Artículos (Citología e Histología Normal y Patológica)

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Adequacy of pharmacological prescription in patients at very high risk of fracture within the FLS in Spain: analysis of the REFRA FLS-SEIOMM registry
(Springer Science and Business Media LLC; Springer london LTD, 2025-09-12) Montoya García, María José; Carbonell-Abella, Cristina; Giner García, Mercedes; Hernández-Cruz, Blanca; Gómez‐Vaquero, Carmen; Naranjo, Antonio; Cancio Trujillo, José Manuel; GRUPO REFRA_FLS; Vázquez Gámez, María de los Ángeles; Medicina; Citología e Histología Normal y Patológica; Instituto de Biomedicina de Sevilla (IBIS); CTS211: Metabolismo Cálcico, Hipertensión y Arteriosclerosis
This study classifies osteoporotic patients treated in 16 FLS in Spain, evaluating therapeutic alignment with SEIOMM recommendations and imminent risk fracture. Findings indicate that 26.8% of patients are at very high-risk fracture, highlighting the need for better prescription practices for osteoanabolics. Fall prevention is pivotal in reducing new fractures. Objective: To classify patients treated in 16 Fracture Liaison Services (FLS) in Spain according to high-risk fracture (HRF) and very high-risk fracture (VHRF) and evaluate the alignment of their pharmacological treatment with the Spanish Society for Bone and Mineral Metabolism Research (SEIOMM) guidelines. Additionally, we assessed the incidence of new fractures over a one-year follow-up period and analyzed associated risk factors. Methods: This retrospective, multicenter, population-based observational cohort study included patients aged ≥ 50 years with at least one fragility fracture in the preceding year. Data were collected from medical records from January 2015 to April 2024, capturing sociodemographic information, fracture characteristics, comorbidities, pharmacological treatments, and fall risk. Results: Of 7161 patients, 1413 had one year of follow-up and sufficient baseline data for classification as either VHRF or HRF. Among these, 1034 (73.2%) were classified as HRF and 379 (26.8%) as VHRF. The median age was significantly higher in the VHRF group (76 vs. 72 years in HRF; p < 0.001). Pharmacological treatment was initiated in 86.5% of patients. Alendronate was predominantly prescribed for the HRF group, while parenteral treatments (zoledronate, denosumab) were more common in the VHRF group. During the first year, 84 patients (5.9%) experienced a new fracture, with 2 or more falls significantly associated with these subsequent fractures. Conclusion: 26.8% of patients were classified as VHRF. Treatment partially aligned with SEIOMM guidelines, though improved adherence to sequential osteoanabolic treatment is essential in VHRF patients. Fall prevention remains critical to reducing fracture recurrence.
Health outcomes in fragility fractures in the Spanish registry of osteoporotic fractures according to the FLS care model
(Elsevier, 2025-05-26) Cuadra-LLopart, Leonor; Zorrilla, Samantha Santana; Martínez-Laguna, Daniel; Giner García, Mercedes; Aviñó, Rafael Izquierdo; Montoya García, María José; Crespo, Diana Ovejero; Mora-Fernández, Jesús; Citología e Histología Normal y Patológica; Medicina; Instituto de Biomedicina de Sevilla (IBIS); Sociedad Española de Investigación Ósea y del Metabolismo Mineral; CRUE-CSIC; Prensa de la Universidad de Oxford; Amgen; UCB; Gedeon Richter; CTS211: Metabolismo Cálcico, Hipertensión y Arteriosclerosis
Background: Fracture Liaison Services (FLS) are the gold standard for secondary fracture prevention, but their characteristics vary depending on the care model. This study describes the differences between Orthogeriatric (FLS-ORT) and Bone Metabolism (FLS-MET) models in Spain, based on data from the national osteoporotic fracture registry. Methods: We conducted a retrospective, multicenter cohort study including 8,962 patients aged ≥50 years with fragility fractures from 25 active FLS in Spain (2019-2023). Patients were classified based on the care model: FLS-ORT (n = 3,695) or FLS-MET (n = 5,267). Baseline characteristics, fracture types, treatment initiation, adherence, and 12-month outcomes were compared. Results: FLS-ORT patients were older (85 vs. 78 years, p <0.001), had more comorbidities, and a higher risk of falls. Hip fractures were predominant in FLS-ORT (75.8%), while vertebral fractures were more frequent in FLS-MET (p <0.001). Time from fracture to FLS assessment was shorter in FLS-ORT (0.1 vs. 1.6 months, p <0.001). At 12 months, fracture recurrence was higher in FLS-ORT (7.7 vs. 5.5 per 100 patient-years), and mortality was significantly greater (p <0.0001). However, osteoporosis treatment initiation (84.6%) and adherence (85.2%) were comparable across models. Conclusions: FLS are the gold standard for secondary fracture prevention. Both FLS care models (FLS-ORT and FLS-MET) were effective in reducing the risk of new fractures in patients and minimizing the impact on the quality of life of patients who suffer a fragility fracture. Future integration into a unified model assessing all fractures is anticipated.
