The importance of basic and translational research in caring for children with malignant solid tumors in Latin America.

Objective: Basic and translational research in pediatric cancer are essential to improve patient care. To critically assess the developments achieved in these areas in Latin America, we systematically reviewed information published between 2013 and 2023. Methods: Studies of basic and translational research performed by investigators in Latin America evaluating pediatric malignant solid and central nervous system tumors were retrieved from PubMed. Original articles published in English between 2013 and 2023 were included. Collaborations among Latin American authors or among Latin American authors working with researchers from other continents were also included. Studies were excluded if they focused only on adults or on basic research in tumor biology not specifically related to the tumor types analyzed in this review. Results: A total of 550 articles were retrieved, but after removal of duplicates, 514 articles were included in the analysis, the majority of which were authored by researchers affiliated with institutions in Argentina, Brazil and Mexico. These countries also had the highest number of collaborations on original articles published with authors from Europe and North America. Argentina had the highest number of collaborations on original publications, with coauthors from Brazil and Uruguay. The median impact factor of the 244 journals in which articles were published was 3.5. The most commonly studied tumors were osteosarcomas, neuroblastomas and medulloblastomas; the most commonly studied areas were molecular analysis, tumor cell biology and biomarkers. Conclusions: In Latin America, research in pediatric oncology is on the agenda, despite a notable disparity in publication rates and frequency of collaboration between countries. There is a need to strengthen scientific collaboration within Latin America and with countries from other continents to promote research and to develop novel treatment strategies that reflect the local needs of children in Latin America who have solid tumors and brain cancer.

Experiencia de la administración de hierro endovenoso en hospitalización a domicilio mediante elastómeros / Experience of the administration of intravenous iron in hospitalization at home using elastomers

Objetivo: analizar las características clínicas y demográficas de las personas atendidas por la unidad de hospitalización a domicilio (HAD) que recibieron tratamiento de hierro endovenoso en perfusión por bomba elastomérica. Estudio retrospectivo desde enero del 2022 a noviembre del 2023.En total se administró hierro endovenoso con bomba elastomérica en el domicilio a un total de 53 personas siendo estas en un 74% pacientes crónicos complejos o pacientes con enferme-dad crónica avanzada. Ninguna de las personas a las que se les administró el tratamiento de hierro endovenoso presentaron reacciones adversas. Por ello, la administración de hierro endovenoso en el domicilio por el HAD supone una práctica eficaz y segura mejora la calidad de vida de las personas usuarias y su entorno familiar (AU)

Objective: to analyze the clinical and demographic characteristics of the people treated by the home hospitalization unit (HAD) who received intravenous iron treatment in infusion by elastomeric pump. Retrospective study from January 2022 to November 2023. In total, intravenous iron was administered with an elastomeric pump at home to a total of 53 people, 74% of whom were complex chronic patients or patients with advanced chronic disease. None of the people who were administered intravenous iron treatment had adverse reactions.This is why the administration of intravenous iron at home by the HAD is an effective and safe practice and improves the quality of life of users and their family environment. (AU)

The importance of basic and translational research in caring for children with malignant solid tumors in Latin America / La importancia de la investigación básica y aplicada para la atención de pacientes pediátricos con tumores sólidos malignos en América Latina / A importância da pesquisa básica e translacional no tratamento de crianças com tumores sólidos malignos na América Latina

[ABSTRACT]. Objective. Basic and translational research in pediatric cancer are essential to improve patient care. To critically assess the developments achieved in these areas in Latin America, we systematically reviewed information published between 2013 and 2023. Methods. Studies of basic and translational research performed by investigators in Latin America evaluating pediatric malignant solid and central nervous system tumors were retrieved from PubMed. Original articles published in English between 2013 and 2023 were included. Collaborations among Latin American authors or among Latin American authors working with researchers from other continents were also included. Studies were excluded if they focused only on adults or on basic research in tumor biology not specifically related to the tumor types analyzed in this review. Results. A total of 550 articles were retrieved, but after removal of duplicates, 514 articles were included in the analysis, the majority of which were authored by researchers affiliated with institutions in Argentina, Brazil and Mexico. These countries also had the highest number of collaborations on original articles published with authors from Europe and North America. Argentina had the highest number of collaborations on original publications, with coauthors from Brazil and Uruguay. The median impact factor of the 244 journals in which articles were published was 3.5. The most commonly studied tumors were osteosarcomas, neuroblastomas and medulloblastomas; the most commonly studied areas were molecular analysis, tumor cell biology and biomarkers. Conclusions. In Latin America, research in pediatric oncology is on the agenda, despite a notable disparity in publication rates and frequency of collaboration between countries. There is a need to strengthen scientific collaboration within Latin America and with countries from other continents to promote research and to develop novel treatment strategies that reflect the local needs of children in Latin America who have solid tumors and brain cancer.

