Estudios del efecto antiagregante plaquetario in vitro de compuestos quinolinicos y tetrahidroquinolinicos

45 p.Hoy en día las Enfermedades Cardiovasculares (ECV) son la principal causa de muerte en el mundo. El suceso final en las ECV es la trombosis arterial, siendo,las plaquetas actoras muy importantes en este evento. Hoy se sabe que las plaquetas, además de participar en la patogenia de estados precursores de la aterogénesis, también participan en la fase final (trombosis). Existen diversos tratamientos para las ECV, entre ellos el uso de fármacos antiagregantes plaquetarios, sin embargo, algunos de éstos conllevan efectos secundarios adversos y además existe un porcentaje de pacientes que no obtiene los resultados esperados debido a resistencia a la terapia antiagregante, en dicho contexto, es importante la búsqueda de nuevos antiagregantes plaquetarios, los que permitirían nuevas alternativas para aquellos pacientes que presenten las situaciones antes mencionadas. Este estudio consistió en la búsqueda de efecto antiagregante en diez compuestos de la familia de quinolinas y tetrahidroquinolinas, sintetizadas en el laboratorio del Dr. Luis Astudillo, del Instituto de Química de Productos Naturales de la Universidad de Talca. El efecto antiagregante de dichas moléculas se estudió in vitro a través del método de agregación plaquetaria, utilizando cuatro agonistas: adenosín difosfato (ADP), ácido araquidónico, péptido activador del receptor de trombina (TRAP) y colágeno. Se consideró que presentaban efecto antiagregante a aquellos compuestos químicos que presentaron disminución significativa del porcentaje de agregación plaquetaria en comparación a control negativo. Las quinolinas 47S y 47HS y las tetrahidroquinolinas 45 y 59 inhibieron la agregación plaquetaria en alrededor 50%. El efecto antiplaquetario observado en algunas de las moléculas estudiadas permiten proponer estudios posteriores, tendientes a conocer los mecanismos del efecto antiplaquetario encontrado

Two RNA-binding motifs in eIF3 direct HCV IRES-dependent translation.

The initiation of protein synthesis plays an essential regulatory role in human biology. At the center of the initiation pathway, the 13-subunit eukaryotic translation initiation factor 3 (eIF3) controls access of other initiation factors and mRNA to the ribosome by unknown mechanisms. Using electron microscopy (EM), bioinformatics and biochemical experiments, we identify two highly conserved RNA-binding motifs in eIF3 that direct translation initiation from the hepatitis C virus internal ribosome entry site (HCV IRES) RNA. Mutations in the RNA-binding motif of subunit eIF3a weaken eIF3 binding to the HCV IRES and the 40S ribosomal subunit, thereby suppressing eIF2-dependent recognition of the start codon. Mutations in the eIF3c RNA-binding motif also reduce 40S ribosomal subunit binding to eIF3, and inhibit eIF5B-dependent steps downstream of start codon recognition. These results provide the first connection between the structure of the central translation initiation factor eIF3 and recognition of the HCV genomic RNA start codon, molecular interactions that likely extend to the human transcriptome

Genomic Instability in Newborn with Short Telomeres

Telomere length is considered to be a risk factor in adults due to its proved association with cancer incidence and mortality. Since newborn present a wide interindividual variation in mean telomere length, it is relevant to demonstrate if these differences in length can act also as an early risk indicator. To answer this question, we have measured the mean telomere length of 74 samples of cord blood from newborns and studied its association with the basal genetic damage, measured as the frequency of binucleated cells carrying micronuclei. In addition, we have challenged the cells of a subgroup of individuals (N = 35) against mitomycin-C (MMC) to establish their sensitivity to induced genomic instability. Results indicate that newborn with shorter telomeres present significantly higher levels of genetic damage when compared to those with longer telomeres. In addition, the cellular response to MMC was also significantly higher among those samples from subjects with shorter telomeres. Independently of the causal mechanisms involved, our results show for the first time that telomere length at delivery influence both the basal and induced genetic damage of the individual

Erratum: Fernandez-Palomo, C., et al. Animal Models in Microbeam Radiation Therapy: A Scoping Review. Cancers 2020, 12, 527.

The authors wish to make the following corrections to this paper [...]

