Grupos de Investigación

NOTCH1 signaling is dysregulated by loss of the deubiquitinase USP28 with del(11q), uncovering USP28 inhibition as novel therapeutic target in CLL

Wed, 01 Jan 2025 00:00:00 GMT

[EN]Aberrant active NOTCH1 signaling is a key pathogenic factor in chronic lymphocytic leukemia (CLL), detectable in half of patients and associated with disease progression. While some cases of active NOTCH1 signaling can be explained by mutations in NOTCH1 or its regulators, like FBXW7, alternative mechanisms remain elusive. Here, we identified the deubiquitinase USP28 as regulator of NOTCH1 signaling in CLL. Notably, USP28 is located within the frequently deleted chr11q23 region and is deleted in 90% of del(11q) patients, resulting in its decreased expression. USP28 interacts with the NOTCH1 intracellular domain (NICD) independently of FBXW7 and the NICD-PEST domain, stabilizing NICD and enhancing NOTCH1 signaling. Integrating RBPJ-occupied genes in HG3 cells, RNA-Seq of USP28WT/KO cells and gene expression from del(11q) CLL patients, we identified 15 NOTCH1 target genes specifically dysregulated by deletion of USP28 and del(11q) potentially influencing CLL pathogenesis. Pharmacological inhibition of USP28 with the small molecule AZ1 suppressed NOTCH1 activation in primary CLL cells. AZ1 combined with the BCL-2 inhibitor venetoclax reduced CLL cell viability, particularly in samples with high NOTCH1 activity. Our findings highlight USP28 as promising therapeutic target and provide a rationale for combined inhibition of USP28 and BCL-2 in CLL patients with active NOTCH1 signaling.

Centros eclesiásticos locales de titularidad femenina en León (siglos X-XII)

Thu, 01 Jan 2026 00:00:00 GMT

[ES] Este artículo analiza la titularidad femenina de iglesias y monasterios locales en el Reino de León entre los siglos X y XII, con el objetivo de comprender el papel de las mujeres de las comunidades y élites locales en la gestión de estos espacios clave en la articulación de las micropolíticas. A partir del análisis documental cualitativo, se estudian los mecanismos a través de los cuales las mujeres accedieron al control de estos centros como parte de las parentelas y de los grupos locales. Se concluye que, lejos de ser figuras pasivas, las mujeres ejercieron agencia propia y utilizaron estos espacios como plataformas de poder y de mediación social dentro de las comunidades y en relación con poderes supralocales.

Bayesian estimates of the marine radiocarbon reservoir effect during the Magdalenian in northern Iberia

Thu, 01 Jan 2026 00:00:00 GMT

[EN] Quantifying marine reservoir effects (MREs) across time and space is crucial for establishing accurate archaeological chronologies, including the activities of past hominines. Although the northern Iberian Peninsula shows a high density of Upper Paleolithic sites and marine shells are frequently found in these assemblages, quantification of MREs in this coastal region remains limited. We performed Bayesian modeling of radiocarbon measurements from both terrestrial (Capra pyrenaica, Cervus elaphus and other herbivores unidentified at species level) and marine (Littorina littorea Linnaeus, 1758 and Patella vulgata Linnaeus, 1758 taxa) archaeological samples recovered from the Tito Bustillo cave (Asturias, Spain) in order to determine the ΔR values for northern Iberia during the Lower Magdalenian period (ca. 20–17 ka cal BP). For the time span between 18.6 and 18.2 ka cal BP we estimated ΔR values of –298±44 14C yr and –495±122 14C yr for the periwinkle L. littorea and the common limpet P. vulgata, respectively. This finding has significant implications for future archaeological research in the northern Iberian Peninsula, as researchers must apply distinct ΔR values depending on the mollusk species selected for radiocarbon dating. Furthermore, the consistency between our calculated ΔR value for P. vulgata and previously recorded data for the same taxon from a neighboring coastal region (Cantabria, Spain) suggests remarkable stability in the marine environment of this area during the Lower Magdalenian period.

