Depósito Académico
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- Impact of a longitudinal course on medical professionalism on the empathy of medical students(Elsevier, 2024) García-del-Barrio, L. (Loreto); Rodriguez-Diez, M.C. (María Cristina); Arbea, L. (Leire); Diez-Goñi, N. (Nieves); Gea, A. (Alfredo); Pereira, J. (José)Objective: Medical education should enhance empathy. We examined, using self-assessment instruments and standardized patients (SPs), the impact on empathy, of a multi-year intervention (years 4–6 of medical training) that uses reflective learning approaches. Methods: 241 final-year medical students participated; 110 from the 2018 graduation class (non-intervention group) and 131 from the 2019 graduation class (intervention group). Participants completed two self-reported empathy questionnaires – the Jefferson Scale of Empathy-Students (JSE-S) and the Interpersonal Reactivity Index (IRI) – and a personality questionnaire, the NEO Five-Factor Inventory. Additionally, SPs in a simulated station assessed participants’ empathy with two patient-reported instruments: the Consultation and Relational Empathy (CARE) scale and the Jefferson Scale of Patient Perceptions of Physician Empathy (JSPPPE). Results: Empathy scores were significantly higher in the intervention group compared to the non-intervention group when assessed by the SP (p < 0.001). No differences were found in self-reported questionnaires between the two groups. Conclusion: A longitudinal, multi-year reflection-based intervention enhanced empathy amongst medical students as assessed by SPs, but not when assessed by student self-reported measures. Practice Implications: Multi-year reflective learning interventions during clinical training nurture empathy in medical students. Assessments completed by SPs or patients may enhance the evaluation of empathy.
- PD-1/PD-L1 blockers in NSCLC brain metastases: Challenging paradigms and clinical practice(American Association for Cancer Research, 2020) Gil-Bazo, I. (Ignacio); Lu, B.Y. (Benjamin Y.); Eguren-Santamaría, I. (Iñaki); Goldberg, S. (S.); Kluger, H. (Harriet); Herbst, R.S. (Roy S.); Idoate, M.A. (Miguel Ángel); Corral, J. (Jesús); Schalper, K.A. (Kurt A.); Fernandez-Sanmamed, M. (Miguel)Immune checkpoint inhibitors (ICI) have revolutionized the management of advanced non-small cell lung cancer (NSCLC). However, most pivotal phase III trials systematically excluded patients with active brain metastases, precluding the generalization of the results. Although theoretically restricted from crossing the blood-brain barrier, the novel pharmacokinetic/pharmacodynamic profiles of anti-PD-1/PD-L1 drugs have prompted studies to evaluate their activity in patients with NSCLC with active central nervous system (CNS) involvement. Encouraging results have suggested that ICI could be active in the CNS in selected patients with driver-negative advanced NSCLC with high PD-L1 expression and low CNS disease burden. Single-agent CNS response rates around 30% have been reported. Beyond this particular setting, anti-PD-1/PD-L1 antibodies have been evaluated in patients receiving local therapy for brain metastases (BM), addressing concerns about potential neurologic toxicity risks associated with radiotherapy, more specifically, radionecrosis (RN). Accordingly, a variety of clinical and imaging strategies are being appropriately developed to evaluate tumor response and to rule out pseudoprogression or radionecrosis. Our purpose is to critically summarize the advances regarding the role of systemic anti-PD-1/PD-L1 antibodies for the treatment of NSCLC BM. Data were collected from the PubMed database, reference lists, and abstracts from the latest scientific meetings. Recent reports suggest anti-PD-1/PD-L1 agents are active in a subset of patients with NSCLC with BM showing acceptable toxicity. These advances are expected to change soon the management of these patients but additional research is required to address concerns regarding radionecrosis and the appropriate sequencing of local and systemic therapy combinations.
