Pasteur Institute of Lille

Valve interstitial cells (VICs) play a critical role in aortic valve calcification and angiogenic processes associated with calcific aortic valve stenosis (CAVS). Within the same valve, VICs from differently calcified regions can exhibit diverse phenotypic and functional properties. We hypothesised that VICs isolated from noncalcified (NC-VICs) and calcified (C-VICs) areas of human aortic valves possess distinct angiogenic characteristics. In this study, we isolated C-VICs and NC-VICs from 23 valves obtained after aortic valve replacement due to CAVS. Both VIC types exhibited similar phenotypes in culture, characterised by morphology, expression of mesenchymal/fibroblastic markers, proliferation and osteogenic differentiation. No significant differences were observed in the secretion of angiogenic factors, including VEGF-A, Ang-1, Ang-2, PlGF, bFGF between NC-VICs and C-VICs. However, when co-injected with endothelial colony-forming cells (ECFCs) into Matrigel implants invivo in mice, implants containing NC-VICs showed significantly higher microvessel density compared to those with C-VICs (p < 0.001). Additionally, NC-VICs co-cultured with ECFCs expressed significantly higher levels of the perivascular markers αSMA and calponin compared to C-VICs (p < 0.001 and p < 0.05, respectively). In conclusion, our study reveals the heterogeneity in VIC plasticity within the aortic valve during CAVS. The diminished capacity of VICs from calcified areas to differentiate into perivascular cells suggests a loss of function as valve disease progresses. Furthermore, the ability of VICs to undergo perivascular differentiation may provide insights into valve homeostasis, angiogenesis and the exacerbation of calcification.

In hereditary papillary renal cell carcinoma (HPRCC), the hepatocyte growth factor receptor (MET) receptor tyrosine kinase (RTK) mutations recorded to date are located in the kinase domain and lead to constitutive MET activation. This contrasts with MET mutations identified in non-small cell lung cancer (NSCLC), which lead to exon 14 skipping and deletion of a regulatory domain: in this latter case, the mutated receptor still requires ligand stimulation. Sequencing of MET in samples from 158 HPRCC and 2808 NSCLC patients revealed ten uncharacterized mutations. Four of these, all found in HPRCC and leading to amino acid substitutions in the N-lobe of the MET kinase, proved able to induce cell transformation, which was further enhanced by hepatocyte growth factor (HGF) stimulation: His1086Leu, Ile1102Thr, Leu1130Ser and Cis1125Gly. Similar to the variant resulting in MET exon 14 skipping, the two N-lobe MET variants His1086Leu and Ile1102Thr were found to require stimulation by HGF in order to strongly activate downstream signaling pathways and epithelial cell motility. The Ile1102Thr mutation also displayed transforming potential, promoting tumor growth in a xenograft model. In addition, the N-lobe-mutated MET variants were found to trigger a common HGF-stimulation-dependent transcriptional program, consistent with an observed increase in cell motility and invasion. Altogether, this functional characterization revealed that N-lobe variants still require ligand stimulation, in contrast to other RTK variants. This suggests that HGF expression in the tumor microenvironment is important for tumor growth. The sensitivity of these variants to MET inhibitors opens the way for use of targeted therapies for patients harboring the corresponding mutations.

A diet rich in lipids can lead to many deleterious conditions, which involve many regulatory molecules, such as non-coding (nc)RNAs. We aimed to analyze the effects of high dietary lipid exposure on the expression of intestinal ncRNAs (long non-coding[lncRNAs] and circular [circRNAs]). lncRNAs and circRNAs were screened, both in vivo (mice) and in vitro (human intestinal organoids). In vivo, 15 lncRNAs (9 up- and 6 downregulated) and 41 circRNAs (13 up- and 28 downregulated) were modulated 3h after a lipid challenge, while the expression of 11 lncRNAs (4 up- and 7 downregulated) was altered after 4 days of daily high-fat diet intake. In vitro, 251 up- and 387 downregulated lncRNAs, along with 19 up- and 16 downregulated circRNAs, were found 3h after the exposure to a dietary-lipid stimulus, whereas 111 up- and 86 downregulated lncRNAs were found 24h after exposure. Concord between the differently expressed ncRNAs found in both studies was scarce. Numerous differentially expressed lncRNAs and circRNAs have been found in response to dietary lipids both in mice and humans organoids. A potential association between many of these ncRNAs and lipid metabolism is suggested, but ncRNAs found differ greatly between humans and mice.

