Eficacia y posible posicionamiento del tezepelumab para tratar el asma grave

Phenotype; Thymic stromal lymphopoietin; Uncontrolled asthmaFenotip; Limfopoetina estromal tímica; Asma no controladaFenotipo; Linfopoyetina estromal tímica; Asma no controladaThe excellent results for monoclonal antibodies in the treatment of severe uncontrolled asthma (SUCA) represent a milestone in current treatment of asthmatic disorders. Remaining, however, are several subsidiary areas for improvement in which new biologics are expected to make a decisive contribution. These biologics include tezepelumab, a monoclonal antibody that blocks thymic stromal lymphopoietin (TSLP). TSLP is an epithelial-release cytokine (alarmin) that plays a key role in initiating both the innate (group 2 innate lymphoid cell (ILC) pathway) and the acquired (T helper 2 (Th2) pathway) immune responses by activating the type 2 (T2) asthma inflammatory pathway through both. It is also thought that it may additionally intervene in the neutrophilic non-T2 inflammatory pathway (via interaction with ILC3 and interleukin-17). Six clinical trials that included 2187 patients with uncontrolled asthma, with 2 or more exacerbations in the previous year, on medium/high-dose inhaled corticosteroids and at least 1 other controller, have demonstrated – irrespective of T2 endotype (and possibly also non-T2 endotype) – the efficacy and safety of tezepelumab, as it significantly reduces exacerbations (61.7%–66%) and bronchial hyperresponsiveness, and improves lung function, disease control, and quality of life. Tezepelumab could be indicated for the treatment of patients with, independently of the T2 phenotype (eosinophilic and non-eosinophilic), and may even be the only biologic available for treatment of non-T2 SUCA.Los excelentes resultados de los anticuerpos monoclonales en el tratamiento del asma grave no controlada (AGNC) constituyen un hito en el tratamiento actual de los trastornos asmáticos. Sin embargo, aún quedan varios aspectos complementarios susceptibles de mejorar para los que se esperan contribuciones decisivas de los nuevos biofármacos, entre los cuales se encuentra el tezepelumab, un anticuerpo monoclonal que bloquea la linfopoyetina estromal tímica (TSLP). La TSLP es una citocina de liberación epitelial (alarmina) que desempeña una función clave en el inicio de las respuestas inmunitarias tanto innata (vía de las células linfocíticas innatas [ILC] del grupo 2) como adaptativa (vía de los linfocitos T cooperadores 2 [Th2]), activando la vía inflamatoria del asma del tipo 2 (T2) mediante ambas. También se cree que puede intervenir en la vía inflamatoria neutrofílica con T2 baja (mediante la interacción con los ILC3 y la interleucina 17). En seis ensayos clínicos que incluyeron a 2.187 pacientes con asma no controlada, dos o más exacerbaciones en el año anterior, a tratamiento con corticosteroides inhalados en dosis medias o altas y con un mínimo de un tratamiento preventivo adicional, se ha demostrado la eficacia y seguridad del tezepelumab sin importar el endotipo T2 (y posiblemente tampoco el endotipo no T2), ya que reduce significativamente las exacerbaciones (61,7-66%) y la hiperreactividad bronquial y mejora la función pulmonar, el control de la enfermedad y la calidad de vida. El tezepelumab puede estar indicado para tratar a pacientes con asma grave, independientemente del fenotipo T2 (eosinofílico y no eosinofílico), y tal vez sea incluso el único biofármaco existente para el tratamiento del AGNC no T2.This article was funded by the Barcelona Respiratory Network (BRN) who did not participate in the articles selected or writing of the manuscript

Hepatitis C virus molecular evolution: Transmission, disease progression and antiviral therapy