- Signature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer(2023) Gil-Bazo, I. (Ignacio); Drosten, M. (Mathias); Barbacid, M. (Mariano); Kovalski, J. (Joanna); Pineda-Lucena, A. (Antonio); Román, M. (Marta); Jantus-Lewintre, E. (Eloisa); Calabuig-Fariñas, S. (Silvia); Vicent, S. (Silvestre); Ludwig, I.A. (Iziar Amaia); Entrialgo-Cadierno, R. (Rodrigo); Palomino-Echeverría, S. (Sara); Salmon, M. (Marina); Fernandez-Irigoyen, J. (Joaquín); Ruggero, D. (Davide); Lara-Astiaso, D. (David); Santos, A. (Alba); Ponz-Sarvise, M. (Mariano); Macaya, I. (Irati); Feliu, I. (Iker); Rodríguez-Remírez, M. (M.); Guruceaga, E. (Elizabeth); Paz-Ares, L. (Luis); Ferrer, I. (Irene); Narayanan, S. (Shruthi); Ferrero, M. (Macarena); Lecanda, F. (Fernando); Welch, C. (Connor); Lopez, I. (Inés); Lonfgren, S.M. (Shane M.); Santamaria, E. (Enrique); Khatri, P. (Purvesh)Drug combinations are key to circumvent resistance mechanisms compromising response to single anti-cancer targeted therapies. The implementation of combinatorial approaches involving MEK1/2 or KRASG12C inhibitors in the context of KRAS-mutated lung cancers focuses fundamentally on targeting KRAS proximal activators or effectors. However, the antitumor effect is highly determined by compensatory mechanisms arising in defined cell types or tumor subgroups. A potential strategy to find drug combinations targeting a larger fraction of KRAS-mutated lung cancers may capitalize on the common, distal gene expression output elicited by oncogenic KRAS. By integrating a signature-driven drug repurposing approach with a pairwise pharmacological screen, here we show synergistic drug combinations consisting of multi-tyrosine kinase PKC inhibitors together with MEK1/2 or KRASG12C inhibitors. Such combinations elicit a cytotoxic response in both in vitro and in vivo models, which in part involves inhibition of the PKC inhibitor target AURKB. Proteome profiling links dysregulation of MYC expression to the effect of both PKC inhibitor-based drug combinations. Furthermore, MYC overexpression appears as a resistance mechanism to MEK1/2 and KRASG12C inhibitors. Our study provides a rational framework for selecting drugs entering combinatorial strategies and unveils MEK1/2- and KRASG12C-based therapies for lung cancer.
- Stabilization of 14-3-3 protein-protein interactions with Fusicoccin-A decreases alpha-synuclein dependent cell-autonomous death in neuronal and mouse models(Elsevier, 2023) Aymerich, M.S. (María S.); González-Aseguinolaza, G. (Gloria); Perez-Mediavilla, L.A. (Luis Alberto); Vales, A. (África); Fernandez-Irigoyen, J. (Joaquín); Boncristiani, C. (Chiara); Bravo-González, J.J. (Jorge Juan); Basurco, L. (Leyre); Aragón, T. (Tomás); Marcilla, I. (Irene); Arrasate, M. (Montserrat); Luquin, M.R. (María Rosario); Santamaria, E. (Enrique); Vinueza-Gavilanes, R. (Rodrigo)Synucleinopathies are a group of neurodegenerative diseases without effective treatment characterized by the abnormal aggregation of alpha-synuclein (aSyn) protein. Changes in levels or in the amino acid sequence of aSyn (by duplication/triplication of the aSyn gene or point mutations in the encoding region) cause familial cases of synucleinopathies. However, the specific molecular mechanisms of aSyn-dependent toxicity remain