Debida diligencia en derechos humanos : análisis del derecho al agua potable en el marco del reasentamiento de la comunidad indígena de Tamaquito II

A nivel internacional se ha surtido un largo camino para regular la responsabilidad de las empresas transnacionales por los impactos de sus operaciones sobre los derechos humanos. Como parte de estos esfuerzos, fueron creados los Principios Rectores sobre empresas y derechos humanos y con ellos el concepto de debida diligencia empresarial. Esta implica un proceso continuo para identificar, prevenir, mitigar y responder por dichos impactos. En esta investigación se tomó como caso de estudio el estado del derecho al agua en el reasentamiento de la comunidad indígena Tamaquito II en La Guajira, Colombia, ocasionado por la actividad minera de la empresa Carbones del Cerrejón Limited. Para esto, se hizo un análisis deductivo, comenzando por el estudio de las iniciativas para regular la responsabilidad de las empresas y en particular de la debida diligencia. Luego se revisó el desarrollo progresivo del derecho al agua a nivel internacional y nacional. Después, se estudiaron las características de los actores involucrados en el caso de estudio. Finalmente, se confrontó el tratamiento del derecho al agua de la comunidad en el reasentamiento frente a los elementos de la debida diligencia y se encontró que muchas de las dificultades enfrentadas por las partes en el proceso, se logran explicar desde los elementos de la debida diligencia empresarial, por lo que esta presenta un mecanismo efectivo para estudiar los impactos en los derechos humanos ocasionados por cualquier empresa, así como la conducta que estas ejecuten para abordar estas situaciones

Targeting Tumor-Associated Macrophages in Anti-Cancer Therapies: Convincing the Traitors to Do the Right Thing

In the last decade, it has been well-established that tumor-infiltrating myeloid cells fuel not only the process of carcinogenesis through cancer-related inflammation mechanisms, but also tumor progression, invasion, and metastasis. In particular, tumor-associated macrophages (TAMs) are the most abundant leucocyte subset in many cancers and play a major role in the creation of a protective niche for tumor cells. Their ability to generate an immune-suppressive environment is crucial to escape the immune system and to allow the tumor to proliferate and metastasize to distant sites. Conventional therapies, including chemotherapy and radiotherapy, are often not able to limit cancer growth due to the presence of pro-tumoral TAMs; these are also responsible for the failure of novel immunotherapies based on immune-checkpoint inhibition. Several novel therapeutic strategies have been implemented to deplete TAMs; however, more recent approaches aim to use TAMs themselves as weapons to fight cancer. Exploiting their functional plasticity, the reprogramming of TAMs aims to convert immunosuppressive and pro-tumoral macrophages into immunostimulatory and anti-tumor cytotoxic effector cells. This shift eventually leads to the reconstitution of a reactive immune landscape able to destroy the tumor. In this review, we summarize the current knowledge on strategies able to reprogram TAMs with single as well as combination therapiesF.T.A. was supported by the AECC (“Asociación Española Contra el Cáncer, Spain). E.D. was supported by AIRC (Associazione Italiana per la Ricerca contro il Cancro)S

Copper-catalyzed O-alkenylation of phosphonates

Copper catalysis allows the direct oxygen alkenylation of dialkyl phosphonates with alkenyl(aryl)iodonium salts with selective transfer of the alkenyl group. This novel methodology proceeds with a wide range of phosphonates under mild conditions and gives straightforward access to valuable enol phosphonates in very good yields.Financial support from the AEI (CTQ2017-88451-R), Xunta de Galicia (ED431F 2016/006; ED431C 2018/04; Centro singular de investigación de Galicia accreditation 2016-2019, ED431G/09) and the European Union (ERDF) is gratefully acknowledged. N. V.-G. thanks AEI for a predoctoral FPI fellowshipS

Zebrafish Models for the Safety and Therapeutic Testing of Nanoparticles with a Focus on Macrophages

