Integrating stakeholders' inputs to co-design climate resilience adaptation measures in Mediterranean areas with conflicts between wetland conservation and intensive agriculture

[EN] Designing sustainable management strategies in groundwater-dependent socio-economic systems in areas with scarce water resources and protected wetlands is a challenging issue. The high vulnerability of these systems to droughts will be exacerbated even further under future climate change (CC) and socio-economic scenarios. A novel integrated bottom-up/top-down approach is used to identify “climate resilient pathways”, from which to co-design adaptation strategies to reduce the impact of potential future CC and socio-economic scenarios. The approach followed two steps (1) the generation of local CC and socio-economic scenarios by downscaling global/regional climate models and (2) the identification and assessment of potential adaptation strategies through an iterative bottom-up/top-down approach. Top-down assessments of the impact of CC have been undertaken by propagating local scenarios within a chain of mathematical models based on expert criteria/assumptions. This allowed us to analyse of the physical vulnerability of the system under different potential CC and socio-economic scenarios by simulating them with a sequential modelling of rainfall–recharge, agriculture, and hydrological processes through a distributed groundwater finite difference model. These model results were discussed with the stakeholders at a first workshop, which aimed to identify potential adaptation strategies. The influence of the adaptation strategies on the future hydrological status was assessed by simulating them through the chain of models. These results were the inputs into the discussions at a second workshop, which aimed to validate and/or improve the results of the first workshop. The methodology was applied in the Upper Guadiana River Basin, where there is a long-standing conflict between wetland conservation and groundwater overexploitation for intensive agriculture. The future horizon 2016–2045 is analysed with the scenarios compatible with the emission scenario RCP4.5. The research has allowed us to conclude that groundwater pumping reduction would be the most robust and effective measure to reduce the impact of CC in the area.This research was partially supported by the research projects SIGLO-AN (RTI2018-101397-B-I00) and SIGLO-PRO (PID2021-128021OB-I00) from the Spanish Ministry of Science, Innovation and Universities (Programa Estatal de ICDCI orientado a los Retos de la Sociedad), the GeoE.171.008-TACTIC Project funded by European Union's Horizon 2020 - Research and Innovation Framework Programme, and the NextGenerationEU Fund through the programme “Fondos de Recuperación”.Peer reviewe

La arquitectura y el urbanismo del Campus de la Universidad de Alicante como recurso a[tra]ctivo

Es evidente que uno de los principales recursos con los que cuenta la Universidad de Alicante es su Campus, no solo el de San Vicente del Raspeig sino también y además la constelación de Sedes Universitarias y Estaciones Científicas que lo componen. La calidad de sus edificios, todos ellos dignísimos para el fin al que sirven y algunos sencillamente magníficas obras de arquitectura, tanto las de nueva planta como las históricas que albergan las Sedes; la ordenación ejemplar de sus espacios libres donde la vegetación es, por derecho propio, protagonista indiscutible de un proyecto paisajístico modélico; o las esculturas, placas y homenajes y donaciones, embajadas y mecenazgos que salpican el espacio público dotándolo de identidad y cualificándolo, componen un conjunto notable poseedor de un enorme atractivo para la vida de la comunidad universitaria, para sus visitantes y para sus posibles futuros habitantes (nuevos estudiantes, PDI y PAS). El presente proyecto tiene como objetivo poner en valor todo ese patrimonio mediante su conocimiento y difusión a través de diversos canales que pretenden llegar al mayor público posible desde el rigor de la investigación y el atractivo de la presentación de sus resultados

Inhibición de HSP90 como nueva estrategia antitumoral contra el cáncer de páncreas exocrino y el cáncer de colon y recto

