Downregulation of protein tyrosine phosphatase PTPL1 alters cell cycle and upregulates invasion-related genes in prostate cancer cells

The final publication is available at link.springer.comPTPL1, a non-receptor type protein tyrosine phosphatase, has been involved in the regulation of apoptosis and invasiveness of various tumour cell types, but its role in prostate cancer remained to be investigated. We report here that downregulation of PTPL1 by small interfering RNA in PC3 cells decreases cell proliferation and concomitantly reduces the expression of cell cycle-related proteins such as cyclins E and B1, PCNA, PTTG1 and phospho-histone H3. PTPL1 downregulation also increases the invasion ability of PC3 cells through Matrigel coated membranes. cDNA array of PTPL1-silenced PC3 cells versus control cells showed an upregulation of invasion-related genes such as uPA, uPAR, tPA, PAI-1, integrin α6 and osteopontin. This increased expression was also confirmed in PTPL1-silenced DU145 prostate cancer cells by quantitative real time PCR and western blot. These findings suggest that PTPL1 is an important mediator of central cellular processes such as proliferation and invasion. © 2012 Springer Science+Business Media B.V.This work was supported by Grants from the Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III, Spain (FIS PI10/02026 and SAF2008-05046-C02-02), ISCIIIRETIC-RD06/0020-FEDER, Consejería de Salud (PI-2009-0589, AI-2010-003 to M.A.J.), and Consejería de Innovación, Ciencia y Empresa (CTS-6243), Junta de Andalucía (06/189, PI-2009-0589, and AI-2010-003 to M. A. J.). C. C. was supported by a pre-doctoral Grant from the Spanish Ministerio de Educación (F.P.I.: BES200612419) co-financiated by Fondo Social Europeo. C. S. was supported by a contract from Instituto de Salud Carlos III/FIS and Fundación Progreso y Salud, Consejería de Salud, Junta de Andalucía, Miguel Servet Program.Peer Reviewe

Metal Node Control of Brønsted Acidity in Heterobimetallic Titanium–Organic Frameworks

Compared to indirect framework modification, synthetic control of cluster composition can be used to gain direct access to catalytic activities exclusive of specific metal combinations. We demonstrate this concept by testing the aminolysis of epoxides with a family of isostructural mesoporous frameworks featuring five combinations of homometallic and heterobimetallic metal-oxo trimers (Fe3, Ti3, TiFe2, TiCo2, and TiNi2). Only TiFe2 nodes display activities comparable to benchmark catalysts based on grafting of strong acids, which here originate from the combination of Lewis Ti4+ and Brønsted Fe3+–OH acid sites. The applicability of MUV-101(Fe) to the synthesis of β-amino alcohols is demonstrated with a scope that also includes the gram scale synthesis of propranolol, a natural β-blocker listed as an essential medicine by the World Health Organization, with excellent yield and selectivity

Detection of mild cognitive impairment in people older than 65 years of age and its relationship to cardiovascular risk factors (DECRIVAM)

[ENG]Background: Studies centered on the detection of cognitive impairment and its relationship to cardiovascular risk factors in elderly people have gained special relevance in recent years. Knowledge of the cardiovascular risk factors that may be associated to cognitive impairment could be very useful for introducing treatments in early stagesthereby possibly contributing to improve patient quality of life. The present study explores cognitive performance in people over 65 years of age in Salamanca (Spain), with special emphasis on the identification of early symptoms of cognitive impairment, with the purpose of detecting mild cognitive impairment and of studying the relationships between this clinical situation and cardiovascular risk factors. Methods/Design: A longitudinal study is contemplated. The reference population will consist of 420 people over 65 years of age enrolled through randomized sampling stratified by healthcare area, and who previously participated in another study. Measurement: a) Sociodemographic variables; b) Cardiovascular risk factors; c) Comorbidity; d) Functional level for daily life activities; and e) Study of higher cognitive functions based on a neuropsychological battery especially adapted to the evaluation of elderly people. Discussion: We hope that this study will afford objective information on the representative prevalence of cognitive impairment in the population over 65 years of age in Salamanca. We also hope to obtain data on the relationship between cognitive impairment and cardiovascular risk factors in this specific population group. Based on the results obtained, we also will be able to establish the usefulness of some of the screening tests applied during the study, such as the Mini-Mental State Examination and the 7 Minute Screen test. Trial registration: ClinicalTrials.gov: NCT0132719

Genetic complexity impacts the clinical outcome of follicular lymphoma patients

© The Author(s) 2021.Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma (NHL, 20–30%) after diffuse large B-cell lymphoma (DLBCL). Despite the introduction of rituximab and the high response rate to first-line treatment, approximately 20% of the FL patients relapse or progress within 2 years of receiving first-line therapy. Therefore, the major challenge is finding biomarkers that identify high-risk patients at diagnosis.This work was partially supported by the Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness PI15/01393, PI18/00410, CIBERONC-CB16/12/00233, and “Una manera de hacer Europa” (Innocampus; CEI-2010-1-0010)”, the Education Council or Health Council of the Junta de Castilla y León (CAS102P17, GRS 1180/A/15), Spanish Association Against Cancer (AECC; PROYE18020BEA), and Gilead Sciences (GLD17/00334). CJ, MES, and AMe are supported by the ISCII (CD19/00030, CPII18/00028, and FI19/00320). MGA, IPC, and CJ were supported by the Spanish Society of Hematology Foundation (FEHH). All Spanish funding is co-sponsored by the European Union FEDER program

