Search

An Id1 gene signature is dependent of KEAP1-related genes and a FOSL1 network.

Clinical implication of Id1 expression in LUAD patients.

Supplementary tables and figure's headings

Because of the refractory nature of mutant KRAS lung adenocarcinoma (LUAD) to current therapies, identification of new molecular targets is essential. Genes with a prognostic role in mutant KRAS LUAD have proven to be potential molecular targets for therapeutic development. Here we determine the clinical, functional, and mechanistic role of inhibitor of differentiation-1 (Id1) in mutant KRAS LUAD. Analysis of LUAD cohorts from TCGA and SPORE showed that high expression of Id1 was a marker of poor survival in patients harboring mutant, but not wild-type KRAS. Abrogation of Id1 induced G2–M arrest and apoptosis in mutant KRAS LUAD cells. In vivo, loss of Id1 strongly impaired tumor growth and maintenance as well as liver metastasis, resulting in improved survival. Mechanistically, Id1 was regulated by the KRAS oncogene through JNK, and loss of Id1 resulted in downregulation of elements of the mitotic machinery via inhibition of the transcription factor FOSL1 and of several kinases within the KRAS signaling network. Our study provides clinical, functional, and mechanistic evidence underscoring Id1 as a critical gene in mutant KRAS LUAD and warrants further studies of Id1 as a therapeutic target in patients with LUAD.Significance:These findings highlight the prognostic significance of the transcriptional regulator Id1 in KRAS-mutant lung adenocarcinoma and provide mechanistic insight into how it controls tumor growth and metastasis.

A shRNA-resistant Id1 cDNA rescues Id1 loss.

Regulation of kinases by Id1 expression

Variegate porphyria (VP) results from haploinsufficiency of protoporphyrinogen oxidase (PPOX), the seventh enzyme in the heme synthesis pathway. There is no VP model that recapitulates the clinical manifestations of acute attacks. Combined administrations of 2-allyl-2-isopropylacetamide and rifampicin in rabbits halved hepatic PPOX activity, resulting in increased accumulation of a potentially neurotoxic heme precursor, lipid peroxidation, inflammation, and hepatocyte cytoplasmic stress. Rabbits also showed hypertension, motor impairment, reduced activity of critical mitochondrial hemoprotein functions, and altered glucose homeostasis. Hemin treatment only resulted in a slight drop in heme precursor accumulation but further increased hepatic heme catabolism, inflammation, and cytoplasmic stress. Hemin replenishment did protect against hypertension, but it failed to restore action potentials in the sciatic nerve or glucose homeostasis. Systemic porphobilinogen deaminase (PBGD) mRNA administration increased hepatic PBGD activity, the third enzyme of the pathway, and rapidly normalized serum and urine porphyrin precursor levels. All features studied were improved, including those related to critical hemoprotein functions. In conclusion, the VP model recapitulates the biochemical characteristics and some clinical manifestations associated with severe acute attacks in humans. Systemic PBGD mRNA provided successful protection against the acute attack, indicating that PBGD, and not PPOX, was the critical enzyme for hepatic heme synthesis in VP rabbits., Graphical abstract, No model recapitulates clinical manifestations of variegate porphyria. Combined administration of 2-allyl-2-isopropylacetamide and rifampicin in rabbits reproduced the biochemical derangements associated with acute attacks, and it induced hypertension and motor impairment. Systemic porphobilinogen deaminase mRNA administration protected from these alterations, thus providing a proof of concept for mRNA-based strategies for the management of variegate porphyria.