[RESUMEN]. Objetivo. La investigación básica y aplicada en el campo de la oncología pediátrica es fundamental para mejorar la atención al paciente. Con el objetivo de realizar una evaluación crítica de los avances logrados en este campo en América Latina, hemos realizado una revisión sistemática de la información publicada entre el 2013 y el 2023. Metodología. Se recopilaron de PubMed los artículos de investigación básica y traslacional publicados por investigadores de América Latina en los que se evaluaron tumores malignos sólidos y del sistema nervioso central en la población infantil. Se incluyeron artículos originales publicados en inglés entre el 2013 y el 2023. También se incluyeron artículos fruto de la colaboración científica entre autores e investigadores de América Latina y otros continentes. Se excluyeron aquellos estudios que se centraron solo en personas adultas o en la investigación básica en biología tumoral no relacionada específicamente con los tipos de tumores analizados en esta revisión. Resultados. Se encontraron 550 artículos en total. Después de eliminar los artículos duplicados, se incluyeron 514 artículos en la revisión, la mayoría de los cuales fueron escritos por investigadores vinculados a centros de investigación de Argentina, Brasil y México. También procedieron de estos tres países la mayor parte de los artículos originales escritos en colaboración con autores de Europa y América del Norte. Argentina tuvo el mayor número de colaboraciones en publicaciones originales, con coautores de Brasil y Uruguay. La mediana del índice de impacto de las 244 revistas en las que se publicaron los artículos fue de 3,5. Los tumores más estudiados fueron osteosarcomas, neuroblastomas y meduloblastomas. Los temas más estudiados fueron el análisis molecular, la biología de las células tumorales y los biomarcadores. Conclusiones. La investigación en oncología pediátrica forma parte de la agenda de investigación de América Latina, si bien hay una disparidad notoria en las tasas de publicación y la frecuencia de la colab- oración entre países. Es necesario fortalecer la colaboración científica dentro de América Latina y con los países de otros continentes para promover la investigación y desarrollar estrategias de tratamiento novedosas que respondan a las necesidades locales de los niños y niñas de América Latina que tienen tumores sólidos o cáncer del sistema nervioso central.

[RESUMO]. Objetivo. A pesquisa básica e translacional em câncer pediátrico é essencial para melhorar o atendimento dos pacientes. No intuito de realizar uma avaliação crítica dos avanços alcançados nessa área na América Latina, fez-se uma revisão sistemática de informações publicadas entre 2013 e 2023. Métodos. Pesquisas básicas e translacionais realizadas por pesquisadores da América Latina que avaliaram tumores sólidos malignos e tumores do sistema nervoso central em crianças foram obtidas da base de dados PubMed. Foram incluídos artigos originais publicados em inglês entre 2013 e 2023. Também foram incluídas colaborações entre autores latino-americanos ou entre autores latino-americanos que trabalham com pesqui- sadores de outros continentes. Estudos que tratavam apenas de adultos ou pesquisas básicas sobre biologia tumoral não especificamente relacionadas aos tipos de tumor analisados nesta revisão foram excluídos. Resultados. No total, a busca recuperou 550 artigos da base de dados. Após a remoção dos artigos duplicados, foram incluídos 514 artigos na análise, a maioria de autoria de pesquisadores de instituições da Argentina, do Brasil e do México. Esses países também tiveram o maior número de colaborações em artigos originais publicados com autores da Europa e da América do Norte. A Argentina teve o maior número de colaborações em publicações originais, com coautores do Brasil e do Uruguai. O fator de impacto mediano dos 244 periódicos nos quais os artigos foram publicados era de 3,5. Os tumores mais estudados foram osteossarcomas, neuroblastomas e meduloblastomas; as áreas mais estudadas foram análise molecular, biologia de células tumorais e biomarcadores. Conclusões. Na América Latina, a pesquisa em oncologia pediátrica está na ordem do dia, apesar de uma evidente disparidade nos índices de publicação e na frequência de colaboração entre os países. É necessário fortalecer a colaboração científica dentro da América Latina e com países de outros continentes a fim de pro- mover a pesquisa e desenvolver novas estratégias de tratamento que reflitam as necessidades locais das crianças latino-americanas com tumores sólidos e câncer cerebral.

