 patients were homogenously treated by IC in Amiens and Lille University Hospital Centers. We included in our study 147 patients who were alive beyond two years, without ASCT. The correlation between clinical and biological characteristics (including cytogenetic and molecular landscape) and PFS were specifically analysed in univariate and multivariate following a step-wise backward algorithm. Secondary outcomes were predictive factors of CR and overall survival (OS). Results: Median age was 53 years old IQR [45-63] and sex-ratio was 1.13. Patients had mainly de novo AML (91.16%) with recurrent genetic abnormalities (80.95%) and 2022 ELN risk group was favourable in 72.41%, intermediate in 11.72% and adverse in 15.86%. CR was obtained after IC (one or 2 cycles) for all patients. ASCT was indicated for 31.03% but was not performed, mainly due to lack of donor. Among our cohort, 100 patients were relapse-free at 2 years (named relapse-free), and 47 relapsed within that timeframe (named relapse). Relapse patients had less transcription factor gene fusions or mutations than the relapse-free patients (42.55% versus 62%, p=0.042) and more adverse 2022 ELN risk AML (17.02% versus 15.31%, p=0.037). With a median follow-up of 86.77 months [62.6-124.5], median OS was not reached. In univariate analysis, the predictive factors of OS > 2 years for the 100 patients without relapse were: age < 65 years (HR 4.00 [1.85-8.64], p<0.001), absence of comorbidities (3.68 [1.65-8.20], p=0.001), abnormal cytogenetic (0.26 [0.10-0.68], p=0.006) and the absence of ASCT indication (3.31 [1.53 - 7.16], p= 0.002). In multivariate analysis, only age as continuous variable (1.08 [1.04-1.13], p<0.001) was predictive of OS > 2 years. Global median PFS was 66.6 months (95% IC [44.22-145.54]) (13.08 months [11.2-14.67] in the relapse group versus not reached in the relapse-free group). Relapse was observed for 47 patients (100%) in the relapse group and for 29 patients (29%) in the relapse-free group. In multivariate analysis, only age as continuous variable (1.10 [1.05-1.15], p < 0.001), abnormal karyotype (0.21 [0.08-0.58], p = 0.003) and adverse or intermediate 2022 ELN risk (7.96 [3.27-19.40] p < 0.001) were predictive of PFS > 2 years. Conclusion: In our homogenously treated population without ASCT, 2-year PFS was only influenced by younger age, cytogenetic and ELN risks
From Molecule to Meaning: Click and Bioorthogonal Chemical Reporters for Plant Systems, Biological Imaging, and Artistic Expression
No full textInternational audienceChemical biology has reshaped the ability to investigate complex biological systems at the molecular level. In this context, chemical reporters have become important tools for labeling and tracking biomolecules in living systems with spatial and temporal precision. In plant biology, they provide an alternative to genetic approaches and allow the study of dynamic processes in species or organs that are not easily accessible. Through the use of click and bioorthogonal chemistry, small-molecule probes can be metabolically incorporated into specific molecular scaffolds such as sugars, monolignols, amino acids, and lipids. These probes make it possible to follow events like glycosylation, lignification, lipid turnover, or protein synthesis in living plant tissues. This review presents an overview of current chemical reporter strategies, from molecular design and synthetic considerations to their application in plant imaging. Herein, how these tools have contributed to the development of plant chemical biology by enabling precise and modular investigations of plant structure and metabolism is described. Herein, it is also examined how chemical reporters have entered interdisciplinary contexts, including collaborations between science and the arts. By converting molecular-level information into visual and sensory formats, these approaches open new perspectives for research, education, and communication across scientific and creative disciplines
Uncommon N-Glycan Structures in Anhydrobiotic Tardigrades
