Instituto de Investigación de Enfermedades Raras (IIER)

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12105/19616

El Instituto de Investigación de Enfermedades Raras (IIER), forma parte de la estructura del Instituto de Salud Carlos III (ISCIII) desde noviembre de 2003 bajo la dependencia de la Subdirección General de Servicios Aplicados, Formación e Investigación. La Orden Ministerial de creación del IIER contempla un área denominada Unidad de Investigación del Síndrome del Aceite Tóxico (UISAT), aunque en la práctica funciona con tres unidades: Enfermedades Raras, Trastornos del Espectro del Autismo y Epidemiología de las enfermedades relacionadas con el ambiente, y se coordina con el Centro de Investigación en Anomalías Congénitas (CIAC) en lo referente a estas patologías. El IIER es un Centro Colaborador de la OMS en epidemiología de las enfermedades relacionadas con el ambiente, oficialmente designado por esta organización para estos fines desde el año 1996.

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Exploring the anti-inflammatory activity of fupenzic acid using network pharmacology and experimental validation.
(Nature Publishing Group, 2025-04-24) Boukerouis, Djoudi; Cuadrado, Irene; Benaida, Nadjet Debbache; Estévez-Braun, Ana; de Las Heras, Beatriz; Amesty, Angel; Hortelano, Sonsoles; Hortelano, Sonsoles; Instituto de Salud Carlos III; Ministerio de Ciencia e Innovación (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
Crataegus azarolus L. (Rosaceae), commonly known as Mediterranean hawthorn, has long been valued in Traditional Medicine for treating cardiovascular and inflammation-related diseases, including diabetes, cancer, and rheumatism. Pharmacological benefits of Crataegus azarolus L. are notably linked to its anti-inflammatory properties. Fupenzic acid, a pentacyclic triterpene isolated from its leaves, holds significant pharmacological potential that remains elusive. This study investigates the unexplored capacity of fupenzic acid as a promising anti-inflammatory agent. Using a multidisciplinary approach that integrates network pharmacology, molecular docking, in vitro assays, and predictive in silico analyses of drug-like properties, ADME, and toxicity, the mechanisms and properties of fupenzic acid have been elucidated. Network pharmacology analysis identified the potential targets for fupenzic acid, with enrichment analyses revealing key processes like inflammatory response, cytokine signaling, innate immune system, and MAPK cascade regulation. Transcription factors such as RELA, SP1, and NFKB1 were predicted to play crucial roles in its therapeutic effects. PPI network analysis underscored NF-κB as a central hub, linking these pathways to its anti-inflammatory effects. In vitro experiments demonstrated that fupenzic acid effectively suppressed inflammatory mediators like NOS-2 and COX-2, through the NF-κB pathway. Molecular docking further confirmed its favorable interaction with NF-κB, reinforcing its mechanism of action. Additionally, in silico ADMET profiling revealed favorable drug-like properties including pharmacokinetics and toxicity profiles, emphasizing its suitability as a drug candidate. This study represents a major step forward in understanding the therapeutic potential of fupenzic acid, establishing it as a distinctive and promising anti-inflammatory agent. The findings identified it as a pharmacological agent for clinical development targeting inflammation-driven diseases and also provide a foundation for future translational research.
Dehydroisohispanolone alleviates NLRP3-driven inflammation in gout arthritis.
(Elsevier, 2025-10) González-Cofrade, Laura; Green, Jack P; de Las Heras, Beatriz; Terencio, María Carmen; Hortelano, Sonsoles; Brough, David; Estévez-Braun, Ana; Ferrándiz, María Luisa; Cuadrado, Irene; Ministerio de Ciencia, Innovación y Universidades (España); Agencia Estatal de Investigación (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Instituto de Salud Carlos III
Natural products constitute an important resource for drug discovery with hispanolone derivatives recognized as bioactive diterpenes due to their broad therapeutic potential. Dehydroisohispanolone (DIH) is an anti-inflammatory labdane diterpene, that acts as a multi-target agent through various inflammation pathways. Aberrant activation of the Nod-like receptor protein 3 (NLRP3) inflammasome is involved in several inflammatory diseases, including gout. This study explores the mechanisms underlying the effects of DIH on the NLRP3 inflammasome and pyroptosis in vitro and evaluates its therapeutic effects on gouty arthritis in mice. DIH suppresses interleukin (IL)-1β secretion and pyroptosis in lipopolysaccharide (LPS)-primed bone-marrow-derived macrophages (BMDMs) elicited by broad stimuli. DIH exerts its action by disrupting adaptor apoptosis-associated speck-like protein (ASC) oligomerization, thereby inhibiting the assembly of inflammasome complex. Notably, DIH specifically inhibits NLRP3 inflammasome activation in murine BMDMs without affecting the absent in melanoma-2 (AIM2) or NOD-like receptor family CARD domain containing 4 (NLRC4) inflammasomes. In animal models, DIH significantly mitigated monosodium urate (MSU)-induced joint inflammation, reducing cytokine levels and myeloperoxidase (MPO) secretion. Overall, this study identified DIH as a specific inhibitor of the NLRP3 inflammasome, providing new insights into its potential as a therapeutic agent for NLRP3-mediated inflammatory diseases.
p19ARF Deficiency Disrupts Lung and Lipid Homeostasis Resembling the Human Alveolar Proteinosis.
