Histiocitosis de células de Langerhans: avances en la patogenia y práctica clínica

Histiocitosis; Granuloma eosinófilo; Inhibidores BRAFHistiocitosi; Granuloma eosinòfil; Inhibidors BRAFHistiocytosis; Eosinophilic granuloma; BRAF inhibitorsLangerhans cell histiocytosis (LCH) is a type of myeloid neoplasia that can affect different organs or tissues and exhibits substantial variability in its clinical presentation and biological behaviour, so it may mimic different diseases. Performance of different clinical assessments and laboratory and imaging tests is recommended to determine the extent of involvement, which may be of a single location or multisystemic, and the presence or absence of dysfunction in risk organs, such as the haematopoietic system, liver and spleen. The diagnosis must be confirmed by histological examination of a biopsy sample. Molecular tests have identified mutations in the mitogen-activated protein kinase (MAPK) pathway, which has expanded treatment options. The diagnosis is complex and there is controversy regarding the management of certain cases. Treatment recommendations depend on the location of the lesions and the extent of involvement. International collaborative studies have demonstrated the effectiveness of prolonged combination therapies such as vinblastine and prednisone in severe or multisystemic forms, and anti-inflammatory drugs such as indomethacin and other cytostatic combinations have proven beneficial. Langerhans cell histiocytosis is a good example of the importance of precision medicine and the benefit of identifying molecular targets, common to different neoplasms, to develop new therapies. MAPK pathway inhibitors offer an alternative treatment option in refractory cases and neurodegenerative forms of LCH. Molecular testing can contribute to the prognosis, treatment and follow-up of LCH, especially in severe forms of disease.La histiocitosis de células de Langerhans es un tipo de neoplasia hematológica de origen mieloide, que puede afectar a diferentes órganos o tejidos, con gran variabilidad en la presentación clínica y comportamiento biológico, por lo que puede simular diferentes enfermedades. Se recomienda realizar diversas pruebas clínicas, analíticas y de imagen, para determinar la extensión de la afectación, que puede ser única o multisistémica, y la presencia o no de disfunción en órganos de riesgo como sistema hematopoyético, hígado y bazo. El diagnóstico se debe confirmar mediante biopsia y estudio histológico. Los estudios moleculares han permitido identificar mutaciones en la vía MAPK, lo que han ampliado las opciones terapéuticas. El diagnóstico es complejo y existe controversia en el manejo de ciertos casos. Las recomendaciones terapéuticas dependen de la localización de las lesiones y la extensión de la afectación. Los estudios colaborativos internacionales han demostrado la efectividad de terapias prolongadas combinadas como vinblastina y prednisona en formas graves o multisistémicas y destaca el papel beneficioso de fármacos antinflamatorios como indometacina y de otras combinaciones de citostáticos. HCL representa un buen ejemplo de la importancia de la medicina de precisión y del beneficio de la identificación de dianas moleculares, comunes a diferentes neoplasias, para desarrollar nuevas terapias dirigidas. Los inhibidores de la vía MAPK representan una alternativa terapéutica en casos refractarios y en las formas neurodegenerativas de HCL. Los estudios moleculares pueden contribuir en el pronóstico, tratamiento y seguimiento, especialmente en las formas graves.The study was partially funded by a grant allocated to the Histiocytosis Research Project of the Fundación Vasca de Innovación e Investigación Sanitaria BIOEF (BIO16/ER/020/BC) and the Asociación Española contra la Histiocitosis-ACHE (BC/A/15/012, BIOEF11/017, BIOEF09/047), whose principal investigator is Itziar Astigarraga

Identification of a panel of serum protein markers in early stage of sepsis and its validation in a cohort of patients

Background: Sepsis is a life-threatening illness with a challenging diagnosis. Current serum biomarkers are not sensitive enough for diagnosis. With the aim of finding proteins associated with sepsis, serum protein profile was compared between patients and healthy donors and serum classical inflammatory proteins were analyzed in both groups. Methods: Serum protein profiles were characterized by two-dimensional electrophoresis (2DE). Identification of the proteins was carried out by mass spectrophotometry and their validation was performed by Enzyme-Linked-lmmunoSorbent Assay (ELISA) in a cohort of 85 patients and 67 healthy donors. Seven classical inflammatory proteins were analyzed in the same cohort by ELISA: interleukin-2 receptor alpha-chain (sCD25), scavenger receptor cysteine