The importance of basic and translational research in caring for children with malignant solid tumors in Latin America / La importancia de la investigación básica y aplicada para la atención de pacientes pediátricos con tumores sólidos malignos en América Latina / A importância da pesquisa básica e translacional no tratamento de crianças com tumores sólidos malignos na América Latina

ABSTRACT Objective. Basic and translational research in pediatric cancer are essential to improve patient care. To critically assess the developments achieved in these areas in Latin America, we systematically reviewed information published between 2013 and 2023. Methods. Studies of basic and translational research performed by investigators in Latin America evaluating pediatric malignant solid and central nervous system tumors were retrieved from PubMed. Original articles published in English between 2013 and 2023 were included. Collaborations among Latin American authors or among Latin American authors working with researchers from other continents were also included. Studies were excluded if they focused only on adults or on basic research in tumor biology not specifically related to the tumor types analyzed in this review. Results. A total of 550 articles were retrieved, but after removal of duplicates, 514 articles were included in the analysis, the majority of which were authored by researchers affiliated with institutions in Argentina, Brazil and Mexico. These countries also had the highest number of collaborations on original articles published with authors from Europe and North America. Argentina had the highest number of collaborations on original publications, with coauthors from Brazil and Uruguay. The median impact factor of the 244 journals in which articles were published was 3.5. The most commonly studied tumors were osteosarcomas, neuroblastomas and medulloblastomas; the most commonly studied areas were molecular analysis, tumor cell biology and biomarkers. Conclusions. In Latin America, research in pediatric oncology is on the agenda, despite a notable disparity in publication rates and frequency of collaboration between countries. There is a need to strengthen scientific collaboration within Latin America and with countries from other continents to promote research and to develop novel treatment strategies that reflect the local needs of children in Latin America who have solid tumors and brain cancer.

RESUMEN Objetivo. La investigación básica y aplicada en el campo de la oncología pediátrica es fundamental para mejorar la atención al paciente. Con el objetivo de realizar una evaluación crítica de los avances logrados en este campo en América Latina, hemos realizado una revisión sistemática de la información publicada entre el 2013 y el 2023. Metodología. Se recopilaron de PubMed los artículos de investigación básica y traslacional publicados por investigadores de América Latina en los que se evaluaron tumores malignos sólidos y del sistema nervioso central en la población infantil. Se incluyeron artículos originales publicados en inglés entre el 2013 y el 2023. También se incluyeron artículos fruto de la colaboración científica entre autores e investigadores de América Latina y otros continentes. Se excluyeron aquellos estudios que se centraron solo en personas adultas o en la investigación básica en biología tumoral no relacionada específicamente con los tipos de tumores analizados en esta revisión. Resultados. Se encontraron 550 artículos en total. Después de eliminar los artículos duplicados, se incluyeron 514 artículos en la revisión, la mayoría de los cuales fueron escritos por investigadores vinculados a centros de investigación de Argentina, Brasil y México. También procedieron de estos tres países la mayor parte de los artículos originales escritos en colaboración con autores de Europa y América del Norte. Argentina tuvo el mayor número de colaboraciones en publicaciones originales, con coautores de Brasil y Uruguay. La mediana del índice de impacto de las 244 revistas en las que se publicaron los artículos fue de 3,5. Los tumores más estudiados fueron osteosarcomas, neuroblastomas y meduloblastomas. Los temas más estudiados fueron el análisis molecular, la biología de las células tumorales y los biomarcadores. Conclusiones. La investigación en oncología pediátrica forma parte de la agenda de investigación de América Latina, si bien hay una disparidad notoria en las tasas de publicación y la frecuencia de la colaboración entre países. Es necesario fortalecer la colaboración científica dentro de América Latina y con los países de otros continentes para promover la investigación y desarrollar estrategias de tratamiento novedosas que respondan a las necesidades locales de los niños y niñas de América Latina que tienen tumores sólidos o cáncer del sistema nervioso central.

RESUMO Objetivo. A pesquisa básica e translacional em câncer pediátrico é essencial para melhorar o atendimento dos pacientes. No intuito de realizar uma avaliação crítica dos avanços alcançados nessa área na América Latina, fez-se uma revisão sistemática de informações publicadas entre 2013 e 2023. Métodos. Pesquisas básicas e translacionais realizadas por pesquisadores da América Latina que avaliaram tumores sólidos malignos e tumores do sistema nervoso central em crianças foram obtidas da base de dados PubMed. Foram incluídos artigos originais publicados em inglês entre 2013 e 2023. Também foram incluídas colaborações entre autores latino-americanos ou entre autores latino-americanos que trabalham com pesquisadores de outros continentes. Estudos que tratavam apenas de adultos ou pesquisas básicas sobre biologia tumoral não especificamente relacionadas aos tipos de tumor analisados nesta revisão foram excluídos. Resultados. No total, a busca recuperou 550 artigos da base de dados. Após a remoção dos artigos duplicados, foram incluídos 514 artigos na análise, a maioria de autoria de pesquisadores de instituições da Argentina, do Brasil e do México. Esses países também tiveram o maior número de colaborações em artigos originais publicados com autores da Europa e da América do Norte. A Argentina teve o maior número de colaborações em publicações originais, com coautores do Brasil e do Uruguai. O fator de impacto mediano dos 244 periódicos nos quais os artigos foram publicados era de 3,5. Os tumores mais estudados foram osteossarcomas, neuroblastomas e meduloblastomas; as áreas mais estudadas foram análise molecular, biologia de células tumorais e biomarcadores. Conclusões. Na América Latina, a pesquisa em oncologia pediátrica está na ordem do dia, apesar de uma evidente disparidade nos índices de publicação e na frequência de colaboração entre os países. É necessário fortalecer a colaboração científica dentro da América Latina e com países de outros continentes a fim de promover a pesquisa e desenvolver novas estratégias de tratamento que reflitam as necessidades locais das crianças latino-americanas com tumores sólidos e câncer cerebral.

