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Bacterial biofilms are structured communities of bacterial cells enclosed in a self-produced polymeric matrix, which can adhere to biotic or abiotic surfaces. This mode of existence permits these bacteria to endure in adverse conditions, including the presence of antibiotics Bacteria within biofilms are responsible for numerous infections in humans and animals, including bovine mastitis. It is therefore important to develop new therapeutic strategies to control and treat biofilm-associated infections. The results obtained by our group during the study of mixed bacterial biofilm communities showed that four isolates of coagulase-negative staphylococci (CNS; two Staphylococcus chromogenes and two Staphylococcus simulans) that produce only a small amount of biofilm can significantly reduce biofilm formation in approximatively 80% of pathogenic staphylococci associated with bovine mastitis. Furthermore, supernatants of S. chromogenes reduced secondary intramammary colonization by S. aureus in a murine model of mastitis. However, information regarding the mechanism and the effector molecule(s) involved is lacking. The objective of this study was therefore to investigate and characterize the antibiofilm molecule(s) produced by these four CNS isolates. In this context, we prepared culture supernatants from two isolates of S. chromogenes (C and E) and two isolates of S. simulans (F and H) to evaluate their effect on biofilm production of pathogenic bacterial species involved in bovine mastitis. Using a standard biofilm microtiter plate assay, we demonstrated that the four CNS supernatants not only have a significant impact on biofilms of pathogenic staphylococci (68% of tested isolates) but also on those of other important mastitis pathogens such as Streptococcus spp., Trueperella pyogenes, Klebsiella spp. and Escherichia coli (61.3% of tested isolates). The isolation and characterization of the antibiofilm molecule(s) contained in the supernatants were then conducted using a filtration process with membranes of different porosities, as well as through physicochemical and enzymatic treatments. We were then able to confirm that antibiofilm activity against staphylococci was present in the < 3kDa fractions of CNS culture supernatants and that this activity was heat-stable and protease-resistant, but sensitive to RNase A, suggesting that the antibiofilm activity might be due, at least in part, to an RNA molecule. Preliminary results showed that the antibiofilm activity was maintained with RNA extracts from fractioned supernatants (<3kDa). In conclusion, these results confirmed that some CNS have an antibiofilm activity, which represents a promising new avenue in the fight against biofilm-associated infections, particularly bovine mastitis.
Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options and poor prognosis. Understanding the underlying molecular mechanisms, particularly immune-related gene networks, is critical for identifying novel therapeutic targets. This study aimed to identify immune-related hub genes involved in TNBC progression by integrating microarray and RNA sequencing data. We integrated microarray and RNA sequencing datasets from five Gene Expression Omnibus (GEO) studies (GSE36295, GSE37751, GSE61724, GSE38959, and GSE58135) to identify differentially expressed genes (DEGs). Protein-protein interaction (PPI) networks were constructed using the STRING database. Key modules and hub genes were identified through network analysis. Functional enrichment was performed to elucidate biological pathways, while immune infiltration analysis assessed associations with the tumor microenvironment. Drug-gene interaction databases were queried for FDA-approved compounds targeting hub genes. The PPI network revealed 179 nodes and 781 edges, indicating high connectivity. Module analysis highlighted a significant cluster with the identified key genes such as CDK1, BUB1B, CCNA2, BUB1, CCNB1, KIF20A, CENPF, TOP2A, KIF11 and MELK validated at both mRNA and protein levels. Functional enrichment revealed pathways related to cell cycle control, chromosome segregation, and kinase activity. Immune infiltration analysis indicated involvement of B cells, macrophages, and neutrophils in the TNBC microenvironment. Drug-gene mapping revealed a lack of FDA-approved drugs targeting certain key hub genes. This integrative study identified key immune-related hub genes driving TNBC progression, with KIF20A emerging as a promising yet underexplored target. Drug repurposing strategies focusing on KIF20A and other identified hub genes may accelerate the development of effective treatments, offering valuable insights for future therapeutic and prognostic evaluations in TNBC.
