Comprehensive strategy for identifying extracellular vesicle surface proteins as biomarkers for chronic kidney disease.

Chronic kidney disease (CKD) poses a significant health burden worldwide. Especially, obesity-induced chronic kidney disease (OCKD) is associated with a lack of accuracy in disease diagnostic methods. The identification of reliable biomarkers for the early diagnosis and monitoring of CKD and OCKD is crucial for improving patient outcomes. Extracellular vesicles (EVs) have emerged as potential biomarkers in the context of CKD. In this review, we focused on the role of EVs as potential biomarkers in CKD and OCKD and developed a comprehensive list of EV membrane proteins that could aid in the diagnosis and monitoring of the disease. To assemble our list, we employed a multi-step strategy. Initially, we conducted a thorough review of the literature on EV protein biomarkers in kidney diseases. Additionally, we explored papers investigating circulating proteins as biomarkers in kidney diseases. To further refine our list, we utilized the EV database Vesiclepedia.org to evaluate the qualifications of each identified protein. Furthermore, we consulted the Human Protein Atlas to assess the localization of these candidates, with a particular focus on membrane proteins. By integrating the information from the reviewed literature, Vesiclepedia.org, and the Human Protein Atlas, we compiled a comprehensive list of potential EV membrane protein biomarkers for CKD and OCKD. Overall, our review underscores the potential of EVs as biomarkers in the field of CKD research, providing a foundation for future studies aimed at improving CKD and OCKD diagnosis and treatment.

Neural and computational underpinnings of biased confidence in human reinforcement learning.

While navigating a fundamentally uncertain world, humans and animals constantly evaluate the probability of their decisions, actions or statements being correct. When explicitly elicited, these confidence estimates typically correlates positively with neural activity in a ventromedial-prefrontal (VMPFC) network and negatively in a dorsolateral and dorsomedial prefrontal network. Here, combining fMRI with a reinforcement-learning paradigm, we leverage the fact that humans are more confident in their choices when seeking gains than avoiding losses to reveal a functional dissociation: whereas the dorsal prefrontal network correlates negatively with a condition-specific confidence signal, the VMPFC network positively encodes task-wide confidence signal incorporating the valence-induced bias. Challenging dominant neuro-computational models, we found that decision-related VMPFC activity better correlates with confidence than with option-values inferred from reinforcement-learning models. Altogether, these results identify the VMPFC as a key node in the neuro-computational architecture that builds global feeling-of-confidence signals from latent decision variables and contextual biases during reinforcement-learning.

Strategies for Strengthening the Resilience of Public Health Systems for Pandemics, Disasters, and Other Emergencies.

OBJECTIVE: The aim of this study was to identify and prioritize strategies for strengthening public health system resilience for pandemics, disasters, and other emergencies using a scorecard approach. METHODS: The United Nations Public Health System Resilience Scorecard (Scorecard) was applied across 5 workshops in Slovenia, Turkey, and the United States of America. The workshops focused on participants reviewing and discussing 23 questions/indicators. A Likert type scale was used for scoring with zero being the lowest and 5 the highest. The workshop scores were analyzed and discussed by participants to prioritize areas of need and develop resilience strategies. Data from all workshops were aggregated, analyzed, and interpreted to develop priorities representative of participating locations. RESULTS: Eight themes emerged representing the need for better integration of public health and disaster management systems. These include: assessing community disease burden; embedding long-term recovery groups in emergency systems; exploring mental health care needs; examining ecosystem risks; evaluating reserve funds; identifying what crisis communication strategies worked well; providing non-medical services; and reviewing resilience of existing facilities, alternate care sites, and institutions. CONCLUSIONS: The Scorecard is an effective tool for establishing baseline resilience and prioritizing actions. The strategies identified reflect areas in most need for investment to improve public health system resilience.

