Oncogenic context shapes the fitness landscape of tumor suppression

We are grateful to all members of D2G Oncology for expert advice and helpful comments. We thank Explora and The Jackson Laboratory for expert animal care. We would like to acknowledge the American Association for Cancer Research and its financial and material support in the development of the AACR Project GENIE registry, as well as members of the consortium for their commitment to data sharing (interpretations are the responsibility of the study authors). We thank AstraZeneca, Bristol-Myers Squibb, Revolution Medicines, Merck KGaA, and CureTeq for generously allowing the inclusion of data generated in collaboration with D2G Oncology. L.E.D. is the Burt Gwirtzman Research Scholar in Lung Cancer. D.A.P. and M.M.W. are supported by NIH R01-CA 234349. This work was supported in part by NIH SBIR R44-CA250672.Tumors acquire alterations in oncogenes and tumor suppressor genes in an adaptive walk through the fitness landscape of tumorigenesis. However, the interactions between oncogenes and tumor suppressor genes that shape this landscape remain poorly resolved and cannot be revealed by human cancer genomics alone. Here, we use a multiplexed, autochthonous mouse platform to model and quantify the initiation and growth of more than one hundred genotypes of lung tumors across four oncogenic contexts: KRAS G12D, KRAS G12C, BRAF V600E, and EGFR L858R. We show that the fitness landscape is rugged—the effect of tumor suppressor inactivation often switches between beneficial and deleterious depending on the oncogenic context—and shows no evidence of diminishing-returns epistasis within variants of the same oncogene. These findings argue against a simple linear signaling relationship amongst these three oncogenes and imply a critical role for off-axis signaling in determining the fitness effects of inactivating tumor suppressors.American Association for Cancer ResearchACR Project GENIEAstraZenecaBristol-Myers Squibb R01-CA 234349, SBIR R44-CA250672Merck KGa

Mutation affecting the proximal promoter of Endoglin as the origin of hereditary hemorrhagic telangiectasia type 1

[Background] Hereditary hemorrhagic telangiectasia (HHT) is a vascular multi-organ system disorder. Its diagnostic criteria include epistaxis, telangiectases in mucocutaneous sites, arteriovenous malformations (AVMs), and familial inheritance. HHT is transmitted as an autosomal dominant condition, caused in 85% of cases by mutations in either Endoglin (ENG) or Activin receptor-like kinase (ACVRL1/ACVRL1/ALK1) genes. Pathogenic mutations have been described in exons, splice junctions and, in a few cases with ENG mutations, in the proximal promoter, which creates a new ATG start site. However, no mutations affecting transcription regulation have been described to date in HHT, and this type of mutation is rarely identified in the literature on rare diseases.[Methods] Sequencing data from a family with HHT lead to single nucleotide change, c.-58G > A. The functionality and pathogenicity of this change was analyzed by in vitro mutagenesis, quantitative PCR and Gel shift assay. Student t test was used for statistical significance.[Results] A single nucleotide change, c.-58G > A, in the proximal ENG promoter co-segregated with HHT clinical features in an HHT family. This mutation was present in the proband and in 2 other symptomatic members, whereas 2 asymptomatic relatives did not harbor the mutation. Analysis of RNA from activated monocytes from the probands and the healthy brother revealed reduced ENG mRNA expression in the HHT patient (p = 0.005). Site-directed mutagenesis of the ENG promoter resulted in a three-fold decrease in luciferase activity of the mutant c.-58A allele compared to wild type (p = 0.005). Finally, gel shift assay identified a DNA-protein specific complex.[Conclusions] The novel ENG c.-58G > A substitution in the ENG promoter co-segregates with HHT symptoms in a family and appears to affect the transcriptional regulation of the gene, resulting in reduced ENG expression. ENG c.-58G > A may therefore be a pathogenic HHT mutation leading to haploinsufficiency of Endoglin and HHT symptoms. To the best of our knowledge, this is the first report of a pathogenic mutation in HHT involving the binding site for a transcription factor in the promoter of ENG.This study has been supported by grants from Ministerio de Economia y Competitividad of Spain (SAF2011-23475 and SAF2014-52374-R) to L.M. Botella and Centro de Investigación Biomedica en Red de Enfermedades Raras (CIBERER).Peer reviewe

Suppressors of Cytokine Signaling 3 Expression in Eosinophils: Regulation by PGE2 and Th2 Cytokines

