Skip regulates TGF- β 1-induced extracellular matrix degrading proteases expression in human PC-3 prostate cancer cells

Purpose. To determine whether Ski-interacting protein (SKIP) regulates TGF-β1-stimulated expression of urokinase-type plasminogen activator (uPA), matrix metalloproteinase-9 (MMP-9), and uPA Inhibitor (PAI-1) in the androgen-independent human prostate cancer cell model. Materials and Methods. PC-3 prostate cancer cell line was used. The role of SKIP was evaluated using synthetic small interference RNA (siRNA) compounds. The expression of uPA, MMP-9, and PAI-1 was evaluated by zymography assays, RT-PCR, and promoter transactivation analysis. Results. In PC-3 cells TGF-β1 treatment stimulated uPA, PAI-1, and MMP-9 expressions. The knockdown of SKIP in PC-3 cells enhanced the basal level of uPA, and TGF-β1 treatment inhibited uPA production. Both PAI-1 and MMP-9 production levels were increased in response to TGF-β1. The ectopic expression of SKIP inhibited both TGF-β1-induced uPA and MMP-9 promoter transactivation, while PAI-1 promoter response to the factor was unaffected. Conclusions. SKIP regulates the expression of uPA, PAI-1, and MMP-9 stimulated by TGF-β1 in PC-3 cells. Thus, SKIP is implicated in the regulation of extracellular matrix degradation and can therefore be suggested as a novel therapeutic target in prostate cancer treatment. © 2013 Victor Villar et al

Spred2 inhibits TGF-beta 1-induced urokinase type plasminogen activator expression, cell motility and epithelial mesenchymal transition

TGF-beta 1 is a potent inductor of malignance in cancer cells. TGF-beta 1 stimulates the expression of extracellular matrix degrading proteases, cell migration and it is also involved in the epithelial-mesenchymal transition (EMT). In the present work, we analyzed the role of Spred2 in the urokinase-type plasminogen activator (uPA) stimulation, EMT and cell migration by TGF-beta 1. We found that both the expression of mRNA and the protein level of Spred2 were lower in transformed keratinocytes PDV compared with immortalized keratinocytes MCA-3D. The transient ectopic expression of Spred2 in PDV cells inhibited the TGF-beta 1-transactivated SRE-Luc reporter which is related with the ERK1,2 signal. The stable ectopic expression of Spred2 in PDV cells (SP cells) led to the loss of ERK 1,2 activation by TGF-beta 1, although Smad2 activation was not affected, and the knockdown of Spred2 enhanced the activation of ERK1,2 signal by TGF-beta 1. The increment of uPA expression induced by TGF-beta 1 was suppressed in SP cells. In contrast, the stimulus on PAI-1 expression was not affected and comparable to parental PDV cells. SP cells under TGF-beta 1 treatment were unable to display the EMT, since the overexpression of Spred2 abolished the TGF-beta 1-induced disruption of the E-cadherin cell to cell interactions, reorganization of the actin cytoskeleton and upregulation of the mesenchymal marker vimentin. Finally, SP cells could not respond to the TGF-beta 1 stimulus on cell migration. Taken together, the data in the present study suggests that Spred2 is a regulator of TGF-beta 1-induced malignance in transformed keratinocytes

The Metabolic Features of Tumor-Associated Macrophages: Opportunities for Immunotherapy?

Besides transformed cells, the tumors are composed of various cell types that contribute to undesirable tumor progression. Tumor-associated macrophages (TAMs) are the most abundant innate immune cells in the tumor microenvironment (TME). Within the TME, TAMs exhibit high plasticity and undergo specific functional metabolic alterations according to the availability of tumor tissue oxygen and nutrients, thus further contributing to tumorigenesis and cancer progression. Here, we review the main functional TAM metabolic patterns influenced by TME, including glycolysis, amino acid, and fatty acid metabolism. Moreover, this review discusses antitumor immunotherapies that affect TAM functionality by inducing cell repolarizing and metabolic profiles towards an antitumoral phenotype. Also, new macrophage-based cell therapeutic technologies recently developed using chimeric antigen receptor bioengineering are exposed, which may overcome all solid tumor physical barriers impeding the current adoptive cell therapies and contribute to developing novel cancer immunotherapies

Definiendo Requisitos Usando RqBS o EDR (Estructura de Desglose de Requisitos) en Proyectos

