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Glycemic and renal effects of SGLT2 Inhibitors in Prader-Willi syndrome: Benefits and risks
No full textInternational audienceObjective: Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are widely used in type 2 diabetes (T2D) management, but their efficacy and tolerance in Prader-Willi syndrome (PWS) remains unknown. Given the early onset of diabetes and treatment challenges, evaluating SGLT2is in this population is essential.Research and methods: In this retrospective, multicenter study, 48 adults with PWS and T2D, among whom 24 patients receiving SGLT2is, were followed over 6 months. Glycemic and renal parameters were analyzed at baseline and 6 months.Results: HbA1c was higher in the SGLT2i group and significantly improved (P < 0.05) while it remained stable in controls. The albumin-to-creatinine ratio also decreased significantly. No significant weight change was noted. Adverse events occurred in 37.5 % of treated patients, including acute kidney injury in 8.3 %.Conclusions: SGLT2is improve glycemic control and renal markers in PWS with no weight loss. Close safety monitoring is warranted, particularly regarding renal function in PWS and more generally towards all complex obesity with neurodevelopmental disorders
Modeling the PAX5P80R Mutation Reveals HIF2α Activation as a Common Feature and Therapeutic Target in B-cell Acute Lymphoblastic Leukemia
No full textInternational audienceAbstract The transcription factor PAX5 is a major target of genetic alterations in human B-cell precursor acute lymphoblastic leukemia (B-ALL). Among the alterations, the P80R mutation affecting the DNA-binding domain represents the most frequent PAX5 point mutation in B-ALL. In contrast to other somatic PAX5 mutations, PAX5P80R defines a distinct B-ALL subtype characterized by a unique transcriptional program. In this study, we aimed to develop a model to elucidate the mechanism by which PAX5P80R perturbs normal B-cell differentiation and the oncogenic relays involved in PAX5P80R-driven malignant progression. A retroviral complementation approach of Pax5-deficient murine fetal liver cells demonstrated at the functional and molecular levels that PAX5P80R failed to rescue definitive B-cell commitment but maintained the repression of T-cell development. Moreover, PAX5P80R eventually led to clonal B-ALL transformation after transplantation through the acquisition of secondary mutations in genes involved in the JAK/STAT and RAS/MAPK pathways. Finally, transcriptomic analyses combined with pharmacologic investigation revealed ectopic activation of HIF2α as a common feature of B-ALL and identified acriflavine as a potent drug against B-ALL. Hence, this study provides a strategy to model the multistep process of B-ALL and sheds light on the biological mechanism by which the PAX5P80R mutation leads to leukemia. Significance: PAX5P80R perturbs normal B-cell development, leads to clonal transformation, and activates HIF2α as an oncogenic relay, providing mechanistic insights that could improve treatment of B-cell acute lymphoblastic leukemia
ELN regulates cellular senescence: Emerging hypothesis for a non-canonical role
No full textInternational audienceElastic fibers are well-known extracellular matrix components that are essential for elastic properties and thus function of many tissues. Tropoelastin is encoded by the ELN gene which is the main component of the elastic fibers. Elastic fibers decrease with aging and this decrease is proposed to contribute to this process. Senescent cells, cells that stop to proliferate and that instruct their microenvironment, accumulate with aging and promote it. Until recently, whether ELN expression and function is linked to cellular senescence was unknown. Here we will comment and extend recent results supporting a function of the ELN gene in protecting cells from cellular senescence. We will also discuss hypotheses on mechanisms by which ELN could regulate cellular senescence, and especially a hypothesis that involves a non-canonical function of ELN regulating the mitochondrial respiratory chain activity, thereby controlling oxidative stress and cellular senescence. These findings provide critical insights into the molecular and cellular processes potentially underlying the phenotypes driven by ELN deletion in the context of aging
Radiopharmaceutical application of TRK-950, an anti-CAPRIN-1 therapeutic antibody
No full textInternational audiencePurposeTumor imaging or therapy using cancer specific carriers combined with a radioisotope has huge potential. In radiopharmaceutical development, it is important to ensure target specificity and minimal binding to normal tissues for both tumor detection and treatment. In previous studies, we identified CAPRIN-1 as a cancer-specific antigen, which is widely expressed on the cell surface membrane in many types of solid cancers, and created TRK-950, a humanized monoclonal antibody raised against CAPRIN-1, followed by conducting clinical development. In this proof-of-concept study, we prepared radiolabeled form of TRK-950 and investigated their potential as tumor imaging or therapeutic agents.MethodsAn [111In]In-DOTA-TRK-950 was prepared and administered to tumor-bearing mice, and its tumor accumulation and pharmacokinetics were evaluated with SPECT/CT imaging. Next, the anti-tumor effect of a [177Lu]Lu-DOTA-TRK-950 was evaluated. Additionally, radiolabeled TRK-950-F(ab’)2, an antibody fragment of TRK-950, was similarly evaluated for their potential.ResultsAt 72 h after administration of [111In]In-DOTA-TRK-950, tumor accumulation was high at 24.8% IA/g for 4T1 and 18.9% IA/g for HT-29, both of which are CAPRIN-1-high cancer cells, while tumor accumulation remained low at 7.5% IA/g for MNNG/HOS, which are CAPRIN-1-low cancer cells. Regarding therapeutic evaluations, strong anti-tumor effects and prolonged survival were observed after administration of [177Lu]Lu-DOTA-TRK-950 to 4T1 and HT-29 tumor-bearing mice. Furthermore, these results were also observed in the 4T1 tumor-bearing model with radiolabeled TRK-950-F(ab’)2, which has shorter pharmacokinetics.ConclusionThis study demonstrates that radiopharmaceuticals targeting CAPRIN-1, including radiolabeled TRK-950 and TRK-950-F(ab’)2, have high potential as radiopharmaceuticals