Asthma and nonasthmatic eosinophilic bronchitis (NAEB) are respiratory disorders characterized by a predominance of Th2 cells and eosinophilic inflammation. Suppressors of cytokine signaling (SOCS) proteins play an important role in Th2-mediated allergic responses through control of the balance between Th1 and Th2 cells, particularly, SOCS3 and SOCS5. The aim of this study was to analyze SOCS expression in human peripheral blood eosinophils from patients with asthma, NAEB and healthy controls. SOCS expression in eosinophils from subjects was demonstrated by different techniques. Results showed that expression of SOCS3 in eosinophils and CD4 T cells from patients was higher than in healthy subjects. In addition, we demonstrated that prostaglandin E2 (PGE2) and Th2 cytokines are able to upregulate SOCS3 production in eosinophils and attenuate its degranulation. In conclusion, eosinophils are able to transcribe and translate SOCS3 protein and can contribute to the regulation of the Th1/Th2 balance through SOCS3 production

Preclinical models of idiosyncratic drug-induced liver injury (iDILI): Moving towards prediction

Idiosyncratic drug-induced liver injury (iDILI) encompasses the unexpected harms that pre- scription and non-prescription drugs, herbal and dietary supplements can cause to the liver. iDILI remains a major public health problem and a major cause of drug attrition. Given the lack of biomarkers for iDILI prediction, diagnosis and prognosis, searching new models to predict and study mechanisms of iDILI is necessary. One of the major limitations of iDILI preclinical assessment has been the lack of correlation between the markers of hepatotoxicity in animal toxicological studies and clinically significant iDILI. Thus, major advances in the understanding of iDILI susceptibility and pathogenesis have come from the study of well-phenotyped iDILI patients. However, there are many gaps for explaining all the complexity of iDILI susceptibility and mechanisms. Therefore, there is a need to optimize preclinical hu- man in vitro models to reduce the risk of iDILI during drug development. Here, the current experimental models and the future directions in iDILI modelling are thoroughly discussed, focusing on the human cellular models available to study the pathophysiological mechanisms of the disease and the most used in vivo animal iDILI models. We also comment about in silico approaches and the increasing relevance of patient-derived cellular models.This work was supported by grants of Instituto de Salud Carlos III cofounded by Fondo Europeo de Desarrollo Regional-FEDER (contract numbers: PI18/01804, PI19-00883, PT20/00127, UMA18-FEDERJA-194, PY18-3364, Spain) and grants of Consejería de Salud de Andalucía cofounded by FEDER (contract number: PEMP-0127-2020, Spain). M.V.P. holds a Sara Borrell (CD21/00198, Spain) research contract from ISCIII and Consejería de Salud de Andalucía. C.L.G. holds a Juan de la Cierva Incorporación (IJCI-2017-31466, Spain) research contract from Ministerio de Ciencia del Gobierno de España. SCReN and CIBERehd are funded by ISCIII (Spain). This publication is based upon work from COST Action “CA17112dProspective European Drug-Induced Liver Injury Network” supported by COST (European Cooperation in Science and Technology); www.cost.eu. The figures in this review were created with Biorender.com

Asma y proteínas supresoras de la señalización de citocinas (SOCS): evaluación del papel de SOCS3 en la regulación del asma y su aplicación como nueva diana terapéutica para el control del asma

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Biológicas, Departamento de Bioquímica y Biología Molecular, leída el 17-06-2014Sección Deptal. de Bioquímica y Biología Molecular (Biológicas)Fac. de Ciencias BiológicasTRUEunpu

Effect of Graphene Flakes Modified by Dispersion in Surfactant Solutions on the Fluorescence Behaviour of Pyridoxine

The influence of graphene (G) dispersions in different types of surfactants (anionic, non-ionic, and cationic) on the fluorescence of vitamin B6 (pyridoxine) was studied. Scanning electron microscopy (SEM) was used to evaluate the quality of the G dispersions via measuring their flake thickness. The effect of surfactant type and concentration on the fluorescence intensity was analyzed, and fluorescence quenching effects were found for all of the systems. These turn out to be more intense with increasing both surfactant and G concentrations, albeit they do not depend on the G/surfactant weight ratio. For the same G concentration, the magnitude of the quenching follows the order: cationic > non-ionic ≥ anionic. The cationic surfactants, which strongly adsorb onto G via electrostatic attraction, are the most effective dispersing agents and they enable a stronger interaction with the zwitterionic form of the vitamin; the dispersing power improves with increasing the surfactant chain length. The fit of the experimental data to the Stern-Volmer equation suggests either a static or dynamic quenching mechanism for the dispersions in non-ionic surfactants, while those in ionic surfactants show a combined mechanism. The results that were obtained herein have been compared to those that were reported earlier for the quenching of another vitamin, riboflavin, to elucidate how the change in the vitamin structure influences the interactions with G in the surfactant dispersions

Biased binding of Class IA phosphatidyl inositol 3-kinase subunits to Inducible Costimulator (CD278)