Review[Abstract] New nanoparticles and biomaterials are increasingly being used in biomedical research for drug delivery, diagnostic applications, or vaccines, and they are also present in numerous commercial products, in the environment and workplaces. Thus, the evaluation of the safety and possible therapeutic application of these nanomaterials has become of foremost importance for the proper progress of nanotechnology. Due to economical and ethical issues, in vitro and in vivo methods are encouraged for the testing of new compounds and/or nanoparticles, however in vivo models are still needed. In this scenario, zebrafish (Danio rerio) has demonstrated potential for toxicological and pharmacological screenings. Zebrafish presents an innate immune system, from early developmental stages, with conserved macrophage phenotypes and functions with respect to humans. This fact, combined with the transparency of zebrafish, the availability of models with fluorescently labelled macrophages, as well as a broad variety of disease models offers great possibilities for the testing of new nanoparticles. Thus, with a particular focus on macrophage–nanoparticle interaction in vivo, here, we review the studies using zebrafish for toxicological and biodistribution testing of nanoparticles, and also the possibilities for their preclinical evaluation in various diseases, including cancer and autoimmune, neuroinflammatory, and infectious diseases.Xunta de Galicia; ED481A-2018/095A.P.-L. is supported by the Xunta de Galicia Pre-doctoral Fellowship (ED481A-2018/095); F.T.A. is recipient of a grant by the AECC (“Asociación Española Contra el Cáncer”, Spain). J.F.-R. was supported by a scholarship awarded by “Fundación Barrié”

Cellular and Molecular Mechanisms Underlying Glioblastoma and Zebrafish Models for the Discovery of New Treatments

Glioblastoma (GBM) is the most common of all brain malignant tumors; it displays a median survival of 14.6 months with current complete standard treatment. High heterogeneity, aggressive and invasive behavior, the impossibility of completing tumor resection, limitations for drug administration and therapeutic resistance to current treatments are the main problems presented by this pathology. In recent years, our knowledge of GBM physiopathology has advanced significantly, generating relevant information on the cellular heterogeneity of GBM tumors, including cancer and immune cells such as macrophages/microglia, genetic, epigenetic and metabolic alterations, comprising changes in miRNA expression. In this scenario, the zebrafish has arisen as a promising animal model to progress further due to its unique characteristics, such as transparency, ease of genetic manipulation, ethical and economic advantages and also conservation of the major brain regions and blood–brain–barrier (BBB) which are similar to a human structure. A few papers described in this review, using genetic and xenotransplantation zebrafish models have been used to study GBM as well as to test the anti-tumoral efficacy of new drugs, their ability to interact with target cells, modulate the tumor microenvironment, cross the BBB and/or their toxicity. Prospective studies following these lines of research may lead to a better diagnosis, prognosis and treatment of patients with GBMF.T.A. has been supported by the AECC (“Asociación Española Contra el Cáncer”, Spain). We would also like to thank the following: the Talento Program from Madrid Government, Spain (2017-T1/BMD-5333); Convocatoria 2018 de proyectos de I+D+i «RETOS INVESTIGACIÓN» (RTI2018-095061-B-I00) (to C.M.R.); “Convocatoria de ayudas para la contratación de ayudantes de investigación” (PEJ-2018-AI/BMD-9724) (to M.T.-P.); the Xunta de Galicia Pre-doctoral Fellowship (ED481A-2018/095) (to A.P.L.)S

Introducing WikiPathways as a Data-Source to Support Adverse Outcome Pathways for Regulatory Risk Assessment of Chemicals and Nanomaterials

A paradigm shift is taking place in risk assessment to replace animal models, reduce the number of economic resources, and refine the methodologies to test the growing number of chemicals and nanomaterials. Therefore, approaches such as transcriptomics, proteomics, and metabolomics have become valuable tools in toxicological research, and are finding their way into regulatory toxicity. One promising framework to bridge the gap between the molecular-level measurements and risk assessment is the concept of adverse outcome pathways (AOPs). These pathways comprise mechanistic knowledge and connect biological events from a molecular level toward an adverse effect outcome after exposure to a chemical. However, the implementation of omics-based approaches in the AOPs and their acceptance by the risk assessment community is still a challenge. Because the existing modules in the main repository for AOPs, the AOP Knowledge Base (AOP-KB), do not currently allow the integration of omics technologies, additional tools are required for omics-based data analysis and visualization. Here we show how WikiPathways can serve as a supportive tool to make omics data interoperable with the AOP-Wiki, part of the AOP-KB. Manual matching of key events (KEs) indicated that 67% could be linked with molecular pathways. Automatic connection through linkage of identifiers between the databases showed that only 30% of AOP-Wiki chemicals were found on WikiPathways. More loose linkage through gene names in KE and Key Event Relationships descriptions gave an overlap of 70 and 71%, respectively. This shows many opportunities to create more direct connections, for example with extended ontology annotations, improving its interoperability. This interoperability allows the needed integration of omics data linked to the molecular pathways with AOPs. A new AOP Portal on WikiPathways is presented to allow the community of AOP developers to collaborate and populate the molecular pathways that underlie the KEs of AOP-Wiki. We conclude that the integration of WikiPathways and AOP-Wiki will improve risk assessment because omics data will be linked directly to KEs and therefore allow the comprehensive understanding and description of AOPs. To make this assessment reproducible and valid, major changes are needed in both WikiPathways and AOP-Wiki

