Small Extracellular Vesicles Harboring PD-L1 in Obstructive Sleep Apnea.

Obstructive sleep apnea syndrome (OSA) has been associated with increased cancer incidence and aggressiveness. One hypothesis to support this association is the implication of immune response, particularly the programmed cell death pathway, formed by the receptor PD-1 and its ligand PD-L1. Recent studies have shown dysregulation of this pathway in severe OSA patients. It has also been shown that small extracellular vesicles (sEVs) carrying PD-L1 induce lymphocyte dysfunction. Thus, the aim of our study was to analyze the expression of PD-L1 on sEVs of OSA patients and to evaluate the role of sEVs on lymphocyte activation and cytotoxicity. Circulating sEVs were isolated from OSA patients and the control group. Lymphocytes were isolated from the control group. Circulating sEVs were characterized by western blot, nanotracking analysis, and flow cytometry and were incubated with lymphocytes. Our results show no differences in the quantity and composition of sEVs in OSA patients and no significant effects of sEVs in OSA patients on lymphocyte activation and cytotoxicity. These results suggest that OSA does not modify PD-L1 expression on sEVs, which does not contribute to dysregulation of cytotoxic lymphocytes.

Surgical treatment of retrorectal tumors: a plea for a laparoscopic approach.

INTRODUCTION: Retrorectal tumors (RRTs) are rare and often surgically excised due to the risk of malignant degeneration and compressive or obstructive symptoms. The approach for excision has traditionally been based on tumor location and performed using either a transabdominal or perineal approach depending on the position of the tumor. The advent of minimally invasive surgery, however, has challenged this paradigm. Here, we determined the applicability and potential advantages of a laparoscopic transabdominal approach in a series of 23 patients with RRTs. MATERIAL AND METHODS: We included 23 patients presenting with RRTs treated at the Surgical Gastrointestinal Unit at Hospital de Sant Pau that were registered prospectively since 1998. The preoperative evaluation consisted of colonoscopy, CT scan and/or MRI, mechanical bowel lavage, and antibiotic therapy. Signed consent was obtained from all patients for a laparoscopic transabdominal approach unless the tumor was easily accessible via a perineal approach. In case of recurrence, a transanal endoscopic microsurgery (TEM) approach was considered. Surgical details, immediate morbidity, and short- and long-term outcomes were recorded. RESULTS: Of the 23 RRT cases evaluated, 16 patients underwent a laparoscopic transabdominal approach and 6 underwent a perineal approach. No patients required conversion to open surgery. In the laparoscopic transabdominal group, the mean operating time was 158 min, the average postoperative hospital stay was 5 days, and postoperative morbidity was 18%. Three patients had recurrent RRTs, two of the three underwent surgical reintervention. The third patient was radiologically stable and close follow-up was decided. CONCLUSION: Our results show that laparoscopic transabdominal excision of RRT is a safe and effective technique, offering the potential advantages of less invasive access and reduced morbidity. This approach challenges the traditional paradigm of excision of these infrequent tumors based solely on tumor location and offers a viable alternative for the treatment of these infrequent tumors.

'Yapping' with extracellular vesicles in fatty liver metastasis.

Liver metastasis is a major cause of death in patients with colorectal cancer (CRC). A recent study by Wang et al. has deciphered unprecedented prometastatic and immunosuppressive properties of the tumor microenvironment (TME) mediated by hepatocyte-derived extracellular vesicles (EVs) in fatty liver, paving the way for therapeutic innovations to treat patients with CRC and liver metastasis.

Enhancement of the In Vitro Antitumor Effects of Berberine Chloride When Encapsulated within Small Extracellular Vesicles.

Berberine hydrochloride (BRB) is an isoquinoline alkaloid with promising anticancer efficacies. However, application of BRB had been hampered by its poor aqueous solubility, low gastrointestinal absorption, and rapid metabolism. The present study takes advantage of small extracellular vesicles (sEVs) to increase both stability and efficacy of BRB. sEVs from immature dendritic cells were produced and loaded with BRB. Proliferation, migration and Matrigel assay were performed, cycle arrest and nitric oxide (NO) production were evaluated in human breast cancer cell line (MDA-MB-231) and human umbilical vein endothelial cells (HUVECs). sEVs loaded with BRB formed a stable and homogenous population with a drug entrapment efficiency near to 42%. BRB loaded into sEVs was more potent than free BRB for MDA-MB-231 and endothelial proliferation, migration, and capillary-like formation in HUVECs. The mechanisms involved a blockade of cell cycle in G0/G1 phase, increased S phase and decreased of G2/M in MDA-MB-231 and HUVECs, and inhibition of NO production in HUVECs. Altogether, sEV-loaded BRB displayed higher effects than free BRB on different steps leading to its antitumor activity and anti-angiogenic properties in vitro. Thus, sEV formulation may be considered as an innovative approach and promising delivery of BRB to prevent tumorigenesis and angiogenesis.

