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Re-sensitization of antimony-resistant Leishmania by highly potent SbV-porphyrin through the involvement of ERG6-coding gene
No full textInternational audienceLeishmaniasis chemotherapy faces significant challenges, including high costs, severe side effects, and the emergence of drug-resistant parasites, demanding global efforts to identify novel antileishmanial agents. Pentavalent antimony (Sb V ), the primary treatment for over 78 years, suffers from reduced efficacy and high toxicity, underscoring the urgent need for alternatives. We have synthesized metalloporphyrins with potent antileishmanial properties, including the Sb V -porphyrin complex (Sb V T4MPP). Sb V T4MPP exhibited high potency against both Sb-sensitive and Sb-resistant Leishmania spp. with IC 50 as low as 0.05 and 0.12 µM, respectively, for amastigotes and promastigotes; 170-fold more effective than Sb V and with a 28-37-fold selectivity index, highlighting the importance of host cells on drug activity. Sterol profiling of L. infantum revealed that Sb V T4MPP ablated ergosterol production while accumulating cholestane-based sterols (e.g., cholesta-5,7,22trien-3β-ol). Additional sterols appeared exclusively under Sb V T4MPP treatment, accompanied by upregulated erg6, encoding sterol-C-24 methyltransferase (SMT), a key enzyme in sterol biosynthesis. Overexpression of ERG6 reduced Sb V T4MPP potency, increasing the IC 50 by 2.5-fold, confirming ERG6's role in its mode of action. Disruption of ergosterol biosynthesis was indirectly confirmed through hypoosmotic shock assays, which indicated increased membrane fluidity in Sb V T4MPP-treated Leishmania. In vivo studies revealed a 96 % reduction in parasite load, highlighting Sb V T4MPP's efficacy in visceral leishmaniasis model. Since ERG6 is absent in mammals, it represents a selective and promising pharmacological target. Our findings position Sb V T4MPP as a novel chemical entity with potent in vitro and in vivo antileishmanial efficacy, providing mechanistic insights and warranting further preclinical investigation as a promising drug candidate for leishmaniasis treatment
Contemporary management of patients with native mitral regurgitation in heart valve centres
No full textInternational audienceBackground: Despite a key role in the latest guidelines, the screening process of patients with mitral regurgitation (MR) referred to Heart Valve Centres (HVCs) remains unexplored.Aims: To investigate characteristics, management and outcomes of patients with native MR referred to HVCs.Methods: Between January 2017 and May 2021, all patients with MR referred to seven French HVCs for medico-surgical evaluation were included. Individual management was left to the local interdisciplinary HVC. Patients eligible to mitral valve (MV) intervention were compared with those deemed ineligible and left on medical therapy. The primary endpoint was 2-year all-cause mortality.Results: After exclusion for treatment refusal or non-MV surgery, a total of 823 patients were analysed: 662 eligible versus 161 ineligible to MV intervention. Among the 662 eligible patients, 382 (57.7%) underwent transcatheter edge-to-edge repair, 215 (32.5%) MV surgery, 40 (6.0%) transcatheter MV replacement and 25 (3.8%) were either on the waiting list at the end of follow-up (n=12) or had died before intervention (n=13). Ineligible patients had higher surgical risk scores (median EuroSCORE II 4.2% vs. 3.3%; P=0.003; median Society of Thoracic Surgeons mortality risk score 4.3% vs. 3.5%; P=0.023) and more advanced left ventricular (LV) impairment (mean LV ejection fraction 49.7% vs. 56.6%; P<0.001). At 2years, all-cause mortality was significantly higher in ineligible versus eligible patients (36.3% vs. 18.0%; P<0.0001). After multivariable adjustment, HVC-defined eligibility for MV intervention was associated with lower 2-year mortality (hazard ratio: 0.54, 95% confidence interval: 0.35-0.84; P=0.006).Conclusion: HVC interdisciplinary evaluation of severe native MR results in MV intervention in most cases. Eligibility for MV intervention was associated with lower risk of 2-year mortality
Caractéristiques histologiques associées à la survie rénale dans la crise rénale sclérodermique
