Hydroeconomic Analysis of the Sustainable Use of Land and Water Resources under Droughts and Climate Change

El objetivo principal de la tesis es desarrollar un modelo hidroeconómico integrado de la cuenca del Ebro para el análisis de la política del agua. El modelo se utiliza para evaluar los impactos de las sequías y la escasez de agua en el contexto del cambio climático. Los resultados y las implicaciones políticas pueden utilizarse como guías para otras regiones semiáridas y áridas que enfrentan problemas similares de escasez de agua. Los resultados brindan información a las partes interesadas y los tomadores de decisiones sobre los impactos de las sequías y el cambio climático, y cómo las diferentes alternativas de gestión del agua podrían contribuir a abordar sus efectos. Se analiza la sostenibilidad del sistema hídrico del Ebro teniendo en cuenta la fiabilidad, resiliencia y vulnerabilidad del sector del riego, junto con la protección de los ecosistemas dependientes del agua.Los modelos matemáticos que reproducen las interacciones temporales y espaciales del uso del agua son la base del análisis hidroeconómico. Estos modelos optimizan y simulan los sistemas de agua para identificar las compensaciones en los usos del agua por sector y ubicación espacial. Se pueden examinar muchos problemas relacionados con el agua, como el crecimiento económico, el suministro de agua, la adaptación y mitigación del cambio climático, los daños por control de inundaciones o los caudales ambientales. La mejora de la resiliencia del sistema de agua, para reducir las pérdidas por escasez de agua, implica acciones que incluyen la expansión del almacenamiento de presas, la reutilización del agua, la desalinización del agua de mar, el precio del agua y el comercio del agua. El análisis hidroeconómico incorpora múltiples disciplinas como los procesos biofísicos, las actividades económicas o los ecosistemas acuáticos en un marco capaz de abordar las dimensiones temporales y espaciales del problema de la escasez de agua. En este sentido, el análisis hidroeconómico puede contribuir a resolver los problemas de escasez de agua, dando respuesta a las inquietudes sobre la gestión del agua.La investigación principal se muestra en tres capítulos (capítulos 2 a 4), donde se utiliza el análisis hidroeconómico para abordar el cambio climático y los problemas de gestión del agua. La cuenca del Ebro en España es nuestro caso de estudio, aunque los hallazgos podrían ser útiles para otras cuencas áridas y semiáridas con características económicas y climáticas similares. El estudio compara las alternativas de gestión del agua y su contribución a la sostenibilidad del sistema hídrico, logrando tanto la protección de la seguridad hídrica humana como la biodiversidad del ecosistema de los impactos de la escasez de agua, las sequías y el cambio climático. Los hallazgos en el Ebro podrían contribuir a los avances en la política del agua en cuencas de todo el mundo que enfrentan problemas de escasez de agua y empeoran la degradación de los ecosistemas, como las cuencas en la región mediterránea, el Medio Oriente y Asia Central, el suroeste de los Estados Unidos o Australia.El primer estudio del Capítulo 2, presenta el modelo hidroeconómico de la cuenca del Ebro. El modelo integrado vincula tres componentes: el componente hidrológico de forma reducida, el componente económico regional y el componente ambiental. El componente hidrológico de forma reducida se calibra mediante la inclusión de variables no observadas para cerrar el balance de masa entre los caudales estimados y observados. El componente económico regional está calibrado con programación matemática positiva (PMP), reproduciendo el uso de agua y suelo observado en condiciones de línea base. Este método supone que los agricultores maximizan los beneficios del uso del agua y la tierra, y se utilizan las condiciones de primer orden para la calibración. La restricción de caudal ambiental mínimo en la desembocadura del río representa el componente ambiental. El modelo se utiliza para analizar las distribuciones espaciales y sectoriales del agua en condiciones de sequía, comparando el instrumento económico de los mercados de agua con el instrumento institucional de cooperación de los actores. El cumplimiento de los caudales ambientales en la desembocadura del río se evalúa tomando diferentes prioridades para la asignación de agua entre las regiones aguas arriba y aguas abajo. Bajo políticas alternativas, el análisis identifica los impactos de sequías y escasez de agua, y su distribución entre regiones y sectores.En el Capítulo 3, se incluye el uso del agua por parte de los ecosistemas en el modelo hidroeconómico. Representar los beneficios de los ecosistemas requiere vincular la salud de los ecosistemas con las variaciones hidrológicas y también determinar el valor económico de los servicios ecosistémicos. La integración de los beneficios ambientales en el modelo hidroeconómico es el método para capturar las interacciones entre los beneficios privados (provistos por las actividades económicas) y los beneficios públicos (provistos por los ecosistemas). La simulación de la distribución del agua en condiciones de sequía se utiliza para evaluar políticas hídricas que combinan instrumentos económicos e institucionales.El componente ambiental del modelo vincula los beneficios que los ecosistemas brindan a la sociedad, el estado ambiental y los flujos de agua que sustentan el ecosistema acuático. La relación entre las condiciones ambientales y los caudales se establece y calibra mediante estudios previos sobre los procesos biofísicos involucrados.La Autoridad de la Cuenca del Ebro ha utilizado estos estudios para fijar los caudales ambientales mínimos en la cuenca.El componente ambiental incluye la representación del estado de salud y los consiguientes beneficios ambientales, cubriendo los principales tramos de la cuenca del río. Esta es una mejora significativa con respecto a la literatura hidroeconómica anterior, donde la representación ambiental se limita a ciertas partes y ubicaciones específicas de los ríos. La representación ambiental captura la interacción espacial entre las asignaciones de agua para