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Selective serotonin reuptake inhibitors enhance cancer immunosurveillance by pleiotropic mechanisms
No full textInternational audienceIn a recent paper published in Cell, Li et al. suggest that selective serotonin reuptake inhibitors (SSRIs) antidepressants act on serotonin transporters on CD8 + T cells to enhance antitumor immunity. Beyond this mechanism, SSRIs can act on malignant cells, as well as on other immune cells, to improve cancer immunosurveillance
The rising tides of cancers among young adults
No full textInternational audienceThe rising tides of cancers among young adultsCancer is a disease traditionally associated with aging, yet recent trends show a troubling rise in cancers occurring at younger ages, often referred to as 'early-onset' cancers. 1 Nevertheless, these malignancies remain comparatively understudied, despite their unique challenges and the significant burden they impose. Traditionally, 'early onset' referred to patients diagnosed in their adulthood before the age of 50 years, although this definition may be overly simplistic. With nearly 1 million cancers occurring among young adults worldwide, early-onset cancers now represent the leading cause of mortality in this age group in regions with a middle-to-high socio-demographic index--surpassing cardiovascular diseases. People younger than 50 years were the only age group to experience a sustained increase in cancer incidence from 1995 through 2021. 2 Between 1990 and 2019, the global incidence of earlyonset cancer in this age group rose by 79.1%, while mortality from these cancers increased by 27.7%. 3 The incidence of various cancers across multiple organ systems has been rising among adults under 50 years in many regions worldwide, including digestive cancers (colorectum, esophagus, extrahepatic bile duct, gall-bladder, stomach, pancreas, and liver), gynecological cancers (breast and endometrium), urogenital cancers (kidney and prostate), as well as head and neck and thyroid cancers. 4 Recent epidemiological data also suggest an increasing trend in the incidence of lung cancer among never smokers, with ∼12.5% of cases observed in this demographic occurring among young adults. 5 Concurrently, sex disparities in cancer incidence among young adults have become increasingly pronounced, reflecting distinct evolving trends over time. 2 Historically, women under 50 years have carried a heavier cancer burden than men in the same age group, and this disparity has widened considerably over time. In 2021, the incidence rate among young women was 141.1 per 100 000-82% higher than in young men (77.4 per 100 000) compared with a 51% difference reported in 2002. Overall, cancer incidence in young women rose by ∼20%, driven primarily by surges in breast and thyroid cancers, which together now account for nearly half of all cancers in this age group. 2 In contrast, between 2002 and 2021, the overall cancer incidence in young men declined slightly, mostly due to falling rates of melanoma, non-Hodgkin lymphoma, and prostate cancer, despite increases in the</div
Impact of Muscle Mass on the Performance of Creatinine‐Based eGFR Equations and Mortality Risk Assessment After Kidney Transplantation
No full textInternational audienceABSTRACT Background Estimating glomerular filtration rate (eGFR) in kidney transplant recipients (KTR) typically relies on plasma creatinine, which is influenced by muscle mass. Reduced muscle mass is suspected to reduce eGFR performance in this population but this effect has not been rigorously evaluated. This study quantified the impact of muscle mass on eGFR accuracy and its confounding effect on the association between kidney function and mortality in KTR. Methods We studied a prospective and consecutive cohort of 1829 KTR (mean age 52 ± 14 years; 38.9% female) who underwent GFR measurement using iohexol clearance (ioGFR). Muscle mass was assessed by creatinine excretion rate (CER) from timed urine collections. We evaluated the impact of muscle mass on the performance of five eGFR equations (MDRD, CKDEPI 2009 , CKDEPI 2021 , EKFC and RFKTS) using multiple regression and subgroup analysis. The association between eGFRs, ioGFR and mortality was examined using Cox proportional hazards models. Results All eGFR equations showed a significant negative correlation with CER. EKFC was the least sensitive to CER ( β coefficient 95% confidence interval [CI]: −0.17 to −0.12). All eGFR equations demonstrated reduced accuracy in the lowest muscle mass tertile. In multivariable analyses, ioGFR was significantly associated with mortality (hazard ratio 95% CI: 0.972–0.995) but eGFRs were not. Including CER in the Cox models resulted in convergence of the mortality hazard ratios for ioGFR and eGFRs (hazard ratio 95% CI: ioGFR: 0.98–0.999; MDRD: 0.98–0.999; CKDEPI 2021 : 0.99–1; EKFC (0.98–1) RFKS: 0.98–0999). Conclusion The performance of all tested creatinine‐based eGFR equations is strongly impacted by muscle mass. Muscle mass is also a key confounder in the mortality risk assessment using eGFR. Incorporating muscle mass into KTR's evaluations may improve kidney function assessments in KTR
Improving Advanced-Line Multiple Myeloma Care: Insights and Real-World Challenges from the EMMY Study
No full textInternational audienceManaging multiple myeloma (MM) patients receiving advanced (four or more) lines of treatment is a complex challenge. Therefore, real-world data are essential to better understand and address the medical need of this challenging population. We used the EMMY cohort, a French longitudinal real-world study, to describe the characteristics and outcomes of 2127 MM patients receiving advanced-line treatments between 2017 and 2020. A wide variety of treatments were used without a predominant combination showing an evolution over time. Patients exhibited median time to next treatment and overall survival ranging from 7.8 months (95% CI: 6.7-7.8) and 19.4 months (95% CI: 17.4-22.5) in Line 4 (L4) to 4.8 months (95% CI: 3.5-6) and 12.6 months (95% CI: 8.7-16.6) in L8, respectively. The EMMY study provides valuable insights into the real-world application of advanced-line treatments, demonstrating rapid disease progression and poor outcomes in these patients before the novel anti-B-cell maturation antigen (BCMA) directed therapies. These findings highlight the critical need for novel therapies in this population
Curieux et cognitivement engagé : vers une compréhension intégrée de la curiosité et de la charge cognitive dans l’apprentissage en réalité étendue.
