CIMA (Centro de Investigación Médica Aplicada)

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    NetActivity enhances transcriptional signals by combining gene expression into robust gene set activity scores through interpretable autoencoders
    (Oxford University Press, 2024) Ruiz, C. (Carlos); Wang, L. (Liewei); Perez-Jurado, L.A. (Luis A.); Ochoa, I. (Idoia); Hernaez, M. (Mikel); Marín-Goñi, I. (Irene)
    Grouping gene expression into gene set activity scores (GSAS) provides better biological insights than studying individual genes. However, existing gene set projection methods cannot return representative, robust, and interpretable GSAS. We developed NetActivity, a machine learning framework that generates GSAS based on a sparsely-connected autoencoder, where each neuron in the inner layer represents a gene set. We proposed a three-tier training that yielded representative, robust, and interpretable GSAS. NetActivity model was trained with 1518 GO biological processes terms and KEGG pathways and all GTEx samples. NetActivity generates GSAS robust to the initialization parameters and representative of the original transcriptome, and assigned higher importance to more biologically relevant genes. Moreover, NetActivity returns GSAS with a more consistent definition and higher interpretability than GSVA and hipathia, state-of-the-art gene set projection methods. Finally, NetActivity enables combining bulk RNA-seq and microarray datasets in a meta-analysis of prostate cancer progression, highlighting gene sets related to cell division, key for disease progression. When applied to metastatic prostate cancer, gene sets associated with cancer progression were also altered due to drug resistance, while a classical enrichment analysis identified gene sets irrelevant to the phenotype. NetActivity is publicly available in Bioconductor and GitHub.
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    Cortical activation in REM behavior disorder mimics voluntary movement. An electroencephalography study
    (Elsevier B.V., 2024) Alegre, M. (Manuel); Horrillo-Maysonnial, A. (Alejandro); Valencia, M. (Miguel); Manzanilla-Zapata, Ó. (Óscar); Urrestarazu, E. (Elena)
    Objectives: Motor symptoms of Parkinson’s disease improve during REM sleep behavior disorder movement episodes. Our aim was to study cortical activity during these movement episodes, in patients with and without Parkinson’s disease, in order to investigate the cortical involvement in the generation of its electromyographic activity and its potential relationship with Parkinson’s disease. Methods: We looked retrospectively in our polysomnography database for patients with REM sleep behavior disorder, analyzing fifteen patients in total, seven with idiopathic REM sleep behavior disorder and eight associated with Parkinson’s disease. We selected segments of REM sleep with the presence of movements (evidenced by electromyographic activation), and studied movement-related changes in cortical activity by averaging the electroencephalographic signal (premotor potential) and by means of time/ frequency transforms. Results: We found a premotor potential and an energy decrease of alpha–beta oscillatory activity preceding the onset of electromyographic activity, together with an increase of gamma activity for the duration of the movement. All these changes were similarly present in REM sleep behavior disorder patients with and without Parkinson’s disease. Conclusions: Movement-related changes in electroencephalographic activity observed in REM sleep behavior disorder are similar to those observed during voluntary movements, regardless of the presence of Parkinson’s disease motor symptoms. Significance: These results suggest a main involvement of the cortex in the generation of the movements during REM sleep.
