Depósito Académico
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Results
- Association of SDF1 and MMP12 with atherosclerosis and inflammation: clinical and experimental study(MDPI, 2021) Paramo, J.A. (José Antonio); Colina, I. (Inmaculada); Machado, F. J. D. (Florencio J.D.); Marcos-Jubilar, M. (María); Orbe, J. (Josune); Rodriguez, J.A. (José Antonio); Rodil-Fraile, R. (Raquel); Fernandez-Montero, A. (Alejandro); Roncal, C. (Carmen); Pastrana-Delgado, J. (Juan)Background: Atherosclerosis is the main etiology of cardiovascular diseases (CVD), associated to systemic inflammation. Matrix metalloproteinases (MMPs) are related to atherosclerosis progression through the SDF1/CXCR4 axis promoting macrophages recruitment within the vascular wall. The goal was to assess new circulatory inflammatory markers in relation to atherosclerosis. Methods: Measurement of SDF1, MMP12 and CRP in blood samples of 298 prospective patients with cardiovascular risk. To explore atherosclerosis progression, CXCR4/SDF1 axis and MMP12 expression were determined by RT-qPCR and by immunohistochemistry in the aorta of accelerated and delayed atherosclerosis mice models (Apoe-/- and Apoe-/-Mmp10-/-). Results: SDF1, MMP12 and CRP were elevated in patients with clinical atherosclerosis, but after controlling by confounding factors, only SDF1 and CRP remained increased. Having high levels of both biomarkers showed 2.8-fold increased risk of presenting clinical atherosclerosis (p = 0.022). Patients with elevated SDF1, MMP12 and CRP showed increased risk of death in follow-up (HR = 3.2, 95%CI: 1.5-7.0, p = 0.004). Gene and protein expression of CXCR4 and MMP12 were increased in aortas from Apoe-/- mice. Conclusions: The combination of high circulating SDF1, MMP12 and CRP identified patients with particular inflammatory cardiovascular risk and increased mortality. SDF1/CXCR4 axis and MMP12 involvement in atherosclerosis development suggests that they could be possible atherosclerotic targets.
- LIBRA: an adaptative integrative tool for paired single-cell multi-omics data(2023) Gomez-Cabrero, D. (David); Khan, S.A. (Sumeer A.); Tegner, J. (Jesper); Qu, S. (Sisi); Lehmann, R. (Robert); Martinez-de-Morentin, X. (Xabier); Maillo, A. (Alberto); Kiani, N.A. (Narsis A.); Prosper-Cardoso, F. (Felipe)Background: Single-cell multi-omics technologies allow a profound system-level biology understanding of cells and tissues. However, an integrative and possibly systems-based analysis capturing the different modalities is challenging. In response, bioinformatics and machine learning methodologies are being developed for multi-omics single-cell analysis. It is unclear whether current tools can address the dual aspect of modality integration and prediction across modalities without requiring extensive parameter fine-tuning. Methods: We designed LIBRA, a neural network based framework, to learn translation between paired multi-omics profiles so that a shared latent space is constructed. Additionally, we implemented a variation, aLIBRA, that allows automatic fine-tuning by identifying parameter combinations that optimize both the integrative and predictive tasks. All model parameters and evaluation metrics are made available to users with minimal user iteration. Furthermore, aLIBRA allows experienced users to implement custom configurations. The LIBRA toolbox is freely available as R and Python libraries at GitHub (TranslationalBioinformaticsUnit/LIBRA).Results: LIBRA was evaluated in eight multi-omic single-cell data-sets, including three combinations of omics. We observed that LIBRA is a state-of-the-art tool when evaluating the ability to increase cell-type (clustering) resolution in the integrated latent space. Furthermore, when assessing the predictive power across data modalities, such as predictive chromatin accessibility from gene expression, LIBRA outperforms existing tools. As expected, adaptive parameter optimization (aLIBRA) significantly boosted the performance of learning predictive models from paired data-sets.Conclusion: LIBRA is a versatile tool that performs competitively in both integration and prediction tasks based on single-cell multi-omics data. LIBRA is a data-driven robust platform that includes an adaptive learning scheme.