Two RNA-binding motifs in eIF3 direct HCV IRES-dependent translation

The initiation of protein synthesis plays an essential regulatory role in human biology. At the center of the initiation pathway, the 13-subunit eukaryotic translation initiation factor 3 (eIF3) controls access of other initiation factors and mRNA to the ribosome by unknown mechanisms. Using electron microscopy (EM), bioinformatics and biochemical experiments, we identify two highly conserved RNA-binding motifs in eIF3 that direct translation initiation from the hepatitis C virus internal ribosome entry site (HCV IRES) RNA. Mutations in the RNA-binding motif of subunit eIF3a weaken eIF3 binding to the HCV IRES and the 40S ribosomal subunit, thereby suppressing eIF2-dependent recognition of the start codon. Mutations in the eIF3c RNA-binding motif also reduce 40S ribosomal subunit binding to eIF3, and inhibit eIF5B-dependent steps downstream of start codon recognition. These results provide the first connection between the structure of the central translation initiation factor eIF3 and recognition of the HCV genomic RNA start codon, molecular interactions that likely extend to the human transcriptome. © 2013 The Author(s)National Institutes of Health (NIH) [R56-AI095687 to J.H.D.C.; P50-GM102706 to J.A.D. and J.H.D.C.]; Spanish Ministry of Education through the Programa Nacional de Movilidad de Recursos Humanos del Plan Nacional de I-D+i 2008-2011 (to E.A.-P.). J.A.D. and E.N. are Howard Hughes Medical Institute Investigators. Funding for open access charge: NIH [P50-GM102706]Peer Reviewe

TRANSMISSION OF SIGNALS FROM RATS RECEIVING HIGH DOSES OF MICROBEAM RADIATION TO CAGE MATES: AN INTER-MAMMAL BYSTANDER EFFECT

Inter-animal signaling from irradiated to non-irradiated organisms has been demonstrated for whole body irradiated mice and also for fish. The aim of the current study was to look at radiotherapy style limited exposure to part of the body using doses relevant in preclinical therapy. High dose homogenous field irradiation and the use of irradiation in the microbeam radiation therapy mode at the European Synchrotron Radiation Facility (ESRF) at Grenoble was tested by giving high doses to the right brain hemisphere of the rat. The right and left cerebral hemispheres and the urinary bladder were later removed to determine whether abscopal effects could be produced in the animals and also whether effects occurred in cage mates housed with them. The results show strong bystander signal production in the contra-lateral brain hemisphere and weaker effects in the distant bladder of the irradiated rats. Signal strength was similar or greater in each tissue in the cage mates housed for 48hrs with the irradiated rats. Our results support the hypothesis that proximity to an irradiated animal induces signalling changes in an unirradiated partner. If similar signaling occurs between humans, the results could have implications for caregivers and hospital staff treating radiotherapy patients

Targeted Accumulation of Macrophages Induced by Microbeam Irradiation in a Tissue-Dependent Manner

Radiation therapy (RT) is a vital component of multimodal cancer treatment, and its immunomodulatory effects are a major focus of current therapeutic strategies. Macrophages are some of the first cells recruited to sites of radiation-induced injury where they can aid in tissue repair, propagate radiation-induced fibrogenesis and influence tumour dynamics. Microbeam radiation therapy (MRT) is a unique, spatially fractionated radiation modality that has demonstrated exceptional tumour control and reduction in normal tissue toxicity, including fibrosis. We conducted a morphological analysis of MRT-irradiated normal liver, lung and skin tissues as well as lung and melanoma tumours. MRT induced distinct patterns of DNA damage, reflecting the geometry of the microbeam array. Macrophages infiltrated these regions of peak dose deposition at variable timepoints post-irradiation depending on the tissue type. In normal liver and lung tissue, macrophages clearly demarcated the beam path by 48 h and 7 days post-irradiation, respectively. This was not reflected, however, in normal skin tissue, despite clear DNA damage marking the beam path. Persistent DNA damage was observed in MRT-irradiated lung carcinoma, with an accompanying geometry-specific influx of mixed M1/M2-like macrophage populations. These data indicate the unique potential of MRT as a tool to induce a remarkable accumulation of macrophages in an organ/tissue-specific manner. Further characterization of these macrophage populations is warranted to identify their organ-specific roles in normal tissue sparing and anti-tumour responses

Microbeam Radiation Therapy controls local growth of radioresistant melanoma and treats out-of-field locoregional metastasis.