No full textInternational audienceKey Points Kidney pathology in scleroderma renal crisis was heterogeneous, with three histologic patterns of kidney injury identified by hierarchical cluster analysis. Creatinine, acute arteriolar thrombotic microangiopathy, and onion skinning in small arteries were associated with a higher risk of kidney failure. Complement system was activated in these injured vessels. Background Scleroderma renal crisis (SRC) is a severe complication of systemic sclerosis that is associated with higher morbidity and mortality. However, limited data are currently available regarding the factors affecting kidney outcome during SRC. The objective of this study was to describe kidney histopathology in SRC and to evaluate its association with kidney failure. Methods We performed a French multicenter retrospective study that included 65 patients who underwent a kidney biopsy in the context of SRC between 2006 and 2020. Nonsupervised hierarchical cluster analysis was used to identify histologic patterns. Cox model was performed to estimate the hazard ratios associated with histologic parameters for kidney failure, defined as the need for long-term dialysis therapy or eGFR <15 ml/min per 1.73 m 2 at the last follow-up. Multiplexed sequential immunofluorescence and proximity ligation assay was used in kidney biopsies to analyze complement system activation. Results Kidney pathology in SRC was more heterogeneous than expected, with three histologic patterns of kidney injury identified by cluster analysis. Multivariable analysis showed that together with creatinine at presentation, acute arteriolar thrombotic microangiopathy and onion skinning in small arteries were independently associated with the risk of kidney failure. Multiplex immunofluorescence identified fractions from the complement classical pathway in arterioles and arteries in SRC, while proximity ligation experiments confirmed the in situ activation of classical pathway C3 convertase. Complement terminal pathway fraction C5b-9 was localized in injured arteries. Conclusions This study shows that the clinical definition of SRC encompasses heterogeneity in the patterns of kidney injury. Acute arteriolar thrombotic microangiopathy and onion skinning were associated with kidney failure. Complement system was activated in these injured vessels.Key Points Kidney pathology in scleroderma renal crisis was heterogeneous, with three histologic patterns of kidney injury identified by hierarchical cluster analysis. Creatinine, acute arteriolar thrombotic microangiopathy, and onion skinning in small arteries were associated with a higher risk of kidney failure. Complement system was activated in these injured vessels. Background Scleroderma renal crisis (SRC) is a severe complication of systemic sclerosis that is associated with higher morbidity and mortality. However, limited data are currently available regarding the factors affecting kidney outcome during SRC. The objective of this study was to describe kidney histopathology in SRC and to evaluate its association with kidney failure. Methods We performed a French multicenter retrospective study that included 65 patients who underwent a kidney biopsy in the context of SRC between 2006 and 2020. Nonsupervised hierarchical cluster analysis was used to identify histologic patterns. Cox model was performed to estimate the hazard ratios associated with histologic parameters for kidney failure, defined as the need for long-term dialysis therapy or eGFR <15 ml/min per 1.73 m 2 at the last follow-up. Multiplexed sequential immunofluorescence and proximity ligation assay was used in kidney biopsies to analyze complement system activation. Results Kidney pathology in SRC was more heterogeneous than expected, with three histologic patterns of kidney injury identified by cluster analysis. Multivariable analysis showed that together with creatinine at presentation, acute arteriolar thrombotic microangiopathy and onion skinning in small arteries were independently associated with the risk of kidney failure. Multiplex immunofluorescence identified fractions from the complement classical pathway in arterioles and arteries in SRC, while proximity ligation experiments confirmed the in situ activation of classical pathway C3 convertase. Complement terminal pathway fraction C5b-9 was localized in injured arteries. Conclusions This study shows that the clinical definition of SRC encompasses heterogeneity in the patterns of kidney injury. Acute arteriolar thrombotic microangiopathy and onion skinning were associated with kidney failure. Complement system was activated in these injured vessels
Two chromosomal reference genome sequences for the malaria mosquito, Anopheles (Nyssorhynchus) darlingi, Root, 1926 from French Guiana and Peru
No full textInternational audienceWe present two genome assemblies, each generated from individual female Anopheles ( Nyssorhynchus ) darlingi (the malaria mosquito; Arthropoda; Insecta; Diptera; Culicidae), from wild populations in French Guiana and Peru. The genome sequences are approximately 180 megabases in span. The majority of each assembly is scaffolded into three chromosomal pseudomolecules with the X sex chromosome assembled. The complete mitochondrial genomes were also assembled and are both 15.4 kilobases in length. The assemblies differ by two inversions in chromosome arm 2R
International real-world study of combination immunotherapy sequences in metastatic melanoma