Role of the S1P/S1PR axis in inflammation and structural damage in psoriatic arthritis: a cross-sectional study with clinical, biochemical and imaging correlation
(BMJ publishing group, 2026-06-08) Ruiz-Montesinos, Dolores; Mendoza-Mendoza, Dolores; Bocio-Núñez, Jesús; Domínguez-Quesada, Carmen; Serrano-Guijo, María Luisa; Vázquez Gámez, María de los Ángeles; Rico Corral, Miguel Ángel; Colmenero, Miguel Ángel; Pérez-Venegas, JJ; Montoya García, María José; Giner García, Mercedes; Citología e Histología Normal y Patológica; Medicina; Fundación Andaluza de Reumatología; CTS211: Metabolismo Cálcico, Hipertensión y Arteriosclerosis
Introduction: Psoriatic arthritis (PsA) is a chronic inflammatory disease with a complex clinical spectrum. Sphingosine-1-phosphate (S1P) and its receptor (S1PR) are key lipid mediators involved in immunity and bone remodelling. This study evaluates the inter-relationship between serum levels of S1P and S1PR and clinical activity, radiological findings and different stages of PsA. Methods: A cross-sectional observational study was conducted including 64 subjects: 21 healthy controls and 43 patients with PsA: 16 with recent-onset PsA and 27 with established PsA (EPsA). Clinical variables such as disease activity in PsA (DAPSA), bone mineral density (BMD), Trabecular Bone Score, 3D-Shaper and inflammatory activity by Doppler ultrasound and MRI were assessed. S1P and S1PR levels were measured by ELISA. Results: S1P levels were significantly higher in the PsA group compared with controls (p=0.013), with the highest values observed in the EPsA subgroup (p=0.009). Although no significant correlation was observed with the DAPSA Score, S1PR levels were significantly higher in patients with Achilles enthesitis detected by ultrasound (p=0.046) and in those with bone proliferation/structural damage (p=0.03). Patients with EPsA showed significantly higher cortical volumetric BMD compared with controls (p=0.027). Conclusions: The S1P/S1PR axis is dysregulated in PsA and is associated with disease progression. Its correlation with ultrasound findings of enthesitis and new bone formation suggests that S1P acts as a critical mediator in the osteoimmunology of the enthesis, positioning it as a potential biomarker of structural damage and a novel therapeutic target.
Domain generalisation challenges in breast cancer molecular classification using foundation models: a cross-cohort exploratory study
(Springer; Springer heidelberg; Springer Science and Business Media LLC, 2026-05-11) Fernández Romero, Jesús; Ramos-Berciano, Pablo; Pérez-Pérez, Manuel; Benavides Cuevas, David Felipe; Robles-Frias, Antonio; García Gutiérrez, Jorge; Macías García, Laura; Citología e Histología Normal y Patológica; Lenguajes y Sistemas Informáticos; TIC267: Grupo de Dispositivos y Sistemas Electrónicos; CTS-1157: Patología y Reconocimiento Automático en Entornos Distribuidos
Molecular classification guides breast cancer treatment, but PAM50 and immunohistochemistry (IHC) remain costly and unavailable in many settings. Foundation models (FMs) combined with multiple instance learning (MIL) show promise for predicting molecular subtypes from haematoxylin-and-eosin-stained slides, yet most studies report only internal validation. This study evaluates FMs with MIL across cohorts and identifies factors associated with domain-induced performance degradation. We evaluate 13 FMs and 3 complementary MIL architectures for PAM50 subtyping and IHC biomarker prediction using cross-validation on TCGA-BRCA (n = 1, 079) and external validation on CPTAC-BRCA (n = 120). Virchow v2 achieves the best overall performance but exhibits severe degradation upon external validation, consistent across all three MIL architectures especially for HER2-enriched and Normal-like PAM50 subtypes and HER2-positive IHC prediction. Four hypothesised domain shift factors are quantified through exploratory regression analysis to explain relative performance drop (RPD). Staining variability, feature space divergence and morphological separability reach significance in univariate analysis, whilst prevalence shift does not. Staining variability and feature space divergence as covariate-level factors jointly account for 80.0% of RPD variance in the most parsimonious multivariate model (R2 = 0.800, R2 adj = 0.750). Although based on a limited number of class-level observations and therefore exploratory in nature, these findings highlight the need for domain generalisation strategies targeting covariate shift, even when specialised FMs are used as feature encoders.