Immunosuppression mechanisms mediated by regulatory T cells (Tregs) can lead to poor clinical outcomes in patients undergoing immune-based therapies. Activation markers, such as inducible T-cell co-stimulator (ICOS), are highly expressed on the surface of tumor-infiltrating Tregs and present as relevant targets for targeted depletion of these cells. Here, we present clinical outcomes from a Phase 1 study (NCT03829501) of an anti-ICOS antibody of alomfilimab (SAR445256 or KY1044) as monotherapy and in combination with the anti-programmed death-ligand 1 (PD-L1) antibody, atezolizumab, in patients with advanced solid tumors. Alomfilimab was administered intravenously once every 3 weeks (Q3W) ±3 days at six dose levels (DLs; 0.8 mg to 240 mg) as monotherapy and five DLs (0.8 mg to 80 mg) in combination with atezolizumab (1,200 mg Q3W ±3 days). Eligible patients must have had advanced metastatic disease as determined by Response Evaluation Criteria in Solid Tumors V.1.1 and no viable treatment options according to National Comprehensive Cancer Network guidelines. Overall 38 patients were enrolled in the monotherapy cohort, and 102 patients were enrolled in the combination therapy cohort. Alomfilimab had a manageable safety profile and showed a trend toward modest efficacy in tumor growth control when combined with anti-PD-L1 in selected malignancies. At least one treatment-emergent adverse event was reported in 35 patients (89.7%) in the monotherapy cohort, and in 99 (98%) patients in the combination cohort. Objective response was not observed in the monotherapy cohort. In the combination cohort, seven patients had an objective response. Median time to progression-free survival was 2 months for both cohorts. Furthermore, alomfilimab showed evidence of target engagement on T-cell subsets, specifically cluster of differentiation (CD)4+memory cells, in both single-agent and in combination treatment with atezolizumab. This was accompanied by transient elevation of granulocyte-macrophage colony-stimulating factor, interferon-γ, and tumor necrosis factor-α levels and dose-dependent reduction of ICOS+Tregs in the tumor microenvironment. Alomfilimab treatment was associated with an acceptable safety profile across both mono and combination approaches, accompanied by decreased ICOS+Tregs populations and enhanced CD4+ and CD8+ effector T cells cell activity. Limited clinical activity was observed despite evidence of biological activity. NCT03829501.
This paper aims at reviewing some of the major French innovations in lower limb arthroplasty. This achievement could happen only through substantial efforts from pioneers that understood they had to adhere to the general principles of research through well designed studies, robust evaluation tools, and long-term follow-up studies. One of the major inventions in total hip arthroplasty (THA) was dual mobility cups (DMC). The concept of DMC has clearly demonstrated clinical efficiency in the prevention and treatment of postoperative dislocation both in primary and revision THAs. Another landmark progress in THA was introduced through alumina ceramic bearings. This material has exceptional tribological properties leading to an extremely low volume production of wear particles. Concerning major bone defects in revision THAS, Marcel Kerboull introduced a reinforcement device that could bridge the inferior margin of the acetabulum to the ilium in association with bone reconstruction using allograft. The reported results have been favorable, and together with DMC, this type of construct has become largely diffused internationally, in particular in Japan. Another topic that has emerged from France is related to total ankle arthroplasty (TAA). Major progress was made in the mid-90 s including a keeled tibial component, talar resurfacing, and a mobile PE insert. The French TAA registry also represents a major advancement demonstrating the French contribution to the development of TAA. In total knee arthroplasty (TKA), an original approach was introduced by the Lyon school of surgery through the third condyle concept to reproduce knee kinematics and reduce complications related to the post-cam mechanism. This design provided favorable clinical outcomes and high survival, and was the basis of modern implants and personalized knee arthroplasty. Also an innovative fixed-hinge TKA, the GUEPAR, was designed by French surgeons in the 1970s with further versions to deal with complex situations. However, due to specific complications related to the use of polyethylene and later metallic bushings and to the transverse axle, fixed-hinge TKAs were progressively abandoned and currently replaced by rotating-hinge designs. These examples demonstrate the extremely active participation of the French orthopaedic community to the development and knowledge of lower limb arthroplasty in order to provide the patients with optimal care. LEVEL OF EVIDENCE: V; expert opinion.