(Oxford University Press, 2026-02-05) Jimenez-Garcia, Lidia; Pérez-Montero, Andrea; Herranz, Sandra; Luque, Alfonso; Tarín, Carlos; Castillo, Diego; Lopez-Vilaro, Laura; Mariñas-Pardo, Luis; McCarthy, Cormac; Acebo, Paloma; Hortelano, Sonsoles; Instituto de Salud Carlos III; Comunidad de Madrid (España)
The alternative reading frame (ARF) protein, encoded by the CDKN2A locus, is well-recognized for its role in tumor suppression. Emerging evidence has highlighted ARF as a critical regulator of innate immunity and inflammation, with links to increased susceptibility to cardio-metabolic diseases. This study investigates the role of ARF in lung homeostasis and reveals that its deficiency in mice affects lipid metabolism and leads to pulmonary abnormalities resembling pulmonary alveolar proteinosis (PAP). ARF-deficient mice exhibited abnormal surfactant clearance, characterized by lipid and protein accumulation in the alveoli, foamy alveolar macrophages (AMs) with enlarged and vacuolated morphology, and increased bronchoalveolar lavage fluid (BALF) turbidity. These changes were linked to disrupted surfactant homeostasis resulting from an imbalance between increased lipid uptake (via upregulation of scavenger receptors such as SR-A1 and CD36) and impaired lipid efflux, evidenced by reduced expression of the cholesterol transporter SR-BI. These mice also display reduced AMs numbers, increased eosinophil and neutrophil infiltration, consistent with secondary PAP. Additionally, a distinctive chemokine and cytokine profile (elevated Ccl12, Ccl2, Cxcl1, and IL10) was observed, which may be associated with type 2 immune responses and alternative AMs polarization. Interestingly, ARF deficiency also appears to compromise AMs maintenance through effects on self-renewal and survival. Pulmonary function tests revealed increased tissue elastance and damping, suggesting early-stage lung stiffness. Collectively, these findings highlight the essential role of ARF in lung homeostasis and lipid regulation, providing insights into its potential involvement in PAP pathogenesis.
Drosophila as a Model for Human Disease: Insights into Rare and Ultra-Rare Diseases
(Multidisciplinary Digital Publishing Institute (MDPI), 2024-11-06) Casas-Tinto, Sergio
Rare and ultra-rare diseases constitute a significant medical challenge due to their low prevalence and the limited understanding of their origin and underlying mechanisms. These disorders often exhibit phenotypic diversity and molecular complexity that represent a challenge to biomedical research. There are more than 6000 different rare diseases that affect nearly 300 million people worldwide. However, the prevalence of each rare disease is low, and in consequence, the biomedical resources dedicated to each rare disease are limited and insufficient to effectively achieve progress in the research. The use of animal models to investigate the mechanisms underlying pathogenesis has become an invaluable tool. Among the animal models commonly used in research, Drosophila melanogaster has emerged as an efficient and reliable experimental model for investigating a wide range of genetic disorders, and to develop therapeutic strategies for rare and ultra-rare diseases. It offers several advantages as a research model including short life cycle, ease of laboratory maintenance, rapid life cycle, and fully sequenced genome that make it highly suitable for studying genetic disorders. Additionally, there is a high degree of genetic conservation from Drosophila melanogaster to humans, which allows the extrapolation of findings at the molecular and cellular levels. Here, I examine the role of Drosophila melanogaster as a model for studying rare and ultra-rare diseases and highlight its significant contributions and potential to biomedical research. High-throughput next-generation sequencing (NGS) technologies, such as whole-exome sequencing and whole-genome sequencing (WGS), are providing massive amounts of information on the genomic modifications present in rare diseases and common complex traits. The sequencing of exomes or genomes of individuals affected by rare diseases has enabled human geneticists to identify rare variants and identify potential loci associated with novel gene-disease relationships. Despite these advances, the average rare disease patient still experiences significant delay until receiving a diagnosis. Furthermore, the vast majority (95%) of patients with rare conditions lack effective treatment or a cure. This scenario is enhanced by frequent misdiagnoses leading to inadequate support. In consequence, there is an urgent need to develop model organisms to explore the molecular mechanisms underlying these diseases and to establish the genetic origin of these maladies. The aim of this review is to discuss the advantages and limitations of Drosophila melanogaster, hereafter referred as Drosophila, as an experimental model for biomedical research, and the applications to study human disease. The main question to address is whether Drosophila is a valid research model to study human disease, and in particular, rare and ultra-rare diseases.
Adult neurogenesis through glial transdifferentiation in a CNS injury paradigm.