No full textExtended Reality (XR) technologies, including Virtual Reality (VR) and Augmented Reality (AR), are reshaping education by offering new ways to visualize and interact with complex knowledge domains, especially those requiring 3D content such as neuroanatomy. However, their pedagogical effectiveness remains contested, particularly due to contradictory findings regarding their impact on learners’ intrinsic motivation and cognitive load.This doctoral research proposes an integrative perspective by bridging two major theoretical frameworks: Cognitive Load Theory (CLT), which explains how cognitive resources are allocated during learning, and the Learning Progress Hypothesis (LPH), which posits that curiosity-driven exploration fosters intrinsic motivation and enhances learning. The core objective was to examine how XR can optimize learning by balancing cognitive demands with learners’ intrinsic motivation.First, a systematic review highlighted how AR tends to decrease unnecessary cognitive demands, benefiting novices, while VR often risks cognitive overload. The review also identified significant methodological limitations in how intrinsic motivation is assessed, calling into question the assumed motivational benefits of XR.Building on this, an empirical study with medical students explored how different modes of interaction in VR affect curiosity, cognitive load, and learning. Results indicated that while VR generally enhanced learning, higher interactivity was not necessarily beneficial. Intrinsic motivation correlated strongly with germane cognitive load, suggesting a meaningful bridge between curiosity and cognitive load. A detailed analysis of participants’ hand and head movements further demonstrated that movement entropy and exploration patterns can serve as behavioral indicators of curiosity-driven learning and cognitive engagement in immersive environments.An additional experiment investigated AR’s potential to guide anatomical drawing tasks. Though direct learning gains were modest, AR significantly reduced extraneous cognitive load and increased learners’ motivation and perceived usability. Individual factors such as visuospatial abilities and prior knowledge were found to moderate the effectiveness of these immersive interventions.The final part of the thesis brings together these empirical findings in a broader discussion, introducing a conceptual model that unifies CLT and LPH, empirically tested through structural equation modeling. This model highlights how intrinsic motivation and perceived learning progress dynamically interact with cognitive load to influence learning performance in XR-based learning.Altogether, this thesis provides new understanding of the balance between cognitive efficiency and motivational engagement in immersive learning, renewing research avenues in XR for education and offering valuable recommendations for educators and designers seeking to fully harness the potential of these technologies.Les technologies de Réalité Étendue (XR), incluant la Réalité Virtuelle (VR) et la Réalité Augmentée (AR), transforment l’éducation en proposant de nouvelles façons de visualiser et d’interagir avec des connaissances complexes, impliquant notamment des contenus 3D comme la neuroanatomie. Toutefois, leur efficacité pédagogique reste discutée, notamment en raison de résultats contradictoires quant à leur impact sur la motivation intrinsèque et la charge cognitive des apprenants.Cette thèse s’appuie sur deux cadres théoriques majeurs : la théorie de la charge cognitive (CLT), qui explique la manière dont les ressources cognitives sont utilisées durant l’apprentissage, et l’hypothèse du progrès d’apprentissage (LPH), selon laquelle la curiosité stimulée par le progrès favorise la motivation intrinsèque et améliore les apprentissages. L’objectif principal était ainsi d’explorer comment la XR peut optimiser l’apprentissage en conciliant exigences cognitives et motivation intrinsèque.Une revue systématique a montré que l’AR tend à diminuer la charge cognitive inutile, particulièrement bénéfique aux apprenants novices, alors que la VR présente souvent un risque accru de surcharge cognitive. Cette revue a également mis en évidence d’importantes limites méthodologiques dans l’évaluation de la motivation intrinsèque, remettant en question les bénéfices motivationnels fréquemment attribués à la XR.Sur cette base, une étude expérimentale menée auprès d’étudiants en médecine ont exploré comment différents modes d’interaction en VR influencent la curiosité, la charge cognitive et les apprentissages. Les résultats ont indiqué que, si globalement, la VR améliore l’apprentissage, une interactivité accrue n’est pas nécessairement plus bénéfique. De plus, une forte corrélation entre