A Novel Circulating MicroRNA for the Detection of Acute Myocarditis.

The diagnosis of acute myocarditis typically requires either endomyocardial biopsy (which is invasive) or cardiovascular magnetic resonance imaging (which is not universally available). Additional approaches to diagnosis are desirable. We sought to identify a novel microRNA for the diagnosis of acute myocarditis. To identify a microRNA specific for myocarditis, we performed microRNA microarray analyses and quantitative polymerase-chain-reaction (qPCR) assays in sorted CD4+ T cells and type 17 helper T (Th17) cells after inducing experimental autoimmune myocarditis or myocardial infarction in mice. We also performed qPCR in samples from coxsackievirus-induced myocarditis in mice. We then identified the human homologue for this microRNA and compared its expression in plasma obtained from patients with acute myocarditis with the expression in various controls. We confirmed that Th17 cells, which are characterized by the production of interleukin-17, are a characteristic feature of myocardial injury in the acute phase of myocarditis. The microRNA mmu-miR-721 was synthesized by Th17 cells and was present in the plasma of mice with acute autoimmune or viral myocarditis but not in those with acute myocardial infarction. The human homologue, designated hsa-miR-Chr8:96, was identified in four independent cohorts of patients with myocarditis. The area under the receiver-operating-characteristic curve for this novel microRNA for distinguishing patients with acute myocarditis from those with myocardial infarction was 0.927 (95% confidence interval, 0.879 to 0.975). The microRNA retained its diagnostic value in models after adjustment for age, sex, ejection fraction, and serum troponin level. After identifying a novel microRNA in mice and humans with myocarditis, we found that the human homologue (hsa-miR-Chr8:96) could be used to distinguish patients with myocarditis from those with myocardial infarction. (Funded by the Spanish Ministry of Science and Innovation and others.).Supported by a grant (PI19/00545, to Dr. Martín) from the Ministry of Science and Innovation through the Carlos III Institute of Health–Fondo de Investigación Sanitaria; by a grant from the Biomedical Research Networking Center on Cardiovascular Diseases (to Drs. Martín, Sánchez-Madrid, and Ibáñez); by grants (S2017/BMD-3671-INFLAMUNE-CM, to Drs. Martín and Sánchez-Madrid; and S2017/BMD-3867-RENIM-CM, to Dr. Ibáñez) from Comunidad de Madrid; by a grant (20152330 31, to Drs. Martín, Sánchez-Madrid, and Alfonso) from Fundació La Marató de TV3; by grants (ERC-2011-AdG 294340-GENTRIS, to Dr. Sánchez-Madrid; and ERC-2018-CoG 819775-MATRIX, to Dr. Ibáñez) from the European Research Council; by grants (SAF2017-82886R, to Dr. Sánchez-Madrid; RETOS2019-107332RB-I00, to Dr. Ibáñez; and SAF2017-90604-REDT-NurCaMeIn and RTI2018-095928-BI00, to Dr. Ricote) from the Ministry of Science and Innovation; by Fondo Europeo de Desarrollo Regional (FEDER); and by a 2016 Leonardo Grant for Researchers and Cultural Creators from the BBVA Foundation to Dr. Martín. The National Center for Cardiovascular Research (CNIC) is supported by the Carlos III Institute of Health, the Ministry of Science and Innovation, the Pro CNIC Foundation, and by a Severo Ochoa Center of Excellence grant (SEV-2015-0505). Mr. Blanco-Domínguez is supported by a grant (FPU16/02780) from the Formación de Profesorado Universitario program of the Spanish Ministry of Education, Culture, and Sports. Ms. Linillos-Pradillo is supported by a fellowship (PEJD-2016/BMD-2789) from Fondo de Garantía de Empleo Juvenil de Comunidad de Madrid. Dr. Relaño is supported by a grant (BES-2015-072625) from Contratos Predoctorales Severo Ochoa para la Formación de Doctores of the Ministry of Economy and Competitiveness. Dr. Alonso-Herranz is supported by a fellowship from La Caixa–CNIC. Dr. Caforio is supported by Budget Integrato per la Ricerca dei Dipartimenti BIRD-2019 from Università di Padova. Dr. Das is supported by grants (UG3 TR002878 and R35 HL150807) from the National Institutes of Health and the American Heart Association through its Strategically Focused Research Networks.S

Wage inequality, segregation by skill and the price of capital in an assignment model

Some pieces of empirical evidence suggest that in the U.S., over the last few decades, (i) wage inequality between-plants has risen much more than wage inequality within-plants and (ii) there has been an increase in the segregation of workers by skill into separate plants. This paper presents a frictionless assignment model in which these two features can be explained simultaneously as the result of the decline in the relative price of capital. Additional implications of the model regarding the skill premium and the dispersion in labor productivity across plants are also consistent with the empirical evidence. [resumen de autor

Integration or integrations: The cultural-educational integration.