- Endothelial NOX5 overexpression induces changes in the cardiac gene profile: potential impact in myocardial infarction?(Springer, 2023) Ainzúa-Pérez, E. (Elena); Miguel-Vázquez, C. (Carlos) de; Cortés, A. (Adriana); Ansorena-Artieda, E. (Eduardo); Pejenaute-Martínez-de-Lizarrondo, Á. (Álvaro); Marqués, J. (Javier); Prosper-Cardoso, F. (Felipe); Zalba, G. (Guillermo); Abizanda-Sarasa, G. (Gloria)Cardiovascular diseases and the ischemic heart disease specifically constitute the main cause of death worldwide. The ischemic heart disease may lead to myocardial infarction, which in turn triggers numerous mechanisms and pathways involved in cardiac repair and remodeling. Our goal in the present study was to characterize the effect of the NADPH oxidase 5 (NOX5) endothelial expression in healthy and infarcted knock-in mice on diverse signaling pathways. The mechanisms studied in the heart of mice were the redox pathway, metalloproteinases and collagen pathway, signaling factors such as NFκB, AKT or Bcl-2, and adhesion molecules among others. Recent studies support that NOX5 expression in animal models can modify the environment and predisposes organ response to harmful stimuli prior to pathological processes. We found many alterations in the mRNA expression of components involved in cardiac fibrosis as collagen type I or TGF-β and in key players of cardiac apoptosis such as AKT, Bcl-2, or p53. In the heart of NOX5-expressing mice after chronic myocardial infarction, gene alterations were predominant in the redox pathway (NOX2, NOX4, p22phox, or SOD1), but we also found alterations in VCAM-1 and β-MHC expression. Our results suggest that NOX5 endothelial expression in mice preconditions the heart, and we propose that NOX5 has a cardioprotective role. The correlation studies performed between echocardiographic parameters and cardiac mRNA expression supported NOX5 protective action.
- Generation of heart and vascular system in rodents by blastocyst complementation(2023) Ullate-Agote, A. (Asier); Abizanda-Sarasa, G. (Gloria María); Aranguren-López, X. (Xabier); San-Martín-Uriz, P. (Patxi); Barreda, C. (Carolina); Coppiello, G. (Giulia); Larequi-Ardanaz, E. (Eduardo); Carvajal-Vergara, X. (Xonia); Pelacho-Samper, B. (Beatriz); Ruiz-Villalba, A. (Adrián); Mazo, M. (Manuel); Arellano-Viera, E. (Estíbaliz); Pérez-Pomares, J.M. (José María); Linares, J. (Javier); Pogontke, C. (Cristina); Iglesias, E. (Elena); Prosper-Cardoso, F. (Felipe); Moya-Jódar, M. (Marta); Barlabé-Ginesta, P. (Paula)Generating organs from stem cells through blastocyst complementation is a promising approach to meet the clinical need for transplants. In order to generate rejection-free organs, complementation of both parenchymal and vascular cells must be achieved, as endothelial cells play a key role in graft rejection. Here, we used a lineage-specific cell ablation system to produce mouse embryos unable to form both the cardiac and vascular systems. By mouse intraspecies blastocyst complementation, we rescued heart and vascular system development separately and in combination, obtaining complemented hearts with cardiomyocytes and endothelial cells of exogenous origin. Complemented chimeras were viable and reached adult stage, showing normal cardiac function and no signs of histopathological defects in the heart. Furthermore, we implemented the cell ablation system for rat-to-mouse blastocyst complementation, obtaining xenogeneic hearts whose cardiomyocytes were completely of rat origin. These results represent an advance in the experimentation towards the invivo generation of transplantable organs.
