Artículos de revista (CUN)
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- 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.
- Anti-PD1 associated fulminant myocarditis after a single pembrolizumab dose: the role of occult pre-existing autoimmunity(Ferrata Storti Foundation, 2018) Martinez-Calle, N. (Nicolas); Villar-Fernández, S. (Sara); Mejías-Sosa, L.D. (Luis D.); Melero, I. (Ignacio); Rodriguez-Otero, P. (Paula); Idoate, M.A. (Miguel Ángel); Paiva, B. (Bruno); Marinello, P. (Patricia); Prosper-Cardoso, F. (Felipe); San-Miguel, J.F. (Jesús F.)Multiple myeloma is a promising candidate for anti-PD1 checkpoint inhibitor therapy.1–3 Results of phase I trials of pembrolizumab, in combination with lenalidomide or pomalidomide in relapsed/refractory patients have shown encouraging results. These trials showed a 35% and 65% response rate in patients already refractory to IMIDs with a median PFS of 7.2 and 14 months for the lenalidomide and pomalidomide combinations, respectively.4,5 These positive results prompted the activation of phase III trials, which are currently underway in relapsed (clinicaltrials.gov identifier 02576977) and first-line setting (clinicaltrials.gov identifier 02579863). Immune-related adverse events (irAE) as a result of uncontrolled activation of autoreactive T-cells,6 are the most important emerging safety issues of checkpoint inhibitors. Myocarditis is rare among the irAE; however, several cases of lethal immune-related myocarditis have recently been published.7–9 The Nivolumab patient database has revealed an incidence of myocarditis of 0.09% in over 20,000 patients already treated;7 however, this figure may be an underestimation since only symptomatic cases were recorded. Myocarditis seems to be frequent with the nivolumab-ipilimumab combination (0.27%), with two reports of a lethal outcome.8 To the best of our knowledge, no fatal cases have been reported with pembrolizumab or nivolumab as single checkpoint inhibitor agents. Here, we report a newly diagnosed multiple myeloma patient who developed a lethal immune-related myocarditis after a single dose of pembrolizumab, which was combined with lenalidomide and dexamethasone, not with other checkpoint inhibitors.
- A single prior course of BCNU-cisplatin chemotherapy has a significant deleterious effect on mobilization kinetics of otherwise untreated patients(Springer Nature, 2004) Pérez-Calvo, J. (J.); Martin-Algarra, S. (Salvador); Aristu-Mendioroz, J.J. (José Javier); Rifon, J. J. (Jose J.); Rocha, E. (Eduardo); Fernandez, O. (O.); Aramendia, J.M. (J.M.); Bendandi, M. (Maurizio); Prosper-Cardoso, F. (Felipe)Extensive prior treatment with cytotoxic agents is associated with impaired mobilization of hematopoietic cells. To assess the effect of a single course of standarddose chemotherapy (CT), we compared the results of filgrastim-induced mobilization among two sequential groups of grade III–IV malignant glioma patients included in a hematopoietic transplantation program. The first group (21 patients) had never been treated with CT until 2 days after surgery, when they received a course of 100 mg/m2 BCNU (IV) and 100 mg intracarotid cisplatin for cytoreduction (not for mobilization). At 1 month after this CT, they were mobilized with 12 lg/kg filgrastim. The second group (22 patients) was mobilized with the same dose of filgrastim directly after the surgery, without having ever received any prior CT. The blood level of CD34 þ cells was significantly lower in the CT-treated patients, both on the fourth day of filgrastim (15 vs 36 cells 106 /l; P ¼ 0.01) and on the fifth (25 vs 58 cells 106 /l; P ¼ 0.003), as it was the number of CD34 þ cells collected per apheresis (1.3 vs 3.5 106 /l; Po0.0005). The toxic effect of a single course of BCNUcisplatin CT led to significant impairment of the filgrastim-induced mobilization response.
