IIS La Fe - Fundación para la Investigación del Hospital Universitario La Fe (C. Valenciana)

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12105/16975

El Instituto de Investigación Sanitaria La Fe (IIS La Fe) está constituido por el Hospital Universitario y Politécnico La Fe, la Universidad de Valencia, la Universidad Politécnica de Valencia, el Consejo Superior de Investigaciones Científicas, la Fundación para la Investigación del Hospital Universitario La Fe de la Comunidad Valenciana y la Fundación IVI. Tiene por objeto impulsar, promover y fomentar la investigación de excelencia, el conocimiento científico y tecnológico y su posterior traslación al sector productivo, así como la docencia y la formación. Acreditado por el Instituto de Salud Carlos III como Instituto de Investigación Sanitaria en 2009, y renovando esta acreditación cada 5 años, forma parte así del total de 34 Institutos de Investigación Sanitaria acreditados existentes en la actualidad.

Browse

Now showing 1 - 20 of 38

Mammographic density and breast cancer pathological subtypes by menopausal status and body mass index.
(BioMed Central (BMC), 2025-10-24) Fernández-Morata, Julia; Pollan-Santamaria, Marina; Fernandez de Larrea-Baz, Nerea; Pachón-Olmos, Vanessa; García-Pérez, Javier; Castelló Pastor, Adela; Sierra, Maria Angeles; de Lucas, Maria Pilar; Llobet, Rafael; Stradella, Agostina; Cantos, Blanca; Ramón Y Cajal, Teresa; Santisteban, Marta; Seguí, Miguel Ángel; Santaballa Bertrán, Ana; Granja, Mónica; Camps-Herrero, Julia; Recalde, Sabela; Núñez-García, Beatriz; Calvo Verges, Nuria; Perez-Gomez, Beatriz; Pastor-Barriuso, Roberto; Lope Carvajal, Virginia; Instituto de Salud Carlos III
Background: Mammographic density (MD) is an established biomarker of breast cancer (BC) risk. However, its relationship to BC pathological subtypes remains unclear. This study aimed to investigate this association and assess whether it differs by body mass index (BMI) and menopausal status. Methods: MD percentage was assessed in the diagnostic mammograms of the contralateral breast of 714 BC patients recruited from eight Spanish hospitals. Participants completed an epidemiological questionnaire, and hospital researchers collected clinical and pathological data. Standardized prevalences (SPs) and standardized prevalence ratios (SPRs) for each BC pathological subtype across MD categories were estimated based on multinomial logistic regression models, both overall and stratified by BMI and menopausal status. Results: Mean MD was 26.1% (SD = 17.3). Although no statistically significant differences were detected, women with MD ≥ 50% had a 13% lower SP of hormone receptor positive tumors (SPR = 0.87; 95% CI 0.67-1.13), a 36% higher SP of human epidermal growth factor receptor 2 positive (HER2+) tumors (SPR = 1.36; 95% CI 0.72-2.58), and a 23% higher SP of triple negative (TN) tumors (SPR = 1.23; 95% CI 0.47-3.22), compared to those with MD < 10%. These patterns were mainly observed in pre/perimenopausal women and in those with BMI ≥ 25 kg/m. Conclusions: High MD might be mainly associated with the development of more aggressive and non-hormone-dependent cancers, such as HER2+ and TN BC, especially among pre/perimenopausal an overweight women.
Patient and Public Involvement in Malnutrition Disorders Health Research: A Methodological Systematic Review Protocol
(Multidisciplinary Digital Publishing Institute (MDPI), 2025-04-07) Garcia-Garcia, Arturo; Carretero-Randez, Cristina; Camacho-Bejarano, Rafaela; Roldán-Chicano, María Teresa; Castellano-Santana, Pedro Raúl; Camacho-Montaño, Lucia; Montero-Marco, Jesica; Charlo-Bernardos, Marta; Orts-Cortes, Maria Isabel
Background/Objectives: Older adults are particularly susceptible to undernutrition and conditions that can aggravate it, such as frailty and conditions associated with swallowing difficulties or dysphagia. To address these challenges, it is important to consider the perspectives of older adults and their caregivers, especially those with conditions such as frailty or cognitive impairment, as they can provide valuable insights on supporting nutrition in these vulnerable populations. This participatory approach requires structures formed by scientific research committees working together with other stakeholders, involving various actors at all stages of the research process. The aim of this study is to analyze the methodology for involving patients aged 65 and older with malnutrition or at risk of malnutrition as co-investigators in research. Methods: This protocol has been developed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-P) checklist. A literature search will be carried out in the following electronic databases: PubMed/MEDLINE, EMBASE and CINAHL. Through the COVIDENCE program, the research team will independently review the different screening phases of the identified studies for possible inclusion or exclusion. Expected Results: This systematic review will provide up-to-date evidence on the use of non-scientific actors at different stages of research. The main limitation stems from the use of non-scientific agents in a topic as specific as adults with or at risk of undernutrition, which may make it difficult to extrapolate the results to other settings. The registration number in PROSPERO is CRD42024444374.
