Fetal undernutrition is associated with perinatal sex-dependent alterations in oxidative status

This is the published version of a work that was accepted for publication in The Journal of Nutritional Biochemestry. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in The Journal of Nutritional Biochemestry 26.12 (2015). DOI: 10.1016/jnubio.2015.09.004Intrauterine growth retardation predisposes to hypertension development, known as fetal programming. Females are less susceptible, which has been mainly attributed to estrogen influence. We hypothesize that perinatal differences in oxidative status might also contribute. We studied 21-day-old (prepuberal) and 6-month-old male and female Intrauterine growth retardation predisposes to hypertension development, known as fetal programming. Females are less susceptible, which has been mainly attributed to estrogen influence. We hypothesize that perinatal differences in oxidative status might also contribute. We studied 21-day-old (prepuberal) and 6-month-old male and female offspring from rats fed ad libitum during gestation (Control) or with 50% of Control daily intake from day 10 to delivery (maternal undernutrition, MUN). We assessed in vivo blood pressure and the following plasma biomarkers of oxidative status: protein carbonyls, thiols, reduced glutathione (GSH), total antioxidant capacity, superoxide anion scavenging activity (SOSA) and catalase activities; we calculated a global score (oxy-score) from them. Estradiol and melatonin concentration was measured in young rats. Prepuberal MUN males were normotensive but already exhibited increased carbonyls and lower thiols, GSH, SOSA and melatonin; oxy-score was significantly lower compared to Control males. Prepuberal MUN females only exhibited reduced SOSA compared to Control females. Adult rats from all experimental groups showed a significant increase in carbonyls and a decrease in antioxidants compared to prepuberal rats; oxy-score was negative in adult rats suggesting the development of a prooxidative status as rat age. Adult MUN males were hypertensive and exhibited the highest increase in carbonyls despite similar or even higher antioxidant levels compared to Controls. Adult MUN females remained normotensive and did not exhibit differences in any of the biomarkers compared to Controls. The better global antioxidant status developed by MUN females during perinatal life could contribute to their protection against hypertension programming.offspring from rats fed ad libitum during gestation (Control) or with 50% of Control daily intake from day 10 to delivery (maternal undernutrition, MUN). We assessed in vivo blood pressure and the following plasma biomarkers of oxidative status: protein carbonyls, thiols, reduced glutathione (GSH), total antioxidant capacity, superoxide anion scavenging activity (SOSA) and catalase activities; we calculated a global score (oxy-score) from them. Estradiol and melatonin concentration was measured in young rats. Prepuberal MUN males were normotensive but already exhibited increased carbonyls and lower thiols, GSH, SOSA and melatonin; oxy-score was significantly lower compared to Control males. Prepuberal MUN females only exhibited reduced SOSA compared to Control females. Adult rats from all experimental groups showed a significant increase in carbonyls and a decrease in antioxidants compared to prepuberal rats; oxy-score was negative in adult rats suggesting the development of a prooxidative status as rat age. Adult MUN males were hypertensive and exhibited the highest increase in carbonyls despite similar or even higher antioxidant levels compared to Controls. Adult MUN females remained normotensive and did not exhibit differences in any of the biomarkers compared to Controls. The better global antioxidant status developed by MUN females during perinatal life could contribute to their protection against hypertension programming.This work was supported by Ministerio de Economía y Competitividad Spain (grant number FEM2012-37634-C03-01 to S. M. Arribas) and Universidad Autónoma de Madrid Banco - Santander (Interuniversity Cooperation Project, Center for Latin American Studies, Santander, USA 2013–2014 to M. A. Martín-Cabrejas)

Interferon-alpha decreases cancer stem cell properties and modulates exosomes in malignant melanoma