Randomized phase II trial of FOLFIRI-panitumumab compared with FOLFIRI alone in patients with RAS wild-type circulating tumor DNA metastatic colorectal cancer beyond progression to first-line FOLFOX-panitumumab: the BEYOND study (GEMCAD 17-01).

PURPOSE: Panitumumab plus FOLFOX (P-FOLFOX) is standard first-line treatment for RAS wild-type (WT) metastatic colorectal cancer. The value of panitumumab rechallenge is currently unknown. We assessed addition of panitumumab to FOLFIRI (P-FOLFIRI) beyond progression to P-FOLFOX in patients with no RAS mutations in liquid biopsy (LB). METHODS: In this randomized phase II trial, patients were assigned (3:2 ratio) to second-line P-FOLFIRI (arm A) or FOLFIRI alone (arm B). LB for circulating tumor DNA analysis was collected at study entry and at disease progression. Primary endpoint was 6-month progression-free survival. Two-stage Simon design required 85 patients to be included (EudraCT 2017-004519-38). RESULTS: Between February 2019 and November 2020, 49 patients were screened (16 RAS mutations in LB detected) and 31 included (18 assigned to arm A and 13 to arm B). The study was prematurely closed due to inadequate recruitment. Serious adverse events were more frequent in arm A (44% vs. 23%). Overall response rate was 33% (arm A) vs. 7.7% (arm B). Six-month progression-free survival rate was 66.7% (arm A) and 38.5% (arm B). Median progression-free survival was 11.0 months (arm A) and 4.0 months (arm B) (hazard ratio, 0.58). At disease progression, RAS or BRAF mutations in LB were found in 4/11 patients (36%) in arm A and 2/10 (20%) in arm B. CONCLUSIONS: The BEYOND study suggests a meaningful benefit of P-FOLFIRI beyond progression to P-FOLFOX in metastatic colorectal cancer patients with WT RAS status selected by LB. This strategy deserves further investigation.

Pharmacology active microcarriers delivering HGF associated with extracellular vesicles for myocardial repair.

Despite the curative approaches developed against myocardial infarction, cardiac cell death causes dysfunctional heart contractions that depend on the extent of the ischemic area and the reperfusion period. Cardiac regeneration may allow neovascularization and limit the ventricular remodeling caused by the scar tissue. We have previously found that large extracellular vesicles, carrying Sonic Hedgehog (lEVs), displayed proangiogenic and antioxidant properties, and decreased myocardial infarction size when administrated by intravenous injection. We propose to associate lEVs with pharmacology active microcarriers (PAMs) to obtain a combined cardioprotective and regenerative action when administrated by intracardiac injection. PAMs made of poly-D,L-lactic-coglycolic acid-poloxamer 188-poly-D,L-lactic-coglycolic acid and covered by fibronectin/poly-D-lysine provided a biodegradable and biocompatible 3D biomimetic support for the lEVs. When compared with lEVs alone, lEVs-PAMs constructs possessed an enhanced in vitro pro-angiogenic ability. PAMs were designed to continuously release encapsulated hepatocyte growth factor (PAMsHGF) and thus, locally increase the activity of the lEVs by the combined anti-fibrotic properties and regenerative properties. Intracardiac administration of either lEVs alone or lEVs-PAMsHGF improved cardiac function in a similar manner, in a rat model of ischemia-reperfusion. Moreover, lEVs alone or the IEVs-PAMsHGF induced arteriogenesis, but only the latter reduced tissue fibrosis. Taken together, these results highlight a promising approach for lEVs-PAMsHGF in regenerative medicine for myocardial infarction.

Presentation and Follow-up of Familial Adenomatous Polyposis: Differences Between APC and MUTYH Mutations. / Presentación y seguimiento de poliposis adenomatosa familiar (PAF): diferencias entre las mutaciones APC y MUTYH.