unclear. Increased aSyn protein levels or pathological mutations may favor abnormal protein-protein interactions (PPIs) that could either promote neuronal death or belong to a coping response program against neurotoxicity. Therefore, the identification and modulation of aSyn-dependent PPIs can provide new therapeutic targets for these diseases. To identify aSyn-dependent PPIs we performed a proximity biotinylation assay based on the promiscuous biotinylase BioID2. When expressed as a fusion protein, BioID2 biotinylates by proximity stable and transient interacting partners, allowing their identification by streptavidin affinity purification and mass spectrometry. The aSyn interactome was analyzed using BioID2-tagged wild-type (WT) and pathological mutant E46K aSyn versions in HEK293 cells. We found the 14-3-3 epsilon isoform as a common protein interactor for WT and E46K aSyn. 14-3-3 epsilon correlates with aSyn protein levels in brain regions of a transgenic mouse model overexpressing WT human aSyn. Using a neuronal model in which aSyn cell-autonomous toxicity is quantitatively scored by longitudinal survival analysis, we found that stabilization of 14-3-3 protein-proteins interactions with Fusicoccin-A (FC-A) decreases aSyn-dependent toxicity. Furthermore, FC-A treatment protects dopaminergic neuronal somas in the substantia nigra of a Parkinson's disease mouse model. Based on these results, we propose that the stabilization of 14-3-3 epsilon interaction with aSyn might reduce aSyn toxicity, and highlight FC-A as a potential therapeutic compound for synucleinopathies.
- Trichostatin a affects developmental reprogramming of bread wheat microspores towards an embryogenic route(MDPI AG, 2020) Allué, S. (Sandra); Costar, M.A. (María Asunción); Burrell, M.A. (María Ángela); Valero-Rubira, I. (Isabel); Vallés, M.P. (María Pilar); Castillo, A.M. (Ana María)Microspores can be developmentally reprogrammed by the application of different stress treatments to initiate an embryogenic pathway leading to the production of doubled haploid (DH) plants. Epigenetic modifications are involved in cell reprogramming and totipotency in response to stress. To increase microspore embryogenesis (ME) efficiency in bread wheat, the effect of the histone deacetylase inhibitor trichostatin A (TSA) has been examined in two cultivars of wheat with different microspore embryogenesis response. Diverse strategies were assayed using 0–0.4 µM TSA as a single induction treatment and after or simultaneously with cold or mannitol stresses. The highest efficiency was achieved when 0.4 µM TSA was applied to anthers for 5 days simultaneously with a 0.7 M mannitol treatment, producing a four times greater number of green DH plants than mannitol. Ultrastructural studies by transmission electron microscopy indicated that mannitol with TSA and mannitol treatments induced similar morphological changes in early stages of microspore reprogramming, although TSA increased the number of microspores with ’star-like’ morphology and symmetric divisions. The effect of TSA on the transcript level of four ME marker genes indicated that the early signaling pathways in ME, involving the TaTDP1 and TAA1b genes, may be mediated by changes in acetylation patterns of histones and/or other proteins.
