Suppressor of fused associates with dissemination patterns in patients with glioma

Gliomas are the most common brain tumors, which present poor prognosis, due, in part, to tumor cell migration and infiltration into distant brain areas. However, the underlying mechanisms causing such effects are unknown. Hedgehog (HH)-Gli axis is one of the signaling pathways involved, with a high number of molecular mediators. In this study, we investigated the association between HH-Gli intermediates and clinical parameters. We found that high levels of SuFu are associated with high dissemination patterns in patients with glioma. Therefore, we analyzed SuFu expression data in three glioma cohorts of surgical samples (N =1,759) and modified its expression in Glioblastoma Cancer Stem Cells (GB CSC) in vitro models. Our data reveal that SuFu overexpression increases cancer stemness properties together with a migratory phenotype. This work identifies SuFu as a new molecular player in glioma cell migration and a promising target to develop blocking agents to decrease GB dissemination.This research was funded by grants from the "Proyectos de Investigación en Salud" (PI21/01353) and La Universidad Francisco de Vitoria-Banco Santander (UFV2021-23).S

Beyond the Warburg Effect: Oxidative and Glycolytic Phenotypes Coexist within the Metabolic Heterogeneity of Glioblastoma.

Glioblastoma (GBM) is the most aggressive primary brain tumor, with a median survival at diagnosis of 16–20 months. Metabolism represents a new attractive therapeutic target; however, due to high intratumoral heterogeneity, the application of metabolic drugs in GBM is challenging. We characterized the basal bioenergetic metabolism and antiproliferative potential of metformin (MF), dichloroacetate (DCA), sodium oxamate (SOD) and diazo-5-oxo-L-norleucine (DON) in three distinct glioma stem cells (GSCs) (GBM18, GBM27, GBM38), as well as U87MG. GBM27, a highly oxidative cell line, was the most resistant to all treatments, except DON. GBM18 and GBM38, Warburg-like GSCs, were sensitive to MF and DCA, respectively. Resistance to DON was not correlated with basal metabolic phenotypes. In combinatory experiments, radiomimetic bleomycin exhibited therapeutically relevant synergistic effects with MF, DCA and DON in GBM27 and DON in all other cell lines. MF and DCA shifted the metabolism of treated cells towards glycolysis or oxidation, respectively. DON consistently decreased total ATP production. Our study highlights the need for a better characterization of GBM from a metabolic perspective. Metabolic therapy should focus on both glycolytic and oxidative subpopulations of GSCs.post-print3439 K

Cancer stem cells from human glioblastoma resemble but do not mimic original tumors after in vitro passaging in serum-free media

Human gliomas harbour cancer stem cells (CSCs) that evolve along the course of the disease, forming highly heterogeneous subpopulations within the tumour mass. These cells possess self-renewal properties and appear to contribute to tumour initiation, metastasis and resistance to therapy. CSC cultures isolated from surgical samples are considered the best preclinical in vitro model for primary human gliomas. However, it is not yet well characterized to which extent their biological and functional properties change during in vitro passaging in the serum-free culture conditions. Here, we demonstrate that our CSC-enriched cultures harboured from one to several CSC clones from the human glioma sample. When xenotransplanted into mouse brain, these cells generated tumours that reproduced at least three different dissemination patterns found in original tumours. Along the passages in culture, CSCs displayed increased expression of stem cell markers, different ratios of chromosomal instability events, and a varied response to drug treatment. Our findings highlight the need for better characterization of CSC-enriched cultures in the context of their evolution in vitro, in order to uncover their full potential as preclinical models in the studies aimed at identifying molecular biomarkers and developing new therapeutic approaches of human gliomas.Peer reviewe

Identification of CRF66_BF, a New HIV-1 Circulating Recombinant Form of South American Origin