Pain modulation relies on complex molecular interactions among ion channels, G protein-coupled receptors, and intracellular signaling cascades. The Transient Receptor Potential Vanilloid 1 (TRPV1) channel serves as a polymodal detector and integrator of noxious stimuli, linking sensory transduction with broader neuromodulatory systems. This review delineates the mechanistic crosstalk between TRPV1, endocannabinoid, and opioid pathways in nociceptive regulation. TRPV1 activation by heat, protons, or endogenous lipids induces calcium influx and engages protein kinase C (PKC), protein kinase A (PKA), and mitogen-activated protein kinase (MAPK) pathways that modulate channel phosphorylation and neuronal excitability. Endocannabinoids such as anandamide act as dual CB1 and TRPV1 agonists, establishing feedback loops that adjust nociceptive thresholds, while μ-opioid receptor activation inhibits adenylate cyclase and TRPV1 sensitization through Gi/o-mediated signaling. Given the recent progress in cryo-electron microscopy and molecular modeling, simulation studies have been possible, revealing key structural determinants underlying key receptor interactions. Integrating pharmacophore modeling, molecular docking, and artificial intelligence-based screening enables rational design of multi-target ligands that exploit TRPV1-endocannabinoid-opioid synergy. This mechanistic framework supports the development of next-generation analgesics that achieve potent, sustained, and safe modulation of nociceptive signaling.
Chromatin serves as the dynamic carrier of genetic and epigenetic information in eukaryotic cells, playing a pivotal role in maintaining nuclear shape, mechanical stability, and cellular function. Aberrant nuclear morphology, often observed in mechanically stressed environments or diseases such as progeria and muscular dystrophy, correlates with nuclear dysfunction, DNA damage, and disrupted mechanotransduction. Chromatin exists in two main configurations - compacted heterochromatin and decompacted euchromatin - each regulating gene expression and cellular behaviour through epigenetic modifications. Histone acetyltransferases and deacetylases modulate chromatin compaction, while histone methylation introduces further regulatory complexity. Chromatin's viscoelastic properties enable it to store and restore mechanical energy, acting as a mechanosensitive component within the nucleus. External forces propagate from the extracellular matrix through focal adhesions, the cytoskeleton, and the nuclear lamina to chromatin, forming a direct mechanotransduction pathway. However, the reverse pathway - how internal nuclear forces generated during chromatin remodelling influence the nuclear membrane, cytoskeleton, and cell adhesion - remains poorly understood. This review explores the role of chromatin as a tensegrity element, capable of generating mechanical forces through condensate formation. It examines evidence supporting chromatin decompaction as a regulator of reverse mechanotransduction and identifies potential mechanical partners involved in this process. Understanding these mechanisms may elucidate how chromatin dynamics contribute to cellular fate decisions and disease pathogenesis.
Bai-Zhu (Atractylodes macrocephala Koidz. [Asteraceae]) is classified in traditional Chinese medicine (TCM) as an herb that targets the gastric and pancreatic meridians to support normal nutrient uptake. As such, Bai-Zhu is commonly included in herbal formulations for treating gastrointestinal dysfunction and alleviating pain and swelling. Formulae containing Bai-Zhu are also frequently used as complementary or alternative therapies to mitigate the side effects of tumor treatments. However, their direct effects on cancer cells remain inadequately understood in modern biomedical science. This study aims to characterize the impact of Bai-Zhu-containing formulae on breast cancer cells using contemporary molecular and cellular biology approaches. A tetrazolium-based semiautomated colorimetric (MTT) assay was used to assess cell viability. Western blotting was performed to evaluate protein expression. Quantitative RT-PCR was employed to measure the relative expression levels of selected genes. A Matrigel invasion assay was used to assess the invasive capacity of cancer cells. Water extracts of Bai-Zhu or formulae containing Bai-Zhu increased the expression of metastasis-related proteins Zeb1 and Slug in breast cancer cells. Moreover, these formulae further enhanced Zeb1 and Slug expression when combined with the chemotherapeutic drug doxorubicin. Matrigel invasion assays confirmed that these treatments promoted the invasive activity of breast cancer cells. The use of Bai-Zhu-containing formulae should be carefully evaluated, particularly in cancer patients who use them as complementary or alternative treatments, due to their potential to promote tumor metastasis.