Los proyectos tienen usualmente problemas para definir requisitos, lo cual genera serias discrepancias entre los interesados claves, como clientes, contratistas, reguladores, consorciado y comunidades con la entidad ejecutante.Este documento presenta la importancia de definir con claridad el requisito, principalmente con el uso del criterio de aceptacion. Tambien, propone el uso de una estructura de desglose de requisitos, con sus respectivos ejemplos practicos, de tal manera, que sirva como guia para una buena y completa definicion de requisitos. Defining Requirements Using RqBS (Requirement Breakdown Structure) in ProjectsProjects usually have difficulty in defining requirements, which creates serious discrepancies between the key stakeholders, including clients, contractors, regulators, consortium members and communities with the implementing entity.This document presents the importance of clearly defining requirements, primarily by using the criteria of acceptance. It also proposes the use of a requirement breakdown structure, with practical examples, such that it may be a guide for a full and precise definition of requirements

The metabolic features of tumor-associated macrophages : opportunities for immunotherapy?

Funding: This work was supported by the Ministry of Education, Science, and Technological Development of the Republic of Serbia.Besides transformed cells, the tumors are composed of various cell types that contribute to undesirable tumor progression. Tumor-associated macrophages (TAMs) are the most abundant innate immune cells in the tumor microenvironment (TME). Within the TME, TAMs exhibit high plasticity and undergo specific functional metabolic alterations according to the availability of tumor tissue oxygen and nutrients, thus further contributing to tumorigenesis and cancer progression. Here, we review the main functional TAM metabolic patterns influenced by TME, including glycolysis, amino acid, and fatty acid metabolism. Moreover, this review discusses antitumor immunotherapies that affect TAM functionality by inducing cell repolarizing and metabolic profiles towards an antitumoral phenotype. Also, new macrophage-based cell therapeutic technologies recently developed using chimeric antigen receptor bioengineering are exposed, which may overcome all solid tumor physical barriers impeding the current adoptive cell therapies and contribute to developing novel cancer immunotherapies.Publisher PDFPeer reviewe

Aprendizaje cooperativo e higiene de manos en estudiantes de enfermería

Objective. The study sought to evaluate the effectiveness of an educational intervention based on cooperative learning on the acquisition of knowledge and skills on hand washing. In addition, the interest and self-perception was studied of the participants on the acquisition of knowledge and skills. Methods. This was a pre-post intervention study with 49 students from the second course of the Nursing degree, evaluating: i) acquisition of knowledge with an ad hoc questionnaire; ii) skills on hand washing by conducting the technique with reagent solution and verifcation with fluorescent lamp; and iii) interest and self-perception of the importance of acquiring knowledge and skills with specifc questions. Results. The mean age was 21.8 years, 83.7% were women, and 32.6% had prior studies related with health. Signifcant post-intervention improvement was evident in the level of knowledge (p<0.001) and skills (p<0.001). Interest for the intervention (m=4.1±0.6) and perception on the acquisition of knowledge (m=4.4±0.6) and skills (m=4.3±0.5) were scored high (scale from 1 to 5). Conclusion. The cooperative learning intervention improved knowledge and skills on hand washing in nursing students and awakened their interest.Objetivo. Evaluar la efectividad de una intervención educativa basada en el aprendizaje cooperativo sobre la adquisición de conocimientos y habilidades en lavado de manos. Métodos. Estudio pre-posintervención realizado con la participación de 49 estudiantes de segundo curso de grado en enfermería. Se evaluaron los siguientes aspectos: i) adquisición de conocimientos con un cuestionario ad hoc, ii) habilidades en lavado de manos mediante la realización de la técnica con solución reactiva y verifcación con lámpara fluorescente, y iii) interés y autopercepción de la importancia de adquisición de conocimientos y habilidades con preguntas específcas. Resultados. La edad media fue 21.8 años, 83.7% mujeres y el 32.6% tenía estudios previos relacionados con salud. Hubo una mejoría signifcativa postintervención en el nivel de conocimientos (p<0.001) y habilidades (p<0.001). El interés por la intervención (m=4.1±0.6) y la percepción sobre la adquisición de conocimientos (m=4.4±0.6) y habilidades (m=4.3±0.5) se califcaron como elevados (escala de 1 a 5). Conclusión. La intervención de aprendizaje cooperativo mejoró los conocimientos y habilidades sobre lavado de manos en estudiantes de enfermería, además, despertó su interés