No full textInternational audienceWe characterized the N-glycosylation profiles of anhydrobiotic tardigrades, Ramazzottius varieornatus and Hypsibius exemplaris, identifying high-mannose, paucimannose, and complex-type oligosaccharides, while hybrid-type glycans were undetectable. Notably, paucimannose-type oligosaccharides accounted for 39% of the N-glycans in R. varieornatus and 17% in H. exemplaris, with a substantial proportion of them exhibiting fucosylation of the innermost GlcNAc via an α1,6-linkage. This core fucosylation pattern, common to all animals, was observed alongside a distinctive glycosylation signature prominently observed in tardigrades: complex-type glycans lacking galactosylation but containing α1,3-fucosylated GlcNAc at non-reducing termini. This structure was more prevalent in H. exemplaris, with 22 out of 87 identified glycoproteins expressing the Fucα1,3-GlcNAc motif, including eight induced during anhydrobiosis. Key glycoproteins such as Cu/Zn-superoxide dismutase and papilin, implicated in oxidative stress protection and extracellular matrix remodeling, were among those modified. Comparative analyses reveal that non-reducing terminal α1,3-fucosylation in tardigrades is distinct from the mammalian Lewis X antigen and similar structures found in invertebrates, suggesting a unique substrate specificity of fucosyltransferases in these species. Genomic analysis identified homologs of FUT9 and FucTC, indicating potential candidates responsible for this glycosylation pattern. Our findings provide new insights into the molecular mechanisms of glycosylation in tardigrades and their relevance to their extreme stress tolerance
La peste à l’ère moderne, comprendre la transmission de la bactérie Yersinia pestis par les puces
No full textInternational audienceLa peste, causée par la bactérie Yersinia pestis, demeure une maladie mortelle à l’échelle mondiale. Ce pathogène est transmis principalement par les puces, dans lesquelles il s’adapte à l’environnement hostile de leur tube digestif, s’y multiplie et forme alors un biofilm dense qui obstrue l’entrée de sang. Cette obstruction favorise la transmission de la bactérie par régurgitation lors d’un repas sanguin. Ce processus repose sur un programme moléculaire initié chez le rongeur et prolongé chez l’insecte. Dans cette synthèse, nous décrivons l’environnement dans lequel Y. pestis évolue pour infecter les puces, ainsi que les modes de transmission et les mécanismes moléculaires impliqués, tout en adoptant une approche critique pour mieux comprendre les interactions entre Y. pestis et son vecteur, et explorer de nouvelles stratégies de lutte contre la propagation de l’agent de la peste
Immune consequences of exposure to β-pinene oxidation aerosols: adult versus gestational murine models
No full textInternational audienceWhile studies demonstrating the adverse effects of air pollution on human health are accumulating, studies on secondary organic aerosol (SOA) are scarce. However, SOA accounts for a significant portion of airborne particulate matter. In particular, pinene biogenic SOA contributes predominantly to SOA loading in the outdoor atmosphere of natural and urban areas and are also emitted indoors because of the presence of terpenes in numerous consumer products. Our aim was to study the immune consequences of acute exposure to β-pinene ozonolysis gaseous and SOA products in mice. This reaction was generated in an atmospheric simulation chamber, and the mice were exposed to the particulate and gaseous products, to the gaseous products only, or to synthetic air 2 h per day for 3 days in real time in a whole-body inhalation chamber. Exposures were performed in adulthood or in utero. Since some adverse effects only occur in individuals weakened by existing immune activation, such as low-grade inflammation, the immune response was measured in the steady state or in a state of moderate systemic inflammation induced by lipopolysaccharide administration. Exposure of healthy adult mice caused minor immunosuppression in the lungs. However, in adult mice weakened by moderate systemic inflammation, the same exposure conditions revealed that mice exposed to the β-pinene ozonolysis particulate and gaseous products presented deficient pulmonary and systemic immune responses, including excessive recruitment of B lymphocytes, CD4 T lymphocytes, CD11b dendritic cells, inflammatory monocytes and neutrophils in the lungs and defective recruitment of regulatory T cells in the spleen. In offspring exposed to β-pinene ozonolysis products in utero, the LPS-induced upregulation of Ccl2, Cxcl10 and Icam1 mRNA levels in the lungs and the activation of dendritic cells in the spleen were excessive in female mice. The male offspring developed a normal response to moderate systemic inflammation, except for impaired activation of CD4 T cells and increased activation of CD103 dendritic cells in the spleen. In mice, pulmonary and systemic immune reactions in response to moderate systemic inflammation are dysregulated by exposure to common secondary oxidation products, highlighting interest in the role of these neglected atmospheric compounds in immune disease development and susceptibility to infections
Sequence-based genome-wide association study reveals host genomic regions and candidate genes influencing the fecal microbiota of Holstein cows