(eLife Sciences Publications, 2025-03-07) Casas-Tinto, Sergio; Garcia-Guillen, Nuria; Losada-Perez, María
As the global population ages, the prevalence of neurodegenerative disorders is fast increasing. This neurodegeneration as well as other central nervous system (CNS) injuries cause permanent disabilities. Thus, generation of new neurons is the rosetta stone in contemporary neuroscience. Glial cells support CNS homeostasis through evolutionary conserved mechanisms. Upon damage, glial cells activate an immune and inflammatory response to clear the injury site from debris and proliferate to restore cell number. This glial regenerative response (GRR) is mediated by the neuropil-associated glia (NG) in , equivalent to vertebrate astrocytes, oligodendrocytes (OL), and oligodendrocyte progenitor cells (OPCs). Here, we examine the contribution of NG lineages and the GRR in response to injury. The results indicate that NG exchanges identities between ensheathing glia (EG) and astrocyte-like glia (ALG). Additionally, we found that NG cells undergo transdifferentiation to yield neurons. Moreover, this transdifferentiation increases in injury conditions. Thus, these data demonstrate that glial cells are able to generate new neurons through direct transdifferentiation. The present work makes a fundamental contribution to the CNS regeneration field and describes a new physiological mechanism to generate new neurons.
VP3.15, a dual GSK-3β/PDE7 inhibitor, reduces glioblastoma tumor growth though changes in the tumor microenvironment in a PTEN wild-type context.
(Elsevier, 2025-07) Castello-Pons, Maria; Ramírez-González, María A; Iglesias-Hernandez, Patricia; Lendo, Nermina Logo; Rodriguez-Martin, Carlos; Quiralte, Laura; Sepúlveda-Sánchez, Juan-Manuel; Dios Huerta, Olaya de; Gil, Carmen; Martínez, Ana; Sánchez-Gómez, Pilar; Casas-Tinto, Sergio
Glioblastoma (GB) is an incurable cancer of the brain, and there is an urgent need to identify effective treatments. This may be achieved by either identifying new molecules or through drug repurposing. To ascertain the therapeutic potential of known GSK-3β and/or PDE7 inhibitors in GB, a drug screening was conducted using a Drosophila melanogaster glioma model. VP3.15, a dual inhibitor with anti-inflammatory and neuroprotective roles in multiple sclerosis, was selected for further investigation. VP3.15 demonstrated robust anti-tumor efficacy against a panel of human and mouse GB cells; however, its capacity to inhibit orthotopic growth was only observed in a wild-type PTEN cell line. The in vivo dependence on PTEN was further suggested with the results in fly gliomas. The analysis of the VP3.15-treated tissues revealed a notable reduction in the number of myeloid cells and in the degree of vascularization. Mechanistic studies indicate that VP3.15 diminishes the production of GAL9, a key molecule that stimulates pro-angiogenic macrophages. Our findings substantiate the pro-tumoral function of GSK-3β, which might depend on the PTEN genetic status. Furthermore, we have delineated the therapeutic potential of VP3.15, which acts through the inhibition of the supportive role of the GB microenvironment. This molecule could be safely and effectively utilized after PTEN characterization in GB patients.
CRISPR-mediated targeting of the LMNA c.745C>T pathogenic mutation enhances survival and cardiac function in congenital muscular dystrophy.
(Elsevier, 2025-12) Gomez-Dominguez, Deborah; Epifano, Carolina; Hernández Martínez, Iván; Vilaplana-Marti, Borja; Martin, Alberto; Amarilla-Quintana, Sandra; Cesar, Sergi; de Molina-Iracheta, Antonio; Sena-Esteves, Miguel; Sarquella-Brugada, Georgia; Perez de Castro, Ignacio
LMNA-associated congenital muscular dystrophy is a currently incurable rare genetic disorder characterized by early-onset muscle weakness, dilated cardiomyopathy and respiratory failure, resulting from mutations in the LMNA gene. In this study, we assessed the potential of a CRISPR-mediated strategy to eliminate the mutant allele Lmna c.745C>T, p.R249W using a mutation specific guide (sg745T). Results from R249W-mutation-carrying cellular models showed specific activity of the Cas9/sg745T complex towards the mutant allele. This property varied depending on the concentration of CRISPR components, with a loss of specificity observed with increased dosage. We tested this strategy in vivo using adeno-associated virus delivery in LmnaR249W mice. Despite being associated with a modest CRISPR activity, this therapeutic approach led to a 10% (non-significant) increase in the survival of R249W homozygous mice. Interestingly, a comparable CRISPR activity significantly ameliorated the cardiac pathology observed in Lmna+/R249W animals, resulting in a significant 24.3% extension of their median survival. These results represent the first therapeutic validation of a CRISPR/Cas9-mediated gene editing strategy for the treatment of LMNA-associated congenital muscular dystrophy.
Risk of neuroblastoma and residential proximity to industrial and urban sites: A case-control study.