PURPOSE Synchrotron-generated microbeam radiotherapy (MRT) represents an innovative preclinical type of cancer radiotherapy with an excellent therapeutic ratio. Beyond local control, metastatic spread is another important endpoint to assess the effectiveness of radiotherapy treatment. Currently, no data exists on an association between MRT and metastasis. Here, we evaluated the ability of MRT to delay B16F10 murine melanoma progression and locoregional metastatic spread. METHODS AND MATERIALS We assessed the primary tumor response and the extent of metastasis in sentinel lymph nodes in two cohorts of C57BL/6J mice, one receiving a single MRT and another receiving two MRT delivered with a 10-day interval. We compared these two cohorts with synchrotron broad beam-irradiated and non-irradiated mice. In addition, using multi-plex quantitative platforms, we measured plasma concentrations of 34 pro- and anti-inflammatory cytokines and frequencies of immune cell subsets infiltrating primary tumors that received either one or two MRT treatments. RESULTS Two MRT treatments were significantly more effective for local control than single MRT. Remarkably, the second MRT also triggered a pronounced regression of out-of-radiation field locoregional metastasis. Augmentation of CXCL5, CXCL12 and CCL22 levels after the second MRT indicated that inhibition of melanoma progression could be associated with increased activity of anti-tumor neutrophils and T-cells. Indeed, we demonstrated elevated infiltration of neutrophils and activated T-cells in the tumors following the second MRT. CONCLUSIONS Our study highlights the importance of monitoring metastasis following MRT and provides the first MRT fractionation schedule that promotes local and locoregional control with the potential to manage distant metastasis

Developing multiscale and integrative nature–people scenarios using the Nature Futures Framework

1. Scientists have repeatedly argued that transformative, multiscale global scenarios are needed as tools in the quest to halt the decline of biodiversity and achieve sustainability goals. 2. As a first step towards achieving this, the researchers who participated in the scenarios and models expert group of the Intergovernmental Science‐Policy Platform on Biodiversity and Ecosystem Services (IPBES) entered into an iterative, participatory process that led to the development of the Nature Futures Framework (NFF). 3. The NFF is a heuristic tool that captures diverse, positive relationships of humans with nature in the form of a triangle. It can be used both as a boundary object for continuously opening up more plural perspectives in the creation of desirable nature scenarios and as an actionable framework for developing consistent nature scenarios across multiple scales. 4. Here we describe the methods employed to develop the NFF and how it fits into a longer term process to create transformative, multiscale scenarios for nature. We argue that the contribution of the NFF is twofold: (a) its ability to hold a plurality of perspectives on what is desirable, which enables the development of joint goals and visions and recognizes the possible convergence and synergies of measures to achieve these visions and (b), its multiscale functionality for elaborating scenarios and models that can inform decision‐making at relevant levels, making it applicable across specific places and perspectives on nature. 5. If humanity is to achieve its goal of a more sustainable and prosperous future rooted in a flourishing nature, it is critical to open up a space for more plural perspectives of human–nature relationships. As the global community sets out to develop new goals for biodiversity, the NFF can be used as a navigation tool helping to make diverse, desirable futures possible

Developing multiscale and integrative nature–people scenarios using the Nature Futures Framework

1. Scientists have repeatedly argued that transformative, multiscale global scenarios are needed as tools in the quest to halt the decline of biodiversity and achieve sustainability goals. 2. As a first step towards achieving this, the researchers who participated in the scenarios and models expert group of the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services (IPBES) entered into an iterative, participatory process that led to the development of the Nature Futures Framework (NFF). 3. The NFF is a heuristic tool that captures diverse, positive relationships of humans with nature in the form of a triangle. It can be used both as a boundary object for continuously opening up more plural perspectives in the creation of desirable nature scenarios and as an actionable framework for developing consistent nature scenarios across multiple scales. 4. Here we describe the methods employed to develop the NFF and how it fits into a longer term process to create transformative, multiscale scenarios for nature. We argue that the contribution of the NFF is twofold: (a) its ability to hold a plurality of perspectives on what is desirable, which enables the development of joint goals and visions and recognizes the possible convergence and synergies of measures to achieve these visions and (b), its multiscale functionality for elaborating scenarios and models that can inform decision-making at relevant levels, making it applicable across specific places and perspectives on nature. 5. If humanity is to achieve its goal of a more sustainable and prosperous future rooted in a flourishing nature, it is critical to open up a space for more plural per- spectives of human–nature relationships. As the global community sets out to de- velop new goals for biodiversity, the NFF can be used as a navigation tool helping to make diverse, desirable futures possible