Crustal Imbrication in an Alpine Intraplate Mountain Range: A Wide-Angle Cross-Section Across the Spanish-Portuguese Central System

Sat, 02 Jul 2022 00:00:00 GMT

[EN]Intraplate ranges are topographic features that can occur far from plate boundaries, the expected position of orogens as described in the plate tectonics theory. To understand the lithospheric structure of intraplate ranges, we focused on the Spanish-Portuguese Central System (SPCS), the most outstanding topographic feature in the central Iberian Peninsula. The SPCS is an Alpine range that exhumes Precambrian-Paleozoic rocks and is located at >200 km from the northern border of the Iberian microplate. Here, we provide a P-wave velocity model based on wide-angle seismic reflection/refraction data of the central SPCS (Gredos sector). Our results show: (a) a layered lithosphere characterized by three major interfaces: Conrad, Mohorovicic, and Hales discontinuities, (b) an asymmetry of the crust-mantle boundary under the SPCS, (c) the extent of the Variscan batholith forming the main outcrops of Gredos, and (d) the thinning of the lower crust toward the south. This model suggests that the exhumation of the SPCS basement was driven by a south-vergent thick-skinned thrust system, developed in the southern part of the SPCS and that promoted crustal imbrication and a Mohorovicic discontinuity's offset under the SPCS. Thus, the deformation mechanisms of the crust seem to be controlled by the presence of the late- to post-Variscan granitoids that assimilated the Variscan mid-crustal detachment creating a new rheological boundary. This tectonic structure allowed the formation of Alpine crustal-scale thrust systems that eased coupled deformation of the upper and lower crust, leading to limited underthrusting of both crustal layers.

UNESCO Global Geoparks as useful sceneries to disseminate science and raise awareness of geological risks: the case of Las Loras Geopark (Spain)

Sat, 01 Mar 2025 00:00:00 GMT

[EN]This paper is focused on discussing the case of Las Loras UNESCO Global Geopark, in Spain, as an example to show the contribution of Geoparks to the dissemination of science and the relevance of preserving geoheritage by implementing simple measures based on communication and prevention. Natural and anthropic hazards derived from climate change are endangering heritage and the wellness of the society. Geoheritage is vulnerable. Nowadays we are witnessing the destruction of monuments with high emotional significance due to wars, but climate change is also contributing to the loss of the same cultural heritage. Prevention is often the best way to protect geoheritage from disappearing and society is the best agent to implement preventive measures. Citizens are often unaware of the important treasures they have around them. Geoparks have been a great tool to bring awareness in society, since by involving the public in the whole process of recognition and promotion, they protect the space and the cultural and economic values associated with them. It is important to communicate the initiatives taking place in the Geoparks to explain the importance of geology and the risk of losing the geoheritage if natural hazards increase. Las Loras study is a good practice to implement in other Geoparks.

Optimizing patient registries for regulatory decision making - key learnings from an HMA/EMA multistakeholder workshop

Mon, 01 Sep 2025 00:00:00 GMT

[EN]The Joint Heads of Medicines Agencies and European Medicines Agency's (HMA/EMA) big data initiative paves the way for better integration of real-world data, including data from patient registries, into regulatory decisions on medicines. This article focuses on the outcome of a two-day multistakeholder workshop organized by EMA in 2024, which explored ways to optimize the EMA qualification procedure for patient registries, and to establish the value and enable the use of these data across the full spectrum of research questions. Key recommendations include the need to clarify the aim, scope, and added value of the qualification of registries, coupled with a review of the procedural steps to ensure the process is fit-for-purpose to evaluate the use of registries in specific regulatory contexts. Further recommendations focused on strengthening interactions between stakeholders, as well as providing them with enhanced support by increasing awareness of publicly available tools that could leverage the potential of registry data, together with existing guidance. The European Medicines Regulatory Network is now working together with all relevant stakeholders, including the EMA scientific committees and working parties, the Joint HMA/EMA Network Data Steering Group and existing focus groups with external partners, to implement concrete actions that will address these recommendations. Among others, the update of existing guidance, the development of templates and Questions & Answers documents, and the design of appropriate communication and stakeholder engagement plans will aid in achieving the common goal of making optimal use of patient registry data to support public health in the European Union.

