http://hdl.handle.net/10366/4512 2026-05-11T18:13:12Z http://hdl.handle.net/10366/171350 [EN]Patients with newly diagnosed multiple myeloma (NDMM) show heterogeneous outcomes, and approximately 60% of them are at intermediate-risk according to the Revised International Staging system (R-ISS), the standard-of-care risk stratification model. Moreover, chromosome 1q gain/amplification (1q+) recently proved to be a poor prognostic factor. In this study, we revised the R-ISS by analyzing the additive value of each single risk feature, including 1q+. The European Myeloma Network, within the HARMONY project, collected individual data from 10,843 patients with NDMM enrolled in 16 clinical trials. An additive scoring system on the basis of top features predicting progression-free survival (PFS) and overall survival (OS) was developed and validated. In the training set (N = 7,072), at a median follow-up of 75 months, ISS, del(17p), lactate dehydrogenase, t(4;14), and 1q+ had the highest impact on PFS and OS. These variables were all simultaneously present in 2,226 patients. A value was assigned to each risk feature according to their OS impact (ISS-III 1.5, ISS-II 1, del(17p) 1, high lactate dehydrogenase 1, and 1q+ 0.5 points). Patients were stratified into four risk groups according to the total additive score: low (Second Revision of the International Staging System [R2-ISS]-I, 19.2%, 0 points), low-intermediate (II, 30.8%, 0.5-1 points), intermediate-high (III, 41.2%, 1.5-2.5 points), high (IV, 8.8%, 3-5 points). Median OS was not reached versus 109.2 versus 68.5 versus 37.9 months, and median PFS was 68 versus 45.5 versus 30.2 versus 19.9 months, respectively. The score was validated in an independent validation set (N = 3,771, of whom 1,214 were with complete data to calculate R2-ISS) maintaining its prognostic value. The R2-ISS is a simple prognostic staging system allowing a better stratification of patients with intermediate-risk NDMM. The additive nature of this score fosters its future implementation with new prognostic variables. 2022-10-10T00:00:00Z http://hdl.handle.net/10366/171347 [EN]Chronic myeloid leukaemia (CML) is a haematological neoplasm driven by the BCR/ABL fusion oncogene. The monogenic aspect of the disease and the feasibility of ex vivo therapies in haematological disorders make CML an excellent candidate for gene therapy strategies. The ability to abolish any coding sequence by CRISPR-Cas9 nucleases offers a powerful therapeutic opportunity to CML patients. However, a definitive cure can only be achieved when only CRISPR-edited cells are selected. A gene-trapping approach combined with CRISPR technology would be an ideal approach to ensure this. Here, we developed a CRISPR-Trap strategy that efficiently inserts a donor gene trap (SA-CMV-Venus) cassette into the BCR/ABL-specific fusion point in the CML K562 human cell line. The trapping cassette interrupts the oncogene coding sequence and expresses a reporter gene that enables the selection of edited cells. Quantitative mRNA expression analyses showed significantly higher level of expression of the BCR/Venus allele coupled with a drastically lower level of BCR/ABL expression in Venus+ cell fractions. Functional in vitro experiments showed cell proliferation arrest and apoptosis in selected Venus+ cells. Finally, xenograft experiments with the selected Venus+ cells showed a large reduction in tumour growth, thereby demonstrating a therapeutic benefit in vivo. This study represents proof of concept for the therapeutic potential of a CRISPR-Trap system as a novel strategy for gene elimination in haematological neoplasms. 2022-06-07T00:00:00Z http://hdl.handle.net/10366/171344 [EN]Interstitial 14q32 deletions involving IGH gene are infrequent events in chronic lymphocytic leukemia (CLL), affecting less than 5% of patients. To date, little is known about their clinical impact and molecular underpinnings, and its mutational landscape is currently unknown. In this work, a total of 871 CLLs were tested for the IGH break-apart probe, and 54 (6.2%) had a 300 kb deletion of 3'IGH (del-3'IGH CLLs), which contributed to a shorter time to first treatment (TFT). The mutational analysis by next-generation sequencing of 317 untreated CLLs (54 del-3'IGH and 263 as the control group) showed high mutational frequencies of NOTCH1 (30%), ATM (20%), genes involved in the RAS signaling pathway (BRAF, KRAS, NRAS, and MAP2K1) (15%), and TRAF3 (13%) within del-3'IGH CLLs. Notably, the incidence of TRAF3 mutations was significantly higher in del-3'IGH CLLs than in the control group (p < .001). Copy number analysis also revealed that TRAF3 loss was highly enriched in CLLs with 14q deletion (p < .001), indicating a complete biallelic inactivation of this gene through deletion and mutation. Interestingly, the presence of mutations in the aforementioned genes negatively refined the prognosis of del-3'IGH CLLs in terms of overall survival (NOTCH1, ATM, and RAS signaling pathway genes) and TFT (TRAF3). Furthermore, TRAF3 biallelic inactivation constituted an independent risk factor for TFT in the entire CLL cohort. Altogether, our work demonstrates the distinct genetic landscape of del-3'IGH CLL with multiple molecular pathways affected, characterized by a TRAF3 biallelic inactivation that contributes to a marked poor outcome in this subgroup of patients. 