Resumen Objetivo Optimizar el radiomarcaje con 99mTc y 67Ga de nanoparticulas de albumina recubiertas con 4 polimeros sinteticos distintos y evaluar su estabilidad in vivo e in vitro, asi como su biodistribucion in vivo tras su administracion intravenosa. Material y metodos Las nanoparticulas se prepararon empleando albumina y albumina modificada con NOTA mediante el metodo de desolvatacion y se recubrieron con 4 polimeros distintos; HPMC, GMN2, GPM2 y GTM2. Se purificaron, liofilizaron y caracterizaron. El marcaje con 99mTc se realizo con 74 MBq de pertecnetato [99mTc] sodico previamente reducido con una disolucion acida de cloruro de estano a diferentes concentraciones (0,003; 0,005; 0,007; 0,01; 0,05 y 0,1 mg/ml), a distintos tiempos (5, 10, 15, 30 y 60 min) y temperaturas (temperatura ambiente, 40 °C y 60 °C). El marcaje con 67Ga se llevo a cabo mediante incubacion de las nanoparticulas con 37 MBq de cloruro de 67Ga (obtenido a partir de citrato de 67Ga comercial) a distintos tiempos (10 y 30 min) y temperaturas (temperatura ambiente, 30 °C y 60 °C) y posterior purificacion con microconcentradores. La pureza radioquimica de ambos marcajes se evaluo mediante TLC. Se llevaron a cabo estudios de estabilidad de las nanoparticulas marcadas en suero fisiologico y plasma sanguineo. Los estudios de biodistribucion de las nanoparticulas recubiertas con el polimero GPM2 se llevaron a cabo en ratas Wistar tras la administracion intravenosa de las nanoparticulas. Se realizaron animales control con pertecnetato [99mTc] sodico y cloruro de 67Ga. Posteriormente, los animales fueron sacrificados y se midio la actividad de los organos en un contador gamma. Resultados El marcaje con 99mTc se llevo a cabo de forma optima con una concentracion de estano de 0,007 mg/ml para las nanoparticulas GPM2 y de 0,005 mg/ml para el resto de formulaciones, con un tiempo de marcaje de 10 min y a temperatura ambiente. En el caso del 67Ga el marcaje se optimizo a 30 °C de temperatura y 30 min de incubacion. En ambos casos, la pureza radioquimica obtenida fue superior al 97%. Las nanoparticulas presentaron una elevada estabilidad in vitro pasadas las 48 h del marcaje (70% las nanoparticulas marcadas con 99mTc y 90% las marcadas con 67Ga). Los estudios de biodistribucion de las nanoparticulas [99mTc]-GPM2 y [67Ga]-NOTA-GPM2 mostraron una elevada acumulacion de actividad en el higado tanto a las 2 h como a las 24 h de la administracion intravenosa. Conclusion El procedimiento de marcaje con 99mTc y 67Ga de nanoparticulas de albumina y albumina modificada con NOTA permite la obtencion de nanoparticulas con elevados rendimientos de marcaje y una adecuada estabilidad in vitro, permitiendo su utilizacion para la realizacion de estudios in vivo.

Bevacizumab (as other monoclonal antibodies) has now become a mainstay in the treatment of several cancers in spite of some limitations, including poor tumour penetration and the development of resistance mechanisms. Its nanoencapsulation may be an adequate strategy to minimize these problems. The aim of this work was to evaluate the efficacy of bevacizumab-loaded nanoparticles (B-NP-PEG) on a xenograft model of human colorectal cancer. For this purpose, human serum albumin nanoparticles were prepared by coacervation, then coated with poly(ethylene glycol) and freeze-dried. B-NP-PEG displayed a mean size of about 300 nm and a bevacizumab loading of approximately 145 μg/mg. An in vivo study was conducted in the HT-29 xenograft model of colorectal cancer. Both, free and nanoencapsulated bevacizumab, induced a similar reduction in the tumour growth rate of about 50%, when compared to controls. By microPET imaging analysis, B-NP-PEG was found to be a more effective treatment in decreasing the glycolysis and metabolic tumour volume than free bevacizumab, suggesting higher efficacy. These results correlated well with the capability of B-NP-PEG to increase about fourfold the levels of intratumour bevacizumab, compared with the conventional formulation. In parallel, B-NP-PEG displayed six-times lower amounts of bevacizumab in blood than the aqueous formulation of the antibody, suggesting a lower incidence of potential undesirable side effects. In summary, albumin-based nanoparticles may be adequate carriers to promote the delivery of monoclonal antibodies (i.e. bevacizumab) to tumour tissues. Graphical abstract.