Prognostic impact of myelodysplasia-related gene mutations in FLT3-ITD-mutated acute myeloid leukemia

Sun, 01 Mar 2026 00:00:00 GMT

[EN]The inclusion of nine myelodysplasia-related gene (MRG) mutations (ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) as adverse risk factors in the ELN risk classification has reshaped classification in acute myeloid leukemia (AML). AML with FLT3-ITD mutations and co-occurring MRG alterations is now classified to the ELN adverse risk group although supporting evidence remains limited. Among 4,078 patients with AML with available molecular information included in the HARMONY platform, 862 harbored FLT3-ITD mutations and underwent intensive chemotherapy. Of these, 171 (20%) exhibited co-occurring MRG mutations at diagnosis. In this cohort, MRGs were not independently associated with relapse-free survival (RFS) or overall survival (OS). In the FLT3-ITD/NPM1 co-mutated subgroup, MRG mutations were rare (9%) and showed no prognostic impact. Conversely, in FLT3-ITD/NPM1 wildtype AML, MRG mutations were predictive of shorter RFS (HR 1.37, 95%CI 1.01 - 1.88, p = 0.046) and OS (HR 1.34, 95%CI 1.02-1.74, p = 0.032) in multivariable analysis with survival times comparable to the ELN adverse risk category. The allelic ratio of FLT3-ITD did not further stratify OS and RFS in this subgroup. These findings suggest that the prognostic relevance of MRG mutations in FLT3-ITD AML is modulated by NPM1 co-mutational status and mirror findings in AML lacking FLT3-ITD.

Unravelling co-mutational patterns with prognostic implications in NPM1 mutated adult acute myeloid leukemia - a HARMONY study

Thu, 01 Jan 2026 00:00:00 GMT

[EN]NPM1-mutated (NPM1-mut) acute myeloid leukemia (AML) is generally associated with a more favorable outcome, although the presence of additional gene mutations can influence patient prognosis. We analyzed intensively-treated adult NPM1-mut AML patients included in the HARMONY Alliance database. A newly developed risk classification, which included combinations of co-mutations in FLT3-ITD, DNMT3A, IDH1/IDH2, and TET2 genes, was applied to a training cohort of NPM1-mut AML patients included in clinical trials (n = 1001), an internal validation cohort more representative of real-world settings (n = 762), and an external validation cohort enrolled in UK-NCRI trials (n = 585). The HARMONY classification considered 51.8% of the NPM1-mut AML training cohort patients as favorable, 24.8% as intermediate, and 23.4% as adverse risk, with median overall survival (OS) of 14.4, 2.2, and 0.9 years, respectively; p < 0.001), thereby reclassifying 42.7% of NPM1-mut patients into a different European LeukemiaNet (ELN) 2022 risk category. These results were confirmed both in an internal and external validation cohort. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) showed the highest benefit in the NPM1-mut adverse-risk subgroup. The HARMONY classification provides the basis for a refined genetic risk stratification for adult NPM1-mut AML with potential clinical impact on allo-HSCT decision-making.

El escriptovisual como práctica didáctica en la enseñanza

Wed, 01 Jan 2025 00:00:00 GMT

[ES] La presente contribución lleva sobre el escriptovisual como práctica didáctica en la enseñanza– aprendizaje del español en Camerún. Pretende diseñar una práctica didáctica del escriptovisual en comprensión del texto para desarrollar las habilidades comunicativas socioculturales e interculturales en los alumnos del sexto curso de ELE. Es a partir del enfoque de la ingeniería didáctica de Artigue y del enfoque experimental con un plan de experiencia grupo testigogrupo experimental que ha sido posible de poner en evidencia el impacto positivo del escriptovisual sobre el desarrollo de las competencias.

El sermón Cunctorum (in natali sancti Vincentii) (CPL 1185): estudio, edición y traducción

Wed, 01 Jan 2025 00:00:00 GMT

[ES] Este artículo propone, en primer lugar, un estudio del sermón Cunctorum (CPL 1185), compuesto para la festividad del famoso mártir hispano san Vicente de Zaragoza. Para ello, se analizan sus contenidos, sus fuentes, su posteridad literaria y su tradición manuscrita. Además, se ofrece la primera edición crítica de esta misma obra a partir del análisis de toda su tradición manuscrita conocida. Este trabajo viene a confirmar que este sermón, atribuido inicialmente tanto a Agustín de Hipona, como a León Magno, es, sin duda, una obra de origen hispano-visigodo. Además, el estudio de su tradición manuscrita lleva a concluir que el manuscrito Paris, BnF, lat. 13760, ejecutado en Saint Germain des Prés hacia el año 870, es, verosímilmente, el arquetipo conservado de toda la tradición. Finalmente, debido al estilo altamente retórico de este sermón, que no siempre favorece su comprensión, nos ha parecido conveniente incluir una traducción completa.