2022-07-01T00:00:00Z http://hdl.handle.net/10366/171340 [EN]The knowledge of chronic lymphocytic leukemia (CLL) has progressively deepened during the last forty years. Research activities and clinical studies have been remarkably fruitful in novel findings elucidating multiple aspects of the pathogenesis of the disease, improving CLL diagnosis, prognosis and treatment. Whereas the diagnostic criteria for CLL have not substantially changed over time, prognostication has experienced an expansion with the identification of new biological and genetic biomarkers. Thanks to next-generation sequencing (NGS), an unprecedented number of gene mutations were identified with potential prognostic and predictive value in the 2010s, although significant work on their validation is still required before they can be used in a routine clinical setting. In terms of treatment, there has been an impressive explosion of new approaches based on targeted therapies for CLL patients during the last decade. In this current chemotherapy-free era, BCR and BCL2 inhibitors have changed the management of CLL patients and clearly improved their prognosis and quality of life. In this review, we provide an overview of these novel advances, as well as point out questions that should be further addressed to continue improving the outcomes of patients. 2021-05-10T00:00:00Z http://hdl.handle.net/10366/171330 [EN]The need for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adults with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) with high-risk (HR) features and adequate measurable residual disease (MRD) clearance remains unclear. The aim of the ALL-HR-11 trial was to evaluate the outcomes of HR Ph- adult ALL patients following chemotherapy or allo-HSCT administered based on end-induction and consolidation MRD levels. Patients aged 15 to 60 years with HR-ALL in complete response (CR) and MRD levels (centrally assessed by 8-color flow cytometry) <0.1% after induction and <0.01% after early consolidation were assigned to receive delayed consolidation and maintenance therapy up to 2 years in CR. The remaining patients were allocated to allo-HSCT. CR was attained in 315/348 patients (91%), with MRD <0.1% after induction in 220/289 patients (76%). By intention-to-treat, 218 patients were assigned to chemotherapy and 106 to allo-HSCT. The 5-year (±95% confidence interval) cumulative incidence of relapse (CIR), overall survival (OS), and event-free survival probabilities for the whole series were 43% ± 7%, 49% ± 7%, and 40% ± 6%, respectively, with CIR and OS rates of 45% ± 8% and 59% ± 9% for patients assigned to chemotherapy and of 40% ± 12% and 38% ± 11% for those assigned to allo-HSCT, respectively. Our results show that avoiding allo-HSCT does not hamper the outcomes of HR Ph- adult ALL patients up to 60 years with adequate MRD response after induction and consolidation. Better postremission alternative therapies are especially needed for patients with poor MRD clearance. This trial was registered at www.clinicaltrials.gov as # NCT01540812. 2021-04-08T00:00:00Z http://hdl.handle.net/10366/171327 [EN] In the present paper we systematically evaluate the radiometric database underlying the Middle to Upper Palaeolithc transition in southwestern Europe.The different models which attempt to explain the demographical processes underlying this transition rely to a large degree on radiocarbon chronology. We observe that: 1) with increasing age, dates on bone samples show large offsets against those on charcoal, often underestimating these for several thousand years BP and; 2) there is no proof for a persistence of Middle Palaeolithic industries into the time of the earliest Aurignacian in SW Europe. These data contradict the “Ebro- Frontier” model that distinguishes Late Middle Palaeolithic industries in the SW of the Iberian Peninsula from early Aurignacian ones in the NE. On the contrary, our data 3) imply a model of interregional shifts of populations contracting during severe cold and arid phases and expanding under warmer, interstadial conditions, raising ideas on a regional in situ development of the SW European Aurignacian out of Latest Middle Palaeolithic industries made by Neanderthals some 40.0 kyr cal BC. 2023-01-01T00:00:00Z http://hdl.handle.net/10366/171326 [ES] Estudio de las conchas marinas de la especie Columbella rustica en los sitios mesolíticos europeos 2003-01-01T00:00:00Z http://hdl.handle.net/10366/171325 [EN] A spatula recovered from the Late Palaeolithic site of Boppard is manufactured on a fragment of the plantar face of a metatarsal bone of red deer (Cervus elaphus). Along its narrow side, the tool exhibits numerous parallel notches at right angles to the longitudinal axis of the bone. These are arranged in groups separated by notch-free areas of bone. Comparable bone tools are described, mainly from Cantabrian Spain, but also from France, Italy, Germany, the Czech Republik and Sweden. The best paralells for the Boppard specimen are, insofar as they are dated, known from the Later Upper Palaeolithic. 