Management of cerebral vasculopathy in sickle cell anemia (SCA) includes standard-care, that is, chronic transfusion (CT) or hydroxyurea, and hematopoietic cell transplantation (HCT). DREPAGREFFE-1 (December 2010/June 2013), a French multicenter trial, was the first prospective trial comparing standard-care to match sibling donor (MSD)-HCT in 67 (35F/32M) SCA children (5-15 year) on CT for abnormal time-averaged mean maximum velocities (TAMMV ≥ 200 cm/s). Seven had a stroke history. We reported that MSD-HCT reduced the highest TAMMVs at 1- and 3-year (p < 0.001) and improved quality of life (QoL) for physical and school functioning. In stroke-free patients, the 3-year stenosis score was lower (p = 0.010). Nevertheless, no significant difference was observed for silent cerebral infarcts (SCI) and cognitive performance. This prompted us to initiate DREPAGREFFE-2 to reevaluate the outcomes at 10 years (September 2022/August 2024) with the same 67 SCA children. No death or stroke occurred in either arm. No rejection or chronic-GvHD arose in the MSD-HCT group (n = 32). In the standard-care group (n = 35), 16 were on hydroxyurea, and 16 on CT at Year 10, and 3 received haploidentical-HCT. After MSD-HCT, the QoL was better, even for social functioning, and the number of hospitalizations, hospitalized days (p < 0.001), and crises (p = 0.001) was lower than on standard-care. In stroke-free patients, stenosis (p = 0.027) and SCI scores (p = 0.041) decreased significantly more after MSD-HCT than on standard-care; working memory (p = 0.016) and processing speed (p = 0.011) improved significantly after MSD-HCT, but worsened on standard-care. These effects were not previously detected with shorter follow-up. This supports earlier consideration of HCT for SCA children with MSD to preserve neurologic function and QoL for a more productive future.
Sex equity in organ donation and access to transplantation represents a key priority of the European Committee on Organ Transplantation of the Council of Europe (CD-P-TO). To increase our knowledge on sex-related differences in transplantation in the Council of Europe Member States, a specifically designed questionnaire was distributed to the CD-P-TO countries. Results confirm that, irrespective of the organ, males represent the majority of patients on the transplant waiting list. For all organs except for heart the time spent on the waiting list was shorter for men compared to women. Women represent the majority of living kidney donors (58%), whilst males are the major source of livers from living donation (54%). Across all organ types, men received 64% of deceased donor organs and 58% of living donor organs. We have found sex-related differences in transplantation activities conducted in the Council of Europe Member States. However, these may be the consequence of the higher incidence of some diseases in men, organ size mismatch, or the greater difficulty in finding immunologically compatible donors in women. At this stage, the CD-P-TO will continue its monitoring activity on this highly relevant topic and possibly extend its commitment beyond sex to include gender related aspects.
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Clozapine remains the gold-standard antipsychotic for treatment-resistant schizophrenia, but its use is hindered by rare but serious adverse effects, such as hematologic abnormalities and myocarditis. This study investigated the adverse impacts of clozapine on blood markers and electrocardiographic (ECG) findings among patients with schizophrenia, emphasizing in early detection of life-threatening complications. All patients initiated on clozapine at a psychiatric hospital in Athens, Greece, between January 2022 and June 2024 were considered for inclusion. Thirty-one patients with complete clinical and laboratory data were monitored for hematological, biochemical, and ECG changes at baseline, days 5-10, and after 1-2 months. Parameters evaluated included white blood cell (WBC) counts, differential counts, C-reactive protein (CRP), hepatic enzymes, creatine phosphokinase (CPK), troponin, and ECG changes. Of the 31 patients, two (6.5%) developed clozapine-induced myocarditis within the first three weeks, confirmed by clinical symptoms, ECG abnormalities, and elevated troponin levels, necessitating immediate clozapine discontinuation. Four patients exhibited prolonged QTc, two overlapping with myocarditis cases. Eleven experienced elevated CRP, while eosinophilia and transient hepatic or muscular enzyme elevations were also common, especially during rapid titration phases; indicating inflammatory responses or mild organ involvement. No cases of agranulocytosis or severe eosinophilic complications occurred. Clozapine can induce significant hematologic, inflammatory, hepatic, muscular, and cardiac adverse effects, particularly during rapid titration. Systematic monitoring of blood markers and ECGs was vital in early detection and management of these complications, especially myocarditis. The findings underscore the importance of cautious titration protocols and tailored surveillance strategies to enhance clozapine safety in clinical practice.
