Molecular profiling of circulating tumor cells links plasticity to the metastatic process in endometrial cancer

Background: About 20% of patients diagnosed with endometrial cancer (EC) are considered high-risk with unfavorable prognosis. In the framework of the European Network for Individualized Treatment in EC (ENITEC), we investigated the presence and phenotypic features of Circulating Tumor Cells (CTC) in high-risk EC patients. Methods: CTC isolation was carried out in peripheral blood samples from 34 patients, ranging from Grade 3 Stage IB to Stage IV carcinomas and recurrences, and 27 healthy controls using two methodologies. Samples were subjected to EpCAM-based immunoisolation using the CELLection™ Epithelial Enrich kit (Invitrogen, Dynal) followed by RTqPCR analysis. The phenotypic determinants of endometrial CTC in terms of pathogenesis, hormone receptor pathways, stem cell markers and epithelial to mesenchymal transition (EMT) drivers were asked. Kruskal-Wallis analysis followed by Dunn's post-test was used for comparisons between groups. Statistical significance was set at p < 0.05. Results: EpCAM-based immunoisolation positively detected CTC in high-risk endometrial cancer patients. CTC characterization indicated a remarkable plasticity phenotype defined by the expression of the EMT markers ETV5, NOTCH1, SNAI1, TGFB1, ZEB1 and ZEB2. In addition, the expression of ALDH and CD44 pointed to an association with stemness, while the expression of CTNNB1, STS, GDF15, RELA, RUNX1, BRAF and PIK3CA suggested potential therapeutic targets. We further recapitulated the EMT phenotype found in endometrial CTC through the up-regulation of ETV5 in an EC cell line, and validated in an animal model of systemic dissemination the propensity of these CTC in the accomplishment of metastasis. Conclusions: Our results associate the presence of CTC with high-risk EC. Gene-expression profiling characterized a CTC-plasticity phenotype with stemness and EMT features. We finally recapitulated this CTC-phenotype by over-expressing ETV5 in the EC cell line Hec1A and demonstrated an advantage in the promotion of metastasis in an in vivo mouse model of CTC dissemination and homing

Gene Therapy Corrects Mitochondrial Dysfunction in Hematopoietic Progenitor Cells and Fibroblasts from Coq9R239X Mice

This study has been submitted to the patent's offices at the "University of Granada" and "Fundación Progreso y Salud". Please note that the results of this manuscript have been submitted to patent protection (application number P201630630; title: “Uses of Coenzyme Q biosynthetic proteins”; date:05/16/2016).Recent clinical trials have shown that in vivo and ex vivo gene therapy strategies can be an option for the treatment of several neurological disorders. Both strategies require efficient and safe vectors to 1) deliver the therapeutic gene directly into the CNS or 2) to genetically modify stem cells that will be used as Trojan horses for the systemic delivery of the therapeutic protein. A group of target diseases for these therapeutic strategies are mitochondrial encephalopathies due to mutations in nuclear DNA genes. In this study, we have developed a lentiviral vector (CCoq9WP) able to overexpress Coq9 mRNA and COQ9 protein in mouse embryonic fibroblasts (MEFs) and hematopoietic progenitor cells (HPCs) from Coq9R239X mice, an animal model of mitochondrial encephalopathy due to primary Coenzyme Q (CoQ) deficiency. Ectopic over-expression of Coq9 in both cell types restored the CoQ biosynthetic pathway and mitochondrial function, improving the fitness of the transduced cells. These results show the potential of the CCoq9WP lentiviral vector as a tool for gene therapy to treat mitochondrial encephalopathies.This work was supported by grants from Ministerio de Economía y Competitividad (Spain) and the European Regional Development Fund (ERDF) from the European Union, to LCL through the research grants SAF2013-47761-R and SAF2015-65786-R; by Fondo de Investigaciones Sanitarias ISCIII (Spain) and the European Regional Development Fund (ERDF) from the European Union through the research grants PI12/01097 and ISCIII Red de Terapia Celular TerCel RD12/0019/0006 to FM; by the Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía-FEDER/Fondo de Cohesion Europeo (FSE) de Andalucía through the research grants P10-CTS-6133 to LCL; P09-CTS-04532, PI-57069, PI-0001/2009 and PAIDI-Bio-326 to F.M.; PI-0160/2012 to KB and PI-0407/2012 to MC; by the NIH through the research P01HD080642 to LCL and by the foundation “todos somos raros, todos somos únicos” to LCL. LCL is supported by the ‘Ramón y Cajal’ National Programme, Ministerio de Economía y Competitividad, Spain (RYC-2011-07643)

