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Persistent Organic Pollutants, such as polychlorinated biphenyls (PCBs), are environmental pollutants for their resistance to degradation and adverse health effects. Despite extensive toxicological data in mammalian system, the use of alternative models such as Dictyostelium discoideum offers an opportunity to dissect evolutionarily conserved molecular mechanisms underlying pollutant-induced cellular dysfunction. In this study, we used Dictyostelium to investigate the effects of PCB 138 and PCB 153 revealing, for the first time, a direct impairment of both growth and multicellular development. PCBs exposure reduced cell proliferation and led to the formation of smaller fruiting bodies. These phenotypic effects were accompanied by altered expression of iron-regulatory genes, including upregulation of abcb7 and ferroportin , and downregulation of ferritin , consistent with intracellular iron depletion confirmed by calcein assay. We used THP-1 human cells to confirm the effect of PCBs on hamp gene, supporting the relevance of iron homeostasis as a target pathway. In Dictyostelium , iron imbalance was associated with increased ROS levels, downregulation of superoxide dismutase genes, and altered mitochondrial morphology. Under starvation, PCBs-treated cells also showed transcriptional upregulation of key development genes involved in cAMP signaling ( acaA, carA, regA, gtaC ), while proteomic analysis revealed changes in proteins linked to cell adhesion, stress response, and development. Together these findings support a model in which PCBs induce iron efflux, oxidative stress, and disruption of developmental signaling, ultimately both proliferation and morphogenesis. This study highlights the potential of Dictyostelium discoideum as a sensitive and cost-effective model to uncover conserved cellular responses to environmental pollutants.

The clinical management of myeloid neoplasms increasingly relies on the accurate detection and longitudinal monitoring of disease-defining genetic alterations. Many clinically relevant mutations are often present at very low variant allele frequencies, below the detection limits of conventional approaches routinely used in diagnostic workflows. In recent years, a growing number of ultra-sensitive molecular technologies have been developed to overcome these limitations, enabling the detection of rare variants with unprecedented precision, offering complementary strengths in terms of sensitivity, quantification, throughput, and clinical applicability. This review provides a comprehensive overview of established and emerging ultra-sensitive technologies for the diagnosis and molecular monitoring of myeloid neoplasms, discussing their technical principles, advantages, and limitations.

R-loops are three-stranded nucleic acid structures composed of an RNA:DNA hybrid duplex and a displaced single-stranded DNA loop. Unscheduled or persistent R-loops drive genome instability by creating conflicts with transcription and replication. Up to 75% of the human genome comprises repetitive DNA elements that are prone to R-loop formation. We show that the RNA binding protein SFPQ suppresses R-loop mediated replication stress and DNA damage at repeat elements such as telomeres, (peri)-centromeres, LINE-1 and SINE elements. SFPQ exhibits in-vitro R-loop binding activity, associates with chromatin containing R-loops, and recruits the histone H3.3 specific chaperon DAXX to preserve a correct nucleosome template that counteracts R-loop accumulation. Loss of SFPQ results in DAXX displacement from repeat elements, reduced histone H3.3 incorporation, replication stress-mediated genome instability and the emergence of cytoplasmatic DNA. This leads to activation of innate immune signaling via the cGAS/STING pathway, ultimately correlating with improved survival of sarcoma patients. R-loops cause genome instability by creating conflicts with transcription and replication. Here the authors show that SFPQ binds R-loops at repetitive elements, recruits DAXX and maintains H3.3 deposition. Loss of SFPQ leads to genome instability and cGAS–STING activation, correlating with improved sarcoma patient survival.

The FLT3-ITD mutation is a critical prognostic marker in acute myeloid leukemia (AML) and recent clinical trials demonstrate that FLT3-based measurable residual disease (MRD) is both prognostic and predictive, guiding therapeutic interventions in intensive and post-transplant settings. Conventional detection methods lack the sensitivity required for effective MRD monitoring. We developed a patient-specific droplet digital PCR (ddPCR) approach achieving analytical sensitivity of 10−5 (0.001%) for FLT3-ITD quantification. In our cohort, ddPCR enabled longitudinal monitoring of clonal dynamics, allowing the detection of re-emerging FLT3-ITD clones months before hematologic relapse and earlier than standard capillary electrophoresis. Notably, 25% of patients who relapsed as FLT3-ITD positive despite being classified as FLT3-negative at diagnosis harbored detectable microclones when retrospectively analyzed by ddPCR, suggesting that FLT3-ITD-positive relapse frequently originates from pre-existing subclones below conventional detection thresholds. These findings challenge current diagnostic classification and may influence risk stratification and treatment decisions, particularly regarding FLT3 inhibitor eligibility. While ddPCR is limited to tracking known dominant clones, it represents a practical, cost-effective solution for high-sensitivity MRD surveillance. In the era of targeted FLT3 therapies, integrating sensitive molecular monitoring into routine AML management may enable timely therapeutic adjustments and improve patient outcomes.