actividades económicas y para los ecosistemas. El modelo hidroeconómico se ha utilizado para analizar las compensaciones entre los beneficios públicos y privados proporcionados por las actividades económicas y los ecosistemas. El análisis de las alternativas de gestión del agua contribuye a identificar las asignaciones de agua adecuadas que mantienen el sistema de agua en buen estado.El tercer estudio en el Capítulo 4 es una mejora del modelo hidroeconómico presentado en el Capítulo 2. El modelo hidroeconómico incluye la dimensión temporal, agregando aspectos dinámicos al modelo presentado en el Capítulo 2, y el paso de tiempo se ha cambiado de anual a mensual. Las principales represas de la cuenca están incluidas en el modelo, lo que permite la simulación y evaluación de alternativas de política hídrica a través de múltiples periodos de tiempo. La capacidad de las presas, los aportes de agua a la cuenca y la operación y evaporación de las presas son algunas de las variables que incorpora el modelo para representar las presas.La escala temporal del modelo hidroeconómico es mensual, promoviendo el análisis de una variedad de períodos de sequía, desde varios meses hasta varios años. El modelo hidroeconómico compara la sustentabilidad del sistema de agua bajo condiciones climáticas cambiantes. Como consecuencia del cambio climático, en zonas áridas y semiáridas, como la cuenca del Ebro, los episodios de sequía serán más intensos, frecuentes y prolongados. Por lo tanto, los impactos económicos y ambientales de las sequías se verán agravados en estas condiciones.Las simulaciones de cambio climático se basan en datos históricos, proyecciones de cambio climático y en un método avanzado de simulación de flujo de agua llamado Cópulas. Este método ajusta la distribución conjunta de dos meses consecutivos para capturar su interdependencia. La ventaja de este procedimiento es que puede generar flujos de corriente que replican las condiciones climáticas históricas y proyectadas con sequías más intensas y duraderas.La incertidumbre y el riesgo relacionados con la sequía y el cambio climático se identifican mediante las funciones de distribución acumulativa de la disponibilidad de agua y las pérdidas de beneficios. El análisis revela la exposición del sistema de agua a pérdidas, y luego se consideran políticas alternativas para reducir los impactos de las sequías y el cambio climático. Bajo estas políticas de gestión, se evalúa la confiabilidad, resiliencia y vulnerabilidad del sistema de agua para enfrentar la escasez de agua por el cambio climático.Esta tesis presenta algunas innovaciones metodológicas y empíricas sobre estudios previos sobre escasez de agua. El análisis hidroeconómico realizado aquí muestra la relevancia de la modelización integrada de los recursos hídricos para avanzar en la gestión sostenible a escala de cuenca. Los resultados sostenibles requieren información adecuada de los procesos complejos que subyacen al ciclo del agua en las cuencas, para una evaluación precisa de las compensaciones ambientales y económicas. La representación de los beneficios ambientales y de cambio climático realizada en esta investigación contribuye al fortalecimiento de la metodología de modelación hidroeconómica. Empíricamente, los resultados muestran la superioridad de la cooperación institucional para la gestión sostenible del agua, en relación con otras políticas como los mercados de agua o las inversiones en eficiencia del riego. La investigación informa sobre la contribución de las diferentes opciones de gestión del agua para reducir los riesgos de los impactos económicos y ambientales del cambio climático.The main objective of the thesis is developing an integrated hydroeconomic model of the Ebro basin for water policy analysis. The model is used to assess the impacts from droughts and water scarcity in the context of climate change. The results and policy implications can be used as guides for other semiarid and arid regions, facing similar water scarcity problems. The results provide information to stakeholders and decision makers on the impacts of droughts and climate change, and how different water management alternatives could contribute in addressing their effects. The sustainability of the Ebro water system is analyzed taking into account the reliability, resilience and vulnerability of the irrigation sector, together with the protection of water dependent ecosystems. Mathematical models that reproduce the temporal and spatial interactions of water use are the basis for hydroeconomic analysis. These models optimize and simulate water systems to identify trade-offs in water uses by sector and spatial location. Many water related problems can be examined, such as economic growth, water supply, climate change adaptation and mitigation, flood control damage or environmental flows. The enhancement of water system resilience, to reduce losses from water shortages, involves actions that include expanding dam storage, water reuse, seawater desalination, water pricing, and water trading. Hydro-economic analysis incorporates multiple disciplines such as biophysical processes, economic activities, or aquatic ecosystems in a framework capable of addressing the temporal and spatial dimensions of the water scarcity problem. In this regard, hydro-economic analysis can contribute to solve water scarcity problems, giving answers to water management concerns. The main investigation is displayed in three chapters (chapters 2 to 4), where hydroecomic analysis is used to address climate change and water management issues. The Ebro basin in Spain is our case of study, although findings could be useful for other arid and semi-arid basins with similar economic and climatic characteristics. The study compares water management alternatives and their contribution to the sustainability of the water system, by achieving both the protection human water security and ecosystem biodiversity from the impacts of water scarcity, droughts, and climate change. The findings in the Ebro could contribute to the water policy advancements in basins around the world facing water scarcity problems and worsening ecosystem degradation, such as basins in the Mediterranean