Hotspot mutant p53-R273H enhances mitochondrial biogenesis and cell migration in primary colorectal cancer in response to oxaliplatin

Oxaliplatin is commonly known as a successful chemotherapy for advanced colorectal cancer, improving patient survival and eradicating micro-metastases, but its use in early stages remains controversial. Mitochondria fuel energy-intensive programs such as cell migration, yet how oxaliplatin regulates the mitochondrial network in CRC - and how TP53 context shapes this - remains unclear. We investigated a matched pair of CRC cell lines from the same patient - SW480 (primary) and SW620 (lymph-node metastasis) - both harboring TP53-R273H mutation, to define differential responses in mitochondrial biogenesis, dynamics and respiration and the mechanisms underlying them. The results indicate that primary-derived colorectal cancer cell line increased cell migration, mitochondrial biogenesis, and mitochondrial respiration capacity in response to oxaliplatin through a new and firstly described gain-of-function (GOF) of p53-R273H. Additionally, in the primary-derived CRC line, oxaliplatin elicited fate heterogeneity - coexisting apoptotic and senescent fractions alongside an R273H-driven, bioenergetically primed migratory subpopulation - together with increased mitochondrial biogenesis and respiratory capacity; by contrast, the metastatic-derived line was more sensitive and displayed structural mitochondrial injury with reduced maximal respiration. More broadly, this work underscores the importance of p53 gain-of-function mutations in CRC: the same GOF (TP53-R273H) amplifies cell migration by coupling an enhanced mitochondrial biogenesis/OXPHOS program to motility. Oxaliplatin further accentuates this energetically primed, pre-metastatic state, arguing for mitochondrial-targeted combination strategies in early-stage CRC

Gene therapy device-based delivery of progranulin, prosaposin, and GDNF as a combined precision and neurorestorative therapy in the rat 6-OHDA model of parkinsonism

: Parkinson's disease (PD) is a complex, multifactorial neurodegenerative disorder, characterized by a progressive degeneration of dopaminergic neurons, leading to significant motor impairments frequently associated with cognitive dysfunction and comorbidities in the elderly. Current treatments of PD are primarily symptomatic, highlighting the urgent need for disease-modifying therapies. An increasing body of evidence supports the pivotal role of lysosomal dysfunction in PD pathogenesis, providing new targets for therapeutic approaches. Particularly, recent studies suggest that among the genes implicated in PD are GRN and PSAP, encoding for progranulin (PGRN) and prosaposin (PSAP), respectively. We proved that conditioned media from a Gene Therapy Device-based delivery system (GTD)-PGRN, -PSAP, and -PGRN+PSAP were internalized by primary cortical neurons, leading to enhanced glucocerebrosidase (GCase) activity. Furthermore, we developed a GTD-delivered therapy to target lysosomal dysfunction and support the dopaminergic system, combining the lysosomal factors PGRN and PSAP with the neurorestorative glial cell line-derived neurotrophic factor (GDNF). Interestingly, each factor provided neuroprotection to dopaminergic neurons and preserved motor function in a 6-hydroxydopamine (6-OHDA)-induced neurotoxicity model. Furthermore, eight-month treatments with GTD-PSAP and PSAP+GDNF resulted in significant neurorecovery effects on dopaminergic neurons and motor deficits following 6-OHDA injection

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Practical recommendations for diagnosis and management

