Computed tomography assesment in the characterization of mouse model for Costello Syndrome

Proceeding of: 2008 World Molecular Imaging Congress (WMIC 2008), 10-13 september 2008. Nice, Franc

Clickable albumin nanoparticles for pretargeted drug delivery toward PD-L1 overexpressing tumors in combination immunotherapy

We present a simple methodology to design a pretargeted drug delivery system, based on clickable anti-programmed death ligand 1 (anti-PD-L1) antibodies (Abs) and clickable bovine serum albumin (BSA) nanoparticles (NPs). Pretargeted drug delivery is based on the decoupling of a targeting moiety and a drug-delivering vector which can then react in vivo after separate injections. This may be key to achieve active targeting of drug-delivering NPs toward cancerous tissue. In pretargeted approaches, drug-delivering NPs were observed to accumulate in a higher amount in the targeted tissue due to shielding-related enhanced blood circulation and size-related enhanced tissue penetration. In this work, BSA NPs were produced using the solvent precipitation methodology that renders colloidally stable NPs, which were subsequently functionalized with a clickable moiety based on chlorosydnone (Cl-Syd). Those reactive groups are able to specifically react with dibenzocyclooctyne (DBCO) groups in a click-type fashion, reaching second-order reaction rate constants as high as 1.9 M-1·s-1, which makes this reaction highly suitable for in vivo applications. The presence of reactive Cl-Syd was demonstrated by reacting the functionalized NPs with a DBCO-modified sulfo-cyanine-5 dye. With this reaction, it was possible to infer the number of reactive moieties per NPs. Finally, and with the aim of demonstrating the suitability of this system to be used in pretargeted strategies, functionalized fluorescent NPs were used to label H358 cells with a clickable anti-PD-L1 Ab, applying the reaction between Cl-Syd and DBCO as corresponding clickable groups. The results of these experiments demonstrate the bio-orthogonality of the system to perform the reaction in vitro, in a period as short as 15 mi

Analysis of Y chromosome STR haplotypes in the European part of Russia reveals high diversities but non-significant genetic distances between populations

A total of 17 Y-specific STR loci were studied in 12 districts of the European part of Russia aiming to ascertain the amount of substructure required for the construction of a representative regional database. All groups exhibited high haplotype diversities but low inter-population variance as measured by an analysis of molecular variance. However, when Western Russia is taken as a whole, the genetic distances to the neighbouring populations were significant. Whereas gradual change in the Y chromosome pool exists between Russia and the Slavic-speaking populations to the West, remarkable discontinuities were observed with neighbouring populations in the East, North and South

DNA methylation epigenotypes in breast cancer molecular subtypes

12 páginas, 3 figuras, 3 tablas.-- et al.[Introduction]: Identification of gene expression-based breast cancer subtypes is considered a critical means of prognostication. Genetic mutations along with epigenetic alterations contribute to gene-expression changes occurring in breast cancer. So far, these epigenetic contributions to sporadic breast cancer subtypes have not been well characterized, and only a limited understanding exists of the epigenetic mechanisms affected in those particular breast cancer subtypes. The present study was undertaken to dissect the breast cancer methylome and to deliver specific epigenotypes associated with particular breast cancer subtypes. [Methods]: By using a microarray approach, we analyzed DNA methylation in regulatory regions of 806 cancer-related genes in 28 breast cancer paired samples. We subsequently performed substantial technical and biologic validation by pyrosequencing, investigating the top qualifying 19 CpG regions in independent cohorts encompassing 47 basal-like, 44 ERBB2+ overexpressing, 48 luminal A, and 48 luminal B paired breast cancer/adjacent tissues. With the all-subset selection method, we identified the most subtype-predictive methylation profiles in multivariable logistic regression analysis. [Results]: The approach efficiently recognized 15 individual CpG loci differentially methylated in breast cancer tumor subtypes. We further identified novel subtype-specific epigenotypes that clearly demonstrate the differences in the methylation profiles of basal-like and human epidermal growth factor 2 (HER2)-overexpressing tumors. [Conclusions]: Our results provide evidence that well-defined DNA methylation profiles enable breast cancer subtype prediction and support the utilization of this biomarker for prognostication and therapeutic stratification of patients with breast cancer.This work was supported by grants from project CGL2008-01131 (Departamento de Sanidad del Gobierno Vasco), S-PE08UN45 and PE09BF02 (Departamento de Ciencia y Tecnologia del Gobierno Vasco), BIO2008-04212, and RD06/0020/1019 (Red Tematica de Investigacion Cooperativa en Cancer, RTICC) from the MICINN. The CIBER de Enfermedades Raras is an initiative of the ISCIII. NGB had a doctoral fellowship from the Basque Government (Departamento de Educacion, Universidades e Investigacion).Peer reviewe