Machine learning improves risk stratification in myelofibrosis: An analysis of the Spanish registry of myelofibrosis

Sun, 01 Jan 2023 00:00:00 GMT

[EN]Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) with heterogeneous clinical course. Allogeneic hematopoietic cell transplantation remains the only curative therapy, but its morbidity and mortality require careful candidate selection. Therefore, accurate disease risk prognostication is critical for treatment decision-making. We obtained registry data from patients diagnosed with MF in 60 Spanish institutions (N = 1386). These were randomly divided into a training set (80%) and a test set (20%). A machine learning (ML) technique (random forest) was used to model overall survival (OS) and leukemia-free survival (LFS) in the training set, and the results were validated in the test set. We derived the AIPSS-MF (Artificial Intelligence Prognostic Scoring System for Myelofibrosis) model, which was based on 8 clinical variables at diagnosis and achieved high accuracy in predicting OS (training set c-index, 0.750; test set c-index, 0.744) and LFS (training set c-index, 0.697; test set c-index, 0.703). No improvement was obtained with the inclusion of MPN driver mutations in the model. We were unable to adequately assess the potential benefit of including adverse cytogenetics or high-risk mutations due to the lack of these data in many patients. AIPSS-MF was superior to the IPSS regardless of MF subtype and age range and outperformed the MYSEC-PM in patients with secondary MF. In conclusion, we have developed a prediction model based exclusively on clinical variables that provides individualized prognostic estimates in patients with primary and secondary MF. The use of AIPSS-MF in combination with predictive models that incorporate genetic information may improve disease risk stratification.

Mepolizumab for hypereosinophilic syndrome: effectiveness and safety from real-world evidence

Wed, 01 Jan 2025 00:00:00 GMT

[EN]Hypereosinophilic syndrome (HES) is a rare condition characterized by elevated eosinophil levels and related symptoms of eosinophil-mediated organ damage. We reviewed the effectiveness and safety of mepolizumab for the treatment of HES. A scoping review was conducted following the PRISMA Scoping Reviews Checklist to identify real-world evidence of mepolizumab use in HES. In total, 36 references were identified as relevant and selected for review. Overall, 105 patients previously treated with glucocorticoids received mepolizumab at different dosages (range: 100-750 mg), routes of administration (subcutaneous/intravenous), and schedules (every 2-12 weeks). Remission rates were 57.1-76.0%. Most studies reported a range of 71.4-99.1% reduction in mean blood eosinophil counts with mepolizumab treatment. In addition, a glucocorticoid-sparing effect was observed; 85.7% of patients discontinued glucocorticoids after 12 months of mepolizumab administration. Mepolizumab was considered safe and well-tolerated and severe adverse events were rare. Mepolizumab provided clinically significant benefits in patients with HES in a real-world setting.

Adverse prognostic impact of complex karyotype (≥3 cytogenetic alterations) in adult T-cell acute lymphoblastic leukemia (T-ALL).

Fri, 01 Oct 2021 00:00:00 GMT

[EN]The potential prognostic value of conventional karyotyping in adult T-cell acute lymphoblastic leukemia (T-ALL) remains an open question. We hypothesized that a modified cytogenetic classification, based on the number and type of cytogenetic abnormalities, would allow the identification of high-risk adult T-ALL patients. Complex karyotype defined by the presence of ≥3 cytogenetic alterations identified T-ALL patients with poor prognosis in this study. Karyotypes with ≥3 abnormalities accounted for 16 % (22/139) of all evaluable karyotypes, corresponding to the largest poor prognosis cytogenetic subgroup of T-ALL identified so far. Patients carrying karyotypes with ≥3 cytogenetic alterations showed a significantly inferior response to therapy, and a poor outcome in terms of event-free survival (EFS), overall survival (OS) and cumulative incidence of relapse (CIR), independently of other baseline characteristics and the end-induction minimal residual disease (MRD) level. Additional molecular analyses of patients carrying ≥3 cytogenetic alterations showed a unique molecular profile that could contribute to understand the underlying molecular mechanisms of resistance and to evaluate novel targeted therapies (e.g. IL7R directed) with potential impact on outcome of adult T-ALL patients.

