Treatment with FRAX486 rescues neurobehavioral and metabolic alterations in a female mouse model of CDKL5 deficiency disorder

Introduction: CDKL5 deficiency disorder (CDD) is a rare neurodevelopmental condition, primarily affecting girls for which no cure currently exists. Neuronal morphogenesis and plasticity impairments as well as metabolic dysfunctions occur in CDD patients. The present study explored the potential therapeutic value for CDD of FRAX486, a brain-penetrant molecule that was reported to selectively inhibit group I p21-activated kinases (PAKs), serine/threonine kinases critically involved in the regulation of neuronal morphology and glucose homeostasis.Methods: The effects of treatment with FRAX486 on CDD-related alterations were assessed in vitro (100 nM for 48h) on primary hippocampal cultures from Cdkl5-knockout male mice (Cdkl5-KO) and in vivo (20 mg/Kg, s.c. for 5 days) on Cdkl5-KO heterozygous females (Cdkl5-Het).Results: The in vitro treatment with FRAX486 completely rescued the abnormal neuronal maturation and the number of PSD95-positive puncta in Cdkl5-KO mouse neurons. In vivo, FRAX486 normalized the general health status, the hyperactive profile and the fear learning defects of fully symptomatic Cdkl5-Het mice. Systemically, FRAX486 treatment normalized the levels of reactive oxidizing species in the whole blood and the fasting-induced hypoglycemia displayed by CdklS-Het mice. In the hippocampus of Cdkl5-Het mice, treatment with FRAX486 rescued spine maturation and PSD95 expression and restored the abnormal PAKs phosphorylation at sites which are critical for their activation (P-PAK-Ser144/141/139) or for the control cytoskeleton remodeling (P-PAK1-Thr212).Conclusions: Present results provide evidence that PAKs may represent innovative therapeutic targets for CDD

Circular technologies in construction

The report emphasizes the importance of standardisation in promoting circular construction and the circular economy. It discusses the need for future standardisation and pre-normative research for circular construction in terminology, metrology, such as indicators, performance characterisation, compatibility and operability assessments. Several opportunities for synergies are uncovered, such as collaboration between the New European Bauhaus and circular construction. The report presents a gap analysis carried out by CEN/TC350 on circularity in the construction sector and emphasizes the importance to overcome cradle-to-grave construction frameworks. Strategies to bridge these gaps include enhancing standardisation, collaboration, and innovation. Four strategic areas could benefit from standardisation: a) frameworks and indicators to measure circularity, b) quality assurance of reused and recycled material, end-of-waste criteria, c) design for circularity, adaptability and disassembly, and d) building information. The report also highlights the need for clear objectives, focused standards, cost-effectiveness, common future scenarios, resource indicators, and practical implementation aspects to advance circularity in the construction industry. The recommendations provided aim to guide future standardisation activities, aligning with circular principles to drive industry competitiveness and environmental stewardship. Taking first steps towards a standardisation roadmap, the study highlights specific areas that CEN/TC 350 may consider in their future work programme and suggests high priority topics based on discussions with stakeholders.JRC.S.4 - Scientific Development Programme

Novel prognostic nomogram for predicting recurrence-free survival in medullary thyroid carcinoma

AimsRecently, there have been attempts to improve prognostication and therefore better guide treatment for patients with medullary thyroid carcinoma (MTC). In 2022, the International MTC Grading System (IMTCGS) was developed and validated using a multi-institutional cohort of 327 patients. The aim of the current study was to build upon the findings of the IMTCGS to develop and validate a prognostic nomogram to predict recurrence-free survival (RFS) in MTC.Methods and ResultsData from 300 patients with MTC from five centres across the USA, Europe, and Australia were used to develop a prognostic nomogram that included the following variables: age, sex, AJCC stage, tumour size, mitotic count, necrosis, Ki67 index, lymphovascular invasion, microscopic extrathyroidal extension, and margin status. A process of 10-fold cross-validation was used to optimize the model's performance. To assess discrimination and calibration, the area-under-the-curve (AUC) of a receiver operating characteristic (ROC) curve, concordance-index (C-index), and dissimilarity index (D-index) were calculated. Finally, the model was externally validated using a separate cohort of 87 MTC patients. The model demonstrated very strong performance, with an AUC of 0.94, a C-index of 0.876, and a D-index of 19.06. When applied to the external validation cohort, the model had an AUC of 0.9.ConclusionsUsing well-established clinicopathological prognostic variables, we developed and externally validated a robust multivariate prediction model for RFS in patients with resected MTC. The model demonstrates excellent predictive capability and may help guide decisions on patient management. The nomogram is freely available online at .Building upon the International Medullary Thyroid Carcinoma (MTC) Grading System (IMTCGS) developed in 2022, this study presents a prognostic nomogram to predict recurrence-free survival in MTC. The model was created using data from 300 MTC patients and was externally validated in a separate cohort. The nomogram is available at . imag

Association of the Genomic Profile of Medullary Thyroid Carcinoma with Tumor Characteristics and Clinical Outcomes in an International Multicenter Study

