In vivo evaluation of the role of Delta-like 4/Notch signaling in the development of intestinal tumors

Tese de Doutoramento em Ciências Veterinárias, especialidade de Ciências Biológicas e BiomédicasColorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer-related death in the Western world. Dll4/Notch signaling has been shown to regulate tumor angiogenesis and cancer stem cell maintenance in CRC, but how it affects the intestinal precancerous lesions that lead to CRC initiation is not known. Therefore we evaluated the role of Dll4/Notch pathway during intestinal tumorigenesis. For that we used two well-established mouse models of CRC, the ApcMin/+ autochthonous transgenic model and the azoxymethane plus dextran sodium sulphate chemically induced model of chronic colitis associated-cancer (CAC). First we analyzed the protein expression pattern of Dll4 and other Notch pathway members in these settings relatively to that in the normal gut. Then we evaluated the effect of endothelial-specific or ubiquitous Dll4 deregulation and performed a therapeutic trial with the Dll4 inhibitor Dll4-Fc. This protein was administered alone, and in combination with the epidermal growth factor receptor (EGFR)-specific tyrosine kinase inhibitor erlotinib to assess if the anti-Dll4 therapy mediated vascular defects impaired the delivery of other anti-cancer drugs to the tumors. We observed that the Notch pathway is activated in the two studied models of CRC. The normal protein expression pattern of Notch pathway members in the gut is altered in chronic colitis and in ApcMin/+ and colitis-driven intestinal tumors. Dll4 is the most upregulated ligand in the intestinal adenomas in both models of CRC and is present in both tumor epithelium and stroma. Both Dll4 blockade (endothelial-specific and ubiquitously) and activation (endothelial-specific) have an inhibitory effect on intestinal tumor initiation and growth by promoting a noncompetent vasculature or decreasing the vessel density, respectively. Besides its angiogenic related effects, Dll4/Notch pathway promotes excessive inflammation in CAC, sustains the tumor stem cell pool and tumor proliferation synergistically with Wnt signaling, and inhibits differentiation mainly of the secretory cells. In addition, the effectiveness of erlotinib is not affected by Dll4-Fc, where these therapies additively inhibit intestinal tumorigenesis.RESUMO - Avaliação in vivo da função da sinalização intercelular Dll4/Notch no desenvolvimento de tumores intestinais - O cancro colo-rectal (CCR) é o terceiro tipo de cancro mais comum e é uma das principais causas de morte no Mundo Ocidental. O CCR geralmente desenvolve-se esporadicamente, mas também pode ser hereditário como na síndrome polipose adenomatosa familiar (PAF). A PAF está associada à ativação da via de sinalização Wnt através de mutações no gene supressor tumoral Adenomatous Polyposis Coli (APC), que também ocorre frequentemente nos CCR esporádicos. O desenvolvimento do CCR também pode estar associado a inflamação crónica, nomeadamente à doença de Crohn (CD) e à colite ulcerativa (UC). Infelizmente o desenvolvimento de novas estratégias terapêuticas ou preventivas que tenham como alvo vias de sinalização críticas no desenvolvimento do CCR continua a ser extremamente necessário. Uma dessas estratégias tem como alvo a angiogénese tumoral. O primeiro agente anti-angiogénico a ser aprovado foi o Bevacizumab, que é usado em combinação com outros fármacos no tratamento do CCR metastático. No entanto, a utilização deste fármaco leva ao aparecimento de efeitos secundários e resistência tumoral e em tumores não metastáticos não se tem mostrado eficaz. Assim, continua a ser necessário desenvolver melhores estratégias terapêuticas anti-angiogénicas...Centro de Investigação Interdisciplinar em Sanidade Animal (CIISA) e União Europeia: Fundo Social Europe

Combination of Dll4/Notch and Ephrin-B2/EphB4 targeted therapy is highly effective in disrupting tumor angiogenesis

<p>Abstract</p> <p>Background</p> <p>Dll4/Notch and Ephrin-B2/EphB4 pathways play critical roles in tumor vessel development and maturation. This study evaluates the efficacy of the inhibition of both signaling pathways, alone and in combination, in reducing the growth of an autochthonous mouse tumor and assesses potential adverse effects.</p> <p>Methods</p> <p>We used the transgenic RIP1-Tag2 tumor model to study the effects of 1) inhibition of Dll4/Notch by either <it>Dll4 </it>allelic deletion or use of a soluble extracellular Dll4 (sDll4), 2) inhibition of Ephrin-B2/EphB4 signaling by a soluble extracellular EphB4 fused to albumin (sEphB4-Alb), and 3) inhibition of both pathways by sEphB4-Alb combined with either <it>Dll4 </it>allelic deletion or sDll4. To investigate adverse effects, we used inducible endothelial-specific <it>Dll4 </it>knock-out mice, treated with sEphB4-Alb, and carried out histopathological analysis.</p> <p>Results</p> <p><it>Dll4 </it>allele deletion or soluble Dll4 treatment resulted in increased tumor vessel density, reduced mural cell recruitment and vessel perfusion which resulted in reduced tumor size. The soluble EphB4 instead reduced vessel density and vessel perfusion, leading to reduction of tumor size. Greater efficacy was observed when sEphB4-Alb was combined with either <it>Dll4 </it>allele deletion or sDll4 in regards to tumor size, vessel perfusion and mural cell recruitment. Induced endothelial specific <it>Dll4 </it>loss-of-function caused hepatic vascular alterations, which were prevented by concomitant sEphB4-Alb treatment.</p> <p>Conclusion</p> <p>Combination targeting of Dll4/Notch and Ephrin-B2/EphB4 has potential for clinical investigation, providing cumulative efficacy and increased safety over Dll4/Notch inhibition alone.</p