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    Protein biomarkers in lung cancer screening: technical considerations and feasibility assessment
    (Elsevier, 2024) Seijo, L. (Luis); Calle-Arroyo, C. (Carlos) de la; Pineda-Lucena, A. (Antonio); Detterbeck, F. (Frank); Bernasconi-Bisio, F. (Franco); Johansson, M. (Mattias); Montuenga-Badia, L.M. (Luis M.); Orive-Mauleón, D. (Daniel); Hung, J.R. (Rayjean); Valencia, K. (Karmele); Echepare, M. (Mirari); Robbins, H.A. (Hilary); Fernandez-Sanmamed, M. (Miguel)
    Lung cancer remains the leading cause of cancer-related deaths worldwide, mainly due to late diagnosis and the presence of metastases. Several countries around the world have adopted nation-wide LDCT-based lung cancer screening that will benefit patients, shifting the stage at diagnosis to earlier stages with more therapeutic options. Biomarkers can help to optimize the screening process, as well as refine the TNM stratification of lung cancer patients, providing information regarding prognostics and recommending management strategies. Moreover, novel adjuvant strategies will clearly benefit from previous knowledge of the potential aggressiveness and biological traits of a given early-stage surgically resected tumor. This review focuses on proteins as promising biomarkers in the context of lung cancer screening. Despite great efforts, there are still no successful examples of biomarkers in lung cancer that have reached the clinics to be used in early detection and early management. Thus, the field of biomarkers in early lung cancer remains an evident unmet need. A more specific objective of this review is to present an up-to-date technical assessment of the potential use of protein biomarkers in early lung cancer detection and management. We provide an overview regarding the benefits, challenges, pitfalls and constraints in the development process of protein-based biomarkers. Additionally, we examine how a number of emerging protein analytical technologies may contribute to the optimization of novel robust biomarkers for screening and effective management of lung cancer.
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    Gene therapy for liver diseases — progress and challenges
    (Springer Nature, 2023) González-Aseguinolaza, G. (Gloria); Zabaleta-Lasarte, N. (Nerea); Weber, N.D. (Nicholas D.); Unzu, C. (Carmen)
    Gene therapy is poised to revolutionize modern medicine, with seemingly unlimited potential for treating and curing genetic disorders. For otherwise incurable indications, including most inherited metabolic liver disorders, gene therapy provides a realistic therapeutic option. In this Review, we discuss gene supplementation and gene editing involving the use of recombinant adeno-associated virus (rAAV) vectors for the treatment of inherited liver diseases, including updates on several ongoing clinical trials that are producing promising results. Clinical testing has been essential in highlighting many key translational challenges associated with this transformative therapy. In particular, the interaction of a patient's immune system with the vector raises issues of safety and the duration of treatment efficacy. Furthermore, several serious adverse events after the administration of high doses of rAAVs suggest greater involvement of innate immune responses and pre-existing hepatic conditions than initially anticipated. Finally, permanent modification of the host genome associated with rAAV genome integration and gene editing raises concerns about the risk of oncogenicity that require careful evaluation. We summarize the main progress, challenges and pathways forward for gene therapy for liver diseases.
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    New insights into the regulation of bile acids synthesis during the early stages of liver regeneration: A human and experimental study
    (Elsevier B.V., 2024) Latasa, M.U. (María Ujué); Lopez-Pascual, A. (Amaya); Corrales, F.J. (Fernando José); Lucena-Ramírez, J.F. (Juan Felipe); Berasain, C. (Carmen); Arechederra, M. (María); Rotellar, F. (Fernando); Fernández-Barrena, M.G. (Maite G.); Pardo, F. (Fernando); Uriarte, I. (Iker); Irigaray-Miramon, A. (Ainara); Avila, M.A. (Matías Antonio); Sangro, B. (Bruno); Basualdo, J. (Jorge); Monte, M.J. (María J.); Herranz, J.M. (José M.); Merlen, G. (Gregory); Santamaría, E. (Eva); Tordjmann, T. (Thierry); Adán-Villaescusa, E. (Elena); Herrero, I. (Ignacio); Rainteau, D. (Dominique); Argemí, J. (Josepmaria); Marin, J.J.G (Jose J.G.)