Malignant melanoma (MM) can spread to other organs and is resistant in part due to the presence of cancer stem cell subpopulations (CSCs). While a controversial high dose of interferon-alpha (IFN-α) has been used to treat non-metastatic high-risk melanoma, it comes with undesirable side effects. In this study, we evaluated the effect of low and high doses of IFN-α on CSCs by analyzing ALDH activity, side population and specific surface markers in established and patient-derived primary cell lines. We also assessed the clonogenicity, migration and tumor initiation capacities of IFN-α treated CSCs. Additionally, we investigated genomic modulations related to stemness properties using microRNA sequencing and microarrays. The effect of IFN-α on CSCs-derived exosomes was also analyzed using NanoSight and liquid chromatography (LC-HRMS)-based metabolomic analysis, among others. Our results showed that even low doses of IFN-α reduced CSC formation and stemness properties, and led to a significant decrease in the ability to form tumors in mice xenotransplants. IFN-α also modulated the expression of genes and microRNAs involved in several cancer processes and metabolomics of released exosomes. Our work suggests the utility of low doses of interferon, combined with the analysis of metabolic biomarkers, as a potential clinical approach against the aggressiveness of CSCs in melanoma.This research was funded by the Ministerio de Ciencia, Innovación y Universidades (MICIU, projects noº MAT2015-62644.C2.2.R and RTI2018-101309-B-C2, FEDER Funds), by the Instituto de Salud Carlos III (PIE16-00045), by Consejería de Economía, Conocimiento, Empresas y Universidad de la Junta de Andalucía and European Regional Development Fund (ERDF), ref. SOMM17/6109/UGR (UCE-PP2017-3), by Consejería de Salud y Familias de la Junta de Andalucía (projects noº PEMP0205-2020 FEDER funds), and by the Chair “Doctors Galera-Requena in cancer stem cell research” (CMC-CTS963). J.L.P. (Ref. FPU15/03682) acknowledge the MICIU for providing a PhD fellowship (FPU).info:eu-repo/semantics/publishedVersio

Identification of IL-6 Signalling Components as Predictors of Severity and Outcome in COVID-19

IL-6 is one of the major mediators of the hyper-inflammatory responses with complex biological functions as it can signal via different modes of action. IL-6 by classical signalling has anti-inflammatory and antibacterial activities, while trans-signalling mediates pro-inflammatory effects. The net biological effect of IL-6 is established by multiple factors beyond its absolute concentration. Here, we assess the relationship between IL-6 signalling variables [IL-6, soluble IL-6R (sIL-6R) and soluble gp130 (sgp130)] and outcomes in a cohort of 366 COVID-19 patients. The potential trans-signalling was evaluated by a ratio between the pro-inflammatory binary IL-6:sIL-6R complex and the inactive ternary IL-6:sIL-6R:sgp130 complex (binary/ternary complex) and the fold molar excess of sgp130 over sIL-6R (FME). Our data provide new evidence that high levels of IL-6, sIL-6R, sgp130, binary/ternary complex ratio, and low FME are independent predictors of COVID-19 severity in survivor patients (without death), and the combination of IL-6 + sIL-6R + sgp130 exhibited the most robust classification capacity. Conversely, in a subgroup of patients with a very poor prognosis, we found that high levels of IL-6 and low levels of sIL-6R, sgp130, and binary/ternary complex ratio were predictors of death. In this context, the highest predictive capacity corresponded to the combined analysis of IL-6 + FME + lymphopenia + creatinine. Herein, we present IL-6 signalling variables as a helpful tool for the early identification and stratification of patients with clear implications for treatment and clinical decision-making.The research work was supported by the Spanish Institute of Health Carlos III (COV-20/00792) and by the European Commission - NextgenerationEU (Regulation EU 2020/2094), through CSIC's Global Health Platform (PTI Salud Global). MAR-H acknowledges support from the Spanish Institute of Health Carlos III and the European Commission - NextgenerationEU (Regulation EU 2020/2094), through CSIC's Global Health Platform (PTI Salud Global). DC is supported by a predoctoral iPFIS (IFI 19/00048) funded by Spanish Institute of Health Carlos III. MN-N is supported by the Rio Hortega contract (CM20/00074)

Role of targeted therapies in rheumatic patients on COVID-19 outcomes: results from the COVIDSER study

Objectives: To analyse the effect of targeted therapies, either biological (b) disease-modifying antirheumatic drugs (DMARDs), targeted synthetic (ts) DMARDs and other factors (demographics, comorbidities or COVID-19 symptoms) on the risk of COVID-19 related hospitalisation in patients with inflammatory rheumatic diseases. Methods: The COVIDSER study is an observational cohort including 7782 patients with inflammatory rheumatic diseases. Multivariable logistic regression was used to estimate ORs and 95% CIs of hospitalisation. Antirheumatic medication taken immediately prior to infection, demographic characteristics, rheumatic disease diagnosis, comorbidities and COVID-19 symptoms were analysed. Results: A total of 426 cases of symptomatic COVID-19 from 1 March 2020 to 13 April 2021 were included in the analyses: 106 (24.9%) were hospitalised and 19 (4.4%) died. In multivariate-adjusted models, bDMARDs and tsDMARDs in combination were not associated with hospitalisation compared with conventional synthetic DMARDs (OR 0.55, 95% CI 0.24 to 1.25 of b/tsDMARDs, p=0.15). Tumour necrosis factor inhibitors (TNF-i) were associated with a reduced likelihood of hospitalisation (OR 0.32, 95% CI 0.12 to 0.82, p=0.018), whereas rituximab showed a tendency to an increased risk of hospitalisation (OR 4.85, 95% CI 0.86 to 27.2). Glucocorticoid use was not associated with hospitalisation (OR 1.69, 95% CI 0.81 to 3.55). A mix of sociodemographic factors, comorbidities and COVID-19 symptoms contribute to patients' hospitalisation. Conclusions: The use of targeted therapies as a group is not associated with COVID-19 severity, except for rituximab, which shows a trend towards an increased risk of hospitalisation, while TNF-i was associated with decreased odds of hospitalisation in patients with rheumatic disease. Other factors like age, male gender, comorbidities and COVID-19 symptoms do play a role.This Project has been financed by Bristol-Myers Squibb, Galapagos Biopharma Spain SLU, Gebro Pharma, Roche Farma and Sanofi Aventis