Metabolic bone disorders and the promise of marine osteoactive compounds.

Metabolic bone disorders and associated fragility fractures are major causes of disability and mortality worldwide and place an important financial burden on the global health systems. These disorders result from an unbalance between bone anabolic and resorptive processes and are characterized by different pathophysiological mechanisms. Drugs are available to treat bone metabolic pathologies, but they are either poorly effective or associated with undesired side effects that limit their use. The molecular mechanism underlying the most common metabolic bone disorders, and the availability, efficacy, and limitations of therapeutic options currently available are discussed here. A source for the unmet need of novel drugs to treat metabolic bone disorders is marine organisms, which produce natural osteoactive compounds of high pharmaceutical potential. In this review, we have inventoried the marine osteoactive compounds (MOCs) currently identified and spotted the groups of marine organisms with potential for MOC production. Finally, we briefly examine the availability of in vivo screening and validation tools for the study of MOCs.

Establishment and Comprehensive Characterization of a Novel Preclinical Platform of Metastatic Retinoblastoma for Therapeutic Developments.

Purpose: Although there have been improvements in the management of metastatic retinoblastoma, most patients do not survive, and all patients suffer from multiple short- and long-term treatment toxicities. Reliable and informative models to assist clinicians are needed. Thus we developed and comprehensively characterized a novel preclinical platform of primary cell cultures and xenograft models of metastatic retinoblastoma to provide insights into the molecular biology underlying metastases and to perform drug screening for the identification of hit candidates with the highest potential for clinical translation. Methods: Orbital tumor, bone marrow, cerebrospinal fluid, and lymph node tumor infiltration specimens were obtained from seven patients with metastatic retinoblastoma at diagnosis, disease progression, or relapse. Tumor specimens were engrafted in immunodeficient animals, and primary cell lines were established. Genomic, immunohistochemical/immunocytochemical, and pharmacological analysis were performed. Results: We successfully established five primary cell lines: two derived from leptomeningeal, two from orbital, and one from lymph node tumor dissemination. After the intravitreal or intraventricular inoculation of these cells, we established cell-derived xenograft models. Both primary cell lines and xenografts accurately retained the histological and genomic features of the tumors from which they were derived and faithfully recapitulated the dissemination patterns and pharmacological sensitivity observed in the matched patients. Conclusions: Ours is an innovative and thoroughly characterized preclinical platform of metastatic retinoblastoma developed for the understanding of tumor biology of this highly aggressive tumor and has the potential to identify drug candidates to treat patients who currently lack effective treatment options.

RINT1 deficiency disrupts lipid metabolism and underlies a complex hereditary spastic paraplegia.

The Rad50 interacting protein 1 (Rint1) is a key player in vesicular trafficking between the ER and Golgi apparatus. Biallelic variants in RINT1 cause infantile-onset episodic acute liver failure (ALF). Here, we describe 3 individuals from 2 unrelated families with novel biallelic RINT1 loss-of-function variants who presented with early onset spastic paraplegia, ataxia, optic nerve hypoplasia, and dysmorphic features, broadening the previously described phenotype. Our functional and lipidomic analyses provided evidence that pathogenic RINT1 variants induce defective lipid-droplet biogenesis and profound lipid abnormalities in fibroblasts and plasma that impact both neutral lipid and phospholipid metabolism, including decreased triglycerides and diglycerides, phosphatidylcholine/phosphatidylserine ratios, and inhibited Lands cycle. Further, RINT1 mutations induced intracellular ROS production and reduced ATP synthesis, affecting mitochondria with membrane depolarization, aberrant cristae ultrastructure, and increased fission. Altogether, our results highlighted the pivotal role of RINT1 in lipid metabolism and mitochondria function, with a profound effect in central nervous system development.

Characteristics and outcomes of advanced melanoma patients with complete response and elective discontinuation of first-line anti-programmed death-1 monotherapy: A real-world multicentre observational cohort study.