Comprehensive Strategy for Identifying Extracellular Vesicle Surface Proteins as Biomarkers for Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is a liver disorder that has become a global health concern due to its increasing prevalence. There is a need for reliable biomarkers to aid in the diagnosis and prognosis of NAFLD. Extracellular vesicles (EVs) are promising candidates in biomarker discovery, as they carry proteins that reflect the pathophysiological state of the liver. In this review, we developed a list of EV proteins that could be used as diagnostic biomarkers for NAFLD. We employed a multi-step strategy that involved reviewing and comparing various sources of information. Firstly, we reviewed papers that have studied EVs proteins as biomarkers in NAFLD and papers that have studied circulating proteins as biomarkers in NAFLD. To further identify potential candidates, we utilized the EV database Vesiclepedia.org to qualify each protein. Finally, we consulted the Human Protein Atlas to search for candidates' localization, focusing on membrane proteins. By integrating these sources of information, we developed a comprehensive list of potential EVs membrane protein biomarkers that could aid in diagnosing and monitoring NAFLD. In conclusion, our multi-step strategy for identifying EV-based protein biomarkers for NAFLD provides a comprehensive approach that can also be applied to other diseases. The protein candidates identified through this approach could have significant implications for the development of non-invasive diagnostic tests for NAFLD and improve the management and treatment of this prevalent liver disorder.

Newt A1 cell-derived extracellular vesicles promote mammalian nerve growth.

Newts have the extraordinary ability to fully regenerate lost or damaged cardiac, neural and retinal tissues, and even amputated limbs. In contrast, mammals lack these broad regenerative capabilities. While the molecular basis of newts' regenerative ability is the subject of active study, the underlying paracrine signaling factors involved remain largely uncharacterized. Extracellular vesicles (EVs) play an important role in cell-to-cell communication via EV cargo-mediated regulation of gene expression patterns within the recipient cells. Here, we report that newt myogenic precursor (A1) cells secrete EVs (A1EVs) that contain messenger RNAs associated with early embryonic development, neuronal differentiation, and cell survival. Exposure of rat primary superior cervical ganglion (SCG) neurons to A1EVs increased neurite outgrowth, facilitated by increases in mitochondrial respiration. Canonical pathway analysis pinpointed activation of NGF/ERK5 signaling in SCG neurons exposed to A1EV, which was validated experimentally. Thus, newt EVs drive neurite growth and complexity in mammalian primary neurons.

Linking confidence biases to reinforcement-learning processes.

We systematically misjudge our own performance in simple economic tasks. First, we generally overestimate our ability to make correct choices-a bias called overconfidence. Second, we are more confident in our choices when we seek gains than when we try to avoid losses-a bias we refer to as the valence-induced confidence bias. Strikingly, these two biases are also present in reinforcement-learning (RL) contexts, despite the fact that outcomes are provided trial-by-trial and could, in principle, be used to recalibrate confidence judgments online. How confidence biases emerge and are maintained in reinforcement-learning contexts is thus puzzling and still unaccounted for. To explain this paradox, we propose that confidence biases stem from learning biases, and test this hypothesis using data from multiple experiments, where we concomitantly assessed instrumental choices and confidence judgments, during learning and transfer phases. Our results first show that participants' choices in both tasks are best accounted for by a reinforcement-learning model featuring context-dependent learning and confirmatory updating. We then demonstrate that the complex, biased pattern of confidence judgments elicited during both tasks can be explained by an overweighting of the learned value of the chosen option in the computation of confidence judgments. We finally show that, consequently, the individual learning model parameters responsible for the learning biases-confirmatory updating and outcome context-dependency-are predictive of the individual metacognitive biases. We conclude suggesting that the metacognitive biases originate from fundamentally biased learning computations. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Oncostatin M-Enriched Small Extracellular Vesicles Derived from Mesenchymal Stem Cells Prevent Isoproterenol-Induced Fibrosis and Enhance Angiogenesis.

Myocardial fibrosis is a pathological hallmark of cardiac dysfunction. Oncostatin M (OSM) is a pleiotropic cytokine that can promote fibrosis in different organs after sustained exposure. However, OSM released by macrophages during cardiac fibrosis suppresses cardiac fibroblast activation by modulating transforming growth factor beta 1 (TGF-ß1) expression and extracellular matrix deposition. Small extracellular vesicles (SEVs) from mesenchymal stromal cells (MSCs) are being investigated to treat myocardial infarction, using different strategies to bolster their therapeutic ability. Here, we generated TERT-immortalized human MSC cell lines (MSC-T) engineered to overexpress two forms of cleavage-resistant OSM fused to CD81TM (OSM-SEVs), which allows the display of the cytokine at the surface of secreted SEVs. The therapeutic potential of OSM-SEVs was assessed in vitro using human cardiac ventricular fibroblasts (HCF-Vs) activated by TGF-ß1. Compared with control SEVs, OSM-loaded SEVs reduced proliferation in HCF-V and blunted telo-collagen expression. When injected intraperitoneally into mice treated with isoproterenol, OSM-loaded SEVs reduced fibrosis, prevented cardiac hypertrophy, and increased angiogenesis. Overall, we demonstrate that the enrichment of functional OSM on the surface of MSC-T-SEVs increases their potency in terms of anti-fibrotic and pro-angiogenic properties, which opens new perspectives for this novel biological product in cell-free-based therapies.