15 páginas, 8 figuras, 1 tabla -- PAGS nros. 3065-3079To better understand T lymphocyte costimulation by inducible costimulator (ICOS; H4; CD278), we analyzed proteins binding to ICOS peptides phosphorylated at the Y191MFM motif. Phosphorylated ICOS binds class IA phosphatidyl inositol 3-kinase (PI3-K) p85α, p50-55α and p85β regulatory subunits and p110α, p110δ and p110β catalytic subunits. Intriguingly, T cells expressed high levels of both p110α or p110δ catalytic subunits, yet ICOS peptides, cell surface ICOS or PI3-kinase class IA regulatory subunits preferentially coprecipitated p110α catalytic subunits. Silencing p110α or p110δ partially inhibited Akt/PKB activation induced by anti-CD3 plus anti-ICOS antibodies. However, silencing p110α enhanced and silencing p110δ inhibited Erk activation. Both p110α- and p110δ-specific inhibitors blocked cytokine secretion induced by TCR/CD3 activation with or without ICOS costimulus, but only p110α inhibitors blocked ICOS-induced cell elongation. Thus, p110α and p110δ are essential to optimal T cell activation, but their abundance and activity differentially tune up distinct ICOS signaling pathwaysThis work was supported by grants PI070620 and PI070484 (Fondo de Investigación Sanitaria, Ministerio de Ciencia e Innovación, Spain) and by AIRC (Milan) (to U.D.)Peer reviewe

Estudio de la presión intraocular y del glaucoma en una población de la Región de Murcia / Juan José Zafra Pérez ; Directores Jaime Miralles de Imperial Mora-Figueroa, Mª Paz Villegas Pérez, Manuel Canteras Jordana.

Tesis - Universidad de Murcia.MEDICINA ESPINARDO. DEPOSITO. MU-Tesis 687.Consulte la tesis en: BCA. GENERAL. DEPOSITO. T.M-2098

Endoglin (CD105) and VEGF as potential angiogenic and dissemination markers for colorectal cancer

12 p.-5 fig.-2 tab.Background: Colorectal cancer (CRC) is an important current problem concerning public health due to its high incidence and mortality. Advances in molecular and cellular knowledge and the detection of new disease biomarkers are very important to improve prognosis, prediction, and early diagnosis. In this study, we aimed to analyze the gene and protein expression levels of two angiogenic markers, VEGF and soluble Endoglin, during different tumor stages as well as at different stages of cancer treatment, to predict the diagnosis and evolution of colon and rectal cancer.Material and methods: This study includes 133 CRC patients (93 with colon cancer and 40 with rectal cancer) on which the gene and protein expression of Endoglin (membrane and soluble form) and VEGF were analyzed by molecular and immunohistochemical techniques on different tumor stage samples and plasma obtained preoperatively as well as 3, 6, and 9months after resection of the tumor.Results: VEGF and Endoglin gene expressions were higher in tumor tissue than in surrounding non-tumoral tissue for both types of cancer. The VEGF levels in plasma were found to decrease in less aggressive tumors, whereas soluble Endoglin was increased in preoperative samples of patients with metastasis. Membrane Endoglin expression was higher on the vascular endothelium of more aggressive tumors. In contrast, Endoglin expression was mainly in the colon epithelium in less aggressive stage tumorsConclusion: Endoglin and VEGF are proteins with a major role in the tumor angiogenesis process. This study performed with a wide cohort of human samples shows that both proteins seem to be valuable biomarkers in the diagnosis and prognosis of CRC.The authors thank Laura Barrios (Statistic Department, CSIC) for statistic and bioinformatics support, Marina Arranz Álvarez (IdiPaz Biobank) for technical samples support, “Fundación de Investigación Médica Mutua Madrileña” for its financial support granted to the research project, and to the Coloproctology Unit of the University Hospital La Paz (Madrid) for their collaboration.Peer reviewe

Ciencias de la naturaleza: 3ero ESO : Física y Química

El hilo conductor en torno al cúal se articulan los contenidos es la Materia, su naturaleza y sus cambios. El material elaborado está formado por 5 unidades didácticas que cubren los siguientes contenidos: 1.Introducción al método científico. 2.La materia. 3.Elementos y compuestos, iniciación a las reacciones químicas. 4.Naturaleza atómica de la materia. 5.Naturaleza eléctrica de la materia. Cada una de estas unidades consta de una introducción en la que se plantean los contenidos conceptuales, procedimentales y actitudinales que se abordan en ella, así como un conjunto de actividades estructurales y otras de refuerzo y/o consolidación final..Castilla La ManchaBiblioteca de Educación del Ministerio de Educación, Cultura y Deporte; Calle San Agustín, 5; 28014 Madrid; Tel. +34917748000; [email protected]