Negatively charged microspheres (NCMs) are postulated as a new form of treatment for chronic wounds. Despite the efficacy shown at clinical level, more studies are required to demonstrate their safety and local effect. The objective of the work was to confirm the lack of NCM systemic absorption performing a biodistribution study of the NCMs in an open wound rat animal model. To this end, radiolabeling of NCMs with technetium-99 m was optimized and biodistribution studies were performed by in vivo SPEC/CT imaging and ex vivo counting during 24 h after topical administration. The studies were performed on animals treated with a single or repeated dose to study the effect of macrophages during a prolonged treatment. NCM radiolabeling was achieved in a simple, efficient and stable manner with high yield. SPECT/CT images showed that almost all NCMs (about 85 %) remained on the wound for 24 h either after single or multiple administrations. Ex vivo biodistribution studies confirmed that there was no accumulation of NCMs in any organ or tissue except in the wound area, suggesting a lack of absorption. In conclusion, NCMs can be considered safe as local wound treatment since they remain at the administration area., This project was partially supported by the Basque Government (HAZITEK, ZE-2017/00014) and co-funded by the European Regional Development Fund (ERDF).

Dopaminergic denervation in patients with Parkinson's disease is associated with changes in brain metabolism. Cerebral in-vivo mapping of glucose metabolism has been studied in severe stable parkinsonian monkeys, but data on brain metabolic changes in early stages of dopaminergic depletion of this model is lacking. Here, we report cerebral metabolic changes associated with progressive nigrostriatal lesion in the pre-symptomatic and symptomatic stages of the progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model of Parkinson's Disease. Monkeys (Macaca fascicularis) received MPTP injections biweekly to induce progressive grades of dopamine depletion. Monkeys were sorted according to motor scale assessments in control, asymptomatic, recovered, mild, and severe parkinsonian groups. Dopaminergic depletion in the striatum and cerebral metabolic patterns across groups were studied in vivo by positron emission tomography (PET) using monoaminergic ([11C]-dihydrotetrabenazine; 11C-DTBZ) and metabolic (2-[18F]-fluoro-2-deoxy-d-glucose; 18F-FDG) radiotracers. 11C-DTBZ-PET analysis showed progressive decrease of binding potential values in the striatum of monkeys throughout MPTP administration and the development of parkinsonian signs. 18F-FDG analysis in asymptomatic and recovered animals showed significant hypometabolism in temporal and parietal areas of the cerebral cortex in association with moderate dopaminergic nigrostriatal depletion. Cortical hypometabolism extended to involve a larger area in mild parkinsonian monkeys, which also exhibited hypermetabolism in the globus pallidum pars interna and cerebellum. In severe parkinsonian monkeys, cortical hypometabolism extended further to lateral-frontal cortices and hypermetabolism also ensued in the thalamus and cerebellum. Unbiased histological quantification of neurons in Brodmann's area 7 in the parietal cortex did not reveal neuron loss in parkinsonian monkeys versus controls. Early dopaminergic nigrostriatal depletion is associated with cortical, mainly temporo-parietal hypometabolism unrelated to neuron loss. These findings, together with recent evidence from Parkinson's Disease patients, suggest that early cortical hypometabolism may be associated and driven by subcortical changes that need to be evaluated appropriately. Altogether, these findings could be relevant when potential disease modifying therapies become available.

Castillo Solórzano hérite, dans une large mesure, de Lope ; il fréquente assidument les imprimeurs et cultive presque tous les genres littéraires. À ce titre il offre un terrain propice pour une analyse des stratégies d’auto-représentation de l’écrivain. Celles-ci sont analysées, pour ce qui est de la suite de ses publications, à partir de la notion de carrière littéraire ; elles sont étudiées également à travers les réseaux de sociabilité et du positionnement de l’auteur dans le champ littéraire, tel qu’il l’adopte dans ses prologues ; finalement, on les examine à travers les portraits burlesques qu’il trace de lui-même dans ses premières œuvres de poésie. Ainsi est dessiné tout un projet d’écriture, avec les diverses modalités de son affirmation. Heir to a great extent to Lope, regular attender of the printing press and cultivator of almost all genres, Castillo Solórzano offers a propitious field for the analysis of self-representation strategies. These strategies are analyzed considering his publication sequence (from the notion of literary career), his sociability network, the field positions that he establishes in his prologues and, finally, his burlesque portraits published in his early volumes of poetry. Thus, this analysis permits to reveal a writing project and its various forms of affirmation. Heredero en gran medida de Lope, profuso frecuentador de la imprenta y cultivador de casi todos los géneros, Castillo Solórzano ofrece un campo propicio para el análisis de las estrategias de autorrepresentación como escritor. Se analizan a partir de la noción de carrera literaria para su secuencia de publicaciones, en las redes de sociabilidad y las posiciones de campo que establece en sus prólogos, y, finalmente, desde sus retratos burlescos en sus tempranos volúmenes de poesía. Se dibuja así un proyecto de escritura y las diversas formas de su afirmación.

