Development of novel dual-action coatings with osteoinductive and antibacterial properties for 3D-printed titanium implants

Gallium (Ga) has been recently proposed as a novel therapeutic agent, since it promotes bone formation and exhibits antibacterial properties. This work focuses on the optimization of a thermochemical treatment that incorporates Ga ions by the addition of the body-friendly Ga nitrate approved by the Food and Drug Administration. The objective was to simultaneously provide the inner and the outer surfaces of porous-titanium surfaces obtained by 3D-printing with bioactivity and antibacterial properties. The apatite-forming ability of the coating, as well as the antibacterial activity and SaOS-2 cell adhesion, proliferation, differentiation and mineralization were evaluated and compared with untreated Ti surfaces. The characterization of the surfaces revealed the presence of a Ga-containing calcium titanate layer, which was non cytotoxic and in simulated body fluid produced a homogeneous apatite coating well adhered to the substrate. The formation of this apatite layer was accelerated with increasing Ga amounts present on the surface, resulting also in an increase in thickness. An initial quick release of Ga ion promoted the antibacterial effect against gram positive strains, especially for Pseudomonas aeruginosa, one of the most frequent resistant pathogens in nosocomial infections. SaOS-2 cells adhered and proliferated on the Ga-doped Ti surfaces, its presence contributed to cell differentiation and to considerably increase the mineralization levels. Thus, the developed multifunctional coatings could provide bioactivity to the porous Ti implants while protecting them from the most frequent gram-negative pathogens.Peer ReviewedPostprint (author's final draft

Dual-action effect of gallium and silver providing osseointegration and antibacterial properties to calcium titanate coatings on porous titanium implants

Previously, functional coatings on 3D-printed titanium implants were developed to improve their biointegration by separately incorporating Ga and Ag on the biomaterial surface. Now, a thermochemical treatment modification is proposed to study the effect of their simultaneous incorporation. Different concentrations of AgNO3 and Ga(NO3)3 are evaluated, and the obtained surfaces are completely characterized. Ion release, cytotoxicity, and bioactivity studies complement the characterization. The provided antibacterial effect of the surfaces is analyzed, and cell response is assessed by the study of SaOS-2 cell adhesion, proliferation, and differentiation. The Ti surface doping is confirmed by the formation of Ga-containing Ca titanates and nanoparticles of metallic Ag within the titanate coating. The surfaces generated with all combinations of AgNO3 and Ga(NO3)3 concentrations show bioactivity. The bacterial assay confirms a strong bactericidal impact achieved by the effect of both Ga and Ag present on the surface, especially for Pseudomonas aeruginosa, one of the main pathogens involved in orthopedic implant failures. SaOS-2 cells adhere and proliferate on the Ga/Ag-doped Ti surfaces, and the presence of gallium favors cell differentiation. The dual effect of both metallic agents doping the titanium surface provides bioactivity while protecting the biomaterial from the most frequent pathogens in implantology.Peer ReviewedPostprint (published version

Ver la literatura. Una nueva metodología para el estudio de la relación texto e imagen: la cultura italiana y su impacto en Europa

A lo largo de su historia y particularmente desde la implantación e integración en el EEES a través del Grado en Lenguas Modernas y sus Literaturas, la especialidad en Italiano ha mantenido y aumentado su interés entre los estudiantes. Uno de los nuevos retos para continuar (sostener) e incrementar este interés es el de idear unas metodologías docentes y materiales que acerquen y clarifiquen la complejidad del sistema cultural italiano en el contexto limitado de los Grados, especialmente teniendo en cuenta que la especialidad se ofrece siempre como parte (Maior o Minor) de una doble formación. Debe por otra parte acercar sus contenidos a través de unas metodologías que respondan al creciente interés por estudios de enfoque transversal y multidisciplinar. Por un enfoque es decir, que abre perspectivas siempre nuevas no solo en el proceso de aprendizaje e investigación, sino especialmente en la ampliación de las posibilidades de aplicación profesional de ambos. Este proyecto se propone la realización de una experiencia docente basada en la aproximación visual y multimedial al estudio de la literatura, historia y cultura italianas, que permita asociar textos, corrientes, tendencias e innovaciones en general circunscritas a esas áreas específicas, con el rico patrimonio visual italiano. Para ello no se limitará la selección a obras estrictamente plásticas, sino que se ampliará a un repertorio que incluya obras arquitectónicas fotográficas, cinematográficas. Objetivo de este proyecto es ofrecer una metodología multidisciplinar y amplia que, manteniendo el rigor y la especificidad formativa exigida en los estudios lingüísticos y literarios, abra perspectivas no solo de aprendizaje, del todo nuevas

MicroRNA-33b Suppresses Epithelial-Mesenchymal Transition Repressing the MYC-EZH2 Pathway in HER2+ Breast Carcinoma

