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Abstract The energetic demands of proliferating cells during tumorigenesis require close coordination between the cell cycle and metabolism. While CDK4 is known for its role in cell proliferation, its metabolic function in cancer, particularly in triple-negative breast cancer (TNBC), remains unclear. Our study, using genetic and pharmacological approaches, reveals that CDK4 inactivation only modestly impacts TNBC cell proliferation and tumor formation. Notably, CDK4 depletion or long-term CDK4/6 inhibition confers resistance to apoptosis in TNBC cells. Mechanistically, CDK4 enhances mitochondria-endoplasmic reticulum contact (MERCs) formation, promoting mitochondrial fission and ER-mitochondrial calcium signaling, which are crucial for TNBC metabolic flexibility. Phosphoproteomic analysis identified CDK4’s role in regulating PKA activity at MERCs. In this work, we highlight CDK4’s role in mitochondrial apoptosis inhibition and suggest that targeting MERCs-associated metabolic shifts could enhance TNBC therapy.

The shift in the energetic demands of proliferating cells during tumorigenesis requires intense crosstalk between the cell cycle and metabolism. Beyond their role in cell proliferation, cell cycle regulators also modulate intracellular metabolism in normal tissues. However, in the context of cancer, where CDK4 is upregulated or stabilized, the metabolic role of CDK4 is barely understood. Using both genetic and pharmacological approaches, we aimed to determine the metabolic role of CDK4 in TNBC cells. Unexpectedly, deletion of CDK4 only slightly reduced triple-negative breast cancer (TNBC) cell proliferation and allowed tumor formation in vivo. Furthermore, proapoptotic stimuli failed to induce appropriate cell death in TNBC cells with CDK4 depletion or long-term CDK4/6 inhibitor treatment. Mechanistically, CDK4 enhances mitochondria-ER contact (MERC) formation, thus promoting mitochondrial fission and ER-mitochondrial calcium signaling. Phosphoproteomic analysis also revealed a role for CDK4 in regulating PKA activity at MERCs to sustain ER-mitochondrial calcium signaling. This proper CDK4-mediated mitochondrial calcium signaling is then required for metabolic flexibility of TNBC cells. Taken together, these results demonstrate that CDK4 inhibition leads to cell death resistance, inhibiting mitochondrial apoptosis and functions through attenuated MERCs formation and ER-mitochondrial calcium signaling in TNBC. Overall, this study provides new insights into the mechanisms of TNBC resistance to CDK4/6i therapy and paves the way to explore potential synergistic therapeutic targeting MERCs-associated metabolic shifts.

In this article we have expanded the analysis of the new dataset we created in Santella, Paone, Drago (2005) which analysed and quantified corporate disclosure on directors formally identified as independent by the forty Italian Blue Chips. We find here a general low level of compliance with independence requirements for both financial and non-financial companies, particularly with regard to the two key independence criteria of not having too many concurring commitments and not having business relationships with the company or an associated company. We also find that financial companies show a lower level of compliance than non-financial ones and are connected with each other and with a few non-financial companies through networks of cross-directorships: two directors (one independent and one executive) who also sit at the same time on another company board. Finally, those non-financial companies that have a relatively fragmented shareholder structure tend to be characterised by higher levels of compliance and disclosure (but not always by lower levels of not compliance) than tightly-controlled non-financial companies, presumably because of sensitivity to a larger pool of small shareholders. Peculiarly, financial companies with fragmented shareholder structure tend to be characterised by low disclosure levels, although such companies are also subject to strong financial supervision.

Background and Aims: Current changes in family structures make the development of models for sustainably ensuring high-quality care for older people in the province of Bolzano–Bozen increasingly necessary to identify new solutions to address the needs of older people. This research project explores support options that enable older individuals to live independently in their homes for as long as possible, based on data collected through a quantitative survey. Special attention is devoted to recent transformations in family dynamics, highlighting the urgency of rethinking care strategies for older people. Data and Methods: The study focuses on a sample of individuals aged 60 and older who reside in their own homes in South Tyrol. Data were collected through 536 interviews conducted in 2020, using a questionnaire administered in both German and Italian. A Latent Class Model (LCA) was used to identify latent categorical indicators, with each category representing a specific combination of factors derived from the data. Results: The findings underscore the critical role of eliminating architectural barriers, fostering social connections, and promoting volunteer activities as key factors in enhancing the quality of life and independence of older adults.

Background: Langerhans Cell Histiocytosis (LCH) is a rare histiocytic hematological disorder that frequently involves the lungs. Due to a lack of data about sex-related differences in LCH, the aim of this study is to evaluate sex-related differences in pulmonary function in a cohort of patients with LCH. Methods: We retrospectively analyzed data from 79 adult patients diagnosed with LCH. Demographic, clinical, and spirometric data were collected and compared by sex. Continuous variables were analyzed using the Mann–Whitney test and categorical variables were analyzed with the Chi-square test. Results: Out of 79 patients, 47 (59.5%) were females and 32 (40.5%) were males. Women showed significantly lower diffusing capacity of the lungs for carbon monoxide (DLCO%) and lower diffusing capacity of the lungs for carbon monoxide per unit of alveolar volume (DLCO/VA%) compared to men. Females showed a trend toward lower small airway indices, including maximal expiratory flow at 25 (MEF25%) and forced expiratory flow at 25–75% (FEF25–75%), though this was not statistically significant, while the residual volume-to-total lung capacity (RV/TLC) ratio was significantly higher in women. Among the functional parameters, DLCO% showed the highest accuracy (AUC 0.70) in the identification of lung involvement after multivariate regression analysis. Conclusions: Our findings suggest that the combination of lower gas exchange efficiency and increased peripheral air trapping secondary to small airway involvement in female patients may reflect the presence of a distinct functional LCH phenotype in women characterized by early small airway involvement and altered ventilation–perfusion dynamics, which may influence the clinical management of these patients. Furthermore, the moderate predictive value of DLCO% for lung involvement at baseline in LCH women suggests that DLCO may contribute to the detection of LCH women with lung involvement, although it should not be considered a definitive diagnostic test without a prospective and independent external validation.

