Heritable Genetic Variability in Ovarian Tumours: Exploring Venous Thromboembolism Susceptibility and Cancer Prognosis in a Hospital-Based StudyTavares, Savva-Bordalo, Rei
et alGene (2025) 950, 149378
Abstract: Venous thromboembolism (VTE) is a frequently encountered paraneoplastic syndrome in patients with ovarian cancer (OC), an inflamm-aging entity. VTE is known to exacerbate their already poor prognosis, which is partially attributed to the contribution of the haemostatic system to ovarian tumourigenesis. In the past decade, numerous single-nucleotide polymorphisms (SNPs) implicated in VTE pathways have been proposed to influence tumour susceptibility and progression. These SNPs represent potential tools to improve the prognosis accuracy of OC patients. Hence, this study explored the influence of 12 haemostasis-associated SNPs on the risk for VTE, risk of OC progression and related death among 98 OC patients. The findings revealed a 20.5 % incidence of VTE, which was associated with more rapid disease progression and shorter survival times (log-rank test, p < 0.05). PROCR rs10747514 (AA/AG vs. GG; odds ratio (OR) = 3.67, p = 0.037) and SERPINE1 rs2070682 (CC/CT vs. TT; OR = 9.28, p = 0.040) were predictors of OC-related VTE development. Regarding patients' prognosis regardless of venous thrombogenesis, RGS7 rs2502448, F3 rs1361600, FGG rs2066865, and SERPINE1 rs2070682 were the most relevant biomarkers in different patient groups. These genetic variants might constitute attractive prognostic indicators among OC patients, offering insights to refine disease management strategies. However, due to the small cohort size and the study's retrospective nature, external validation is necessary to assess the generalisation of the findings.Copyright © 2025 Elsevier B.V. All rights reserved.
Identification of mouse and human embryonic pancreatic cells with adult Procr+ progenitor transcriptomic and epigenomic characteristicsHeidenreich, Bacigalupo, Rossotti
et alFront Endocrinol (Lausanne) (2025) 16, 1543960
Abstract: The quest to find a progenitor cell in the adult pancreas has driven research in the field for decades. Many potential progenitor cell sources have been reported, but so far this is a matter of debate mainly due to reproducibility issues. The existence of adult Procr+ progenitor cells in mice islets has been recently reported. These were shown to comprise ~1% of islet cells, lack expression of Neurog3 and endocrine hormones, and to be capable of differentiating into all endocrine cell types. However, these findings had limited impact, as further evidence supporting the existence and function of Procr+ progenitors has not emerged.We report here an unbiased comparison across mouse and human pancreatic samples, including adult islets and embryonic tissue, to track the existence of Procr+ progenitors originally described based on their global gene expression signature. We could not find Procr+ progenitors on other mouse or human adult pancreatic islet samples. Unexpectedly, our results revealed a transcriptionally close mesothelial cell population in the mouse and human embryonic pancreas. These Procr-like mesothelial cells of the embryonic pancreas share the salient transcriptional and epigenomic features of previously reported Procr+ progenitors found in adult pancreatic islets. Notably, we report here that Procr-like transcriptional signature is gradually established in mesothelial cells during mouse pancreas development from E12.5 to E17.5, which has its largest amount. Further supporting a developmentally relevant role in the human pancreas, we additionally report that a transcriptionally similar population is spontaneously differentiated from human pluripotent stem cells cultured in vitro along the pancreatic lineage.Our results show that, although the previously reported Procr+ progenitor cell population could not be found in other adult pancreatic islet samples, a mesothelial cell population with a closely related transcriptional signature is present in both the mouse and human embryonic pancreas. Several lines of evidence presented in this work support a developmentally relevant function for these Procr-like mesothelial cells.Copyright © 2025 Heidenreich, Bacigalupo, Rossotti and Rodríguez-Seguí.
Recombinant factor VIIa: new insights into the mechanism of action through product innovationEscobar, Hoffman, Castaman
et alRes Pract Thromb Haemost (2025) 9 (1), 102670
Abstract: Management of bleeding in persons with hemophilia and inhibitors involves treatment with bypassing agents, including recombinant activated factor VII (rFVIIa). Two rFVIIa products are commercially approved for use in the United States and the European Union. Eptacog alfa and eptacog beta share the same amino acid sequence but differ in posttranslational modifications. Although rFVIIa has been used to manage bleeding in persons with hemophilia and inhibitors for over 30 years, its mechanisms of action is still being studied. In vitro and in vivo studies have suggested that rFVIIa could promote hemostasis by (1) increasing tissue factor-dependent activation of factor (F)X (FX); (2) directly activating FX on the surface of activated platelets; and (3) downregulating protein C anticoagulant activity through binding to the endothelial protein C receptor (EPCR). Studies of rFVIIa and rFVIIa variants in murine models demonstrate that platelet-dependent activity is sufficient for hemostatic efficacy. Dosing levels required in clinical practice are most consistent with a platelet-dependent mechanism of action. However, in vivo models also suggest that pathways involving EPCR binding contribute to rFVIIa hemostatic activity. Eptacog beta displays increased platelet- and EPCR-dependent endothelial cell binding compared to eptacog alfa. Thus, the relative contribution of these mechanisms to the overall hemostatic efficacy of eptacog alfa and eptacog beta may differ. Further research is required to assess the clinical relevance of these differences. A better understanding of the mechanisms by which rFVIIa promotes hemostasis in patients will provide insights when evaluating clinical outcomes of safety and efficacy for innovative bypassing therapies.© 2025 The Authors.
Tissue factor-dependent colitogenic CD4+ T cell thrombogenicity is regulated by activated protein C signallingLeon, Klavina, Rehill
et alNat Commun (2025) 16 (1), 1677
Abstract: Patients with inflammatory bowel disease (IBD) have an increased risk of venous thromboembolism (VTE), but the underlying mechanistic basis remains poorly defined. Here, we find that colitogenic CD4+ T cells express tissue factor (TF) and promote rapid TF-dependent plasma thrombin generation. TF+CD3+CD4+ T cells are present in both the colons of mice with experimental colitis and blood and colonic tissue from patients with IBD. Expression of genes involved in regulating coagulation, including Protein C (PC; encoded by PROC) and its receptor (PROCR), are dysregulated in IBD patient gut biopsy tissues. Moreover, activated PC signalling reduces the procoagulant activity mediated by TF+CD4+ T cells. Our data thus identify TF-induced, colitogenic T cell-mediated thrombogenicity, and also demonstrate a new function for activated PC signalling in regulating T cell thrombo-inflammatory activity.© 2025. The Author(s).
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