(Elsevier, 2016-04) García-Pérez, Javier; Morales-Piga, Antonio; Gomez-Barroso, Diana; Tamayo-Uria, Ibon; Pardo Romaguera, Elena; Fernandez-Navarro, Pablo L; Lopez-Abente, Gonzalo; Ramis, Rebeca; Instituto de Salud Carlos III
Background: Neuroblastoma is the most common extracranial solid tumor in children but its etiology is not clearly understood. While a small fraction of cases might be attributable to genetic factors, the role of environmental pollution factors needs to be assessed. Objectives: To ascertain the effect of residential proximity to both industrial and urban areas on neuroblastoma risk, taking into account industrial groups and toxic substances released. Methods: We conducted a population-based case-control study of neuroblastoma in Spain, including 398 incident cases gathered from the Spanish Registry of Childhood Tumors (period 1996-2011), and 2388 controls individually matched by year of birth, sex, and region of residence. Distances were computed from the respective subject's residences to the 1271 industries and the 30 urban areas with ≥75,000 inhabitants located in the study area. Using logistic regression, odds ratios (ORs) and 95% confidence intervals (95%CIs) for categories of distance (from 1km to 5km) to industrial and urban pollution sources were calculated, with adjustment for matching variables and socioeconomic confounders. Results: Excess risk (OR; 95%CI) of neuroblastoma was detected for the intersection between industrial and urban areas: (2.52; 1.20-5.30) for industrial distance of 1km, and (1.99; 1.17-3.37) for industrial distance of 2km. By industrial groups, excess risks were observed near 'Production of metals' (OR=2.05; 95%CI=1.16-3.64 at 1.5km), 'Surface treatment of metals' (OR=1.89; 95%CI=1.10-3.28 at 1km), 'Mines' (OR=5.82; 95%CI=1.04-32.43 at 1.5km), 'Explosives/pyrotechnics' (OR=4.04; 95%CI=1.31-12.42 at 4km), and 'Urban waste-water treatment plants' (OR=2.14; 95%CI=1.08-4.27 at 1.5km). Conclusions: These findings support the need for more detailed exposure assessment of certain substances released by these industries.
Risk of bone tumors in children and residential proximity to industrial and urban areas: New findings from a case-control study.
(Elsevier, 2017-02-01) García-Pérez, Javier; Morales-Piga, Antonio; Gomez-Barroso, Diana; Tamayo-Uria, Ibon; Pardo Romaguera, Elena; Lopez-Abente, Gonzalo; Ramis, Rebeca; Instituto de Salud Carlos III; Asociación Española Contra el Cáncer
Few epidemiologic studies have explored risk factors for bone tumors in children, and the role of environmental factors needs to be analyzed. Our objective was to ascertain the association between residential proximity to industrial plants and urban areas and risk of bone tumors in children, taking into account industrial groups and toxic pollutants released. A population-based case-control study of childhood bone cancer in Spain was carried out, covering 114 incident cases obtained from the Spanish Registry of Childhood Tumors (between 1996 and 2011), and 684 controls individually matched by sex, year of birth, and autonomous region of residence. Distances from the subject's residences to the 1271 industries and the 30 urban areas (towns) with ≥75,000 inhabitants located in the study area were computed. Unconditional logistic regression models were fitted to estimate odds ratios (ORs) and 95% confidence intervals (95%CIs) for categories of distance (from 1km to 3km) to industrial and urban areas, with adjustment for matching variables and sociodemographic indicators. Excess risk (OR; 95%CI) of bone tumors in children was detected for children close to industrial facilities as a whole (2.33; 1.17-4.63 at 3km) - particularly surface treatment of metals (OR=2.50; 95%CI=1.13-5.56 at 2km), production and processing of metals (OR=3.30; 95%CI=1.41-7.77 at 2.5km), urban waste-water treatment plants (OR=4.41; 95%CI=1.62-11.98 at 2km), hazardous waste (OR=4.63; 95%CI=1.37-15.61 at 2km), disposal or recycling of animal waste (OR=4.73; 95%CI=1.40-15.97 at 2km), cement and lime (OR=3.89; 95%CI=1.19-12.77 at 2.5km), and combustion installations (OR=3.85; 95%CI=1.39-10.66 at 3km)-, and urban areas (4.43; 1.80-10.92). These findings support the need for more detailed exposure assessment of certain toxics released by these facilities.
Targeted inactivation of EWSR1 : : FLI1 gene in Ewing sarcoma via CRISPR/Cas9 driven by an Ewing-specific GGAA promoter
(Nature Publishing Group, 2025-04) Cervera Mayor, Saint Thomas; Martinez Rodríguez, Selene; Iranzo-Martínez, Maria; Notario, Laura; Melero-Fernández de Mera, Raquel María; Alonso, Javier; Instituto de Salud Carlos III; Asociación Pablo Ugarte contra el cáncer infantil; Fundación la Sonrisa de Alex para la investigación y el tratamiento del sarcoma de Ewing; Asociación Todos somos Iván; Candela Ribera. Asociación contra el sarcoma de Ewing; Centro de Investigación Biomédica en Red - CIBERER (Enfermedades Raras); Fundación FEDER
We have recently demonstrated that genetic inactivation of EWSR1 : : FLI1 by CRISPR/Cas9, successfully blocks cell proliferation in a cell model of Ewing sarcoma. However, CRISPR/Cas9-mediated gene editing can exhibit off-target effects, and thus, precise regulation of Cas9 expression in target cells is essential to develop gene-editing strategies to inactivate EWSR1 : : FLI1 in Ewing sarcoma cells. In this study, we demonstrate that Cas9 can be specifically expressed in Ewing sarcoma cells when located downstream a promoter consisting of GGAA repeats and a consensus TATA box (GGAAprom). Under these conditions, Cas9 is selectively expressed in Ewing sarcoma cells that express EWSR1 : : FLI1 oncoproteins, but not in cells expressing wild-type FLI1. Consequently, Ewing sarcoma cells infected with GGAAprom>Cas9 and a specific gRNA designed to inactivate EWSR1 : : FLI1, showed successful EWSR1 : : FLI1 inactivation and the subsequent blockade of cell proliferation. Notably, GGAAprom>Cas9 can be efficiently delivered to Ewing sarcoma cells via adenoviral vectors both in vitro and in vivo, highlighting the potential of this approach for Ewing sarcoma treatment. Our results demonstrate that the CRISPR/Cas9 machinery is safe and specific for Ewing sarcoma cells when driven under a GGAAprom, paving the way for the development of cancer gene therapies based on the selective expression of genes with therapeutic potential.