    Background and aims: Liver regeneration is essential for the preservation of homeostasis and survival. Bile acids (BAs)-mediated signaling is necessary for liver regeneration, but BAs levels need to be carefully controlled to avoid hepatotoxicity. We studied the early response of the BAs-fibroblast growth factor 19 (FGF19) axis in healthy individuals undergoing hepatectomy for living donor liver transplant. We also evaluated BAs synthesis in mice upon partial hepatectomy (PH) and acute inflammation, focusing on the regulation of cytochrome-7A1 (CYP7A1), a key enzyme in BAs synthesis from cholesterol. Methods: Serum was obtained from twelve human liver donors. Mice underwent 2/3-PH or sham-operation. Acute inflammation was induced with bacterial lipopolysaccharide (LPS) in mice fed control or antoxidant-supplemented diets. BAs and 7α-hydroxy-4-cholesten-3-one (C4) levels were measured by HPLC-MS/MS; serum FGF19 by ELISA. Gene expression and protein levels were analyzed by RT-qPCR and western-blot. Results: Serum BAs levels increased after PH. In patients with more pronounced hypercholanemia, FGF19 concentrations transiently rose, while C4 levels (a readout of CYP7A1 activity) dropped 2 h post-resection in all cases. Serum BAs and C4 followed the same pattern in mice 1 h after PH, but C4 levels also dropped in shamoperated and LPS-treated animals, without marked changes in CYP7A1 protein levels. LPS-induced serum C4 decline was attenuated in mice fed an antioxidant-supplemented diet. Conclusions: In human liver regeneration FGF19 upregulation may constitute a protective response from BAs excess during liver regeneration. Our findings suggest the existence of post-translational mechanisms regulating CYP7A1 activity, and therefore BAs synthesis, independent from CYP7A1/Cyp7a1 gene transcription.
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    Exploring current and emerging therapies for porphyrias
    (John Wiley & Sons, 2024) Deybach, J.C. (Jean-Charles); Anderson, K.E. (Karl E.); Avila, M.A. (Matías Antonio); Córdoba, K.M. (Karol M.); Urigo, F. (Francesco); Enriquez-de-Salamanca, R. (Rafael); Fontanellas-Romá, A. (Antonio); Jericó-Asenjo, D. (Daniel)
    Porphyrias are rare, mostly inherited disorders resulting from altered activity of specific enzymes in the haem synthesis pathway that lead to accumulation of pathway intermediates. Photocutaneous symptoms occur when excess amounts of photoreactive porphyrins circulate in the blood to the skin, whereas increases in potentially neurotoxic porphyrin precursors are associated with neurovisceral symptoms. Current therapies are suboptimal and their mechanisms are not well established. As described here, emerging therapies address underlying disease mechanisms by introducing a gene, RNA or other specific molecule with the potential to cure or slow progression of the disease. Recent progress in nanotechnology and nanoscience, particularly regarding particle design and formulation, is expanding disease targets. More secure and efficient drug delivery systems have extended our toolbox for transferring specific molecules, especially into hepatocytes, and led to proof-of-concept studies in animal models. Repurposing existing drugs as molecular chaperones or haem synthesis inhibitors is also promising. This review summarizes key examples of these emerging therapeutic approaches and their application for hepatic and erythropoietic porphyrias.
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    Automatic segmentation and quantification of Nigrosome-1 Neuromelanin and Iron in MRI: a candidate biomarker for Parkinson’s disease
    (Wiley Periodicals LLC, 2023) Martinez, M. (Martín); Castellanos, G. (Gabriel); Ortiz-de-Solorzano, C. (Carlos); Pastor, P. (Pau); Fernández-Seara, M.A. (María A.); Pastor, M.A. (María A.); Álvarez, I. (Ignacio); Ariz, M. (Mikel)
    Parkinson’s disease (PD) is caused by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). The incidence of PD increases with age and is one of the major causes of disability. PD early diagnosis is still a challenge as it is based on the clinical assessment of the subject discarding other potential causes of parkinsonism, and the patient’s positive response to Levodopa therapy, leading to a misdiagnosis rate of approximately 16%. The substantia nigra (SN), located in the ventral tegmentum of the midbrain, is divided into two main regions: the iron-rich ventral SN pars reticulata (SNr), and the dorsal SNc, where the neuromelanin-containing dopaminergic neurons (NM) are located. NM is believed to have a neuroprotective function against the toxicity of iron-mediated oxidative processes. Specifically, the death of dopaminergic neurons of the SNc causes NM depigmentation, followed by an increase of iron load. Indeed, it has been reported that a relative decrease of SNc NM leads to a relative increase of SNc iron in PD patients, when compared with age-matched healthy controls (HCs).