Recommendations for the prevention of fragility fractures: a consensus from international experts and Ibero-American scientific societies
(Springer, 2025-06-12) Sáez-López, Pilar; Aldecoa Álvarez-Santullano, César; Arboiro-Pinel, Rosa; Baquero Úbeda, José Luis; Bastida Calvo, José Carlos; Baixaulí García, Francisco; Giner García, Mercedes; Tarazona-Santabalbina, Francisco José; Citología e Histología Normal y Patológica; Instituto de Biomedicina de Sevilla (IBIS); CRUE-CSIC agreement with Springer Nature; CTS211: Metabolismo Cálcico, Hipertensión y Arteriosclerosis
Purpose: To develop a multidisciplinary consensus outlining key recommendations to prevent fragility fractures and improve care through coordinated efforts across healthcare sectors. Methods: An international group of experts, coordinated by the Spanish National Hip Fracture Registry (RNFC), engaged over 300 professionals and 31 scientific societies. Using a nominal group technique, the committee reviewed scientific evidence and collaboratively developed ten core recommendations. The consensus was refined through multiple telematic reviews and finalized at the 7th RNFC Annual Meeting in March 2024. Results: The consensus presents ten actionable recommendations: (1) inclusion of osteoporosis and fragility fractures in health policies, (2) early detection and management of frailty and falls, (3) implementation of clinical practice guidelines, (4) promotion of fracture registries and audits, (5) support for Orthogeriatric Units and Fracture Liaison Services (FLS), (6) adoption of a "Fragility Fracture Code," (7) empowerment of Primary Care in fracture prevention, (8) increased patient association involvement, (9) public awareness campaigns, and (10) promotion of research including patient-reported outcomes. Conclusions: Fragility fractures are a major public health issue with rising incidence, disability, and healthcare costs. This consensus offers unified, evidence-based guidance for policy makers, healthcare professionals, and patient organizations. Broad dissemination and implementation of these recommendations aim to reduce fracture rates and enhance patient outcomes through coordinated, multidisciplinary care.
Optimizing Alternating Current Electrical Stimulation Parameters to Enhance Osteoblasts Differentiation
(Wiley, 2026-04-12) Bocio-Núñez, Jesús; Montoya García, María José; Vázquez Gámez, María de los Ángeles; Martín Fernández, Daniel; Chacón, Pedro; Rico Corral, Miguel Ángel; Colmenero, Miguel Ángel; Yúfera García, Alberto; Giner García, Mercedes; Citología e Histología Normal y Patológica; Medicina; Tecnología Electrónica; Junta de Andalucía; CTS211: Metabolismo Cálcico, Hipertensión y Arteriosclerosis; BIO132: CitoQuímica Ultraestructural; TIC178: Diseño y Test de Circuitos Integrados de Señal Mixta
Electrical stimulation (ES) has emerged as a promising technique in the field of bioengineering and biomedicine, particularly in bone regeneration and cell differentiation. ES using alternating current (AC) is based on the periodic reversal of current direction, which generates oscillating electric fields. The application of an electric field has effects on cell growth and differentiation, as well as on morphology and migration. This study aimed to explore the effect of applying AC electrostimulation within the proliferation, differentiation, and morphology process of osteoblastic cells. The electrical stimulation signals were daily applied for 3 h during 14 days. Different frequencies were tested (1 Hz, 10 Hz, 100 Hz, and 1 kHz), with amplitudes of 125, 250, 500, 750, 1000, and 1500 mV/mm. Cell viability was estimated using the AlamarBlue, and MC3T3-E1 differentiation levels were evaluated through alkaline phosphatase (ALP) activity. RUNX2, OSX, ALP, OPG, and RANKL gene expression was assessed by RT-PCR. Morphological analysis was performed through cell transfection followed by immunofluorescence. Statistical analysis was conducted by SPSS.23 and graphs generated through Graph-pad. Viability and ALP activity were optimal at 10 Hz. Once the frequency was defined, RUNX2, OSX, ALP, OPG, and RANKL gene expression revealed an increase in the differentiation and osteogenic activity levels at 10 Hz and 500–750 mV/mm. As well as, morphological studies showed an increase in the area, pseudopodia length, and numbers at 500 mV 10 Hz conditions. The optimal ES condition to differentiate MC3T3-E1 cells is 10 Hz 500–750 mV/mm. Electrostimulation has emerged as a promising technique in the field of bioengineering and biomedicine, particularly in bone regeneration and cell early maturation.
Biodegradable polyacrylamide-based hydrogels with unique bactericidal and osteoinductive properties to improve the clinical success of porous titanium implants
(Elsevier, 2026-01) Martínez Muñoz, Guillermo; Castellano Pozo, Maikel; Merinero de los Santos, Manuel; Casado Jurado, David; Huertas Sánchez, Pablo; Pajuelo Domínguez, Eloísa; Miguel Rodríguez, Manuel de; Begines Ruiz, Belén; Torres Hernández, Yadir; Alcudia Cruz, Ana; Química Orgánica; Genética; Microbiología y Parasitología; Citología e Histología Normal y Patológica; Ingeniería y Ciencia de los Materiales y del Transporte; Química Orgánica y Farmacéutica; Ministerio de Ciencia, Innovación y Universidades (MICIU). España
Stress-shielding phenomenon, infections, and limited bone integration are traditional drawbacks associated with titanium implants. Biodegradable polyacrylamide-based hydrogels synthesized with an 8-fold scaled up, disulfide bond-containing crosslinker, were prepared to overcome these limitations. Hydrogels' biodegradability in the presence of glutathione has been demonstrated. Additionally, hydrogels exhibited strong antibacterial activity against pathogens such as P. aeruginosa and S. aureus, along with promising osseointegrative properties, in vitro fibroblast (CCL-1) viability, and in vivo biocompatibility in C. elegans. Porous titanium (Ti) fabricated via space-holder technique were infiltrated with previously described hydrogels. The optimal system, featuring a 4 wt% crosslinked acrylamide-based hydrogel infiltrated into 60 vol%, 355–500 μm Ti substrate, showed excellent biomechanical integrity and biofunctionality, supporting its potential as a safe and effective bone implant. Additionally, the study introduces streamlined, cost-effective methodologies for implant testing and characterization.