Development of newborn screening policies in Spain 2003-2022: what do we actually need to reach an agreement?
(OAE Publishing, 2023-09-13) Valcárcel-Nazco, Cristina; García-Pérez, Lidia; Linertová, Renata; Guirado-Fuentes, Carmen; Hernández-Yumar, Aránzazu; Paz-Valiñas, Lucinda; Cantero-Muñoz, Paula; Posada De la Paz, Manuel; Serrano-Aguilar, Pedro
Newborn screening (NBS) for inherited disorders is recognized as an essential public health intervention to improve health outcomes in the newborn population. The implementation of an NBS programme requires an evaluation of effectiveness, safety, cost-effectiveness, feasibility, and budget impact. Determining which of the known disorders should be included in NBS programmes is a public health policy challenge. In this context, economic evaluation aims to contribute to the sustainability of public health systems, but the appropriate economic evaluation framework for these interventions is still unclear. Existing NBS programmes vary widely in the number and type of disorders screened, even among the most developed European countries, despite the fact that the core criteria for guiding policy decision-making are standard. In Spain, where delivery of NBS programmes is marked by heterogeneity between regions, guidelines based on the best available scientific evidence are being established in order to achieve standardization of NBS policies and programmes at a national level. This paper provides a general overview of existing evidence-based health-policy initiatives aimed at enhancing the equity and efficiency of the NBS programme in Spain and their impact on health decisions. We also describe existing challenges to reduce uncertainty, and the variations observed in decisions relating to the content and procedures used in NBS programmes.
Silicosis mortality in Spain (1999-2020): A temporal and geographical approach
(AIMS Press, 2024) Sanchez-Diaz, German; Arias-Merino, Greta; Gallego, Elisa; Sarmiento Suárez, Rodrigo; Alonso-Ferreira, Veronica; Instituto de Salud Carlos III
Background: Silicosis is an occupational respiratory disease linked to silica dust inhalation. The main driver was traditional coal mining, but in recent decades, new sources of exposure have emerged. Our aim in this study was to assess the temporal and spatial distribution of mortality due to this disease over a 22-year period in Spain. Methods: Silicosis records, as an Underlying Cause of Death, were extracted from the National Institute of Statistics from 1999 to 2020 using the International Classification of Diseases 10th revision (code J62.8). Age- and sex-adjusted mortality rates per 1,000,000 inhabitants were calculated for the territory and by province. A geographic analysis was performed, and clusters of deaths were identified at the municipal level, and then the outcomes were compared in two periods of 11 years. Results: There were 2618 deaths due to silicosis in Spain. The mean age of death increased significantly by 0.66% annually from 1999 to 2013. The age-adjusted mortality rate decreased by 7.30% per year, falling from 3.00 to 0.65 per 1,000,000 inhabitants. The temporal pattern showed a significant decrease of mortality rate in 31% of the provinces (16 out of 52), while it increased in Pontevedra. Regarding the spatial analysis, 11 clusters were found in both periods, but some variations were observed in terms of their distribution in the Spanish territory, as well as in the affected municipalities. Conclusions: The decrease in mortality due to Silicosis could be related to less exposure to silica dust over the years and an improvement in the survival of those affected. It is thus essential to analyze the role of preventive measures for this occupational disease.
Performance of the Idylla microsatellite instability test in endometrial cancer
(Elsevier, 2024-10) Mendiola, Marta; Heredia-Soto, Victoria; Ruz-Caracuel, Ignacio; Baillo, Amparo; Ramon-Patino, Jorge Luis; Berjon, Alberto; Escudero Ruiz, Francisco Javier; Peláez-García, Alberto; Hernandez, Alicia; Feliu, Jaime; Hardisson, David; Redondo, Andres; Agencia Estatal de Investigación (España); Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
Context: DNA mismatch repair (MMR) deficiency (dMMR) testing is now recommended in endometrial cancer. Defect identification in the molecules participating in this pathway, or the presence of microsatellite instability, are commonly employed for this purpose. Novel methods are continuously evolving to report dMMR/microsatellite instability and to easily perform routine diagnoses. Objective: The main aim of this study was to compare the concordance of the Idylla microsatellite instability test for the identification of dMMR endometrial cancer samples defined by immunohistochemistry and MMR genomic status. Design: We applied the Idylla MSI test to 126 early-stage endometrial cancer cases with MMR testing by immunohistochemistry and genomic characterization (methylation in MLH1 and sequence alterations in MLH1, PMS2, MSH2 and MSH6). Individual markers and overall specific performance indicators were explored. Results: The Idylla platform achieved a higher global concordance rate with MMR genomic status than with immunohistochemistry (75 % and 66 %, respectively). Sensitivity and specificity are also higher (75 % vs 66 % and 96 % vs 90 %, respectively). Clustering analysis split the patients into 2 well-differentiated clusters, the pMMR and the dMMR group, represented by MLH1/PMS2 loss and the MLH1 methylated promoter. Overall, immunohistochemistry and MMR genomic status identified more dMMR cases than did the Idylla test, although correlations were improved with a modified Idylla test cut-off. Conclusions: Performance of the Idylla test was better correlated with MMR genomic status than MMR immunohistochemistry status, which improved with a modified test cut-off. Further studies are needed to confirm the cut-off accuracy.