motivation intrinsèque et charge cognitive germaine a été observée, indiquant un lien important entre curiosité et efficacité cognitive. L’analyse des mouvements corporels (mains et tête) des participants a aussi permis d’identifier des indicateurs comportementaux pertinents (entropie gestuelle, schémas d’exploration) du processus d’apprentissage motivé par la curiosité et de l’engagement cognitif.Une autre expérimentation s’est intéressée au potentiel de l’AR pour guider des tâches de dessin anatomique. Les résultats ont montré des gains d’apprentissage modestes, mais une réduction significative de la charge cognitive extrinsèque et une augmentation notable de la motivation. L’efficacité de ces interventions immersives était modulée par des facteurs individuels, tels que les capacités visuospatiales et les connaissances préalables.Au cœur de notre discussion de ces résultats, un modèle conceptuel unifiant la CLT et la LPH a été développé et testé empiriquement par une modélisation par équations structurelles (SEM). Ce modèle révèle une interaction dynamique entre motivation intrinsèque, perception du progrès d’apprentissage et charge cognitive pour expliquer la performance en contexte XR.En somme, cette thèse offre une compréhension renouvelée de l’équilibre entre efficience cognitive et motivation dans les environnements immersifs et propose des recommandations pratiques pour concevoir des expériences pédagogiques en XR pleinement efficaces
Surfactant Protein (SP)-A Benefits Over SP-A Mutant: A Preliminary Study for ILD Treatment
No full textInternational audienceSurfactant protein (SP)-A, an octadecamer composed of SP-A1 and SP-A2 is secreted into the alveolar space. Heterozygous variations in SFTPA1 and SFTPA2, reported to impair protein secretion, have been associated with interstitial lung disease (ILD) and lung adenocarcinoma. To date, no specific treatment is available. Here, the impact of wild type (WT) SP-A1 or SP-A2 on the localization, oligomerization, and secretion of deleterious SP-A1 or SP-A2 variants is investigated. To achieve this, we used expression vectors carrying 4 previously described variations as well as a newly identified variation, in SFTPA1 and SFTPA2 or WT sequences. Proteins were transiently expressed in HEK293T, and after extraction, SP-A1 and SP-A2 were analyzed by Western blot to assess their stability, ability to form oligomers and secretion. Additionally, the subcellular localization of these proteins in HEK293 cells was examined using immunofluorescence microscopy. Consistent with previous reports, we observed that all the variations impair SP-A1 or SP-A2 secretion. Localization of mutated proteins was also disrupted. Furthermore, all variations in SFTPA1 and SFTPA2 exhibited defects in oligomerization of mutated proteins, along with lower expression levels. Interestingly, co-expression of SP-A1 or SP-A2 WT resulted in an increased expression of the mutated proteins, restored a proper oligomerization profile, and partially restored SP-A secretion. This study reveals the beneficial effect of SP-A WT on oligomerization and secretion of mutant SP-A suggesting that SP-A may be studied as a potential targeted treatment in ILD linked to SP-A molecular variations
Quantifying the potential of thermal highways to facilitate long-range proton transport in enzymes
No full textInternational audienceProton transport in enzymes is often portrayed as a purely static, hydrogen-bond-mediated relay, yet this view neglects how ultrafast vibrational coherence within the protein fold can mechanically drive long-range transfer. Here, we introduce the vibrational entropy flux tensor to identify thermal highways-evolutionarily conserved networks of residues whose synchronized terahertz-frequency phonons transiently compress donor-acceptor distances. Using parameter-free coarse-grained elastic-network models of [Fe-Fe] hydrogenase, we show that these highways boost quantum-tunneling probabilities by 10-100 × (depending on mode frequency), directly linking picosecond-scale dynamics to increased proton flux. A single-value descriptor, Tlim, defined as the minimum entropy flux along a proton wire, explains 90% of the variance in H2-production rates across ten enzyme variants (R=0.90). Crucially, mutations >10 Å from the active site that disrupt thermal highway connectivity proportionally attenuate both Tlim and catalytic turnover-evidence that long-range, fold-encoded phonon coherence is a mechanistic driver of proton transport. Our multiscale framework unifies static chemical models with dynamic phonon-mediated enhancement, offering a predictive route for engineering proton-coupled catalysts in bioenergy and beyond