2014-01-01T00:00:00Z http://hdl.handle.net/10366/171301 [EN]NGS Establishment in Multidisciplinary Healthcare (NEMHESYS) is an Erasmus+ programme with the purpose of providing qualified staff with the essential technical and bioinformatic knowledge and skills on next-generation sequencing (NGS) to be able to carry out NGS studies and perform some of the most common types of analyses. The clinical application of NGS has become easier with advancements in technologies. However, the investment needed to bring NGS into medical practice remains significant, with the scale of knowledge required being unprecedented at most hospitals. In addition, these novel technologies bring new challenges in translating NGS to clinical practice, at both technical and regulatory level, in terms of data management, interpretation of the results, and genetic counseling. All these aspects justify the consideration of what will be the precise role of NGS in diagnosis, risk assessment, response prediction, and treatment monitoring, today and tomorrow. Thus, to evaluate the implementation of NGS in European healthcare/research centers, a mapping survey was carried out, based on previous NGS mapping studies. 2021-02-01T00:00:00Z http://hdl.handle.net/10366/171292 [EN]Myelodysplastic syndromes (MDS) are hematological disorders at high risk of progression to secondary acute myeloid leukemia (sAML). However, the mutational dynamics and clonal evolution underlying disease progression are poorly understood at present. To elucidate the mutational dynamics of pathways and genes occurring during the evolution to sAML, next generation sequencing was performed on 84 serially paired samples of MDS patients who developed sAML (discovery cohort) and 14 paired samples from MDS patients who did not progress to sAML during follow-up (control cohort). Results were validated in an independent series of 388 MDS patients (validation cohort). We used an integrative analysis to identify how mutations, alone or in combination, contribute to leukemic transformation. The study showed that MDS progression to sAML is characterized by greater genomic instability and the presence of several types of mutational dynamics, highlighting increasing (STAG2) and newly-acquired (NRAS and FLT3) mutations. Moreover, we observed cooperation between genes involved in the cohesin and Ras pathways in 15-20% of MDS patients who evolved to sAML, as well as a high proportion of newly acquired or increasing mutations in the chromatin-modifier genes in MDS patients receiving a disease-modifying therapy before their progression to sAML. 2021-08-01T00:00:00Z http://hdl.handle.net/10366/171259 [EN] Archaeologically-oriented petrography has changed the way of conceiving economic and social practices during the Palaeolithic. Research on quartzite, the second most widely used lithic resource, has experienced a notable increase thanks to the formal definition of the material, methodological improvements, and case studies that are shedding light on the economy and social interactions during the Palaeolithic. This paper briefly presents the progress made during the last years by our research team, particularly in quartzite petrology, together with some thoughts about its future evolution. These advances are based on the petrography of the material and particularly on the application of petrogenesis (a research field in geology that deals with the origin and transformation of rocks) to establish reliable and universal types that are useful for understanding quartzite from a geoarchaeological perspective. Furthermore, we present preliminary results derived from the application of scanning electron microscopy in quartzite petrogenesis. Finally, we propose some perspectives and methodological advances to continue untangling the prehistoric knowledge enclosed in quartzite artefacts 2026-01-01T00:00:00Z http://hdl.handle.net/10366/171258 Este trabajo analiza la transición tecnológica hacia la Web 3.0 y el desarrollo del metaverso, centrando su estudio en el impacto de los tokens no fungibles (NFTs) sobre el sistema de propiedad intelectual. La investigación comienza con una clarificación técnica y conceptual, definiendo los NFTs como representaciones digitales de valor que, gracias a la tecnología blockchain, garantizan la unicidad, inalterabilidad y trazabilidad de los activos. El núcleo jurídico de la obra desmitifica creencias comunes al precisar que un NFT no es una obra en sí misma, sino un certificado digital de autenticidad vinculado a un archivo o derecho. Se examina pormenorizadamente cómo la adquisición de estos activos suele implicar únicamente una licencia de uso limitado sobre el soporte digital, sin que suponga necesariamente la transferencia de la propiedad del activo subyacente ni de sus derechos de explotación. Asimismo, el capítulo aborda la utilidad de los smart contracts para automatizar procesos como el pago de regalías y propone un debate innovador sobre el agotamiento digital del derecho de distribución y el derecho de participación (droit de suite) en entornos descentralizados. Finalmente, se analizan los riesgos emergentes, tales como las infracciones por minteo no autorizado, el fraude mediante wash trading y los desafíos que plantea la aplicación del Reglamento de Servicios Digitales (DSA) y el marco de las DAOs a los mercados de activos digitales. 