Determinants of Adherence to World Cancer Research Fund/American Institute for Cancer Research Recommendations in Women with Breast Cancer
(Multidisciplinary Digital Publishing Institute (MDPI), 2025-02-19) Pachón Olmos, Vanessa; Pollan-Santamaria, Marina; Fernandez de Larrea-Baz, Nerea; Fernández-Morata, Julia; Ruiz Moreno, Emma; García-Pérez, Javier; Castelló Pastor, Adela; Sierra, Maria Angeles; de Lucas, Maria Pilar; Alonso Ledesma, Isabel; Stradella, Agostina; Cantos, Blanca; Ramón Y Cajal, Teresa; Santisteban, Marta; Seguí, Miguel Ángel; Santaballa Bertrán, Ana; Granja, Mónica; Camps-Herrero, Julia; Recalde, Sabela; Mendez, Miriam; Calvo Verges, Nuria; Perez-Gomez, Beatriz; Pastor-Barriuso, Roberto; Lope Carvajal, Virginia; Instituto de Salud Carlos III
Background/objectives: The 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations benefit primary prevention and survivor outcomes. This study evaluated the adherence to these recommendations during the year prior to breast cancer diagnosis and identified related clinical and sociodemographic factors. Methods: A total of 915 patients with breast cancer were recruited from eight hospitals in four regions of Spain. The participants completed an epidemiologic questionnaire and a food frequency questionnaire. The compliance with the WCRF/AICR recommendations was assessed using a standardized score based on seven recommendations. Standardized prevalences and standardized prevalence ratios (SPRs) for moderate and high adherence were calculated based on participant characteristics using binary and multinomial logistic regression models. Results: The mean adherence was 3.5 points out of 7. The recommendations with the best and worst adherence were avoiding sugar-sweetened drinks (54.4% adherence) and maintaining a fiber-rich diet (4.4% consumed ≥30 g/day). The overall adherence was better in women aged ≥60 years (SPR = 1.55; 95% CI = 1.09-2.22), and worse in those with a caloric intake ≥2000 kcal/day (SPR = 0.48; 95% CI = 0.37-0.62) or ≥2 comorbidities (SPR = 0.66; 95% CI = 0.49-0.89). The adherence to maintaining a healthy weight was worse in those with ≥2 comorbidities and stage III-IV tumors. The physical activity adherence was worse in working women and those with ≥2 comorbidities. The alcohol restriction adherence was worse in smokers. Younger women, smokers and those with a low calorie intake were less adherent to the fruit/vegetable recommendation. The consumption of fiber and limited consumption of red/processed meat adherence was poor in all the subgroups. The adherence to a limited consumption of fast food and sugary drinks was worse in younger women and high-calorie-diet consumers. Conclusions: The differences in the adherence to recommendations according to patient characteristics justify the design of personalized interventions for breast cancer patients.
Novel risk loci for COVID-19 hospitalization among admixed American populations
(eLife Sciences Publications, 2024-10-03) Diz-de Almeida, Silvia; Cruz, Raquel; Luchessi, Andre D; Lorenzo-Salazar, José M; López de Heredia, Miguel; Quintela, Inés; González-Montelongo, Rafaela; Nogueira Silbiger, Vivian; Porras, Marta Sevilla; Tenorio Castaño, Jair Antonio; Nevado, Julián; Aguado, José María; Aguilar, Carlos; Aguilera-Albesa, Sergio; Almadana, Virginia; Almoguera, Berta; Alvarez, Nuria; Andreu-Bernabeu, Álvaro; Arana-Arri, Eunate; Arango, Celso; Arranz, María J; Artiga, Maria-Jesus; Baptista-Rosas, Raúl C; Barreda-Sánchez, María; Belhassen-García, Moncef; Bezerra, Joao F; Bezerra, Marcos A C; Boix-Palop, Lucía; Brion, María; Brugada, Ramón; Bustos, Matilde; Calderón, Enrique J; Carbonell, Cristina; Castano, Luis; Castelao, Jose E; Conde-Vicente, Rosa; Cordero-Lorenzana, M Lourdes; Cortes-Sanchez, Jose L; Corton, Marta; Darnaude, M Teresa; De Martino-Rodríguez, Alba; Del Campo-Pérez, Victor; Diaz de Bustamante, Aranzazu; Domínguez-Garrido, Elena; Eirós, Rocío; Fariñas, María Carmen; Fernandez-Nestosa, María J; Fernández-Robelo, Uxía; Fernandez-Rodriguez, Amanda; Fernández-Villa, Tania; Gago-Dominguez, Manuela; Gil-Fournier, Belén; Gómez-Arrue, Javier; González Álvarez, Beatriz; González Bernaldo de Quirós, Fernan; González-Neira, Anna; González-Peñas, Javier; Gutiérrez-Bautista, Juan F; Herrero, María José; Herrero-Gonzalez, Antonio; Jimenez-Sousa, Maria Angeles; Lattig, María Claudia; Liger