Non-classical Notch signaling by MDA-MB-231 breast cancer cell-derived small extracellular vesicles promotes malignancy in poorly invasive MCF-7 cells.

Aberrant Notch signaling is implicated in breast cancer progression, and recent studies have demonstrated links between the Notch pathway components Notch1 and Notch1 intracellular domain (N1ICD) with poor clinical outcomes. Growing evidence suggests that Notch signaling can be regulated by small extracellular vesicles (SEVs). Here, we used breast cancer cell models to examine whether SEVs are involved in functional Notch signaling. We found that Notch components are packaged into MDA-MB-231- and MCF-7-derived SEVs, although higher levels of N1ICD were detected in SEVs from the more aggressive MDA-MB-231 cell line than from poorly invasive MCF-7 cells. SEV-Notch components were functional, as SEVs cargo from MDA-MB-231 cells induced the expression of Notch target genes in MCF-7 cells and triggered a more invasive and proliferative phenotype concomitant with the acquisition of mesenchymal features. Neutralization of the N1ICD cargo in MDA-MB-231-derived SEVs significantly reduced their potential to enhance the aggressiveness of MCF-7 cells in vitro and in a xenograft model. Overall, our results indicate that a SEV-mediated non-classical pathway of Notch signal transduction in breast cancer models bypasses the need for classical ligand-receptor interactions, which may have important implications in cancer.

Polymer Conjugation of Docosahexaenoic Acid Potentiates Cardioprotective Therapy in Preclinical Models of Myocardial Ischemia/Reperfusion Injury.

While coronary angioplasty represents an effective treatment option following acute myocardial infarction, the reperfusion of the occluded coronary artery can prompt ischemia-reperfusion (I/R) injury that significantly impacts patient outcomes. As ω-3 polyunsaturated fatty acids (PUFAs) have proven, yet limited cardioprotective abilities, an optimized polymer-conjugation approach is reported that improves PUFAs bioavailability to enhance cardioprotection and recovery in animal models of I/R-induced injury. Poly-l-glutamic acid (PGA) conjugation improves the solubility and stability of di-docosahexaenoic acid (diDHA) under physiological conditions and protects rat neonatal ventricular myocytes from I/R injury by reducing apoptosis, attenuating autophagy, inhibiting reactive oxygen species generation, and restoring mitochondrial membrane potential. Enhanced protective abilities are associated with optimized diDHA loading and evidence is provided for the inherent cardioprotective potential of PGA itself. Pretreatment with PGA-diDHA before reperfusion in a small animal I/R model provides for cardioprotection and limits area at risk (AAR). Furthermore, the preliminary findings suggest that PGA-diDHA administration in a swine I/R model may provide cardioprotection, limit edema and decrease AAR. Overall, the evaluation of PGA-diDHA in relevant preclinical models provides evidence for the potential of polymer-conjugated PUFAs in the mitigation of I/R injury associated with coronary angioplasty.

Extracellular Vesicles Secreted by Hypoxic AC10 Cardiomyocytes Modulate Fibroblast Cell Motility.

Extracellular vesicles (EVs) are small membrane vesicles secreted by most cell types with important roles in cell-to-cell communication. To assess their relevance in the context of heart ischemia, EVs isolated from the AC10 ventricular cardiomyocyte cell line (CM-EVs), exposed to normoxia (Nx) or hypoxia (Hx), were incubated with fibroblasts (Fb) and endothelial cells (EC). CM-EVs were studied using electron microscopy, nanoparticle tracking analysis (NTA), western blotting and proteomic analysis. Results showed that EVs had a strong preference to be internalized by EC over fibroblasts, suggesting an active exosome-based communication mechanism between CM and EC in the heart. In Matrigel tube-formation assays, Hx CM-EVs were inferior to Nx CM-EVs in angiogenesis. By contrast, in a wound-healing assay, wound closure was faster in fibroblasts treated with Hx CM-EVs than with Nx CM-EVs, supporting a pro-fibrotic effect of Hx CM-EVs. Overall, these observations were consistent with the different protein cargoes detected by proteomic analysis under Nx and Hx conditions and the biological pathways identified. The paracrine crosstalk between CM-EVs, Fb, and EC in different physiological conditions could account for the contribution of CM-EVs to cardiac remodeling after an ischemic insult.