Because of the refractory nature of mutant KRAS lung adenocarcinoma (LUAD) to current therapies, identification of new molecular targets is essential. Genes with a prognostic role in mutant KRAS LUAD have proven to be potential molecular targets for therapeutic development. Here we determine the clinical, functional, and mechanistic role of inhibitor of differentiation-1 (Id1) in mutant KRAS LUAD. Analysis of LUAD cohorts from TCGA and SPORE showed that high expression of Id1 was a marker of poor survival in patients harboring mutant, but not wild-type KRAS. Abrogation of Id1 induced G2–M arrest and apoptosis in mutant KRAS LUAD cells. In vivo, loss of Id1 strongly impaired tumor growth and maintenance as well as liver metastasis, resulting in improved survival. Mechanistically, Id1 was regulated by the KRAS oncogene through JNK, and loss of Id1 resulted in downregulation of elements of the mitotic machinery via inhibition of the transcription factor FOSL1 and of several kinases within the KRAS signaling network. Our study provides clinical, functional, and mechanistic evidence underscoring Id1 as a critical gene in mutant KRAS LUAD and warrants further studies of Id1 as a therapeutic target in patients with LUAD. Significance: These findings highlight the prognostic significance of the transcriptional regulator Id1 in KRAS-mutant lung adenocarcinoma and provide mechanistic insight into how it controls tumor growth and metastasis.

Mutations in the GBA1 gene coding for glucocerebrosidase (GCase) are the main genetic risk factor for Parkinson’s disease (PD). Indeed, identifying reduced GCase activity as a common feature underlying the typical neuropathological signatures of PD—even when considering idiopathic forms of PD—has recently paved the way for designing novel strategies focused on enhancing GCase activity to reduce alpha-synuclein burden and preventing dopaminergic cell death. Here we have performed bilateral injections of a viral vector coding for the mutated form of alpha-synuclein (rAAV9-SynA53T) for disease modeling purposes, both in mice as well as in nonhuman primates (NHPs), further inducing a progressive neuronal death in the substantia nigra pars compacta (SNpc). Next, another vector coding for the GBA1 gene (rAAV9-GBA1) was unilaterally delivered in the SNpc of mice and NHPs one month after the initial insult, together with the contralateral delivery of an empty/null rAAV9 for control purposes. Obtained results showed that GCase enhancement reduced alpha-synuclein burden, leading to improved survival of dopaminergic neurons. Data reported here support using GCase gene therapy as a disease-modifying treatment for PD and related synucleinopathies, including idiopathic forms of these disorders.

Brown adipose tissue (BAT) dysfunction in aging and obesity has been related to chronic unresolved inflammation, which could be mediated by an impaired production of specialized proresolving lipid mediators (SPMs), such as Lipoxins-LXs, Resolvins-Rvs, Protectins-PDs, and Maresins-MaRs. Our aim was to characterize the changes in BAT SPMs signatures and their association with BAT dysfunction during aging, especially under obesogenic conditions, and their modulation by a docosahexaenoic acid (DHA)-rich diet. Lipidomic, functional, and molecular studies were performed in BAT of 2-and 18-month- old lean (CT) female mice and in 18-month- old diet-induced obese (DIO) mice fed with a high-fat diet (HFD), or a DHA-enriched HFD. Aging downregulated Prdm16 and UCP1 levels, especially in DIO mice, while DHA partially restored them. Arachidonic acid (AA)-derived LXs and DHA-derived MaRs and PDs were the most abundant SPMs in BAT of young CT mice.Interestingly, the sum of LXs and of PDs were significantly lower in aged DIO mice compared to young CT mice. Some of the SPMs most significantly reduced in obese-aged mice included LXB4, MaR2, 4S,14S-diHDHA, 10S,17S-diHDHA (a.k.a. PDX), and RvD6. In contrast, DHA increased DHA-derived SPMs, without modifying LXs. However, MicroPET studies showed that DHA was not able to counteract the impaired cold exposure response in BAT of obese-aged mice. Our data suggest that a defective SPMs production could underlie the decrease of BAT activity observed in obese-aged mice, and highlight the relevance to further characterize the physiological role and therapeutic potential of specific SPMs on BAT development and function.