Borja, Anabel; Lopez-Rodriguez, Rosario; Mancebo, Esther; Martín-López, Caridad; Martín, Vicente; Martinez-Nieto, Oscar; Martinez-Lopez, Iciar; Martinez-Resendez, Michel F; Martinez-Perez, Angel; Mazzeu, Juliana F; Merayo Macías, Eleuterio; Minguez, Pablo; Moreno Cuerda, Victor; Oliveira, Silviene F; Ortega-Paino, Eva; Pompa-Mera, Ericka N; Parellada, Mara; Paz-Artal, Estela; Santos, Ney PC; Pérez-Matute, Patricia; Perez, Patricia; Pérez-Tomás, M Elena; Perucho, Teresa; Pinsach-Abuin, Mel·lina; Pita, Guillermo; Porras-Hurtado, Gloria L; Pujol, Aurora; Ramiro León, Soraya; Resino, Salvador; Fernandes, Marianne R; Rodríguez-Ruiz, Emilio; Rodríguez-Artalejo, Fernando; Rodriguez-Garcia, José A; Ruiz-Cabello, Francisco; Ruiz-Hornillos, Javier; Ryan, Pablo; Soria, José Manuel; Souto, Juan Carlos; Tamayo, Eduardo; Tamayo-Velasco, Álvaro; Taracido-Fernandez, Juan Carlos; Teper, Alejandro; Torres-Tobar, Lilian; Urioste, Miguel; Valencia-Ramos, Juan; Yáñez, Zuleima; Zarate, Ruth; de Rojas, Itziar; Ruiz, Agustín; Sánchez, Pascual; Real, Luis Miguel; SCOURGE Cohort Group; Guillén-Navarro, Encarna; Ayuso, Carmen; Parra, Esteban; Riancho, José A; Rojas-Martinez, Augusto; Flores, Carlos; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Banco Santander; Fundación La Caixa; Agencia Estatal de Investigación (España); Gobierno de Canarias (España); Fundación Canaria de Investigación Sanitaria; Xunta de Galicia (España); Fundación Amancio Ortega; Estrella de Levante; Colabora Mujer
The genetic basis of severe COVID-19 has been thoroughly studied, and many genetic risk factors shared between populations have been identified. However, reduced sample sizes from non-European groups have limited the discovery of population-specific common risk loci. In this second study nested in the SCOURGE consortium, we conducted a genome-wide association study (GWAS) for COVID-19 hospitalization in admixed Americans, comprising a total of 4702 hospitalized cases recruited by SCOURGE and seven other participating studies in the COVID-19 Host Genetic Initiative. We identified four genome-wide significant associations, two of which constitute novel loci and were first discovered in Latin American populations ( and ). A trans-ethnic meta-analysis revealed another novel cross-population risk locus in . Finally, we assessed the performance of a cross-ancestry polygenic risk score in the SCOURGE admixed American cohort. This study constitutes the largest GWAS for COVID-19 hospitalization in admixed Latin Americans conducted to date. This allowed to reveal novel risk loci and emphasize the need of considering the diversity of populations in genomic research.
A genome-wide association meta-analysis of all-cause and vascular dementia
(Wiley, 2024-09) Mega Vascular Cognitive Impairment and Dementia (MEGAVCID) consortium; Calero, Miguel; NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos); NIH - National Institute on Aging (NIA) (Estados Unidos); NIH - National Institute of Neurological Disorders and Stroke (NINDS) (Estados Unidos)
Introduction: Dementia is a multifactorial disease with Alzheimer's disease (AD) and vascular dementia (VaD) pathologies making the largest contributions. Yet, most genome-wide association studies (GWAS) focus on AD. Methods: We conducted a GWAS of all-cause dementia (ACD) and examined the genetic overlap with VaD. Our dataset includes 800,597 individuals, with 46,902 and 8702 cases of ACD and VaD, respectively. Known AD loci for ACD and VaD were replicated. Bioinformatic analyses prioritized genes that are likely functionally relevant and shared with closely related traits and risk factors. Results: For ACD, novel loci identified were associated with energy transport (SEMA4D), neuronal excitability (ANO3), amyloid deposition in the brain (RBFOX1), and magnetic resonance imaging markers of small vessel disease (SVD; HBEGF). Novel VaD loci were associated with hypertension, diabetes, and neuron maintenance (SPRY2, FOXA2, AJAP1, and PSMA3). Discussion: Our study identified genetic risks underlying ACD, demonstrating overlap with neurodegenerative processes, vascular risk factors, and cerebral SVD. Highlights: We conducted the largest genome-wide association study of all-cause dementia (ACD) and vascular dementia (VaD). Known genetic variants associated with AD were replicated for ACD and VaD. Functional analyses identified novel loci for ACD and VaD. Genetic risks of ACD overlapped with neurodegeneration, vascular risk factors, and cerebral small vessel disease.