Brain organoid as a model to study the role of mitochondria in neurodevelopmental disorders: achievements and weaknesses
(Frontiers Media, 2024) Coronel Lopez, Raquel; García-Moreno, Enrique; Siendones, Emilio; Barrero, Maria; Martinez-Delgado, Beatriz; Santos-Ocaña, Carlos; Liste-Noya, Isabel; Cascajo-Almenara, M V; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
Mitochondrial diseases are a group of severe pathologies that cause complex neurodegenerative disorders for which, in most cases, no therapy or treatment is available. These organelles are critical regulators of both neurogenesis and homeostasis of the neurological system. Consequently, mitochondrial damage or dysfunction can occur as a cause or consequence of neurodevelopmental or neurodegenerative diseases. As genetic knowledge of neurodevelopmental disorders advances, associations have been identified between genes that encode mitochondrial proteins and neurological symptoms, such as neuropathy, encephalomyopathy, ataxia, seizures, and developmental delays, among others. Understanding how mitochondrial dysfunction can alter these processes is essential in researching rare diseases. Three-dimensional (3D) cell cultures, which self-assemble to form specialized structures composed of different cell types, represent an accessible manner to model organogenesis and neurodevelopmental disorders. In particular, brain organoids are revolutionizing the study of mitochondrial-based neurological diseases since they are organ-specific and model-generated from a patient's cell, thereby overcoming some of the limitations of traditional animal and cell models. In this review, we have collected which neurological structures and functions recapitulate in the different types of reported brain organoids, focusing on those generated as models of mitochondrial diseases. In addition to advancements in the generation of brain organoids, techniques, and approaches for studying neuronal structures and physiology, drug screening and drug repositioning studies performed in brain organoids with mitochondrial damage and neurodevelopmental disorders have also been reviewed. This scope review will summarize the evidence on limitations in studying the function and dynamics of mitochondria in brain organoids.
Mosaicism and intronic variants in RB1 gene revealed by next generation sequencing in a cohort of Spanish retinoblastoma patients
(Elsevier, 2025-02) Gomez-Mariano, Gema Maria; Hernandez-SanMiguel, Esther; Fernandez-Prieto, Marta; Ramos-Del Saz, Sheila; Baladron-Jimenez, Beatriz Isabel; Mirela Mielu, Lidia; Rivera Pinto, Daniel; Moneo Ocaña, Victoria; López-Jiménez, Lidia; Rodriguez-Martin, Carlos; Fernandez-Teijeiro Álvarez, Ana; Sabado, Constantino; Bermejo-Sanchez, Eva; Alonso, Javier; Martinez-Delgado, Beatriz; Instituto de Salud Carlos III
Constitutional variants in the RB1 gene predispose individuals to the development of Retinoblastoma (RB) and the occurrence of second tumors in adulthood. Detection of causal RB1 gene variants is essential to establish the genetic diagnosis and to performing familial studies and counseling. In our cohort of 579 Spanish RB patients, 15% of cases suspected to have a genetic origin remained negative after traditional Sanger sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA) of RB1 gene, likely due to the possibility of mosaicism or non-coding variants. A specific next-generation sequencing (NGS) gene panel was designed to analyze the complete sequence of the RB1 gene. While many familial RB cases showed variants through Sanger and MLPA, the analysis of 65 available sporadic RB patients using the NGS gene panel identified a causative variant in an additional 6 of 26 (23%) bilateral cases and 6 of 39 (15.4%) unilateral cases. Seven of these cases exhibited different degrees of mosaicism (26%, 20%, 15.8%, 8%, 6%, 5.9% and 3%) while 5 cases had heterozygous deep intronic variants, all of them previously described in RB patients. Additional cases with suspected variants, not detected in blood but present in tumor tissue, were also analyzed using NGS PCR amplicons, and mosaicism was confirmed in other 10 sporadic cases. Altogether, the use of NGS increased the diagnostic yield, particularly for patients with sporadic RB in 10 bilateral cases and in 12 unilateral cases.
Preparing Data at the Source to Foster Interoperability across Rare Disease Resources.
