Piedmont University

Clinical laboratories play a vital role in healthcare but are also among the most resource-intensive hospital units. High energy and water consumption, extensive use of single-use plastics, and the generation of non-recyclable biomedical waste present major environmental challenges. This study aimed to quantify the environmental and economic burden associated with common and avoidable practices in clinical laboratory medicine, including: excessive blood collection, inappropriate test ordering, and unnecessary tube duplication in pre-analytical workflows. Real-world data from the Clinical Biochemistry Laboratory of the AOU Maggiore della Carità (Novara, Italy) for the year 2024 were analysed to quantify the environmental and economic impact of inappropriate test ordering based on minimum retesting intervals, as well as pre-analytical practices, including redundant sample tube collection and excessive blood volumes relative to analytical requirements. Inappropriate retesting of selected biomarkers resulted in 2,931 unnecessary tubes, generating over 26.7 kg of avoidable waste. Redundant EDTA tubes for complete blood count, glycated haemoglobin, erythrocyte sedimentation rate, and haemoglobin electrophoresis led to 356.14 kg of excess waste, which could be eliminated through sample consolidation. In haematology, 264,834 CBC tests generated 2.62 tonnes of biological waste. For biochemistry, 3 million tests produced 36.98 tonnes ofwaste. Excessive blood collection and unnecessary test repetition contribute to significant but avoidable environmental and financial burdens. Pre-analytical interventions, such as reducing tube volume and consolidating tests, could prevent over 40 tonnes of waste and save more than € 60,800 annually in a single laboratory.

Mentalising skills may be conceptualised as composed by both personal and interpersonal competencies, in turn shaped by early adverse experiences and coping strategies. Although cross-sectional observations described a role for mentalising skills in burnout development, large-scale longitudinal studies on the topic remain limited, especially in relation to psychiatry training. The primary aim was to investigate protective and risk factors for higher burnout scores across time. Secondary aims included testing whether psychiatry exhibited different burnout scores across time in comparison to other medical residents. A cohort of 1803 medical residents (1131 psychiatry residents) was assessed for mentalising skills, conceptualised as composed of emotional regulation (Difficulties in Emotion Regulation Scale), interpersonal competencies (Interpersonal Competence Questionnaire), coping strategies (Coping Orientation to Problems Experienced) and burnout dimensions (Maslach Burnout Inventory). One-year follow-up was available for 520 psychiatry residents (73.03% response rate) and 234 other medical residents (35.94% response rate). Longitudinal mixed models and bivariate latent change models were employed. Across all residents, greater levels of burnout were associated with higher scores in insecure attachment, emotional dysregulation and maladaptive coping, as well as lower scores in interpersonal skills. Attending at least one supervision per month was associated with lower burnout scores across time. According to a bivariate latent change model, emotional regulation improvements through years were associated with lower burnout scores across time. In psychiatry residents, lower burnout scores across time were observed as compared to other medical residents. Psychiatry residents benefited from a higher protective effect of interpersonal competencies (group by moderator by time interaction) and coping strategies against burnout. Mentalising skills may mitigate burnout development. Training in psychiatry emerged as a potential mitigating factor against burnout increases. Structured supervisions may foster professional development and emotional resilience.

Abstract The Trimethyl guanosine Synthase (TGS1) is a highly conserved enzyme mediating di-methylation of the 5’-cap 7-methylguanosine of RNA to generate 2,2,7-trimethylguanosine (m 2,2,7 G). Known TGS1 targets include snRNAs, snoRNAs, the telomeric RNA component and a limited number of mRNAs encoding selenoproteins. TGS1 is highly expressed in acute myeloid leukaemia (AML) cells, and its expression correlates with poor prognosis. Here, we report that TGS1 directly methylates the cap of more than 500 mRNAs in AML cells. Specifically, we demonstrate that TGS1 modifies nuclear mRNAs encoding mitochondrial proteins, including critical components of complexes involved in both the TCA cycle and oxidative phosphorylation, promoting their translation mediated by mitochondria associated cytosolic ribosomes. Functionally, we report that TGS1 depletion impairs mitochondrial respiration and increases oxidative stress. This, in turn, impairs the growth of AML cells causing differentiation and cell cycle arrest in vitro and in vivo . Finally, we demonstrate that TGS1 depletion sensitizes AML cells to RSL3, a small molecule promoting ferroptosis. Taken together, our findings establish TGS1 as a key regulator of oxidative phosphorylation and mitochondrial redox status of AML cells and highlight its potential as a therapeutic target in leukaemia.