region, the Middle East and Central Asia, Southwestern United States, or Australia. The first study in Chapter 2, presents the hydroeconomic model of the Ebro Basin. The integrated model links three components: the reduced form hydrological component, the regional economic component, and the environmental component. The reduced form hydrological component is calibrated by including non-observed variables to close the mass balance between estimated and observed stream flows. The economic regional component is calibrated with positive mathematical programming (PMP), reproducing the observed water and land use under baseline conditions. This method assumes that farmers maximize benefits from water and land use, and the first order conditions are used for calibration. The constraint of minimum environmental flow at the river mouth represents the environmental component. The model is used to analyze the spatial and sectoral distributions of water under drought conditions, comparing the economic instrument of water markets with the institutional instrument of stakeholders’ cooperation. Compliance with environmental flows in the river mouth is evaluated by taking different priorities for water allocation between upstream and downstream regions. Under alternative policies, the analysis identifies the impacts of droughts and water scarcity, and their distribution among regions and sectors. In Chapter 3, the use of water by ecosystems is included in the hydroeconomic model. Representing the benefits of ecosystems requires linking the health of ecosystems with hydrological variations, and also determining the economic value of the ecosystem services. The integration of environmental benefits into the hydroeconomic model is the method for capturing the interactions between private benefits (provided by economic activities) and public benefits (provided by ecosystems). The simulation of water distribution under drought conditions is used to evaluate water policies that combine economic and institutional instruments. The environmental component of the model links the benefits that ecosystems provided to society, the environmental status, and the stream flows that sustain the aquatic ecosystem. The relationship between environmental conditions and stream flows is established and calibrated by previous studies on the involved biophysical processes. The Ebro Basin Authority has used these studies to settle the minimum environmental flows in the basin. The environmental component includes the representation of health status and subsequent environmental benefits, covering the main sections of the river basin. This is an significant improvement over previous hydroeconomic literature, where the environmental representation is limited to certain parts and specific locations of rivers. The environmental representation captures the spatial interaction between water allocations for economic activities and for ecosystems. The hydroeconomic model has been used to analyze the trade-offs between private and public benefits provided by economic activities and ecosystems. The analysis of water management alternatives contributes to identify suitable water allocations that maintain the water system in good status. The third study in Chapter 4 is an enhancement of the hydroeconomic model presented in Chapter 2. The hydroeconomic model includes the temporal dimension, adding dynamic aspects to the model presented in Chapter 2, and the time step has been changed from yearly to montly. The main dams in the basin are included in the model, allowing the simulation and evaluation of water policy alternatives through multiple time periods. Dam capacity, water inflows into the basin, and dam operation and evaporation are some of the variables that incorporate the model to represent dams. The temporal scale of the hydroeconomic model is monthly, promoting the analysis of a variety of drought spells, from several months to multiple years. The hydroeconomic model compares the sustainability of the water system under changing climatic conditions. As a result of climate change, in arid and semi-arid areas, such as the Ebro basin, drought events will be more intense, frequent, and longer. Therefore, the economic and environmental impacts of droughts will be aggravated under these conditions. Climate change simulations rely on historic data, climate change projections, and on an advance method of water inflow simulation called Copulas. This method fits the joint distribution of two consecutive months to capture their interdependence. The advantage of this procedure is that it can generate stream flows that replicate historical and projected climatic conditions with long-lasting and more intense droughts. Uncertainty and risk related to drought and climate change are identified by the cumulative distribution functions of water availability and benefit losses. The analysis reveals the exposition of the water system to losses, and then alternative policies are considered for reducing the impacts of droughts and climate change. Under these management policies, the reliability, resilience, and vulnerability of the water system are evaluated to confront water scarcity from climate change. This thesis presents some methodological and empirical innovations over previous studies on water scarcity. The hydroeconomic analysis conducted here shows the relevance of the integrated modeling of water resources in order to advance sustainable management at basin scale. Sustainable outcomes require adequate information of the complex processes underlying the water cycle in basins, for an accurate assessment of the environmental and economic trade-offs. The representation of environmental benefits and climate change undertaken in this research contributes to the strengthening of the hydroeconomic modeling methodology. Empirically, the results show the superiority of institutional cooperation for sustainable water management, in relation to other policies such as water markets or investments in irrigation efficiency. The research informs about the contribution of different water management options in reducing the risks of economic and environmental impacts from climate change.<br /