Competencias Personales para un Director de Proyecto Exitoso

Tanto la literatura del Project Management Institute (PMI©) como la práctica nos demuestran que la exitosa gestión de un proyecto no solo requiere de project managers calificados con conocimiento y habilidad en aplicar los estándares globales del PMI©, sino también es importante sus competencias personales (Project Management Institute, 2007; 2012). Este artículo buscó analizar las ventajas de contar con competencias personales desarrolladas en los directores de proyecto del Perú para el éxito de sus proyectos mediante entrevistas con experimentados directores de proyectos y especialistas de selección de los mismos. Personal Competencies for a Successful Project ManagerBoth the PMI© literature and practice demonstrate that knowledge and skills are necessary but insufficient conditions for successful professional performance. Therefore, the authors conducted research to analyze the advantages that personal competencies can provide project managers in Peru. The results indicate that personal competencies are valued because they remain to be strengthened among project managers in Peru

Trotabresib (CC-90010) in combination with adjuvant temozolomide or concomitant temozolomide plus radiotherapy in patients with newly diagnosed glioblastoma

BET inhibitors; Glioblastoma; PharmacokineticsInhibidores de BET; Glioblastoma; FarmacocinéticaInhibidors de BET; Glioblastoma; FarmacocinèticaBackground Standard-of-care treatment for newly diagnosed glioblastoma (ndGBM), consisting of surgery followed by radiotherapy (RT) and temozolomide (TMZ), has improved outcomes compared with RT alone; however, prognosis remains poor. Trotabresib, a novel bromodomain and extraterminal inhibitor, has demonstrated antitumor activity in patients with high-grade gliomas. Methods In this phase Ib, dose-escalation study (NCT04324840), we investigated trotabresib 15, 30, and 45 mg combined with TMZ in the adjuvant setting and trotabresib 15 and 30 mg combined with TMZ+RT in the concomitant setting in patients with ndGBM. Primary endpoints were to determine safety, tolerability, maximum tolerated dose, and/or recommended phase II dose (RP2D) of trotabresib. Secondary endpoints were assessment of preliminary efficacy and pharmacokinetics. Pharmacodynamics were investigated as an exploratory endpoint. Results The adjuvant and concomitant cohorts enrolled 18 and 14 patients, respectively. Trotabresib in combination with TMZ or TMZ+RT was well tolerated; most treatment-related adverse events were mild or moderate. Trotabresib pharmacokinetics and pharmacodynamics in both settings were consistent with previous data for trotabresib monotherapy. The RP2D of trotabresib was selected as 30 mg 4 days on/24 days off in both settings. At last follow-up, 5 (28%) and 6 (43%) patients remain on treatment in the adjuvant and concomitant settings, respectively, with 1 patient in the adjuvant cohort achieving complete response. Conclusions Trotabresib combined with TMZ in the adjuvant setting and with TMZ+RT in the concomitant setting was safe and well tolerated in patients with ndGBM, with encouraging treatment durations. Trotabresib 30 mg was established as the RP2D in both settings.This study was sponsored by Celgene, a Bristol Myers Squibb company

Testing Diagnostics of Nuclear Activity and Star Formation in Galaxies at z>1

We present some of the first science data with the new Keck/MOSFIRE instrument to test the effectiveness of different AGN/SF diagnostics at z~1.5. MOSFIRE spectra were obtained in three H-band multi-slit masks in the GOODS-S field, resulting in two hour exposures of 36 emission-line galaxies. We compare X-ray data with the traditional emission-line ratio diagnostics and the alternative mass-excitation and color-excitation diagrams, combining new MOSFIRE infrared data with previous HST/WFC3 infrared spectra (from the 3D-HST survey) and multiwavelength photometry. We demonstrate that a high [OIII]/Hb ratio is insufficient as an AGN indicator at z>1. For the four X-ray detected galaxies, the classic diagnostics ([OIII]/Hb vs. [NII]/Ha and [SII]/Ha) remain consistent with X-ray AGN/SF classification. The X-ray data also suggest that "composite" galaxies (with intermediate AGN/SF classification) host bona-fide AGNs. Nearly 2/3 of the z~1.5 emission-line galaxies have nuclear activity detected by either X-rays or the classic diagnostics. Compared to the X-ray and line ratio classifications, the mass-excitation method remains effective at z>1, but we show that the color-excitation method requires a new calibration to successfully identify AGNs at these redshifts.Comment: 7 pages, 4 figures. Accepted to ApJ Letter