2023-01-01T00:00:00Z http://hdl.handle.net/10366/171245 [EN]In this Letter we report the demonstration of the first cyan Pr-based waveguide laser, fabricated inscribing depressed-cladding waveguides in Pr:Ba(Y0.8Lu0.2)2F8 by direct femtosecond laser writing. With an optimized waveguide geometry for the monoclinic crystal matrix, we demonstrate lasing at 495 nm, observing a maximum output power of 22 mW and a maximum slope efficiency of 7% in a compact 6 mm-long laser cavity. These values are comparable with those reported in the literature for solid-state devices based on bulk crystals. Incidentally, this is also the first, to our knowledge, demonstration of a waveguide visible laser based on a monoclinic crystal matrix. 2025-11-01T00:00:00Z http://hdl.handle.net/10366/171244 [EN]Ultrafast-laser inscription enables the fabrication of three-dimensional photonic microstructures in laser-active dielectric crystals, yet the interplay between geometry and laser-induced refractive-index changes remains insufficiently quantified. We investigate depressed-cladding waveguides written in a uniaxial Er3+:LiYF4 fluoride crystal using spatially resolved confocal luminescence and Raman spectroscopy with sub-micrometric resolution. The measurements reveal partial amorphization within the irradiated zones, as well as a complex distribution of local stress fields—compressive within the cladding and tensile at the periphery of the core. These stress patterns, and the associated refractive-index modifications, are found to be highly sensitive to the cladding geometry. From the spectroscopic analysis, we estimate a maximum compressive stress of 1 GPa and a refractive-index change of −2.6 × 10−3 for the e-wave within the damage tracks. Complementary differential interference contrast (Nomarski) microscopy yields quantitative maps of stress-induced birefringence, on the order of 10−6—well below the intrinsic birefringence of LiYF4 and therefore not detrimental to the polarization properties of laser waveguides. Based on these findings, we provide design guidelines for optimizing mid-infrared waveguide structures. 2026-03-01T00:00:00Z http://hdl.handle.net/10366/171243 [EN]In this work we present the power scaling of diode-pumped waveguide lasers fabricated in a Pr:LiLuF4 crystal by direct femtosecond writing. We demonstrated a maximum output power of 360 mW at 604 nm, 420 mW at 721 nm, and 55 mW at 523 nm. Moreover, we demonstrated what we believe to be the first operation of a waveguide laser at 545 nm. In the end, we achieved stable lasing at 604 nm with an extraction of 96%, demonstrating the high gain achievable in waveguide devices. 2025-02-01T00:00:00Z http://hdl.handle.net/10366/171242 [ES]Los capítulos (86 pp en total) se dedican a comentar el nuevo régimen de la capacidad posesoria (art. 443 CC) y el de Sucesiones (resto) tras las modificaciones introducidas por la Ley 8/2021 que incorpora al Derecho Común la Convención de Nueva York de 2006, poniendo de relieve la importancia del nuevo paradigma que supone el reconocimiento de capacidad plena en estas sedes a las personas con discapacidad. Fue uno de los primeros comentarios al nuevo régimen, con el objetivo de esclarecer su aplicación y respetar los derechos de las personas con discapacidad. Cabe destacar el estudio de la oportunidad de la supresión de la sustitución ejemplar en el testamento (y su régimen transitorio) o el nuevo mayor alcance permitido al gravamen de las legítimas, así como el papel de los discapacitados en la tramitación de la herencia (aceptación, y partición). [EN]The chapters (86 pages in total) are dedicated to commenting on the new legal framework governing possessory capacity (Art. 443 of the Civil Code) and the inheritance law (remaining articles) following the amendments introduced by Law 8/2021, which incorporates the 2006 New York Convention into Spanish law. They highlight the importance of the new paradigm represented by the recognition of full legal capacity for people with disabilities in these matters. This was one of the first commentaries on the new legal framework, aiming to clarify its application and ensure respect for the rights of people with disabilities. Of particular note is the analysis of the appropriateness of eliminating the provision for exemplary substitution in wills (and its transitional provisions), the broader scope now permitted for encumbrances on forced heirship shares, and the role of people with disabilities in inheritance proceedings (acceptance and division). 2022-01-01T00:00:00Z