Neurodegeneation treatment in lysosomal diseases. An update

Las enfermedades lisosomales son un conjunto de enfermedades raras donde el déficit genético de determinadas enzimas da lugar a la acumulación de sustratos a nivel multiorgánico. El tratamiento de estos errores innatos del metabolismo sigue en continua investigación puesto que cuando existen, presentan limitaciones tratando de aumentar la síntesis de la enzima o disminuir el depósito de sustrato, sin llegar a la solución definitiva y, por tanto, a la curación. La neurodegeneración progresiva y limitante que la mayor parte de ellas producen desde edades pediátricas, supone uno de los mayores desafíos. El trasplante de células hematopoyéticas y la terapia de reemplazo enzimático son tratamientos aceptados para algunas de estas enfermedades; sin embargo, sus resultados sobre el control y la progresión de la sintomatología neurológicas en muchas ocasiones siguen siendo desalentadores. Sin duda, atravesar la barrera hematoencefálica es uno de los obstáculos que numerosos ensayos clínicos, que se están desarrollando en la actualidad, pretenden solventar. La terapia génica y aquella sobre las vías neurofisiológicas desencadenadas por la falta de degradación parcial o total de moléculas constituyen una nueva vía de estudio cuyo objetivo principal también se basa en evitar la progresión en el deterioro de la función cognitiva. Por tanto, el objetivo de este trabajo es realizar una revisión para conocer las terapias aprobadas y las líneas de investigación en curso en relación a la neurodegeneración de las enfermedades lisosomales. Es fundamental seguir avanzando en este campo con mayor desarrollo de estos enfoques y la búsqueda de nuevas perspectivas en las terapias que pueden suponer un gran impacto en la calidad de vida de estos pacientes.Lysosomal diseases are a set of rare diseases where the genetic deficiency of certain enzymes gives rise to the accumulation of substrates at the multi-organ level. The treatment of these inborn errors of metabolism is still under continuous investigation since when they exist, they present limitations trying to increase the synthesis of the enzyme or decrease the deposit of substrate, without reaching the definitive solution, and therefore a cure. The progressive and limiting neurodegeneration that most of them produce from pediatric ages, is one of the greatest challenges. Hematopoietic cell transplantation and enzyme replacement therapy are accepted treatments for some of these diseases; however,its results on the control and progression of neurological symptoms often remain disappointing. Undoubtedly, crossing the blood-brain barrier is one of the obstacles that many clinical trials currently underway aim to overcome. Gene therapy and neurophysiological pathways triggered by the lack of partial or total degradation of molecules also constitute a new avenue of study whose main objective is also based on preventing progression in the deterioration of cognitive function. Therefore, the objective of this work is to carry out a review to know the approved therapies and the lines of research in progress in relation to the neurodegeneration of lysosomal diseases and It is essential to continue advancing in this field with further development of these approaches and the search new perspectives on therapies that can have a great impact on the quality of life of these patients

A Functional Pipeline of Genome-Wide Association Data Leads to Midostaurin as a Repurposed Drug for Alzheimer’s Disease

Genome-wide association studies (GWAS) constitute a powerful tool to identify the different biochemical pathways associated with disease. This knowledge can be used to prioritize drugs targeting these routes, paving the road to clinical application. Here, we describe DAGGER (Drug Repositioning by Analysis of GWAS and Gene Expression in R), a straightforward pipeline to find currently approved drugs with repurposing potential. As a proof of concept, we analyzed a meta-GWAS of 1.6 × 107 single-nucleotide polymorphisms performed on Alzheimer’s disease (AD). Our pipeline uses the Genotype-Tissue Expression (GTEx) and Drug Gene Interaction (DGI) databases for a rational prioritization of 22 druggable targets. Next, we performed a two-stage in vivo functional assay. We used a C. elegans humanized model over-expressing the Aβ1-42 peptide. We assayed the five top-scoring candidate drugs, finding midostaurin, a multitarget protein kinase inhibitor, to be a protective drug. Next, 3xTg AD transgenic mice were used for a final evaluation of midostaurin’s effect. Behavioral testing after three weeks of 20 mg/kg intraperitoneal treatment revealed a significant improvement in behavior, including locomotion, anxiety-like behavior, and new-place recognition. Altogether, we consider that our pipeline might be a useful tool for drug repurposing in complex diseases.Department of Surgery, Biochemistry and Immunology, School of Medicine, University of Malaga, Boulevard Louis Pasteur s/n, 29071 Malaga, Spain Departamento de Biología Molecular e Ingeniería Bioquímica, Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo de Olavide (UPO), UPO/CSIC/JA, Ctra Utrera Km1, 41013 Sevilla, Spain Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), 28029 Madrid, Spain Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Malaga, Spain Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Facultad de Psicología, Universidad de Málaga, 29071 Malaga, Spain Research Center and Memory Clinic, Ace Alzheimer Center Barcelona—Universitat Internacional de Catalunya, 08017 Barcelona, Spain Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), National Institute of Health Carlos III, 28029 Madrid, Spain Unidad de Gestion Clinica de Salud Mental, Hospital Universitario Regional de Malaga, 29010 Malaga, Spain Funding for open Access charge: Universidad de Málaga / CBU

Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer’s Disease Aetiopathogenesis in Men