Electrospun poly(hydroxybutyrate) scaffolds promote engraftment of human skin equivalents via macrophage M2 polarization and angiogenesis.

Human dermo-epidermal skin equivalents (DE) comprising in vitro expanded autologous keratinocytes and fibroblasts are a good option for massive burn treatment. However, the lengthy expansion time required to obtain sufficient surface to cover an extensive burn together with the challenging surgical procedure limits their clinical use. The integration of DE and biodegradable scaffolds has been proposed in an effort to enhance their mechanical properties. Here, it is shown that poly(hydroxybutyrate) electrospun scaffolds (PHB) present good biocompatibility both in vitro and in vivo and are superior to poly-ε-caprolactone electrospun scaffolds as a substrate for skin reconstruction. Implantation of PHB scaffolds in healthy rats polarized macrophages to an M2-type that promoted constructive in vivo remodelling. Moreover, implantation of DE-PHB composites in a NOD/SCID mouse xenograft model resulted in engraftment accompanied by an increase in angiogenesis that favoured the survival of the human graft. Thus, PHB scaffolds are an attractive substrate for further exploration in skin reconstruction procedures, probably due in part to their greater angiogenic and M2 macrophage polarization properties. Copyright © 2017 John Wiley & Sons, Ltd.

Analysis of Exosome Transfer in Mammalian Cells by Fluorescence Recovery after Photobleaching.

During the course of evolution, prokaryote and eukaryote cells have developed elegant and to some extent analogous strategies to communicate with each other and to adapt to their surrounding environment. Eukaryotic cells communicate with each other through direct interaction via juxtracrine signaling and/or by secreting soluble factors. These secreted factors can subsequently act on the cell itself (autocrine signaling) or interact with neighboring (paracrine signaling) and distant (endocrine signaling) cells. The transmission of signals between cells and tissues has been traditionally thought to be regulated by a protein-based signaling system. Typically, proteins destined for secretion into the extracellular milieu by exocytosis contain a canonical secretion-targeting sequence ( Théry et al., 2002 ). However, proteins with a non-continuous and stimulus-dependent secretion, proteins that do not contain a canonical secretion-targeting sequence, and species that might be too labile within the extracellular environment (DNA, mRNA, peptides, metabolites, miRNA and other RNA species), can be secreted in small membranous extracellular vesicles (EVs) in a specific manner ( Hagiwara et al., 2014 ). Exosomes represent one broad class of these secreted membrane vesicles with a diameter of 30-130 nm ( Cocucci et al., 2009 ; Théry et al., 2009 ; Kowal et al., 2014 ), which are formed inside the secreting cells in endosomal compartments called multivesicular bodies. Molecules loaded into exosomes as well as the intensity of the exosome transfer between cells are important parameters for the subsequent conditioning of recipient cells. Current knowledge on secretion of exosomes and their internalization in recipient cells remains incomplete. It is known that secretion intensity of exosomes varies according to the cellular type and its physiological state ( Garcia et al., 2016 ). Moreover, the different combination of transmembrane proteins on the surface of exosomes that facilitate the adhesion to the cell-extracellular matrix vary the avidity with which a recipient cell captures exosomes ( Hoshino et al., 2015 ). Here, we have developed an in vitro system by which the transfer of exosomes between cells in co-culture can be quantified using FRAP ('Fluorescence Recovery After Photobleaching') technology. This protocol has been used to analyze the effects of exosome transfer of hypoxia inducible factor 1-α (HIF-1α) in Mesenchymal Stem Cells (MSC; HIF-MSC) to Human Umbilical Cord Vein Endothelial Cells (HUVEC) (Gonzalez-King et al., 2017).

Hydrogen Sulfide Improves Cardiomyocyte Function in a Cardiac Arrest Model.