Expression of concern for 'Innovative transdermal delivery of insulin using gelatin methacrylate-based microneedle patches in mice and mini-pigs' by Bilal Demir et al., Nanoscale Horiz., 2022, 7, 174-184, https://doi.org/10.1039/D1NH00596K.

The prevention and management of allergic reactions at school is now recognized as a public health concern in many countries, with around 10% of pediatric anaphylaxis cases occurring at school [1]. In France, prevention measures in allergic children at school have been updated in 2021 and national policies mandated secondary schools to stock undesignated adrenaline auto-injectors (AAI) since 2019 [2]. There are only few published data on anaphylaxis at school, many from the United States [3]. The aim of our study was to analyze data on food-induced anaphylaxis (FIA) at school and describe their main characteristics and time trends. We conducted a retrospective analysis of an FIA cohort based on the Allergy-Vigilance Network (AVN) database (2002–2023) (see Supporting Information for Methods). Of the 3119 FIA reactions recorded by the AVN, 1762 (56.5%) involved school-age children (3–18 years) and 157 (8.9%) occurred at school. The main characteristics and treatment of these 157 cases are detailed in Table 1 (see Supporting Information for additional results). Three groups of children have been identified according to a history of food allergy (group 1: no prior food allergy; group 2: known food allergy to the culprit food; group 3: food allergy for another culprit food) with no difference between the three groups, except a history of asthma which was more frequently observed in group 3 compared to both other groups (p = 0.03) (Table 1). Of the 112 food allergic children, 52 (46.4%) had received an individual healthcare plan (IHP) with an AAI available in 43 (82.7%). 5 (3.2) 4 deaths 4 (5.6) 4 deaths The main foods involved in the FIA at school were peanut (n = 33; 21.0%) and cow, goat, and sheep milk (n = 18; 11.5%) (Figure S1). According to severity (Ring classification modified by Behrendt), 41 (26.1%) cases were classified as grade 3 and 5 (3.2%) as grade 4, including four deaths (all induced by milk) [4]. Intramuscular adrenaline was administered in 41 (26.1%) children but only in 22 (14.0%) at school (with an AAI in 17 [10.8%]). Comparing the three time periods, there was an increase in the absolute number of FIA cases at school and in adrenaline use (p < 10−3) but no significant variation in the rate of FIA cases among the number of FIA cases in school-aged children (p = 0.71), in the distribution of cases according to severity (p = 0.99) or food triggers (peanut or other foods) (p = 0.48 and p = 0.28, respectively) (Figure 1 and Figure S2). Our data illustrate how difficult it is to prevent the occurrence of anaphylaxis at school, with 29% of FIA occurring in children with no food allergy and a large variety of food allergens. Conversely, 45% of FIA occurred in children with a known food allergy and should be therefore avoidable. Most cases were related to accidental exposure and resulted in a complex series of avoidable errors or shortcomings from all parties. Peanut remains the most frequent food involved in FIA as reported throughout the world [1, 5]. To address issues regarding food avoidance, some schools have opted for allergen restrictions in school settings, but there is a lack of evidence that they are effective strategies [6]. A number of countries now require schools to have specific policies and procedures to keep food-allergic children safe. Our data also highlight shortcomings regarding recognition and management of FIA cases with an alarming underuse (26%) of adrenaline. However, we found an increasing rate of adrenaline use over time, rising at 41% of cases from 2016 to 2023. In conclusion, our study highlights that anaphylaxis occurring at school may lead to severe reactions, including death, with frequent unknown allergy to the culprit food and insufficient adrenaline use. There is a huge room for improvement in the prevention and management of anaphylaxis at school to focus on IHP use for food allergic children, promotion of training programs to school-canteen staff. G.P. analyzed, interpreted the data, and wrote the draft. Y.K.-A. performed the statistical analysis, interpreted the data, and reviewed the draft. G.P., A.D.-C., Y.K.-A., C.B., and D.S.-L. were major contributors in reviewing the draft and improving the paper with critical analysis. S.T. collected data from the Allergy-Vigilance Network. We acknowledge all the Allergy-Vigilance Network members who participated in this study and collected data. G.P. has provided consultation and speaker services for AI Therapeutics, Bausch+Lomb, Stallergenes, Novartis, DVB technology, ALK-Abello; serves as a medical consultant/advisor for Bioprojet, Theravia. The authors have nothing to report. Data S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Abstract BackgroundBIN1 is a major susceptibility gene for AD and BIN1 protein interacts with Tau. However, the contribution of BIN1 and its isoforms to AD pathogenesis remains unclear. We recently described that human BIN1 isoform1 (BIN1iso1) induces an accumulation of early endosome vesicles leading to neurodegeneration in Drosophila retina and that the early endosome size regulation was conserved in human induced neurons. This role was specific to BIN1iso1, as compared to BIN1iso8 and BIN1iso9. Because endosomal trafficking is essential for synapse, we further analyzed BIN1 isoforms neurotoxicity at the synaptic level.MethodWe first used electrophysiology, immunofluorescence and electron microscopy in vivo in transgenic Drosophila adult retina photoreceptor neurons and larval neuromuscular junction. We then tested a functional conservation in transduced rat primary neurons using tricompartment microfluidic devices, immunofluorescence and Multi‐Electrode‐Array to assess a presynaptic vs post‐synaptic role.ResultWe observed an early loss of synaptic transmission upon BIN1iso1 expression specifically, in Drosophila retina photoreceptor neurons. This was characterized by a strong accumulation of abnormally large vesicles in the presynaptic compartment. In addition, expression of BIN1iso1 in motoneurons of the neuromuscular junction altered the morphology of synaptic boutons, with an increase in their number and a decrease in their size, and the appearance of satellite boutons. BIN1iso1 synaptic toxicity could be partially rescued by modulating endosomal regulators, suggesting that an endosomal defect would be the cause of synaptotoxicity. Finally, we observed a functional conservation in rat primary neurons as shown by the loss of synaptic connectivity only when expressing BIN1iso1 in the presynaptic compartment.ConclusionOur results suggest that BIN1 has an isoform‐specific, deleterious effect on synaptic integrity when expressed in the presynaptic terminal. This effect could contribute to the synaptic loss observed early in AD.