Purpose: The prognostic importance of RET and RAS mutations and their relationship to clinicopathologic parameters and outcomes in medullary thyroid carcinoma (MTC) need to be clarified. Experimental Design: A multicenter retrospective cohort study was performed utilizing data from 290 patients with MTC. The molecular profile was determined and associations were examined with clinicopathologic data and outcomes. Results: RET germ line mutations were detected in 40 patients (16.3%). Somatic RET and RAS mutations occurred in 135 (46.9%) and 57 (19.8%) patients, respectively. RETM918T was the most common somatic RET mutation (n = 75). RET somatic mutations were associated with male sex, larger tumor size, advanced American Joint Committee Cancer (AJCC) stage, vascular invasion, and high International Medullary Thyroid Carcinoma Grading System (IMTCGS) grade. When compared with other RET somatic mutations, RETM918T was associated with younger age, AJCC (eighth edition) IV, vascular invasion, extrathyroidal extension, and positive margins. RET somatic or germ line mutations were significantly associated with reduced distant metastasis-free survival on univariate analysis, but there were no significant independent associations on multivariable analysis, after adjusting for tumor grade and stage. There were no significant differences in outcomes between RET somatic and RET germ line mutations, or between RETM918T and other RET mutations. Other recurrent molecular alterations included TP53 (4.2%), ARID2 (2.9%), SETD2 (2.9%), KMT2A (2.9%), and KMT2C (2.9%). Among them, TP53 mutations were associated with decreased overall survival (OS) and disease-specific survival (DSS), independently of tumor grade and AJCC stage. Conclusions: RET somatic mutations were associated with high-grade, aggressive primary tumor characteristics, and decreased distant metastatic-free survival but this relationship was not significant after accounting for tumor grade and disease stage. RETM918T was associated with aggressive primary tumors but was not independently associated with clinical outcomes. TP53 mutation may represent an adverse molecular event associated with decreased OS and DSS in MTC, but its prognostic value needs to be confirmed in future studies

Report from Working Group 3: Beyond the standard model physics at the HL-LHC and HE-LHC

This is the third out of five chapters of the final report [1] of the Workshop on Physics at HL-LHC, and perspectives on HE-LHC [2]. It is devoted to the study of the potential, in the search for Beyond the Standard Model (BSM) physics, of the High Luminosity (HL) phase of the LHC, defined as $3$ ab$^{-1}$ of data taken at a centre-of-mass energy of 14 TeV, and of a possible future upgrade, the High Energy (HE) LHC, defined as $15$ ab$^{-1}$ of data at a centre-of-mass energy of 27 TeV. We consider a large variety of new physics models, both in a simplified model fashion and in a more model-dependent one. A long list of contributions from the theory and experimental (ATLAS, CMS, LHCb) communities have been collected and merged together to give a complete, wide, and consistent view of future prospects for BSM physics at the considered colliders. On top of the usual standard candles, such as supersymmetric simplified models and resonances, considered for the evaluation of future collider potentials, this report contains results on dark matter and dark sectors, long lived particles, leptoquarks, sterile neutrinos, axion-like particles, heavy scalars, vector-like quarks, and more. Particular attention is placed, especially in the study of the HL-LHC prospects, to the detector upgrades, the assessment of the future systematic uncertainties, and new experimental techniques. The general conclusion is that the HL-LHC, on top of allowing to extend the present LHC mass and coupling reach by $20-50\%$ on most new physics scenarios, will also be able to constrain, and potentially discover, new physics that is presently unconstrained. Moreover, compared to the HL-LHC, the reach in most observables will, generally more than double at the HE-LHC, which may represent a good candidate future facility for a final test of TeV-scale new physics

Safer Sound : wie Prävention von Gehörschäden bei Mitarbeitenden in Zürcher Clubs gelingen kann

Einleitung: Menschen, die in Clubs arbeiten, sind regelmassig lauter Musik ausgesetzt. Diese Exposition ist ein Risikofaktor für die Entstehung von Gehörschaden. Schaden des Gehörs sind irreversibel und stellen eine der häufigsten Berufskrankheiten dieser Berufsgruppe dar. Deshalb thematisiert die vorliegende Arbeit Massnahmen zur Prävention in Zürcher Clubs. Fragestellung: Welche Massnahmen muss ein Schutzkonzept zum Thema Gehörschutz beinhalten, sodass Mitarbeitende von Zürcher Clubs am Arbeitsplatz vor Gehörschaden geschützt sind? Methoden: Ausgehend von einer selektiven Literaturrecherche beruht der Hauptteil auf qualitativen Einzelinterviews. Es wurden vier Personen interviewt. Zwei davon arbeiten selbst in Clubs. Zwei Personen sind Expert:innen aus den Bereichen Lärmschutz und Prävention in Clubs. Ergebnisse: Die Ergebnisse zeigen, dass das Thema Gehörschutz für die Praxis relevant ist. Aus den Interviews entstanden unterschiedliche Massnahmen auf verschiedenen Ebenen, die in das Schutzkonzept integriert wurden. Schlussfolgerungen: Die Problematik ist in der Praxis weitgehend bekannt und wird durch die bestehenden gesetzlichen Grundlagen adressiert. Aufgrund der Herausforderungen bei der Kontrolle dieser Gesetze, ist die Übernahme von Verantwortung durch Führungspersonen unerlässlich. Ein entsprechendes Schutzkonzept kann einen Beitrag zur Bewältigung dieser Herausforderung leisten und eine offene Arbeitskultur schaffen