Ibero-American Consensus on Low- and No-Calorie Sweeteners: Safety, Nutritional Aspects and Benefits in Food and Beverages

International scientific experts in food, nutrition, dietetics, endocrinology, physical activity, paediatrics, nursing, toxicology and public health met in Lisbon on 2-4 July 2017 to develop a Consensus on the use of low- and no-calorie sweeteners (LNCS) as substitutes for sugars and other caloric sweeteners. LNCS are food additives that are broadly used as sugar substitutes to sweeten foods and beverages with the addition of fewer or no calories. They are also used in medicines, health-care products, such as toothpaste, and food supplements. The goal of this Consensus was to provide a useful, evidence-based, point of reference to assist in efforts to reduce free sugars consumption in line with current international public health recommendations. Participating experts in the Lisbon Consensus analysed and evaluated the evidence in relation to the role of LNCS in food safety, their regulation and the nutritional and dietary aspects of their use in foods and beverages. The conclusions of this Consensus were: (1) LNCS are some of the most extensively evaluated dietary constituents, and their safety has been reviewed and confirmed by regulatory bodies globally including the World Health Organisation, the US Food and Drug Administration and the European Food Safety Authority; (2) Consumer education, which is based on the most robust scientific evidence and regulatory processes, on the use of products containing LNCS should be strengthened in a comprehensive and objective way; (3) The use of LNCS in weight reduction programmes that involve replacing caloric sweeteners with LNCS in the context of structured diet plans may favour sustainable weight reduction. Furthermore, their use in diabetes management programmes may contribute to a better glycaemic control in patients, albeit with modest results. LNCS also provide dental health benefits when used in place of free sugars; (4) It is proposed that foods and beverages with LNCS could be included in dietary guidelines as alternative options to products sweetened with free sugars; (5) Continued education of health professionals is required, since they are a key source of information on issues related to food and health for both the general population and patients. With this in mind, the publication of position statements and consensus documents in the academic literature are extremely desirable

Combined search for neutrinos from dark matter self-annihilation in the Galactic Center with ANTARES and IceCube