- Microglia and astrocyte activation is region-dependent in the alfa-synuclein mouse model of Parkinson's disease(Wiley, 2023) Vilas, A. (Amaia); González-Aseguinolaza, G. (Gloria); Alonso-Roldán, M.M. (Marta María); Vales, A. (África); Abellanas-Sánchez, M.A. (Miguel Ángel); San-Martín-Uriz, P. (Patxi); Aymerich-Soler, M.S. (María Soledad); Ayerra, L. (Leyre); Basurco, L. (Leyre); Hervas-Stubbs, S. (Sandra); Hernaez, M. (Mikel); Mengual, E. (Elisa); Clavero, P. (P.); Arrasate, M. (Montserrat); Tamayo, I. (Ibon); Conde, E. (Enrique); Luquin, E. (Esther); Vinueza-Gavilanes, R. (Rodrigo)Inflammation is a common feature in neurodegenerative diseases that contributes to neuronal loss. Previously, we demonstrated that the basal inflammatory tone differed between brain regions and, consequently, the reaction generated to a pro-inflammatory stimulus was different. In this study, we assessed the innate immune reaction in the midbrain and in the striatum using an experimental model of Parkinson's disease. An adeno-associated virus serotype 9 expressing the α-synuclein and mCherry genes or the mCherry gene was administered into the substantia nigra. Myeloid cells (CD11b+ ) and astrocytes (ACSA2+ ) were purified from the midbrain and striatum for bulk RNA sequencing. In the parkinsonian midbrain, CD11b+ cells presented a unique anti-inflammatory transcriptomic profile that differed from degenerative microglia signatures described in experimental models for other neurodegenerative conditions. By contrast, striatal CD11b+ cells showed a pro-inflammatory state and were similar to disease-associated microglia. In the midbrain, a prominent increase of infiltrated monocytes/macrophages was observed and, together with microglia, participated actively in the phagocytosis of dopaminergic neuronal bodies. Although striatal microglia presented a phagocytic transcriptomic profile, morphology and cell density was preserved and no active phagocytosis was detected. Interestingly, astrocytes presented a pro-inflammatory fingerprint in the midbrain and a low number of differentially displayed transcripts in the striatum. During α-synuclein-dependent degeneration, microglia and astrocytes experience context-dependent activation states with a different contribution to the inflammatory reaction. Our results point towards the relevance of selecting appropriate cell targets to design neuroprotective strategies aimed to modulate the innate immune system during the active phase of dopaminergic degeneration.
- Microspore embryogenesis induction by mannitol and TSA results in a complex regulation of epigenetic dynamics and gene expression in bread wheat(2023) Burrell, M.A. (María Ángela); Valero-Rubira, I. (Isabel); Vallés, M.P. (María Pilar); Castillo, A.M. (Ana María)Reprogramming of microspores development towards embryogenesis mediated by stress treatment constitutes the basis of doubled haploid production. Recently, compounds that alter histone post-translational modifications (PTMs) have been reported to enhance microspore embryogenesis (ME), by altering histones acetylation or methylation. However, epigenetic mechanisms underlying ME induction efficiency are poorly understood. In this study, the epigenetic dynamics and the expression of genes associated with histone PTMs and ME induction were studied in two bread wheat cultivars with different ME response. Microspores isolated at 0, 3 and 5 days, treated with 0.7M mannitol (MAN) and 0.7M mannitol plus 0.4 mu M trichostatin A (TSA), which induced ME more efficiently, were analyzed. An additional control of gametophytic development was included. Microspores epigenetic state at the onset of ME induction was distinctive between cultivars by the ratio of H3 variants and their acetylated forms, the localization and percentage of labeled microspores with H3K9ac, H4K5ac, H4K16ac, H3K9me2 and H3K27me3, and the expression of genes related to pollen development. These results indicated that microspores of the high responding cultivar could be at a less advanced stage in pollen development. MAN and TSA resulted in a hyperacetylation of H3.2, with a greater effect of TSA. Histone PTMs were differentially affected by both treatments, with acetylation being most concerned. The effect of TSA was observed in the H4K5ac localization pattern at 3dT in the mid-low responding cultivar. Three gene networks linked to ME response were identified. TaHDT1, TaHAG2, TaYAO, TaNFD6-A, TabZIPF1 and TaAGO802-B, associated with pollen development, were down-regulated. TaHDA15, TaHAG3, TaHAM, TaYUC11D, Ta-2B-LBD16 TaMS1 and TaDRM3 constituted a network implicated in morphological changes by auxin signaling and cell wall modification up-regulated at 3dT. The last network included TaHDA18, TaHAC1, TaHAC4, TaABI5, TaATG18fD, TaSDG1a-7A and was related to ABA and ethylene hormone signaling pathways, DNA methylation and autophagy processes, reaching the highest expression at 5dT. The results indicated that TSA mainly modified the regulation of genes related to pollen and auxin signaling. This study represents a breakthrough in identifying the epigenetic dynamics and the molecular mechanisms governing ME induction efficiency, with relevance to recalcitrant wheat genotypes and other crops.