Diagnosis and treatment of disorders of intracranial pressure: consensus statement of the Spanish Society of Neurology's Headache Study Group
(Elsevier, 2024-02-29) García-Ull, J; González-García, N; Torres-Ferrus, Marta; García-Azorín, D; Molina-Martinez, Francisco José; Beltrán-Blasco, I; Santos-Lasaosa, Sonia; Latorre, G; Gago-Veiga, A B; Láinez, J M; Porta-Etessam, J; Nieves-Castellanos, C; Mínguez-Olaondo, A; López-Bravo, A; Quintas, S; Morollón, N; Díaz-Insa, S; Belvís, R; Irimia, P
[EN] Primary intracranial pressure disorders include idiopathic intracranial hypertension and spontaneous intracranial hypotension. These two entities have presented a remarkable advance in diagnostic and therapeutic techniques in recent years. Therefore, the Spanish Society of Neurology's Headache Study Group (GECSEN) considered it necessary to prepare this consensus document with the inclusion of diagnostic and therapeutic algorithms to facilitate and improve their management in clinical practice. This document was created by a committee of experts of the GECSEN based on a systematic review of the literature, incorporating the experience of the participants, and establishing practical recommendations with levels of evidence and grades of recommendation. [ES] Los trastornos primarios de la presión intracraneal incluyen la hipertensión intracraneal idiopática y la hipotensión intracraneal espontánea. El diagnóstico y tratamiento de ambas entidades ha presentado un avance destacable en los últimos años; por lo que desde el Grupo de Estudio de Cefaleas de la Sociedad Española de Neurología (GECSEN) consideramos necesaria la elaboración de este documento de consenso con la inclusión de algoritmos diagnósticos y terapéuticos para mejorar su manejo en la práctica diaria. Este documento ha sido redactado por un comité de expertos del GECSEN tras realizar una revisión sistemática de la bibliografía, incorporando la experiencia de los participantes y estableciendo unas recomendaciones prácticas con niveles de evidencia y grados de recomendación.
Comparison of the 2022 and 2017 European LeukemiaNet risk classifications in a real-life cohort of the PETHEMA group
(Nature Publishing Group, 2023-05-12) Sargas, Claudia; Ayala, Rosa; Larráyoz, María J; Chillón, María C; Rodriguez-Arboli, Eduardo; Bilbao, Cristina; Prados de la Torre, Esther; Martínez-Cuadrón, David; Rodríguez-Veiga, Rebeca; Boluda, Blanca; Gil, Cristina; Bernal, Teresa; Bergua, Juan; Algarra, Lorenzo; Tormo, Mar; Martínez-Sánchez, Pilar; Soria, Elena; Serrano, Josefina; Alonso-Dominguez, Juan M; García, Raimundo; Amigo, María Luz; Herrera-Puente, Pilar; Sayas, María J; Lavilla-Rubira, Esperanza; Martinez-Lopez, Joaquin; Calasanz, María J; García-Sanz, Ramón; Pérez-Simón, José A; Gómez Casares, María T; Sánchez-García, Joaquín; Barragán, Eva; Montesinos, Pau; PETHEMA cooperative study group; Ministerio de Ciencia, Innovación y Universidades (España); Instituto de Salud Carlos III
Next-Generation Sequencing is needed for the accurate genetic risk stratification of acute myeloid leukemia according to European LeukemiaNet (ELN) guidelines. We validated and compared the 2022 ELN risk classification in a real-life cohort of 546 intensively and 379 non-intensively treated patients. Among fit patients, those aged ?65 years old showed worse OS than younger regardless risk classification. Compared with the 2017 classification, 14.5% of fit patients changed the risk with the 2022 classification, increasing the high-risk group from 44.3% to 51.8%. 3.7% and 0.9% FLT3-ITD mutated patients were removed from the favorable and adverse 2017 categories respectively to 2022 intermediate risk group. We suggest that midostaurin therapy could be a predictor for 3 years OS (85.2% with vs. 54.8% without midostaurin, P = 0.04). Forty-seven (8.6%) patients from the 2017 intermediate group were assigned to the 2022 adverse-risk group as they harbored myelodysplasia (MDS)-related mutations. Patients with one MDS-related mutation did not reach median OS, while patients with ?2 mutations had 13.6 months median OS (P = 0.002). Patients with TP53 � complex karyotype or inv(3) had a dismal prognosis (7.1 months median OS). We validate the prognostic utility of the 2022 ELN classification in a real-life setting providing supportive evidences to improve risk stratification guidelines.