Anti-programmed death-1 (anti-PD1) treatment has significantly improved outcomes of advanced melanoma with a considerable percentage of patients achieving complete response (CR). This real-world study analyzed the feasibility of elective anti-PD1 discontinuation in advanced melanoma patients with CR and evaluated factors related to sustained response. Thirty-five patients with advanced cutaneous or primary unknown melanoma with CR to nivolumab or pembrolizumab from 11 centers were included. Mean age was 66.5 years, and 97.1% had ECOG PS 0-1. 28.6% had ≥3 metastatic sites with 58.8% having M1a-M1b disease; 8.6% had liver and 5.7% had brain metastases. At baseline, 80% had normal LDH, and 85.7% had a neutrophil-to-lymphocyte ratio ≤3. 74.3% of patients had CR confirmed in PET-CT. Median duration of anti-PD1 was 23.4 months (range 1.3-50.5). 24 months after therapy discontinuation, 91.9% of patients were progression-free. Estimated PFS and OS at 36, 48, and 60 months from the start of anti-PD1 were 94.2%, 89.9%, 84.3%, and 97.1%, 93.3%, 93.3%, respectively. Antibiotics use after anti-PD1 discontinuation increased the odds of progression (OR 16.53 [95% CI 1.7, 226.03]). The study confirms the feasibility of elective anti-PD1 discontinuation in advanced melanoma patients with CR and favorable prognostic factors at baseline.

Bioacoustic differentiation of calls in the chiffchaff complex.

The chiffchaff complex is a group of common forest bird species, notorious for the number of cryptic taxa recently discovered, being a great example of speciation in action. Vocalizations have been crucial to unveil its hidden diversity. In this study we quantitatively analyze the acoustic characteristics of their calls with permutational analysis of variance, canonical variate analysis and a self-organizing map, to determine their variability and differences. We related these differences with the geographical and genetic distances between taxonomic groups, by means of Pearson correlations. We used recordings from Xeno-canto, an open database of bird vocalizations. Inter-taxa distances based on call traits were broadly consistent with geographic distances but not correlated with genetic distances. The Iberian Chiffchaff (Phylloscopus ibericus), presumably the most ancient lineage, was the most central in the variation space, while the Siberian Chiffchaff (P. collybita tristis) was the most peripheric and also very uniform, in contrast with the Canarian Chiffchaff (P. canariensis) highly variable, as expected by the "character release hypothesis" on islands. Calls proved to be an excellent tool, especially amenable for non-biased mathematical analyses which, combined with the wide availability of records in Xeno-canto, greatly facilitates the widespread use of this methodology in a wide range of species and geographical areas.

Treatment of Retinoblastoma: What Is the Latest and What Is the Future.

The management of retinoblastoma, the most common intraocular malignancy in children, has changed drastically over the last decade. Landmark developments in local drug delivery, namely, safer techniques for intravitreal chemotherapy injection and ophthalmic artery chemosurgery, have resulted in eye globe salvages that were not previously attainable using systemic chemotherapy or external beam irradiation. Novel drugs, oncolytic viruses, and immunotherapy are promising approaches in the treatment of intraocular retinoblastoma. Importantly, emerging studies of the pattern of tumor dissemination and local drug delivery may provide the first steps toward new treatments for metastatic disease. Here, we review recent advances in retinoblastoma treatment, especially with regard to local drug delivery, that have enabled successful conservative management of intraocular retinoblastoma. We also review emerging data from preclinical and clinical studies on innovative approaches that promise to lead to further improvement in outcomes, namely, the mechanisms and potential uses of new and repurposed drugs and non-chemotherapy treatments, and discuss future directions for therapeutic development.

Reversal of Doxorubicin-Induced Bone Loss and Mineralization by Supplementation of Resveratrol and MitoTEMPO in the Early Development of Sparus aurata.

Doxorubicin is a widely used chemotherapeutic drug known to induce bone loss. The mechanism behind doxorubicin-mediated bone loss is unclear, but oxidative stress has been suggested as a potential cause. Antioxidants that can counteract the toxic effect of doxorubicin on the bone would be helpful for the prevention of secondary osteoporosis. We used resveratrol, a natural antioxidant, and MitoTEMPO, a mitochondria-targeted antioxidant, to counteract doxorubicin-induced bone loss and mineralization on Sparus aurata larvae. Doxorubicin supplemented Microdiets increased bone deformities, decreased mineralization, and lipid peroxidation, whereas Resveratrol and MitoTEMPO supplemented microdiets improved mineralization, decreased bone deformities, and reversed the effects of doxorubicin in vivo and in vitro, using osteoblastic VSa13 cells. Partial Least-Squares Discriminant Analysis highlighted differences between groups on the distribution of skeletal anomalies and mineralization of skeleton elements. Calcium and Phosphorus content was negatively affected in the doxorubicin supplemented group. Doxorubicin reduced the mRNA expression of antioxidant genes, including catalase, glutathione peroxidase 1, superoxide dismutase 1, and hsp90 suggesting that ROS are central for Doxorubicin-induced bone loss. The mRNA expression of antioxidant genes was significantly increased on resveratrol alone or combined treatment. The length of intestinal villi was increased in response to antioxidants and reduced on doxorubicin. Antioxidant supplements effectively prevent bone deformities and mineralization defects, increase antioxidant response and reverse doxorubicin-induced effects on bone anomalies, mineralization, and oxidative stress. A combined treatment of doxorubicin and antioxidants was beneficial in fish larvae and showed the potential for use in preventing Doxorubicin-induced bone impairment.