BACKGROUND Cardioplegic arrest is a common procedure for many types of cardiac surgery, and different formulations have been proposed to enhance its cardio-protective effect. Hydrogen sulfide is an important signaling molecule that has cardio-protective properties. We therefore studied the cardio-protective effect of hydrogen sulfide in cardiac cell culture and its potential therapeutic use in combination with cardioplegia formulations. MATERIAL AND METHODS We added hydrogen sulfide donor GYY4137 to HL-1 cells to study its protective effect in nutrient starved conditions. In addition, we tested the potential use of GYY4137 when it is added into two different cardioplegia formulations: Cardi-Braun® solution and del Nido solution in an ex vivo Langendorff perfused rat hearts model. RESULTS We observed that eight-hour pre-treatment with GYY4137 significantly suppressed apoptosis in nutrient-starved HL-1 cells (28% less compared to untreated cells; p<0.05), maintained ATP content, and reduced protein synthesis. In ex vivo experiments, Cardi-Braun® and del Nido cardioplegia solutions supplemented with GYY4137 significantly reduced the pro-apoptotic protein caspase-3 content and preserved ATP content. Furthermore, GYY4137 supplemented cardioplegia solutions decreased the S-(5-adenosyl)-L-methionine/S-(adenosyl)-L-homocysteine ratio, reducing the oxidative stress in cardiac tissue. Finally, heart beating analysis revealed the preservation of the inter-beat interval and the heart rate in del Nido cardioplegia solution supplemented with GYY4137. CONCLUSIONS GYY4137 preconditioning preserved energetic state during starved conditions, attenuating the cardiomyocytes apoptosis in vitro. The addition of GYY4137 to cardioplegia solutions prevented apoptosis, ATP consumption, and oxidative stress in perfused rat hearts, restoring its electrophysiological status after cardiac arrest. These findings suggested that GYY4137 sulfide donor may improve the cardioplegia solution performance during cardiac surgery.

Mesenchymal Stem Cell Migration and Proliferation Are Mediated by Hypoxia-Inducible Factor-1α Upstream of Notch and SUMO Pathways.

Mesenchymal stem cells (MSCs) are effective in treating several pathologies. We and others have demonstrated that hypoxia or hypoxia-inducible factor 1 alpha (HIF-1α) stabilization improves several MSC functions, including cell adhesion, migration, and proliferation, thereby increasing their therapeutic potential. To further explore the mechanisms induced by HIF-1α in MSCs, we studied its relationship with Notch signaling and observed that overexpression of HIF-1α in MSCs increased protein levels of the Notch ligands Jagged 1-2 and Delta-like (Dll)1, Dll3, and Dll4 and potentiated Notch signaling only when this pathway was activated. Crosstalk between HIF and Notch resulted in Notch-dependent migration and spreading of MSCs, which was abolished by γ-secretase inhibition. However, the HIF-1-induced increase in MSC proliferation was independent of Notch signaling. The ubiquitin family member, small ubiquitin-like modifier (SUMO), has important functions in many cellular processes and increased SUMO1 protein levels have been reported in hypoxia. To investigate the potential involvement of SUMOylation in HIF/Notch crosstalk, we measured general SUMOylation levels and observed increased SUMOylation in HIF-1-expressing MSCs. Moreover, proliferation and migration of MSCs were reduced in the presence of a SUMOylation inhibitor, and this effect was particularly robust in HIF-MSCs. Immunoprecipitation studies demonstrated SUMOylation of the intracellular domain of Notch1 (N1ICD) in HIF-1-expressing MSCs, which contributed to Notch pathway activation and resulted in increased levels of N1ICD nuclear translocation as assessed by subcellular fractionation. SUMOylation of N1ICD was also observed in HEK293T cells with stabilized HIF-1α expression, suggesting that this is a common mechanism in eukaryotic cells. In summary, we describe, for the first time, SUMOylation of N1ICD, which is potentiated by HIF signaling. These phenomena could be relevant for the therapeutic effects of MSCs in hypoxia or under conditions of HIF stabilization.

Hypoxia Inducible Factor-1α Potentiates Jagged 1-Mediated Angiogenesis by Mesenchymal Stem Cell-Derived Exosomes.