Mitochondrial dysfunction in PRRSV-2-infected macrophages
No full textInternational audienceIntroduction Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most economically devastating viruses for the global swine industry. PRRSV has a known tropism for lung macrophages, where it causes impaired immune responses. This study evaluated the metabolic and immune profiles of primary porcine alveolar macrophages (PAMs) and pulmonary intravascular macrophages (PIMs) infected with different strains of PRRSV-2 isolated from North Carolina (NC) pig herds (NC134, NC18-9–7 referred to as NC174, and NC20–1 referred to as NC144), and VR2232, a PRRSV-2 prototype strain. Materials and methods Primary enriched mononuclear phagocytes were infected in vitro with NC134 and NC174, sorted, and processed. The total RNA was used for a transcriptomic approach; additionally, gene expression was further validated using RT-qPCR and NanoString technology. Complementary functional assays with additional NC strains were used to further investigate the mitochondrial and metabolic dysfunction, as well as the oxidative stress induced by PRRSV-2 infection. Results PAMs infected with both NC PRRSV-2 strains NC174 and NC134 showed similar transcriptomic profiles during the early stage of infection, with downregulation of genes involved in the oxidative phosphorylation and electron transport chain pathways. PIMs infected with both NC174 and NC134 strains showed limited alteration in the transcriptomic profiles compared to uninfected cells. Genetic reprogramming matched the PRRSV-2-induced mitochondrial impairment observed in functional assays performed using Seahorse technology. Mitochondrial respiration displayed slightly different profiles between PIMs and PAMs infected with the different PRRSV-2 strains, with PAMs showing a more substantial decrease in mitochondrial fitness compared to control cells. When reactive oxygen species (ROS) and nitric oxide (NO) production were evaluated, no differences were observed between PRRSV-2-infected PAMs and PIMs and control cells. Conclusion These results provide valuable insights into the pathogenetic mechanism of different NC PRRSV-2 strains by focusing on the alteration in mitochondrial function in lung macrophages during early infection and highlighting differences in lung macrophage responses to distinct PRRSV-2 strains
Hybrid Antibiotics Targeting the Bacterial Ribosome
No full textInternational audienceAntimicrobial resistance remains a formidable challenge to modern medicine, with bacterial resistance mechanisms increasingly eroding the utility of clinically important antibiotics. While recent efforts have expanded the antibacterial pipeline, the development of resistance in priority pathogens continues to exceed the pace of new drug development. One emerging strategy to overcome resistance is the rational design of hybrid antibiotics that engage multiple binding sites. Here we describe the design, synthesis, and microbiological and structural characterization of hybrid antibiotics of azithromycin, tedizolid, and chloramphenicol that span the peptidyltransferase center (PTC) and nascent peptide exit tunnel (NPET) in the bacterial ribosome. We characterize the binding of four such hybrids by cryo-electron microscopy, granting insight into their molecular mechanisms of action. We identify a hybrid of azithromycin and tedizolid that is active against a diverse panel of multidrug-resistant Gram-positive bacteria and is minimally affected by ribosomal protection (ABC-F) resistance mechanisms. These results extend our understanding of ribosome inhibition and provide a pipeline for the rational design of dual-action antibiotics that target the ribosome. In a broader context, this work offers a framework for developing bifunctional inhibitors that engage adjacent binding sites by means of a rational cycle of synthetic optimization, biological evaluation, and structural characterization
Multiple maternal occupational exposures during pregnancy and intrauterine growth: analysis of the French Longitudinal Study of Children - ELFE cohort, using data-driven approaches
No full textInternational audienceObjective: To use data-driven approaches to investigate maternal multi-occupational exposures during pregnancy and their effects on intrauterine growth.Methods: Maternal occupational exposure to 47 factors during pregnancy was evaluated with job-exposure matrices in the French ELFE cohort. The outcomes of interest were birthweight (BW), small for gestational age (SGA) and head circumference (HC). Occupational exposures associated with these outcomes were identified by EWAS, LASSO, and random forest. The five exposures with the strongest effects selected with these approaches were included in a final multivariate model with significant interactions.Results: We included 12,851 women. The most important occupational factors predictive of SGA were endocrine disruptors, high strain, kneeling/squatting, job demands, physical effort. No significant associations were detected when these variables were combined