Method for Nest Detection of the Yellow-Legged Hornet in High Density Areas.

The Asian hornet Vespa velutina is a social predator that has invaded several countries of Europe and Asia, impacting pollinators, apiculture and human health. One of the few effective control methods developed so far is the early destruction of nests. However, they are often built within dense vegetation, being difficult to detect. The aim of the method described here is to detect nests with a simple procedure, utilizing readily available materials, for widespread use in infested areas. The method has two phases, the first phase involves capturing and marking hornets, lured to a protein bait, and recording the flight directions of individuals to the nest and the time needed to complete a bait-nest-bait round trip, to estimate the distance. Collecting this information from two (or more) bait stations allows to delineate the approximate location of the nest. The second phase aims to determine the precise location of the nest, using sugary baits in the vicinity of the nest and conspicuous marks attached to the released hornets, to visually follow them up to their nest. This method is an alternative to other methods that are either ineffective in areas with high nest density or require expensive equipment and specialized training.

A decision process for drug discovery in retinoblastoma.

Intraocular retinoblastoma treatment has changed radically over the last decade, leading to a notable improvement in ocular survival. However, eyes that relapse remain difficult to treat, as few alternative active drugs are available. More challenging is the scenario of central nervous system (CNS) metastasis, in which almost no advancements have been made. Both clinical scenarios represent an urgent need for new drugs. Using an integrated multidisciplinary approach, we developed a decision process for prioritizing drug selection for local (intravitreal [IVi], intrathecal/intraventricular [IT/IVt]), systemic, or intra-arterial chemotherapy (IAC) treatment by means of high-throughput pharmacological screening of primary cells from two patients with intraocular tumor and CNS metastasis and a thorough database search to identify clinical and biopharmaceutical data. This process identified 169 compounds to be cytotoxic; only 8 are FDA-approved, lack serious toxicities and available for IVi administration. Four of these agents could also be delivered by IT/IVt. Twelve FDA-approved drugs were identified for systemic delivery as they are able to cross the blood-brain barrier and lack serious adverse events; four drugs are of oral usage and six compounds that lack vesicant or neurotoxicity could be delivered by IAC. We also identified promising compounds in preliminary phases of drug development including inhibitors of survivin, antiapoptotic Bcl-2 family proteins, methyltransferase, and kinesin proteins. This systematic approach may be applied more broadly to prioritize drugs to be repurposed or to identify novel hits for use in retinoblastoma treatment.

[Argentine Consensus in effective management of anticoagulation clinics for the use of vitamin k antagonists]. / Consenso Argentino en gestión efectiva de clínicas de anticoagulación para el uso de antagonistas de la vitamina k.

Treating an anticoagulated patient with vitamin K antagonists (VKA) remains a challenge, especially in areas where dicoumarins are still the first drug of choice due to the cost of other oral anticoagulants. Anticoagulation clinics have proven to be the most efficient and safe way to avoid thrombotic and hemorrhagic complications and to keep patients in optimal treatment range. However, they require adequate infrastructure and trained personnel to work properly. In this Argentine consensus we propose a series of guidelines for the effective management of the anticoagulation clinics. The goal is to achieve the excellence in both the clinical healthcare and the hemostasis laboratory for the anticoagulated patient. The criteria developed in the document were agreed upon by a large group of expert specialists in hematology and biochemistry from all over the country. The criteria presented here must always be considered when indicating VKA although they had to be adapted to the unequal reality of each center. Taking these premises into consideration will allow us to optimize the management of the anticoagulated patient with VKA and thus minimize thrombotic and hemorrhagic intercurrences, in order to honor our promise not to harm the patient.