Prospective evaluation of copy number alterations validates chromosome 1q gain as an independent marker of poor prognosis in localized Ewing sarcoma
(Academic press inc elsevier science, 2025-11-17) Díaz-Martín, Juan; Ranft, Andreas; Blanquer-Maceiras, Maite; Noguera, Rosa; Salguero Aranda, Carmen; Delgado-Bellido, Daniel; Romero Pérez, Laura; Álava Casado, Enrique de; Anatomía y Embriología Humana; Instituto de Biomedicina de Sevilla (IBIS); Citología e Histología Normal y Patológica; CIBERONC; CRIS Foundation against Cancer; ISCIII-FEDER; NEN Association (Nico against Childhood Cancer); University Hospital Muenster; CTS1035: Patología Molecular del Cáncer Sólido
Background Ewing sarcoma is a rare and aggressive tumor affecting mainly adolescents and young adults. Accurate risk stratification is critical for treatment tailoring, yet traditional clinical parameters lack sufficient predictive accuracy. While retrospective studies have identified potential molecular biomarkers, prospective validation is required for clinical implementation. Methods The international PROVABES consortium (PROspective Validation of Biomarkers in Ewing Sarcoma) aims to evaluate molecular prognostic markers in European patients treated under international phase III trials. This study focuses on copy number alterations (CNAs), in 305 primary tumors. Tissue microarrays were analyzed by FISH for chromosome 1q gain (n = 297) and 16q loss (n = 266). Genome-wide CNAs were further assessed using SNP arrays in 139 samples. Associations with clinical outcomes were evaluated via Kaplan-Meier and multivariate Cox regression, with event-free survival (EFS) and overall survival (OS) as endpoints. Results Chromosome 1q gain was significantly associated with shorter OS in both localized cases and the overall cohort, and with inferior EFS specifically in localized patients. In contrast, 16q loss showed no significant prognostic impact. Multivariate analysis confirmed 1q gain as an independent predictor of poor EFS in localized disease. Notably, a higher fraction of genome altered was associated with inferior OS and EFS not only in localized patients but also in the entire cohort, and remained an independent predictor of outcome despite the smaller subset analyzed. Conclusions This prospective study validates chromosome 1q gain as an independent marker of poor prognosis in localized Ewing sarcoma. Furthermore, the extent of genomic alteration emerges as a promising predictor of both OS and EFS. Incorporating these biomarkers may improve individualized risk stratification and ultimately enhance patient outcomes.
Comprehensive DSRCT multi-omics analyses unveil CACNA2D2 as a diagnostic hallmark and super-enhancer-driven WSR1::WT1signature gene
(WILEY, 2025-03-15) Geyer, FH; Ritter, A; Kinn-Gurzo, S; Faehling, T; Li, J; Jarosch, A; Romero Pérez, Laura; Álava Casado, Enrique de; Cidre-Aranaz, F; Anatomía y Embriología Humana; Citología e Histología Normal y Patológica; Instituto de Biomedicina de Sevilla (IBIS); Equipo del Centro Alemán de Investigación del Cáncer (DKFZ); CTS1035: Patología Molecular del Cáncer Sólido
Melatonin controls experimental autoimmune encephalomyelitis by altering the T effector/regulatory balance
(Elsevier, 2015-06-26) Álvarez Sánchez, Nuria; Cruz Chamorro, Iván; López González, Antonio; Utrilla Alcolea, José Carmelo; Fernández-Santos, José María; Martínez López, Alicia; Lardone, Patricia Judith; Guerrero Montávez, Juan Miguel; Carrillo Vico, Antonio; Bioquímica Médica y Biología Molecular e Inmunología; Citología e Histología Normal y Patológica; Bioquímica y Biología Molecular; Instituto de Salud Carlos III; Gobierno de España; Junta de Andalucía; CTS439: Sistema Neuroendocrino Difuso; CTS160: NeuroInmunoEndocrinología Molecular
Experimental autoimmune encephalomyelitis (EAE), the experimental model for multiple sclerosis (MS), is triggered by myelin-specific Th1 and Th17 cells. The immunomodulatory activities of melatonin have been shown to be beneficial under several conditions in which the immune system is exacerbated. Here, we sought to elucidate the basis of the melatonin protective effect on EAE by characterizing the T effector/regulatory responses, particularly those of the memory cell subsets. Melatonin was tested for its effect on Th1, Th17 and T regulatory (Treg) cells in the lymph nodes and CNS of immunodominant peptide of myelin oligodendrocyte glycoprotein (pMOG)-immunized and EAE mice, respectively. The capacity of melatonin to ameliorate EAE as well as modifying both T cell response and effector/regulatory balance was surveyed. T cell memory subsets and CD44, a key activation marker involved in the EAE pathogenesis, were also examined. Melatonin protected from EAE by decreasing peripheral and central Th1/Th17 responses and enhancing both the Treg frequency and IL-10 synthesis in the CNS. Melatonin reduced the T effector memory population and its pro-inflammatory response and regulated CD44 expression, which was decreased in T effector cells and increased in Tregs. The alterations in the T cell subpopulations were associated with a reduced mononuclear infiltration (CD4 and CD11b cells) of the melatonin-treated mice CNS. For the first time, we report that melatonin protects against EAE by controlling peripheral and central T effector/regulatory responses, effects that might be partially mediated by CD44. This immunomodulatory effect on EAE suggests that melatonin may represent an effective treatment option for MS.