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    Biomarker-based assessment of collagen cross-linking identifies patients at risk of heart failure more likely to benefit from spironolactone effects on left atrial remodelling. Insights from the HOMAGE clinical trial
    (2021) Moreno, M.U. (María Ujué); Clark, A.L. (Andrew L.); Petutschnigg, J. (Johannes); Edelmann, F. (Frank); Staessen, J.A. (Jan A.); Ferreira, J.P. (João Pedro); Mariottoni, B. (Beatrice); Verdonschot, J.A.J. (Job A. J.); Hazebroek, M.R. (Mark R.); Ravassa, S. (Susana); Cosmi, F. (Franco); Heymans, S. (Stephane); Zannad, F. (Faiez); Gonzalez, A. (Arantxa); Cuthbert, J. (Joe); Pieske, B. (Burkert); Pellicori, P. (Pierpaolo); Girerd, N. (Nicolas); López, B. (Begoña); Diez, J. (Javier); Cleland, J.G. (John G.); Bozec, E. (Erwan)
    Aims The HOMAGE randomized trial found that spironolactone reduced left atrial volume index (LAVI), E:A ratio, and a marker of collagen type I synthesis (procollagen type I C-terminal propeptide) in patients at risk of heart failure (HF). Previous trials showed that patients with HF, preserved ejection fraction and low serum collagen type I C-terminal telopeptide to matrix metalloproteinase-1 ratio (CITP:MMP-1), associated with high collagen cross-linking, had less improvement in diastolic function with spironolactone. We evaluated the interaction between serum CITP:MMP-1 and spironolactone on cardiac function in the HOMAGE trial. Methods and results Patients at risk of HF were randomized to spironolactone (n = 260) or not (n = 255). Blood sampling and echocardiography were done at baseline, one and nine months. CITP:MMP-1 was used as an indirect measure of collagen cross-linking. Higher baseline CITP:MMP-1 (i.e. lower collagen cross-linking) was associated with greater reductions in LAVI with spironolactone at both one (p = 0.003) and nine (p = 0.01) months, but no interaction was observed for E:A ratio. Spironolactone reduced LAVI after one and nine months only for those patients in the third tertile of CITP:MMP-1 (estimated lowest collagen cross-linking) [mean differencesspiro/control: −1.77 (95% confidence interval, CI −2.94 to −0.59) and −2.52 (95% CI −4.46 to −0.58) mL/m2; interaction pacross-tertiles = 0.005; interaction pthird tertile = 0.008] with a similar trend for N-terminal pro-B-type natriuretic peptide which was consistently reduced by spironolactone only in the lowest collagen cross-linking tertile [mean differencesspiro/control: −0.47 (95% CI −0.66 to −0.28) and −0.31 (95% CI −0.59 to −0.04) ng/L; interaction pacross-tertiles = 0.09; interaction pthird tertile < 0.001]. Conclusions These findings suggest that, for patients at risk of HF, the effects of spironolactone on left atrial remodelling may be more prominent in patients with less collagen cross-linking (indirectly assessed by serum CITP:MMP-1).
