BURA Collection:

Phosphatidylinositol‐4,5‐bisphosphate 3‐kinase (PI3K) inhibitors reduce vascular inflammation in vitro and in vivo

Mon, 18 Aug 2025 00:00:00 GMT

Title: Phosphatidylinositol‐4,5‐bisphosphate 3‐kinase (PI3K) inhibitors reduce vascular inflammation in vitro and in vivo Authors: Chaudhry, H; Zarban, AA; Trevelin, SC; Kodji, X; Cerutti, C; Xiong, X; Argunhan, F; Shah, AM; Ridley, AJ; Brain, SD Abstract: Background and Purpose: Endothelial cells play central roles in increasing vascular permeability and leukocyte recruitment. Therapeutic approaches for treating endothelial cell barrier dysfunction to reduce unwanted fluid accumulation in tissues are limited. Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) enzymes are implicated in signalling inflammatory endothelial permeability and leukocyte recruitment. We investigated the ability of PI3K inhibitors to influence cutaneous oedema formation and neutrophil accumulation. Experimental Approach: We used cultured endothelial cells to determine the effects of inflammatory mediators on permeability and vascular leakage, and a murine model of vascular inflammation in mouse skin in vivo. The effects of inflammatory mediators that induce vascular leakage and neutrophil accumulation (TNFα, IL-1β and C5a) were examined, with the neuropeptides substance P and α-CGRP used as controls. The ability of PI3K inhibitors to modulate inflammatory responses was studied. Key Results: A broad spectrum PI3K inhibitor (PI-103) and a selective inhibitor of the class 1A p110α catalytic subunit (BYL-719/alpelisib) inhibited endothelial morphological changes and permeability induced by TNFα and IL-1β in vitro. In vivo>/i>, oedema and neutrophil accumulation induced by TNFα and IL-1β, but not by the complement fragment C5a, is inhibited by BYL-719, whereas PI-103 blocks effects of all three mediators. Neither influences the acute oedema formation induced by neuropeptides. Conclusions and Implications: Selective p110α inhibition of vascular inflammation may provide a novel therapeutic pathway for limiting adverse tissue swelling. Moreover, the limited effect of BYL-719 on C5a-mediated responses implies that this innate component of the immune response will continue to provide essential defence activity during p110α blockade. Description: Data Availability Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request. Some data may not be made available because of privacy or ethical restrictions.; Supporting Information is available online at: https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.70152#support-information-section .

Deciphering the Role of Cancer Stem Cells in Breast Cancer Brain Colonization Using a Novel Patient‐Derived Model

Fri, 27 Mar 2026 00:00:00 GMT
Title: Deciphering the Role of Cancer Stem Cells in Breast Cancer Brain Colonization Using a Novel Patient‐Derived Model Authors: Faletti, S; Richichi, C; Osti, D; Ceccacci, E; Bertalot, G; Cerutti, C; Giardina, G; Marinaro, A; Costanza, B; Gambino, V; Zaccheroni, E; Tosoni, D; Filippone, MG; Del Corvo, M; Zhan, Y; Gravina, T; Corà, D; Patanè, M; Pollo, B; Giovanna Jodice, M; Pece, S; Weksler, BB; Romero, IA; Couraud, P; Munzone, E; Del Bene, M; DiMeco, F; Pelicci, G Abstract: Brain metastases from breast cancer (BCBM) are fatal and lack effective treatments. Their cellular and molecular drivers remain poorly understood, partly due to limited preclinical models that fail to capture patient tumor heterogeneity. Cancer stem-like cells (CSCs) are implicated in metastatic dissemination; however, their specific role in brain metastasis remains unclear. In this study, CSCs are isolated from human BCBM specimens and characterized for stem-like properties, including CD44 and ALDH1 expression, sphere formation, tumorigenicity, and in vitro and in vivo self-renewal. Intra-nipple and intra-cardiac xenograft models demonstrate CSC ability to generate brain and bone metastases that recapitulate patient-specific dissemination patterns. Transcriptomic and functional analyses reveal cellular heterogeneity and identify a metastasis-initiating cell (MIC) subpopulation enriched in stemness and adhesion-related pathways. These MICs exhibit enhanced adhesion to brain endothelium and undergo brain-specific transcriptomic reprogramming that enables vascular co-option, resistance to stromal stress, and survival-promoting interactions with brain-resident cells. High-throughput drug screening indicates broad therapeutic resistance within the CSC compartment. Through the comprehensive characterization of BCBM-derived CSCs, this study establishes a clinically relevant model that identifies CSCs and the MIC subpopulation as key drivers of brain metastatic progression and as promising targets for the development of effective therapeutic strategies. Description: Data Availability Statement: Access to the NGS data by qualified researchers who wish to work with these data or validate our findings can be requested by contacting giuliana.pelicci@ieo.it .; Supporting Information is available online at: https://advanced.onlinelibrary.wiley.com/doi/10.1002/adhm.202505789#support-information-section .