Prospective Randomized Study Comparing Myeloablative Unrelated Umbilical Cord Blood Transplantation versus HLA-Haploidentical Related Stem Cell Transplantation for Adults with Hematologic Malignancies
(Elsevier, 2020-02) Sanz, Jaime; Montoro, Juan; Solano, Carlos; Valcarcel, David; Sampol Mayol, Antonia; Ferra, Christelle; Parody, Rocio; Lorenzo, Ignacio; Montesinos, Pau; Orti, Guillermo; Hernandez-Boluda, Juan-Carlos; Balaguer-Rosello, Aitana; Guerreiro, Manuel; Carretero, Carlos; Sanz, Guillermo F; Sanz, Miguel A; Pinana, Jose Luis
In this prospective randomized study, we compared the outcomes of single-unit umbilical cord blood transplantation (UCBT) and unmanipulated haploidentical stem cell transplantation (haplo-SCT) with post-transplantation cyclophosphamide (PTCy) in adults with hematologic malignancies. All patients received a myeloablative conditioning (MAC) regimen consisting of thiotepa, busulfan, and fludarabine, with antithymocyte globulin (ATG) added for UCBT recipients. Nineteen patients were randomized to UCBT and the other 26 to haplo-HSCT. Four patients (15%) allocated to the haplo-HSCT arm lacked a suitable donor and were crossed over to the UCBT arm. Finally, 23 underwent UCBT and 22 underwent haplo-HSCT. The cumulative incidence of neutrophil recovery was 87% at a median of 19 days (range, 13 to 24 days) in the UCBT arm versus 100% at a median of 17 days (range, 13 to 25 days) in the haplo-SCT arm (P=.04). Platelet recovery was 70% at a median of 40 days (range, 18 to 129 days) in the UCBT arm versus 86% at a median of 24 days (range, 12 to 127 days) in the haplo-HCT arm (P=.02). Rates of acute graft-versus-host disease (GVHD) grade II-IV or grade overall chronic GVHD, and extensive chronic GVHD in the UCBT and Haplo-SCT arms were 43% versus 36% (P=.8), 9% versus 9% (P=1), 66% versus 43% (P=.04), and 41% versus 23% (P=.2), respectively. Two-year nonrelapse mortality and relapse in the 2 arms were 52% versus 23% (P=.06) and 17% versus 23% (P=.5), respectively. Two-year disease-free survival, overall survival, and GVHD/relapse-free survival in the 2 arms were 30% versus 54% (P=.2), 35% versus 59% (P=.1), and 17% versus 40% (P=.04), respectively. Our data show that in the context of an MAC regimen, haplo-SCT with PTCy provides improved outcomes compared with ATG-containing single-unit UCBT.
Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2
(Nature Publishing Group, 2024-02-19) Pérez-Jurado, Luis Alberto; Cáceres, Alejandro; Balagué-Dobón, Laura; Esko, Tonu; López de Heredia, Miguel; Quintela, Inés; Cruz, Raquel; Lapunzina, Pablo; Carracedo, Ángel; SCOURGE Cohort Group; González, Juan R; Meijome, Xose M; Brochado-Kith, Oscar; Ceballos, Francisco C; Fernandez-Rodriguez, Amanda; Jimenez-Sousa, Maria Angeles; Martin-Vicente, Maria; Resino, Salvador; Virseda-Berdices, Ana; Government of Catalonia (España); Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España); Ministerio de Ciencia e Innovación (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Estonian Research Council; Instituto de Salud Carlos III; Amancio Ortega Foundation; Banco Santander
The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people.
A second update on mapping the human genetic architecture of COVID-19
(Nature Publishing Group, 2023-09) COVID-19 Host Genetics Initiative; Fernandez-Rodriguez, Amanda; Jimenez-Sousa, Maria Angeles; Ceballos, Francisco C; Resino, Salvador
Restoring cellular magnesium balance through Cyclin M4 protects against acetaminophen-induced liver damage.
(2022-11-25) González-Recio, Irene; Simón, Jorge; Goikoetxea-Usandizaga, Naroa; Serrano-Maciá, Marina; Mercado-Gómez, Maria; Rodríguez-Agudo, Rubén; Lachiondo-Ortega, Sofía; Gil-Pitarch, Clàudia; Fernández-Rodríguez, Carmen; Castellana, Donatello; Latasa, Maria U; Abecia, Leticia; Anguita, Juan; Delgado, Teresa C; Iruzubieta, Paula; Crespo, Javier; Hardy, Serge; Petrov, Petar D; Jover, Ramiro; Avila, Matías A; Martín, César; Schaeper, Ute; Tremblay, Michel L; Dear, James W; Masson, Steven; McCain, Misti Vanette; Reeves, Helen L; Andrade, Raul J; Lucena, M Isabel; Buccella, Daniela; Martínez-Cruz, Luis Alfonso; Martínez-Chantar, Maria L
Acetaminophen overdose is one of the leading causes of acute liver failure and liver transplantation in the Western world. Magnesium is essential in several cellular processess. The Cyclin M family is involved in magnesium transport across cell membranes. Herein, we identify that among all magnesium transporters, only Cyclin M4 expression is upregulated in the liver of patients with acetaminophen overdose, with disturbances in magnesium serum levels. In the liver, acetaminophen interferes with the mitochondrial magnesium reservoir via Cyclin M4, affecting ATP production and reactive oxygen species generation, further boosting endoplasmic reticulum stress. Importantly, Cyclin M4 mutant T495I, which impairs magnesium flux, shows no effect. Finally, an accumulation of Cyclin M4 in endoplasmic reticulum is shown under hepatoxicity. Based on our studies in mice, silencing hepatic Cyclin M4 within the window of 6 to 24 h following acetaminophen overdose ingestion may represent a therapeutic target for acetaminophen overdose induced liver injury.