No full textInternational audienceIn recent decades, the digestive tract microbiota of livestock has been extensively studied, revealing associations with host phenotypes, including production-and health-related traits. The effect of host genetics on gut microbes has been documented in several species; however, in dairy cattle, the specific genomic regions that influence microbial communities remain relatively unexplored. This study aimed to conduct a sequence-based GWAS and a gene-based association study to identify the genomic regions and candidate genes affecting fecal microbiota diversity and composition in a population of 1,875 commercial Holstein cows. From the sequencebased GWAS conducted on 116 fecal microbiota taxonomic levels, 6 QTL were significantly associated with the abundances of Paeniclostridium, an unclassified genus from the Paludibacteraceae family, Sutterella, Turicibacter, and Akkermansia genera, as well as the associated family Akkermansiaceae. These QTL explained between 2.0% and 25.5% of the phenotypic variances of the taxa abundances. Conversely, no genomic variants were found significant for either the α-or the β-diversity of the fecal microbiota. A gene-based association study subsequently conducted on the sequence-based GWAS results revealed significant effects of 90 genes across the bovine genome, effecting the relative abundances of some fecal taxa. Many of these genes were located within the major histocompatibility complex and enriched in immune response pathways. By combining GWAS with gene-based association studies, we specifically identified an association between the ABO gene and the fecal abundance of Akkermansia and Akkermansiaceae. The study represents a significant step forward in understanding the genetic determinism of the complex interactions between the fecal microbiota and their host. It provides new insights into the biological mechanisms underlying host-microbiota interaction in dairy cattle and unveils strong associations between host genomic regions and fecal microbiota in a commercial population. This study holds promise for large-scale breeding strategies to shape the fecal microbiota in Holstein cows and benefit from the host-microbiota interactions
Assessment of quitting versus using aspirin therapy in patients with stabilized coronary artery disease after stenting who require long-term oral anticoagulation: Rationale for and design of the AQUATIC double-blind randomized trial
No full textInternational audienceBackground: Antithrombotic management in patients with chronic coronary syndrome and previous stent implantation who require long-term oral anticoagulation is highly challenging in daily practice, especially in those at high residual risk of coronary and vascular events. Dual therapy with oral anticoagulation and aspirin may lead to a higher risk of bleeding, whereas stopping aspirin in high-risk patients with coronary artery disease after percutaneous coronary intervention may lead to recurrent ischaemic events.Aim: To assess the optimal antithrombotic regimen that should be pursued long term (often lifelong) in these patients.Methods: The AQUATIC study is a prospective, randomized, double-blind, placebo-controlled, parallel-group, multicentre study conducted in patients with chronic coronary syndrome at high risk of ischaemic events (i.e. stent implantation [> 6 months before inclusion] in a context of previous acute coronary syndrome and/or with high-risk features of ischaemic event recurrences) and requiring long-term oral anticoagulation. For superiority, we ensure 80% power at level α = 0.05 to detect a 25% reduction in hazard in the experimental group relative to the control group. Overall, 2000 patients will be randomized in a 1:1 ratio to receive either oral anticoagulation and aspirin or oral anticoagulation and placebo. The primary efficacy endpoint is a composite of cardiovascular death, myocardial infarction, stroke, systemic embolism, coronary revascularization and acute limb ischaemia. Major bleeding according to the International Society on Thrombosis and Haemostasis definition is a secondary safety endpoint that will be assessed as a priority.Conclusion: The AQUATIC trial will test the efficacy and safety of adding aspirin to long-term oral anticoagulation in patients with chronic coronary syndrome and previous coronary stenting who are at high residual risk of recurrent ischaemic events and require oral anticoagulation
Characterizing extracellular vesicles of human fungal pathogens