in a final model. For BW, the most important variables were leaning forward/sideways, using a computer screen, ultrafine particles, physical effort, airborne germs, repetitive actions. The use of a computer screen significantly decreased BW and, for women not exposed to airborne germs, leaning forward/sideways significantly increased BW. For HC, repetitive actions, oxygenated solvents, kneeling/squatting, airborne germs, working outdoors were the most important predictive factors. Repetitive actions and working outdoors significantly decreased HC. HC also decreased in women exposed to both airborne germs, and oxygenated solvents. Similar results were found for women who worked during the third trimester.Conclusion: Our findings highlight potential roles of chemical, biological and postural factors and their interactions in determining intrauterine growth. These results highlight the importance of considering multiple exposures in occupational health studies
Cool routes: Assessing how green space and paved paths modify heat's effects on urban bicycling
No full textInternational audienceBackground: Understanding how heat’s effect on bicycling varies spatially across the urban environment can inform who may be bicycling in the heat and how urban-planning measures can improve thermal comfort for bicyclists. Objective: We estimated effects of heat on recreational and commute bicycling in Denver, Colorado, USA using city-wide, finely resolved bicycling data and assessed heterogeneity in effects by area-level social vulnerability and proximity to the city center and whether off-street paths and green-space measures, if intervened upon, modify these effects.Methods: From Strava Metro, we obtained daily data on recreational and commute bicycling in Denver on each street segment (N = 218,641) during the summer months of 2019–2023. We estimated effects of hot (95–99 ◦F [35–37 ◦C]) and very hot (100–104 ◦F [38–40 ◦C]) temperature on daily bicycling using model-based standardization, controlling for temporally varying confounders. We assessed effect heterogeneity by area-level social vulnerability and proximity to the city center. To assess effect modification by intervention (defined in text) of paved paths and green-space measures, we additionally controlled for social vulnerability and proximity to the urban core.Results: Heat’s attenuating effects on recreational and commute bicycling were stronger in central Denver but did not differ across area-level social vulnerability. Heat’s attenuating effects were somewhat weaker on off-street paths and considerably weaker in greener areas and near blue space.Conclusions: Results support the provision of paved paths and access to green and blue space to support bicycling during hot weathe
Silencing PTPN2 with nanoparticle-delivered small interfering RNA remodels tumor microenvironment to sensitize immunotherapy in hepatocellular carcinoma
No full textInternational audienceProtein tyrosine phosphatase nonreceptor type 2 (PTPN2) is a promising target for sensitizing solid tumors to immune checkpoint blockades. However, the highly polar active sites of PTPN2 hinder drug discovery efforts. Leveraging small interfering RNA (siRNA) technology, we developed a novel glutathione-responsive nano-platform HPssPT (HA/PEIss@siPtpn2) to silence PTPN2 and enhance immunotherapy efficacy in hepatocellular carcinoma (HCC). HPssPT showed potent transfection and favorable safety profiles. PTPN2 deficiency induced by HPssPT amplified the interferon γ signaling in HCC cells by increasing the phosphorylation of Janus-activated kinase 1 and signal transducer and activator of transcription 1, resulting in enhanced antigen presentation and T cell activation. The nano-platform was also able to promote the M1-like polarization of macrophages in vitro. The unique tropism of HPssPT towards tumor-associated macrophages, facilitated by hyaluronic acid coating and CD44 receptor targeting, allowed for simultaneous reprogramming of both tumor cells and tumor-associated macrophages, thereby synergistically reshaping tumor microenvironment to an immunostimulatory state. In HCC, colorectal cancer, and melanoma animal models, HPssPT monotherapy provoked robust antitumor immunity, thereby sensitizing tumors to PD-1 blockade, which provided new inspiration for siRNA-based drug discovery and tumor immunotherapy
Dynamic fibroblast–immune interactions shape recovery after brain injury
No full textInternational audienceAbstract Fibroblasts and immune cells coordinate tissue regeneration and necessary scarring after injury. In the brain, fibroblasts are border-enriched cells whose dynamic molecular states and immune interactions after injury remain unclear 1 . Here we define the shared fibroblast–immune response to brain injury. Early profibrotic myofibroblasts develop from pre-existing brain fibroblasts and infiltrate brain lesions, orchestrated by fibroblast TGFβ signalling, profibrotic macrophages and microglia, and perilesional glia. Myofibroblasts transition into several late fibroblast states, including lymphocyte-interactive fibroblasts. Interruption of the early myofibroblast state exacerbated sub-acute brain injury, tissue loss and secondary neuroinflammation, with increased mortality in the transient middle cerebral artery occlusion stroke model. Disruption of late lymphocyte–fibroblast niches via selective loss of fibroblast chemokine CXCL12 led to late brain-specific innate inflammation and lymphocyte dispersal with increased IFNγ production. These data indicate the response to brain injury is coordinated by evolving temporal and spatial fibroblast states that limit functional tissue loss and chronic neuroinflammation