CAR T-cell therapy has delivered durable remissions in several hematologic cancers, yet activity in solid tumors and extension to immune-mediated diseases remain constrained by recurring failure modes: imperfect antigen specificity, inadequate trafficking, progressive dysfunction under chronic stimulation, and toxic inflammatory syndromes. Early reports of CAR-based immune "resets" in refractory autoimmune disease amplify both promise and stakes, because acceptable risk is lower than in cancer and "on-target" effects may still be clinically unacceptable if they create long-term immunodeficiency. This review treats CAR T optimization as multi-layer reprogramming across genetic circuitry, epigenetic state, metabolism, and the tissue microenvironment. We argue that many celebrated single-layer upgrades (stronger signaling, checkpoint deletion, constitutive cytokine armoring) often trade one failure mode for another. Instead, the most credible path to simultaneously improving efficacy and safety is disciplined, failure-mode-driven design: (i) programmable antigen logic and titratable activation to reduce off-tissue damage; (ii) epigenetic programming that preserves renewable functional states without removing essential restraints; (iii) metabolic rewiring evaluated under physiologic stress conditions; and (iv) microenvironment-aware strategies that prioritize access and local control over brute-force potency.
Chronic hemodialysis patients are at risk of Vancomycin-resistant Enterocci (VRE) and carbapenemase-producing Enterobacteriaceae (CPE) carriage. France has released guidelines to prevent the spread of VRE-CPE carriage in hospitals. However, the hemodialysis setting is confronted with specific problems that are not always addressed by guidelines. Infection control practices regarding VRE-CPE transmission in the hemodialysis setting have not been described in the literature. The aim of our survey was to assess declared practices regarding VRE-CPE identification and management in French hemodialysis units (HDU). A cross-sectional survey was conducted in a random sample of 200 French HDU (excluding peritoneal dialysis and exclusive pediatric hemodialysis units) regarding their declared organization for identifying VRE-CPE carriers, the type and duration of precautions implemented, and reported difficulties. Data were collected via an e-mail questionnaire, and completed by a short telephone interview with an infection control nurse. 103 HDU agreed to participate. A minority of HDU had implemented a system to identify patients requiring screening or were able to keep track of VRE-CPE carriers and contacts via a computerized system. When managing VRE-CPE carriers, less than one-third of HDU employed caregivers, and strategies to discontinue precautions varied widely between HDU. HDU staff complained mainly about the lack of national specific guidelines for VRE-CPE in the hemodialysis setting, insufficient information regarding patients' VRE-CPE status, and difficulties in convincing patients to accept screening. This survey highlights heterogeneous practices and routine difficulties in VPE-CPE patients' management which would probably benefit from guidelines tailored to the hemodialysis setting. Bei Patienten mit chronischer Hämodialyse besteht das Risiko einer Übertragung von Vancomycin-resistenten Enterocci (VRE) und Carbapenemase-produzierenden Enterobacteriacae (CPE). Frankreich hat Richtlinien veröffentlicht, um die Ausbreitung vvon VRE-CPE in Krankenhäusern zu verhindern. Allerdings ist das Hämodialyse-Setting mit spezifischen Problemen konfrontiert, die nicht immer in Leitlinien behandelt werden. Infektionskontrollpraktiken im Hinblick auf die VRE-CPE-Übertragung im Hämodialysebereich wurden in der Literatur nicht beschrieben. Unser Ziel war es, die festgelegten Praktiken zur Identifizierung und Behandlung von VRE-CPE in französischen Hämodialyseeinheiten (HDE) zu bewerten. In einer Zufallsstichprobe von 200 französischen HDE (ausgenommen Peritonealdialyse- und pädiatrische Hämodialyseeinheiten) wurde eine Querschnittsstudie hinsichtlich der Organisation zur Identifizierung von VRE-CPE-Trägern, der Art und Dauer der umgesetzten Vorsichtsmaßnahmen sowie der gemeldeten Schwierigkeiten durchgeführt. Die Daten wurden über einen E-Mail-Fragebogen erhoben, der durch ein kurzes Telefoninterview mit einer Krankenschwester für Infektionskontrolle ergänzt wurde. 