Major Adverse Cardiovascular Events in Coronary Type 2 Diabetic Patients: Identification of Associated Factors Using Electronic Health Records and Natural Language Processing.
(2022-10-11) González-Juanatey, Carlos; Anguita-Sánchez, Manuel; Barrios, Vivencio; Núñez-Gil, Iván; Gómez-Doblas, Juan José; García-Moll, Xavier; Lafuente-Gormaz, Carlos; Rollán-Gómez, María Jesús; Peral-Disdier, Vicente; Martínez-Dolz, Luis; Rodríguez-Santamarta, Miguel; Viñolas-Prat, Xavier; Soriano-Colomé, Toni; Muñoz-Aguilera, Roberto; Plaza, Ignacio; Curcio-Ruigómez, Alejandro; Orts-Soler, Ernesto; Segovia, Javier; Fanjul, Víctor; Cequier, Ángel; Savana Research Group,
Patients with Type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) are at high risk of developing major adverse cardiovascular events (MACE). This is a multicenter, retrospective, and observational study performed in Spain aimed to characterize these patients in a real-world setting. Unstructured data from the Electronic Health Records were extracted by EHRead®, a technology based on Natural Language Processing and machine learning. The association between new MACE and the variables of interest were investigated by univariable and multivariable analyses. From a source population of 2,184,662 patients, we identified 4072 adults diagnosed with T2DM and CAD (62.2% male, mean age 70 ± 11). The main comorbidities observed included arterial hypertension, hyperlipidemia, and obesity, with metformin and statins being the treatments most frequently prescribed. MACE development was associated with multivessel (Hazard Ratio (HR) = 2.49) and single coronary vessel disease (HR = 1.71), transient ischemic attack (HR = 2.01), heart failure (HR = 1.32), insulin treatment (HR = 1.40), and percutaneous coronary intervention (PCI) (HR = 2.27), whilst statins (HR = 0.73) were associated with a lower risk of MACE occurrence. In conclusion, we found six risk factors associated with the development of MACE which were related with cardiovascular diseases and T2DM severity, and treatment with statins was identified as a protective factor for new MACE in this study.
Peripheral Neutrophil-to-Lymphocyte Ratio in Bronchiectasis: A Marker of Disease Severity.
(2022-09-30) Martinez-García, Miguel Ángel; Olveira, Casilda; Girón, Rosa; García-Clemente, Marta; Máiz-Carro, Luis; Sibila, Oriol; Golpe, Rafael; Méndez, Raúl; Rodríguez Hermosa, Juan Luis; Barreiro, Esther; Prados, Concepción; Rodríguez López, Juan; de la Rosa, David
Most patients with bronchiectasis have a predominantly neutrophilic inflammatory profile, although other cells such as lymphocytes (as controllers of bronchial inflammation) and eosinophils also play a significant pathophysiological role. Easy-to-interpret blood biomarkers with a discriminative capacity for severity or prognosis are needed. The objective of this study was to assess whether the peripheral neutrophil-to-lymphocyte ratio (NLR) is associated with different outcomes of severity in bronchiectasis. A total of 1369 patients with bronchiectasis from the Spanish Registry of Bronchiectasis were included. To compare groups, the sample was divided into increasing quartiles of NLR ratio. Correlations between quantitative variables were established using Pearson's P test. A simple linear regression (with the value of exacerbations as a quantitative variable) was used to determine the independent relationship between the number and severity of exacerbations and the NLR ratio. The area under the curve (AUC)-ROC was used to determine the predictive capacity of the NLR for severe bronchiectasis, according to the different multidimensional scores. Mean age: 69 (15) years (66.3% of women). The mean NLR was 2.92 (2.03). A higher NLR was associated with more severe bronchiectasis (with an especially significant discriminative power for severe forms) according to the commonly used scores (FACED, E-FACED and BSI), as well as with poorer quality of life (SGRQ), more comorbidities (Charlson index), infection by pathogenic microorganisms, and greater application of treatment. Furthermore, the NLR correlated better with severity scores than other parameters of systemic inflammation. Finally, it was an independent predictor of the incident number and severity of exacerbations. In conclusion, the NLR is an inexpensive and easy-to-measure marker of systemic inflammation for determining severity and predicting exacerbations (especially the most severe) in patients with bronchiectasis.