Specialized proresolving mediators protect against experimental autoimmune myocarditis by modulating Ca2+ handling and NRF2 activation

Specialized proresolving mediators and, in particular, 5(S), (6)R, 7-trihydroxyheptanoic acid methyl ester (BML-111) emerge as new therapeutic tools to prevent cardiac dysfunction and deleterious cardiac damage associated with myocarditis progression. The cardioprotective role of BML-111 is mainly caused by the prevention of increased oxidative stress and nuclear factor erythroid-derived 2-like 2 (NRF2) down-regulation induced by myocarditis. At the molecular level, BML-111 activates NRF2 signaling, which prevents sarcoplasmic reticulum–adenosine triphosphatase 2A down-regulation and Ca2+ mishandling, and attenuates the cardiac dysfunction and tissue damage induced by myocarditis.This work was supported by the Spanish Ministry of Economy and Competitiveness and the European Regional Development Fund (SAF-2017-84777R), Instituto de Salud Carlos III (ISCIII) (PI17/01093, PI17/01344, and PI20/01482), Sociedad Española de Cardiología, Proyecto Traslacional 2019 and Asociación del Ritmo Cardiaco (SEC, España), Proyecto Asociación Insuficiencia Cardiaca (Trasplante Cardiaco) 2020, Fondo Europeo de Desarrollo Regional, Fondo Social Europeo, and CIBERCV, a network funded by ISCIII, Spanish Ministry of Science, Innovation and Universities (PGC2018-097019-B-I00), Ministerio de Economía, Industria y Competitividad/Agencia Estatal de Investigación 10.13039/501100011033 PID2020-113238RB-I00, PID2019-105600RB-I00, the Instituto de Salud Carlos III (Fondo de Investigación Sanitaria grant PRB3 [PT17/0019/0003-ISCIII-SGEFI/ERDF, ProteoRed]), and “la Caixa” Foundation (project code HR17-00247). The Centro Nacional de Investigaciones Cardiovasculares is supported by the ISCIII, the Ministerio de Ciencia, Innovación y Universidades. Dr Ruiz-Hurtado is Miguel Servet I researcher of ISCIII (CP15/00129 Carlos III Health Institute). Dr Tamayo and R.I. Jaén, and M. Gil-Fernández were or currently are PhD students funded by the Formación de Profesorado Universitario program of the Spanish Ministry of Science, Innovation and Universities (FPU17/06135; FPU16/00827, FPU1901973)

Macrophages direct cancer cells through a LOXL2-mediated metastatic cascade in pancreatic ductal adenocarcinoma

