AMPK activation by oncogenesis is required to maintain cancer cell proliferation in astrocytic tumors

5'-AMP-activated protein kinase (AMPK) is an energy sensor that controls cell metabolism, and it has been related to apoptosis and cell-cycle arrest. Although its role in metabolic homeostasis is well documented, its function in cancer is much less clear. In this study, we examined the role of AMPK in a mouse model of astrocytoma driven by oncogenic H-Ras(V12) and/or with PTEN deletion based on the common constitutive activation of the Raf/MEK/ERK and PI3K/AKT cascades in human astrocytomas. We also evaluated the activity and role of AMPK in human glioblastoma cells and xenografts. AMPK was constitutively activated in astrocytes expressing oncogenic H-Ras(V12) in parallel with high cell division rates. Genetic deletion of AMPK or attenuation of its activity in these cells was sufficient to reduce cell proliferation. The levels of pAMK were always related to the levels of phosphorylated retinoblastoma (Rb) at Ser804, which may indicate an AMPK-mediated phosphorylation of Rb. We confirmed this AMPK-Rb relationship in human glioblastoma cell lines and xenografts. In clinical specimens of human glioblastoma, elevated levels of activated AMPK appeared especially in areas of high proliferation surrounding the blood vessels. Together, our findings indicate that the initiation and progression of astrocytic tumors relies upon AMPK-dependent control of the cell cycle, thereby identifying AMPK as a candidate therapeutic target in this setting

Terapia de exposición: revisión sistemática sobre su eficacia en la reducción del miedo y la ansiedad en personas con fobias específicas.

Esta revisión sistemática tiene como objetivo evaluar si la técnica de exposición puede ser eficaz para la reducción del miedo y la ansiedad en personas con diagnóstico de fobias específicas. Con dicho fin se realizó una búsqueda sistemática de ensayos controlados aleatorizados en PubMed y PsycINFO (EBSCOhost). Finalmente, se incluyeron 8 estudios con un riesgo de sesgo alto, bajo o poco claro en varias dimensiones. La evidencia revisada muestra cómo la terapia de exposición sí es eficaz como tratamiento, encontrando resultados significativamente sólidos a favor de la utilización de dicha técnica. Incluso, ha resultado eficaz desde diferentes modalidades (in vivo, realidad virtual, con o sin orientación terapéutica, con o sin conductas de seguridad asociadas) y ha resaltado su eficacia frente a otros tipos de técnicas empleadas con el mismo fin. Los resultados son lo suficientemente sólidos como para poder tener una conclusión contundente. Sin embargo, se necesitan más ensayos controlados aleatorizados de la técnica para obtener un resultado aún más contundente.This systematic review aims to assess whether the exposure technique can be effective in reducing fear and anxiety in people diagnosed with specific phobias. For this purpose, a systematic search for randomised controlled trials was conducted in PubMed and PsycINFO (EBSCOhost). Finally, 8 studies with a high, low or unclear risk of bias on several dimensions were included. The evidence reviewed shows that exposure therapy is indeed effective as a treatment, finding significantly strong results in favour of the use of this technique. It has even been found to be effective in different modalities (in vivo, virtual reality, with or without therapeutic guidance, with or without associated safety behaviours) and has highlighted its efficacy compared to other types of techniques used for the same purpose. The results are sufficiently robust to be able to draw a strong conclusion. However, more randomised controlled trials of the technique are needed to obtain an even stronger result

Combining offshore wind and solar photovoltaic energy to stabilize energy supply under climate change scenarios: a case study on the western Iberian Peninsula

The expansion of marine renewable power is a major alternative for the reduction of greenhouse gases emissions. In Europe, however, the high penetration of offshore wind brings intermittency and power variability into the existing power grid. Offshore solar photovoltaic power is another technological alternative under consideration in the plans for decarbonization. However, future variations in wind, air temperature or solar radiation due to climate change will have a great impact on both renewable energy resources. In this context, this study focusses on the offshore energy assessment off the coast of Western Iberia, a European region encompassing Portugal and the Northwestern part of Spain. Making use of a vast source of data from 35 simulations of a research project called CORDEX, this study investigates the complementarity of offshore wind and solar energy sources with the aim of improving the energy supply stability of this region up to 2040. Although the offshore wind energy resource has proven to be higher than solar photovoltaic resource at annual scale, both renewable resources showed significant spatiotemporal energy variability throughout the western Iberian Peninsula. When both renewable resources are combined, the stability of the energy resource increased considerably throughout the year. The proposed wind and solar combination scheme is assessed by a performance classification method called Delphi, considering stability, resource, risk, and economic factors. The total index classification increases when resource stability is improved by considering hybrid offshore wind-photovoltaic solar energy production, especially along the nearshore waterX. Costoya is supported by the Spanish Government through a Juan de la Cierva Postdoctoral Fellowship (FJCI-2017-32577). This work was partially supported by Xunta de Galicia under project ED431C 2021/44 (Grupos de Referencia Competitiva) and Ministry of Science and Innovation of the Government of Spain under the project SURVIWEC PID2020-113245RB-I00. D. Carvalho acknowledges the Portuguese Foundation for Science and Technology (FCT) for his researcher contract (CEECIND/01726/2017) and the FCT/MCTES for the financial support to CESAM (UIDP/50017/2020+UIDB/50017/2020), through national fundsS