Creación de una revista musical digital : K-Stage

Aquest projecte s'ha centrat en crear una revista digital especialitzada en l'estil musical K-Pop, provinent de Corea del Sud. La revista s'anomena K-Stage i tindrà un fort component informatiu donant a conèixer als lectors les principals novetats dels cantants. A banda de l'apartat de notícies, també comptarà amb una secció de crítiques de discos i vídeos musicals i de cròniques de concerts. A K-Stage es donarà molta importància als locals, botigues i esdeveniments del territori espanyol que promoguin aspectes relacionats amb el K-Pop.Este proyecto se ha centrado en crear una revista digital especializada en el estilo musical K-Pop, proveniente de Corea del Sur. La revista lleva por nombre K-Stage y tendrá un fuerte componente informativo dando a conocer a los lectores las principales novedades de los artistas. A parte del apartado de noticias, también contará con una sección de críticas de discos y vídeos musicales y de crónicas de conciertos. En K-Stage se dará mucha importancia a los locales, tiendas y eventos del territorio español que promuevan aspectos relacionados con el K-Pop.This project has focused on creating a digital magazine specialized in the K-Pop musical style, coming from South Korea. Said magazine is called K-Stage and it will have a strong informative component letting the readers know about the latest news of the artists. Besides from the news section, it will also have a segment focalized on musical reviews and articles about concerts. K-Stage will give great importance to the stores, bars and events in the Spanish territory that promote aspects related to the K-Pop style

Close companions around young stars

Multiplicity is a fundamental property that is set early during stellar lifetimes, and it is a stringent probe of the physics of star formation. The distribution of close companions around young stars is still poorly constrained by observations. We present an analysis of stellar multiplicity derived from APOGEE-2 spectra obtained in targeted observations of nearby star-forming regions. This is the largest homogeneously observed sample of high-resolution spectra of young stars. We developed an autonomous method to identify double lined spectroscopic binaries (SB2s). Out of 5007 sources spanning the mass range of $\sim$0.05--1.5 \msun, we find 399 binaries, including both RV variables and SB2s. The mass ratio distribution of SB2s is consistent with a uniform for $q0.95$. The period distribution is consistent with what has been observed in close binaries ($<10$ AU) in the evolved populations. Three systems are found to have $q\sim$0.1, with a companion located within the brown dwarf desert. There are not any strong trends in the multiplicity fraction (MF) as a function of cluster age from 1 to 100 Myr. There is a weak dependence on stellar density, with companions being most numerous at $\Sigma_*\sim30$ stars/pc$^{-2}$, and decreasing in more diffuse regions. Finally, disk-bearing sources are deficient in SB2s (but not RV variables) by a factor of $\sim$2; this deficit is recovered by the systems without disks. This may indicate a quick dispersal of disk material in short-period equal mass systems that is less effective in binaries with lower $q$.Comment: 25 pages, 20 figures. Accepted to A

The Close Binary Fraction as a Function of Stellar Parameters in APOGEE:A Strong Anti-Correlation With α Abundances

We use observations from the APOGEE survey to explore the relationship between stellar parameters and multiplicity. We combine high-resolution repeat spectroscopy for 41,363 dwarf and subgiant stars with abundance measurements from the APOGEE pipeline and distances and stellar parameters derived using \textit{Gaia} DR2 parallaxes from \cite{Sanders2018} to identify and characterise stellar multiples with periods below 30 years, corresponding to \drvm$\gtrsim$ 3 \kms, where \drvm\ is the maximum APOGEE-detected shift in the radial velocities. Chemical composition is responsible for most of the variation in the close binary fraction in our sample, with stellar parameters like mass and age playing a secondary role. In addition to the previously identified strong anti-correlation between the close binary fraction and \feh\, we find that high abundances of $\alpha$ elements also suppress multiplicity at most values of \feh\ sampled by APOGEE. The anti-correlation between $\alpha$ abundances and multiplicity is substantially steeper than that observed for Fe, suggesting C, O, and Si in the form of dust and ices dominate the opacity of primordial protostellar disks and their propensity for fragmentation via gravitational stability. Near \feh{} = 0 dex, the bias-corrected close binary fraction ($a<10$ au) decreases from $\approx$ 100 per cent at \alh{} = $-$0.2 dex to $\approx$ 15 per cent near \alh{} = 0.08 dex, with a suggestive turn-up to $\approx$20 per cent near \alh{} = 0.2. We conclude that the relationship between stellar multiplicity and chemical composition for sun-like dwarf stars in the field of the Milky Way is complex, and that this complexity should be accounted for in future studies of interacting binaries.Comment: 15 pages, 10 figures, plus appendices; accepted to MNRA