Hepatitis C virus (HCV) infection represents an important public health problem worldwide. Reduction of HCV morbidity and mortality is a current challenge owned to several viral and host factors. Virus molecular evolution plays an important role in HCV transmission, disease progression and therapy outcome. The high degree of genetic heterogeneity characteristic of HCV is a key element for the rapid adaptation of the intrahost viral population to different selection pressures (e.g., host immune responses and antiviral therapy). HCV molecular evolution is shaped by different mechanisms including a high mutation rate, genetic bottlenecks, genetic drift, recombination, temporal variations and compartmentalization. These evolutionary processes constantly rearrange the composition of the HCV intrahost population in a staging manner. Remarkable advances in the understanding of the molecular mechanism controlling HCV replication have facilitated the development of a plethora of direct-acting antiviral agents against HCV. As a result, superior sustained viral responses have been attained. The rapidly evolving field of anti-HCV therapy is expected to broad its landscape even further with newer, more potent antivirals, bringing us one step closer to the interferon-free era.Fil: Preciado, María Victoria. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños ; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Valva, Pamela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños ; ArgentinaFil: Escobar Gutierrez, Alejandro. Instituto de Diagnóstico y Referencia Epidemiológicos; MéxicoFil: Rahal, Paula. Universidade Estadual Paulista Julio de Mesquita Filho; BrasilFil: Ruiz Tovar, Karina. Instituto de Diagnóstico y Referencia Epidemiológicos; MéxicoFil: Yamasaki, Lilian. Universidade Estadual Paulista Julio de Mesquita Filho; BrasilFil: Vazquez Chacon, Carlos. Instituto de Diagnóstico y Referencia Epidemiológicos; MéxicoFil: Martinez Guarneros, Armando. Instituto de Diagnóstico y Referencia Epidemiológicos; MéxicoFil: Carpio Pedroza, Juan Carlos. Instituto de Diagnóstico y Referencia Epidemiológicos; MéxicoFil: Fonseca Coronado, Salvador. Universidad Nacional Autónoma de México; MéxicoFil: Cruz Rivera, Mayra. Universidad Nacional Autónoma de México; Méxic

Plan estratégico de la Caja Rural de Ahorro y Crédito Los Andes S.A.

El presente trabajo desarrolla el plan estratégico de la Caja Rural de Ahorro y Crédito Los Andes dentro de un horizonte de 10 años. Para su elaboración se ha usado el modelo propuesto por el doctor Fernando D’Alessio, lo cual ha permitido proponer una visión basada principalmente en convertir a la institución en una entidad competitiva, y con una oferta de productos y servicios financieros rentables y socialmente responsables, a fin de satisfacer las necesidades actuales y potenciales de personas naturales, medianas, pequeñas y microempresas, de tal modo que la entidad se convierta en el principal aliado de su crecimiento y en la construcción de un futuro próspero para sus familias, organizaciones y la sociedad. Actualmente, la organización es reconocida como una entidad confiable, solvente, y como una alternativa de apoyo al desarrollo empresarial, principalmente del segmento rural, sin embargo, mantiene desafíos importantes en relación a la agresiva competencia en el sector microfinanciero, al crecimiento de los índices de morosidad, al tamaño de sus operaciones, a su capacidad de respuesta frente a la competencia y de influir en el mercado, a la concentración relativa de sus colocaciones, a los importantes niveles de rotación de personal, y a la escasez de cuadros con perfiles adecuados. Como resultado del proceso estratégico, se determinaron cinco Objetivos de Largo Plazo (OLP), con el fin de: (a) reducir el índice de morosidad; (b) incrementar los ratios de rentabilidad; y (c) reducir los gastos operativos de la CRAC Los Andes, y con ello alcanzar la visión deseada de la institución. Asimismo, se plantea implementar un tablero de control que permita controlar el cumplimiento y medir los resultados de cada Objetivo de Corto Plazo (OCP) propuestoThe present work develops the strategic plan of the Caja Rural de Ahorro y Crédito Los Andes within a period of 10 years. To elaborate the present work, we have used the model proposed by Dr. Fernando D’Alessio, which has allowed us the propose a vision focusing mainly on making the company turn into a competitive one, offering profitable and socially responsible financial services in order to satisfy the present and future needs of individuals, medium, small and micro enterprises, so that the company becomes the principal ally of this growth and help build a prosperous future for their families, organizations and the society. At present, the organization is known as a reliable and creditworthy business, as well as well as an alternative support of business development, principally in the rural area. Nevertheless, it still faces important challenges concerning the aggressive competition in the microfinance sector, the increase in the late payment ratio, the size of its operations, its capacity to respond to competition and to influence the market, the relatively high concentration of its placements, the important level of personnel rotation, and the lack of qualified workers. As a result of the strategic process, five long-term objectives (LTO) were determined in order to: a) reduce the ratio of late payment, b) increase the levels of profitability, and c) reduce the operating expenses of the CRAC Los Andes, and by doing so, finally reach the desired vision of the institution. Additionally, we have planned to implement a balanced scorecard, which will let us control the accomplishment and measure the results of each of the proposed short-term objectivesTesi