El tratamiento de un paciente anticoagulado con antagonistas de la vitamina K (AVK) sigue siendo un desafío, especialmente en regiones donde, por el costo, los dicumarínicos son todavía la alternativa más buscada a la hora de elegir un anticoagulante oral. Las clínicas de anticoagulación han demostrado ser la forma más eficiente y segura de evitar complicaciones trombóticas y hemorrágicas y de mantener al paciente en rango óptimo de tratamiento. Sin embargo, requieren de una adecuada infraestructura y personal capacitado para que funcionen eficientemente. En este consenso argentino se propone una serie de parámetros para la gestión efectiva de una clínica de anticoagulación. El objetivo es lograr una elevada calidad desde el punto de vista clínico-asistencial a través de un laboratorio de hemostasia de excelencia. Los criterios desarrollados en el documento fueron consensuados por un amplio grupo de expertos especialistas en hematología y en bioquímica de todo el país. Estos criterios deben adaptarse a la irregular disponibilidad de recursos de cada centro, pero siempre se los debe tener en cuenta a la hora de indicar el tratamiento anticoagulante con estas drogas. Tener en consideración estas premisas nos permitirá optimizar la atención del enfermo anticoagulado con AVK y de esta forma minimizar las intercurrencias trombóticas y hemorrágicas a las que está expuesto, para así honrar nuestra promesa de no dañar al paciente.

Consenso argentino en gestión efectiva de clínicas de anticoagulación para uso de antagonistas de la vitamina K / Argentine consensus in effective management of anticoagulation clinics for the use of vitamin K antagonists

Resumen El tratamiento de un paciente anticoagulado con antagonistas de la vitamina K (AVK) sigue siendo un desafío, especialmente en regiones donde, por el costo, los dicumarínicos son todavía la alternativa más buscada a la hora de elegir un anticoagulante oral. Las clínicas de anticoagulación han demostrado ser la forma más eficiente y segura de evitar complicaciones trombóticas y hemorrágicas y de mantener al paciente en rango óptimo de tratamiento. Sin embargo, requieren de una adecuada infraestructura y personal capacitado para que funcionen eficientemente. En este consenso argentino se propone una serie de parámetros para la gestión efectiva de una clínica de anticoagulación. El objetivo es lograr una elevada calidad desde el punto de vista clínico-asistencial a través de un laboratorio de hemostasia de excelencia. Los criterios desarrollados en el documento fueron consensuados por un amplio grupo de expertos especialistas en hematología y en bioquímica de todo el país. Estos criterios deben adaptarse a la irregular disponibilidad de recursos de cada centro, pero siempre se los debe tener en cuenta a la hora de indicar el tratamiento anticoagulante con estas drogas. Tener en consideración estas premisas nos permitirá optimizar la atención del enfermo anticoagulado con AVK y de esta forma minimizar las intercurrencias trombóticas y hemorrágicas a las que está expuesto, para así honrar nuestra promesa de no dañar al paciente.

Abstract Treating an anticoagulated patient with vitamin K antagonists (VKA) remains a challenge, especially in areas where dicoumarins are still the first drug of choice due to the cost of other oral anticoagulants. Anticoagulation clinics have proven to be the most efficient and safe way to avoid thrombotic and hemorrhagic complications and to keep patients in optimal treatment range. However, they require adequate infrastructure and trained personnel to work properly. In this Argentine consensus we propose a series of guidelines for the effective management of the anticoagulation clinics. The goal is to achieve the excellence in both the clinical healthcare and the hemostasis laboratory for the anticoagulated patient. The criteria developed in the document were agreed upon by a large group of expert specialists in hematology and biochemistry from all over the country. The criteria presented here must always be considered when indicating VKA although they had to be adapted to the unequal reality of each center. Taking these premises into consideration will allow us to optimize the management of the anticoagulated patient with VKA and thus minimize thrombotic and hemorrhagic intercurrences, in order to honor our promise not to harm the patient.

Predators and dispersers: Context-dependent outcomes of the interactions between rodents and a megafaunal fruit plant.

Many plant species bear fruits that suggest adaptation to seed dispersal by extinct megafauna. Present-day seed dispersal of these megafaunal plants is carried out by rodents, which can act as predators or dispersers; whether this interaction is primarily positive or negative can depend on the context. Here, we parameterized a stochastic model using data from the field and experimental arenas to estimate the effect of rodents on the recruitment of Myrcianthes coquimbensis -an Atacama Desert shrub with megafaunal fruits- and examine whether environmental conditions can alter the sign and strength of these rodent-plant interactions. We show that the outcome of these interactions is context-dependent: in wet conditions seed removal by rodents negatively impacts the recruitment probability of M. coquimbensis; in contrast, in dry conditions, the interaction with rodents increases recruitment success. In all cases, the strength of the effect of rodents on the recruitment success was determined mainly by their role as dispersers, which could be positive or negative. This study demonstrates that by caching seeds, rodents can be effective dispersers of a megafaunal fruit plant, but that the sign and magnitude of their effect on recruitment changes as a function of the environmental context in which the interaction occurs.

Context dependency, co-introductions, novel mutualisms, and host shifts shaped the ectomycorrhizal fungal communities of the alien tree Eucalyptus globulus.