Deletion of iRhom2 protects against diet-inducedobesity by increasing thermogenesis

Objective:Obesity is the result of positive energy balance. It can be caused by excessive energy consumption but also by decreased energydissipation, which occurs under several conditions including when the development or activation of brown adipose tissue (BAT) is impaired. Herewe evaluated whether iRhom2, the essential cofactor for the Tumour Necrosis Factor (TNF) sheddase ADAM17/TACE, plays a role in thepathophysiology of metabolic syndrome.Methods:We challenged WT versus iRhom2 KO mice to positive energy balance by chronic exposure to a high fat diet and then compared theirmetabolic phenotypes. We also carried outex vivoassays with primary and immortalized mouse brown adipocytes to establish the autonomy ofthe effect of loss of iRhom2 on thermogenesis and respiration.Results:Deletion of iRhom2 protected mice from weight gain, dyslipidemia, adipose tissue inflammation, and hepatic steatosis and improvedinsulin sensitivity when challenged by a high fat diet. Crucially, the loss of iRhom2 promotes thermogenesis via BAT activation and beigeadipocyte recruitment, enabling iRhom2 KO mice to dissipate excess energy more efficiently than WT animals. This effect on enhanced ther-mogenesis is cell-autonomous in brown adipocytes as iRhom2 KOs exhibit elevated UCP1 levels and increased mitochondrial proton leak.Conclusion:Our data suggest that iRhom2 is a negative regulator of thermogenesis and plays a role in the control of adipose tissue homeostasisduring metabolic diseaseWellcome Trust strategic award (100574/Z/12/Z) and MRC MDU (MC_UU_12012/

Low-Dosage Inhibition of DII4 Signaling Promotes Wound Healing by Inducing Functional Neo-Angiogenesis

Recent findings regarding Dll4 function in physiological and pathological conditions indicate that this Notch ligand may constitute an important therapeutic target. Dll4 appears to be a major anti-angiogenic agent, occupying a central role in various angiogenic pathways. The first trials of anti-Dll4 therapy in mice demonstrated a paradoxical effect, as it reduced tumor perfusion and growth despite leading to an increase in vascular density. This is seen as the result of insufficient maturation of the newly formed vasculature causing a circulatory defect and increased tumor hypoxia. As Dll4 function is known to be closely dependent on expression levels, we envisioned that the therapeutic anti-Dll4 dosage could be modulated to result in the increase of adequately functional blood vessels. This would be useful in conditions where vascular function is a limiting factor for recovery, like wound healing and tissue hypoxia, especially in diabetic patients. Our experimental results in mice confirmed this possibility, revealing that low dosage inhibition of Dll4/Notch signaling causes improved vascular function and accelerated wound healing

The Eighteenth Data Release of the Sloan Digital Sky Surveys: Targeting and First Spectra from SDSS-V

The eighteenth data release of the Sloan Digital Sky Surveys (SDSS) is the first one for SDSS-V, the fifth generation of the survey. SDSS-V comprises three primary scientific programs, or "Mappers": Milky Way Mapper (MWM), Black Hole Mapper (BHM), and Local Volume Mapper (LVM). This data release contains extensive targeting information for the two multi-object spectroscopy programs (MWM and BHM), including input catalogs and selection functions for their numerous scientific objectives. We describe the production of the targeting databases and their calibration- and scientifically-focused components. DR18 also includes ~25,000 new SDSS spectra and supplemental information for X-ray sources identified by eROSITA in its eFEDS field. We present updates to some of the SDSS software pipelines and preview changes anticipated for DR19. We also describe three value-added catalogs (VACs) based on SDSS-IV data that have been published since DR17, and one VAC based on the SDSS-V data in the eFEDS field.Comment: Accepted to ApJ

The eighteenth data release of the Sloan Digital Sky Surveys : targeting and first spectra from SDSS-V

The eighteenth data release of the Sloan Digital Sky Surveys (SDSS) is the first one for SDSS-V, the fifth generation of the survey. SDSS-V comprises three primary scientific programs, or "Mappers": Milky Way Mapper (MWM), Black Hole Mapper (BHM), and Local Volume Mapper (LVM). This data release contains extensive targeting information for the two multi-object spectroscopy programs (MWM and BHM), including input catalogs and selection functions for their numerous scientific objectives. We describe the production of the targeting databases and their calibration- and scientifically-focused components. DR18 also includes ~25,000 new SDSS spectra and supplemental information for X-ray sources identified by eROSITA in its eFEDS field. We present updates to some of the SDSS software pipelines and preview changes anticipated for DR19. We also describe three value-added catalogs (VACs) based on SDSS-IV data that have been published since DR17, and one VAC based on the SDSS-V data in the eFEDS field.Publisher PDFPeer reviewe