Methionine Cycle Rewiring by Targeting miR-873-5p Modulates Ammonia Metabolism to Protect the Liver from Acetaminophen.
(2022-04-30) Rodríguez-Agudo, Rubén; Goikoetxea-Usandizaga, Naroa; Serrano-Maciá, Marina; Fernández-Tussy, Pablo; Fernández-Ramos, David; Lachiondo-Ortega, Sofía; González-Recio, Irene; Gil-Pitarch, Clàudia; Mercado-Gómez, María; Morán, Laura; Bizkarguenaga, Maider; Lopitz-Otsoa, Fernando; Petrov, Petar; Bravo, Miren; Van Liempd, Sebastiaan Martijn; Falcon-Perez, Juan Manuel; Zabala-Letona, Amaia; Carracedo, Arkaitz; Castell, Jose Vicente; Jover, Ramiro; Martínez-Cruz, Luis Alfonso; Delgado, Teresa Cardoso; Cubero, Francisco Javier; Lucena, María Isabel; Andrade, Raúl Jesús; Mabe, Jon; Simón, Jorge; Martínez-Chantar, María Luz
Drug-induced liver injury (DILI) development is commonly associated with acetaminophen (APAP) overdose, where glutathione scavenging leads to mitochondrial dysfunction and hepatocyte death. DILI is a severe disorder without effective late-stage treatment, since N-acetyl cysteine must be administered 8 h after overdose to be efficient. Ammonia homeostasis is altered during liver diseases and, during DILI, it is accompanied by decreased glycine N-methyltransferase (GNMT) expression and S-adenosylmethionine (AdoMet) levels that suggest a reduced methionine cycle. Anti-miR-873-5p treatment prevents cell death in primary hepatocytes and the appearance of necrotic areas in liver from APAP-administered mice. In our study, we demonstrate a GNMT and methionine cycle activity restoration by the anti-miR-873-5p that reduces mitochondrial dysfunction and oxidative stress. The lack of hyperammoniemia caused by the therapy results in a decreased urea cycle, enhancing the synthesis of polyamines from ornithine and AdoMet and thus impacting the observed recovery of mitochondria and hepatocyte proliferation for regeneration. In summary, anti-miR-873-5p appears to be an effective therapy against APAP-induced liver injury, where the restoration of GNMT and the methionine cycle may prevent mitochondrial dysfunction while activating hepatocyte proliferative response.
Next-Generation DNA Sequencing-Based Gene Panel for Diagnosis and Genetic Risk Stratification in Onco-Hematology.
(2022-04-14) Gargallo, Pablo; Molero, Merche; Bilbao, Cristina; Stuckey, Ruth; Carrillo-Cruz, Estrella; Hermosín, Lourdes; Pérez-López, Olga; Jiménez-Velasco, Antonio; Soria, Elena; Lázaro, Marián; Carbonell, Paula; Yáñez, Yania; Gómez, Iria; Izquierdo-García, Marta; Valero-García, Jennifer; Ruiz, Carlos; Such, Esperanza; Calabria, Inés
A suitable diagnostic classification of myeloid neoplasms and acute leukemias requires testing for a large number of molecular biomarkers. Next-generation sequencing is a technology able to integrate identification of the vast majority of them in a single test. This manuscript includes the design, analytical validation and clinical feasibility evaluation of a molecular diagnostic kit for onco-hematological diseases. It is based on sequencing of the coding regions of 76 genes (seeking single-nucleotide variants, small insertions or deletions and CNVs), as well as the search for fusions in 27 target genes. The kit has also been designed to detect large CNVs throughout the genome by including specific probes and employing a custom bioinformatics approach. The analytical and clinical feasibility validation of the Haematology OncoKitDx panel has been carried out from the sequencing of 170 patient samples from 6 hospitals (in addition to the use of commercial reference samples). The analytical validation showed sensitivity and specificity close to 100% for all the parameters evaluated, with a detection limit of 2% for SNVs and SVs, and 20% for CNVs. Clinically relevant mutations were detected in 94% of all patients. An analysis of the correlation between the genetic risk classification of AML (according to ELN 2017) established by the hospitals and that obtained by the Haematology OncoKitDx panel showed an almost perfect correlation (K = 0.94). Among the AML samples with a molecular diagnosis, established by the centers according to the WHO, the Haematology OncoKitDx analysis showed the same result in 97% of them. The panel was able to adequately differentiate between MPN subtypes and also detected alterations that modified the diagnosis (FIP1L1-PDGFRA). Likewise, the cytogenetic risk derived from the CNV plot generated by the NGS panel correlated substantially with the results of the conventional karyotype (K = 0.71) among MDS samples. In addition, the panel detected the main biomarkers of prognostic value among patients with ALL. This validated solution enables a reliable analysis of a large number of molecular biomarkers from a DNA sample in a single assay.