Insufficient vessel growth associated with ischemia remains an unresolved issue in vascular medicine. Mesenchymal stem cells (MSCs) have been shown to promote angiogenesis via a mechanism that is potentiated by hypoxia. Overexpression of hypoxia inducible factor (HIF)-1α in MSCs improves their therapeutic potential by inducing angiogenesis in transplanted tissues. Here, we studied the contribution of exosomes released by HIF-1α-overexpressing donor MSCs (HIF-MSC) to angiogenesis by endothelial cells. Exosome secretion was enhanced in HIF-MSC. Omics analysis of miRNAs and proteins incorporated into exosomes pointed to the Notch pathway as a candidate mediator of exosome communication. Interestingly, we found that Jagged1 was the sole Notch ligand packaged into MSC exosomes and was more abundant in HIF-MSC than in MSC controls. The addition of Jagged1-containing exosomes from MSC and HIF-MSC cultures to endothelial cells triggered transcriptional changes in Notch target genes and induced angiogenesis in an in vitro model of capillary-like tube formation, and both processes were stimulated by HIF-1α. Finally, subcutaneous injection of Jagged 1-containing exosomes from MSC and HIF-MSC cultures in the Matrigel plug assay induced angiogenesis in vivo, which was more robust when they were derived from HIF-MSC cultures. All Jagged1-mediated effects could be blocked by prior incubation of exosomes with an anti-Jagged 1 antibody. All together, the results indicate that exosomes derived from MSCs stably overexpressing HIF-1α have an increased angiogenic capacity in part via an increase in the packaging of Jagged1, which could have potential applications for the treatment of ischemia-related disease. Stem Cells 2017;35:1747-1759.

Molecular disturbance underlies to arrhythmogenic cardiomyopathy induced by transgene content, age and exercise in a truncated PKP2 mouse model.

Arrhythmogenic cardiomyopathy (ACM) is a disorder characterized by a progressive ventricular myocardial replacement by fat and fibrosis, which lead to ventricular arrhythmias and sudden cardiac death. Mutations in the desmosomal gene Plakophilin-2 (PKP2) accounts for >40% of all known mutations, generally causing a truncated protein. In a PKP2-truncated mouse model, we hypothesize that content of transgene, endurance training and aging will be determinant in disease progression. In addition, we investigated the molecular defects associated with the phenotype in this model. We developed a transgenic mouse model containing a truncated PKP2 (PKP2-Ser329) and generated three transgenic lines expressing increasing transgene content. The pathophysiological features of ACM in this model were assessed. While we did not observe fibro-fatty replacement, ultrastructural defects were exhibited. Moreover, we observed transgene content-dependent development of structural (ventricle dilatation and dysfunction) and electrophysiological anomalies in mice (PR interval and QRS prolongation and arrhythmia induction). In concordance with pathological defects, we detected a content reduction and remodeling of the structural proteins Desmocollin-2, Plakoglobin, native Plakophilin-2, Desmin and ß-Catenin as well as the electrical coupling proteins Connexin 43 and cardiac sodium channel (Nav1.5). Surprisingly, we observed structural but not electrophysiological abnormalities only in trained and old mice. We demonstrated that truncated PKP2 provokes ACM in the absence of fibro-fatty replacement in the mouse. Transgene dose is essential to reveal the pathology, whereas aging and endurance training trigger limited phenotype. Molecular abnormalities underlay the structural and electrophysiological defects.

Liquid biopsy and tumor derived exosomes in clinical practice / Biopsia líquida y exosomas derivados del tumor en la práctica clínica

Tumors are complex tissues that interact in many different ways. Tissue biopsies provide a great amount of information and remain the gold standard for tumor diagnosis. However, they cannot always be performed due to the invasive nature of the procedure and in such circumstances, a liquid biopsy could provide a solution. Liquid biopsy is defined as the search of biomarkers in peripheral blood. To date, there are three main research fields: (1) circulating tumor cells (CTCs); (2) circulating free tumor nucleic acids (cfNA) and (3) exosomes, small vesicles containing various types of signaling molecules capable of modulating a tumor-immune response. In recent years, exosomes have arisen as a powerful tool both to further our understanding of cancer biology and to improve clinical management. We review how the isolation and study of exosomes from liquid biopsies may affect clinical practice (AU)