Re-thinking the Etiological Framework of Neurodegeneration

Neurodegenerative diseases are among the leading causes of disability and death worldwide. The disease-related socioeconomic burden is expected to increase with the steadily increasing life expectancy. In spite of decades of clinical and basic research, most strategies designed to manage degenerative brain diseases are palliative. This is not surprising as neurodegeneration progresses "silently" for decades before symptoms are noticed. Importantly, conceptual models with heuristic value used to study neurodegeneration have been constructed retrospectively, based on signs and symptoms already present in affected patients;a circumstance that may confound causes and consequences. Hence, innovative, paradigm-shifting views of the etiology of these diseases are necessary to enable their timely prevention and treatment. Here, we outline four alternative views, not mutually exclusive, on different etiological paths toward neurodegeneration. First, we propose neurodegeneration as being a secondary outcome of a primary cardiovascular cause with vascular pathology disrupting the vital homeostatic interactions between the vasculature and the brain, resulting in cognitive impairment, dementia, and cerebrovascular events such as stroke. Second, we suggest that the persistence of senescent cells in neuronal circuits may favor, together with systemic metabolic diseases, neurodegeneration to occur. Third, we argue that neurodegeneration may start in response to altered body and brain trophic interactions established via the hardwire that connects peripheral targets with central neuronal structures or by means of extracellular vesicle (E\-mediated communication. Lastly, we elaborate on how lifespan body dysbiosis may be linked to the origin of neurodegeneration. We highlight the existence of bacterial products that modulate the gut-brain axis causing neuroinflammation and neuronal dysfunction. As a concluding section, we end by recommending research avenues to investigate these etiological paths in the future. We think that this requires an integrated, interdisciplinary conceptual research approach based on the investigation of the multimodal aspects of physiology and pathophysiology. It involves utilizing proper conceptual models, experimental animal units, and identifying currently unused opportunities derived from human data. Overall, the proposed etiological paths and experimental recommendations will be important guidelines for future cross-discipline research to overcome the translational roadblock and to develop causative treatments for neurodegenerative diseases

Microplate assay for the determination of carboxypeptidase A inhibitory activity in Andean potatoes

Metallocarboxypeptidases (MCPs) are zinc-dependent exopeptidases that catalyze the hydrolysis of C-terminal amide bonds in proteins and peptides. MCPs are involved in a wide range of physiological processes and have recently emerged as relevant drug targets in biomedicine (Arolas et. al., 2007). In higher plants, small proteinaceous protease inhibitors are wound-induced molecules produced as a part of its defense system against insect attack (Graham et. al., 1981; Villanueva et. al. 1998). Among such inhibitors, only two are specific for MCPs, i.e. the potato carboxypeptidase inhibitor (PCI) and its close homologue found in tomato plants. In humans, MCP action is exquisitely regulated and dysregulation of their function might lead to disease or even to cell death (Arolas et. al., 2007). In this context, the discovery and characterization of new MCPs inhibitors constitute a valuable approach for the development of new therapeutic strategies. Over the last few decades, the presence of MCPs inhibitors in Solanaceae has been extensively reported, revealing potato (Solanum tuberosum) as one of the most important sources of MCPs inhibitors (Hass et. al.,1979; Lufrano et. al., 2015). In this context, potatos are native from the Andean region of South America, where thousands of different potato varieties coexist, constituting a natural reservoir for the discovery of novel MCP inhibitors (Figure 1). In this protocol, we describe an optimized, simple and accessible microplate method for the measure of the specific and dose-response carboxypeptidase A inhibitory activities present in Andean potatoes tubers.Centro de Investigación de Proteínas Vegetale

Microplate assay for the determination of carboxypeptidase A inhibitory activity in Andean potatoes