Can statistical methods optimize complex multicomponent mixtures for sintering ceramic granular materials? A case of success with synthetic aggregates

The relationship between the proportions of multicomponent mixtures with the technological properties of ceramic granular materials (synthetic aggregates) has been studied using statistical methods. The four phases involved in the formulations have been: kaolin (K) as aluminosilicate source; cork powder (C) as organic carbon source; sodium carbonate (N) as flux and pyrite (P) as source of iron and sulfur. The Mixture Experiments - Design of Experiments (ME-DOE) has been the statistical methodology applied from the initial configuration of the 36 starting formulations to the final validation of the models and optimums. After granulation, artificial aggregates have been obtained by sintering in a rotary kiln, and their main technological properties have been determined. Bloating index (BI), particle density (ρrd), water absorption (WA24) and crushing strength (S) were selected as the four key characteristics to be modeled and optimized, using response surface and effect plots to assess the effect of K, C, N and P on such properties. 32 out of 36 starting varieties met the density criteria for lightweight aggregates. In the optimum formulations obtained, the minimum percentage of K was 83 wt%, so that the variations in the percentages of P, C and N were the critical variables for determining the final properties of the aggregate. The contrast between experimental and estimated data has shown that the models fit adequately, indicating that this type of approach may have enormous potential for future research on artificial aggregates and other ceramic materialsThis research was conducted as a part of the ECO-MET-AL Project, PID2019-109520RB-I00 / AEI / 10.13039/501100011033, “Can industrial and mining metalliferous wastes produce green lightweight aggregates? Applying the Circular Economy” funded by the Spanish Ministry of Science, Innovation and Universities and ERDF funds, framed in the “Ayudas a “Proyectos I + D + i" en el marco de los Programas Estatales de Generación de Conocimiento y Fortalecimiento Científico y Tecnológico del Sistema de I + D + i y de I + D + i orientada a los Retos de la Sociedad, Convocatoria 2019”. Thanks also to the SCAI of the University of Jaén, the University of Castilla-La Mancha and the University of Málaga for their service

Interlaboratory analytical validation of a Next-generation sequencing strategy for clonotypic assessment and minimal residual disease monitoring in multiple myeloma

[Context]: Minimal residual disease (MRD) is a major prognostic factor in multiple myeloma, although validated technologies are limited. [Objective]: To standardize the performance of the LymphoTrack next-generation sequencing (NGS) assays (Invivoscribe), targeting clonal immunoglobulin rearrangements, in order to reproduce the detection of tumor clonotypes and MRD quantitation in myeloma. [Design]: The quantification ability of the assay was evaluated through serial dilution experiments. Paired samples from 101 patients were tested by LymphoTrack, using Sanger sequencing and EuroFlow's next-generation flow (NGF) assay as validated references for diagnostic and follow-up evaluation, respectively. MRD studies using LymphoTrack were performed in parallel at 2 laboratories to evaluate reproducibility. [Results]: Sensitivity was set as 1.3 tumor cells per total number of input cells. Clonality was confirmed in 99% and 100% of cases with Sanger and NGS, respectively, showing great concordance (97.9%), although several samples had minor discordances in the nucleotide sequence of rearrangements. Parallel NGS was performed in 82 follow-up cases, achieving a median sensitivity of 0.001%, while for NGF, median sensitivity was 0.0002%. Reproducibility of LymphoTrack-based MRD studies (85.4%) and correlation with NGF (R2 > 0.800) were high. Bland-Altman tests showed highly significant levels of agreement between flow and sequencing. [Conclusions]: Taken together, we have shown that LymphoTrack is a suitable strategy for clonality detection and MRD evaluation, with results comparable to gold standard procedures. Multiple myeloma (MM) is a plasma-cell dyscrasia characterized by the accumulation of plasma cells in the bone marrow that produces an excess of clonal immunoglobulins (M-protein or monoclonal component).1 New treatment approaches have increased the number of patients achieving complete response (CR),2–5 progressively improving progression-free and overall survival rates in the last 10 years.6–11 Nonetheless, the presence of low levels of drug-resistant cells (known as minimal residual disease, MRD)12–14 that remain undetected by conventional serologic and morphologic methods explains frequent relapses with this disease, which is still considered an incurable illness.Minimal residual disease is currently considered one of the most informative prognostic parameters, since those patients with undetectable disease have shown prolonged survival rates as compared with MRD-positive patients,15–17 and this difference is still significant even when patients achieving only stringent complete response (sCR) are taken into account.18 The International Myeloma Working Group (IMWG) defined MRD positivity as the persistence of clonal malignant plasma cells assessed with a sensitivity of at least 10−5 (1 malignant cell per hundred thousand normal cells)19 ; therefore, MRD should be monitored with only highly sensitive methods. To date, 3 different approaches have been tested for MRD monitoring in hematologic malignancies: immunophenotypic (multiparametric flow cytometry [MFC]),20 molecular (quantitative polymerase chain reaction [PCR], next-generation sequencing [NGS], digital PCR),21–23 and imaging tools (positron emission tomography–computed tomography; magnetic resonance imaging).24,25 However, in MM standardization has been achieved only for MFC26 and NGS.27,28 As a result, the IMWG recommended the use of highly sensitive, standardized flow and sequencing approaches,19 including EuroFlow's next-generation flow (NGF)29 and Adaptive Biotechnologies' ClonoSEQ solutions (Adaptive Biotechnologies, Seattle, Washington). NGF is a 2-tube, 8-color flow assay that allows the simultaneous analysis of 10 million cells, providing a sensitivity of around 2·10−6.This work was partially supported by the Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness PI15/01956, CIBERONC-CB16/12/00233, and “Una manera de hacer Europa” (Innocampus; CEI-2010-1-0010). García-Álvarez, Prieto-Conde, and Jiménez were supported by the Fundación Española de Hematología y Hemoterapia (FEHH, cofunded by Fundación Cris in the latter case), Medina by the European Social Fund through the University of Salamanca and the ISCIII (FI19/00320), and Sarasquete by the ISCIII (CPII18/00028). All Spanish funding is cosponsored by the European Union FEDER program