ABSTRACT This paper will deal with intergenerational justice, focusing on the relationship between coexisting generations. The first section will be reserved for some conceptual clarifications on the concept of justice, on the distinction between age groups and birth cohorts, and on the specificity of age as a category for apportioning benefits and resources. Then, I will take up the issue of what is the analytical unit of justice across overlapping generations: age groups or birth cohorts. I shall try to disentangle the alternative between age groups and birth cohorts, on the one hand, and that between age groups at a snapshot and the whole life view, on the other. After a discussion of the latter alternative, it will become clear that also the whole life view will allow only a simultaneous comparison of age groups at a definite moment of time, though in the context of a distributive theory considering the whole life and its different phases. At the end, the age groups turn out to be the units of justice between overlapping generations in all three dimensions of justice. But while age groups are specifically appropriate for relational and political justice, in the case of distributive fairness, the comparison between simultaneous segments of different age groups should be assessed in the context of a distributive theory justifying the differential distributions at different ages. Any such theory refers to the temporality of human life, with different needs and capabilities at different stages of human life. I shall finally illustrate my age‐sufficiency principle that I deem appropriate for distributive comparisons between simultaneous age segments considered as different age stages of human life.

Recurrence patterns in OPC differ by HPV status and smoking history. HPV-positive heavy smokers represent a distinct high-risk subgroup characterized by increased distant metastasis and inferior survival, warranting refined stratification beyond p16 status alone.

SARS-CoV-2, the causative agent of COVID-19, remains a global concern due to gaps in understanding its pathogenesis. Peptidyl-arginine deiminases (PADs) are emerging as key regulators of viral replication and inflammation. PADs catalyze the conversion of arginine into citrulline, a modification linked to autoimmune diseases. Here, we show that PAD-mediated citrullination plays a crucial role in SARS-CoV-2 infection. Using human cell lines and in K18-hACE2 transgenic mice infected with different SARS-CoV-2 strains, we demonstrate that viral replication is associated with increased PAD4 expression. Mass spectrometry shows 170 distinct differentially citrullinated proteins in infected cells and tissues. Importantly, PAD4 inhibition significantly reduces viral replication and restores a citrullination profile comparable to that of uninfected mice. These findings suggest that SARS-CoV-2 exploits PAD-mediated citrullination to enhance replication and inflammation. Thus, targeting PAD4 may represent a viable strategy to curb viral spread and mitigate COVID-19-associated hyperinflammation.