[Objective]: The lysyl oxidase-like protein 2 (LOXL2) contributes to tumour progression and metastasis in different tumour entities, but its role in pancreatic ductal adenocarcinoma (PDAC) has not been evaluated in immunocompetent in vivo PDAC models.[Design]: Towards this end, we used PDAC patient data sets, patient-derived xenograft in vivo and in vitro models, and four conditional genetically-engineered mouse models (GEMMS) to dissect the role of LOXL2 in PDAC. For GEMM-based studies, K-Ras +/LSL-G12D;Trp53 LSL-R172H;Pdx1-Cre mice (KPC) and the K-Ras +/LSL-G12D;Pdx1-Cre mice (KC) were crossed with Loxl2 allele floxed mice (Loxl2Exon2 fl/fl) or conditional Loxl2 overexpressing mice (R26Loxl2 KI/KI) to generate KPCL2KO or KCL2KO and KPCL2KI or KCL2KI mice, which were used to study overall survival; tumour incidence, burden and differentiation; metastases; epithelial to mesenchymal transition (EMT); stemness and extracellular collagen matrix (ECM) organisation.[Results]: Using these PDAC mouse models, we show that while Loxl2 ablation had little effect on primary tumour development and growth, its loss significantly decreased metastasis and increased overall survival. We attribute this effect to non-cell autonomous factors, primarily ECM remodelling. Loxl2 overexpression, on the other hand, promoted primary and metastatic tumour growth and decreased overall survival, which could be linked to increased EMT and stemness. We also identified tumour-associated macrophage-secreted oncostatin M (OSM) as an inducer of LOXL2 expression, and show that targeting macrophages in vivo affects Osm and Loxl2 expression and collagen fibre alignment.[Conclusion]: Taken together, our findings establish novel pathophysiological roles and functions for LOXL2 in PDAC, which could be potentially exploited to treat metastatic disease.JCL-G received support from a 'la Caixa' Foundation (ID 100010434) fellowship (LCF/BQ/DR21/11880011). This study was supported by ISCIII FIS grants PI18/00757 and PI21/01110 (BSJ) and PI18/00267 (LG-B), and grants from the Spanish Ministry of Economy and Innovation SAF2016-76504-R (ACan and FP), PID2019-111052RB-I00 (FP), PID2019-104644RB-I00 (GM-B), a Ramón y Cajal Merit Award RYC-2012–12104 (BSJ) and ISCIII, CIBERONC, CB16/12/00446 (ACar) and CB16/12/00295 (ACan and GM-B), all of them co-financed through Fondo Europeo de Desarrollo Regional (FEDER) 'Una manera de hacer Europa'; a Fero Foundation Grant (BSJ); a Coordinated grant (GC16173694BARB) from the Fundación Científica Asociación Española Contra el Cáncer (FC-AECC) (BSJ); a Miguel Servet award (CP16/00121) (PS); a DFG, German Research Foundation Grant—Project no: 492 436 553 (KG); and a Max Eder Fellowship of the German Cancer Aid (111746) (PCH

Multicentre, randomised, single-blind, parallel group trial to compare the effectiveness of a Holter for Parkinson's symptoms against other clinical monitoring methods: study protocol

Introduction In recent years, multiple studies have aimed to develop and validate portable technological devices capable of monitoring the motor complications of Parkinson's disease patients (Parkinson's Holter). The effectiveness of these monitoring devices for improving clinical control is not known. Methods and analysis This is a single-blind, cluster-randomised controlled clinical trial. Neurologists from Spanish health centres will be randomly assigned to one of three study arms (1:1:1): (a) therapeutic adjustment using information from a Parkinson?s Holter that will be worn by their patients for 7 days, (b) therapeutic adjustment using information from a diary of motor fluctuations that will be completed by their patients for 7 days and (c) therapeutic adjustment using clinical information collected during consultation. It is expected that 162 consecutive patients will be included over a period of 6 months. The primary outcome is the efficiency of the Parkinson?s Holter compared with traditional clinical practice in terms of Off time reduction with respect to the baseline (recorded through a diary of motor fluctuations, which will be completed by all patients). As secondary outcomes, changes in variables related to other motor complications (dyskinesia and freezing of gait), quality of life, autonomy in activities of daily living, adherence to the monitoring system and number of doctor?patient contacts will be analysed. The noninferiority of the Parkinson's Holter against the diary of motor fluctuations in terms of Off time reduction will be studied as the exploratory objective. Ethics and dissemination approval for this study has been obtained from the Hospital Universitari de Bellvitge Ethics Committee. The results of this study will inform the practical utility of the objective information provided by a Parkinson's Holter and, therefore, the convenience of adopting this technology in clinical practice and in future clinical trials. We expect public dissemination of the results in 2022.Funding This work is supported by AbbVie S.L.U, the Instituto de Salud Carlos III [DTS17/00195] and the European Fund for Regional Development, 'A way to make Europe'

La Recerca en Conservació des de la Visió del Conservador-Restaurador II

Seguint la línia de divulgació científica iniciada durant la Setmana de la Ciència 2013, des de la Secció de Conservació-Restauració de la Facultat de Belles Arts (Universitat de Barcelona volem continuar difonent les investigacions que duem a terme. Des d'aquest any, a més, també volem donar cabuda a la recerca que es desenvolupa des dels Treballs Finals del Master Universitari de Direcció de Projectes de Conservació-Restauraració

Study of breast cancer incidence in patients of lymphangioleiomyomatosis

The online version of this article (doi:10.1007/s10549-016-3737-8) contains supplementary material, which is available to authorized user