El cáncer de páncreas es un tipo de tumor de baja incidencia, pero la mayoría de pacientes no sobreviven a la enfermedad. En el caso del cáncer colorrectal, hay muchos más pacientes que sobreviven, gracias en parte a la detección temprana, pero su incidencia en la población es muy alta y algunos casos son diagnosticados en estadios avanzados de la enfermedad. La búsqueda de nuevas terapias eficaces, capaces de incrementar la supervivencia a estas enfermedades, es un reto de la investigación oncológica.El uso de la proteína de choque térmico 90 (HSP90) como diana farmacológica ha surgido en los últimos años como una posible terapia antineoplásica prometedora. Esta chaperona está involucrada en el mantenimiento de la homeostasis celular, participando en procesos post-traduccionales, como el plegamiento, la translocación o activación de múltiples proteínas conocidas como proteínas "clientes". Muchas de estas proteínas "clientes" son parte clave en el desarrollo, proliferación, invasión y supervivencia de los tumores. Por este motivo, se pensó en el empleo de inhibidores de HSP90 sería una ventajosa estrategia antitumoral, ya que el incorrecto funcionamiento de HSP90 puede alterar simultáneamente numerosas proteínas con un importante función en las células tumorales. En este trabajo, se ha investigado el efecto de dos inhibidores de HSP90 diferentes. Por un lado, hemos estudiado los efectos de un inhibidor de HSP90 de primera generación, llamado 17-AAG o tanespimicina, y por otro, hemos investigado los efectos de un nuevo inhibidor sintético, llamado NVP-AUY922. Ambos tienenun mecanismo de acción común, que consiste en impedir el intercambio ADP/ATP necesario para que HSP90 pueda ejercer su acción, uniéndose de forma potente y selectiva al sitio de unión de ATP. La evaluación de 17-AAG y NVP-AUY922 como agentes antitumorales ha sido realizada en dos modelos celulares de tumores gastrointestinales. Para ello se han utilizado líneas celulares humanas de cáncer de páncreas exocrino y de cáncer colorrectal. Además, se dispuso de cultivos primarios obtenidos de tumores colorrectales extirpados a pacientes. En resumen, los experimentos realizados han mostrado que NVP-AUY922 tiene un potente efecto antitumoral in vitro, por encima de los efectos producidos por 17-AAG, en modelos celulares de cáncer de páncreas y de cáncer colorrecta

PDGFR and IGF-1R Inhibitors Induce a G2/M Arrest and Subsequent Cell Death in Human Glioblastoma Cell Lines

Glioblastomas are highly resistant to radiation and chemotherapy. Currently, there are no effective therapies for this type of tumor. Signaling mechanisms initiated by PDGFR and IGF-1R are important in glioblastoma, and inhibition of the signal transduction pathways initiated by these receptors could be a useful alternative strategy for glioblastoma treatment. We have studied the effects of the PDGFR inhibitor JNJ-10198409 (JNJ) and the IGF-1R inhibitor picropodophyllin (PPP) in glioblastoma cell lines as well as in primary cultures derived from patients affected by this type of tumor. JNJ and PPP treatment blocked PDGFR and IGF-1R signaling respectively and reduced Akt and Erk 1/2 phosphorylation. Both inhibitors diminished cell proliferation, inducing a G2/M block of the cell cycle. Cell death induced by JNJ was caspase-dependent, Annexin-V positive and caused PARP cleavage, especially in T98 cells, suggesting an apoptotic mechanism. However, cell death induced by PPP was not completely inhibited by caspase inhibitors in all cell lines apart from LN-229 cells, indicating a caspase-independent mechanism. Several inhibitors targeted against different cell death pathways could not block this caspase-independent component, which may be a non-programmed necrotic mechanism. Apoptotic arrays performed in T98 and LN-229 cells upon JNJ and PPP treatment revealed that procaspase 3 levels were augmented by both drugs in T98 cells and only by JNJ in LN229-cells. Furthermore, XIAP and survivin levels were much higher in LN-229 cells than in T98 cells, revealing that LN-229 cells are more susceptible to undergo caspase-independent cell death mechanisms. JNJ and PPP combination was more effective than each treatment alone