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a distinct antibody-mediated disease characterized by heterogeneous manifestations. Despite some overlap with other demyelinating CNS disorders, specific clinical-MRI features of MOGAD have been identified that facilitate early diagnosis. Paediatric and adult populations can be similarly affected but differ in the predominant clinical phenotypes, which include optic neuritis, myelitis, acute disseminated encephalomyelitis, brainstem/cerebellar syndromes, and cerebral cortical encephalitis. Based on the recently international MOGAD panel proposed diagnostic criteria, a correct diagnosis of MOGAD relies on the detection of serum or CSF MOG antibodies (Abs) using cell-based assays in patients with compatible clinical-MRI phenotypes. Relapses occur in 40-80 % of cases with no single factor being able to reliably predict the disease course after onset, although monitoring antibody titers may offer some guidance. Intravenous steroids with subsequent tapering and rapid escalation to plasma exchange in case of incomplete recovery are usually administered in the acute stage, with intravenous immunoglobulins considered as a possible alternative. Chronic treatment should be administered in relapsing patients or in case of incomplete recovery from the presenting attack. In this review, we summarise the main features of MOGAD, with a focus on the clinical/imaging characteristics, diagnosis and treatment approach and propose practical recommendations for clinicians

Socio-Emotional Learning and Human Flourishing [Aprendizaje socioemocional y florecimiento humano]

The development of social and emotional competences is a crucial aspect of human flourishing. These competences, including self-awareness, self-management, social awareness, interpersonal skills and responsible decision-making, have been found to demonstrate effective improvements through social and emotional learning (SEL) programs. An analysis of the recent literature on emerging SEL approaches was conducted to provide an overview of current educational proposals, highlighting their strong and critical areas and outlining the lingering challenges, particularly in terms of the necessity to define the theoretical foundations of the programs with utmost clarity and conduct rigorous research on their effectiveness. In light of the aforementioned considerations, this article presents an innovative SEL program entitled The Nous Project that responds to the recommendations highlighted in the literature. Developed for primary school children, The Nous Project is based on a philosophically-grounded theory of socio-emotional education, which primarily focuses on the role of emotional self-understanding. Consequently, the primary objective of The Nous Project is to foster students’ knowledge of their own emotional dimensions and their ability to understand their own emotions. This is achieved by involving them in keeping a reflective diary, where they write down their emotions and analyse them on the basis of a metaphor. The effectiveness of this activity will be discussed starting from the presentation of the findings emerged from the qualitative analysis of the diaries collected during the pilot implementation of the program

How entrepreneurship education and knowledge prevent early school dropouts and the development of NEETs: An exploratory study on italian school cooperatives

This study investigates how entrepreneurship education delivered through school cooperatives can reduce early school dropout rates and prevent the NEET (Not in Education, Employment, or Training) phenomenon. Drawing on social capital theory, we address the following research questions: (1) What benefits do school cooperatives provide to young people involved in entrepreneurship education activities?; (2) What factors create a favorable setting for developing entrepreneurship education that can reduce the NEET phenomenon?; and (3) What is the role of local actors in promoting entrepreneurship education to contribute to transforming NEET young people into EET (in Education, Employment, or Training) people? We analyze a case in Italy with pupils aged 8–13. Data was collected from 16 in-depth interviews with educators, teachers, and social enterprise managers. We then employed reflexive thematic analysis and social network analysis to examine benefits, enabling conditions, and relationships among actors. We identify six enabling factors of entrepreneurship education. Teachers operate as brokers, linking schools, social enterprises, and community partners. School governance sustains strong ties and proximity. Institutional support, partnerships with municipalities, nonprofits, and firms, and alignment with local labor market opportunities further reinforce the educational ecosystem. We find that school cooperatives develop both bonding social capital (trust and belonging) and bridging social capital (networks and resources) that foster engagement, skills development, and pathways toward EET. The study concludes that entrepreneurship education grounded in school cooperatives mobilizes local networks to combat the risk of NEET and suggests practical priorities, including strengthening teacher brokerage and governance capacity, formalizing community partnerships, and designing education programs that cultivate both bonding and bridging social capital

Identità dell’architettura toscana

Riflessione sull'evoluzione della lingua architettonica in Toscana tra Quattro e Cinquecento, per un volume di stampo manualistico, destinato a un pubblico di student

Adaptive minimax-optimal Wasserstein deconvolution with unknown error distributions