BACKGROUND: Familial adenomatous polyposis is described as one of the common two types of genetic disorders: APC and MUTYH gene associated polyposis syndrome and the clinical differences between the two can sometimes be unclear. MATERIALS AND METHODS: A retrospective analysis and comparison was made of clinical, surgical, and histological criteria, mutation types and the long-term results of patients who underwent genetic analysis which resulted in the diagnosis of Familial Adenomatous Polyposis between 1984 and 2018. RESULTS: Of the total 71 patients included in the study, 14 were identified with the MUTYH gene, and 57 with the APC mutation. In patients with the APC mutation, 63% had duodenal adenoma, 61% gastric polyp and 54% had desmoid tumor. Of the patients with the MUTYH mutation, 21% had duodenal adenoma and 21% were diagnosed with gastric polyps. In 21% of the patients with APC mutation, the polyp count was <100, and 64% of those with the MUTYH mutation had >100 polyps in the colon No statistical difference was determined between the groups in respect of the proportion of patients with >100 polyps. CONCLUSION: The pre-operative genetic testing of patients with polyposis coli will be useful in determining the future clinical outcome and helpful in guiding an informed decision as to whether to apply surgical treatment. It is useful to determine the colonic and extra-colonic involvement of genetic mutation diseases in patients with Familial adenomatous polyposis.

Synthesis, Characterization, and In Vitro Studies of an Reactive Oxygen Species (ROS)-Responsive Methoxy Polyethylene Glycol-Thioketal-Melphalan Prodrug for Glioblastoma Treatment.

Glioblastoma (GBM) is the most frequent and aggressive primary tumor of the brain and averages a life expectancy in diagnosed patients of only 15 months. Hence, more effective therapies against this malignancy are urgently needed. Several diseases, including cancer, are featured by high levels of reactive oxygen species (ROS), which are possible GBM hallmarks to target or benefit from. Therefore, the covalent linkage of drugs to ROS-responsive molecules can be exploited aiming for a selective drug release within relevant pathological environments. In this work, we designed a new ROS-responsive prodrug by using Melphalan (MPH) covalently coupled with methoxy polyethylene glycol (mPEG) through a ROS-cleavable group thioketal (TK), demonstrating the capacity to self-assembly into nanosized micelles. Full chemical-physical characterization was conducted on the polymeric-prodrug and proper controls, along with in vitro cytotoxicity assayed on different GBM cell lines and "healthy" astrocyte cells confirming the absence of any cytotoxicity of the prodrug on healthy cells (i.e. astrocytes). These results were compared with the non-ROS responsive counterpart, underlining the anti-tumoral activity of ROS-responsive compared to the non-ROS-responsive prodrug on GBM cells expressing high levels of ROS. On the other hand, the combination treatment with this ROS-responsive prodrug and X-ray irradiation on human GBM cells resulted in an increase of the antitumoral effect, and this might be connected to radiotherapy. Hence, these results represent a starting point for a rationale design of innovative and tailored ROS-responsive prodrugs to be used in GBM therapy and in combination with radiotherapy.

Colorectal Cancer Prognosis: The Impact of Signet Ring Cell.

BACKGROUND: The prognosis for patients with colorectal cancer shows variation. The characteristics of colorectal cancer patients with signet-ring cell carcinoma (SRCC) are still not clear. MATERIALS AND METHODS: A retrospective comparison was made of the data of signet-ring cell colorectal carcinoma patients operated on between 2009 and 2018 in respect of clinicopathological and operative results, morbidity, mortality, and long-term survival. RESULTS: The study included a total of 34 patients comprising 26 (76%) males and 8 (24%) females with a mean age of 58 ± 11.7 years. Incidence of SRCC was determined as 1.8%. Lymphovascular invasion was determined in 22 (64%) patients. Tumors were determined as stage T2 in 8 (32%) patients, stage T3 in 9 (36%), and stage T4 in 8 (32%). According to the TNM classification, 5 (14.7%) patients were diagnosed with stage 1, 7 (20.6%) with stage 2, 15 (44.1%) with stage 3, and 7 (20.6%) with stage 4. The mean follow-up period was 40.6 ± 30.4 months, and mean disease-free follow-up was determined as 33.1 ± 36.1 months. Fifteen (44.1%) patients died because of the disease. CONCLUSION: Although SRCC is a poor prognostic factor, it should be kept in mind when determining adjuvant therapies and prognosis of patients determined with advanced-stage SRCC.