No full textInternational audienceBackground Immune checkpoint inhibitors (ICIs) have revolutionized melanoma treatment, with programmed cell death protein 1 (PD-1) inhibitors—alone or in combination with cytotoxic T-lymphocyte–associated protein 4 or lymphocyte-activation gene 3 inhibitors—demonstrating significant efficacy. However, there is a critical lack of robust data to determine the optimal sequencing of these therapies for individual patients. In particular, the role of relatlimab+nivolumab (rela/nivo) within treatment sequences remains poorly defined. Choosing the right sequence is strategic, as an inappropriate order may compromise the effectiveness of subsequent treatments and limit long-term benefits. Methods This multicenter retrospective and prospective study evaluated 190 patients across three treatment arms: rela/nivo followed by ipilimumab+nivolumab (ipi/nivo) (arm A, N=40), ipi/nivo followed by rela/nivo (arm B, N=71), and anti-PD-1 followed by rela/nivo (arm C, N=79). The study assessed the impact of treatment sequencing on outcomes including response rate, progression-free survival, and overall survival (OS). Results The overall response rate to second treatment was highest in arm C (30.4%), followed by arm B (28.1%) and arm A (17.5%). Patients with secondary resistance to first-treatment ICIs had better responses to second-treatment ICIs than those with primary resistance, particularly in arm B (p=0026). Median OS from date of first ICI treatment was significantly longer in arms B (40.9 months) and C (42.5 months) compared with arm A (16.3 months). Conclusions Our findings indicate that rela/nivo may remain active following anti-PD-1 or ipi/nivo therapy. Additionally, our results suggest that sequencing ipi/nivo before rela/nivo may yield better outcomes than starting with rela/nivo. Patients who respond to the first combination regimen appear to derive greater benefit from the second. Further efforts are needed to optimize sequencing strategies in advanced melanoma, and future studies should consider the impact of prior treatment outcomes
Secondary-type acute myeloid leukemia is associated with a higher risk of invasive fungal infection during intensive induction therapy. a correlative study on the ALFA 0702 trial.
No full textInternational audienceBackground. Invasive fungal infections (IFIs) represent a major cause of morbidity and mortality during intensive induction therapy for acute myeloid leukemia (AML). Although their incidence is increased in this setting, the associated risk factors remain poorly defined. In particular, the impact of somatic gene mutations on IFI risk during induction is not well understood. Secondary-type AML (sAML) gene mutations (ASXL1, BCOR, BCORL1, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2) define a distinct diagnostic and prognostic entity (PMID 35797463), and mutations in ≥2 genes amongst those (sAML2) may allow more robust identification of these patients (PMID 35941135) Objectives. We aimed to investigate whether recurrent AML gene mutations are associated with higher risk of invasive fungal infections during the first time-sequential induction therapy in the ALFA 0702 trial (NCT00932412). Methods. Main results of ALFA0702 were previously reported (PMID 28221862). IFIs were graded according to EORTC guidelines (PMID 34895843). Gene mutations were evaluated at diagnosis (PMID 32871585) and patients were classified as having secondary-type AML (sAML2) if ≥2 genes were mutated among the following: ASXL1, BCOR, BCORL1, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2. Cumulative incidence of IFI was evaluated considering death prior to start of the second course as a competing risk. Results. Of 713 patients (pts) with AML registered in the 0702 trial, 633 (M/F 340/293, median age 47y) had complete genetic and IFI data and did not have a preexisting IFI at inclusion. 447 (71%) pts received anti-fungal prophylaxis during the first intensive course (posaconazole n=360, other n=87). IFIs occurred in 96 (15%) patients during the first induction therapy. IFIs were more frequent in males (M 19%%, F 11%, p=0.007) and in the 21% of pts with baseline Absolute Neutrophil Count (ANC) < 500 x109/L (IFIs in 21% vs 12.5% in pts with ANC ≥ 500 x109/L, p=0.006) whereas time to neutrophil recovery (median 29 days) had no impact on occurrence of IFI (p=0.7). Of 38 genes recurrently mutated in at least 1% of pts, mutations in 4 genes were individually associated with increased risk of IFI when stratifying on receipt of antifungal prophylaxis (false-discovery rate [FDR] threshold 0.1), including SRSF2 (HR=2.36, FDR=0.03), BCOR (HR=1.97, FDR=0.089), CBL (HR=2.99, FDR=0.089) and SETBP1 (HR=3.30, FDR=0.089). Adjusting for sex, baseline ANC and time to neutrophil recovery led to similar results. Mutations in SRSF2 