Identification and Functional Analysis of a Novel CTNNB1 Mutation in Pediatric Medulloblastoma

Medulloblastoma is the primary malignant tumor of the Central Nervous System (CNS) most common in pediatrics. We present here, the histological, molecular, and functional analysis of a cohort of 88 pediatric medulloblastoma tumor samples. The WNT-activated subgroup comprised 10% of our cohort, and all WNT-activated patients had exon 3 CTNNB1 mutations and were immunostained for nuclear β-catenin. One novel heterozygous CTNNB1 mutation was found, which resulted in the deletion of β-catenin Ser37 residue (ΔS37). The ΔS37 β-catenin variant ectopically expressed in U2OS human osteosarcoma cells displayed higher protein expression levels than wild-type β-catenin, and functional analysis disclosed gain-of-function properties in terms of elevated TCF/LEF transcriptional activity in cells. Our results suggest that the stabilization and nuclear accumulation of ΔS37 β-catenin contributed to early medulloblastoma tumorigenesis.This work was funded by Asociación Pablo Ugarte APU (BC/A/14/015), Pequerropa (BC/A/15/010), and the childhood cancer support Platform from EITB Media, SAU (BIO13/CI/016/BC). R.P. was funded by Ministerio de Economía y Competitividad (Spain and Fondo Europeo de Desarrollo Regional, grant number SAF2016-79847-R). C.E.N.-X. was funded by Instituto de Salud Carlos III (Spain and the European Social Fund+, grant number: CP20/00008). P.A.-P. was supported by a Basque Government fellowship (PRE_2020_2_0116)

Lifestyle in Undergraduate Students and Demographically Matched Controls during the COVID-19 Pandemic in Spain

Few studies have used a multidimensional approach to describe lifestyle changes among undergraduate students during the COVID-19 pandemic or have included controls. This study aimed to evaluate lifestyle behaviors and mental health of undergraduate students and compare them with an age and sex-matched control group. A cross-sectional web survey using snowball sampling was conducted several months after the beginning of COVID-19 pandemic in Spain. A sample of 221 students was recruited. The main outcome was the total SMILE-C score. Students showed a better SMILE-C score than controls (79.8 + 8.1 vs. 77.2 + 8.3; p < 0.001), although these differences disappeared after controlling for covariates. While groups did not differ in the screenings of depression and alcohol abuse, students reported lower rates of anxiety (28.5% vs. 37.1%; p = 0.042). A lower number of cohabitants, poorer self-perceived health and positive screening for depression and anxiety, or for depression only were independently associated (p < 0.05) with unhealthier lifestyles in both groups. History of mental illness and financial difficulties were predictors of unhealthier lifestyles for students, whereas totally/moderate changes in substance abuse and stress management (p < 0.05) were predictors for the members of the control group. Several months after the pandemic, undergraduate students and other young adults had similar lifestyles