(Springer, 2017) Roos, Marco; Lopez-Martin, Estrella; Wilkinson, Mark D
The ability to combine heterogeneous data distributed across the globe is critically important to boost research on rare diseases, but it presents a number of methodological, representational and automation challenges. In this scenario, biomedical ontologies are of critical importance for enabling computers to aid in information retrieval and analysis across data collections.This chapter presents an approach to preparing rare disease data for integration through the application of a global standard for computer-readable data and knowledge. This includes the use of common data elements, ontological codes and computer-readable data. This approach was developed under a number of domain-relevant requirements, such as controlled access to data, independence of the original sources, and the desire to combining the data sources with other computational workflows and data platforms.
Open-label phase II clinical trial of ketoconazole as CYP17 inhibitor in metastatic or advanced non-resectable granulosa cell ovarian tumors: the GREKO (GRanulosa Et KetOconazole) trial, GETHI 2011-03
(Springer, 2023-07) Garcia-Donas, Jesus; Hurtado, Alicia; Garrigos, Laia; Santaballa, Ana; Redondo, Andres; Vidal, Laura; Lainez, Nuria; Guerra, Eva; Rodriguez, Victor; Cueva, Juan; Bover, Isabel; Palacio, Isabel; Rubio, Maria Jesus; Prieto, Mario; Lopez-Guerrero, Jose Antonio; Rodriguez-Moreno, Juan Francisco; Garcia-Casado, Zaida; Garcia-Martinez, Elena; Taus, Alvaro; Perez de Castro, Ignacio; Navarro, Paloma; Grande, Enrique; Spanish Group for Research in Orphan, Infrequent Tumors (GETHI); Ministerio de Sanidad, Consumo y Bienestar Social (España)
Background: Granulosa cell ovarian tumor (GCT) is characterized by a pathognomonic mutation in the FOXL2 gene (402 C > G) that leads to an overactivation of steroidogenesis. CYP17 is a key enzyme in such process and can be inhibited by ketoconazole. Methods: We designed a phase II clinical trial to assess the efficacy of ketoconazole in advanced GCT and conducted several in vitro studies to support the clinical findings. Results: From October 1st 2012 to January 31st 2014, six evaluable patients were recruited in ten hospitals of the Spanish Group for Transversal Oncology and Research in Orphan and Infrequent Tumors" (GETTHI). FOXL2 (402C > G) mutation was confirmed in three; two cases were wild type and it could not be assessed in one. No objective response by RECIST was observed, but five cases achieved stable disease longer than 12 months. Median progression-free survival was 14.06 months (CI 95% 5.43-22.69) for the whole study population (3.38 and 13.47 months for wild-type cases and 14.06, 20.67 and 26.51 for those with confirmed FOXL2 mutation). Median overall survival was 22·99 months (CI 95% 8.99-36.99). In vitro assays confirmed the activity of ketoconazole in this tumor and suggested potential synergisms with other hormone therapies. Conclusion: Ketoconazole has shown activity in advanced GCT in clinical and in vitro studies. Based on these data, an orphan designation was granted by the European Medicines Agency for ketoconazole in GCT (EU/3/17/1857). Gov identifier: NCT01584297.
Using a health observance event to raise awareness: An assessment of World Birth Defects Day.
(Wiley, 2023-07-01) Kleven, Danielle L; Mai, Cara T; Bermejo-Sanchez, Eva; Groisman, Boris; Walani, Salimah; Peck, Jessica; Cosentino, Viviana; Botto, Lorenzo D; Zezza, Simonetta; Romitti, Paul A; Mastroiacovo, Pierpaolo
World Birth Defects Day (WorldBDDay), observed annually on March 3, was launched in 2015 to advocate for public health surveillance, research, and prevention of birth defects, along with improved care and treatment for affected individuals. Following its fifth observance in 2019, we assessed WorldBDDay by analyzing: (a) engagement and content of over 2000 WorldBDDay posts on Facebook, Twitter, and Instagram; (b) interview responses from 9 WorldBDDay charter (founding) organizations on their perceptions of strengths and areas for improvement for WorldBDDay; (c) survey responses from 61 WorldBDDay 2019 partner (participating) organizations on their WorldBDDay 2019 activities; and (d) post-2019 social media engagement. Most social media posts (60%) occurred from organizations using Twitter (80% vs. 14% for Instagram and 6% for Facebook), although posts from individuals had higher levels of engagement (e.g., likes and comments). The highest engagement occurred for posts focused on general awareness, prevention, or events. Charter organizations reported the need for existing and new partner engagement, including a designated WorldBDDay contact for regular communication and coordination of activities and prepared prevention-focused messaging. Partner organizations reported using the WorldBDDay toolkit, especially key messages and social media tips, and suggested expanding the toolkit with relevant resources. Post-2019 Twitter engagement was lower than 2019 WorldBDDay (peak event) but showed similar reach to WorldBDDay events prior to 2019. Our assessment identified WorldBDDay health observance events as an important tool to support knowledge dissemination and global community engagement around birth defects. Moving forward, engagement with more individuals and organizations may improve the reach of WorldBDDay.
Prevalence and mortality in children with congenital diaphragmatic hernia: a multicountry study.