Sometidos a esclavitud: los africanos y sus descendientes en el Caribe Hispano

Con autorización de la editorial para este libro. La edición estuvo a cargo de Consuelo Naranjo Orovio.Sometidos a esclavitud: los africanos y sus descendientes en el Caribe hispano contribuye al estudio de la historia Atlántica en la que la esclavización de millones de africanos fue uno de principales factores que generaron e impulsaron el desarrollo del mundo moderno. La formación de redes comerciales, compañías mercantiles y negocios particulares contribuyeron a conectar mundos y a hacerlos interdependientes. Junto a las mercancías, individuos y productos, viajaron ideas y tradiciones que fueron tejiendo la historia atlántica. En ella, la esclavización, los esclavizados y los afrodescendientes fueron y son partes destacadas, como muestra su legado presente de las culturas americanas. Estos estudios de la obra se suman a investigaciones que, desde distintos países, proyectos, grupos de investigación y enfoques, se están realizando sobre un tema tan rico, diverso y complejo como es la esclavitud atlántica. El espacio temporal que recorren los capítulos se prolonga en el tiempo como lo hizo la trata y el sistema esclavista. Lo mismo ocurre con los territorios afectados por este fenómeno. Su cartografía es una larga sombra que se expande por el mundo atlántico desde el siglo XVI hasta las últimas décadas del siglo XIX. Distintos actores y puntos de África, Europa y América emergen como protagonistas del sometimiento, el comercio y la esclavización de más de doce millones y medio de africanos.Este libro se inserta en el proyecto europeo Connected Worlds: The Caribbean, Origin of Modern World. This project has received funding from the European Union´s Horizon 2020 research and innovation programme under the Marie Sklodowska Curie grant agreement Nº 823846. This project is directed by professor Consuelo Naranjo Orovio, Institute of History-CSIC.Peer reviewe

Slavery and the african cultural legacy in the Caribbean

Con autorización de la editorial para este libro.[EN] The purpose of this book is to raise awareness among a wide audience of one of the most significant and shameful phenomena for humanity, as was the enslavement of over twelve and a half million Africans who were brought to America and forced to work and live as slaves. Many countries participated in the slave trade at different times and withvaried intensity (Great Britain, Portugal, France, Spain, Denmark, Netherlands, Germany, United States...).[ES] El propósito de esta obra es dar a conocer a un público amplio uno de los fenómenos de mayor trascendencia y vergüenza para la humanidad como fue la esclavización de más de doce millones y medio de africanos que fueron trasladados a América, obligados a trabajar y vivir como esclavos. Muchos países participaron en la trata de esclavos en distintos momentos y con diferente intensidad (Gran Bretaña, Portugal, Francia, España, Dinamarca, Países Bajos, Alemania, Estados Unidos…).Connected Worlds: The Caribbean, Origin of Modern World. This project has received funding from the European Union´s Horizon 2020 research and innovation programme under the Marie Sklodowska Curie grant agreement Nº 823846. This project is directed by professor Consuelo Naranjo Orovio, Institute of History-CSIC.Peer reviewe

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Calcineurin undergoes a conformational switch evoked via peptidyl-prolyl isomerization

Copyright: © 2015 Guasch et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. A limited repertoire of PPP family of serine/threonine phosphatases with a highly conserved catalytic domain acts on thousands of protein targets to orchestrate myriad central biological roles. A major structural reorganization of human calcineurin, a ubiquitous Ser/Thr PPP regulated by calcium and calmodulin and targeted by immunosuppressant drugs cyclosporin A and FK506, is unveiled here. The new conformation involves trans- to cis- isomerization of proline in the SAPNY sequence, highly conserved across PPPs, and remodels the main regulatory site where NFATc transcription factors bind. Transitions between cis- and trans- conformations may involve peptidyl prolyl isomerases such as cyclophilin A and FKBP12, which are known to physically interact with and modulate calcineurin even in the absence of immunosuppressant drugs. Alternative conformations in PPPs provide a new perspective on interactions with substrates and other protein partners and may foster development of more specific inhibitors as drug candidates.This work was supported by grants SAF2009-08216-BFU2012-36827 from Ministerio de Ciencia e Innovación and 2009SGR1490-2014SGR987 from the Generalitat de Catalunya. A. A.-I. was a recipient of an FI PhD fellowship from Generalitat de CatalunyaPeer Reviewe

Therapeutic inhibition of TRF1 impairs the growth of p53-deficient K-RasG12V-induced lung cancer by induction of telomeric DNA damage

We are indebted to R. Serrano for animal care. We thank C. Guerra, R. Blasco, and D. Santamaria for scientific and technical advice. M.A.B.'s laboratory is funded with the Spanish Ministry of Science and Innovation, projects SAF2008-05384 and 2007-A-200950 (TELOMARKER), European Research Council Advanced grant GA#232854, the Korber Foundation, Fundacion Botin, and Fundacion Lilly.Telomeres are considered anti-cancer targets, as telomere maintenance above a minimum length is necessary for cancer growth. Telomerase abrogation in cancer-prone mouse models, however, only decreased tumor growth after several mouse generations when telomeres reach a critically short length, and this effect was lost upon p53 mutation. Here, we address whether induction of telomere uncapping by inhibition of the TRF1 shelterin protein can effectively block cancer growth independently of telomere length. We show that genetic Trf1 ablation impairs the growth of p53-null K-Ras(G12V)-induced lung carcinomas and increases mouse survival independently of telomere length. This is accompanied by induction of telomeric DNA damage, apoptosis, decreased proliferation, and G2 arrest. Long-term whole-body Trf1 deletion in adult mice did not impact on mouse survival and viability, although some mice showed a moderately decreased cellularity in bone marrow and blood. Importantly, inhibition of TRF1 binding to telomeres by small molecules blocks the growth of already established lung carcinomas without affecting mouse survival or tissue function. Thus, induction of acute telomere uncapping emerges as a potential new therapeutic target for lung cancer.S