Bacteria present a promising delivery system for treating human diseases. Here, we engineered the genome-reduced human lung pathogen Mycoplasma pneumoniae as a live biotherapeutic to treat biofilm-associated bacterial infections. This strain has a unique genetic code, which hinders gene transfer to most other bacterial genera, and it lacks a cell wall, which allows it to express proteins that target peptidoglycans of pathogenic bacteria. We first determined that removal of the pathogenic factors fully attenuated the chassis strain in vivo. We then designed synthetic promoters and identified an endogenous peptide signal sequence that, when fused to heterologous proteins, promotes efficient secretion. Based on this, we equipped the chassis strain with a genetic platform designed to secrete antibiofilm and bactericidal enzymes, resulting in a strain capable of dissolving Staphylococcus aureus biofilms preformed on catheters in vitro, ex vivo, and in vivo. To our knowledge, this is the first engineered genome-reduced bacterium that can fight against clinically relevant biofilm-associated bacterial infections., This work has been supported by the European Research Council (ERC) underthe European Union’s Horizon2020research and innovation program, undergrant agreement 670216(MYCOCHASSIS). We also acknowledge the support ofthe Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to theEMBL partnership, the Centro de Excelencia Severo Ochoa, the CERCA Programfrom the Generalitat de Catalunya, the European Union’s Horizon2020research and innovation program under grant agreement 634942 (Myco-SynVac), and the LaCaixa Fundation grant (Livetherapeutics HR18-00058).M.L.-S. acknowledges the support from FEDER project from Instituto Carlos III(ISCIII, Accion Estrategica en Salud2016) (reference CP16/00094). We alsoacknowledge the staff of CRG/UPF Proteomics Unit, which is part of the Span-ish Infrastructure for Omics Technologies (ICTS OmicsTech) unit is a memberof the ProteoRed PRB3consortium, which is supported by grant PT17/0019ofthe PE I+D+i2013-2016from the Instituto de Salud Carlos III (ISCIII) and ERDF. We also acknowledge Margarita Ecay for her assistance in the PETimages analysis and Samuel Miravet-Verde for the bioinformatic support.

The use of PD-1/PD-L1 checkpoint inhibitors in advanced NSCLC is associated with longer survival. However, many patients do not benefit from PD-1/PD-L1 blockade, largely because of immunosuppression. New immunotherapy-based combinations are under investigation in an attempt to improve outcomes. Id1 (inhibitor of differentiation 1) is involved in immunosuppression. In this study, we explored the potential synergistic effect of the combination of Id1 inhibition and pharmacological PD-L1 blockade in three different syngeneic murine KRAS-mutant lung adenocarcinoma models. TCGA analysis demonstrated a negative and statistically significant correlation between PD-L1 and Id1 expression levels. This observation was confirmed in vitro in human and murine KRAS-driven lung cancer cell lines. In vivo experiments in KRAS-mutant syngeneic and metastatic murine lung adenocarcinoma models showed that the combined blockade targeting Id1 and PD-1 was more effective than each treatment alone in terms of tumor growth impairment and overall survival improvement. Mechanistically, multiplex quantification of CD3+/CD4+/CD8+ T cells and flow cytometry analysis showed that combined therapy favors tumor infiltration by CD8+ T cells, whilst in vivo CD8+ T cell depletion led to tumor growth restoration. Co-culture assays using CD8+ cells and tumor cells showed that T cells present a higher antitumor effect when tumor cells lack Id1 expression. These findings highlight that Id1 blockade may contribute to a significant immune enhancement of antitumor efficacy of PD-1 inhibitors by increasing PD-L1 expression and harnessing tumor infiltration of CD8+ T lymphocytes.