Abstract Abstract Doxorubicin (DOX) is a highly effective chemotherapeutic agent limited by dose-dependent cardiotoxicity. A key pathogenic event involves mitochondrial accumulation in cardiomyocytes, however, the resulting metabolic adaptations remain poorly understood. Therefore, this study characterizes DOX-induced alterations in cardiac metabolism and highlights their potential as novel therapeutic targets. Methods Female BALB/c mice received DOX over two weeks (12 mg/kg) and were sacrificed at early (3 days) or late (6 weeks) timepoints. Cardiac metabolism was assessed by metabolomics, 13C₆-glucose flux analysis, proteomics and metabolic enzymes activity in whole hearts and isolated mitochondria. Oxygen consumption was measurd in vitro (Seahorse) and ex vivo (Oroboros). The contribution to DOX-induced metabolic rewiring of PI3Kγ, that has been previously showed to be activated by DOX, was studied in mice expressing a kinase-inactive enzyme (PI3Kγ kinase-dead; KD). To unravel the role of PDK4-PDH axis, PDK4 overexpression was induced in mice using AAV9 viral vector, followed by DOX treatment. Results Following acute DOX administration, hearts exhibited an unexpected hypermetabolic response characterized by increased mitochondrial respiration and enhanced substrate flexibility, particularly for glucose, as confirmed by 13C₆-glucose tracing. Untargeted metabolomics revealed pyruvate depletion and acetyl-CoA accumulation, accompanied by altered protein acetylation, as evidenced by proteomics for lysine acetylation, and buildup of TCA intermediates. These changes, together with increased glutamine utilization reminiscent of cancer cell metabolism, marked an acute adaptive response. However, the persistence of this hypermetabolic state led to maladaptation, resulting in mitochondrial overload, energetic uncoupling, oxidative stress, and ultimately cardiac dysfunction. Notably, inhibition of the PI3Kγ–PDK4–PDH axis, either through PI3Kγ blockade or PDK4 overexpression, fully prevented chronic metabolic alterations, identifying PI3Kγ as a key regulator of substrate selection and metabolic remodeling during DOX treatment. Metabolic rewiring also involved cardiac fibroblasts, which showed reduced glycolysis, altered lipid handling, and increased glutamine metabolism, promoting cytosolic acetyl-CoA production via ACLY in the early phase. This shift may drive sustained fibroblast activation in the long-term, through post-translational and epigenetic mechanisms, contributing to cardiotoxicity via metabolic crosstalk with cardiomyocytes and induction of senescence. Conclusions Overall, this work demonstrates that DOX induces an acute increase in metabolic activity, with a reprogramming of different cardiac cells metabolism. While initially adaptive, this response becomes maladaptive over time, ultimately leading to chronic cardiac dysfunction.

IntroductionFrontotemporal lobar degeneration (FTLD) encompasses heterogeneous clinical syndrome within the frontotemporal spectrum, where clinicopathological associations may be misleading. This case series illustrates clinicopathological variability and mismatches.MethodsA retrospective case series was conducted within the brain donation program at the Golgi Cenci Foundation. Cases presenting at onset with a frontotemporal-spectrum phenotype, longitudinal clinical data, and post-mortem neuropathological characterization were included.ResultsFive cases (mean age at onset 65.4 years) were clinically diagnosed with major neurocognitive disorder due to frontotemporal dementia (FTD). Neuropathological examination revealed clinicopathological heterogeneity: two cases showed FTLD-TDP-A associated with GRN mutations, including a classic case and one with posterior (parieto-occipital) involvement; one non-fluent variant primary progressive aphasia (nfvPPA) case demonstrated FTLD-TDP-A with multiple co-pathologies; one semantic-variant-like case was driven by high Alzheimer’s disease neuropathological changes; and one behavioral variant FTD-like case corresponded to frontal-variant Alzheimer’s disease (fvAD) with extensive mixed pathology, including Lewy body disease, LATE-NC, and vascular pathology.DiscussionFindings indicate that clinical phenotypes are more influenced by the anatomical distribution of pathology than by the specific molecular substrate. Frequent coexisting proteinopathies and asymmetric involvement contribute to phenotypic variability, reinforcing the role of neuropathological examination of both hemispheres for accurate clinicopathological correlations and definitive etiological diagnosis.