Los cannabinoides: una perspectiva en la esclerosis múltiple
(Wanceulen Editorial S.L., 2024) Pérez Rodríguez, Marta; Barbado González, Mª Victoria; Citología e Histología Normal y Patológica; CTS1047: Fisiopatología Asociada a las Acuaporinas
El estudio del uso de los cannabinoides debido sus diferentes propiedades terapéuticas ha resultado un tema de interés en los últimos años, especialmente el uso de estos en la esclerosis múltiple. Los objetivos de este trabajo fueron revisar los conocimientos actuales del uso terapéutico de los cannabinoides en la esclerosis múltiple, así como encontrar evidencias de una mejora en la calidad de vida de los pacientes tratados con cannabinoides y conocer avances científicos en el tratamiento con cannabinoides en la esclerosis múltiple. Para ello se han consultado diferentes bases de datos, entre ellas Pubmed, Epistemonikos, Cochrane library, Scopus y Dialnet. Los resultados mostraron una eficacia limitada de los cannabinoides en la espasticidad, el dolor neuropático y la disfunción neurogénica del trato urinario inferior, además se revisa la inmunomodulación de los cannabinoides en la esclerosis múltiple. Concluyendo que estos alivian la sintomatología de la esclerosis múltiple, debido a su eficacia moderada, la necesidad más de estudios de calidad a gran escala y el posible efecto inmunomodulador de los cannabinoides en la esclerosis múltiple.
Oleocanthal Supplemented Diet Improves Renal Damage And Endothelial Dysfunction In Pristane-Induced Systemic Lupus Erythematosus In Mice
(Elsevier, 2023) Montoya García, Tatiana; Sánchez Hidalgo, Marina; Castejón Martínez, María Luisa; Vázquez Román, María Victoria; Álvarez de Sotomayor Paz, María; Ortega Vidal, Juan; González Rodríguez, María Luisa; Alarcón de la Lastra Romero, Catalina; Farmacología; Citología e Histología Normal y Patológica; Farmacia y Tecnología Farmacéutica; Ministerio de Economía y Competitividad (MINECO). España; Junta de Andalucía
Systemic lupus erythematosus (SLE) is a multiorgan disorder with a deregulated immune-inflammatory response. Nutritional therapy has been considered a promising approach to SLE management. Oleocanthal (OLE), the main extra virgin olive oil (EVOO)-derived secoiridoid, has shown to regulate the immune-inflammatory response in various disease contexts; however, its possible beneficial effects on SLE remain unclear. This study sought to evaluate the effects of OLE enriched diet on renal damage and aortic endothelial dysfunction in murine pristane-induced SLE, focusing on the action mechanisms and signaling pathways involved. BALB/c mice were injected with pristane and fed with OLE supplemented diet (0.01 % (w/w)) for six months. Levels of cytokines were measured by ELISA in lipopolysaccharide (LPS)-stimulated peritoneal macrophages and splenocytes. Presence of IgG and IgM immune complexes was examined by immunofluorescence and immunohistochemistry. Thoracic aortas were used to evaluate endothelial dysfunction. Western blotting was employed to detect signaling pathways and oxidative-inflammatory-related mediators. Dietary OLE supplementation reduced Th1/Th17 pro-inflammatory cytokines production and alleviated renal damage by decreasing immunoglobulin complexes deposition, and inflammation-mediating enzymes expression. The mechanisms underlying these protective effects could be related to the regulation of nuclear factor erythroid 2-related factor 2/Haem oxygenase 1 (Nrf-2/HO-1), mitogen-activated protein kinases (MAPKs), signal transducer and transcription activator of transcription (STAT-3), inflammasome and, nuclear factor kappa B (NF-B) signaling pathways. Also, dietary OLE improved aortic endothelial dysfunction and vascular reactivity, normalizing endothelial nitric oxide synthase (eNOS) uncoupling, and NADPH oxidase-1 (NOX-1) overexpression. This study shows the immunomodulatory effects of OLE in an in vivo model of SLE by improving renal damage and regulating aortic endothelial dysfunction. These preliminary results provide OLE as a new therapeutic strategy in SLE management.