No full textInternational audienceSince their discovery in 2007, there has been growing awareness of the importance of fungal extracellular vesicles (EVs) for fungal physiology, host-pathogen interactions and virulence. Fungal EVs are nanostructures comprising bilayered membranes and molecules of various types that participate in several pathophysiological processes in fungal biology, including secretion, cellular communication, immunopathogenesis and drug resistance. However, many questions remain regarding the classification of EVs, their cellular origin, passage across the cell wall, experimental models for functional and compositional analyses, production in vitro and in vivo and biomarkers for EVs. Here, we discuss gaps in the literature of fungal EVs and identify key questions for the field. We present the history of fungal EV discovery, discuss five major unanswered questions in fungal EV biology and provide future perspectives for fungal EV research. We primarily focus our discussion on human fungal pathogens, but also extend it to include knowledge of other fungi, such as plant pathogens. With this Perspective we hope to stimulate new approaches and expand studies to understand the biology of fungal EVs
Malagasy flea microbiota results from a combination of vertically transmitted and environmentally acquired microbes
No full textInternational audienceFleas (Insecta, Siphonaptera) are the known vectors of serious bacterial pathogens, such as Yersinia pestis and Rickettsia typhi. The microbiota of fleas has been poorly investigated although it has a known influence on vector competence. Here, we report and analyse the microbiota of 577 flea specimens from Madagascar, a hotspot of plague transmission. Importantly, endemic Malagasy fleas show low host specificity, allowing addressing the importance of vertebrate host species in microbiota composition, as well as that of abiotic variables. We describe through Illumina sequencing of 2 hypervariable regions of 16 S rDNA the bacterial composition of 577 flea specimens of Madagascar. We address the importance of biotic (mammalian host and flea species) and abiotic (season and sampling site) variables on bacterial community composition. Bacterial composition appears driven by flea species and season, but interestingly not by the flea’s vertebrate hosts. These results suggest that the flea microbiota is at least in part acquired before they become adult, possibly in the immature offhost stages. Taken together, our results suggest that the microbiota of sampled fleas are composed of bacterial taxa with vertical transmission, such as Wolbachia which are prevalent in the present dataset, together with several bacterial taxa for which the occurrence is driven by environment factors, especially season and habitat. Given the importance of the microbiota in vector competence, we discuss the epidemiological consequences of environmentally-driven acquisition of microbiota in fleas on plague transmission in Madagascar
An enhanced dual detection of DMB-labeled sialic acids using high-resolution accurate mass spectrometry and fluorescence detection.
No full textInternational audienceSialic acids are important glycan components not only in the conformation of the structure but also in functions of many biological activities. Detection methods for sialic acid have been developed, and fluorescent labeling of sialic acids with 1,2-diamino-4,5-methylenedioxybenzene (DMB) is the best method for its analysis. However, identifying and quantifying sialic acids using mass spectrometry (MS) remains difficult because of the diversity of sialic acids, including O-acetylation. In this study, we initially focused on enhancing the liquid chromatography (LC) separation of DMB-labeled sialic acids in bovine submaxillary mucin (BSM). We successfully achieved highly resolutive separation of 14 types of sialic acids, including multiply O-acetylated species, using a CAPCELL CORE C18 column. These structures were subsequently confirmed through collision-induced dissociation (CID) fragmentation. We then assessed MS and fluorescence detection (FLD) sensitivity using Neu5Ac, Neu5Gc, and Kdn standards, determining detection limits of 32 fmol for MS and 320 amol for FLD, with 320 fmol needed for CID-based structural analysis. These findings highlight the complementary nature of fluorescence and mass spectrometry techniques for DMB-labeled sialic acids identification and quantification. We also examined both CID and electron-activated dissociation (EAD) on the ZenoTOF 7600. CID fragment analysis revealed C5-specific diagnostic fragment ions for Neu5Ac, Neu5Gc, and Kdn. EAD spectra predominantly induced fragmentation of the fluorescent DMB core, regardless of applied variable kinetic energies. This study also led to the discovery of a new structure, Neu5Gc7,8,9Ac3, alongside the previously reported Neu5,7,8,9Ac4 in BSM