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    Combination of Circulating Type I Collagen-Related Biomarkers Is Associated With Atrial Fibrillation
    (2019) Moreno, M.U. (María Ujué); Querejeta, R. (Ramón); Ravassa, S. (Susana); Gonzalez, A. (Arantxa); Ballesteros, G. (Gabriel); Garcia-Bolao, I. (Ignacio); Bragard, J. (Jean); López, B. (Begoña); Vives, E. (Enrique); Ramos, P. (Pablo); Diez, J. (Javier)
    Background A combination of circulating biomarkers associated with excessive myocardial collagen type-I cross-linking or CCL+ (i.e., decreased carboxy-terminal telopeptide of collagen type-I to matrix metalloproteinase-1 ratio) and with excessive myocardial collagen type-I deposition or CD+ (i.e., increased carboxy-terminal propeptide of procollagen type-I) has been described in heart failure (HF) patients and associates with poor outcomes. Objectives The purpose of this study was to investigate whether the CCL+CD+ combination of biomarkers associates with atrial fibrillation (AF). Methods Biomarkers were analyzed in serum samples from 242 HF patients (study 1) and 150 patients referred for AF ablation (study 2). Patients were classified into 3 groups (CCL−CD−, CCL+CD− or CCL−CD+, and CCL+CD+) in accordance to biomarker threshold values. Left atrial electroanatomic high-density mapping was performed in 71 patients from study 2. Results In study 1, 53.7% patients had AF at baseline and 19.6% developed AF (median follow-up 5.5 years). Adjusted odds and hazard ratios associated with baseline and new-onset AF, respectively, were both ≥3.3 (p ≤ 0.050) in CCL+CD+ patients compared with CCL−CD− patients, with nonsignificant changes in the other group. In study 2, 29.3% patients had AF recurrence during 1-year post-ablation. The adjusted hazard ratio for AF recurrence was 3.4 (p = 0.008) in CCL+CD+ patients compared with CCL−CD− patients, with nonsignificant changes in the other group. The CCL+CD+ combination added incremental predictive value over relevant covariables. CCL+CD+ patients exhibited lower left atrial voltage than the remaining patients (p = 0.005). Conclusions A combination of circulating biomarkers reflecting excessive myocardial collagen type-I cross-linking and deposition is associated with higher AF prevalence, incidence, and recurrence after ablation.
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    CT-1 (Cardiotrophin-1)-Gal-3 (Galectin-3) Axis in Cardiac Fibrosis and Inflammation: Mechanistic Insights and Clinical Implications
    (2019) Moreno, M.U. (María Ujué); Brugnolaro, C. (Cristina); Querejeta, R. (Ramón); Jaisser, F. (Frederic); Martínez-Martínez, E. (Ernesto); Buonafine, M. (Mathieu); Ibarrola, J. (Jaime); Ravassa, S. (Susana); Fernandez-Irigoyen, J. (Joaquín); Gonzalez, A. (Arantxa); Rabago, G. (Gregorio); Fernández-Celís, A. (Amaya); Lopez-Andres, N. (Natalia); López, B. (Begoña); Santamaria, E. (Enrique); Diez, J. (Javier)
    Myocardial fibrosis is a main contributor to the development of heart failure (HF). CT-1 (cardiotrophin-1) and Gal-3 (galectin-3) are increased in HF and associated with myocardial fibrosis. The aim of this study is to analyze whether CT-1 regulates Gal-3. Proteomic analysis revealed that Gal-3 was upregulated by CT-1 in human cardiac fibroblasts in parallel with other profibrotic and proinflammatory markers. CT-1 upregulation of Gal-3 was mediated by ERK (extracellular signal-regulated kinase) 1/2 and Stat-3 (signal transducer and activator of transcription 3) pathways. Male Wistar rats and B6CBAF1 mice treated with CT-1 (20 µg/kg per day) presented higher cardiac Gal-3 levels and myocardial fibrosis. In CT-1–treated rats, direct correlations were found between cardiac CT-1 and Gal-3 levels, as well as between Gal-3 and perivascular fibrosis. Gal-3 genetic disruption in human cardiac fibroblasts and pharmacological Gal-3 inhibition in mice prevented the profibrotic and proinflammatory effects of CT-1. Dahl salt-sensitive hypertensive rats with diastolic dysfunction showed increased cardiac CT-1 and Gal-3 expression together with cardiac fibrosis and inflammation. CT-1 and Gal-3 directly correlated with myocardial fibrosis. In HF patients, myocardial and plasma CT-1 and Gal-3 were increased and directly correlated. In addition, HF patients with high CT-1 and Gal-3 plasma levels presented an increased risk of cardiovascular death. Our data suggest that CT-1 upregulates Gal-3 which, in turn, mediates the proinflammatory and profibrotic myocardial effects of CT-1. The elevation of both molecules in HF patients identifies a subgroup of patients with a higher risk of cardiovascular mortality. The CT-1/Gal-3 axis emerges as a candidate therapeutic target and a potential prognostic biomarker in HF.