Sport Management and Sustainability: An Impossible Theorem?

Thu, 18 Jun 2026 00:00:00 GMT
Title: Sport Management and Sustainability: An Impossible Theorem? Authors: Girginov, V Abstract: This conceptual paper extends the debate about sustainability and sport management by transcending the dominant natural environmental perspective and offering a systems approach. Addresses the question, ‘Is sustainability in sport management possible?’ The nature of sustainability in sport management is discussed in the context of the tensions between the current growth model of sport, sport management research and teaching, and the sustainability imperative. Sustainability in sport management is concerned with a composite problem, and its goal is to understand and shape the interactions between complex adaptive natural systems and sport organizations as soft socio-economic entities at individual, organizational, and societal levels. A key feature that distinguishes sustainability in sport management from its current mainstream understanding and practices based on the ideology of growth ought to be its explicit prioritization of all types of sport participants as citizens, as opposed to treating them as consumers. At present, sustainability in sport management remains an impossibility.

Somatic mutation profiles in aged military nuclear test veterans: A comparative whole-genome sequence study

Tue, 30 Jun 2026 00:00:00 GMT
Title: Somatic mutation profiles in aged military nuclear test veterans: A comparative whole-genome sequence study Authors: Ofuso-Dankwa, J; Sisu, C; Anderson, R Abstract: Veterans of the British nuclear testing programme represent an aged group of ex-military personnel who may have been exposed to ionising radiation through their participation at nuclear testing sites. This study aimed to compare the somatic mutational landscape of a cohort of 30 nuclear test veterans with that of an age-matched cohort of 30 control veterans. Variants were identified from publicly available whole-genome sequencing data using a bioinformatics pipeline developed in accordance with the gold standard approaches as defined by the Broad Institute. The resulting set of raw SNV and INDEL variants for each individual veteran were subjected to several filtering steps to reduce the noise arising from common mutations, before the average number and types were compared for each cohort using the Grubbs test. The genomic distribution of these variants was also examined by assessing for any mutation clustering considered characteristic of radiation exposure (SNVs and/or INDELs occurring within 10 bp) using a 10 bp running window and separately, the identification of mutational signatures by fitting SNVs to the COSMIC database Human Cancer v3.4. When comparing the nuclear test veteran and control cohorts, we found no statistically elevated frequency of any variant type or clusters. The dominant SBS signatures in both cohorts were those typically associated with ageing. A qualitative assessment of the functional impact of the most prevalently observed variants in each cohort showed these to also be associated with age. For example, in the control cohort, variants were found in LINC02098-ETS1 and RCL1, genes linked to classic age-related conditions such as hair loss and osteoarthritis. In the nuclear test veteran cohort, we observed multiple variants affecting the CHODL gene in approximately 40% of participants. CHODL encodes chondrolectin, a protein important for maintaining the structural integrity and function of tissues. In conclusion, the absence of significant genetic differences between cohorts, together with the prevalence of age-associated mutations, is consistent with ageing being one of the primary drivers of the observed somatic variation in these veterans, overshadowing any potential environmental, including historical radiation, effects. Description: Data Availability: All relevant data are within the paper and its Supporting Information files (https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0351624#sec018).; Acknowledgments: We thank all veterans for their participation in the wider GCFT study from which data was used in this study.