Abstract Background: Host metabolic status and body composition are increasingly recognized as modulators of treatment response and prognosis in early breast cancer (eBC). Nutritional and exercise interventions during neoadjuvant chemotherapy (NAT) may influence systemic inflammation, insulin sensitivity, and lipid metabolism, factors implicated in therapy resistance. However, prospective randomized data assessing their impact on metabolic health and treatment efficacy are limited. Based on prior findings from the SeNEOAD study we identified a metabolomic signature associated with a higher probability of achieving pCR after NAT. Among 445 small molecules analyzed, 61 were differentially expressed in patients with pCR versus residual disease (RD) (p<0.05); patients with RD showed lower levels of fatty acids, such as 9-hexadecenoic acid (p <0.001) and doconexent (p<0.001). These results support the rationale for a nutritional supplementation of these molecules in order to improve pCR rates. Methods: NEOMET is an ongoing randomized prospective multicenter study whose primary aim is to evaluate whether plasma metabolomic signatures can be modified by lifestyle interventions including dietary supplements and physical exercise in eBC patients undergoing NAT. Eligible patients are randomized to one of four groups: a) NAT according to molecular subtype; b) NAT plus nutritional supplementation; c) NAT plus supervised physical exercise; d) NAT plus nutritional supplementation plus supervised physical exercise. Nutritional supplementation consists of two main long-chain polyunsaturated fatty acids omega-3 (n-3 Lc-PUFA), EPA and DHA, plus a source of palmitoleic acid (hexadecenoic acid). Body composition is assessed by bioelectrical impedance analysis (BIA) at baseline and at the end of NACT, before surgery. Quality of life (QoL) is evaluated using the EORTC QLQ-C30 and QLQ-BR45 questionnaires. In this preliminary analysis we present data on BIA and QoL assessments. Results: Between October 2024 and June 2025, 27 patients with stage I-III eBC were enrolled. Of these, 6 are allocated to arm A, 8 to arm B, 6 to arm C and 7 to arm D. Median age is 53 years (range 30-69), and median BMI is 25 kg/m2. Tumor subtypes included HER2+ (n=12), triple-negative (n=7), and luminal-like (n=8). Fifteen patients completed NACT and had paired data on body composition and quality of life (QoL). QoL assessments using EORTC QLQ-C30 and BR45 revealed a significant deterioration in global health status (mean score from 148.8 to 116.7, p=0.041), fatigue (26.2 to 45.2, p=0.033), and pain (4.8 to 23.8, p=0.017); physical functioning improved significantly (8.1 to 21.0, p=0.009) and emotional functioning remained stable. Paired BIA assessments showed a trend toward improved body composition: fat-free mass increased from a mean of 44.9 kg to 46.4 kg (p=0.096) and skeletal muscle mass increased from 21.2 kg to 22.1 kg; fat mass remained stable (18.9 kg to 19.0 kg, p=0.47). Adverse event rates were assessed after at least 1 cycle in 26 patients. No significant differences in grade ≥2 toxicities (CTCAE v5.0) were observed between patients receiving standard treatment and those in the experimental arms. Conclusion: The preliminary analysis from the ongoing NEOMET trial supports the safety and feasibility of integrating nutritional and exercise interventions during NAT in eBC. Despite the limited sample size, observed trends suggest potential benefits in preserving lean body mass and improving physical functioning. These findings will be further investigated in the NEOMET trial as more patients will be randomized, to clarify the clinical impact on treatment tolerance and patient well-being. Additional clinical and translational results, including omega-3 index and metabolomic analysis, will be presented at the meeting. Citation Format: I. Taglialatela, B. Conte, S. Nardin, F. D'Avanzo, V. Rossi, B. Ruffilli, T. Landolfo, G. Isingrini, G. Griguolo, D. Soldato, A. Coassolo, F. Condorelli, E. Del Grosso, C. Bengala, C. Branni, J. Gennari, G. Di Foggia, M. Rossato, G. Tarantino, M. Manfredi, V. Martini, S. Gobbato, L. Boni, L. Del Mastro, V. Guarneri, A. Gennari. Preliminary Results from the NEOMET Trial: Nutritional and Exercise Interventions During Neoadjuvant Chemotherapy in Early Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-09-23.