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β-Glucuronidase-Responsive Albumin-Binding Prodrug of Colchicine-Site Binders for Selective cancer Therapy
No full textInternational audienceThe development of novel therapeutic strategies enabling the selective destruction of tumors while sparing healthy tissues is of great interest to improve the efficacy of cancer chemotherapy. In this context, we designed a β-glucuronidase-responsive albumin-binding prodrug programmed to release a potent Isocombretastatin A-4 analog within the tumor microenvironment. When injected at a nontoxic dose in mice bearing orthotopic triple-negative mammary tumors, this prodrug produced a significant anticancer activity, therefore offering a valuable alternative to the systemic administration of the parent drug
Photographier le maudit, le portrait de Baudelaire au fauteuil par Nadar
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Dual AmpC and AmpD mutations in Pseudomonas aeruginosa: Unraveling the Mechanisms of Resistance to Ceftazidime and Avibactam
No full textInternational audienceBackgroundCeftazidime/avibactam (CZA) is commonly used against multidrug resistant Pseudomonas aeruginosa (Pa) although resistances are frequently reported. This study assesses the respective impact of AmpCG183D and AmpDH157Y mutations, found in a CZA-resistant clinical isolate, on ceftazidime (CAZ) and avibactam (AVI).MethodsSingle and double mutants ampC (AmpCG183D) and ampD (AmpDH157Y) were previously generated in a PAO1 reference strain1. Minimum inhibitory concentrations (MIC) of CAZ, AVI, and CZA were assessed by broth microdilution2. Time-kill curves (TKC) were performed on PAO1 and its mutant against CAZ and AVI, in monotherapy and in combination with variable concentrations of both molecules. Relative expression of ampC was evaluated using quantitative PCR (qPCR). ResultsqPCR showed no change in ampC expression in PAO1 and the AmpCG183D mutant but revealed overexpression in strains with AmpDH157Y. For all strains, AVI MIC exceeded 256 mg/L (Table 1). No differences were observed in CAZ and CZA MIC of AmpCG183D mutant compared to PAO1. AmpDH157Y single mutant showed increased CAZ MIC and moderately increased CZA MIC. Elevated CZA MICs occurred only in the double mutant. TKC against PAO1 and AmpCG183D mutant, displaying basal expression of ampC, both showed an initial CFU decay followed by regrowth at CAZ MIC (2 mg/L) for all AVI concentrations tested up to 64 mg/L. AmpDH157Y mutant, overexpressing ampC, showed bacterial decay without regrowth at CAZ MIC (16 mg/L) for weak concentrations of AVI from 0.5 mg/L. The double mutant, overexpressing mutated ampC, showed CFU decay without regrowth at CAZ MIC (32 mg/L) for concentrations of AVI from 2 mg/L. ConclusionsOur results demonstrated that the AmpCG183D mutation alone is not sufficient to confer resistance to CAZ and CZA. Moreover, inhibitory effect of avibactam is significant only when wild-type ampC is overexpressed, while it is reduced when mutated ampC (AmpCG183D) is overexpressed. A semi-mechanistic PK/PD model is being developed to characterize the respective contributions of these mutations to the efficacy of both CAZ and AVI
Treatment-free remission in chronic myeloid leukemia with rare ABL1 gene fusions: real-life study from the French CML group Fi-LMC.