- CM-352 Efficacy in a mouse model of anticoagulant-associated intracranial hemorrhage(Thieme, 2022) Navarro-Oviedo, M. (Manuel); Paramo, J.A. (José Antonio); Pineda-Lucena, A. (Antonio); Zandio, B. (Beatriz); Hermida, J. (José); Orbe, J. (Josune); Rodriguez, J.A. (José Antonio); Muñoz, R. (Roberto); Oyarzabal, J. (Julen); Lecumberri, R. (Ramón); Roncal, C. (Carmen); Marta-Enguita, J. (Juan)Background: Intracranial hemorrhage (ICH) is one of the major devastating complications of anticoagulation. Matrix metalloproteinase (MMP) inhibition has been proposed as a novel pharmacological approach for ICH treatment. Objectives: We evaluated the effects of CM-352 (MMP-fibrinolysis inhibitor) in an experimental ICH model associated with oral anticoagulants as compared with clinically used prothrombin complex concentrate (PCC). Methods: ICH was induced by collagenase injection into the striatum of wild type (C57BL/6J) anticoagulated mice (warfarin or rivaroxaban) and Mmp10 -/- mice. Hematoma volume and neurological deficits were measured 24 hours later by diaminobenzidine staining and different behavioral tests. Circulating plasminogen activator inhibitor-1 (PAI-1) activity and interleukin-6 (IL-6) were measured in plasma samples and local inflammation was assessed by neutrophil infiltration. Finally, fibrinolytic effects of MMP-10 and rivaroxaban were evaluated by thromboelastometry and thrombin-activatable fibrinolysis inhibitor (TAFI) activation assays. Results: Only PCC reduced hemorrhage volume and improved functional outcome in warfarin-ICH, but both PCC and CM-352 treatments diminished hemorrhage volume (46%, p < 0.01 and 64%, p < 0.001, respectively) and ameliorated functional outcome in rivaroxaban-ICH. We further demonstrated that CM-352, but not PCC, decreased neutrophil infiltration in the hemorrhage area at 24 hours. The effect of CM-352 could be related to MMP-10 inhibition since Mmp10 -/- mice showed lower hemorrhage volume, better neurological score, reduced IL-6 levels and neutrophil infiltration, and increased PAI-1 after experimental ICH. Finally, we found that CM-352 reduced MMP-10 and rivaroxaban-related fibrinolytic effects in thromboelastometry and TAFI activation. Conclusion: CM-352 treatment, by diminishing MMPs and rivaroxaban-associated fibrinolytic effects, might be a novel antihemorrhagic strategy for rivaroxaban-associated ICH.
- A Fibrosis Biomarker Early Predicts Cardiotoxicity Due to Anthracycline-Based Breast Cancer Chemotherapy(MDPI, 2022) Díaz, A. (Agnes); Sepúlveda, P. (Pilar); Lupón, J. (Josep); Gavira, J.J. (Juan José); Ravassa, S. (Susana); Lopez-Picazo, J.M. (José M.); Santisteban, M. (Marta); Gonzalez, A. (Arantxa); Hernándiz, A. (Amparo); Mazo, M. (Manuel); Rabago, G. (Gregorio); Aramendia, J.M. (J.M.); Fuente, A. (Ana) de la; Garcia-Bolao, I. (Ignacio); Cediel, G. (Germán); López, B. (Begoña); Diez, J. (Javier); Santaballa, A. (Ana); Bayes-Genis, A. (Antoni)Anthracycline-based cancer chemotherapy (ACC) causes myocardial fibrosis, a lesion contributing to left ventricular dysfunction (LVD). We investigated whether the procollagen-derived type-I C-terminal-propeptide (PICP): (1) associates with subclinical LVD (sLVD) at 3-months after ACC (3m-post-ACC); (2) predicts cardiotoxicity 1-year after ACC (12m-post-ACC) in breast cancer patients (BC-patients); and (3) associates with LVD in ACC-induced heart failure patients (ACC-HF-patients). Echocardiography, serum PICP and biomarkers of cardiomyocyte damage were assessed in two independent cohorts of BC-patients: CUN (n = 87) at baseline, post-ACC, and 3m and 12m (n = 65)-post-ACC; and HULAFE (n = 70) at baseline, 3m and 12m-post-ACC. Thirty-seven ACC-HF-patients were also studied. Global longitudinal strain (GLS)-based sLVD (3m-post-ACC) and LV ejection fraction (LVEF)-based cardiotoxicity (12m-post-ACC) were defined according to guidelines. BC-patients: all biomarkers increased at 3m-post-ACC versus baseline. PICP was particularly increased in patients with sLVD (interaction-p < 0.001) and was associated with GLS (p < 0.001). PICP increase at 3m-post-ACC predicted cardiotoxicity at 12m-post-ACC (odds-ratio ≥ 2.95 per doubling PICP, p ≤ 0.025) in both BC-cohorts, adding prognostic value to the early assessment of GLS and LVEF. ACC-HF-patients: PICP was inversely associated with LVEF (p = 0.004). In ACC-treated BC-patients, an early increase in PICP is associated with early sLVD and predicts cardiotoxicity 1 year after ACC. PICP is also associated with LVD in ACC-HF-patients.
- Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial(2020) Bakhshi, S. (Sameer); Follows, G. A. (George Alexander); Hamad, N. (Nada); Gurion, R. (Ronit); Sancho, J. M. (Juan Manuel); Thièblemont, C. (Catherine); Zijlstra-Baalbergen, J. M. (Josse M.); Egyed, M. (Miklós); Schuster, M. W. (Michael W.); Canales-Albendea, M. A. (Miguel Ángel); Casasnovas, R. O. (René Olivier); Goy, A. (Andre); Cavallo, F. (Federica); de la Cruz, F. (Fatima); Vermaat, J. S. P. (Joost S. P.); Bouabdallah, R. (Réda); Kalakonda, N. (Nagesh); Choquet, S. (Sylvain); Maerevoet, M. (Marie); Hill, B. T. (Brian T.); Jaeger, U. I. (Ulrich I.)Background: Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer with a median overall survival of less than 6 months. We aimed to assess the response to single-agent selinexor, an oral selective inhibitor of nuclear export, in patients with relapsed or refractory DLBCL who had no therapeutic options of potential clinical benefit. Methods: SADAL was a multicentre, multinational, open-label, phase 2b study done in 59 sites in 19 countries. Patients aged 18 years or older with pathologically confirmed diffuse large B-cell lymphoma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received two to five lines of previous therapies, and progressed after or were not candidates for autologous stem-cell transplantation were enrolled. Germinal centre B-cell or non-germinal centre B-cell tumour subtype and double or triple expressor status were determined by immunohistochemistry and double or triple hit status was determined by cytogenetics. Patients received 60 mg selinexor orally on days 1 and 3 weekly until disease progression or unacceptable toxicity. The study was initially designed to evaluate both 60 mg and 100 mg twice-weekly doses of selinexor; however, the 100 mg dose was discontinued in the protocol (version 7.0) on March 29, 2017, when an improved therapeutic window was observed at 60 mg. Primary outcome was overall response rate. The primary outcome and safety were assessed in all patients who received 60 mg selinexor under protocol version 6.0, or enrolled under protocol versions 7.0 or higher and received at least one dose of selinexor. This trial is registered at ClinicalTrials.gov, NCT02227251 (active but not enrolling). Findings: Between Oct 21, 2015, and Nov 2, 2019, 267 patients were randomly assigned, with 175 allocated to the 60 mg group and 92 to the discontinued 100 mg group. 48 patients assigned to the 60 mg group were excluded due to enrolment before version 6.0 of the protocol; the remaining 127 patients received selinexor 60 mg and were included in analyses of primary outcome and safety. The overall response rate was 28% (36/127; 95% CI 20·7–37·0); 15 (12%) achieved a complete response and 21 (17%) a partial response. The most common grade 3–4 adverse events were thrombocytopenia (n=58), neutropenia (n=31), anaemia (n=28), fatigue (n=14), hyponatraemia (n=10), and nausea (n=8). The most common serious adverse events were pyrexia (n=9), pneumonia (n=6), and sepsis (n=6). There were no deaths judged as related to treatment with selinexor. Interpretation: Single-drug oral selinexor induced durable responses and had a manageable adverse events profile in patients with relapsed or refractory DLBCL who received at least two lines of previous chemoimmunotherapy. Selinexor could be considered a new oral, non-cytotoxic treatment option in this setting.