Restoring apoptosis in malignant cells represents a central goal of anticancer therapy. Tumour cells often escape cell death by overexpressing anti‐apoptotic members of the BCL‐2 protein family, particularly BCL‐2, BCL‐xL, and MCL1. These proteins inhibit the intrinsic mitochondrial apoptotic pathway through intricate interactions with pro‐apoptotic partners and direct modulation of the mitochondrial outer membrane. Their pivotal role in cell survival has established them as attractive therapeutic targets. Over the past two decades, significant efforts have been devoted to developing selective small‐molecule inhibitors capable of neutralising these proteins and reactivating apoptosis. A first milestone was the discovery of ABT‐263 (navitoclax), a dual BCL‐2/BCL‐xL inhibitor. Building on this achievement, the development of venetoclax, a highly selective BCL‐2 inhibitor, marked a major breakthrough, demonstrating potent pro‐apoptotic activity and clinical efficacy in several leukaemia subtypes. Despite these advances, the design of inhibitors of BCL‐2 family members remains challenging, largely due to the structural characteristics of the BH3‐binding groove, which is both shallow and hydrophobic, complicating the identification of molecules with optimal binding affinity and selectivity. PROTACs targeting BCL‐xL may represent a promising future strategy, potentially overcoming the intrinsic limitations of small molecule inhibitors.

Background/Objectives: Treatment with tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) has revolutionized disease management and has transformed CML from a life-threatening disease to a chronic condition for many patients. However, overcoming resistance, particularly related to leukemic stem cells (LSC) that can persist even when the bulk of the leukemic cells are eliminated, remains a significant challenge. Methods: K562 and KU812 cell lines were treated in vitro with the TKI Imatinib (IM). Gene expression, protein analysis, and metabolomic screening were conducted to investigate the ability of the drug to enhance stem cell (SC) features. Moreover, a gene ontology analysis was performed on different available datasets, to further consolidate our data. Results: 48 h of IM treatment can significantly increase the expression of genes related to SC self-renewal, particularly SOX2 and OCT 3/4. Interestingly, these modulations occur in cells that remain alive after drug treatment and that displayed features consistent with leukemia stem-like CML cells, suggesting that SC genes levels are crucial even in cell population survived upon TKI treatment. Moreover, after in silico analysis of available data, we observed an enrichment of SOX2/NANOG and OCT 3/4 signatures after TKI treatment, thus strengthening our results. Conclusions: Our results confirmed the relevance of LSC features after TKI treatment, highlighting the need for more effective and potentially curative strategies targeting LSCs to overcome resistance in CML.

The physical implementation of quantum information processing relies on individual modules—qubits—and operations that modify such modules either individually or in groups—quantum gates. Two examples of gates that entangle pairs of qubits are the controlled NOT-gate (CNOT) gate, which flips the state of one qubit depending on the state of another, and the gate that brings a two-qubit product state into a superposition involving partially swapping the qubit states. Here we show that through supramolecular chemistry a single simple module, molecular {Cr 7 Ni} rings, which act as the qubits, can be assembled into structures suitable for either the CNOT or gate by choice of linker, and we characterize these structures by electron spin resonance spectroscopy. We introduce two schemes for implementing such gates with these supramolecular assemblies and perform detailed simulations, based on the measured parameters including decoherence, to demonstrate how the gates would operate. The physical implementation of quantum information processing requires individual qubits and entangling gates. Here, the authors demonstrate a modular implementation through chemistry, assembling molecular {Cr 7 Ni} rings acting as qubits, with supramolecular structures realizing gates by choice of the linker.

Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit 1 , 2 . Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic fasting or a fasting-mimicking diet 3 – 5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT–mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both fasting and a fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer. In mice, periodic fasting or a fasting-mimicking diet enhances the efficacy of endocrine therapy for breast cancer and delays acquired resistance to it; in patients with breast cancer, a fasting-mimicking diet recreates the metabolic changes observed in mice.

Macrophages are crucial drivers of innate immunity. Reprogramming macrophages to a restorative phenotype in cancer or autoimmune diseases can stop their cancer‐promoting activity or trigger anti‐inflammatory immunity. Glycans have emerged as key components for immunity as they are involved in many pathophysiological disorders. Previous studies have demonstrated that supraphysiological amounts of mannose (Man) or sialic acid (Sia) can inhibit tumor growth and stimulate differentiation of regulatory T cells. Man is known to affect glucose metabolism in glycolysis by competing for the same intracellular transporters and affecting macrophage polarization, whereas Sia alters macrophage differentiation via signaling through Siglec‐1. Herein, this work describes a macrophage targeting platform using gold nanoparticles (GNPs) functionalized with Man and Sia monosaccharides which exhibit high liver tropism. A single dose of glyco‐GNPs can convert macrophages to a restorative phenotype in two completely different immune environments. Man promotes tumor‐associated macrophages toward an antitumorigenic activity in a MC38 liver colorectal cancer model by secretion of TNF‐α, IL ‐1β, and IL ‐6 in the tumor microenvironment. However, in a proinflammatory environment, as observed in a mouse model of autoimmune disease, primary biliary cholangitis, Man impairs the production of TNF‐α, IL‐1β, Arg1, and IL‐6 cytokines. The results probe the dual role of Man in macrophage repolarization in response to the immune system. This study is a proof‐of‐concept that demonstrates that nanomedicine using specific glycans designed to target other immune cells such as myeloid cells, are a promising strategy not only against cancer but also against other pathologies such as autoimmune diseases. Macrophages play a critical role in several pathophysiological diseases by being involved in the activation of adaptive and innate immune responses. The repolarization of macrophages using gold nanoparticles functionalized with glycans for a more selective targeting toward a restorative phenotype leads to an amelioration of the events. These findings provide important insights for exploiting glycans to treat autoimmune disorders or cancer.

•Regional disparities in food safety and security were assessed in a cross-sectional study.•The South and Islands of Italy exhibited lower food safety knowledge and behaviors.•Participants in the Center had over twice the odds of high food security vs very low.•Multinomial logistic regression identified key sociodemographic determinants.•Findings inform targeted policies to improve food safety and security in Italy. This study examined regional disparities in food security and food safety knowledge and behavior among Italian adults. Between January and June 2024, we conducted a cross-sectional anonymous online survey targeting Italian residents aged ≥18. The sample size was calculated a priori assuming a 50% prevalence, 95% confidence, and 3% margin of error, yielding a target of 1067 participants. Validated Italian versions of the Food Security Survey Module (It-FSSM) and the Food Safety Knowledge and Behavior Questionnaire (It-FSKB) were employed to assess participants’ knowledge and behaviors. Sociodemographic data, including age, sex, body mass index (BMI), educational level, physical activity, smoking habits, and food apps usage, were collected. Multinomial logistic regression—adjusted for age, sex, BMI, and educational level—was used to evaluate regional differences. Among 1752 participants (70.4% women; mean age: 36.01 ± 13.84 y), those in the South area and Islands were significantly less likely to report high food safety knowledge (relative risk ratio [RRR] = 0.66; 95% confidence interval [CI]: 0.54–0.82; P = 0.000) and high food safety behaviors (RRR = 0.64; 95% CI: 0.52–0.79; P < 0.001), and more likely to experience moderate food insecurity (RRR = 1.64; 95% CI: 1.00–2.69; P = 0.048) compared to participants to the North. Participants in the Center were over twice likely than those in the North to report high food security versus very low (RRR = 2.72; 95% CI: 1.15–6.43; P = 0.023) and were also 30% less likely to use food delivery apps rarely rather than not at all (RRR = 0.70; 95% CI: 0.50–0.97; P = 0.034). This study highlights significant regional disparities, with the South area and Islands facing the greatest challenges. These findings provide evidence to guide targeted public health interventions and policies promoting food safety and security across Italy.