[EN] We present the results of the first combined dark matter search targeting the Galactic Center using the ANTARES and IceCube neutrino telescopes. For dark matter particles with masses from 50 to 1000 GeV, the sensitivities on the self-annihilation cross section set by ANTARES and IceCube are comparable, making this mass range particularly interesting for a joint analysis. Dark matter self-annihilation through the ¿+¿¿, ¿+¿¿, b¯b, and W+W¿ channels is considered for both the Navarro-Frenk-White and Burkert halo profiles. In the combination of 2101.6 days of ANTARES data and 1007 days of IceCube data, no excess over the expected background is observed. Limits on the thermally averaged dark matter annihilation cross section h¿A¿i are set. These limits present an improvement of up to a factor of 2 in the studied dark matter mass range with respect to the individual limits published by both collaborations. When considering dark matter particles with a mass of 200 GeV annihilating through the ¿þ¿¿ channel, the value obtained for the limit is 7.44 × 10¿24 cm3 s¿1 for the Navarro-Frenk-White halo profile. For the purpose of this joint analysis, the model parameters and the likelihood are unified, providing a benchmark for forthcoming dark matter searches performed by neutrino telescopes.The authors from the ANTARES Collaboration acknowledge the financial support of the following funding agencies: Centre National de la Recherche Scientifique (CNRS), Commissariat a l'energie atomique et auxenergies alternatives (CEA), Commission Europeenne (FEDER fund and Marie Curie Program), Institut Universitaire de France (IUF), IdEx program and UnivEarthS Labex program at Sorbonne Paris Cite (ANR-10-LABX-0023 and ANR-11IDEX-0005-02), Labex OCEVU (ANR-11-LABX-0060) and the A*MIDEX project (ANR-11-IDEX-0001-02), Region Ile-de-France (DIM-ACAV), Region Alsace (contrat CPER), Region Provence-Alpes-Cote d'Azur, Departement du Var and Ville de La Seyne-sur-Mer, France; Bundesministerium fur Bildung und Forschung (BMBF), Germany; Istituto Nazionale di Fisica Nucleare (INFN), Italy; Nederlandse organisatie voor Wetenschappelijk Onderzoek (NWO), the Netherlands; Council of the President of the Russian Federation for young scientists and leading scientific schools supporting grants, Russia; Executive Unit for Financing Higher Education, Research, Development and Innovation (UEFISCDI), Romania; Ministerio de Ciencia, Innovacion, Investigacion y Universidades (MCIU): Programa Estatal de Generacion de Conocimiento (refs. PGC2018-096663-B-C41, -A-C42, -B-C43, -B-C44) (MCIU/FEDER), Severo Ochoa Centre of Excellence and MultiDark Consolider (MCIU), Junta de Andalucia (ref. SOMM17/6104/UGR), Generalitat Valenciana: Grisolia (ref. GRISOLIA/2018/119), Spain; Ministry of Higher Education, Scientific Research and Professional Training, Morocco. We also acknowledge the technical support of Ifremer, AIM and Foselev Marine for the sea operation and CC-IN2P3 for the computing facilities. The authors from the IceCube Collaboration gratefully acknowledge the support from the following agencies and institutions: USA-U.S. National Science Foundation-Office of Polar Programs, U.S. National Science Foundation-Physics Division, Wisconsin Alumni Research Foundation, Center for High Throughput Computing (CHTC) at the University of Wisconsin-Madison, Open Science Grid (OSG), Extreme Science and Engineering Discovery Environment (XSEDE), U.S. Department of Energy-National Energy Research Scientific Computing Center, Particle astrophysics research computing center at the University of Maryland, Institute for Cyber-Enabled Research at Michigan State University, and Astroparticle physics computational facility at Marquette University; Belgium-Funds for Scientific Research (FRS-FNRS and FWO), FWO Odysseus and Big Science programmes, and Belgian Federal Science Policy Office (Belspo); Germany-Bundesministerium fur Bildung und Forschung (BMBF), Deutsche Forschungsgemeinschaft (DFG), Helmholtz Alliance for Astroparticle Physics (HAP), Initiative and Networking Fund of the Helmholtz Association, Germany-Deutsches Elektronen Synchrotron (DESY), and High Performance Computing cluster of the RWTH Aachen; Sweden-Swedish Research Council, Swedish Polar Research Secretariat, Swedish National Infrastructure for Computing (SNIC), and Knut and Alice Wallenberg Foundation; Australia-Australian Research Council; Canada-Natural Sciences and Engineering Research Council of Canada, Calcul Quebec, Compute Ontario, Canada Foundation for Innovation, WestGrid, and Compute Canada; Denmark-Villum Fonden, Danish National Research Foundation (DNRF), Carlsberg Foundation; New Zealand-Marsden Fund; Japan-Japan Society for Promotion of Science (JSPS) and Institute for Global Prominent Research (IGPR) of Chiba University; Korea-National Research Foundation of Korea (NRF); Switzerland-Swiss National Science Foundation (SNSF); United Kingdom-Department of Physics, University of Oxford. The IceCube collaboration acknowledges the significant contributions to this manuscript from Sebastian Baur, Nadege Iovine and Sara Rebecca Gozzini.Albert, A.; Andre, M.; Anghinolfi, M.; Ardid Ramírez, M.; Aubert, J.; Aublin, J.; Baret, B.... (2020). Combined search for neutrinos from dark matter self-annihilation in the Galactic Center with ANTARES and IceCube. Physical Review D: covering particles, fields, gravitation, and cosmology. 102(8):1-13. https://doi.org/10.1103/PhysRevD.102.082002S113102

ANTARES and IceCube Combined Search for Neutrino Point-like and Extended Sources in the Southern Sky