Contamination by heavy metals is currently one of the most environmental concerns especially due to the toxicity, pervasiveness, and persistence of these substances. As they are not biodegradable, heavy metals are harmful not only for water, air, and soil but also for human health, even in very low traces. There is therefore a pressing need to develop an efficient, economic, and rapid analysis method to be applied in a wide range of conditions and able to detect very low contaminants concentrations. Currently, the most novel solution in this field is represented by the combination of electrospun nanofibers and highly sensitive electrochemical techniques. It has been proved that nanofibers, due to their outstanding properties, perfectly fit as sensing material when trace concentrations of heavy metals were investigated by anodic stripping voltammetry, envisaged as the most sensitive electrochemical technique for this kind of measurements. This work aims to provide an overview of the latest trends in the detection of contaminants by the simultaneous use of electrospun fibers and anodic stripping voltammetry. Indeed, a clear and comprehensive vision of the current status of this research may drive future improvements and new challenges.

Targeting metabolic reprogramming is crucial for cancer treatment. Recent advances highlight RNA’s ability to directly regulate enzyme activity through riboregulation. In this study, we used an RNA-based approach to inhibit the mitochondrial enzyme Serine hydroxymethyltransferase 2 (SHMT2), which lacks a selective in vivo inhibitor. SHMT2, often overexpressed in various cancers, is pivotal in one-carbon metabolism, a pathway vital for cell proliferation. Our results show that RNA effectively inhibits SHMT2’s serine-to-glycine conversion in vitro (IC 50  = 4.4 ± 0.2 nM). By using a mitochondrial import signal, we successfully delivered the inhibitory RNA into the mitochondria of lung cancer cells, reducing cell viability in vitro and tumor growth in vivo in a xenograft mouse model. These findings suggest that RNA-based strategies could be extended to selectively target other RNA-binding metabolic enzymes, offering potential solutions where small molecule inhibitors fall short or to counteract drug resistance.

Conducting nanofibers of polyaniline (PANI) doped with camphor-10-sulfonic acid (HCSA) and blended with different polymers, such as polymethyl methacrylate (PMMA) and polyvinyl acetate (PVAc), have been fabricated using the electrospinning technique. Scanning electron microscopy (SEM) and thermal gravimetric analysis (TGA) were utilized to characterize the morphology and the thermal stability of PANI-blended fibers. An extensive study was performed to understand the copolymer influence on both the structural and surface properties of the realized conductive thin films. Samples main electrical characteristics, as conductivity, specific capacitance and electrochemical performances were tested. The better mats were obtained with the use of PVAc copolymer, which showed a conductivity value two orders of magnitude higher than the PMMA system. Aiming at further improving the electrochemical features of these blended mats, hybrid fibers based on PANI/PVAc/graphene oxide and PANI/PVAc/iron oxide were also produced and characterized. The obtained mats were potentially addressed to numerous practical fields, including sensors, health applications, smart devices and multifunctional textile materials.

The present study aims to explore the forms of psychological parental control that are interconnected with dysfunctional emotional states (i.e., anxiety and depression), and how these internalizing problems may manifest as distorted behaviors (i.e., vigorexic and orthorexic behaviors) during adolescence. Participants included 403 Italian adolescent athletes (231 boys and 172 girls) aged 14 to 18 years. The participants completed self-report questionnaires designed to assess psychological parental control oriented towards dependence and achievement, anxiety and depression, and vigorexia and orthorexia. The results highlight how both forms of psychological parental control predict anxiety and depression. Furthermore, anxiety was found to be linked to both vigorexic and orthorexic behaviors, while depression is connected only to vigorexia. This study delves into the intricacies of parental influence on adolescents, revealing that both dependency-oriented and success-oriented psychological parental control have notable implications for the mental well-being of adolescents. The findings underscore the interconnectedness of these factors, demonstrating that anxiety can set off a chain reaction, leading to engagement in vigorexic and orthorexic behaviors. On the other hand, depression appears to be uniquely associated with vigorexia. These insights contribute to our understanding of the complex dynamics between parental control and adolescent mental health. The implications of this research extend to both theoretical frameworks and practical interventions, emphasizing the need for a nuanced approach to supporting adolescents in navigating these challenges.

> 50). Tale percorso prevede un graduale e strutturato passaggio di questa categoria di pazienti, in carico alle équipe di CPP, alle équipe dell’adulto, garantendo, tuttavia la condivisione fino al 25° anno di vita o comunque fino al raggiungimento di un pieno livello di confidenza da parte dell’équipe dell’adulto con il paziente e la famiglia.