Las biopsias tisulares, aunque otorgan gran cantidad de información y son el gold standard para el diagnóstico tumoral, no pueden ser realizadas continuamente para monitorizar la evolución tumoral dada su inherente naturaleza invasiva. Por otro lado, la biopsia líquida surge como una herramienta capaz de compensar estas limitaciones. En este momento se han identificado 3 tipos principales de biomarcadores en la biopsia líquida: (1) células tumorales circulantes (CTC); (2) ácidos nucleicos tumorales circulantes libres (cfNA), y (3) exosomas. En los últimos años los exosomas (pequeñas vesículas que contienen moléculas capaces de modular la respuesta inmune-tumoral) han surgido como una potente herramienta para comprender mejor la biología del cáncer así como una manera para intentar mejorar el manejo de los pacientes oncológicos. El objetivo de este artículo es presentar una revisión sobre cómo la caracterización de los exosomas a través de la biopsia líquida podría influir sobre la práctica clínica (AU)

Cardiomyocyte exosomes regulate glycolytic flux in endothelium by direct transfer of GLUT transporters and glycolytic enzymes.

AIMS: Cardiomyocytes (CMs) and endothelial cells (ECs) have an intimate anatomical relationship, which is essential for maintaining the metabolic requirements of the heart. Little is known about the mechanisms that regulate nutrient flow from ECs to associated CMs, especially in situations of acute stress when local active processes are required to regulate endothelial transport. We examined whether CM-derived exosomes can modulate glucose transport and metabolism in ECs. METHODS AND RESULTS: In conditions of glucose deprivation, CMs increase the synthesis and secretion of exosomes. These exosomes are loaded with functional glucose transporters and glycolytic enzymes, which are internalized by ECs, leading to increased glucose uptake, glycolytic activity, and pyruvate production in recipient cells. CONCLUSION: These findings establish CM-derived exosomes as key components of the cardio-endothelial communication system which, through intercellular protein complementation, would allow a rapid response from ECs to increase glucose transport and a putative uptake of metabolic fuels from blood to CMs. This CM-EC protein complementation process might have implications for metabolic regulation in health and disease.

Glucose Starvation in Cardiomyocytes Enhances Exosome Secretion and Promotes Angiogenesis in Endothelial Cells.

Cardiomyocytes (CMs) and endothelial cells (ECs) have an intimate anatomical relationship that is essential for maintaining normal development and function in the heart. Little is known about the mechanisms that regulate cardiac and endothelial crosstalk, particularly in situations of acute stress when local active processes are required to regulate endothelial function. We examined whether CM-derived exosomes could modulate endothelial function. Under conditions of glucose deprivation, immortalized H9C2 cardiomyocytes increase their secretion of exosomes. CM-derived exosomes are loaded with a broad repertoire of miRNA and proteins in a glucose availability-dependent manner. Gene Ontology (GO) analysis of exosome cargo molecules identified an enrichment of biological process that could alter EC activity. We observed that addition of CM-derived exosomes to ECs induced changes in transcriptional activity of pro-angiogenic genes. Finally, we demonstrated that incubation of H9C2-derived exosomes with ECs induced proliferation and angiogenesis in the latter. Thus, exosome-mediated communication between CM and EC establishes a functional relationship that could have potential implications for the induction of local neovascularization during acute situations such as cardiac injury.

Evaluación de calidad de vida percibida en población marginal: una experiencia con treinta integrantes de familias residentes en la "Villa 31" de la Ciudad de Buenos Aires / Evaluation of perceived quality of life in marginal population: a study on thirty family members residing in

Conocer cómo viven los sujetos no sólo implica el análisis de sus condiciones objetivas, sino también el grado de satisfacción percibida y las expectativas de transformación que de estas condiciones tienen. Este trabajo se basa en un abordaje que analiza la Calidad de Vida desde las experiencias subjetivas e intersubjetivas de los individuos. Bajo el supuesto de que la pobreza es uno de los indicadores con más peso al momento de medir la Calidad de Vida de una sociedad, se llevó a cabo un trabajo de campo en el cual se evaluó, a través de un instrumento desarrollado para esta investigación, la Calidad de Vida de los habitantes de una población marginal de Buenos Aires.De esta manera, se refleja la importancia de la evaluación subjetiva que las personas hacen de su Calidad de Vida, y sus expectativas de cambio como base de la planificación, desarrollo y evaluación de intervenciones comunitarias.