- A multimodal scaffold for SDF1 delivery improves cardiac function in a rat subacute myocardial infarct model(ACS Publications, 2023) Garcia-de-Yebenes, M. (Manuel); Pérez-Estenaga, I. (Iñigo); Tumin-Chevalier, M. (Merari); Pandit, A. (Abhay); Alsharabasy, A.M. (Amir M.); Larequi-García, E. (Eduardo); Cilla, M. (Myriam); Peña, E. (Estefanía); Prosper-Cardoso, F. (Felipe); Pelacho, B. (Beatriz); Abizanda-Sarasa, G. (Gloria); Perez, M.M. (Marta M.); Gurtubay, J. (Jon)Ischemic heart disease is one of the leading causes of death worldwide. The efficient delivery of therapeutic growth factors could counteract the adverse prognosis of post-myocardial infarction (post-MI). In this study, a collagen hydrogel that is able to load and appropriately deliver pro-angiogenic stromal cell-derived factor 1 (SDF1) was physically coupled with a compact collagen membrane in order to provide the suture strength required for surgical implantation. This bilayer collagen-on-collagen scaffold (bCS) showed the suitable physicochemical properties that are needed for efficient implantation, and the scaffold was able to deliver therapeutic growth factors after MI. In vitro collagen matrix biodegradation led to a sustained SDF1 release and a lack of cytotoxicity in the relevant cell cultures. In vivo intervention in a rat subacute MI model resulted in the full integration of the scaffold into the heart after implantation and biocompatibility with the tissue, with a prevalence of anti-inflammatory and pro-angiogenic macrophages, as well as evidence of revascularization and improved cardiac function after 60 days. Moreover, the beneficial effect of the released SDF1 on heart remodeling was confirmed by a significant reduction in cardiac tissue stiffness. Our findings demonstrate that this multimodal scaffold is a desirable matrix that can be used as a drug delivery system and a scaffolding material to promote functional recovery after MI.
- A phase II trial of autologous dendritic cell vaccination and radiochemotherapy following fuorescence-guided surgery in newly diagnosed glioblastoma patients(BMC, 2017) Espinos, J. (Jaime); Garcia-de-Eulate, R. (Reyes); Alonso-Roldán, M.M. (Marta María); Pastor, F. (Fernando); Aristu-Mendioroz, J.J. (José Javier); Domínguez-Echávarri, P.D. (Pablo Daniel); Lopez-Diaz-de-Cerio, A. (Ascensión); Tejada-Solis, S. (Sonia); Diez-Valle, R. (Ricardo); Andreu, E.J. (Enrique José); Inoges, S. (Susana); Idoate, M.A. (Miguel Ángel); Bendandi, M. (Maurizio); Gallego-Perez-Larraya, J. (Jaime); Prosper-Cardoso, F. (Felipe)Background: Prognosis of patients with glioblastoma multiforme (GBM) remains dismal, with median overall survival (OS) of about 15 months. It is therefore crucial to search alternative strategies that improve these results obtained with conventional treatments. In this context, immunotherapy seems to be a promising therapeutic option. We hypoth‐ esized that the addition of tumor lysate-pulsed autologous dendritic cells (DCs) vaccination to maximal safe resection followed by radiotherapy and concomitant and adjuvant temozolomide could improve patients’ survival. Methods: We conducted a phase-II clinical trial of autologous DCs vaccination in patients with newly diagnosed patients GBM who were candidates to complete or near complete resection. Candidates were fnally included if residual tumor volume was lower than 1 cc on postoperative radiological examination. Autologous DCs were generated from peripheral blood monocytes and pulsed with autologous whole tumor lysate. The vaccination calendar started before radiotherapy and was continued during adjuvant chemotherapy. Progression free survival (PFS) and OS were analyzed with the Kaplan–Meier method. Immune response were assessed in blood samples obtained before each vaccines. Results: Thirty-two consecutive patients were screened, one of which was a screening failure due to insufcient resection. Median age was 61 years (range 42–70). Karnofsky performance score (KPS) was 90–100 in 29%, 80 in 35.5% and 60–70 in 35.5% of cases. MGMT (O6 -methylguanine-DNA-methyltransferase) promoter was methylated in 45.2% of patients. No severe adverse efects related to immunotherapy were registered. Median PFS was 12.7 months (CI 95% 7–16) and median OS was 23.4 months (95% CI 16–33.1). Increase in post-vaccination tumor specifc immune response after vaccines (proliferation or cytokine production) was detected in 11/27 evaluated patients. No correla‐ tion between immune response and survival was found. Conclusions: Our results suggest that the addition of tumor lysate-pulsed autologous DCs vaccination to tumor resection and combined radio-chemotherapy is feasible and safe. A multicenter randomized clinical trial is warranted to evaluate the potential survival beneft of this therapeutic approach.