Simple Summary Lung adenocarcinoma is the most frequent lung cancer subtype. Many of those adenocarcinomas of the lung are driven by the KRAS gene. Although immunotherapy has significantly improved the clinical outcomes of patients with lung adenocarcinomas, many patients do not benefit from that therapeutic strategy. Id1 is a protein involved in immunosuppression. Here we aimed to test whether a combined blockade of Id1 and PD-1 is able to improve outcomes of mice models with KRAS-driven lung adenocarcinoma. Abstract The use of PD-1/PD-L1 checkpoint inhibitors in advanced NSCLC is associated with longer survival. However, many patients do not benefit from PD-1/PD-L1 blockade, largely because of immunosuppression. New immunotherapy-based combinations are under investigation in an attempt to improve outcomes. Id1 (inhibitor of differentiation 1) is involved in immunosuppression. In this study, we explored the potential synergistic effect of the combination of Id1 inhibition and pharmacological PD-L1 blockade in three different syngeneic murine KRAS-mutant lung adenocarcinoma models. TCGA analysis demonstrated a negative and statistically significant correlation between PD-L1 and Id1 expression levels. This observation was confirmed in vitro in human and murine KRAS-driven lung cancer cell lines. In vivo experiments in KRAS-mutant syngeneic and metastatic murine lung adenocarcinoma models showed that the combined blockade targeting Id1 and PD-1 was more effective than each treatment alone in terms of tumor growth impairment and overall survival improvement. Mechanistically, multiplex quantification of CD3+/CD4+/CD8+ T cells and flow cytometry analysis showed that combined therapy favors tumor infiltration by CD8+ T cells, whilst in vivo CD8+ T cell depletion led to tumor growth restoration. Co-culture assays using CD8+ cells and tumor cells showed that T cells present a higher antitumor effect when tumor cells lack Id1 expression. These findings highlight that Id1 blockade may contribute to a significant immune enhancement of antitumor efficacy of PD-1 inhibitors by increasing PD-L1 expression and harnessing tumor infiltration of CD8+ T lymphocytes.

El presente artículo, a modo de catálogo, describe 59 almanaques y pronósticos impresos en el siglo XVIII que se conservan en la Biblioteca Capitular y Archivo de la Catedral de Córdoba. Destacan piscatores de reconocido prestigio como Torres Villarroel, Gonzalo Antonio Serrano, Pedro de Enguera y el Sarrabal de Milán, entre otros. Con esta catalogación se exponen a la luz de la crítica 32 pronósticos desconocidos hasta el momento con el objetivo de abrir nuevas vías de investigación acerca de este género editorial. This article, organised as a catalog, describes 59 astrological almanacs and prognostications printed in the eighteenth century which are kept in the Biblioteca Capitular y Archivo de la Catedral de Córdoba. Remarkable authors stand out, such as Torres Villarroel, Gonzalo Antonio Serrano, Pedro de Enguera, Sarrabal de Milán… With this catalog, 32 so far unknown almanacs and prognostications come to light with the aim to open new investigations into this publishing sector.

Id1 promotes carcinogenesis and metastasis, and predicts prognosis of non-small cell lung cancer (NSCLC)-adenocarcionoma patients. We hypothesized that Id1 may play a critical role in lung cancer colonization of the liver by affecting both tumor cells and the microenvironment. Depleted levels of Id1 in LLC (Lewis lung carcinoma cells, LLC shId1) significantly reduced cell proliferation and migration in vitro. Genetic loss of Id1 in the host tissue (Id1(-/-) mice) impaired liver colonization and increased survival of Id1 animals. Histologically, the presence of Idl in tumor cells of liver metastasis was responsible for liver colonization. Microarray analysis comparing liver tumor nodules from Id1(+/+) mice and Idl(-/-) mice injected with LLC control cells revealed that Id1 loss reduces the levels of EMT-related proteins, such as vimentin. In tissue microarrays containing 532 NSCLC patients' samples, we found that Idl significantly correlated with vimentin and other EMT-related proteins. Idl loss decreased the levels of vimentin, integrin beta 1, TGF beta 1 and snail, both in vitro and in vivo. Therefore, Id1 enables both LLC and the host microenvironment for an effective liver colonization, and may represent a novel therapeutic target to avoid NSCLC liver metastasis. (C) 2017 Elsevier B.V. All rights reserved.

