Esther Roselló-Sastre

Background/Objectives: Homologous recombination deficiency (HRD) is a predictive biomarker in high-grade serous ovarian carcinoma for platinum-based chemotherapy and PARP inhibitors. The implementation of HRD testing in routine diagnostics has generated multiple commercial assays that differ in genomic targets, bioinformatic analysis, and HRD scoring strategies. We aimed to assess the analytical performance and feasibility of a locally semi-automated workflow based on the Agilent SureSelect CD HRR17 panel with SeqOne/SomaHRD analysis, and to compare it with established commercial HRD assays currently used in routine clinical practice: Myriad MyChoice CDx and SOPHiA DDM Dx HRD Solution. Methods: Thirty high-grade serous ovarian carcinoma cases diagnosed between 2019 and 2023 were retrospectively analyzed. HRD status was assessed with the Agilent-SeqOne workflow and compared with Myriad (n = 12) and SOPHiA (n = 18). Concordance and correlation between genomic instability metrics were evaluated. Results: The Agilent/SeqOne workflow showed high concordance with both comparison workflows. Genomic instability metrics strongly correlated across assays (R² up to 0.96). A lower proportion of inconclusive classifications was observed with the Agilent/SeqOne workflow. Discordances were mainly observed in borderline cases near classification thresholds. Variant detection was highly concordant within shared genomic regions. Conclusions: The locally semi-automated HRD workflow demonstrated high analytical concordance with established commercial assays in evaluable cases. Operational advantages related to workflow flexibility and local reanalysis support its potential implementation in routine molecular diagnostics.

The current WHO grading of central nervous system tumors relies exclusively on histopathological criteria for diagnosing lower-grade, IDH-mutant astrocytomas (LGIMAs), overlooking genetic features. The TP53 R273C mutation, frequently observed in brain tumors, may influence LGIMA biology and aggressiveness. We analyzed 14 TP53-mutant LGIMAs using NGS. Five tumors (33.3%) carried the R273C mutation; these were mostly of grade 2 and all from female patients. Ki-67 levels in R273C-mutant tumors were higher compared with those in other TP53-mutant grade 2 tumors but lower than those in grade 3 tumors, which may suggest that R273C defines a more aggressive grade 2 profile. This mutation was linked to loss of the wild-type allele, supporting a loss-of-function mechanism. Its frequency was found to be potentially higher in women, and this sex-based difference reached statistical significance when incorporating TCGA LGIMA data. Overall, the R273C mutation, although mechanistically unclear, is more prevalent than other TP53 variants and defines a distinct biological subset of LGIMAs, marked by increased Ki-67 and female predominance. Incorporating TP53 and broader genetic profiling via NGS could improve our understanding of LGIMAs and support a refined classification system, enhancing diagnostic and prognostic accuracy.

Glioblastoma IDH wild type (GB), the most common malignant primary brain tumor, is characterized by rapid proliferation, extensive infiltration into surrounding brain tissue, and significant resistance to current therapies. Median survival is only 15 months despite extensive clinical efforts. The tumor microenvironment (TME) in GB is highly specialized, supporting the tumor’s aggressive behavior and its ability to evade conventional treatments. One critical component is the aberrant vascular network that complicates the delivery of chemotherapy across the blood–brain barrier. Antiangiogenic therapies emerged as a promising option but have shown limited efficacy in extending the survival of these patients. Comprehension of the complex vascular network of GB may be a key to overcoming the limitations of current therapies. Pericytes are gaining recognition within the context of the TME. These mural cells are essential for vascular integrity and may contribute to tumor progression and therapeutic resistance. Although their role has been evidenced in other tumors, they remain underexplored in GB. Pericytes are known to respond to tumor hypoxia and interact with vascular endothelia, influencing responses to DNA damage and antiangiogenic treatments. They actively regulate not only angiogenesis but also the different vasculogenic strategies for tumor neovascularization. Additionally, they affect leukocyte trafficking and tumor-associated macrophages. This review aims to integrate the various functions controlled by pericytes to favor deeper investigation into their actionable potential. Pericytes may represent a promising target for novel therapeutic strategies in order to improve patient outcomes.

Although atherosclerosis preferentially develops at arterial curvatures and bifurcations where disturbed flow (DF) activates endothelium, therapies targeting flow-dependent mechanosensing pathways in the vasculature are unavailable. Here, we provided experimental evidence demonstrating a previously unidentified causal role of DF-induced endothelial TXNDC5 (thioredoxin domain containing 5) in atherosclerosis. TXNDC5 was increased in human and mouse atherosclerotic lesions and induced in endothelium subjected to DF. Endothelium-specific Txndc5 deletion markedly reduced atherosclerosis in ApoE ^−/− mice. Mechanistically, DF-induced TXNDC5 increases proteasome-mediated degradation of heat shock factor 1, leading to reduced heat shock protein 90 and accelerated eNOS (endothelial nitric oxide synthase) protein degradation. Moreover, nanoparticles formulated to deliver Txndc5 -targeting CRISPR-Cas9 plasmids driven by an endothelium-specific promoter ( CDH5 ) significantly increase eNOS protein and reduce atherosclerosis in ApoE ^−/− mice. These results delineate a new molecular paradigm that DF-induced endothelial TXNDC5 promotes atherosclerosis and establish a proof of concept of targeting endothelial mechanosensitive pathways in vivo against atherosclerosis.