Alternative system to measure hydrogen content in molten aluminium using an electrochemical sensor

The most reliable techniques for the direct measurement of hydrogen content in liquid aluminium are based on Sievert’s law or use electrochemical probes introduced directly in liquid aluminium. The main drawback of these methods is the high cost of the equipment. An alternative apparatus has been developed and tested. This equipment combines a widely used and much cheaper hydrogen electrochemical sensor with the procedure already patented and commonly used by gas recirculation techniques. The device has been constructed and calibrated using gaseous mixtures of known hydrogen content. For validation, the results obtained with this apparatus have been compared with hydrogen content measurements in liquid aluminium using the commercial Alscan equipment in an industrial facility. Experimental results suggest that the apparatus proposed in this work is capable of detecting hydrogen content in liquid aluminium obtaining measurements that are in a good agreement with those obtained using the commercial Alscan equipment. On the other hand, results also suggest that it is important to take into account the operating atmospheric pressure to correct the readings obtained from Alscan when operating at atmospheric pressure levels far from 1 atm

Alternative system to measure hydrogen content in molten aluminium using an electrochemical sensor

1037-1042The most reliable techniques for the direct measurement of hydrogen content in liquid aluminium are based on Sievert’s law or use electrochemical probes introduced directly in liquid aluminium. The main drawback of these methods is the high cost of the equipment. An alternative apparatus has been developed and tested. This equipment combines a widely used and much cheaper hydrogen electrochemical sensor with the procedure already patented and commonly used by gas recirculation techniques. The device has been constructed and calibrated using gaseous mixtures of known hydrogen content. For validation, the results obtained with this apparatus have been compared with hydrogen content measurements in liquid aluminium using the commercial Alscan equipment in an industrial facility. Experimental results suggest that the apparatus proposed in this work is capable of detecting hydrogen content in liquid aluminium obtaining measurements that are in a good agreement with those obtained using the commercial Alscan equipment. On the other hand, results also suggest that it is important to take into account the operating atmospheric pressure to correct the readings obtained from Alscan when operating at atmospheric pressure levels far from 1 atm

Immunity related genes in dipterans share common enrichment of AT-rich motifs in their 5' regulatory regions that are potentially involved in nucleosome formation