High Altitude Headache in Highlanders: A Hallmark Symptom of Chronic Mountain Sickness Related to Excessive Erythrocytosis? A Preliminary Report from the World's Highest City
No full textInternational audienceIntroduction Headache is a hallmark symptom of chronic mountain sickness (CMS), a high altitude disease thought to be induced by excessive erythrocytosis (EE) in highlanders. Nevertheless, headache characteristics related to permanent high altitude residence remain understudied, as does the association between headache occurrence and hemoglobin concentration ([Hb]) in highlanders. Methods A pilot cross-sectional study was conducted in La Rinconada, Peru (altitude 5100 m), over a 2-y period. During all comers’ medical consultations, highlanders with no known history of chronic medical conditions (except EE/CMS) were questioned regarding headache symptoms. Headache characteristics were collected as well as clinical data and [Hb]. Results Headache prevalence was 61% (200 of 330 highlanders). Clinical characteristics of headache attacks (ie, location, onset, intensity, quality, and duration) were similar between highlanders with and without EE. In multivariate analysis, headache occurrence was associated with lower oxygen saturation ( P <0.001), higher body mass index ( P <0.001), and lower self-reported sleep duration ( P <0.001) but not with [Hb] or sex. Conclusions The absence of a statistically significant association between headache occurrence and [Hb] questions the use of headache as a symptom reflecting EE in CMS highlanders
rhPTH(1-84) for hypoparathyroidism: a randomized study of patient-reported outcomes.
No full textInternational audienceObjective: To assess the impact of recombinant human parathyroid hormone (1-84) [rhPTH(1-84)] compared with placebo, in combination with conventional therapy with vitamin D and/or calcium supplements, on health-related quality of life (HRQoL) in patients with symptomatic chronic hypoparathyroidism (cHypoPT).Design: Randomized, double-blind, placebo-controlled, phase 3b-4 study (ClinicalTrials.gov ID: NCT03324880).Methods: Eligible patients with symptomatic cHypoPT were randomized to receive subcutaneous rhPTH(1-84) 25-100 µg/day or placebo. The primary endpoint was the change from baseline to week 26 in Hypoparathyroidism Symptom Diary (HypoPT-SD) symptom subscale score. Key secondary endpoints were changes from baseline to week 26 in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue and in 36-item Short Form Health Survey physical component summary (SF-36v2 PCS).Results: In total, 93 patients were randomized to receive treatment: 45 received rhPTH(1-84) and 48 received placebo. Change from baseline to week 26 in HypoPT-SD symptom subscale score was significantly greater (improved) in the rhPTH(1-84) group than in the placebo group (difference in least-squares mean changes, -0.53; 95% confidence interval, -0.90 to -0.15, P = .003). Key secondary endpoints, changes between baseline and week 26 in the FACIT-Fatigue and SF-36v2 PCS scores were also significantly greater (improved) in the rhPTH(1-84) group than in the placebo group. The safety profile of rhPTH(1-84) was consistent with previous findings, and no new safety signals were identified.Conclusions: rhPTH(1-84) alongside conventional therapy improved symptom burden (as measured by the HypoPT-SD) and HRQoL to a greater extent than conventional therapy alone in patients with symptomatic cHypoPT
Enterococcal cell wall remodelling underpins pathogenesis via the release of the Enteroccocal Polysaccharide Antigen (EPA).
No full textInternational audienceEnterococci are opportunistic pathogens displaying a characteristic ovoid shape, typically forming pairs of cells (diplococci) and short chains. Control of cell chain length in Enterococcus faecalis relies on the activity of the major N-acetylglucosaminidase AtlA. The formation of short chains and diplococci is critical during pathogenesis for dissemination in the host and to limit recognition by innate immune effectors such as complement molecules and phagocytes. Here, we identify AtlE, an N-acetylmuramidase that contributes to septum cleavage during stationary phase in the absence of AtlA. AtlE is encoded by the locus required to produce the decoration subunits of the Enterococcal Polysaccharide Antigen (EPA), which mediate evasion of phagocytosis. We show that peptidoglycan hydrolysis by AtlE is essential for pathogenesis and demonstrate that soluble cell wall fragments containing EPA decorations increase the virulence of E. faecalis, suggesting that EPA plays a role as a decoy molecule to evade host defences. This research sheds light on the complex interplay between bacterial cell division, cell wall remodelling, and the host immune system, providing valuable insights into a novel mechanism underlying the virulence of E. faecalis