Mosaic loss of chromosome Y (mLOY) is a common ageing-related somatic event and has been previously associated with Alzheimer’s disease (AD). However, mLOY estimation from genotype microarray data only reflects the mLOY degree of subjects at the moment of DNA sampling. Therefore, mLOY phenotype associations with AD can be severely age-confounded in the context of genome-wide association studies. Here, we applied Mendelian randomisation to construct an age-independent mLOY polygenic risk score (mloy-PRS) using 114 autosomal variants. The mloy-PRS instrument was associated with an 80% increase in mLOY risk per standard deviation unit (p = 4.22 × 10−20) and was orthogonal with age. We found that a higher genetic risk for mLOY was associated with faster progression to AD in men with mild cognitive impairment (hazard ratio (HR) = 1.23, p = 0.01). Importantly, mloy-PRS had no effect on AD conversion or risk in the female group, suggesting that these associations are caused by the inherent loss of the Y chromosome. Additionally, the blood mLOY phenotype in men was associated with increased cerebrospinal fluid levels of total tau and phosphorylated tau181 in subjects with mild cognitive impairment and dementia. Our results strongly suggest that mLOY is involved in AD pathogenesis.P.G.-G. (Pablo García-González) is supported by CIBERNED employment plan CNV-304-PRF-866. CIBERNED is integrated into ISCIII (Instituto de Salud Carlos III). I.d.R is supported by a national grant from the Instituto de Salud Carlos III FI20/00215. A.C. (Amanda Cano) acknowledges the support of the Spanish Ministry of Science, Innovation, and Universities under the grant Juan de la Cierva (FJC2018-036012-I). M.B. (Mercé Boada) and A.R. (Agustín Ruiz) are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240, and PI19/01301. The Genome Research @ Fundació ACE project (GR@ACE) is supported by Grifols SA, Fundación bancaria “La Caixa”, Fundació ACE, and CIBERNED. Acción Estratégica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)—Subdirección General de Evaluación—and the Fondo Europeo de Desarrollo Regional (FEDER—“Una manera de hacer Europa”). Genotyping of the ACE MCI-EADB samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). This work was supported by a grant (European Alzheimer DNA BioBank, EADB) from the EU Joint Program—Neurodegenerative Disease Research (JPND). Partial funding for open access charge: Universidad de Málag

Ahora / Ara

La cinquena edició del microrelatari per l’eradicació de la violència contra les dones de l’Institut Universitari d’Estudis Feministes i de Gènere «Purificación Escribano» de la Universitat Jaume I vol ser una declaració d’esperança. Aquest és el moment en el qual les dones (i els homes) hem de fer un pas endavant i eliminar la violència sistèmica contra les dones. Ara és el moment de denunciar el masclisme i els micromasclismes començant a construir una societat més igualitària. Cadascun dels relats del llibre és una denúncia i una declaració que ens encamina cap a un món millor

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Mobile application where restaurants can manage the orders process with their providers

Probest es un aplicativo móvil fácil de usar, de suscripción mensual diseñado para que los restaurantes tengan en una sola plataforma a todos sus proveedores. Los beneficios para los restaurantes son: ahorrar hasta un 65% del tiempo en pedidos, comunicación directa con los proveedores reduciendo en un 70% los errores de pedidos y cuenta con una relación de diversos proveedores clasificados por rubros para cotizar precios y emitir la facturación. Los proveedores tienen como beneficios: centralizar sus pedidos en un solo canal, disminuir errores y ahorrar tiempo en sus procesos, la oportunidad de ampliar su cartera de clientes y recibir calificaciones por sus servicios. La compañía se dirige a los restaurantes de 3 a 4 tenedores que tienen acceso a internet y cuentan con teléfonos inteligentes, tienen como un mínimo de 10 proveedores y están ubicados en las zonas 6 y 7 de Lima Metropolitana. El costo de la subscripción es un pago mensual de S/. 120. Para llevar a cabo este proyecto se calculó una inversión de S/.32,695.15, monto que será financiado por un 57% mediante un préstamo bancario y el otro 43% como aporte de las cinco socias fundadoras, que será recuperado en 2.23 año de operaciones. Probest, presenta un VAN financiero de S/.485,744.82 y una TIR de 142%, para el periodo de evaluación de 3 años. La proyección de ventas se ha calculado por tres años y se obtiene. Teniendo en cuenta el análisis realizado concluimos que Probest es un proyecto rentable, escalable e innovador.Probest is a friendly and easy use mobile application which is provided with a monthly subscription. This application is designed for restaurants, so they can have a platform that unifies their providers. One of the benefits that restaurants will have are: save up to 65% of the time in orders and direct communication with providers that will reduce up to 70% in errors. Besides, it also counts with a list of classified providers so they can see prices and raise invoices. The company leads to restaurants from 3 to 4 forks that have internet access and smartphones, have at least minimum 10 providers and are located in 6 and 7 zone from Lima Metropolitana. The subscription has a monthly cost of S/. 120. To accomplish the project we invest S/.32,695.15, that will be financed a 57% with a bank loan and the other 43% with the contribution of the 5 business partners that will be recovered in the xx year. Probest, presents a financial VAN of S/.485,744.82 and a TIR of 142% for the evaluation period of 3 years. The sales projection has been calculated for the first three years. To summarize the analysis we concluded that Probest is a rental project that is scalable and that has innovation.Trabajo de investigació