Circulating recombinant forms (CRFs) are important components of the HIV-1 pandemic. Among 110 reported in the literature, 17 are BF1 intersubtype recombinant, most of which are of South American origin. Among these, all 5 identified in the Southern Cone and neighboring countries, except Brazil, derive from a common recombinant ancestor related to CRF12_BF, which circulates widely in Argentina, as deduced from coincident breakpoints and clustering in phylogenetic trees. In a HIV-1 molecular epidemiological study in Spain, we identified a phylogenetic cluster of 20 samples from 3 separate regions which were of F1 subsubtype, related to the Brazilian strain, in protease-reverse transcriptase (Pr-RT) and of subtype B in integrase. Remarkably, 14 individuals from this cluster (designated BF9) were Paraguayans and only 4 were native Spaniards. HIV-1 transmission was predominantly heterosexual, except for a subcluster of 6 individuals, 5 of which were men who have sex with men. Ten additional database sequences, from Argentina (n = 4), Spain (n = 3), Paraguay (n = 1), Brazil (n = 1), and Italy (n = 1), branched within the BF9 cluster. To determine whether it represents a new CRF, near full-length genome (NFLG) sequences were obtained for 6 viruses from 3 Spanish regions. Bootscan analyses showed a coincident BF1 recombinant structure, with 5 breakpoints, located in p17 gag , integrase, gp120, gp41-rev overlap, and nef, which was identical to that of two BF1 recombinant viruses from Paraguay previously sequenced in NFLGs. Interestingly, none of the breakpoints coincided with those of CRF12_BF. In a maximum likelihood phylogenetic tree, all 8 NFLG sequences grouped in a strongly supported clade segregating from previously identified CRFs and from the CRF12_BF "family" clade. These results allow us to identify a new HIV-1 CRF, designated CRF66_BF. Through a Bayesian coalescent analysis, the most recent common ancestor of CRF66_BF was estimated around 1984 in South America, either in Paraguay or Argentina. Among Pr-RT sequences obtained by us from HIV-1-infected Paraguayans living in Spain, 14 (20.9%) of 67 were of CRF66_BF, suggesting that CRF66_BF may be one of the major HIV-1 genetic forms circulating in Paraguay. CRF66_BF is the first reported non-Brazilian South American HIV-1 CRF_BF unrelated to CRF12_BF.This work was funded through Acción Estratégica en Salud Intramural (AESI), Instituto de Salud Carlos III, projects PI16CIII/00033 and PI19CIII/00042; Red de Investigación en SIDA (RIS), Instituto de Salud Carlos III, Subdirección General de Evaluación y Fondo Europeo de Desarrollo Regional (FEDER), Plan Nacional I+D+I, project RD16ISCIII/0002/0004; and scientific agreements with Consellería de Sanidade, Government of Galicia (MVI 1004/16) and Osakidetza-Servicio Vasco de Salud, Government of Basque Country (MVI 1001/16).S

Plan de Acción en España para la erradicación de la poliomelitis: Vigilancia de la Parálisis Flácida Aguda y Vigilancia de Enterovirus en España. Informe 2020

Centro Nacional de Epidemiología y Centro Nacional de Microbiología. ISCIII. Plan de acción en España para la Erradicación de la Poliomielitis. Vigilancia de la Parálisis Flácida Aguda y Vigilancia de Enterovirus en España, Informe año 2020. Madrid, 5 de noviembre de 2021.[ES] En España la situación libre de polio se monitoriza con la vigilancia de Parálisis Flácida Aguda (PFA) en niños menores de 15 años, como recomienda la Organización Mundial de la Salud (OMS). La vigilancia la realizan los servicios de vigilancia autonómicos y la red de laboratorios de PFA y a nivel nacional se coordina en el Centro Nacional de Epidemiología (CNE, ISCIII) y en el Laboratorio de Poliovirus del Centro Nacional de Microbiología (CNM, ISCIII). En el año 2020 en España no hubo casos de poliomielitis. Se notificaron 0,17 casos de PFA por 100.000 niños menores de 15 años, por debajo del objetivo de sensibilidad establecido por la OMS de un caso de PFA al año por cada 100.000 menores de 15 años. Solamente se detectaron enterovirus no-polio (EVNP) en las muestras de dos casos (EV-D68 y EV-B, respectivamente). En España también se realiza la vigilancia de EVNP en otros síndromes neurológicos para complementar el sistema de vigilancia de PFA. En las muestras investigadas en 2020 no se identificó ningún poliovirus y los EVNP más frecuentemente identificados fueron E-18, CV-A6 y E-21. Mientras haya circulación de poliovirus en el mundo hay que mantener activos los sistemas de vigilancia para detectar a tiempo cualquier importación de poliovirus. [EN] Spain monitors its polio-free status by conducting surveillance for cases of acute flaccid paralysis (AFP) in children less than 15 years of age, as recommended by the World Health Organization (WHO). The AFP surveillance is performed by the 19 Regional Epidemiological Surveillance Units and the AFP Surveillance Laboratory Network, coordinated at national level by the National Centre for Epidemiology (CNE. ISCIII) and the National Poliovirus Laboratory at Nacional Center of Microbiology (CNM. ISCIII) respectively. In 2020, no cases of poliomyelitis were reported from clinical surveillance; Spain reported 0.17 non-polio AFP cases per 100,000 children, below the WHO's performance criterion for a sensitive surveillance system (1 non-polio AFP cases per 100,000 children). The non-polio enteroviruses EV-D68, EV-B were identified from clinical specimens collected from AFP cases. Spain also performs enterovirus surveillance to complement the clinical system In 2020, non poliovirus were identified; The non-polioviruses E-18, CV-A6 y E-21 were the most frequently identified serotypes. As long as poliovirus is circulating in the world, surveillance systems must remain active to detect any importation of poliovirus in a timely manner.1. Resumen. 2. Introducción. 3. Resultados de la vigilancia de Parálisis Flácida Aguda (PFA) en España, 2020. 4. Resultados de la vigilancia de enterovirus, España 2020. 5. Resultados de la vigilancia medioambiental de poliovirus. España, 2020. 6. Sistema de Información Microbiológica (SIM). Meningitis por enterovirus. Tendencia. 7. Conclusiones.N