Resistance to Selumetinib (AZD6244) in Colorectal Cancer Cell Lines is Mediated by p70S6K and RPS6 Activation

Selumetinib (AZD6244, ARRY-142886) is a MEK1/2 inhibitor that has gained interest as an anti-tumour agent. We have determined the degree of sensitivity/resistance to Selumetinib in a panel of colorectal cancer cell lines using cell proliferation and soft agar assays. Sensitive cell lines underwent G1 arrest, whereas Selumetinib had no effect on the cell cycle of resistant cells. Some of the resistant cell lines showed high levels of ERK1/2 phosphorylation in the absence of serum. Selumetinib inhibited phosphorylation of ERK1/2 and RSK and had no effect on AKT phosphorylation in both sensitive and resistant cells. Furthermore, mutations in KRAS, BRAF, or PIK3CA were not clearly associated with Selumetinib resistance. Surprisingly, Selumetinib was able to inhibit phosphorylation of p70 S6 kinase (p70S6K) and its downstream target ribosomal protein S6 (RPS6) in sensitive cell lines. However, p70S6K and RPS6 phosphorylation remained unaffected or even increased in resistant cells. Moreover, in some of the resistant cell lines p70S6K and RPS6 were phosphorylated in the absence of serum. Interestingly, colorectal primary cultures derived from tumours excised to patients exhibited the same behaviour than established cell lines. Pharmacological inhibition of p70S6K using the PI3K/mTOR inhibitor NVP-BEZ235, the specific mTOR inhibitor Rapamycin and the specific p70S6K inhibitor PF-4708671 potentiated Selumetinib effects in resistant cells. In addition, biological inhibition of p70S6K using siRNA rendered responsiveness to Selumetinib in resistant cell lines. Furthermore, combination of p70S6K silencing and PF-47086714 was even more effective. We can conclude that p70S6K and its downstream target RPS6 are potential biomarkers of resistance to Selumetinib in colorectal cancer

Comparative Study of 17-AAG and NVP-AUY922 in Pancreatic and Colorectal Cancer Cells: Are There Common Determinants of Sensitivity?

The use of heat shock protein 90 (Hsp90) inhibitors is an attractive antineoplastic therapy. We wanted to compare the effects of the benzoquinone 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) and the novel isoxazole resorcinol–based Hsp90 inhibitor NVP-AUY922 in a panel of pancreatic and colorectal carcinoma cell lines and in colorectal primary cultures derived from tumors excised to patients. PANC-1, CFPAC-1, and Caco-2 cells were intrinsically resistant to 17-AAG but sensitive to NVP-AUY922. Other cellular models were sensitive to both inhibitors. Human epidermal growth factor receptor receptors and their downstream signaling pathways were downregulated in susceptible cellular models, and concurrently, Hsp70 was induced. Intrinsic resistance to 17-AAG did not correlate with expression of ATP-binding cassette transporters involved in multidrug resistance. Some 17-AAG-resistant, NVP-AUY922–sensitive cell lines lacked NAD(P)H:quinone oxidoreductase 1 (NQO1) enzyme and activity. However, colorectal LoVo cells still responded to both drugs in spite of having undetectable levels and activity of NQO1. Pharmacological and biologic inhibition of NQO1 did not confer resistance to 17-AAG in sensitive cell lines. Therefore, even though 17-AAG sensitivity is related to NQO1 protein levels and enzymatic activity, the absence of NQO1 does not necessarily convey resistance to 17-AAG in these cellular models. Moreover, NVP-AUY922 does not require NQO1 for its action and is a more potent inhibitor than 17-AAG in these cells. More importantly, we show in this report that NVP-AUY922 potentiates the inhibitory effects of chemotherapeutic agents, such as gemcitabine or oxaliplatin, and other drugs that are currently being evaluated in clinical trials as antitumor agents