Promotion of macrophage activation by Tie2 in the context of the inflamed synovia of rheumatoid arthritis and psoriatic arthritis patients

OBJECTIVE: To examine the role of Tie2 signalling in macrophage activation within the context of the inflammatory synovial microenvironment present in patients with RA and PsA. METHODS: Clinical responses and macrophage function were examined in wild-type and Tie2-overexpressing (Tie2-TG) mice in the K/BxN serum transfer model of arthritis. Macrophages derived from peripheral blood monocytes from healthy donors, RA and PsA patients, and RA and PsA synovial tissue explants were stimulated with TNF (10 ng/ml), angiopoietin (Ang)-1 or Ang-2 (200 ng/ml), or incubated with an anti-Ang2 neutralizing antibody. mRNA and protein expression of inflammatory mediators was analysed by quantitative PCR, ELISA and Luminex. RESULTS: Tie2-TG mice displayed more clinically severe arthritis than wild-type mice, accompanied by enhanced joint expression of IL6, IL12B, NOS2, CCL2 and CXCL10, and activation of bone marrow-derived macrophages in response to Ang-2 stimulation. Ang-1 and Ang-2 significantly enhanced TNF-induced expression of pro-inflammatory cytokines and chemokines in macrophages from healthy donors differentiated with RA and PsA SF and peripheral blood-derived macrophages from RA and PsA patients. Both Ang-1 and Ang-2 induced the production of IL-6, IL-12p40, IL-8 and CCL-3 in synovial tissue explants of RA and PsA patients, and Ang-2 neutralization suppressed the production of IL-6 and IL-8 in the synovial tissue of RA patients. CONCLUSION: Tie2 signalling enhances TNF-dependent activation of macrophages within the context of ongoing synovial inflammation in RA and PsA, and neutralization of Tie2 ligands might be a promising therapeutic target in the treatment of these diseases

Las emociones en la enseñanza de las ciencias

En la primera parte del artículo, se incide en la importancia del estudio de las emociones desde la didáctica de las ciencias, así como en la necesidad de establecer programas de intervención metacognitivos y metaemocionales, tanto en el aprendizaje como en la formación del profesorado, para que alumnos y profesores puedan conocer sus emociones, controlarlas y autorregularlas. En la segunda parte, nos centramos en las emociones en el conocimiento didáctico del contenido del profesorado de ciencias, incluyendo algunos resultados tanto del diagnóstico emocional del profesorado, según distintas variables, como del programa de intervención de la Universidad de Extremadura.The first part of this communication highlights the importance of studying emotions in the context of science teaching. It also examines the need for programs of meta-emotional and metacognitive intervention in learning and teacher education that are aimed at both the future teachers'and their pupils' gaining awareness of, and then controlling and self-regulating, their emotions. The second part focuses on the role emotions play in science teachers' pædagogical content knowledge, with the presentation of some results concerning the University of Extremadura's intervention program and the emotional diagnosis of teachers.En la primera part de l'article, s'incideix en la importància de l'estudi de les emocions des de la didàctica de les ciències, així com en la necessitat d'establir programes d'intervenció metacognitivos i metaemocionales, tant en l'aprenentatge com en la formació del professorat, perquè alumnes i professors puguin conèixer les seves emocions, controlar-les i autorregularlas. En la segona part, ens centrem en les emocions en el coneixement didàctic del contingut del professorat de ciències, incloent alguns resultats tant del diagnòstic emocional del professorat, segons diferents variables, com del programa d'intervenció de la Universitat d'Extremadura