- Classification, prevalence, and outcomes of anticancer therapy-induced cardiotoxicity: the CARDIOTOX registry(2020) Cardinale, D. (Daniela); González-Costello, J. (José); Rodríguez-Rodríguez, I. (Isabel); Lyon, A.R. (Alexander R.); López-Fernández, T. (Teresa); Feliu-Batlle, J. (Jaime); Farmakis, D. (Dimitrios); Gómez-Prieto, P. (Pilar); González-Juanatey, J. R. (José Ramón); Zamora-Auñon, P. (Pilar); Cadenas-Chamorro, R. (Rosalía); Martínez-Monzonis, A. (Amparo); Buño-Soto, A. (Antonio); Canales-Albendea, M. A. (Miguel Ángel); Álvarez-Ortega, C. (Carlos); Albaladejo, A. (Ainara); Serrano-Antolín, J. M. (José María); López-Sendón, J.L. (J. L.); Mediavilla, G. (Guimoar); Rodríguez-Fraga, O. (Olaia)Aim: Cardiotoxicity (CTox) is a major side effect of cancer therapies, but uniform diagnostic criteria to guide clinical and research practices are lacking. Methods and results: We prospectively studied 865 patients, aged 54.7 ± 13.9; 16.3% men, scheduled for anticancer therapy related with moderate/high CTox risk. Four groups of progressive myocardial damage/dysfunction were considered according to current guidelines: normal, normal biomarkers (high-sensitivity troponin T and N-terminal natriuretic pro-peptide), and left ventricular (LV) function; mild, abnormal biomarkers, and/or LV dysfunction (LVD) maintaining an LV ejection fraction (LVEF) ≥50%; moderate, LVD with LVEF 40–49%; and severe, LVD with LVEF ≤40% or symptomatic heart failure. Cardiotoxicity was defined as new or worsening of myocardial damage/ventricular function from baseline during follow-up. Patients were followed for a median of 24 months. Cardiotoxicity was identified in 37.5% patients during follow-up [95% confidence interval (CI) 34.22–40.8%], 31.6% with mild, 2.8% moderate, and 3.1% with severe myocardial damage/dysfunction. The mortality rate in the severe CTox group was 22.9 deaths per 100 patients-year vs. 2.3 deaths per 100 patients-year in the rest of groups, hazard ratio of 10.2 (95% CI 5.5–19.2) (P < 0.001). Conclusions: The majority of patients present objective data of myocardial injury/dysfunction during or after cancer therapy. Nevertheless, severe CTox, with a strong prognostic relationship, was comparatively rare. This should be reflected in protocols for clinical and research practices.
- Managing the front-line treatment for diffuse large B cell lymphoma and high-grade B cell lymphoma during the COVID-19 outbreak(2020) López, A. (Andrés); de la Cruz-Benito, B. (Beatriz); Lopez-de-la-Guía, A. (Ana); de Soto-Álvarez, T. (Teresa); Sánchez-Vadillo, I. (Irene); Dos-Santos-Ortas, A. (Abel); Casado-Abad, G. (Gema); Canales-Albendea, M. A. (Miguel Ángel); Lázaro-Del-Campo, P. (Paula); Humala-Barbier, K. (Karem); Jiménez-Yuste, V. (Víctor)The COVID-19 pandemic has dramatically challenged care for cancer patients, especially those with active treatment who represent a vulnerable population for SARS-CoV-2 infection. Aggressive lymphoid neoplasms, such as diffuse large B cell lymphoma and high-grade B cell lymphoma, need to be treated without delay in order to get the best disease outcome. Because of that, our clinical practice was changed to minimise the risk of SARS-CoV-2 infection while continuing haematological treatment. In this report, we analyse the management of front-line therapy in 18 patients during the COVID-19 outbreak, as well as the results of the implemented measures in their outcome.
- Venetoclax ramp-up strategies for chronic lymphocytic leukaemia in the United Kingdom: a real world multicentre retrospective study(Wiley, 2023) Preston, G. (Gavin); Worth, T. (Tina); Munir, T. (Tahla); Martinez-Calle, N. (Nicolas); Ferguson, J.P. (John-Paul); Gohill, S.(Satyen); Kennedy, B. (Ben); Figueroa, R. (Rocío); Halperin, D. (Daniel); Schuh, A. (Anna); Fox, C. P. (Christopher P.); Furtado, M. (Michelle); Dungarwalla, M. (Moez); Eyre, T.A. (Toby A.); Patten, P. (Piers); Melotti, D. (Dario); Rampotas, A. (Alexandros); Elmusharaf, N. (Nagah); Vidler, J. (Jennifer)This retrospective, observational study evaluated patterns of inpatient versus outpatient tumour lysis syndrome (TLS) monitoring during venetoclax ramp-up in 170 patients with chronic lymphocytic leukaemia. The primary outcome was clinical/biochemical TLS. Two clinical and four biochemical TLS occurred (4.1%). Five of the six events occurred in high-risk patients, four occurred at 20 mg dose and three at the 6-h time-point. Inpatient versus outpatient TLS rates within the high-risk subgroup were 15% and 8%. Risk category was the only predictor of TLS events in multivariate analysis. Outpatient escalation did not associate with clinically meaningful TLS events, suggesting outpatient escalation has manageable associated TLS risks, including in high-risk cohorts. These observations require confirmation in larger studies.