Phostine 3.1a as a pharmacological compound with antiangiogenic properties against diseases with excess vascularization.

Angiogenesis is a complex process leading to the growth of new blood vessels from existing vasculature, triggered by local proangiogenic factors such as VEGF. An excess of angiogenesis is a recurrent feature of various pathologic conditions such as tumor growth. Phostines are a family of synthetic glycomimetic compounds that exhibit anticancer properties, and the lead compound 3-hydroxy-4,5-bis-benzyloxy-6-benzyloxymethyl-2-phenyl2-oxo-2λ5-[1,2]oxaphosphinane (PST 3.1a) shows antiglioblastoma properties both in vitro and in vivo. In the present study, we assessed the effect of PST 3.1a on angiogenesis and endothelial metabolism. In vitro, PST 3.1a (10 µM) inhibited all steps that regulate angiogenesis, including migration, proliferation, adhesion, and tube formation. In vivo, PST 3.1a reduced intersegmental vessel formation and vascularization of the subintestinal plexus in zebrafish embryos and also altered pathologic angiogenesis and glioblastoma progression in vivo. Mechanistically, PST 3.1a altered interaction of VEGF receptor 2 and glycosylation-regulating protein galectin-1, a key component regulating angiogenesis associated with tumor resistance. Thus, these data show that use of PST 3.1a is an innovative approach to target angiogenesis.-Bousseau, S., Marchand, M., Soleti, R., Vergori, L., Hilairet, G., Recoquillon, S., Le Mao, M., Gueguen, N., Khiati, S., Clarion, L., Bakalara, N., Martinez, M. C., Germain, S., Lenaers, G., Andriantsitohaina, R. Phostine 3.1a as a pharmacological compound with antiangiogenic properties against diseases with excess vascularization.

Extracellular Vesicles: Mechanisms in Human Health and Disease.

SIGNIFICANCE: Secreted extracellular vesicles (EVs) are now considered veritable entities for diagnosis, prognosis, and therapeutics. These structures are able to interact with target cells and modify their phenotype and function. Recent Advances: Since composition of EVs depends on the cell type of origin and the stimulation that leads to their release, the analysis of EV content remains an important input to understand the potential effects of EVs on target cells. CRITICAL ISSUES: Here, we review recent data related to the mechanisms involved in the formation of EVs and the methods allowing specific EV isolation and identification. Also, we analyze the potential use of EVs as biomarkers in different pathologies such as diabetes, obesity, atherosclerosis, neurodegenerative diseases, and cancer. Besides, their role in these diseases is discussed. Finally, we consider EVs enriched in microRNA or drugs as potential therapeutic cargo able to deliver desirable information to target cells/tissues. FUTURE DIRECTIONS: We underline the importance of the homogenization of the parameters of isolation of EVs and their characterization, which allow considering EVs as excellent biomarkers for diagnosis and prognosis.

Effect of mandibular advancement therapy on inflammatory and metabolic biomarkers in patients with severe obstructive sleep apnoea: a randomised controlled trial.

Systemic inflammation and metabolic disorders are among the mechanisms linking obstructive sleep apnoea (OSA) and cardiovascular disease (CVD). In 109 patients with severe OSA and no overt CVD, biomarkers of inflammation (C reactive protein, interleukin-6, tumour necrosis factor-α and its receptors, adiponectin, leptin and P-selectin), glucose and lipid metabolism, and N-terminal pro-brain natriuretic peptide, were measured before and after 2 months of treatment with a mandibular advancement device (MAD) (n=55) or a sham device (n=54). MAD reduced the Apnoea-Hypopnoea Index (p<0.001) but had no effect on circulating biomarkers compared with the sham device, despite high treatment adherence (6.6 hour/night). TRIAL REGISTRATION NUMBER: NCT01426607.

Phenotyping of circulating extracellular vesicles (EVs) in obesity identifies large EVs as functional conveyors of Macrophage Migration Inhibitory Factor.