CONTENIDO Artículos El archivo histórico de La Grita: Una fenomenología del poder. The historical archive of La Grita: A phenomenology of power. Lugo M., Yariesa Barro/Barroco. Aleijadinho (1737/1814). Mud/Baroque. Aleijadinho (1737/1814). Rosales Cárdenas, Otto Un lugar en la historia de la humanidad. A place in human history. Valero M., Mario A. Energía y ambiente: Pasado, presente y futuro. Parte uno: Sistema energético basado en fuentes fósiles. Energy and environment: Past, present and future. Part one: Energetic system based on fossil sources. Posso, Fausto Diagnóstico de fertilidad de suelos en pendientes inferiores a 25%. Boconó, estado Trujillo. Diagnosis of fertility of soils on slopes under 25%. Boconó, Trujillo state. Bastidas, Arturo El enfoque geohistórico: Una experiencia en la praxis educativa. The geohistorical approach: A experience in educational praxis. Sayago, Aura A. y León de F., Egda Integración o integraciones: La integración cultural-educativa. Integration or integrations: The cultural-educational integration. Garicano Aznarez, Fernando M. Notas y Documentos Homenaje al geógrafo internacional: Milton Santos. Ramírez Suárez, Ricardo Universidad de Los Andes Táchira Consejo de Estudios de Postgrado Programa de Maestría en Educación: Enseñanza de la geografía.277-292Nivel analíticosemestra

Insulinoma asociado a adenoma hipofisario: ¿Un potencial caso de NEM-1 esporádico? Presentación y discusión de un caso

Los insulinomas son tumores neuroendocrinos productoresde insulina derivados de las células β de los islotes pancreáticos,los cuales ocasionan estados de hiperinsulinemiae hipoglicemia severa. Se presenta el caso clínico de unapaciente de 31 años con antecedentes de episodios de hipoglicemiasfrecuentes de unos 6 meses de evolución, cuyaclínica se caracterizó por mareos, palpitaciones, sudoraciónprofusa y debilidad generalizada, síntomas neuropsiquiátricosy convulsiones tónico-clónicas. Incidentalmente, se detectógalactgorrea a la exploración de las glándulas mamarias.Durante el seguimiento los niveles séricos de glucosa sedocumentaron entre 26 mg/dL y 45 mg/dL durante las crisisde hipoglicemia. Los niveles de insulina en ayuno, péptidoC y prolactina fueron cuantificados en 39,8 mUI/mL, 4,7 ng/dL, y 126 ng/dL respectivamente. Bajo la sospecha clínicade insulinoma se realizó ecografía abdominal y tomografíaaxial computarizada abdominopélvica con contraste las cualesno fueron concluyentes. Paralelamente, se encontró unadenoma hipofisario por resonancia magnética nuclear de lasilla turca. Al practicarse ecografía endoscópica se localizóuna lesión de ocupación de espacio ligeramente hipoecogénicacon respecto al parénquima pancreático de 1.9 x 1.3 cmubicada en la porción proximal del cuerpo del páncreas. Labiopsia por punción reportó un tumor neuroendocrino biendiferenciado. Se decide resolver quirúrgicamente mediantepancreatectomía distal con preservación esplénica por víalaparoscópica. El estudio anatomopatológico inmunohistoquímicoreveló la presencia de un adenoma encapsulado deislotes pancreáticos productores de insulina

Insulinoma asociado a adenoma hipofisario: ¿Un potencial caso de NEM-1 esporádico? Presentación y discusión de un caso