- Modification of breast cancer milieu with chemotherapy plus dendritic cell vaccine: an approach to select best therapeutic strategies(2023) Hato-Álvaro, L. (Laura); Espinos, J. (Jaime); Lozano, M.D. (María Dolores); Pérez-Solans, B. (Belén); Lopez-Diaz-de-Cerio, A. (Ascensión); Córdoba-Iturriagagoitia, A. (Alicia); Santisteban, M. (Marta); Inoges, S. (Susana); Guillen-Grima, F. (Francisco); Mejías-Sosa, L.D. (Luis D.); Idoate, M.A. (Miguel Ángel); Sala-Elarre, P. (Pablo); Cruz, S. (S.) de la; López-Janeiro, Á. (Álvaro)Background: The addition of dendritic cell vaccines (DCV) to NAC could induce immune responses in those patients with residual disease (RD) by transforming the tumor microenvironment. Methods: Core diagnostic biopsies and surgical specimens from 80 patients (38 in the vaccinated group plus NAC (VG) and 42 in the control group (CG, treated only with NAC) were selected. We quantify TILs (CD8, CD4 and CD45RO) using immunohistochemistry and the automated cellular imaging system (ACIS III) in paired samples. Results: A CD8 rise in TNBC samples was observed after NAC plus DCV, changing from 4.48% in the biopsy to 6.70% in the surgical specimen, not reaching statistically significant differences (p = 0.11). This enrichment was seen in up to 67% of TNBC patients in the experimental arm as compared with the CG (20%). An association between CD8 TILs before NAC (4% cut-off point) and pathological complete response in the VG was found in the univariate and multivariate analysis (OR = 1.41, IC95% 1.05-1.90; p = 0.02, and OR = 2.0, IC95% 1.05-3.9; p = 0.03, respectively). Conclusion: Our findings suggest that patients with TNBC could benefit from the stimulation of the antitumor immune system by using DCV together with NAC.
- The complement system as a regulator of tumor-promoting activities mediated by myeloid-derived suppressor cells(Elsevier, 2022) Tavira, B. (Beatriz); Pio, R. (Rubén); Senent, Y. (Yaiza); Ajona, D. (Daniel)Tumor progression relies on the interaction between tumor cells and their surrounding tumor microenvironment (TME), which also influences therapeutic responses. The complement system, an essential part of innate im- munity, has been traditionally considered an effector arm against tumors. However, established tumors co-opt complement-mediated immune responses in the TME to support chronic inflammation, activate cancer-related signaling pathways and hamper antitumor immune responses. In this context, myeloid-derived suppressor cells (MDSCs), a heterogeneous population of myeloid progenitors with immunosuppressive functions, are recognized as major mediators of tumor-associated complement activities. This review focuses on the impact of complement activation within the TME, with a special emphasis on MDSC functions and the involvement of the C5a/C5aR1 axis. We also discuss the translation of these findings into therapeutic advances based on comple- ment inhibition.
- Familial primary cutaneous amyloidosis: Caspase activation may be involved in amyloid formation(Wiley, 2022) España, A. (Agustín); Alkorta-Aranburu, G. (Gorka); Pelacho-Samper, B. (Beatriz); Antoñanzas-Perez, J. (Javier); Echeveste, J.I. (José I.)Primary localized cutaneous amyloidosis (PLCA) is a rare form of cutaneous amyloidosis, characterized by the presence of flat-topped papules and macules with amyloid deposits in the superficial dermis. It is a purely cutaneous disease with no association with systemic forms of amyloidosis.1 Although most cases are sporadic, familial cases (FPLCA) represent about 10% of total reports and show an autosomal dominant inheritance, with mutations described in the genes for the oncostatin M receptor (OSMR) and the interleukin-31 receptor A (IL31RA).2 Herein, we present a family affected by FPLCA and underline the role of caspase activation in amyloid formation.