OBJECTIVE: Obesity-associated metabolic dysfunctions are linked to dysregulated production of adipokines. Accumulating evidence suggests a role for fat-derived extracellular vesicles (EVs) in obesity-metabolic disturbances. Since EVs convey numerous proteins we aimed to evaluate their contribution in adipokine secretion. METHODS: Plasma collected from metabolic syndrome patients were used to isolate EV subtypes, namely microvesicles (MVs) and exosomes (EXOs). Numerous soluble factor concentrations were measured successively on total, MV- and EXO-depleted plasma by multiplexed immunoassays. RESULTS: Circulating MVs and EXOs were significantly increased with BMI, supporting a role of EVs as metabolic relays in obesity. Obesity was associated with dysregulated soluble factor production. Sequential depletion of plasma MVs and EXOs did not modify plasma levels of these molecules, with the exception of Macrophage Migration Inhibitory Factor (MIF). Half of plasma MIF circulated within MVs, and this MV secretory pathway was conserved over different MIF-producing cells. Although MV-associated MIF triggered rapid ERK1/2 activation in macrophages, these functional MV-MIF effects specifically relied on MIF tautomerase activity. CONCLUSION: Our results emphasize the importance of reconsidering MIF-metabolic actions with regard to its MV-associated form and opening new EV-based strategies for therapeutic MIF approaches.

Glycosylation as new pharmacological strategies for diseases associated with excessive angiogenesis.

Angiogenesis is a complex process describing the growth of new blood vessels from existing vasculature, and is triggered by local pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), which increase the metabolism of endothelial cells (ECs). Angiogenesis takes part in various physiological conditions such as embryogenesis, placental growth, and in pathological conditions such as tumor growth, diabetic retinopathy, rheumatoid arthritis (RA) and ischemic diseases. Current therapies against excessive angiogenesis target vascular growth signaling. However, tumors often counteract these therapies through adaptive mechanisms, thus novel alternative anti-angiogenic strategies are needed. Targeting metabolism is a new anti-angiogenic paradigm, especially through the inhibition of energy metabolism and glycosylation, with the perspective of maintaining the delicate balance between the beneficial and deleterious effects of excessive angiogenesis in patients. Recent studies described a role for EC glycolysis and its main regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in the regulation of angiogenesis, but only few studies are related to the role of the hexosamine biosynthesis pathway during angiogenesis. Glycosylation allows the formation of glycoproteins, glycolipids and proteoglycans and impacts many pathways. The addition of glycans to N-linked proteins is catalyzed by the enzymatic activity of N-acetylglucosaminyltransferases (GnTs), which regulates the glycosylation status of key angiogenic factors such as VEGF receptor 2 (VEGFR2) and Notch. In addition, glycan-galectin (Gal) interactions regulate vascular signaling programs and may contribute to tumor adaptations to anti-angiogenic strategies. Herein, we review novel pharmacological strategies targeting glycosylation, which could be used to decrease excessive angiogenesis in pathological conditions.

The safety of trifluridine and tipiracil for the treatment of metastatic colorectal cancer.

INTRODUCTION: TAS102 is an oral thymidine-based nucleoside analog that has been approved for the treatment of patients with metastatic colorectal cancer (mCRC) previously treated with, or not candidates for, available therapies including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies, anti-vascular endothelial growth factor (VEGF) agents and, if RAS wild-type, anti-epidermal growth factor receptor (EGFR) therapy. The pivotal RECOURSE phase III trial demonstrated a significant improvement in disease control rate, progression-free survival (PFS), and overall survival (OS) as compared with placebo in patients with refractory mCRC. Areas covered: This manuscript aims to review the clinical development of TAS102 in CRC, with a particular focus on safety, and to provide some perspective regarding its role in clinical practice. A literature search was conducted of MEDLINE and EMBASE databases for published studies (January 2004-December 2016) using the search terms TAS102, trifluridine-tipiracil, metastatic or advanced CRC, clinical trial, toxicity, safety, pharmacology, pharmacokinetics, and therapy. Expert opinion: TAS102 significantly improves survival of patients with refractory mCRC and has manageable toxicity. An expanding role in the treatment of CRC is expected for TAS102 in the near future, as its favorable safety profile makes TAS102 a suitable drug to be combined with other cytotoxic and targeted agents.

Impact of polyphenols on extracellular vesicle levels and effects and their properties as tools for drug delivery for nutrition and health.