EWS::FLI1-DHX9 interaction promotes Ewing sarcoma sensitivity to DNA topoisomerase 1 poisons by altering R-loop metabolism
(Springer Nature, 2025-07-28) Olmedo Pelayo, Joaquín; Granado Calle, Esperanza; Delgado Bellido, Daniel; Lobo Selma, Laura; García-Domínguez, Daniel J.; Gómez Herreros, Fernando; Álava Casado, Enrique de; Bioquímica Médica y Biología Molecular e Inmunología; Citología e Histología Normal y Patológica; Genética; Junta de Andalucía; Universidad de Sevilla; Instituto de Salud Carlos III; Asociación Pablo Ugarte; Asociación Candela Riera; Asociación Todos Somos Iván; Fundación Sonrisa de Alex; Deutsche Forschungsgemeinschaft / German Research Foundation (DFG); German Cancer Aid; Ministerio de Ciencia e Innovación (MICIN). España; Junta de Andalucía
Drug resistance is an ill-defined cause of dismal outcomes in cancer. Ewing sarcoma (EwS), a pediatric cancer characterized by high therapy failure rates, is driven by a single oncogenic event generating EWSR1::ETS gene fusions (primarily EWSR1::FLI1) in a silent genomic background. This provides a straightforward model to study the impact of gene fusions on drug responses. Here, we describe a novel mechanism of sensitivity to DNA topoisomerase 1 poisons in EwS. We discovered that EWS::FLI1 prevents the resolution of R-loops induced by these drugs via sequestering DHX9 helicase, ultimately resulting in R-loop accumulation, replication stress, and genome instability. In turn, excessive DHX9 or reduced EWS::FLI1 levels render EwS cells resistant to the active metabolite of irinotecan (SN-38) independent of proliferation and global transcription rates. This resistance helps explain how elevated DHX9 levels predict worse clinical outcomes. Overall, our research demonstrates the impact of a dominant mutation on cancer drug sensitivity, highlighting its significant clinical implications.
Targeting iysosomal acidification to restore microglial homeostasis and mitigate memory decline during male brain ageing
(Elsevier science; Elsevier BV, 2025-11-04) Barrella, Lorenzo; Ramírez-Ponce, María Pilar; Vázquez Román, María Victoria; Millán-Huang, Marta San; Maldonado y Aibar, María Dolores; Flores Cordero, Juan Antonio; Alés González de la Higuera, Eva María; Citología e Histología Normal y Patológica; Bioquímica Médica y Biología Molecular e Inmunología; Fisiología Médica y Biofísica; CTS439: Sistema Neuroendocrino Difuso; CTS160: Neuroinmunoendocrinología Molecular; CTS151: Bioquímica Medica; BIO236: Biofísica Celular
Lysosomal dysfunction lies at the nexus of inflammaging, microglial dystrophy and synaptic fragility, making it an attractive target for brain rejuvenation. Here we demonstrate that a five-month oral course of ketotifen, an approved H1-antihistamine and mast-cell stabiliser, re-acidifies lysosomes in aged C57BL/6J male mice, restoring the quinacrine signal of peripheral macrophages and SIM-A9 microglia. This proton rebound is coupled to broad anti-cytokine effects: ketotifen attenuates lipopolysaccharide-evoked release of TNF-α, IL-1β and IL-10 in vitro and ex vivo. In the brain, the drug restores a highly ramified, homeostatic microglial morphology throughout the cortex and hippocampus. Ketotifen robustly elevates cortical synaptophysin and PSD-95 above age-matched levels. Behaviourally, ketotifen enhances spatial learning and object-location memory without altering locomotor activity or anxiety-like behaviour. Collectively, these findings identify lysosomal re-acidification as the initiating trigger of a multifaceted rejuvenation cascade that dampens multi-cytokine signalling, restores microglial morphology and preserves synaptic integrity. Because ketotifen is inexpensive, brain-permeable and already licensed for human use, our work unveils an immediately actionable geroprotective strategy to forestall early cognitive decline.
The role of the primary cilium in thyroid function and dysfunction with implications for thyroid disease
(Springer Science and Business Media LLC, 2025-11-06) Martín Lacave, Inés María; Vázquez Román, María Victoria; Pérez-Fernández, Beatriz; Fernández-Santos, José María; Citología e Histología Normal y Patológica; Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía; VII PPIT, CITIUS, Universidad de Sevilla /JMF; CTS439: Sistema Neuroendocrino Difuso
The thyroid gland is a unique endocrine organ, composed of morpho-functional units called thyroid follicles, which are responsible for thyroid hormone (TH) biosynthesis, an iodination process demanding a highly oxidative yet protected environment. Despite primary cilium (PC) being observed in the thyroid gland more than a century ago, its precise role in thyroid activity remains rather unexplored. Given its strategic position at the apical surface of follicular epithelium, projecting into the lumen, PCs are crucial for the regulation of TH biosynthetic processes. Consequently, changes in thyroid function, either physiological or pathological, are reflected in PC characteristics. Similarly, defects in ciliogenesis are expected to lead to different pathological thyroid alterations. This review summarizes the current understanding of PC’s involvement in regulating normal thyroid activity and its modifications in functional and neoplastic thyroid diseases. Particular focus will be given to the notable loss of PCs in certain types of thyroid cancer and the promising potential of their restoration as a tumor suppressor strategy in thyroid tumorigenesis.