From neural stem cells to glioblastoma: A natural history of GBM recapitulated in vitro

Due to its aggressive and invasive nature glioblastoma (GBM), the most common and aggressive primary brain tumour in adults, remains almost invariably lethal. Significant advances in the last several years have elucidated much of the molecular and genetic complexities of GBM. However, GBM exhibits a vast genetic variation and a wide diversity of phenotypes that have complicated the development of effective therapeutic strategies. This complex pathogenesis makes necessary the development of experimental models that could be used to further understand the disease, and also to provide a more realistic testing ground for potential therapies. In this report, we describe the process of transformation of primary mouse embryo astrocytes into immortalized cultures with neural stem cell characteristics, that are able to generate GBM when injected into the brain of C57BL/6 mice, or heterotopic tumours when injected IV. Overall, our results show that oncogenic transformation is the fate of NSC if cultured for long periods in vitro. In addition, as no additional hit is necessary to induce the oncogenic transformation, our model may be used to investigate the pathogenesis of gliomagenesis and to test the effectiveness of different drugs throughout the natural history of GBMThis study was supported in part by Xunta de Galicia (2014-PG029), University of Santiago de Compostela (2018-PU001), Ministerio de Economía y Competitividad (PI15/01129, José A. Costoya), the Centro Singular de Investigación de Galicia accreditation 2016–2019, ED431G/05), and the European Regional Development Fund (ERDF)S

PARP1 Deficiency Reduces Tumour Growth by Decreasing E2F1 Hyperactivation: A Novel Mechanism in the Treatment of Cancer

In recent years, poly (ADP-ribose) polymerase (PARP) inhibitors have been evaluated for treating homologous recombination-deficient tumours, taking advantage of synthetic lethality. However, increasing evidence indicates that PARP1 exert several cellular functions unrelated with their role on DNA repair, including function as a co-activator of transcription through protein-protein interaction with E2F1. Since the RB/E2F1 pathway is among the most frequently mutated in many tumour types, we investigated whether the absence of PARP activity could counteract the consequences of E2F1 hyperactivation. Our results demonstrate that genetic ablation of Parp1 extends the survival of Rb-null embryos, while genetic inactivation of Parp1 results in reduced development of pRb-dependent tumours. Our results demonstrate that PARP1 plays a key role as a transcriptional co-activator of the transcription factor E2F1, an important component of the cell cycle regulation. Considering that most oncogenic processes are associated with cell cycle deregulation, the disruption of this PARP1-E2F1 interaction could provide a new therapeutic target of great interest and a wide spectrum of indicationsThis work received financial support from the Ministerio de Ciencia e Innovación (SAF2008-00543 and SAF2009-08629; J.A.C.) and ISCIII, Ministerio de Economía y Competitividad (PI15/01129), the Consellería de Cultura, Educación e Ordenación Universitaria (GPC2014/030, INCITE08PXIB208091PR and PXIB208091PR; J.A.C.), PRE/2011/131 (I.G.C.), the Centro Singular de Investigación de Galicia accreditation 2016–2019, ED431G/05), and the European Regional Development Fund (ERDF)S

Increased Medial Temporal Tau Positron Emission Tomography Uptake in the Absence of Amyloid-β Positivity