- Identification and experimental validation of druggable epigenetic targets in hepatoblastoma(Elsevier, 2023) Indersie, E. (Emilie); Latasa, M.U. (María Ujué); Berraondo, P. (Pedro); Corrales, F.J. (Fernando José); Berasain, C. (Carmen); Arechederra, M. (María); Domingo-Sàbat, M. (Montserrat); Pineda-Lucena, A. (Antonio); Sancho-Bru, P. (Pau); Zanatto, L. (Laura); Armengol, C. (Carolina); Uriarte, I. (Iker); Ciordia, S. (Sergio); Avila, M.A. (Matías Antonio); Alaggio, R. (Rita); Alonso, C. (Cristina); Sangro, B. (Bruno); García-Fernandez-Barrena, M. (Maite); Herranz, J.M. (José M.); Cairo, S. (Stefano); García-Marin, J.J. (Jose Juan); Francalanci, P. (Paola); Prosper-Cardoso, F. (Felipe); Claveria-Cabello, A. (Alex); Martinez-Chantar, M.L. (María Luz); Zucman-Rossi, J. (Jessica)Background & Aims: Hepatoblastoma (HB) is the most frequent childhood liver cancer. Patients with aggressive tumors have limited therapeutic options; therefore, a better understanding of HB pathogenesis is needed to improve treatment. HBs have a very low mutational burden; however, epigenetic alterations are increasingly recognized. We aimed to identify epigenetic regulators consistently dysregulated in HB and to evaluate the therapeutic efficacy of their targeting in clinically relevant models. Methods: We performed a comprehensive transcriptomic analysis of 180 epigenetic genes. Data from fetal, pediatric, adult, peritumoral (n = 72) and tumoral (n = 91) tissues were integrated. Selected epigenetic drugs were tested in HB cells. The most relevant epigenetic target identified was validated in primary HB cells, HB organoids, a patient-derived xenograft model, and a genetic mouse model. Transcriptomic, proteomic and metabolomic mechanistic analyses were performed. Results: Altered expression of genes regulating DNA methylation and histone modifications was consistently observed in association with molecular and clinical features of poor prognosis. The histone methyltransferase G9a was markedly upregulated in tumors with epigenetic and transcriptomic traits of increased malignancy. Pharmacological targeting of G9a significantly inhibited growth of HB cells, organoids and patient-derived xenografts. Development of HB induced by oncogenic forms of b-catenin and YAP1 was ablated in mice with hepatocyte-specific deletion of G9a. We observed that HBs undergo significant transcriptional rewiring in genes involved in amino acid metabolism and ribosomal biogenesis. G9a inhibition counteracted these pro-tumorigenic adaptations. Mechanistically, G9a targeting potently repressed the expression of c-MYC and ATF4, master regulators of HB metabolic reprogramming. Conclusions: HBs display a profound dysregulation of the epigenetic machinery. Pharmacological targeting of key epigenetic effectors exposes metabolic vulnerabilities that can be leveraged to improve the treatment of these patients.