[EN] A search for point-like and extended sources of cosmic neutrinos using data collected by the ANTARES and IceCube neutrino telescopes is presented. The data set consists of all the track-like and shower-like events pointing in the direction of the Southern Sky included in the nine-year ANTARES point-source analysis, combined with the throughgoing track-like events used in the seven-year IceCube point-source search. The advantageous ¿eld of view of ANTARES and the large size of IceCube are exploited to improve the sensitivity in the Southern Sky by a factor of ~2 compared to both individual analyses. In this work, the Southern Sky is scanned for possible excesses of spatial clustering, and the positions of preselected candidate sources are investigated. In addition, special focus is given to the region around the Galactic Center, whereby a dedicated search at the location of SgrA* is performed, and to the location of the supernova remnant RXJ 1713.7-3946. No signi¿cant evidence for cosmic neutrino sources is found, and upper limits on the ¿ux from the various searches are presented.The authors of the IceCube Collaboration acknowledge the support from the following agencies and institutions: USA-U.S. National Science Foundation-Office of Polar Programs, U.S. National Science Foundation-Physics Division, Wisconsin Alumni Research Foundation, Center for High Throughput Computing (CHTC) at the University of Wisconsin-Madison, Open Science Grid (OSG), Extreme Science and Engineering Discovery Environment (XSEDE), U.S. Department of Energy-National Energy Research Scientific Computing Center, Particle astrophysics research computing center at the University of Maryland, Institute for Cyber-Enabled Research at Michigan State University, and Astroparticle physics computational facility at Marquette University; Belgium-Funds for Scientific Research (FRS-FNRS and FWO), FWO Odysseus and Big Science programmes, and Belgian Federal Science Policy Office (Belspo); Germany-Bundesministerium fur Bildung und Forschung (BMBF), Deutsche Forschungsgemeinschaft (DFG), Helmholtz Alliance for Astroparticle Physics (HAP), Initiative and Networking Fund of the Helmholtz Association, Deutsches Elektronen Synchrotron (DESY), and High Performance Computing Cluster of the RWTH Aachen; Sweden-Swedish Research Council, Swedish Polar Research Secretariat, Swedish National Infrastructure for Computing (SNIC), and Knut and Alice Wallenberg Foundation; Australia - Australian Research Council; Canada-Natural Sciences and Engineering Research Council of Canada, Calcul Quebec, Compute Ontario, Canada Foundation for Innovation, WestGrid, and Compute Canada; Denmark-Villum Fonden, Danish National Research Foundation (DNRF), Carlsberg Foundation; New Zealand-Marsden Fund; Japan-Japan Society for Promotion of Science (JSPS) and Institute for Global Prominent Research (IGPR) of Chiba University; Korea-National Research Foundation of Korea (NRF); Switzerland-Swiss National Science Foundation (SNSF); United Kingdom-Department of Physics, University of Oxford.Albert, A.; Andre, M.; Anghinolfi, M.; Anton, G.; Ardid Ramírez, M.; Aubert, J.; Aublin, J.... (2020). ANTARES and IceCube Combined Search for Neutrino Point-like and Extended Sources in the Southern Sky. The Astrophysical Journal. 892(2):1-12. https://doi.org/10.3847/1538-4357/ab7afbS112892

Multimessenger NuEM Alerts with AMON

The Astrophysical Multimessenger Observatory Network (AMON), has developed a real-time multi-messenger alert system. The system performs coincidence analyses of datasets from gamma-ray and neutrino detectors, making the Neutrino-Electromagnetic (NuEM) alert channel. For these analyses, AMON takes advantage of sub-threshold events, i.e., events that by themselves are not significant in the individual detectors. The main purpose of this channel is to search for gamma-ray counterparts of neutrino events. We will describe the different analyses that make-up this channel and present a selection of recent results

Update on the Combined Analysis of Muon Measurements from Nine Air Shower Experiments

Over the last two decades, various experiments have measured muon densities in extensive air showers over several orders of magnitude in primary energy. While some experiments observed differences in the muon densities between simulated and experimentally measured air showers, others reported no discrepancies. We will present an update of the meta-analysis of muon measurements from nine air shower experiments, covering shower energies between a few PeV and tens of EeV and muon threshold energies from a few 100 MeV to about 10GeV. In order to compare measurements from different experiments, their energy scale was cross-calibrated and the experimental data has been compared using a universal reference scale based on air shower simulations. Above 10 PeV, we find a muon excess with respect to simulations for all hadronic interaction models, which is increasing with shower energy. For EPOS-LHC and QGSJet-II.04 the significance of the slope of the increase is analyzed in detail under different assumptions of the individual experimental uncertainties