103 HDE erklärten sich zur Teilnahme bereit. Eine Minderheit der HDE hatte ein System zur Identifizierung von Patienten implementiert, die ein Screening benötigten, oder war in der Lage, VRE-CPE-Träger und -Kontakte über ein computergestütztes System zu verfolgen. Bei der Behandlung von VRE-CPE-Trägern setzte weniger als ein Drittel der HDE engagierte Pflegekräfte ein, und die Strategien zum Absetzen der Vorsichtsmaßnahmen variierten stark zwischen den HDEs. Das HDE -Personal beklagte sich hauptsächlich über das Fehlen nationaler spezifischer Richtlinien für VRE-CPE im Hämodialysebereich, unzureichende Informationen über den VRE-CPE-Status von Patienten’ und Schwierigkeiten, Patienten dazu zu bringen, das Screening zu akzeptieren. Die Umfrage beleuchtet heterogene Praktiken und Schwierigkeiten bei der Behandlung von VPE-CPE-Patienten, die wahrscheinlich von auf das Hämodialyse-Setting zugeschnittenen Leitlinien profitieren würden.
Cellular senescence drives inflammation and tissue breakdown and is a key hallmark of aging. The accumulation of senescent cells is strongly linked to the degeneration of spinal tissues and back pain. Here, we show that administration of the senolytic agents, o-vanillin and RG-7112, prevents the development of pain-related behavior in sparc-/- mice. Treated mice exhibit a reduced expression of senescence markers in the intervertebral discs, vertebral endplates, vertebral bone, and spinal cord, alongside a dampening of pro-inflammatory senescence-associated secretory factors in these tissues. Early senolytic intervention also preserved intervertebral disc volume and vertebral bone microarchitecture, indicating protection against structural spine degeneration. These findings demonstrate that targeting cellular senescence at an early stage can mitigate degenerative changes and pain, supporting senolytic therapy as a promising preventive strategy for musculoskeletal decline.
Weight loss, partially caused by hypermetabolism, represents a well-documented and therapeutically relevant feature of the amyotrophic lateral sclerosis phenotype worldwide. In this study, we retrospectively analysed the association between thyroid function and clinical, prognostic and metabolic parameters in a cohort of patients with amyotrophic lateral sclerosis in an experienced centre in Germany (n = 1754). Specifically, we examined the relationship between thyroid stimulating hormone levels, age, glucose and body mass index and-in subgroups-phosphorylated neurofilament heavy chain levels in CSF. There was no association between thyroid stimulating hormone levels and body mass index in patients with amyotrophic lateral sclerosis (n = 954). In contrast with other cohorts, thyroid stimulating hormone levels decreased with age in patients with amyotrophic lateral sclerosis indicating hypothalamic deficiency in the ageing patients. There was no association between thyroid stimulating hormone and phosphorylated neurofilament heavy chain (prognostic marker) in CSF of a subcohort (n = 646). Thyroid stimulating hormone levels correlated with glucose levels, an effect more pronounced in male patients. In conclusion, our results suggest that thyroid metabolism does not significantly contribute to amyotrophic lateral sclerosis-related weight loss or disease prognosis as estimated by phosphorylated neurofilament heavy chain; thyroid dysfunction is unlikely to be a primary driver of the metabolic dysregulation observed in amyotrophic lateral sclerosis. Most interestingly, thyroid stimulating hormone levels show an unexpected negative relation to age in patients with amyotrophic lateral sclerosis.