Mannose-modified hyaluronic acid nanocapsules for the targeting of tumor-associated macrophages

Tumor-associated macrophages (TAMs), a class of immune cells that play a key role in tumor immunosuppression, are recognized as important targets to improve cancer prognosis and treatment. Consequently, the engineering of drug delivery nanocarriers that can reach TAMs has acquired special relevance. This work describes the development and biological evaluation of a panel of hyaluronic acid (HA) nanocapsules (NCs), with different compositions and prepared by different techniques, designed to target macrophages. The results showed that plain HA NCs did not significantly influence the polarization of M0 and M2-like macrophages towards an M1-like pro-inflammatory phenotype; however, the chemical functionalization of HA with mannose (HA-Man) led to a significant increase of NCs uptake by M2 macrophages in vitro and to an improved biodistribution in a MN/MNCA1 fibrosarcoma mouse model with high infiltration of TAMs. These functionalized HA-Man NCs showed a higher accumulation in the tumor compared to non-modified HA NCs. Finally, the pre-administration of the liposomal liver occupying agent Nanoprimer™ further increased the accumulation of the HA-Man NCs in the tumor. This work highlights the promise shown by the HA-Man NCs to target TAMs and thus provides new options for the development of nanomedicine and immunotherapy-based cancer treatmentsOpen Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was supported by the 2^2-INTRATARGET project (A20/00028) funded by the ISCIII under the umbrella of the ERA NET EuroNanoMed GA N 723770 of the EU Horizon 2020 Research and Innovation Programme. This work was also supported by the Xunta de Galicia (ED431C 2018/30, and “Centro singular de investigación de Galicia” accreditation 2019 − 2022, ED431G2019/03), and the European Union (European Regional Development Fund-ERDF)S

Time-Dependent Subcellular Distribution and Effects of Carbon Nanotubes in Lungs of Mice

BACKGROUND AND METHODS:Pulmonary deposited carbon nanotubes (CNTs) are cleared very slowly from the lung, but there is limited information on how CNTs interact with the lung tissue over time. To address this, three different multiwalled CNTs were intratracheally instilled into female C57BL/6 mice: one short (850 nm) and tangled, and two longer (4 μm and 5.7 μm) and thicker. We assessed the cellular interaction with these CNTs using transmission electron microscopy (TEM) 1, 3 and 28 days after instillation. RESULTS:TEM analysis revealed that the three CNTs followed the same overall progression pattern over time. Initially, CNTs were taken up either by a diffusion mechanism or via endocytosis. Then CNTs were agglomerated in vesicles in macrophages. Lastly, at 28 days post-exposure, evidence suggesting CNT escape from vesicle enclosures were found. The longer and thicker CNTs more often perturbed and escaped vesicular enclosures in macrophages compared to the smaller CNTs. Bronchoalveolar lavage (BAL) showed that the CNT exposure induced both an eosinophil influx and also eosinophilic crystalline pneumonia. CONCLUSION:Two very different types of multiwalled CNTs had very similar pattern of cellular interactions in lung tissue, with the longer and thicker CNTs resulting in more severe effects in terms of eosinophil influx and incidence of eosinophilic crystalline pneumonia (ECP)

Recent Discoveries in Nanoparticle–Macrophage Interactions: In Vitro Models for Nanosafety Testing and Novel Nanomedical Approaches for Immunotherapy

Nanoparticles (NPs) offer unique properties for biomedical applications, leading to new nanomedicines [...