The identity and relevance of the ectomycorrhizal (ECM) fungal partners of Eucalyptus globulus was investigated in NW Spain, to detect which symbionts mainly support its invasiveness. Root tips of E. globulus and of three common native plant species (Quercus robur, Pinus pinaster and Halimium lasianthum) were collected in eucalypt plantations, Q. robur forests, P. pinaster plantations and shrublands. Fungal taxonomical identity was ascertained by use of rDNA and direct sequencing. We studied diversity, composition and colonization rate of the ECM fungal communities of E. globulus to determine if fungal assemblages are host specific (i.e. similar in different habitats) or more dependent on the neighbourhood context. We also identified the type of associations formed (i.e. co-introductions, familiar or novel associations). Twenty-six ECM taxa were associated with E. globulus. Most of them engaged in novel associations with eucalypts, whereas only three fungal species were co-introduced Australian aliens. Eucalypt fungal richness, diversity and colonization rate differed between habitats, being higher in native oak forests, whereas in shrublands E. globulus showed the lowest colonization rate and diversity. The Australian fungus Descolea maculata dominated the eucalypt fungal assemblage and also spread to the native host plants, in all the habitats, posing the risk of further co-invasion.

Human dimensions of wildfires in NW Spain: causes, value of the burned vegetation and administrative measures.

Exploring the human dimensions of forest fires is a crucial, although often overlooked, aspect of wildfire research, since wildfires often have important socio-economic impacts and humans are nowadays the main cause of wildfires in many areas of the world. We carried out a telephone survey (N = 345 interviews) in one of the most fire-prone areas in Europe (NW Spain) in order to assess citizens' awareness about wildfire causes and risks, their perception of the value of the vegetation and of administrative measures to fight against fires. Perceptions of respondents about fire causes were in general realistic although fires caused by pyromaniacs and for profit were overestimated, while vegetation management was comparatively underestimated. Citizens were broadly aware of the fire risk associated with different vegetation types, rightly considering native oak forests and agricultural fields as less risky than shrublands and pine and eucalypt plantations. Tree-dominated vegetation was more valued than treeless formations, and native forests more than tree plantations, which seems related to a preference for ecological value over utilitarian considerations. In addition, the value of eucalypt plantations was clearly affected by the education level of respondents, being less valued as the education level increased. Most citizens considered that the administration was not doing enough to fight against fires. The law that compels landowners to reduce fuels in wildland-urban interfaces was considered effective by most respondents (72%), but 50% considered it difficult to implement by landowners. This may explain the poor degree of compliance of this law.

Rivaroxaban in the cardiovascular world: a direct anticoagulant useful to prevent stroke and venous and arterial thromboembolism.

INTRODUCTION: Until recently, vitamin K antagonists (VKA) were the only drugs available for long-term anticoagulation. The use of these drugs is laborious due to their variable pharmacokinetics and pharmacodynamics. The advent of direct oral anticoagulants has produced a paradigm shift due to their low incidence of drug interactions, their stable plasma levels, and their lack of monitoring. Rivaroxaban, a factor Xa inhibitor, has been tested in different clinical scenarios and has proved to be effective and safe, even increasing the scope of the old VKA. Areas covered: A non-systematic review of the literature was conducted using the PubMed and Cochrane databases, focusing on randomized clinical trials and real-world observational studies that evaluated rivaroxaban in patients with atrial fibrillation, venous thromboembolism, and atherosclerotic coronary and peripheral vascular disease. Expert commentary: The role of rivaroxaban keeps expanding into areas that were unimaginable few years ago, in the light of solid evidence that has eliminated old strict paradigms. Nonetheless, it will be necessary to adjust costs and better understand the perceived barriers to its widespread implementation, to get fully acceptation of rivaroxaban for the different clinical conditions that have been suggested.

Evidences for a New Role of miR-214 in Chondrogenesis.

miR-214 is known to play a role in mammalian skeletal development through inhibition of osteogenesis and stimulation of osteoclastogenesis, but data regarding other vertebrates, as well as a possible role in chondrogenesis, remain unknown. Here, we show that miR-214 expression is detected in bone and cartilage of zebrafish skeleton, and is downregulated during murine ATDC5 chondrocyte differentiation. Additionally, we observed a conservation of the transcriptional regulation of miR-214 primary transcript Dnm3os in vertebrates, being regulated by Ets1 in ATDC5 chondrogenic cells. Moreover, overexpression of miR-214 in vitro and in vivo mitigated chondrocyte differentiation probably by targeting activating transcription factor 4 (Atf4). Indeed, miR-214 overexpression in vivo hampered cranial cartilage formation of zebrafish and coincided with downregulation of atf4 and of the key chondrogenic players sox9 and col2a1. We show that miR-214 overexpression exerts a negative role in chondrogenesis by impacting on chondrocyte differentiation possibly through conserved mechanisms.