Analysis of the impact of social determinants and primary care morbidity on population health outcomes by combining big data: A research protocol

In recent years, different tools have been developed to facilitate analysis of social determinants of health (SDH) and apply this to health policy. The possibility of generating predictive models of health outcomes which combine a wide range of socioeconomic indicators with health problems is an approach that is receiving increasing attention. Our objectives are twofold: (1) to predict population health outcomes measured as hospital morbidity, taking primary care (PC) morbidity adjusted for SDH as predictors; and (2) to analyze the geographic variability of the impact of SDH-adjusted PC morbidity on hospital morbidity, by combining data sourced from electronic health records and selected operations of the National Statistics Institute (Instituto Nacional de Estadística/INE).MethodsThe following will be conducted: a qualitative study to select socio-health indicators using RAND methodology in accordance with SDH frameworks, based on indicators published by the INE in selected operations; and a quantitative study combining two large databases drawn from different Spain’s Autonomous Regions (ARs) to enable hospital morbidity to be ascertained, i.e., PC electronic health records and the minimum basic data set (MBDS) for hospital discharges. These will be linked to socioeconomic indicators, previously selected by geographic unit. The outcome variable will be hospital morbidity, and the independent variables will be age, sex, PC morbidity, geographic unit, and socioeconomic indicators.AnalysisTo achieve the first objective, predictive models will be used, with a test-and-training technique, fitting multiple logistic regression models. In the analysis of geographic variability, penalized mixed models will be used, with geographic units considered as random effects and independent predictors as fixed effects.DiscussionThis study seeks to show the relationship between SDH and population health, and the geographic differences determined by such determinants. The main limitations are posed by the collection of data for healthcare as opposed to research purposes, and the time lag between collection and publication of data, sampling errors and missing data in registries and surveys. The main strength lies in the project’s multidisciplinary nature (family medicine, pediatrics, public health, nursing, psychology, engineering, geography)

Dendritic Cell‐Mediated Cross‐Priming by a Bispecific Neutralizing Antibody Boosts Cytotoxic T Cell Responses and Protects Mice against SARS‐CoV‐2

SARS-CoV-2 B.1.351 and B.1.167.2 viruses used in this study were obtained through the European Virus Archive Global (EVA-GLOBAL) project that has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 653316. SARS-CoV-2 B.1 (MAD6 isolate) was kindly provided by José M. Honrubia and Luis Enjuanes (CNB-CSIC, Madrid, Spain). The authors thank Centro de Investigación en Sanidad Animal (CISA)-Instituto Nacional de Investigaciones Agrarias (INIA-CSIC) (Valdeolmos, Madrid, Spain) for the BSL-3 facilities. Research in LAV laboratory was funded by the BBVA Foundation (Ayudas Fundación BBVA a Equipos de Investigación Científica SARS-CoV-2 y COVID19); the MCIN/AEI/10.13039/501100011033 (PID2020-117323RB-I00 and PDC2021-121711-I00), partially supported by the European Regional Development Fund (ERDF); the Carlos III Health Institute (ISCIII) (DTS20/00089), partially supported by the ERDF, the Spanish Association Against Cancer (AECC 19084); the CRIS Cancer Foundation (FCRISIFI-2018 and FCRIS-2021-0090), the Fundación Caixa-Health Research (HR21-00761 project IL7R_LungCan), and the Comunidad de Madrid (P2022/BMD-7225 NEXT_GEN_CART_MAD-CM). Work in the DS laboratory was funded by the CNIC; the European Union’s Horizon 2020 research and innovation program under grant agreement ERC-2016-Consolidator Grant 725091; MCIN/AEI/10.13039/501100011033 (PID2019-108157RB); Comunidad de Madrid (B2017/BMD-3733 Immunothercan-CM); Atresmedia (Constantes y Vitales prize); Fondo Solidario Juntos (Banco Santander); and “La Caixa” Foundation (LCF/PR/HR20/00075). The CNIC was supported by the ISCIII, the MCIN and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (CEX2020- 001041-S funded by MCIN/AEI/10.13039/501100011033). Research in RD laboratory was supported by the ISCIII (PI2100989) and CIBERINFEC; the European Commission Horizon 2020 Framework Programme (grant numbers 731868 project VIRUSCAN FETPROACT-2016, and 101046084 project EPIC-CROWN-2); and the Fundación CaixaHealth Research (grant number HR18-00469 project StopEbola). Research in CNB-CSIC laboratory was funded by Fondo Supera COVID19 (Crue Universidades-Banco Santander) grant, CIBERINFEC, and Spanish Research Council (CSIC) grant 202120E079 (to J.G.-A.), CSIC grant 2020E84 (to M.E.), MCIN/AEI/10.13039/501100011033 (PID2020- 114481RB-I00 to J.G-A. and M.E.), and by the European CommissionNextGenerationEU, through CSIC’s Global Health Platform (PTI Salud Global) to J.G.-A. and M.E. Work in the CIB-CSIC laboratory was supported by MCIN/AEI/10.13039/501100011033 (PID2019-104544GB-I00 and 2023AEP105 to CA, and PID2020-113225GB-I00 to F.J.B.). Cryo-EM data were collected at the Maryland Center for Advanced Molecular Analyses which was supported by MPOWER (The University of Maryland Strategic Partnership). I.H.-M. receives the support of a fellowship from la Caixa Foundation (ID 100010434, fellowship code: LCF/BQ/IN17/11620074) and from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 71367. L.R.-P. was supported by a predoctoral fellowship from the Immunology Chair, Universidad Francisco de Vitoria/Merck.S