<p>Abstract</p> <p>Background</p> <p>Understanding the transcriptional regulation mechanisms in response to environmental challenges is of fundamental importance in biology. Transcription factors associated to response elements and the chromatin structure had proven to play important roles in gene expression regulation. We have analyzed promoter regions of dipteran genes induced in response to immune challenge, in search for particular sequence patterns involved in their transcriptional regulation.</p> <p>Results</p> <p>5' upstream regions of <it>D. melanogaster </it>and <it>A. gambiae </it>immunity-induced genes and their corresponding orthologous genes in 11 non-melanogaster drosophilid species and <it>Ae. aegypti </it>share enrichment in AT-rich short motifs. AT-rich motifs are associated with nucleosome formation as predicted by two different algorithms. In <it>A. gambiae </it>and <it>D. melanogaster</it>, many immunity genes 5' upstream sequences also showed NFκB response elements, located within 500 bp from the transcription start site. In <it>A. gambiae</it>, the frequency of ATAA motif near the NFκB response elements was increased, suggesting a functional link between nucleosome formation/remodelling and NFκB regulation of transcription.</p> <p>Conclusion</p> <p>AT-rich motif enrichment in 5' upstream sequences in <it>A. gambiae, Ae. aegypti </it>and the <it>Drosophila </it>genus immunity genes suggests a particular pattern of nucleosome formation/chromatin organization. The co-occurrence of such motifs with the NFκB response elements suggests that these sequence signatures may be functionally involved in transcriptional activation during dipteran immune response. AT-rich motif enrichment in regulatory regions in this group of co-regulated genes could represent an evolutionary constrained signature in dipterans and perhaps other distantly species.</p

Cbfa-1 mediates nitric oxide regulation of MMP-13 in osteoblasts.

During bone development, osteoblast differentiation requires remodeling of the extracellular matrix. Although underlying mechanisms have not been elucidated, evidence points to the participation of the nitric oxide (NO) and cyclic guanosine 3',5'-monophosphate (cGMP) system. Here, we detected increased matrix metalloproteinase (MMP)-13 mRNA, protein and activity, as well as increased inducible NO synthase (iNOS) and NO production during the differentiation of MC3T3-E1 osteoblasts. Transcriptional activity of the MMP-13 promoter was augmented by NO, 8-bromo-cGMP (8-Br-cGMP), and by a dominant-positive form of protein kinase G (PKG1-alpha). The stimulatory effect on the MMP-13 promoter was partially inhibited by mutation of the osteoblast-specific element 2 (OSE-2) binding site. Core binding factor-1 (Cbfa-1) expression peaked at 7 days of differentiation, and was phosphorylated by PKG in vitro. Cbfa-1 was localized to cell nuclei, and its translocation was inhibited by the iNOS inhibitor 1400W. Immunohistological examination revealed that MMP-13 and Cbfa-1 expression levels are both reduced in 17-day-old embryos of iNOS-deficient mice. Silencing of Cbfa-1 mRNA blocked MMP-13 expression without interfering with endogenous NO production, confirming its role in NO-induced MMP-13 expression by MC3T3-E1 cells. The results described here suggest a mechanism by which NO regulates osteogenesis.S

Characterization of Hydrogels for Their Application in Tissue Regeneration

Alterations in neurogenesis result in the inevitable loss of brain nervous tissue and cause neurodegenerative diseases, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and Huntington’s disease (HD). In this regard, hydrogels based on natural biopolymers have attractive properties, such as excellent biocompatibility, a low immune response, and a significant similarity to the extracellular matrix (ECM) of tissues, thus supporting cell proliferation and migration. Human ECM is composed by relatively small amounts of fibrous, proteins, and polysaccharides. For example, scaffolds composed of gelatin and hyaluronic acid are highly abundant components in human ECM. The methacrylation of hyaluronic acid (HAMA) and gelatin (GelMA) through carboxyl and hydroxyl groups under UV light radiation at 365 nm produce polymeric scaffolds with elastic moduli similar to tissues, and, therefore, potential candidates to adhere, host, and facilitate cell proliferation and differentiation, which are dependent on their mechanical properties. In this work, the mechanical, thermal, and morphological properties of HAMA and GelMA hydrogel mixtures were studied and characterized via linear rheological measurements, thermogravimetric analysis (TGA), and scanning electron microscopy (SEM)S