Re-activation of the healing process is a major challenge in the field of chronic wound treatment. For that purpose, lipid-nanoparticles, especially nanostructured lipid carriers (NLC), possess extremely useful characteristics such as biodegradability, biocompatibility and long-term stability, besides being suitable for drug delivery. Moreover, they maintain wound moisture due to their occlusive properties, which have been associated with increased healing rates. In the light of above, NLC have been extensively used topically for wound healing; but to date, there are no safety-preclinical studies concerning such type of application. Thus, in this work, biodistribution studies were performed in rats with the NLC previously developed by our research group, using technetium-99 m (99mTc-NLC) as radiomarker, topically administered on a wound. 99mTc-NLC remained on the wound for 24 h and systemic absorption was not observed after administration. In addition, toxicological studies were performed to assess NLC safety after topical administration. The results obtained demonstrated that NLC were non-cytotoxic, non-sensitizing and non-irritant/corrosive. Overall, it might be concluded that developed NLC remained at the administration area, potentially exerting a local effect, and were safe after topical administration on wounds.

Producción Científica, Packing materials used in biofiltration of gaseous pollutants represent a key design parameter, as a proper selection might not only determine the adequate performance of the system but also its cost-effectiveness. This study systematically assessed and compared the performance of a conventional plastic carrier with that of two novel clay-based materials from SAINT GOBAIN for the abatement of a model odorous stream composed of H2S, methylmercaptan and toluene. The packing materials were tested in biotrickling filters, biofilters and a two-phase biotrickling filter. SAINT GOBAIN materials exhibited a higher adsorption potential under abiotic conditions, a higher buffer capacity and a superior performance compared to conventional plastic rings when implemented in biotrickling filters operating at gas residence times as low as 7.5 s. Among the materials tested in biofilters, Filtralite Air AC supported almost complete H2S and toluene removals at a gas residence time of 20 s, while successfully eliminating methylmercaptan at values of ~80%. Interestingly, under most of the conditions tested, clay-based materials also showed comparable pressure drop values than those of plastic rings., Junta de Castilla y León - (grant CLU 2017-09)

Background Osteosarcoma is the most common malignant bone tumor in children and young adults that produces aberrant osteoid. The aim of this study was to assess the utility of 2-deoxy-2-[18F-] fluoro-D-glucose ([18F] FDG) and sodium [18F] Fluoride (Na [18F] F) PET scans in orthotopic murine models of osteosarcoma to describe the metabolic pattern of the tumors, to detect and diagnose tumors and to evaluate the efficacy of a new treatment based in oncolytic adenoviruses. Methods Orthotopic osteosarcoma murine models were created by the injection of 143B and 531MII cell lines. [18F]FDG and Na [18F] F PET scans were performed 30 days (143B) and 90 days (531MII) post-injection. The antitumor effect of two doses (107 and 108 pfu) of the oncolytic adenovirus VCN-01 was evaluated in 531 MII model by [18F] FDG PET studies. [18F] FDG uptake was quantified by SUVmax and Total Lesion Glycolysis (TLG) indexes. For Na [18F] F, the ratio tumor SUVmax/hip SUVmax was calculated. PET findings were confirmed by histopathological techniques. Results The metabolic pattern of tumors was different between both orthotopic models. All tumors showed [18F] FDG uptake, with a sensitivity and specificity of 100%. The [18F] FDG uptake was significantly higher for the 143B model (p

Because of the refractory nature of mutant

Réflexion sur la fonction et le sens des dédicaces faites à des femmes dans les recueils de poésie publiés entre 1650 et 1750. Sur plus de 300 titres, on compte en effet 38 dédicaces féminines, qui traduisent certains changements quantitatifs et qualitatifs repérables dans ce type de paratexte lors de la période considérée par rapport à la précédente. Ces changements sont à mettre en rapport avec la présence plus marquée de la femme dans la culture du livre et avec son rôle plus actif aussi bien dans la production poétique que dans la sanction littéraire à l’époque en question. The aim of this paper is to reflect on the role and meaning of dedications to women in Spanish poetry books printed between 1650 and 1750. After analyzing 38 poetic works dedicated to women, out of a corpus of over 300 works, it can be assumed that there were quantitative and qualitative changes in this kind of paratext in the transition from Golden Age to Low Baroque. Such changes have to do with the increasing presence of women in book culture and a more active role in both poetic production and literary sanction in the period 1650-1750. El objetivo del presente trabajo es reflexionar sobre la función y el sentido de las dedicatorias femeninas en la poesía española impresa entre 1650 y 1750. Después de analizar 38 obras poéticas dirigidas a mujeres, de entre un corpus de más 300 obras, se puede asumir que existen cambios cuantitativos y cualitativos en esta clase de paratexto en la transición desde el primer Siglo de Oro al bajo barroco. Tales cambios tienen que ver con la mayor presencia de la mujer en la cultura del libro y con un más activo papel tanto en la producción poética como en la sanción literaria en el período 1650-1750.