No full textInternational audienceTyrosine kinase inhibitors of the BCR::ABL1 oncoprotein can be stopped without subsequent molecular relapse or major safety concerns in 40 to 80% of adult patients with P210BCR::ABL1 positive chronic myeloid leukemia with sustained deep molecular responses. In contrast, ending treatment in patients with rare rearrangements located outside the major BCR region or within the exon 3 of ABL1 remains to be explored. Twenty-four patients with chronic phase disease and diverse uncommon BCR::ABL1 transcripts who obtained sustained molecular residual disease negativity and stopped therapy in a real-life setting for various reasons were retrospectively evaluated for treatment-free remission determinants. Six patients relapsed after a median time of 6 months (range; 3-49), relapse being defined as a rise in molecular residual disease above the 3-log threshold. Treatment-free remission probabilities at 12 and 60 months were 83.3% (95% CI: 68.4-98.2%) and 70.6% (95% CI: 49.5-91.6), respectively. The type of BCR::ABL1 transcript was the only relevant baseline factor associated with durable treatment-free remission and patients with fusions lacking exon a2 sequences had the best outcome. To conclude, treatment-free remission is a reasonably achievable goal in patients with rare ABL1 fusion transcripts. Our results pave the way for recommendations in clinical practice. Nevertheless, further research is needed to determine which patients have highest chances to reach deep molecular response levels and become free from therapy and to decipher the biological impact of the different molecular rearrangements of BCR::ABL1 on treatment-free remission
Enhancing colistin efficacy against multidrug-resistant Klebsiella pneumoniae using farnesol-loaded lipid nanoparticles
No full textInternational audienceBackgroundWe previously demonstrated that farnesol-loaded lipid nanoparticles (F-LNPs) enhance colistin (CST) efficacy against Acinetobacter baumannii [1] and Escherichia coli [2]. In this study, we investigated the broader applicability of F-LNPs againstother Gram-negative bacteria, focusing on mechanisms of action and CST resistance prevention.MethodsCheckerboard assays evaluated F-LNPs as a CST adjuvant against Pseudomonas aeruginosa (n=6) and Klebsiella pneumoniae (n=18) isolates. Effects on the bacterial inner (IM) and outer membrane (OM) were studied, followed by resistanceprevention via serial MICs and zeta potential (ZP) measurements. The efficacy of the combinations was evaluated in Galleriamellonella larvae infection models.ResultsF-LNPs had minimal impact on P. aeruginosa but significantly enhanced CST efficacy against all K. pneumoniae isolates in aconcentration- and isolate-dependent manner, achieving up to 1024-fold MIC reduction for an mcr1isolate (Fig.1). Mechanistic studies using nitrocefin, propidium iodide, and SYTOX™ blue showed that F-LNPs alone increased OM and IMpermeability, effects further amplified in combination with CST (Fig.2A-C). To further investigate OM destabilisation, thecombination was tested on CST-resistant K. pneumoniae strains with LPS modifications incorporating phosphoethanolamine (mcr-1), 4-amino-4-deoxy-L-arabinose (arnT), or both. F-LNPs enhanced CST efficacy by 4- to 1024-fold across all isolates,with no clear correlation between LPS modification type/extent and efficacy enhancement. This suggests that F-LNPs do notspecifically interact with lipid A. Additionally, electron microscopy revealed no visible OM alteration with F-LNPs alone,indicating minimal OM destabilisation by F-LNPs alone (Fig.2D). Resistance prevention studies demonstrated that in mcr1 K.pneumoniae , CST alone led to resistance after 11 passages (MIC≥1024 mg/L), while CST-F-LNP combination maintained alow MIC (0.03 mg/L). High CST resistance was associated with a significant ZP shift (-25.5±3.1 to -14.4±2.9 mV), whereasCST-F-LNP preserved a near-initial ZP (Fig.3). Similar trends were observed in arnT and mcr1-arnT bearing isolates.In vivo ,CST-F-LNP combination improved survival in larvae infected with 10^6 CFU/larva, achieving 43% survival on day 7, comparedto 0% with CST alone.ConclusionsOur results highlight the potential of CST-F-LNP combinations to overcome K. pneumoniae resistance by enhancingmembrane permeabilisation and reducing resistance development
Les Ukrainiennes en Europe : exil, passage et refuge au temps d’une guerre européenne
No full textRubrique : Le point sur : Exil, passage, refugesInternational audienceL’enquête « Voices of Ukraine » (VOU), initiée sur les réseaux sociaux en 2022 par une équipe de chercheuses et de chercheurs et un organisme de sondage, donne la parole aux exilé⋅e⋅s ukrainien⋅ne⋅s dispersé⋅e⋅s en Europe. Depuis l’Allemagne, la Pologne ou la France, principalement, les Ukrainien⋅ne⋅s déplacés par la guerre entre leur pays et la Russie reviennent sur leurs expériences du passage des frontières, leur installation dans les pays d’accueil, les obstacles rencontrés pour leur intégration, et leurs craintes et leurs espoirs concernant la guerre en Ukraine
Postural Control in Children with Autism Spectrum Disorders: What are the Most Striking Specificities and How Can They be Quantified?