Polyphenols are found in plant-derived foods and beverages and display numerous protective effects against cancers, cardiovascular, metabolic and neurodegenerative diseases. Extracellular vesicles (EVs), microparticles, exosomes, and apoptotic bodies, originated by different cell types are emerging as a novel mean of cell-to-cell communication in physiology and pathology and represent a new way to convey fundamental information between cells. Polyphenols can act on signaling pathways that interfere with the biogenesis of EVs. Thus, they are able to control EV release from cells and their content and therefore their functional properties. Both EVs and polyphenols are therapeutic tools that can be used against several diseases. In this context, the combination of both tools can increase their therapeutic potential. Three types of strategies can be used: (i) plants are able to produce EVs that encapsulate natural components from vegetables, polyphenols for instance, (ii) mammalian cells can be treated with polyphenols and the subsequent EVs produced are enriched in these components, and (iii) EVs from mammalian cells can be uploaded with polyphenols. We review the novel aspects of the interplay between polyphenols and EVs that could trigger and improve the health benefits in cancer, cardiovascular, metabolic and neurodegenerative diseases.

Non-muscular myosin light chain kinase triggers intermittent hypoxia-induced interleukin-6 release, endothelial dysfunction and permeability.

Obstructive sleep apnea is characterized by intermittent hypoxia (IH) which alters endothelial function, induces inflammation and accelerates atherosclerosis-induced cardiovascular diseases. The non-muscular myosin light chain kinase (nmMLCK) isoform contributes to endothelial cell-cell junction opening. Deletion of nmMLCK protects mice from death in septic shock models and prevents atherosclerosis in high-fat diet-fed mice. The aim of the study was to analyze the implication of nmMLCK in IH-induced vascular inflammation. Human aortic endothelial cells were exposed to 6 hours of IH in absence or presence of nmMLCK inhibitors, ML-7 (5 µM) or PIK (150 µM). IH increased reactive oxygen species (ROS) and nitric oxide (NO) production, p65-NFκB activation and IL-6 secretion. While nmMLCK inhibition did not prevent IH-induced ROS production and p65-NFκB activation, it decreased NO production and partially prevented IL-6 secretion. IH-induced IL-6 secretion and vesicle-associated membrane protein-associated vesicles re-organization were inhibited in presence of the inhibitor of protein secretion, brefeldin A, or ML-7. IH increased monocytes transendothelial migration that was partially prevented by ML-7. Finally, IH reduced endothelium-dependent relaxation to acetylcholine of aortas from wild-type but not those taken from nmMLCK-deficient mice. These results suggest that nmMLCK participates to IH-induced endothelial dysfunction resulting from cytokines secretion and endothelial permeability.

Temporal Cross Talk Between Endoplasmic Reticulum and Mitochondria Regulates Oxidative Stress and Mediates Microparticle-Induced Endothelial Dysfunction.

AIMS: Circulating microparticles (MPs) from metabolic syndrome patients and those generated from apoptotic T cells induce endothelial dysfunction; however, the molecular and cellular mechanism(s) underlying in the effects of MPs remain to be elucidated. RESULTS: Here, we show that both types of MPs increased expression of endoplasmic reticulum (ER) stress markers, X-box binding protein 1, p-eukaryotic translation initiation factor 2 α, and CHOP, and nuclear translocation of activating transcription factor 6 on human aortic endothelial cells (HAoECs). MPs decreased in vitro nitric oxide release by HAoECs, whereas in vivo MP injection into mice impaired the endothelium-dependent relaxation induced by acetylcholine. These effects were prevented when ER stress was inhibited, suggesting that ER stress is implicated in the endothelial effects induced by MPs. MPs affected mitochondrial function and evoked sequential increase of cytosolic and mitochondrial reactive oxygen species (ROS). Pharmacological inhibition of ER stress and silencing of neutral sphingomyelinase (SMase) with siRNA abrogated all MP-mediated effects. Neutralization of Fas ligand carried by MPs abolished effects induced by both MP types, whereas neutralization of low-density lipoprotein receptor on endothelial cells prevented T-lymphocyte MP-mediated effects. Innovation and Conclusion: Collectively, endothelial dysfunction triggered by MPs involves temporal cross talk between ER and mitochondria with respect to spatial regulation of ROS via the neutral SMase and interaction of MPs with Fas and/or low-density lipoprotein receptor. These results provide a novel molecular insight into the manner MPs mediate vascular dysfunction and allow identification of potential therapeutic targets to treat vascular complications associated with metabolic syndrome. Antioxid. Redox Signal. 26, 15-27.