and BCOR contribute to the definition of secondary-type AML. Genetically-defined sAML2 was found in 77 pts (12%) and was associated with increased IFI risk in a similar analysis stratified on antifungal prophylaxis (sAML2: HR=2.2, p=0.001). Specifically, the cumulative incidence of emergent IFI at 60 days from first induction course onset was 21% in sAML2 vs 11% in non-sAML2 pts receiving antifungal prophylaxis, and 45% compared to 19% respectively when not receiving antifungal prophylaxis. The median time to neutrophil recovery was 32 days in sAML2 pts vs 28 days in other pts (p=0.0079). In a multivariable model also accounting for sex (M, HR=1.90, p=0.005), baseline neutropenia (ANC<500 x109/L, HR=1.67, p=0.02) and time to neutrophil recovery (days, as a continuous variable, HR=1.0, p=0.94), sAML2 was independently associated with an increased hazard of IFI (HR=1.96, p=0.01). Of note, the IFI profiles (Candida sp. vs Aspergillus sp. vs other) were similar between sAML2 and non-sAML2 pts (p=0.78). To explore the potential causal link between sAML2 genetic profile and incidence of IFI, we leveraged data from 177 patients treated in the ALFA0701 trial with detailed morphological and genetic annotations (PMID 34615986), including 21 (11.9%) with sAML2 profile. sAML2 was associated with a specific dysgranulopoiesis notable for persistent basophilia (28.3% of sAML2s versus 8.3% of non-sAML2 cases, p=0.018). Across 2 genetically annotated transcriptomic datasets (BEAT-AML2, n=428; ALFA0701, n=180), sAML2 status was robustly associated with increased expression of both type I and II IFN pathways (all FDR < 10-5), also possibly contributing to aberrant antifungal immunity. Conclusion. Genetically-defined secondary-type AML patients might be more susceptible to IFI during intensive AML induction therapy regardless of baseline ANC and duration of neutropenia. These findings may guide personalized IFI prevention policies in this population
Domain mapping of disease mutations reveals pathogenic SORL1 variants in Alzheimer’s disease
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Fibropapillomatosis Dynamics, Severity and Demographic Effect in Caribbean Green Turtles
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Genetic polymorphism of msp2 in Plasmodium falciparum isolates among asymptomatic malaria infections from two ecological settings in Cameroon
No full textInternational audienceBackground: The high genetic diversity of Plasmodium falciparum parasites is one of the challenges for malaria control and elimination in endemic areas. A better knowledge of parasite genotypes circulating in different disease endemic areas could help to optimize local malaria interventions. This study aimed at determining P. falciparum genetic diversity from isolates collected in forest (Mfou) and humid savanna (Tibati) eco-epidemiological settings in Cameroon.Methods: Dried blood spots collected from asymptomatic individuals in 2018 and 2019 were used to determine the Plasmodium infection status and distinguish the Plasmodium spp. by real-time PCR. Allelic polymorphism of the msp2 gene was assessed in the P. falciparum positive samples by nested PCR followed by capillary electrophoresis for revelation of the fragment allelic size. Multiplicity of infection (MOI) was defined as the number of coinfecting genotypes within an infection. General linear mixed models were fitted to evaluate the impact of study site, participant age, gender and bed net ownership on genetic diversity.Results: Malaria prevalence among the asymptomatic individuals reached 59.2% (876/1480) in Mfou and 63.4% (808/1274) in Tibati. A total of 36 and 42 different msp2 alleles were detected in Mfou and Tibati, respectively. No genetic differentiation was observed between the two study sites. The msp2 IC/3D7 family was the most polymorphic and the most prevalent in both areas. Overall, more than 60% of the isolates had multiclonal infections. The frequency of multiclonal infections and MOI was higher in Mfou (68.9%, MOI = 2.08) than in Tibati (57.29%, MOI = 1.80). In Mfou, a negative correlation was found between MOI and age. Similarly, a gender effect was observed in Mfou, with males having higher MOI than females.Conclusion: This study reported high malaria prevalence and a high allelic diversity in the msp2 gene among asymptomatic carriers from two epidemiological settings of Cameroon. Despite results reflects high transmission intensity in both areas, analysis indicated distinct epidemiological patterns in Mfou and Tibati. These findings will provide valuable baseline information to monitor the impact of malaria control measures implemented in these areas
Prediction of Late Ventricular Arrhythmias in Patients with Left Ventricular Assist Device: Insights from the VT-LVAD Consortium
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