(Elsevier, 2021-04) Politis, Maria D; Bermejo-Sanchez, Eva; Canfield, Mark A; Contiero, Paolo; Cragan, Janet D; Dastgiri, Saeed; de Walle, Hermien E K; Feldkamp, Marcia L; Nance, Amy; Groisman, Boris; Gatt, Miriam; Benavides-Lara, Adriana; Hurtado-Villa, Paula; Källén Kärin; Landau, Danielle; Lelong, Nathalie; Lopez-Camelo, Jorge; Martinez, Laura; Morgan, Margery; Mutchinick, Osvaldo M; Pierini, Anna; Rissmann, Anke; Šípek, Antonin; Szabova, Elena; Wertelecki, Wladimir; Zarante, Ignacio; Bakker, Marian K; Kancherla, Vijaya; Mastroiacovo, Pierpaolo; Nembhard, Wendy N; International Clearinghouse for Birth Defects Surveillance and Research; Centers for Disease Control and Prevention (Estado Unidos); Arkansas Biosciences Institute; Ministry of Health Welfare and Sport (Países Bajos); Instituto de Salud Carlos III; Ministerio de Ciencia e Innovación (España); Fundación 1000 sobre Defectos Congénitos; Ministry of Health (República Checa); Public Health Wales
Purpose: This study determined the prevalence, mortality, and time trends of children with congenital diaphragmatic hernia (CDH). Methods: Twenty-five hospital- and population-based surveillance programs in 19 International Clearinghouse for Birth Defects Surveillance and Research member countries provided birth defects mortality data between 1974 and 2015. CDH cases included live births, stillbirths, or elective termination of pregnancy for fetal anomalies. Prevalence, cumulative mortality rates, and 95% confidence intervals (CIs) were calculated using Poisson regression and a Kaplan-Meier product-limit method. Joinpoint regression analyses were conducted to assess time trends. Results: The prevalence of CDH was 2.6 per 10,000 total births (95% CI: 2.5-2.7), slightly increasing between 2001 and 2012 (average annual percent change = 0.5%; 95% CI:-0.6 to 1.6). The total percent mortality of CDH was 37.7%, with hospital-based registries having more deaths among live births than population-based registries (45.1% vs. 33.8%). Mortality rates decreased over time (average annual percent change = -2.4%; 95% CI: -3.8 to 1.1). Most deaths due to CDH occurred among 2- to 6-day-old infants for both registry types (36.3%, hospital-based; 12.1%, population-based). Conclusions: The mortality of CDH has decreased over time. Mortality remains high during the first week and varied by registry type.
Survival of infants born with esophageal atresia among 24 international birth defects surveillance programs.
(Wiley, 2021-07-15) Bell, Jane C; Baynam, Gareth; Bergman, Jorieke EH; Bermejo-Sanchez, Eva; Botto, Lorenzo D; Canfield, Mark A; Dastgiri, Saeed; Gatt, Miriam; Groisman, Boris; Hurtado-Villa, Paula; Källén Kärin; Khoshnood, Babak; Konrad, Victoria; Landau, Danielle; Lopez-Camelo, Jorge; Martinez, Laura; Morgan, Margery; Mutchinick, Osvaldo M; Nance, Amy E; Nembhard, Wendy; Pierini, Anna; Rissmann, Anke; Shan, Xiaoyi; Sipek, Antonin; Szabova, Elena; Tagliabue, Giovanna; Yevtushok, Lyubov S; Zarante, Ignacio; Nassar, Natasha; Ministry of Health Welfare and Sport (Países Bajos); Instituto de Salud Carlos III; Ministerio de Ciencia e Innovación (España); Fundación 1000 sobre Defectos Congénitos; Ministry of Health (República Checa); Health Resources and Services Administration (Estados Unidos)
Background: Esophageal atresia (EA) affects around 2.3-2.6 per 10,000 births world-wide. Infants born with this condition require surgical correction soon after birth. Most survival studies of infants with EA are locally or regionally based. We aimed to describe survival across multiple world regions. Methods: We included infants diagnosed with EA between 1980 and 2015 from 24 birth defects surveillance programs that are members of the International Clearinghouse for Birth Defects Surveillance and Research. We calculated survival as the proportion of liveborn infants alive at 1 month, 1- and 5-years, among all infants with EA, those with isolated EA, those with EA and additional anomalies or EA and a chromosomal anomaly or genetic syndrome. We also investigated trends in survival over the decades, 1980s-2010s. Results: We included 6,466 liveborn infants with EA. Survival was 89.4% (95% CI 88.1-90.5) at 1-month, 84.5% (95% CI 83.0-85.9) at 1-year and 82.7% (95% CI 81.2-84.2) at 5-years. One-month survival for infants with isolated EA (97.1%) was higher than for infants with additional anomalies (89.7%) or infants with chromosomal or genetic syndrome diagnoses (57.3%) with little change at 1- and 5-years. Survival at 1 month improved from the 1980s to the 2010s, by 6.5% for infants with isolated EA and by 21.5% for infants with EA and additional anomalies. Conclusions: Almost all infants with isolated EA survived to 5 years. Mortality was higher for infants with EA and an additional anomaly, including chromosomal or genetic syndromes. Survival improved from the 1980s, particularly for those with additional anomalies.

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