The human papillomavirus type 18 E6 oncoprotein induces Vascular Endothelial Growth Factor 121 (VEGF121) transcription from the promoter through a p53-independent mechanism

Altered angiogenic response is associated with high-grade cervical dysplasia and with invasive squamous carcinoma of the cervix. Vascular Endothelial Growth Factor (VEGF) is one of the most potent inducers of angiogenesis and is up-regulated in carcinoma of the cervix. Infection by high-risk human papillomavirus and persistent expression of viral oncogene E6 are etiologically linked to the development of cervical cancer. E6 is able to immortalize cells and induce malignant transformation by inactivating p53. In cervical cancer, regulation of VEGF expression is poorly described. Thus, we investigated whether E6 oncoprotein could regulate VEGF expression in HPV18-positive cervical cancer-derived HeLa cells harboring a wild-type p53. The alternative splicing of vegf mRNA renders three major isoforms of 121, 165 and 189 amino-acids in humans. We have designed isoform specific real time QRT-PCR assays to quantitate vegf transcripts and VEGF121 was the predominant isoform. Silencing HPV18 E6 mRNA with specific siRNA reduced VEGF121 expression by at least 50% whereas silencing of p53 did not alter its expression. Treatment with cycloheximide did not inhibit E6-induced VEGF121 expression. Collectively, these results suggest that HPV18 E6 oncoprotein contributes to tumor angiogenesis by inducing VEGF transcription from the promoter in a p53-independent manner

A selective retinoid X receptor agonist bexarotene (LGD1069, targretin) inhibits angiogenesis and metastasis in solid tumours

The present study determined the influence of a retinoid X receptor agonist bexarotene on angiogenesis and metastasis in solid tumours. In the experimental lung metastasis xenograft models, treatment with bexarotene inhibited the development of the lung tumour nodule formation compared to control. In vivo angiogenesis assay utilising gelfoam sponges, bexarotene reduced angiogenesis in sponges containing vascular endothelial growth factor, epidermal growth factor and basic fibroblast growth factor to various extent. To determine the basis of these observations, human breast and non-small-cell lung cancer cells were subjected to migration and invasion assays in the presence of bexarotene. Our data showed that bexarotene decrease migration and invasiveness of tumour cells in a dose-dependent manner. Furthermore, bexarotene inhibited angiogenesis by directly inhibiting human umbilical vein endothelial cell growth and indirectly inhibiting tumour cell-mediated migration of human umbilical vein endothelial cells through Matrigel matrix. Analysis of tumour-conditioned medium indicated that bexarotene decreased the secretion of angiogenic factors and matrix metalloproteinases and increased the tissue inhibitor of matrix metalloproteinases. The ability of bexarotene to inhibit angiogenesis and metastasis was dependent on activation of its heterodimerisation partner peroxisome proliferator-activated receptor γ. Collectively, our results suggest a role of bexarotene in treatment of angiogenesis and metastasis in solid tumours

The Antidiabetic Drug Ciglitazone Induces High Grade Bladder Cancer Cells Apoptosis through the Up-Regulation of TRAIL

International audienceBACKGROUND: Ciglitazone belongs to the thiazolidinediones class of antidiabetic drug family and is a high-affinity ligand for the Peroxisome Proliferator-Activated Receptor γ (PPARγ). Apart from its antidiabetic activity, this molecule shows antineoplastic effectiveness in numerous cancer cell lines. METHODOLOGY/PRINCIPAL FINDINGS: Using RT4 (derived from a well differentiated grade I papillary tumor) and T24 (derived from an undifferentiated grade III carcinoma) bladder cancer cells, we investigated the potential of ciglitazone to induce apoptotic cell death and characterized the molecular mechanisms involved. In RT4 cells, the drug induced G2/M cell cycle arrest characterized by an overexpression of p53, p21(waf1/CIP1) and p27(Kip1) in concomitance with a decrease of cyclin B1. On the contrary, in T24 cells, it triggered apoptosis via extrinsic and intrinsic pathways. Cell cycle arrest and induction of apoptosis occurred at high concentrations through PPARγ activation-independent pathways. We show that in vivo treatment of nude mice by ciglitazone inhibits high grade bladder cancer xenograft development. We identified a novel mechanism by which ciglitazone kills cancer cells. Ciglitazone up-regulated soluble and membrane-bound TRAIL and let TRAIL-resistant T24 cells to respond to TRAIL through caspase activation, death receptor signalling pathway and Bid cleavage. We provided evidence that TRAIL-induced apoptosis is partially driven by ciglitazone-mediated down-regulation of c-FLIP and survivin protein levels through a proteasome-dependent degradation mechanism. CONCLUSIONS/SIGNIFICANCE: Therefore, ciglitazone could be clinically relevant as chemopreventive or therapeutic agent for the treatment of TRAIL-refractory high grade urothelial cancers

Predicting the distribution and abundance of abandoned, lost or discarded fishing gear (ALDFG) in the deep sea of the Azores (North Atlantic)