IMPORTANCE: An increased tau positron emission tomography (PET) signal in the medial temporal lobe (MTL) has been observed in older individuals in the absence of amyloid-β (Aβ) pathology. Little is known about the longitudinal course of this condition, and its association with Alzheimer disease (AD) remains unclear. OBJECTIVE: To study the pathologic and clinical course of older individuals with PET-evidenced MTL tau deposition (TMTL+) in the absence of Aβ pathology (A-), and the association of this condition with the AD continuum. DESIGN, SETTING, AND PARTICIPANTS: A multicentric, observational, longitudinal cohort study was conducted using pooled data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain Study (HABS), and the AVID-A05 study, collected between July 2, 2015, and August 23, 2021. Participants in the ADNI, HABS, and AVID-A05 studies (N = 1093) with varying degrees of cognitive performance were deemed eligible if they had available tau PET, Aβ PET, and magnetic resonance imaging scans at baseline. Of these, 128 participants did not meet inclusion criteria based on Aβ PET and tau PET biomarker profiles (A+ TMTL-). EXPOSURES: Tau and Aβ PET, magnetic resonance imaging, cerebrospinal fluid biomarkers, and cognitive assessments. MAIN OUTCOMES AND MEASURES: Cross-sectional and longitudinal measures for tau and Aβ PET, cortical atrophy, cognitive scores, and core AD cerebrospinal fluid biomarkers (Aβ42/40 and tau phosphorylated at threonine 181 p-tau181 available in a subset). RESULTS: Among the 965 individuals included in the study, 503 were women (52.1%) and the mean (SD) age was 73.9 (8.1) years. A total of 51% of A- individuals and 78% of A+ participants had increased tau PET signal in the entorhinal cortex (TMTL+) compared with healthy younger (aged <39 years) controls. Compared with A- TMTL-, A- TMTL+ participants showed statistically significant, albeit moderate, longitudinal (mean [SD], 1.83 [0.84] years) tau PET increases that were largely limited to the temporal lobe, whereas those with A+ TMTL+ showed faster and more cortically widespread tau PET increases. In contrast to participants with A+ TMTL+, those with A- TMTL+ did not show any noticeable Aβ accumulation over follow-up (mean [SD], 2.36 [0.76] years). Complementary cerebrospinal fluid analysis confirmed longitudinal p-tau181 increases in A- TMTL+ in the absence of increased Aβ accumulation. Participants with A- TMTL+ had accelerated MTL atrophy, whereas those with A+ TMTL+ showed accelerated atrophy in widespread temporoparietal brain regions. Increased MTL tau PET uptake in A- individuals was associated with cognitive decline, but at a significantly slower rate compared with A+ TMTL+. CONCLUSIONS AND RELEVANCE: In this study, individuals with A- TMTL+ exhibited progressive tau accumulation and neurodegeneration, but these processes were comparably slow, remained largely restricted to the MTL, were associated with only subtle changes in global cognitive performance, and were not accompanied by detectable accumulation of Aβ biomarkers. These data suggest that individuals with A- TMTL+ are not on a pathologic trajectory toward AD

Aprovechamiento de la energía undimotriz a lo largo de la costa gallega

Ponencia presentada en: XII Congreso de la Asociación Española de Climatología celebrado en Santiago de Compostela entre el 19 y el 21 de octubre de 2022.[ES]Se ha calculado el recurso undimotriz a lo largo de la costa gallega (noroeste de España) durante el periodo 2014-2021 usando datos horarios de alta resolución espacial procedentes del modelo Simulating WAves Nearshore (SWAN). Además, se analizó la potencia eléctrica (PE) y el rendimiento que puede obtenerse del conversor de energía undimotriz (WEC) Wave Dragon. El rendimiento del Wave Dragon se calculó atendiendo a dos parámetros: el factor de carga de potencia (ε) y el ancho de captura normalizado respecto a la geometría del WEC (eficiencia). Los resultados muestran que el recurso undimotriz es menor que 10 kWm-1 cerca de la costa, pero aumenta hasta 55 kWm-1 en mar abierto. Wave Dragon presenta valores de PE menores a 500 kW en el interior de las rías y ~2200 kW en mar abierto. Además, alcanza valores de 25−30% en la costa noroeste y la eficiencia alcanza hasta el 40% en la costa oeste. Debido a su profundidad óptima de operación y a los resultados obtenidos, Wave Dragon parece ser una buena opción para aprovechar la energía undimotriz en la costa gallega.[EN]The wave power resource (WP) has been calculated along the Galician coast (NW Spain) over the period 2014-2021 using high spatial resolution hourly data from the Simulating Waves Nearshore (SWAN) model. In addition, the electrical power energy (PE) that can be extracted for the Wave Dragon wave energy converter (WEC) was analyzed. The performance of Wave Dragon has also been calculated attending to two parameters: the power load factor (ε) and the normalized capture width with respect to the WEC’s geometry (efficiency). Results show that the WP resource is lower than 10 kWm-1 onshore but it increases to about 55 kWm-1 offshore. Wave Dragon presents PE values less than 500 kW inside the estuaries and ~2200 kW offshore. Additionally, ε reaches values of 25−30% on the Northwest Coast and the efficiency reaches up to 40% on the West Coast. Due to its optimum operating depth and the results obtained, Wave Dragon seems to be a good option to implement wave energy on the Galician coast

LiDAR-photogrammetry coverage, bathymetry and infrastructures survey to support flood risk analysis in the Genil River sub-basin