Machine learning risk stratification strategy for multiple myeloma: Insights from the EMN-HARMONY Alliance platform

Wed, 01 Oct 2025 00:00:00 GMT

[EN]Traditional risk stratification in multiple myeloma (MM) relies on clinical and cytogenetic parameters but has limited predictive accuracy. Machine learning (ML) offers a novel approach by leveraging large datasets and complex variable interactions. This study aimed to develop and validate novel ML-driven prognostic scores for newly diagnosed MM (NDMM), with the goal of improving upon existing ones. To this end, we analyzed data from the EMN-HARMONY MM cohort, comprising 14,345 patients, including 10,843 NDMM patients enrolled across 16 clinical trials. Three ML models were developed: (1) a comprehensive model incorporating 20 variables, (2) a reduced model including six key variables (age, hemoglobin, β2-microglobulin, albumin, 1q gain, and 17p deletion), and (3) a cytogenetics-free model. All models were internally validated using out-of-bag cross-validation and externally validated with data from the Myeloma XI trial. Model performance was evaluated using the concordance index (C-index) and time-dependent area under the receiver operating characteristic curve (ROC-AUC). The comprehensive model achieved C-index values of 0.666 (training) and 0.667 (test) for overall survival (OS) and 0.620/0.627 for progression-free survival (PFS). The reduced model maintained accuracy (OS: 0.658/0.657; PFS: 0.608/0.614). The cytogenetics-free model showed C-index values of 0.636/0.643 for OS and 0.600/0.610 for PFS. Incorporating treatment type and best response to first-line treatment further improved performance. The new prognostic models improved over the International Staging System (ISS), Revised International Staging System (R-ISS), and Second Revision of the International Staging System (R2-ISS) and were reproducible in real-world and relapsed/refractory MM, including daratumumab-treated patients. This ML-based risk stratification strategy provides individualized risk predictions, surpassing traditional group-based methods and demonstrating broad applicability across patient subgroups. An online calculator is available at https://taxonomy.harmony-platform.eu/riskcalculator/.

Salir sin guardar. Estética y ficcion

Mon, 01 Jun 2026 00:00:00 GMT

[ES]El presente libro tiene como objetivo analizar diversas formas de repetición, retorno o versión en el arte y la cultura contemporáneos. Para ello, a lo largo de sus capítulos se abordan temas como las copias, los anacronismos, los homenajes, las simulaciones o las retromanías que recorren una parte importante de las prácticas artísticas y culturales de nuestro tiempo. En este sentido, estrategias como las de la ironía y sus distintas versiones actuales, las obsesiones por el pasado y la memoria, o trabajos sobre las tendencias y patrones de reconocimiento, son analizados desde una perspectiva filosófica y estética que se ejemplifica mediante constantes casos ficcionales, tanto artísticos como literarios.

Vitivinicultura, patrimonio y desarrollo territorial en Arribes del Duero

Wed, 01 Jan 2025 00:00:00 GMT

[ES] Arribes del Duero es una comarca con un largo pasado vitivinícola, donde los valores culturales asociados a esta actividad económica están fuertemente asentados en el ideario colectivo, creándose, así, un complejo patrimonial con un gran potencial turístico, pero con grandes problemas estructurales. Desde el año 2007, cuando se aprueba la declaración de la Denominación de Origen Arribes, se ha comenzado a vislumbrar un cierto proceso de desarrollo potenciado por la moviliza-ción del capital territorial (capital natural, capital social, capital productivo y capital intelectual), a lo que hay que sumarle las iniciativas que se están poniendo en marcha desde la Agrupación Europea de Cooperación Territorial Duero-Douro.