ObjectiveTo update the CCAFU recommendations for the management of muscle-invasive bladder cancer (MIBC). MethodsA systematic review (Medline) of the literature from 2022 to 2024 was carried out, taking into account the elements of the diagnosis, the treatment options and the monitoring of NMIBC and MIBC, evaluating the references with their level of evidence. ResultsMIBC is diagosed after the must complete tumor resection possible . CT-Urography coupled with chest CT scans are used to assess the extent of MIBC. Multiparametric pelvic MRI may be an alternative imaging approach. Cystectomy combined with standard lymph node dissection is the standard treatment for nonmetastatic MIBC. Neoadjuvant cispaltine-based chemotherapy should be used in patients in good general health with satisfactory renal function. Enterocystoplasty is proposed for men and women in the absence of contraindications and when urethral recutting is negative on extemporaneous examination; otherwise, transileal cutaneous ureterostomy is the recommended method of urinary diversion. All patients should be included in an improved recovery after surgery (ERAS) protocol. For metastatic MIBC, first-line treatment with enfortumab vedotin and pembrolizumab is recommended. Second-line treatment with platinum-based chemotherapy is recommended. ConclusionUpdating the ccAFU recommendations should improve patient management and enhance the diagnosis and treatment of MIBC.

Background: Transesophageal echocardiography (TEE) is a vital diagnostic tool in clinical practice, particularly in transcatheter interventions where it aids in both pre-operative planning and intra-operative guidance. Traditional TEE probes often require general anesthesia due to patient discomfort. However, the development of miniaturized TEE probes presents a promising alternative, enabling routine examinations and interventions with minimal sedation. This study evaluates the feasibility of performing a complete 2D/4D TEE protocol with the new 4D mini-TEE probe in the echocardiography department and its application in transcatheter interventions. Methods: This is a retrospective study that included 30 consecutive patients from two high-volume European hospitals (Interbalkan Medical Center, Thessaloniki, Greece, and Rennes University, France) that underwent TEE or transcatheter interventions. The new 4D mini-TEE 9VT-D probe (GE Healthcare) was utilized. The quality of the images and the tolerance of the probe were assessed in the cath lab during interventions and in the echocardiography department during routine TEE examinations. Results: Direct comparison of the 4D mini-TEE probe with the standard 6VT-D probe confirmed the excellent image quality of this new pediatric probe. Most of the patients required minimal sedation or local oropharyngeal anesthesia, with satisfactory tolerance reported. Most of the transcatheter procedures did not require general anesthesia and intubation, resulting in shorter procedural time. Both 2D and 4D imaging modalities offered adequate intra-operative guidance for transcatheter procedures. Conclusions: The 4D mini-TEE probe delivers exceptional imaging capabilities for routine examinations and transcatheter interventions without needing sedation. Its use reduces esophageal trauma and the need for general anesthesia, enhancing patient comfort and safety.