Metallocarboxypeptidases (MCPs) are zinc-dependent exopeptidases that catalyze the hydrolysis of C-terminal amide bonds in proteins and peptides. MCPs are involved in a wide range of physiological processes and have recently emerged as relevant drug targets in biomedicine (Arolas et. al., 2007). In higher plants, small proteinaceous protease inhibitors are wound-induced molecules produced as a part of its defense system against insect attack (Graham et. al., 1981; Villanueva et. al. 1998). Among such inhibitors, only two are specific for MCPs, i.e. the potato carboxypeptidase inhibitor (PCI) and its close homologue found in tomato plants. In humans, MCP action is exquisitely regulated and dysregulation of their function might lead to disease or even to cell death (Arolas et. al., 2007). In this context, the discovery and characterization of new MCPs inhibitors constitute a valuable approach for the development of new therapeutic strategies. Over the last few decades, the presence of MCPs inhibitors in Solanaceae has been extensively reported, revealing potato (Solanum tuberosum) as one of the most important sources of MCPs inhibitors (Hass et. al.,1979; Lufrano et. al., 2015). In this context, potatos are native from the Andean region of South America, where thousands of different potato varieties coexist, constituting a natural reservoir for the discovery of novel MCP inhibitors (Figure 1). In this protocol, we describe an optimized, simple and accessible microplate method for the measure of the specific and dose-response carboxypeptidase A inhibitory activities present in Andean potatoes tubers.Centro de Investigación de Proteínas Vegetale

Microplate assay for the determination of carboxypeptidase A inhibitory activity in Andean potatoes

Metallocarboxypeptidases (MCPs) are zinc-dependent exopeptidases that catalyze the hydrolysis of C-terminal amide bonds in proteins and peptides. MCPs are involved in a wide range of physiological processes and have recently emerged as relevant drug targets in biomedicine (Arolas et. al., 2007). In higher plants, small proteinaceous protease inhibitors are wound-induced molecules produced as a part of its defense system against insect attack (Graham et. al., 1981; Villanueva et. al. 1998). Among such inhibitors, only two are specific for MCPs, i.e. the potato carboxypeptidase inhibitor (PCI) and its close homologue found in tomato plants. In humans, MCP action is exquisitely regulated and dysregulation of their function might lead to disease or even to cell death (Arolas et. al., 2007). In this context, the discovery and characterization of new MCPs inhibitors constitute a valuable approach for the development of new therapeutic strategies. Over the last few decades, the presence of MCPs inhibitors in Solanaceae has been extensively reported, revealing potato (Solanum tuberosum) as one of the most important sources of MCPs inhibitors (Hass et. al.,1979; Lufrano et. al., 2015). In this context, potatos are native from the Andean region of South America, where thousands of different potato varieties coexist, constituting a natural reservoir for the discovery of novel MCP inhibitors (Figure 1). In this protocol, we describe an optimized, simple and accessible microplate method for the measure of the specific and dose-response carboxypeptidase A inhibitory activities present in Andean potatoes tubers.Fil: Tellechea, Mariana Edith. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Laboratorio de Investigación de Proteínas Vegetales; Argentina. Universitat Autònoma de Barcelona; EspañaFil: Garcia Pardo Javier. Universitat Autònoma de Barcelona; EspañaFil: Cotabarren, Juliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Laboratorio de Investigación de Proteínas Vegetales; ArgentinaFil: Lufrano, Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Laboratorio de Investigación de Proteínas Vegetales; ArgentinaFil: Avilés, Francesc Xavier. Universitat Autònoma de Barcelona; EspañaFil: Obregon, Walter David. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Laboratorio de Investigación de Proteínas Vegetales; ArgentinaFil: Lorenzo, Julia. Universitat Autònoma de Barcelona; EspañaFil: Tanco, Sebastian. University of Ghent; Bélgica. VIB. Medical Biotechnology Center; Bélgic

Pendred Syndrome in Two Galician Families: Insights into Clinical Phenotypes through Cellular, Genetic, and Molecular Studies

Context: We studied two families from Galicia (northwest Spain) with Pendred syndrome (PS) and unusual thyroid phenotypes. In family A, the proposita had a large goiter and hypothyroxinemia but normal TSH and free T3 (FT3). In family B, some affected members showed deafness but not goiter

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field