No full textInternational audienceAutistic children (AT) are known to exhibit distinct postural control patterns compared to neurotypical (NT) children. However, identifying and interpreting these differences can be complex due to the wide range of variables used to analyse Centre of Pressure (CoP) trajectories. This study aims to elucidate the specific characteristics of postural control in AT children by identifying the most discriminative CoP variables that distinguish them from NT children. The study evaluated 24 AT and 24 NT children while they stood on a force plate for 30 s under three conditions: eyes open (EO), eyes closed (EC), and the feet on a foam pad with eyes open (EOF). A total of 75 variables—including frequential, linear, and non-linear variables—were extracted from the CoP trajectory. These variables, expressed as the rate of change between the EC and EOF conditions relative to the EO condition, were compared between the AT and NT groups. A best-subsets approach was used to identify the most discriminative variables, and Pearson correlations were calculated to assess their relationship with age and Social Responsiveness Scale (SRS) scores. Of the 75 variables analysed, 15 showed significant differences between the AT and NT groups. The best-subsets analysis and the correlations revealed that variables such as the rate of change between the EOF and EO conditions, and the root mean square of the trembling component of the CoP trajectory, were particularly discriminative. Autistic children demonstrated a more rigid and regular CoP trajectory, particularly in the EO condition, compared to NT children. These findings suggest that AT children have greater difficulty integrating multisensory information and an increased reliance on supraspinal processes for postural control
Deep learning-assisted detection of meniscus and anterior cruciate ligament combined tears in adult knee magnetic resonance imaging: a crossover study with arthroscopy correlation
No full textInternational audienceAimWe aimed to compare the diagnostic performance of physicians in the detection of arthroscopically confirmed meniscus and anterior cruciate ligament (ACL) tears on knee magnetic resonance imaging (MRI), with and without assistance from a deep learning (DL) model.MethodsWe obtained preoperative MR images from 88 knees of patients who underwent arthroscopic meniscal repair, with or without ACL reconstruction. Ninety-eight MR images of knees without signs of meniscus or ACL tears were obtained from a publicly available database after matching on age and ACL status (normal or torn), resulting in a global dataset of 186 MRI examinations. The Keros® (Incepto, Paris) DL algorithm, previously trained for the detection and characterization of meniscus and ACL tears, was used for MRI assessment. Magnetic resonance images were individually, and blindly annotated by three physicians and the DL algorithm. After three weeks, the three human raters repeated image assessment with model assistance, performed in a different order.ResultsThe Keros® algorithm achieved an area under the curve (AUC) of 0.96 (95% CI 0.93, 0.99), 0.91 (95% CI 0.85, 0.96), and 0.99 (95% CI 0.98, 0.997) in the detection of medial meniscus, lateral meniscus and ACL tears, respectively. With model assistance, physicians achieved higher sensitivity (91% vs. 83%, p = 0.04) and similar specificity (91% vs. 87%, p = 0.09) in the detection of medial meniscus tears. Regarding lateral meniscus tears, sensitivity and specificity were similar with/without model assistance. Regarding ACL tears, physicians achieved higher specificity when assisted by the algorithm (70% vs. 51%, p = 0.01) but similar sensitivity with/without model assistance (93% vs. 96%, p = 0.13).ConclusionsThe current model consistently helped physicians in the detection of medial meniscus and ACL tears, notably when they were combined.Level of evidenceDiagnostic study, Level III
Des cartes citoyennes
No full textInternational audienceLa carte constitue un outil extrêmement efficace pour faire prendre conscience et témoigner d’enjeux spatiaux relatifs au vécu d’habitant.e.s. Plus particulièrement, les deux approches présentées soulignent comment la carte est un médium dont la pratique libère la parole, et permet de conscientiser collectivement des problèmes socio-spatiaux. Notre exposé insiste sur la question de la pratique sensible et non simplement de la lecture de la carte. À travers nos expériences de recherche-action croisées, avec d’une part le déroulé d’ateliers collectifs de contre-cartographie, et, d’autre part, le déroulé d’une enquête de terrain mobilisant la cartographie transactionnelle, il s’agit pour nous de démontrer comment ce médium favorise l’expression d’opinions souvent tues et l’ouverture d’un débat, même (et surtout) lorsqu’elle est délivrée par des personnes sans compétences en cartographie a priori