Ketotifen reacidifies secretory lysosomes and normalises ageing phenotypes in mast cells
(Academic press inc jnl-comp subscriptions; Academic press inc elsevier science; Elsevier, 2025-10-29) Barrella, Lorenzo; Ramírez-Ponce, María Pilar; Vázquez Román, María Victoria; San Millán-Huang, Marta; Flores Cordero, Juan Antonio; Alés González de la Higuera, Eva María; Citología e Histología Normal y Patológica; Bioquímica Médica y Biología Molecular e Inmunología; Fisiología Médica y Biofísica; CTS439: Sistema Neuroendocrino Difuso; CTS151: Bioquímica Medica; BIO236: Biofísica Celular
Mast-cell (MC) granules are secretory lysosomes whose function depends on a highly acidic lumen. We asked whether lysosomal pH drifts with age and whether this alteration is reversible. Lysosomal acidification was assessed by quinacrine imaging of peritoneal MCs, which revealed very low fluorescence in MCs from 2-month-old mice, consistent with immature granules. As MCs matured, quinacrine signal increased, reflecting expansion of the secretory lysosome pool; however, from 15 to 17 months, fluorescence progressively declined, indicating gradual deacidification. Chronic ketotifen treatment restored and amplified the quinacrine signal, enlarged granules, and reduced late-life MC expansion. Acute pharmacological assays revealed that ketotifen's effect requires V-ATPase activity and dynamin-dependent endocytosis. FM1-43 uptake confirmed enhanced endocytic activity with ketotifen. In the brain, ageing led to hypertrophy of toluidine blue–positive MCs without major changes in cell number; five months of ketotifen treatment reversed these morphometric alterations toward a youthful profile. These findings identify lysosomal deacidification as a hallmark of ageing MCs and demonstrate that ketotifen reacidifies secretory lysosomes via V-ATPase and endocytosis-dependent mechanisms, highlighting lysosomal pH control as a tractable strategy to mitigate MC-driven components of inflammaging.
Dietary freeze-dried beer prevents inflammation in DSS-induced chronic ulcerative colitis in mice
(Royal Society of Chemistry, 2025-07-01) Paredes Sánchez, María; Muñoz García, Rocío; Ávila Román, Francisco Javier; Lobo Prieto, Ana; Orta Cuevas, María del Mar; García González, Diego L.; Vázquez Román, María Victoria; Talero Barrientos, Elena Mª; Sánchez Hidalgo, Marina; Farmacología; Química Analítica; Citología e Histología Normal y Patológica
Inflammatory bowel disease (IBD) is a complex condition that is influenced by numerous factors, including genetic, immune and environmental factors. In the search for new therapies, nutritional interventions including dietary polyphenols are becoming increasingly important in the management of IBD. The present study aimed to investigate the antioxidant and anti-inflammatory effects of commercial freeze-dried beer, an interesting product resulting from the fermentation of cereals, rich in polyphenols, in (I) an in vitro model of inflammation using lipopolysaccharide (LPS)-stimulated THP-1 human derived macrophages and (II) a murine dextran sodium sulfate (DSS)-induced chronic colitis model, for elucidating the action mechanism involved. According to the results, commercial freeze-dried beer exhibits antioxidant, anti-inflammatory and immunomodulatory properties in LPS-stimulated THP-1 human macrophages by reducing reactive oxygen species (ROS), tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels. Moreover, in vivo results showed that preventive treatment with dietary freeze-dried beer improved murine DSS-induced chronic colitis by attenuation of the clinical and histological signs of colonic damage. Colonic cytokine levels in animals fed with commercial freeze-dried beer reached values near basal levels. In addition, pro-inflammatory cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase (mPGES)-1 protein expressions were significantly downregulated via inhibition of nuclear transcription factor kappa B (NF-κB) translocation. This inhibition may be mediated by an induction of the antioxidant nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway and a reduction of signal transducer and activator of transcription (STAT)-3 phosphorylation orchestrating its potent anti-inflammatory and immunomodulatory effects. Overall, our results suggest that dealcoholized beer may be effective in the management of immune-mediated inflammatory diseases in which macrophages are crucial, including IBD, providing clues for developing useful dietary interventions against inflammation-associated pathologies.
The PAD4 inhibitor GSK484 diminishes neutrophil extracellular trap in the colon mucosa but fails to improve inflammatory biomarkers in experimental colitis
(Portland Press, 2025-06-11) Xie, Kangzhe; Hunter, Jordan; Lee, Aaron; Ahmad, Gulfam; Witting, Paul K.; Ortiz Cerda, Tamara Andrea; Citología e Histología Normal y Patológica; Gobierno de España
Inflammatory bowel disease (IBD) is a gastrointestinal disorder characterised by elevated colonic neutrophil extracellular traps (NETs), which are associated with disease severity. Formation of NETs is primarily driven by peptidyl arginine deaminase IV (PAD4) and other enzymes including myeloperoxidase (MPO) and neutrophil elastase. The present study evaluated the effect of MPO and PAD4 inhibition in dextran sodium sulfate (DSS)-induced colitis. Experimental colitis was induced in male C57BL/6 mice by 2% w/v DSS in drinking water ad libitum. Treatment groups received daily oral administration of MPO inhibitor (AZD3241; 30 mg/kg) and/or intraperitoneal injection of PAD4 inhibitor (GSK484; 4 mg/kg) 4 times over 9 days. Inhibition of PAD4 significantly diminished NET density in the colonic mucosa of mice insulted with DSS, reaching levels similar to that detected in control mice. Both inhibitors offered limited improvement in disease-activity-index, a scoring system that considers the extent of weight loss, stool consistency and rectal bleeding. Histology showed that MPO and/or PAD4 inhibition did not recover DSS-induced colon histoarchitectural damage whilst Alcian blue staining demonstrated that PAD4 failed to reduce goblet cell loss. The selected dosage of PAD4 inhibition also yielded no effect on inflammatory markers and antioxidant protein levels. These data sets suggest that other mechanisms may be involved in the pathogenesis of IBD, and the appropriate dosage of GSK484 requires thorough investigation.