We study the problem of deconvolving an unknown distribution function when the error distribution is ordinary smooth and unknown. Using data from an auxiliary experiment that provides information about the error distribution, we establish minimax-optimal convergence rates (up to logarithmic factors) with respect to the $1$-Wasserstein metric for a kernel-based distribution function estimator over the full range of H\"older-type classes of densities on $\mathbb{R}$. Furthermore, we propose a rate-adaptive, data-driven estimation procedure that automatically selects the optimal bandwidth across $\alpha$-H\"older-type classes of mixing densities for $\alpha\geq\frac{1}{2}$, requiring no prior knowledge of the regularity parameters

Innovation Adoption and Research Methods: The Risk of Misuse in Healthcare Management Studies

Innovation adoption in the healthcare industry is a complex process driven by several variables. Laws frequently govern the implementation of healthcare innovations, making modifications more difficult. Both innovation and organizational manager qualities have an impact on the adoption of innovations in the healthcare industry. Numerous studies have sought to investigate the variables that influence and precede healthcare decision-makers to adopt new technologies. The Unified Theory of Acceptance and Use of Technology, or UTAUT, and the Unified Theory of Acceptance and Use of Technology 2, or UTAUT2 [7-8], are two of the most popular research models used for this purpose. This study aims to find out how the two research models—UTAUT and UTAUT2—were really employed in the studies that make this claim. Thus, the purpose is to discuss how the UTAUT and UTAUT2 models have really been applied in research on the uptake of innovation in the healthcare industry, with a methodological perspective. Healthcare innovation adoption is a complex process with theoretical, cultural, and social implications. For innovation adoption in healthcare to be effective, it is essential to comprehend these implications. To the best of our knowledge, some systematic studies have been conducted on the topic, such as literature reviews or bibliometric analyses. Still, no work addresses how and whether UTAUT and UTUT2, as conceived by their creators, have been employed in studying innovation adoption in healthcare

Legal Perspectives for a Sustainable Circular Economy

The open access book invites readers to critically address the new model of a Sustainable Circular Economy also from the legal point of view, tracing new perspectives in order to fairly orient the law in this systemic paradigm transition. The paradigm shift towards a Sustainable Circular Economy is at the core of the EU policy agenda, aiming at revolutionizing the whole economic productive model that characterizes our contemporary society. However, the legal dimension is often underestimated in this framework. Actually, the legal system cannot resort to old schemes if it wants to respond properly to new challenges. In order to achieve effectively the indicated objectives of social progress, it is decisive that also the legal dimension of a Sustainable Circular Economy, and so the regulation of the market and the society on which it impacts, is designed consistently with an innovative approach. That is why this research intends to promote a general reconceptualization of existing legal configurations, exploring new perspectives to strengthen the role of individuals in the socio-economic system, as aware ‘human’ beings that, as such, take care of the world they live in

PR-ENDO: Physically Based Relightable Gaussian Splatting for Endoscopy

Endoluminal endoscopic procedures are essential for diagnosing colorectal cancer and other severe conditions in the digestive tract, urogenital system, and airways. 3D reconstruction and novel-view synthesis from endoscopic images are promising tools for enhancing diagnosis. Moreover, integrating physiological deformations and interaction with the endoscope enables the development of simulation tools from real video data. However, constrained camera trajectories and view-dependent lighting create artifacts, leading to inaccurate or overfitted reconstructions. We present PR-ENDO, a novel 3D reconstruction framework leveraging the unique property of endoscopic imaging, where a single light source is closely aligned with the camera. Our method separates light effects from tissue properties. PR-ENDO enhances 3D Gaussian Splatting with a physically based relightable model. We boost the traditional light transport formulation with a specialized MLP capturing complex light-related effects while ensuring reduced artifacts and better generalization across novel views. PR-ENDO achieves superior reconstruction quality compared to baseline methods on both public and in-house datasets. Unlike existing approaches, PR-ENDO enables tissue modifications while preserving a physically accurate response to light, making it closer to real-world clinical use. Repository: https://github.com/SanoScience/PR-ENDO