Amber in Portugal: state of the art

XXXIV Jornadas de Paleontología y IV Congreso Ibérico de Paleontología (Villareal, Portugal. Sep 2018) p 279-287Portuguese amber has received very little attention from the paleontological and geological points of view. To our knowledge, only twelve amber outcrops or amber-bearing areas have been detected in Portugal. The first outcrops were cited in times as old as 1867 and 1910, and although some of them were considered Jurassic in age, most likely the amber came from Cretaceous deposits. The Portuguese outcrops are poor in amber and, thus far, only a dipteran (Nematocera) insect has been found as bioinclusion (Cascais amber); the area of Estoril-Cascais, near Lisbon, provides amber interesting from the paleoentomological standpoint. In contrast, prehistoric amber from Portugal, namely as diverse types of beads and pendants, has been researched in some detail during the last decades. The 25 archeological localities known occur from north to south, ranging in ages from the Neolithic through the Chalcolithic to the Late Bronze Age. Further research is required to prospect the known paleontological localities, and also to look for new ones, in order to obtain stratigraphically contextualized samples and to perform the first infrared and/or Raman spectroscopy analyses. This will allow comparing these with the infrared and/or Raman spectra of archeological pieces to shed light on the origin of the amber as a raw material during prehistoric times. The potential discovery of a paleontological locality yielding abundant bioinclusions would be of great interest, as it would allow taxonomic and paleoecological comparisons with the rich Cretaceous outcrops from the north and northeastern Iberian PeninsulaMuseo Geominero, Instituto Geológico y Minero de EspañaDepartament de Dinàmica de la Terra i del Oceà and Institut de Recerca de la Biodiversitat (IRBio). Facultat de Ciències de laTerra. Universitat de BarcelonaDepartamento de Prehistoria, Historia Antigua y Arqueología. Universidad de SalamancaDepartamento de Biodiversidad, Ecología y Evolución, Facultad de Biología, Universidad ComplutenseMuseo de Ciencias Naturales de ÁlavaDepartamento de Prehistoria y Arqueología, Universidad de GranadaOxford University Museum of Natural HistoryInstitute of Environmental Science and Technology (ICTA)Facultad de Ciencias, Universidad Autónoma de MadridDepartamento de História, Estudos Europeus, Arqueologia e Artes, Faculdade de Letras, Universidade de Coimbra, Instituto de Arqueologi

Adoptive NK cell transfer as a treatment in colorectal cancer patients: analyses of tumour cell determinants correlating with efficacy in vitro and in vivo

