Depósito Académico
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285 results
Results
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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).
- 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).
- Prediction of Left Ventricular Reverse Remodeling and Outcomes by Circulating Collagen-Derived Peptides(2023) Moreno, M.U. (María Ujué); Lupón, J. (Josep); Ravassa, S. (Susana); Domingo, M. (Mar); Santiago-Vacas, E. (Evelyn); Gonzalez, A. (Arantxa); San-Jose, G. (Gorka); Cediel, G. (Germán); Revuelta-López, E. (Elena); Roncal, C. (Carmen); López, B. (Begoña); Diez, J. (Javier); Bayes-Genis, A. (Antoni); Codina, P. (Pau)Background Myocardial fibrosis may increase vulnerability to poor prognosis in patients with heart failure (HF), even in those patients exhibiting left ventricular reverse remodeling (LVRR) after guideline-based therapies. Objectives This study sought to characterize fibrosis at baseline in patients with HF with left ventricular ejection fraction (LVEF) <50% by determining serum collagen type I–derived peptides (procollagen type I C-terminal propeptide [PICP] and ratio of collagen type I C-terminal telopeptide to matrix metalloproteinase-1) and to evaluate their association with LVRR and prognosis. Methods Peptides were determined in 1,034 patients with HF at baseline. One-year echocardiography was available in 665 patients. Associations of peptides with 1-year changes in echocardiographic variables were analyzed by multivariable linear mixed models. LVEF was considered improved if it increased by ≥15% or to ≥50% or if it increased by ≥10% to >40% in patients with LVEF ≤40%. Cardiovascular death and HF-related outcomes were analyzed in all patients randomized to derivation (n = 648) and validation (n = 386) cohorts. Results Continuous associations with echocardiographic changes were observed only for PICP. Compared with high-PICP (≥108.1 ng/mL) patients, low-PICP (<108.1 ng/mL) patients exhibited enhanced LVRR and a lower risk of HF-related outcomes (P ≤ 0.018), with women and nonischemic patients with HF showing a stronger LVEF increase (interaction P ≤ 0.010). LVEF increase was associated with a better prognosis, particularly in low-PICP patients (interaction P ≤ 0.029). Only patients with both low PICP and improved LVEF exhibited a better clinical evolution than patients with nonimproved LVEF (P < 0.001).
- Hippocampal synaptic failure is an early event in experimental parkinsonism with subtle cognitive deficit(Oxford University Press, 2023) Cotman, C.W. (Carl W.); Quiroga-Varela, A. (Ana); Belloso-Iguerategui, A. (Arantzazu); Prieto, C.A. (C. Aleph); Zamarbide-González, M. (Marta); Fernandez-Irigoyen, J. (Joaquín); Gago, B. (Belén); Rodríguez-Chinchilla, T. (Tatiana); Rodriguez-Oroz, M.C. (María Cruz); Merino-Galán, L. (Leire); Santamaria, E. (Enrique)Learning and memory mainly rely on correct synaptic function in the hippocampus and other brain regions. In Parkinson's disease, subtle cognitive deficits may even precede motor signs early in the disease. Hence, we set out to unravel the earliest hippocampal synaptic alterations associated with human α-synuclein overexpression prior to and soon after the appearance of cognitive deficits in a parkinsonism model. We bilaterally injected adeno-associated viral vectors encoding A53T-mutated human α-synuclein into the substantia nigra of rats, and evaluated them 1, 2, 4 and 16 weeks post-inoculation by immunohistochemistry and immunofluorescence to study degeneration and distribution of α-synuclein in the midbrain and hippocampus. The object location test was used to evaluate hippocampal-dependent memory. Sequential window acquisition of all theoretical mass spectrometry-based proteomics and fluorescence analysis of single-synapse long-term potentiation were used to study alterations to protein composition and plasticity in isolated hippocampal synapses. The effect of L-DOPA and pramipexole on long-term potentiation was also tested. Human α-synuclein was found within dopaminergic and glutamatergic neurons of the ventral tegmental area, and in dopaminergic, glutamatergic and GABAergic axon terminals in the hippocampus from 1 week post-inoculation, concomitant with mild dopaminergic degeneration in the ventral tegmental area. In the hippocampus, differential expression of proteins involved in synaptic vesicle cycling, neurotransmitter release and receptor trafficking, together with impaired long-term potentiation were the first events observed (1 week post-inoculation), preceding cognitive deficits (4 weeks post-inoculation). Later on, at 16 weeks post-inoculation, there was a deregulation of proteins involved in synaptic function, particularly those involved in the regulation of membrane potential, ion balance and receptor signalling. Hippocampal long-term potentiation was impaired before and soon after the onset of cognitive deficits, at 1 and 4 weeks post-inoculation, respectively. L-DOPA recovered hippocampal long-term potentiation more efficiently at 4 weeks post-inoculation than pramipexole, which partially rescued it at both time points. Overall, we found impaired synaptic plasticity and proteome dysregulation at hippocampal terminals to be the first events that contribute to the development of cognitive deficits in experimental parkinsonism. Our results not only point to dopaminergic but also to glutamatergic and GABAergic dysfunction, highlighting the relevance of the three neurotransmitter systems in the ventral tegmental area-hippocampus interaction from the earliest stages of parkinsonism. The proteins identified in the current work may constitute potential biomarkers of early synaptic damage in the hippocampus and hence, therapies targeting these could potentially restore early synaptic malfunction and consequently, cognitive deficits in Parkinson's disease.