Background Index lesion characterization is important in the evaluation of primary prostate carcinoma (PPC). The aim of this study was to analyze the contribution of 11C-Choline PET/CT and the Apparent Diffusion Coefficient maps (ADC) in detecting the Index Lesion and clinically significant tumors in PPC. Methods Twenty-one untreated patients with biopsy-proven PPC and candidates for radical prostatectomy (RP) were prospectively evaluated by means of Ultra-High Definition PET/CT and 3T MRI, which included T2-weighted imaging (T2WI) and ADC maps obtained from diffusion weighted imaging (DWI). Independent experts analyzed all the images separately and were unaware of the pathological data. In each case, the Index lesion was defined as the largest tumor measured on histopathology (Index H). In addition, the largest lesion observed on MRI (Index MRI) and the highest avid 11C-Choline uptake lesion (Index PET) were obtained. The Gleason scores (GS) of the tumors were determined. PET/CT and ADC map quantitative parameters were also calculated. Measures of correlation among imaging parameters as well as the sensitivity (S), specificity (Sp), negative and positive predictive values (NPV and PPV) for tumor detection were analyzed. All data was validated with the pathological study. Results In the morphological study, 139 foci of carcinoma were identified, 47 of which corresponded to clinically significant tumors (>0.5 cm3). The remaining foci presented a maximum diameter (dmax) of 0.1 cm ± SD 0.75 and were not classified as clinically significant. Thirty-two tumors presented a GS (3 + 3), nine GS (3 + 4), and six GS (4 + 3). A total of 21 Index H (dmax = 1.37 cm SD ± 0.61) were identified. The S, Sp, NPV, and PPV for tumor detection with PET were 100%, 70%, 83%, 100%, and for MRI were 46%, 100%, 100%, 54%, respectively. Both Index PET and Index MRI were complementary and identified 95% of the Index H when quantitative criteria were used. Conclusion In spite of the fact that PET imaging has higher tumor sensitivity than MRI, 11C-Choline PET and ADC maps have complementary roles in the evaluation of Index Lesion in PPC. Index PET and Index MRI could be complementary targets in the therapeutic planning of PPC. Prostate © 2015 Wiley Periodicals, Inc.

Automatic evaluation is a challenging field that has been addressed by the academic community in order to reduce the assessment workload. In this work we present a new element for the authoring tool Easy Java Simulations (EJS). This element, which is named automatic evaluation element (AEE), provides automatic evaluation to virtual and remote laboratories built with EJS by using the server application Goodle grading management system (GMS). The integration of both tools entitles a professor to create interactive virtual and remote laboratories and automatically evaluate the work of their students. As a test bed two case studies are presented; a non-linear controller design virtual laboratory used in an advanced control master course and a servomechanism virtual laboratory used in an undergraduate basic control course.

Background— Microvascular endothelium in different organs is specialized to fulfill the particular needs of parenchymal cells. However, specific information about heart capillary endothelial cells (ECs) is lacking. Methods and Results— Using microarray profiling on freshly isolated ECs from heart, brain, and liver, we revealed a genetic signature for microvascular heart ECs and identified Meox2/Tcf15 heterodimers as novel transcriptional determinants. This signature was largely shared with skeletal muscle and adipose tissue endothelium and was enriched in genes encoding fatty acid (FA) transport–related proteins. Using gain- and loss-of-function approaches, we showed that Meox2/Tcf15 mediate FA uptake in heart ECs, in part, by driving endothelial CD36 and lipoprotein lipase expression and facilitate FA transport across heart ECs. Combined Meox2 and Tcf15 haplodeficiency impaired FA uptake in heart ECs and reduced FA transfer to cardiomyocytes. In the long term, this combined haplodeficiency resulted in impaired cardiac contractility. Conclusions— Our findings highlight a regulatory role for ECs in FA transfer to the heart parenchyma and unveil 2 of its intrinsic regulators. Our insights could be used to develop new strategies based on endothelial Meox2/Tcf15 targeting to modulate FA transfer to the heart and remedy cardiac dysfunction resulting from altered energy substrate usage.