[EN] Floods are the natural disasters that affect the most people in the Atlantic Area. In this sense, the AA-Floods project is developed with the objective of developing and highlighting new tools, plans and regulations that improve the management and response to floods. The importance of quality altimetric information for the evaluation of flood danger is based on the fact that it requires knowledge, as detailed and precise as possible, of the relief and the heights of the elements located above the ground. To this end, the acquisition of LIDAR coverage with a density of 21 points/m² and photogrammetric coverage has been carried out to obtain Orthophotographs of 0.10 m for the generation of altimetric products with great positional accuracy and high precision in the study areas of the Genil River basin. Likewise, the bathymetric survey of the Genil River bed has been carried out and the final Topobathymetric Model has been obtained. Furthermore, for the adequate development of hydraulic modeling and determination of flood zones, it is necessary to take into consideration all those structural elements close to the channel that affect flood risk. To achieve this, a combination of geomatic techniques has been used: Classic Topography, GNSS, Lasergrammetry (LST) and Drone Photogrammetry. Analysis of flood areas has been carried out with these improved information sources, contrasting them with analysis of information sources used by the National Mapping System of flood areas. The flood sheet results for the different return periods have been contrasted with the 2010 flood sheets mapped by direct observation using Satellite Radar (SAR) technology.[ES] Las inundaciones son los desastres naturales que afectan a más personas en el Área Atlántica. En este sentido, el proyecto AA-Floods tiene el objetivo de desarrollar y poner en valor nuevas herramientas, planes y regulaciones que mejoren la gestión y la respuesta a las inundaciones. La importancia de la información altimétrica de calidad para la evaluación del peligro de inundación se basa en el conocimiento lo más detallado y preciso posible del relieve y de las alturas de los elementos situados sobre el suelo. Para ello se ha llevado a cabo una cobertura LiDAR de densidad 21 ptos/m² y fotogramétrica de resolución 0,10 m para la generación de productos altimétricos de gran exactitud posicional y alta precisión en los ámbitos de estudio de la cuenca del río Genil. Así mismo, se ha realizado el levantamiento batimétrico del cauce del río Genil y la obtención de Modelo final Topobatimétrico. Además, para el desarrollo adecuado de la modelización hidráulica y determinación de zonas inundables es necesario tomar en consideración todos aquellos elementos estructurales del cauce que afectan a la inundabilidad. Se ha realizado análisis de zonas inundables con estas fuentes de información que mejoran las utilizadas por el SNCZI. Los resultados se han contrastado con las láminas de inundación de 2010 cartografiadas mediante observación directa mediante satélite Radar.Este trabajo se ha financiado por el proyecto EAPA_45/2018_AA-FLOODS. Universidade da Coruña, Grupo de Ingeniería del Agua y del Medio Ambiente, Departamento de Ingeniería Civil, ETSICCP Agencia de Medio Ambiente y Agua. Junta de Andalucía Secretaría General de Sostenibilidad, Medio Ambiente y Economía Azul. Consejería de Sostenibilidad, Medio Ambiente y Economía Azul. Junta de Andalucía.Vales-Bravo, JJ.; Méndez-Caballero, EM.; Prieto-Molina, R.; Granado-Ruíz, L.; Pino-Serrato, I.; Sañudo-Costoya, E.; García-Alén Lores, G.... (2024). Cobertura LiDAR-Fotogramétrica, batimetría y levantamiento de infraestructuras como soporte al análisis de riesgos de inundación en la subcuenca del río Genil. Revista de Teledetección. (63):79-97. https://doi.org/10.4995/raet.2024.2048179976

NK Cell-Based Glioblastoma Immunotherapy

Glioblastoma (GB) is the most aggressive and most common malignant primary brain tumor diagnosed in adults. GB shows a poor prognosis and, unfortunately, current therapies are unable to improve its clinical outcome, imposing the need for innovative therapeutic approaches. The main reason for the poor prognosis is the great cell heterogeneity of the tumor mass and its high capacity for invading healthy tissues. Moreover, the glioblastoma microenvironment is capable of suppressing the action of the immune system through several mechanisms such as recruitment of cell modulators. Development of new therapies that avoid this immune evasion could improve the response to the current treatments for this pathology. Natural Killer (NK) cells are cellular components of the immune system more difficult to deceive by tumor cells and with greater cytotoxic activity. Their use in immunotherapy gains strength because they are a less toxic alternative to existing therapy, but the current research focuses on mimicking the NK attack strategy. Here, we summarize the most recent studies regarding molecular mechanisms involved in the GB and immune cells interaction and highlight the relevance of NK cells in the new therapeutic challenges