Los insulinomas son tumores neuroendocrinos productoresde insulina derivados de las células β de los islotes pancreáticos,los cuales ocasionan estados de hiperinsulinemiae hipoglicemia severa. Se presenta el caso clínico de unapaciente de 31 años con antecedentes de episodios de hipoglicemiasfrecuentes de unos 6 meses de evolución, cuyaclínica se caracterizó por mareos, palpitaciones, sudoraciónprofusa y debilidad generalizada, síntomas neuropsiquiátricosy convulsiones tónico-clónicas. Incidentalmente, se detectógalactgorrea a la exploración de las glándulas mamarias.Durante el seguimiento los niveles séricos de glucosa sedocumentaron entre 26 mg/dL y 45 mg/dL durante las crisisde hipoglicemia. Los niveles de insulina en ayuno, péptidoC y prolactina fueron cuantificados en 39,8 mUI/mL, 4,7 ng/dL, y 126 ng/dL respectivamente. Bajo la sospecha clínicade insulinoma se realizó ecografía abdominal y tomografíaaxial computarizada abdominopélvica con contraste las cualesno fueron concluyentes. Paralelamente, se encontró unadenoma hipofisario por resonancia magnética nuclear de lasilla turca. Al practicarse ecografía endoscópica se localizóuna lesión de ocupación de espacio ligeramente hipoecogénicacon respecto al parénquima pancreático de 1.9 x 1.3 cmubicada en la porción proximal del cuerpo del páncreas. Labiopsia por punción reportó un tumor neuroendocrino biendiferenciado. Se decide resolver quirúrgicamente mediantepancreatectomía distal con preservación esplénica por víalaparoscópica. El estudio anatomopatológico inmunohistoquímicoreveló la presencia de un adenoma encapsulado deislotes pancreáticos productores de insulina

Multi-omics Characterization of Response to PD-1 Inhibitors in Advanced Melanoma

Immunotherapy improves the survival of patients with advanced melanoma, 40% of whom become long-term responders. However, not all patients respond to immunotherapy. Further knowledge of the processes involved in the response and resistance to immunotherapy is still needed. In this study, clinical paraffin samples from fifty-two advanced melanoma patients treated with anti-PD-1 inhibitors were assessed via high-throughput proteomics and RNA-seq. The obtained proteomics and transcriptomics data were analyzed using multi-omics network analyses based on probabilistic graphical models to identify those biological processes involved in the response to immunotherapy. Additionally, proteins related to overall survival were studied. The activity of the node formed by the proteins involved in protein processing in the endoplasmic reticulum and antigen presentation machinery was higher in responders compared to non-responders; the activity of the immune and inflammatory response node was also higher in those with complete or partial responses. A predictor for overall survival based on two proteins (AMBP and PDSM5) was defined. In summary, the response to anti-PD-1 therapy in advanced melanoma is related to protein processing in the endoplasmic reticulum, and also to genes involved in the immune and inflammatory responses. Finally, a two-protein predictor can define survival in advanced disease. The molecular characterization of the mechanisms involved in the response and resistance to immunotherapy in melanoma leads the way to establishing therapeutic alternatives for patients who will not respond to this treatment.ISSN:2072-669

Sorting Transcriptomics Immune Information from Tumor Molecular Features Allows Prediction of Response to Anti-PD1 Therapy in Patients with Advanced Melanoma

Immunotherapy based on anti-PD1 antibodies has improved the outcome of advanced melanoma. However, prediction of response to immunotherapy remains an unmet need in the field. Tumor PD-L1 expression, mutational burden, gene profiles and microbiome profiles have been proposed as potential markers but are not used in clinical practice. Probabilistic graphical models and classificatory algorithms were used to classify melanoma tumor samples from a TCGA cohort. A cohort of patients with advanced melanoma treated with PD-1 inhibitors was also analyzed. We established that gene expression data can be grouped in two different layers of information: immune and molecular. In the TCGA, the molecular classification provided information on processes such as epidermis development and keratinization, melanogenesis, and extracellular space and membrane. The immune layer classification was able to distinguish between responders and non-responders to immunotherapy in an independent series of patients with advanced melanoma treated with PD-1 inhibitors. We established that the immune information is independent than molecular features of the tumors in melanoma TCGA cohort, and an immune classification of these tumors was established. This immune classification was capable to determine what patients are going to respond to immunotherapy in a new cohort of patients with advanced melanoma treated with PD-1 inhibitors Therefore, this immune signature could be useful to the clinicians to identify those patients who will respond to immunotherapy

Optimal information transmission in organizations : search and congestion

We propose a stylized model of a problem-solving organization whose internal communication structure is given by a fixed network. Problems arrive randomly anywhere in this network and must find their way to their respective specialized solvers by relying on local information alone. The organization handles multiple problems simultaneously. For this reason, the process may be subject to congestion. We provide a characterization of the threshold of collapse of the network and of the stock of floating problems (or average delay) that prevails below that threshold. We build upon this characterization to address a design problem: the determination of what kind of network architecture optimizes performance for any given problem arrival rate. We conclude that, for low arrival rates, the optimal network is very polarized (i.e. star-like or centralized), whereas it is largely homogenous (or decentralized) for high arrival rates. These observations are in line with a common transformation experienced by information-intensive organizations as their work flow has risen in recent years