Depression is closely linked to neuroinflammation, and in chronic kidney disease, the accumulation of uremic toxins (UTs) may promote neuroinflammatory processes through the activation of inflammatory pathways. The objective of this longitudinal study was to evaluate the association between UTs and depressive symptoms in a large, well-characterised cohort of non-dialysed adults with chronic kidney disease, a population in which this relationship had not yet been investigated. The Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) cohort comprised 3033 CKD stage 2-5 patients with 5 years of follow-up. Changes over time in depressive symptoms were assessed on the Center for Epidemiologic Studies Depression (CESD) scale. Mixed models were used to examine associations between the change in the CESD score and baseline levels of the UTs phenylacetylglutamine (PAG), indoxyl sulphate (IS), indole-3-acetic acid (IAA), p-cresyl sulphate, kynurenine, kynurenic acid and trimethylamine N-oxide. 2165 patients were included (median age: 68 years; mean estimated glomerular filtration rate (eGFR): 35 mL/min/1.73 m²; median baseline CESD score: 7; mean follow-up time: 4.0 years). After adjustment for confounders, the CESD score was found to have increased by 0.11 (0.04 to 0.18) points per year. A doubling in PAG level was associated with an additional increase of 0.06 (0.01 to 0.18) points per year in the CESD. A doubling in IS and IAA levels was associated with a higher mean CESD score (0.20 (0.01 to 0.39) for IS and 0.28 (0.05 to 0.50) for IAA) but not with the score's change over time. PAG was significantly associated with changes in CESD score over time. Higher IS and IAA levels were linked to higher mean scores. Further studies are needed to confirm these results and to determine whether lowering serum UT levels would help to manage depressive symptoms in patients with CKD. Further research is needed to clarify the role of UTs; a better understanding could uncover novel metabolic pathways and inform new therapeutic strategies to complement the management of depressive symptoms.
FUS is an RNA-binding protein mutated in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive muscle weakness. We show in this work that a heterozygous knock-in mutation in the mouse Fus gene leads to cell-autonomous ultrastructural defects in skeletal muscle, with disruption of sarcomeres and mitochondria. Studies in mouse and Drosophila models demonstrate an evolutionarily conserved cell-autonomous function of FUS in muscle development. Mechanistically, FUS is required for the transcription of MEF2 target genes, binds to the promoter of genes bound by ETS transcription factors, in particular ETV5, and co-activates the transcription of MEF2-dependent genes with ETV5. FUS phase-separates with ETV5 and MEF2A, and stimulation of MEF2-dependent transcription by FUS is dependent upon its phase separation properties. Finally, Etv5 haploinsufficiency exacerbates muscle weakness and atrophy in Fus knock-in mice. Our findings establish a key role for FUS in skeletal muscle differentiation through its phase separation-dependent recruitment of ETV5 and MEF2, defining a novel pathway compromised in FUS-ALS.
