Background:Lurbinectedin is a novel anticancer agent currently undergoing late-stage (Phase II /III) clinical evaluation in platinum-resistant ovarian, BRCA1/2-mutated breast and small-cell lung cancer. Lurbinectedin is structurally related to trabectedin and it inhibits active transcription and the DNA repair machinery in tumour cells.Methods:In this study we investigated whether lurbinectedin has the ability to modulate the inflammatory microenvironment and the viability of myeloid cells in tumour-bearing mice.Results:Administration of lurbinectedin significantly and selectively decreased the number of circulating monocytes and, in tumour tissues, that of macrophages and vessels. Similar findings were observed when a lurbinectedin-resistant tumour variant was used, indicating a direct effect of lurbinectedin on the tumour microenviroment. In vitro, lurbinectedin induced caspase-8-dependent apoptosis of human purified monocytes, whereas at low doses it significantly inhibited the production of inflammatory/growth factors (CCL2, CXCL8 and VEGF) and dramatically impaired monocyte adhesion and migration ability. These findings were supported by the strong inhibition of genes of the Rho-GTPase family in lurbinectedin-treated monocytes.Conclusions:The results illustrate that lurbinectedin affects at multiple levels the inflammatory microenvironment by acting on the viability and functional activity of mononuclear phagocytes. These peculiar effects, combined with its intrinsic activity against cancer cells, make lurbinectedin a compound of particular interest in oncology.
Aberrant microRNA (miR) expression has an important role in tumour progression, but its involvement in bone marrow fibroblasts of multiple myeloma patients remains undefined. We demonstrate that a specific miR profile in bone marrow fibroblasts parallels the transition from monoclonal gammopathy of undetermined significance (MGUS) to myeloma. Overexpression of miR‐27b‐3p and miR‐214‐3p triggers proliferation and apoptosis resistance in myeloma fibroblasts via the FBXW7 and PTEN/AKT/GSK3 pathways, respectively. Transient transfection of miR‐27b‐3p and miR‐214‐3p inhibitors demonstrates a cooperation between these two miRNAs in the expression of the anti‐apoptotic factor MCL1, suggesting that miR‐27b‐3p and miR‐214‐3p negatively regulate myeloma fibroblast apoptosis. Furthermore, myeloma cells modulate miR‐27b‐3p and miR‐214‐3p expression in fibroblasts through the release of exosomes. Indeed, tumour cell‐derived exosomes induce an overexpression of both miRNAs in MGUS fibroblasts not through a simple transfer mechanism but by de novo synthesis triggered by the transfer of exosomal WWC2 protein that regulates the Hippo pathway. Increased levels of miR‐27b‐3p and miR‐214‐3p in MGUS fibroblasts co‐cultured with myeloma cell‐derived exosomes enhance the expression of fibroblast activation markers αSMA and FAP. These data show that the MGUS‐to‐myeloma transition entails an aberrant miRNA profile in marrow fibroblasts and highlight a key role of myeloma cells in modifying the bone marrow microenvironment by reprogramming the marrow fibroblasts' behaviour. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Frigerio et al. report that pro-resolving mechanisms of neuroinflammation are dysregulated during epileptogenesis, thereby promoting a persistent neuroinflammatory response that contributes to seizure generation and cognitive deficits. Boosting endogenous resolution responses by administering a specific lipid mediator improves disease outcomes in a murine epilepsy model, suggesting a novel treatment avenue.
Stage I epithelial ovarian cancer (EOC) represents about 10% of all EOCs and is characterized by good prognosis with fewer than 20% of patients relapsing. As it occurs less frequently than advanced-stage EOC, its molecular features have not been thoroughly investigated. We have demonstrated that in stage I EOC can predict patients' outcome. In the present study, we analyzed the expression of long non-coding RNAs (lncRNA) to enable potential definition of a non-coding transcriptional signature with prognostic relevance for stage I EOC. 202 snap-frozen stage I EOC tumor biopsies, 47 of which relapsed, were gathered together from three independent tumor tissue collections and subdivided into a training set ( = 73) and a validation set ( = 129). Median follow up was 9 years. LncRNAs' expression profiles were correlated in univariate and multivariate analysis with overall survival (OS) and progression-free survival (PFS). The expression of -, and was associated in univariate and multivariate analyses with relapse and poor outcome in both training and validation sets ( < 0.001). Using the expression profiles of -, and simultaneously, it was possible to stratify patients into high and low risk. The OS for high- and low-risk individuals are 36 and 123 months, respectively (OR, 15.55; 95% confidence interval, 3.81-63.36). We have identified a non-coding transcriptional signature predictor of survival and biomarker of relapse for stage I EOC. .
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.