Desarrollo de la competencia social y prevención de problemas de conducta en el aula infantil / Social Competence Development and Behavior Problems Prevention in Preschool Classrooms / Desenvolvimento da competência social e prevenção de problemas de conduta na sala de aula infantil

Objetivo. El propósito del estudio es analizar el efecto longitudinal del programa de prevención universal Aprender a Convivir sobre la competencia social y los problemas de conducta infantiles. Método. 197 niños de tres años participaron en el programa durante tres años consecutivos y fueron evaluados por sus maestros en distintas variables relacionadas con la competencia social y los problemas de conducta. El análisis de datos se llevó a cabo mediante un ANOVA simple de medidas repetidas, incluyendo como factor intragrupo el momento de evaluación pretest (3 años de edad) y postest (5 años de edad). Resultados. Los resultados mostraron una mejora significativa del grupo experimental, tanto en las variables de competencia social (cooperación social d = 1.55; interacción social d = 1.91; e independencia social d = 1.32) como en las de problemas de conducta (interiorizados d=0.40; y exteriorizados d = 0.48) analizadas. Conclusión. El programa de intervención Aprender a Convivir contribuye al desarrollo de la competencia social del alumnado de Educación Infantil, también tiene un efecto indirecto sobre la reducción de problemas de conducta interiorizados y exteriorizados en niños.

Objective. The purpose of the study is to analyze the longitudinal effect of the universal prevention program, Aprender a Convivir, on children' social competence and behavioral problems. Method. 197 three-year-old children participated in the program for three consecutive school years and were assessed by their teachers in different variables related to social competence and behavior problems variables. Data analysis was carried out through a repeated-measures simple ANOVA including as intra-subject factor assessment time-pretest (3-year-old) and postest (5-year-old). Results. A significant improvement was observed in the experimental group both in the variables of social competence (social cooperation d = 1.55; social interaction d = 1.91; and social independence d = 1.32) as in the variables of behavior problems (internalizing d = 0.40; and externalizing d = 0.48) analyzed. Conclusion. The Aprender a Convivir prevention program contributes to social competence development of preschool students, and also has an indirect effect on the reduction of internalizing and externalizing behavior problems.

Escopo. O propósito do estudo é analisar o efeito longitudinal do programa de prevenção universal Aprender a Conviver sobre a competência social e os problemas de conduta infantis. Metodologia. 197 crianças de tres anos de idade participaram no programa durante três anos consecutivos e foram avaliados por seus professores em distintas variáveis relacionadas com a competência social e os problemas de conduta. A análise de dados foi realizada mediante um ANOVA simples de medidas repetidas, incluindo como fator intragrupo o momento de avaliação pré-teste (3 anos de idade) e post-teste (5 anos de idade). Resultados. Os resultados amostraram uma melhora significativa do grupo experimental tanto nas variáveis de competência social (cooperação social d = 1.55; interação social d = 1.91; e independência social d = 1.32) como nas de problemas de conduta (interiorizados d = 0.40; e exteriorizados d = 0.48) analisadas. Conclusão. O programa de intervenção Aprender a Conviver contribui ao desenvolvimento da competência social do alunado de Educação Infantil, também tem um efeito indireto sobre a redução de problemas de conduta interiorizados e exteriorizados em crianças.

Hedgehog associated to microparticles inhibits adipocyte differentiation via a non-canonical pathway.

Hedgehog (Hh) is a critical regulator of adipogenesis. Extracellular vesicles are natural Hh carriers, as illustrated by activated/apoptotic lymphocytes specifically shedding microparticles (MP) bearing the morphogen (MP(Hh+)). We show that MP(Hh+) inhibit adipocyte differentiation and orientate mesenchymal stem cells towards a pro-osteogenic program. Despite a Smoothened (Smo)-dependency, MP(Hh+) anti-adipogenic effects do not activate a canonical Hh signalling pathway in contrast to those elicited either by the Smo agonist SAG or recombinant Sonic Hedgehog. The Smo agonist GSA-10 recapitulates many of the hallmarks of MP(Hh+) anti-adipogenic effects. The adipogenesis blockade induced by MP(Hh+) and GSA-10 was abolished by the Smo antagonist LDE225. We further elucidate a Smo/Lkb1/Ampk axis as the non-canonical Hh pathway used by MP(Hh+) and GSA-10 to inhibit adipocyte differentiation. Our results highlight for the first time the ability of Hh-enriched MP to signal via a non-canonical pathway opening new perspectives to modulate fat development.