Standard chemotherapy regimens for patients with breast cancer are based on epirubicin-cyclophosphamide (EC) and paclitaxel (TAX) administrations. While it has been shown that first EC administration impairs mitochondrial homeostasis, the isolated effects of TAX have not been studied without previous chemotherapy exposure. We conducted a prospective clinical study including five patients with breast cancer who underwent two vastus lateralis muscle biopsies before and 4 days after the first TAX administration, without any prior chemotherapy exposure. Mitochondrial respiratory capacity, reactive oxygen species production, mitochondrial dynamics and ultrastructure, and apoptosis were assessed using high-resolution respirometry, western blotting, transmission electron microscopy, and TUNEL assay, respectively. Post-TAX, the number of intermyofibrillar mitochondria decreased (-18%; P = 0.049), while the proportion of damaged mitochondria increased (+34%; P = 0.012). Mitochondrial area, perimeter and major/minor axis lengths increased (P < 0.05) while intermyofibrillar cristae area decreased (4.29% pre-TAX vs. 2.60% post-TAX; P = 0.044). Despite these morphological changes, oxidative phosphorylation capacity and respiratory control ratio remained unchanged, whereas complex I-linked substrate respiration decreased (-29%; P = 0.046). MFN2 (-43%; P = 0.040) and Fis1 (-46%; P = 0.046) protein levels decreased post-TAX while mitophagy markers were unchanged. Apoptosis was increased, as documented by increased Bax (+58%; P = 0.045) and TUNEL-positive nuclei (+395%; P = 0.041). In only 4 days, the first TAX administration induced severe skeletal muscle mitochondrial remodelling in patients with breast cancer, characterized by impaired mitochondrial dynamics that resulted in swollen and damaged organelles. These findings demonstrate that mitochondrial toxicity, classically documented at the end of treatment, occurs acutely and after only one chemotherapy administration.
Background. Because of the COVID-19 pandemic, we realize that kidney transplantation (KT) suspension may become necessary. Although the impact of KT moratoriums on the mortality of candidates for KT has been reported, health-related quality of life (HRQoL) was usually not considered. For crisis preparedness, we aimed to include quality-adjusted life-years (QALYs) in the balance. Methods. We estimated 1) the health-state evolution of the French end-stage renal disease population using a semi-Markovian approach (76,980 French patients who began dialysis or were registered on the waitlist for KT between 2011 and 2019), 2) the post-KT evolution of HRQoL using a linear mixed-effects model (4,819 EQ-5D questionnaires from 2,835 French KT recipients), and 3) the HRQoL conversion for dialyzed patients according to Li's model. Results. For patients registered on the active waitlist at the beginning of the moratorium, we predicted a loss of 0.96 life-months in perfect health for a 7-mo moratorium (95% confidence interval [0.11, 1.78]). This loss was smaller for patients who become active candidates after a moratorium decision. Regardless, we reported higher losses of QALYs for patients younger than 60 y than for older patients, for every considered moratorium duration. Conclusions. KT moratoriums can be sustainable regarding both quantity and quality of life, provided they do not exceed a prolonged period. In case of future crisis with a long reduction of KT activity, we reported that priority may be proposed to the younger patients. Our results provide arguments supporting the decision of suspending kidney transplantation activity in case of future crises, provided that the moratorium duration does not exceed a few months.We report that patients active on the waitlist at the beginning of the moratorium lose the most quality-adjusted life-years due to the suspension, particularly candidates younger than 60 y. Hence, if another crisis occurs with the possibility of maintaining only small kidney transplantation activity, giving priority to younger patients active on the list may be justified.Considering quality-adjusted life-years rather than raw survival time results in a more complete assessment of the effect of suspending kidney transplantation in patients with end-stage renal disease by taking their quality of life into account.
Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome characterized by macrocytic anemia and physical malformations. The only available curative treatment for patients with DBA is hematopoietic cell transplantation (HCT). Previous studies have included umbilical cord blood transplantation (UCBT) alongside other graft sources. We conducted a retrospective analysis of 41 pediatric patients with DBA who underwent related or unrelated UCBT between 1994 and 2023, using data from the Eurocord/EBMT registry. Twenty patients received related and 21 received unrelated single UCBT. Most patients received myeloablative conditioning and were transplanted after 1999. In related UCBT, median follow-up was 144.8 months, neutrophil engraftment at day +42 was 100% and 5-year overall survival (OS) was also 100%. In unrelated UCBT, median follow-up was 34 months, neutrophil engraftment at day +42 was 90%, and 5-year OS was 66%. The incidence of acute graft-versus-host disease (GvHD) was considerably higher among unrelated UCBT recipients. The incidence of chronic GvHD was similar between the two cohorts; however, extensive disease was more common after unrelated UCBT. UCBT from an HLA-identical sibling should be considered for DBA patients given the favorable short- and long-term outcomes. For the remaining patients, unrelated UCBT could be considered after individualized risk-benefit assessement.