Mritunjoy Dey, Piotr Remiszewski, Ewelina Perdas, Paweł Golik, Jakub Piątkowski, Anna M. Czarnecka
Sarcomas are rare, heterogeneous malignancies of mesenchymal origin whose diagnosis and molecular classification remain challenging. We introduced a oneclass anomaly detection framework to microRNA expression profiles to test whether sarcoma-associated miRNA features are distinguishable from those of epithelial, haematological, and neurological cancers and if these features carry any biological relevance. Candidate miRNAs meeting cross-lineage significance criteria were further evaluated through differential expression analysis against subtype-matched normal mesenchymal reference tissue, pathway enrichment, and survival analysis. A five-miRNA index (“Index 5”), derived by Fisher’s linear discriminant analysis with leave-one-out cross-validation in a TCGA-SARC training cohort, was applied without refitting to an independent external cohort (GSE36982). The five-miRNA index (”Index 5”) achieved an AUC of 0.93 and, applied without refitting to an independent external cohort (GSE36982), an AUC of 0.97. After Benjamini–Hochberg correction, one candidate miRNA (miR-1305) remained significantly associated with overall survival. These findings identify a computationally derived, externally tested candidate miRNA signature associated with sarcoma. While this study lacks experimental and clinical validation, the broader aim of this study was to come up with a framework that would assist and speedup the exploratory candidate biomarker discovery process in rare malignancies.
We investigate the economic impact of controlling the pace of aging through biomarker monitoring and targeted interventions. Using the DunedinPACE epigenetic clock as a measure of biological aging rate, we model how different intervention scenarios affect frailty trajectories and their subsequent influence on healthcare costs, lifespan, and health quality. Our model demonstrates that controlling DunedinPACE from age 50 onward can reduce frailty prevalence, resulting in cumulative healthcare savings of up to CHF 131,608 per person over 40 years in our most optimistic scenario. From an individual perspective, the willingness to pay for such interventions reaches CHF 3.2 million in the most optimistic scenario when accounting for both extended lifespan and improved health quality. When the direct cost of epigenetic testing is included, the healthcare-system case is sensitive to test price and testing frequency, whereas the individual-value case remains strongly positive. These findings suggest substantial economic value in technologies that can monitor and modify biological aging rates, providing evidence for both healthcare systems and consumer-focused business models in longevity medicine.
Lucia Argenziano, Maria Maddalena Marrapodi, Giuseppe Di Feo, Oriana Di Domenico, Francesca Rossi, Alessandra Di Paola
Pediatric immune thrombocytopenia (ITP) is an acquired autoimmune disorder, caused by the production of autoantibodies against platelets which leads to thrombocytopenia. It is characterized by profound alterations in both inflammatory and immune profiles. In this context, the role of microRNAs (miRNAs) as post-transcriptional regulators of immunity and the function of extracellular vesicles (EVs) as key mediators of intercellular communication are two fundamental aspects for understanding ITP pathophysiology. In ITP, altered miRNA expression disrupts immune tolerance, lymphocyte subtype differentiation and platelet production. miRNAs are incorporated into EVs and transferred to recipient cells, which confers greater stability to the miRNAs. To date, the interaction between miRNAs and EVs in pediatric ITP has been relatively understudied. In this review, we examine the landscape of dysregulated miRNAs in ITP, focusing in particular on their role in immune dysregulation and on the contribution of EVs as carriers of pathogenic miRNAs. The relationship between EVs and miRNAs could facilitate the development of non-invasive diagnostic tools and EV-based therapeutic strategies designed to reestablish immune homeostasis in pediatric ITP.
Phytic acid (PA) is the major phosphorus-storage compound in maize kernels, but its strong mineral-chelating capacity limits the bioavailability of essential nutrients in humans and monogastric animals. Although classical low-phytic-acid mutants have demonstrated the feasibility of phytate reduction, their use in breeding has been constrained by pleiotropic effects on seed viability, germination, and agronomic performance. Therefore, identifying natural allelic variation for kernel PA content in elite nutritional backgrounds such as Quality Protein Maize (QPM) is important for biofortification breeding. To our knowledge, no genome-wide association study has yet been reported for kernel PA content in maize. Here, we evaluated 249 QPM inbred lines across two environments and conducted genome-wide association analysis using sequencing-derived SNP markers. Kernel PA content showed substantial phenotypic variation, highly significant genotypic effects, and high broad-sense heritability in both environments, indicating strong genetic control. Of 11,525,180 variants initially called, 115,416 chromosomal biallelic SNPs passed initial filtering, and 26,074 high-quality SNPs were retained for population structure, linkage disequilibrium, and association analyses. Multi-model GWAS identified five high-confidence marker-trait associations on chromosomes 1, 3, 4, and 7. The strongest locus, chr3:236714544, was consistently detected across environments and analytical models and explained up to 17.7% of phenotypic variation. Allelic effect analysis confirmed significant differences among genotype classes at all five loci, with the clearest differentiation observed at chr3:236714544. LD-based haplotype analysis identified a three-SNP chromosome four haplotype block associated with kernel PA variation, with Hap2/GAC showing lower PA content. Integrated candidate-gene analysis prioritized seven putative candidate genes involved in transcriptional regulation, phosphate transport, phosphorylation-dependent signaling, seed development, and lipid/protein storage-related processes. Zm00001eb163880 emerged as the strongest candidate gene at the major chr3:236714544 locus, supported by a predicted missense variant and strong seed-related expression. Together, these results identify robust genomic loci, favorable allelic variation, and prioritized candidate genes for kernel PA content, providing a foundation for marker-assisted selection and future validation toward developing QPM maize with reduced anti-nutritional burden and improved mineral bioavailability.
Alice Scarpa, Diego Ferrarese, Samantha Guidotti, Veronica Scaglia, Angela Rossi
Hybrid-capture next-generation sequencing HLA workflows are increasingly used in clinical histocompatibility laboratories for high-resolution HLA typing. Compared with amplicon-based approaches, they may provide broader coverage of HLA genes, improved ambiguity resolution and the possibility of including additional targets; however, their greater analytical, bioinformatic and interpretative complexity requires a clear definition of intended use, reportable scope and required validation level. A practical and modular framework was developed for the verification and validation of hybrid-capture next-generation sequencing HLA workflows, applicable to IVDR-regulated methods used according to the manufacturer’s instructions for use, locally adapted IVDR workflows, research-use-only workflows converted to clinical use, laboratory-developed or laboratory-adapted workflows and outputs not fully covered by manufacturer claims. Core modules required for clinical HLA typing are distinguished from additional modules activated by specific claims or local adaptations, including analytical performance, bioinformatic validation, risk management and reporting governance. It provides an operational pathway to document fitness for intended use and to distinguish clinically reportable results from technically available outputs not validated for diagnostic use. A dataset generated under routine conditions using a commercial full-length HLA capture-based workflow is used as a practical implementation example. A modular structure integrating analytical performance, bioinformatic control, risk-based thinking, reporting governance and continuous monitoring is provided by this framework in clinical immunogenetics and histocompatibility laboratories.