The combination of epigenetic drugs SAHA and HCI-2509 synergistically inhibits EWS-FLI1 and tumor growth in Ewing sarcoma
(Impact Journals Llc, 2018-07-31) García-Domínguez, Daniel J.; Hontecillas-Prieto, Lourdes; Rodríguez-Núñez, Pablo; Pascual-Pasto, Guillem; Vila-Ubach, Monica; García-Mejías, Rosa; Robles, María José; Tirado, Oscar M.; Mora, Jaume; Carcaboso, Angel M.; Álava Casado, Enrique de; Bioquímica Médica y Biología Molecular e Inmunología; Citología e Histología Normal y Patológica; CTS1035: Patología Molecular del Cáncer Sólido
Purpose: Epigenetic regulation is crucial in mammalian development and maintenance of tissue-cell specific functions. Perturbation of epigenetic balance may lead to alterations in gene expression, resulting in cellular transformation and malignancy. Previous studies in Ewing sarcoma (ES) have shown that the Nucleosome Remodeling Deacetylase (NuRD) complex binds directly to EWS-FLI1 oncoprotein and modulates its transcriptional activity. The role of EWS-FLI1 as a driver of proliferation and transformation in ES is widely known, but the effect of epigenetic drugs on fusion activity remains poorly described. The present study evaluated the combination effects of the histone deacetylases inhibitor suberoylanilide hydroxamic acid (SAHA) and Lysine-specific demethylase1 inhibitor (HCI-2509) on different biological functions in ES and in comparison to monotherapy treatments. Results: The study of proliferation and cell viability showed a synergistic effect in most ES cell lines analyzed. An enhanced effect was also observed in the induction of apoptosis, together with accumulation of cells in G1 phase and a blockage of the migratory capacity of ES cell lines. Treatment, either in monotherapy or in combination, caused a significant decrease of EWS-FLI1 mRNA and protein levels and this effect is mediated in part by fusion gene promoter regulation. The anti-tumor effect of this combination was confirmed in patient-derived xenograft mouse models, in which only the combination treatment led to a statistically significant decrease in tumor volume. Conclusions: The combination of SAHA and HCI-2509 is proposed as a novel treatment strategy for ES patients to inhibit the essential driver of this sarcoma and tumor growth.
Advanced sporadic renal epithelioid angiomyolipoma: Case report of an extraordinary response to sirolimus linked to TSC2 mutation
(Springer Nature, 2018-05-15) Espinosa, Marta; Roldán-Romero, Juan María; Durán, Ignacio; Álava Casado, Enrique de; Apellaniz-Ruiz, María; Cascón, Alberto; Garrigós, Carmen; Robledo, Mercedes; Rodríguez-Antona, Cristina; Citología e Histología Normal y Patológica; Farmacología; Ministerio de Economia, Industria y Competitividad (MINECO). España
Background: Renal epithelioid angiomyolipomas (EAML) are rare tumors with aggressive behavior. EAML can be sporadic or develop within the tuberous sclerosis complex syndrome, where mutations of TSC1 or TSC2 genes (critical negative regulators of mTOR Complex 1) result in an increased activation of mTOR pathway. Optimal EAML treatment, including mTOR inhibitors, remains undetermined. Case presentation: Here we present the case of a young adult with a renal EAML that after radical nephrectomy developed metastases, first in liver and then in lumbar vertebrae. After complete surgical resection of these lesions, liver recurrence was detected, this time with incomplete surgical resection. After finding a new liver lesion, systemic treatment with sirolimus started. The patient exhibited a complete and durable response to this drug, being disease free at the time of publication, after 36 months of treatment. Targeted next generation sequencing (NGS) of MTOR, TSC1 and TSC2 genes in the primary tumor, metastasis and blood of the patient, revealed one inactivating TSC2 mutation (c.2739dup; p.K914*) in the tumor cells. Immunohistochemistry revealed decreased TSC2 protein content and increased phospho-S6 in the tumor cells, demonstrating mTOR pathway activation. Conclusion: NGS on an EAML patient with an extraordinary response to sirolimus uncovered TSC2 inactivation as the mechanism for the response. This study supports NGS as a useful tool to identify patients sensitive to mTOR inhibitors and supports the treatment of malignant EAML with these drugs.

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