6 figures.-- Supplementary material available.Background: Colorectal cancer (CRC) is a heterogeneous disease with variable mutational profile and tumour microenvironment composition that influence tumour progression and response to treatment. While chemoresistant and poorly immunogenic CRC remains a challenge, the development of new strategies guided by biomarkers could help stratify and treat patients. Allogeneic NK cell transfer emerges as an alternative against chemoresistant and poorly immunogenic CRC.Methods: NK cell-related immunological markers were analysed by transcriptomics and immunohistochemistry in human CRC samples and correlated with tumour progression and overall survival. The anti-tumour ability of expanded allogeneic NK cells using a protocol combining cytokines and feeder cells was analysed in vitro and in vivo and correlated with CRC mutational status and the expression of ligands for immune checkpoint (IC) receptors regulating NK cell activity.Results: HLA-I downmodulation and NK cell infiltration correlated with better overall survival in patients with a low-stage (II) microsatellite instability-high (MSI-H) CRC, suggesting a role of HLA-I as a prognosis biomarker and a potential benefit of NK cell immunotherapy. Activated allogeneic NK cells were able to eliminate CRC cultures without PD-1 and TIM-3 restriction but were affected by HLA-I expression. In vivo experiments confirmed the efficacy of the therapy against both HLA+ and HLA− CRC cell lines. Concomitant administration of pembrolizumab failed to improve tumour control.Conclusions: Our results reveal an immunological profile of CRC tumours in which immunogenicity (MSI-H) and immune evasion mechanisms (HLA downmodulation) favour NK cell immunosurveillance at early disease stages. Accordingly, we have shown that allogeneic NK cell therapy can target tumours expressing mutations conferring poor prognosis regardless of the expression of T cell-related inhibitory IC ligands. Overall, this study provides a rationale for a new potential basis for CRC stratification and NK cell-based therapy.Work in the JP laboratory is funded by ASPANOA, CIBER (CB 2021; Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación and Union Europea.NextGenerationEU), Fundacion Inocente, Carrera de la Mujer Monzón, FEDER/Gobierno de Aragón (Group B29_17R), and Ministerio de Ciencia, Innovación e Universidades (MCNU), Agencia Estatal de Investigación (SAF2017‐83120‐C2‐1‐R and PID2020-113963RB-I00). Predoctoral grants/contracts from Gobierno de Aragon (IU-M and JP) are supported by ARAID Foundation. EG is funded by Ministerio de Ciencia, Innovación y Universidades (MCNU), and Agencia Estatal de Investigación (PID2020-113963RB-I00). MA and LS are funded by Postdoctoral Juan de la Cierva Contract. SR, LC, SH, and IU-M are funded by predoctoral contracts from Aragon Government. PL is funded by FPU predoctoral grants from Ministerio de Ciencia, Innovación e Universidades. Work at the Catalan Institute of Oncology is funded by the entity, the Instituto de Salud Carlos III and Ministerio de Economia y Competitividad, and co-funded by FEDER funds—a way to build Europe (PI20/00767), CIBERESP (grant CB07/02/2005), H2020 grant MoTriColor, and the Agency for Management of University and Research Grants (AGAUR) of the Catalan Government grant 2017SGR723. This work is supported by COST Action CA17118.Peer reviewe

EstuPlan: Methodology for the development of creativity in the resolution of scientific and social problems

[EN] Creative thinking is necessary to generate novel ideas and solve problems. "EstuPlan" is a methodology in which knowledge and creativity converge for the resolution of scientific problems with social projection. It is a training programme that integrates teachers, laboratory technicians and PhD students, master and undergraduate students which form working groups for the development of projects. Projects have a broad and essential scope and projection in terms of environmental problems, sustainable use of natural resources, food, health, biotechnology or biomedicine. The results show the success of this significant learning methodology using tools to develop creativity in responding to scientific and social demand for problem-solving to transfer academic knowledge to different professional environments. Bioplastics, Second Life of Coffee, LimBio, Algae oils, Ecomers, Caring for the life of your crop and Hate to Deforestate are currently being developed.Astudillo Calderón, S.; De Díez De La Torre, L.; García Companys, M.; Ortega Pérez, N.; Rodríguez Martínez, V.; Alzahrani, S.; Alonso Valenzuela, R.... (2019). EstuPlan: Methodology for the development of creativity in the resolution of scientific and social problems. En HEAD'19. 5th International Conference on Higher Education Advances. Editorial Universitat Politècnica de València. 711-717. https://doi.org/10.4995/HEAD19.2019.9205OCS71171