Abandoned, lost, or discarded fishing gear (ALDFG), represents a significant percentage of the global plastic pollution, currently considered one of the major sources from sea-based activities. However, there is still limited understanding of the quantities of ALDFG present on the seafloor and their impacts. In this study, data on the presence of ALDFG was obtained from a large archive of seafloor video footage (351 dives) collected by different imaging platforms in the Azores region over 15 years (2006-2020). Most ALDFG items observed in the images relate to the local bottom longline fishery operating in the region, and include longlines but also anchors, weights, cables and buoys. A generalized additive mixed model (GAMM) was used to predict the distribution and abundance of ALDFG over the seafloor within the limits of the Azores Exclusive Economic Zone (EEZ) using a suite of environmental and anthropogenic variables. We estimated an average of 113 ± 310 items km-2 (597 ± 756 per km-2 above 1000 m depth), which could imply that over 20 million ALDFG items are present on the deep seafloor of the Azores EEZ. The resulting model identified potential hotspots of ALDFG along the seabed, some of them located over sensitive benthic habitats, such as specific seamounts. In addition, the interactions between ALDFG and benthic organisms were also analysed. Numerous entanglements were observed with several species of large anthozoans and sponges. The use of predictive distribution modelling for ALDFG should be regarded as a useful tool to support ecosystem-based management, which can provide indirect information about fishing pressure and allow the identification of potential high-risk areas. Additional knowledge about the sources, amounts, fates and impacts of ALDFG will be key to address the global issue of plastic pollution and the effects of fishing on marine ecosystems.This work contributes to the PO2020 PLASTDEEP (ACORES-01-0145-FEDER-000125) and MapGES (Acores-01-0145-FEDER-000056) research projects and to the European Union's Horizon 2020 Research and innovation programme under grant agreements No 678760 (ATLAS) and No 818123 (iAtlantic). This output reflects only the authors' views and the European Union cannot be held responsible for any use that may be made of the information contained therein. We acknowledge all projects and programs that collected images by multiple ROV, submersible and towed video surveys, including those conducted within the MapGES, Estrutura de Missão para Extensão da Plataforma Continental (EMEPC; Cruzeiro Científico EMEPC/LUSO/Açores/2009), MEDWAVES (ATLAS No 678760, with logistic and technical assistance from the UTM –CSIC– and the financial support from the Spanish Ministry of Economy, Industry and Competitivity), Blue Azores 2018 (National Geographic Pristine Seas program, Oceano Azul Foundation, and Waitt Institute), NICO 12 Expedition, Pelagia Rainbow and Terceira 2019 (cruises 64PE441, 64PE454, and 64PE456; Netherlands Organisation for Scientific Research NWO for funding and Royal Netherlands Institute for Sea Research NIOZ for organising the Netherlands Initiative Changing Oceans NICO expedition in 2018). The EXPLOSEA2 cruise was funded by the Spanish Ministry for Science and Innovation as part of the project EXPLOSEA (grant CTM201675947-R). We deeply thank all PIs, crews and scientists that participated in all these surveys. CD-C was supported by the PO2020 projects MapGES and DeepWalls (Acores-01-0145-FEDER-000056 and Acores-01-0145-FEDER-000124) and by the FCT-IP Project UIDP/05634/2020. TM was supported by Program Investigador FCT (IF/01194/2013), and the IFCT Exploratory Project (IF/01194/2013/CP1199/CT0002) from the Fundação para a Ciência e Tecnologia (POPH and QREN). TM and MCS were also supported by the FCT-IP Program Stimulus of Scientific Employment (CCCIND/03345/2020 and CCCIND/03346/2020, respectively) and the H2020 programme No 689518 (MERCES) and No 818123 (iAtlantic). LR was supported by the H2020 programme No 818123 (iAtlantic) and Horizon Europe No 101059407 (MarinePlan). J.M.P. was funded by the Fundação para a Ciência e Tecnologia (FCT) Doctoral Grant 2021.04875.BD. CKP received support from the Operational Program Azores 2020, through the Fund 01-0145-FEDER-000140 “MarAZ Researchers: Consolidate a body of researchers in Marine Sciences in the Azores” of the European Union. We also acknowledge funds through the FCT – Foundation for Science and Technology, I.P., under the project OKEANOS UIDB/05634/2020 and through the FCT Regional Government of the Azores under the project M1.1. A/REEQ.CIENTÍFICO UI&D/2021/010.Peer reviewe

Cubrición pista polideportiva en Viana, Navarra

El objeto de este proyecto fin de carrera es dotar al ayuntamiento de Viana (Navarra), dentro del Complejo Deportivo Municipal Príncipe de Viana, de un espacio multidisciplinar en el que poder desarrollar cualquier tipo de actividad deportiva, fortaleciendo la infraestructura recreativa del municipio y creando una alternativa de ocio sana y saludable. El complejo deportivo será por tanto, de carácter dotacional y propiedad municipal. El volumen de la pista polideportiva a realizar vendrá determinado por las necesidades reglamentarias (medida en planta y alturas libres) de las distintas disciplinas deportivas demandadas en la localidad, carentes de espacios para su práctica y, por tanto, para las que va a ser concebida: una zona de juego de voleibol; una zona de juego de fútbol sala; una zona de juego de baloncesto; tres zonas de juego de mini básquet. Un reciente estudio económico, evaluando los futuros costes de explotación y comparándolos con los costes actuales derivados de la carencia de espacios públicos para la práctica de las actividades descritas, avalan la realización del proyecto.Ingeniería IndustrialIndustria Ingeniaritz