Hollow Gold Nanoparticles Produced by Femtosecond Laser Irradiation

[EN] Metallic hollow nanoparticles exhibit interesting optical properties that can be controlled by geometrical parameters. Irradiation with femtosecond laser pulses has emerged recently as a valuable tool for reshaping and size modification of plasmonic metal nanoparticles, thereby enabling the synthesis of nanostructures with unique morphologies. In this Letter, we use classical molecular dynamics simulations to investigate the solid-to-hollow conversion of gold nanoparticles upon femtosecond laser irradiation. Here, we suggest an efficient method for producing hollow nanoparticles under certain specific conditions, namely that the particles should be heated to a maximum temperature between 2500 and 3500 K, followed by a fast quenching to room temperature, with cooling rates lower than 120 ps. Therefore, we describe the experimental conditions for efficiently producing hollow nanoparticles, opening a broad range of possibilities for applications in key areas, such as energy storage and catalysis.This work has been funded by the Spanish Ministry of Science, Innovation and Universities (MICIU) (Grants RTI2018-095844-B-I00, PGC2018-096444-B-I00, and MAT2017-86659-R), the EUROfusion Consortium through Project ENR-IFE19.CCFE-01, and the Madrid Regional Government (Grants P2018/NMT-4389 and P2018/EMT-4437). A.P. is thankful for the support of FONDECYT under Grants 3190123 and 11180557, as well as from Financiamiento Basal para Centros Cientificos y Tecnologicos de Excelencia FB-0807. K.L. acknowledges the support of the Russian Science Foundation (Project 19-19-00683). The authors acknowledge the computer resources and technical assistance provided by the Centro de Supercomputacion y Visualizacion de Madrid (CeSViMa) and the supercomputing infrastructure of the NLHPC (ECM-02). This Letter is based upon work from COST Action TUMIEE (CA17126)Castro-Palacio, JC.; Ladutenko, K.; Prada, A.; Gonzalez-Rubio, G.; Diaz-Nunez, P.; Guerrero-Martinez, A.; Fernández De Córdoba, P.... (2020). Hollow Gold Nanoparticles Produced by Femtosecond Laser Irradiation. The Journal of Physical Chemistry Letters. 11(13):5108-5114. https://doi.org/10.1021/acs.jpclett.0c01233S51085114111

Dosis de refuerzo con la vacuna BNT162b2 en población que recibió el esquema de vacunación completa para COVID-19 en Perú: Un análisis crítico de la evidencia actual

Background: In Peru, the current immunization schedule for COVID-19 includes BBIBP-CorV, BNT162B2 and ChAdOx1 nCoV-19 vaccines. Although the full immunization schedule is two doses, some countries have recently included a booster dose to their schedule. Methods: We conducted a search for scientific evidence on the efficacy and safety of booster vaccination with BNT162b2 vaccine in a population with a complete vaccination schedule for COVID-19 in Peru. Evidence: Four evidence-based recommendation documents, one observational study and three ongoing phase III clinical trials were included for analysis. Conclusion: To date, there is insufficient evidence on the efficacy of adding a booster dose to the immunization schedule for COVID-19. The available evidence does not justify the use of a booster dose of BNT162B2 vaccine in a population that has previously received two doses of the aforementioned vaccines.Introducción: En el Perú, el programa actual de inmunización para COVID-19 comprende las vacunas BBIBP-CorV, BNT162B2 y ChAdOx1 nCoV-19. Si bien el esquema de inmunización es de dos dosis, algunos países han incluido recientemente una dosis de refuerzo a su esquema.&nbsp;Métodos: Se realizó una búsqueda de evidencia científica sobre la eficacia y seguridad de la vacunación de refuerzo con la vacuna BNT162b2 en población con esquema de vacunación completa para COVID-19 en Perú. Evidencia incluida: Se consideraron cuatro documentos de recomendación basados en evidencia, un estudio observacional y tres ensayos clínicos fase III en curso. Conclusión: A la fecha, no existe evidencia suficiente sobre la eficacia de agregar una dosis de refuerzo al esquema de inmunización para COVID-19. La evidencia disponible no permite justificar el uso de una dosis de refuerzo con la vacuna BNT162B2 en población que recibió previamente dos dosis de las vacunas anteriormente mencionadas