- Adipose-derived mesenchymal stromal cells for the treatment of patients with severe SARS-CoV-2 pneumonia requiring mechanical ventilation. A proof of concept study(Elsevier, 2020) Martínez, C. (Carmen); Santos, A. (Arnoldo); Pérez-Calvo, C. (César); Fernandez-Aviles, F. (Francisco); Soria, B. (Bernat); Hernández-Blasco, L.M. (Luis M.); Soria-Juan, B. (Bárbara); Pozo, J.L. (José Luis) del; Sánchez-Hernández, M.V. (Miguel Vicente); Sagredo, V. (Víctor); Monedero, P. (Pablo); Andreu, E.J. (Enrique José); Lopez-Parra, M. (Miriam); Álvarez-Avello, J.M. (J. M.); Garcia-Olmos, D. (Damián); Sempere, J.M. (José M.); Fernández-Santos, M.E. (María Eugenia); Guerrero, J.E. (José Eugenio); Andreu, E. (Etelvina); Zapata, A. (Agustín); Prosper-Cardoso, F. (Felipe); García-Arranz, M. (Mariano); Moraleda, J. M. (José M.); Sanchez-Guijo, F.M. (Fermín M.)Background: Identification of effective treatments in severe cases of COVID-19 requiring mechanical ventilation represents an unmet medical need. Our aim was to determine whether the administration of adiposetissue derived mesenchymal stromal cells (AT-MSC) is safe and potentially useful in these patients. Methods: Thirteen COVID-19 adult patients under invasive mechanical ventilation who had received previous antiviral and/or anti-inflammatory treatments (including steroids, lopinavir/ritonavir, hydroxychloroquine and/or tocilizumab, among others) were treated with allogeneic AT-MSC. Ten patients received two doses, with the second dose administered a median of 3 days (interquartile range-IQR- 1 day) after the first one. Two patients received a single dose and another patient received 3 doses. Median number of cells per dose was 0.98 £ 106 (IQR 0.50 £ 106 ) AT-MSC/kg of recipient’s body weight. Potential adverse effects related to cell infusion and clinical outcome were assessed. Additional parameters analyzed included changes in imaging, analytical and inflammatory parameters.
- Corrigendum: Cost-effective, safe, and personalized cell therapy for critical limb ischemia in type 2 diabetes mellitus (vol 10, 1151, 2019)(Frontiers Media, 2020) Bedoya, F.J. (Francisco J.); Soria, B. (Bernat); Hmadcha, A. (Abdelkrim); Aguilera, Y. (Yolanda); Tejedo, J.R. (Juan R.); Juan, V. (Verónica); Soria-Juan, B. (Bárbara); Martinez-de-la-Cuesta, A. (Antonio); Llanos, L. (Lucía); Andreu, E.J. (Enrique José); Sackstein, R. (Robert); Castellanos, G. (Gregorio); Garcia-Olmos, D. (Damián); Miralles, M. (Manuel); Lozano, F.S. (Francisco S.); Capilla-González, V. (Vivian); Martín, F. (Franz); Prosper-Cardoso, F. (Felipe); Ruiz-Salmerón, R. (Rafael); García-Arranz, M. (Mariano); Moraleda, J. M. (José M.); Grochowicz, L. (Lukasz); Escacena, N. (Natalia); Sanchez-Guijo, F.M. (Fermín M.); Río-Solá, L. (Lourdes) delReference 86 was also included as “Escacena N. Cellular medication as a therapeutic alternative in chronic critical limb ischemia in diabetic patients without the possibility of revascularization. Dissertation Thesis. Sevilla Spain: University of Sevilla. (2016)”. This reference should be included as number 107 “Escacena N. Cellular medication as a therapeutic alternative in chronic critical limb ischemia in diabetic patients without the possibility of revascularization (Dissertation Thesis). University of Sevilla, Seville, Spain (2016).”