Downregulation of miR-33b has been documented in many types of cancers and is being involved in proliferation, migration, and epithelial-mesenchymal transition (EMT). Furthermore, the enhancer of zeste homolog 2-gene (EZH2) is a master regulator of controlling the stem cell differentiation and the cell proliferation processes. We aim to evaluate the implication of miR-33b in the EMT pathway in HER2+ breast cancer (BC) and to analyze the role of EZH2 in this process as well as the interaction between them. miR-33b is downregulated in HER2+ BC cells vs healthy controls, where EZH2 has an opposite expression in vitro and in patients' samples. The upregulation of miR-33b suppressed proliferation, induced apoptosis, reduced invasion, migration and regulated EMT by an increase of E-cadherin and a decrease of ß-catenin and vimentin. The silencing of EZH2 mimicked the impact of miR-33b overexpression. Furthermore, the inhibition of miR-33b induces cell proliferation, invasion, migration, EMT, and EZH2 expression in non-tumorigenic cells. Importantly, the Kaplan-Meier analysis showed a significant association between high miR-33b expression and better overall survival. These results suggest miR-33b as a suppressive miRNA that could inhibit tumor metastasis and invasion in HER2+ BC partly by impeding EMT through the repression of the MYC-EZH2 loop

Laboratorio escénico de técnicas performativas

Actividades realizadas en el desarrollo del Proyecto de Innovación docente Laboratorio De Técnicas Performativas realizado en el curso 2019-2

Increasing and sustaining blood-borne virus screening in Spain and Portugal throughout the COVID-19 pandemic: a multi-center quality improvement intervention

BackgroundAround 57,000 people in Spain and Portugal currently living with HIV or chronic hepatitis C are unaware of their infection. The COVID-19 pandemic severely disrupted screening efforts for these infections. We designed an intervention to increase and sustain opportunistic blood-borne virus (BBV) screening and linkage to care (SLTC) by implementing the TEST model.MethodsThe Plan Do Study Act (PDSA) method of quality improvement (QI) was implemented in 8 healthcare organizations (HCOs), including four hospitals, two clusters of community health centers, and two community-based organizations (CBOs). Baseline assessment included a review of BBV SLTC practices, testing volume, and results 12 months before the intervention. Changes in BBV testing rates over time were measured before, during, and after the COVID-19 lockdowns in 2020. A mixed ANOVA model was used to analyze the possible effect on testing volumes among HCOs over the three study periods.InterventionBBV testing was integrated into normal clinical flow in all HCOs using existing clinical infrastructure and staff. Electronic health record (EHR) systems were modified whenever possible to streamline screening processes, implement systemic institutional policy changes, and promote QI.ResultsTwo years after the launch of the intervention in screening practices, testing volumes increased by 116%, with formal healthcare settings recording larger increases than CBOs. The start of the COVID-19 lockdowns was accompanied by a global 60% decrease in testing in all HCOs. Screening emergency department patients or using EHR systems to automate screening showed the highest resilience and lowest reduction in testing. HCOs recovered 77% of their testing volume once the lockdowns were lifted, with CBOs making the fullest recovery. Globally, enhanced screening techniques enabled HCOs to diagnose a total of 1,860 individuals over the research period.ConclusionsImplementation of the TEST model enabled HCOs to increase and sustain BBV screening, even during COVID-19 lockdowns. Although improvement in screening was noted in all HCOs, additional work is needed to develop strong patient linkage to care models in challenging times, such as global pandemics

Polymorphisms within the TNFSF4 and MAPKAPK2 Loci influence the risk of developing invasive aspergillosis: A two-stage case control study in the context of the aspBIOmics consortium

Here, we assessed whether 36 single nucleotide polymorphisms (SNPs) within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis (IA). We conducted a two-stage case control study including 911 high-risk patients diagnosed with hematological malignancies that were ascertained through the aspBIOmics consortium. The meta-analysis of the discovery and replication populations revealed that carriers of the TNFSF4rs7526628T/T genotype had a significantly increased risk of developing IA (p = 0.00022). We also found that carriers of the TNFSF4rs7526628T allele showed decreased serum levels of TNFSF14 protein (p = 0.0027), and that their macrophages had a decreased fungicidal activity (p = 0.048). In addition, we observed that each copy of the MAPKAPK2rs12137965G allele increased the risk of IA by 60% (p = 0.0017), whereas each copy of the MAPKAPK2rs17013271T allele was estimated to decrease the risk of developing the disease (p = 0.0029). Mechanistically, we found that carriers of the risk MAPKAPK2rs12137965G allele showed increased numbers of CD38+IgM-IgD- plasmablasts in blood (p = 0.00086), whereas those harboring two copies of the allele had decreased serum concentrations of thymic stromal lymphopoietin (p = 0.00097). Finally, we also found that carriers of the protective MAPKAPK2rs17013271T allele had decreased numbers of CD27-IgM-IgD- B cells (p = 0.00087) and significantly lower numbers of CD14+ and CD14+CD16- cells (p = 0.00018 and 0.00023). Altogether, these results suggest a role of the TNFSF4 and MAPKAPK2 genes in determining IA risk.This study was supported by grants PI20/01845, PI12/02688, and ISCIII-FEDER PI17/02276 from Fondo de Investigaciones Sanitarias (Madrid, Spain), PIM2010EPA-00756 from the ERA-NET PathoGenoMics (0315900A), the Collaborative Research Center/Transregio 124 FungiNet, the Fundacao para a Ciencia e Tecnologia (FCT) (PTDC/SAU-SER/29635/2017, PTDC/MED-GEN/28778/2017, CEECIND/03628/2017, and CEECIND/04058/2018), the European Union's Horizon 2020 research and innovation programme under grant agreement no. 847507, and the "la Caixa" Foundation (ID 100010434) and FCT under the agreement LCF/PR/HP17/52190003)

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9-RAGE-NF-κB-JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.info:eu-repo/semantics/publishedVersio