Importance of genotype for risk stratification in arrhythmogenic right ventricular cardiomyopathy using the 2019 ARVC risk calculator
(2022) Protonotarios, Alexandros; Bariani, Riccardo; Cappelletto, Chiara; Pavlou, Menelaos; García-García, Alba; Cipriani, Alberto; Protonotarios, Ioannis; Rivas, Adrian; Wittenberg, Regitze; Graziosi, Maddalena; Xylouri, Zafeirenia; Larrañaga-Moreira, José M; de Luca, Antonio; Celeghin, Rudy; Pilichou, Kalliopi; Bakalakos, Athanasios; Lopes, Luis Rocha; Savvatis, Konstantinos; Stolfo, Davide; Dal Ferro, Matteo; Merlo, Marco; Basso, Cristina; Freire, Javier Limeres; Rodriguez-Palomares, Jose F; Kubo, Toru; Ripoll-Vera, Tomas; Barriales-Villa, Roberto; Antoniades, Loizos; Mogensen, Jens; Garcia-Pavia, Pablo; Wahbi, Karim; Biagini, Elena; Anastasakis, Aris; Tsatsopoulou, Adalena; Zorio, Esther; Gimeno, Juan R; Garcia-Pinilla, Jose Manuel; Syrris, Petros; Sinagra, Gianfranco; Bauce, Barbara; Elliott, Perry M
Aims: To study the impact of genotype on the performance of the 2019 risk model for arrhythmogenic right ventricular cardiomyopathy (ARVC). Methods and results: The study cohort comprised 554 patients with a definite diagnosis of ARVC and no history of sustained ventricular arrhythmia (VA). During a median follow-up of 6.0 (3.1,12.5) years, 100 patients (18%) experienced the primary VA outcome (sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator intervention, aborted sudden cardiac arrest, or sudden cardiac death) corresponding to an annual event rate of 2.6% [95% confidence interval (CI) 1.9-3.3]. Risk estimates for VA using the 2019 ARVC risk model showed reasonable discriminative ability but with overestimation of risk. The ARVC risk model was compared in four gene groups: PKP2 (n = 118, 21%); desmoplakin (DSP) (n = 79, 14%); other desmosomal (n = 59, 11%); and gene elusive (n = 160, 29%). Discrimination and calibration were highest for PKP2 and lowest for the gene-elusive group. Univariable analyses revealed the variable performance of individual clinical risk markers in the different gene groups, e.g. right ventricular dimensions and systolic function are significant risk markers in PKP2 but not in DSP patients and the opposite is true for left ventricular systolic function. Conclusion: The 2019 ARVC risk model performs reasonably well in gene-positive ARVC (particularly for PKP2) but is more limited in gene-elusive patients. Genotype should be included in future risk models for ARVC.
Protein Binding of Lapatinib and Its N- and O-Dealkylated Metabolites Interrogated by Fluorescence, Ultrafast Spectroscopy and Molecular Dynamics Simulations.
(2020-10-30) Andreu, Inmaculada; Lence, Emilio; González-Bello, Concepción; Mayorga, Cristobalina; Cuquerella, M Consuelo; Vayá, Ignacio; Miranda, Miguel A
Lapatinib (LAP) is an anticancer drug generally used to treat breast and lung cancer. It exhibits hypersensitivity reactions in addition to dermatological adverse effects and photosensitivity. Moreover, LAP binds to serum proteins and is readily biotransformed in humans, giving rise to several metabolites, such as N- and O-dealkylated products (N-LAP and O-LAP, respectively). In this context, the aim of the present work is to obtain key information on drug@protein complexation, the first step involved in a number of hypersensitivity reactions, by a combination of fluorescence, femtosecond transient absorption spectroscopy and molecular dynamics (MD) simulations. Following this approach, the behavior of LAP and its metabolites has been investigated in the presence of serum proteins, such as albumins and α1-acid glycoproteins (SAs and AGs, respectively) from human and bovine origin. Fluorescence results pointed to a higher affinity of LAP and its metabolites to human proteins; the highest one was found for LAP@HSA. This is associated to the coplanar orientation adopted by the furan and quinazoline rings of LAP, which favors emission from long-lived (up to the ns time-scale) locally-excited (LE) states, disfavoring population of intramolecular charge transfer (ICT) states. Moreover, the highly constrained environment provided by subdomain IB of HSA resulted in a frozen conformation of the ligand, contributing to fluorescence enhancement. Computational studies were clearly in line with the experimental observations, providing valuable insight into the nature of the binding sites and the conformational arrangement of the ligands inside the protein cavities. Besides, a good correlation was found between the calculated binding energies for each ligand@protein complex and the relative affinities observed in competition experiments.
Study design of Heart failure Events reduction with Remote Monitoring and eHealth Support (HERMeS).
(2020-09-17) Yun, Sergi; Enjuanes, Cristina; Calero, Esther; Hidalgo, Encarnación; Cobo, Marta; Llàcer, Pau; García-Pinilla, José Manuel; González-Franco, Álvaro; Núñez, Julio; Morales-Rull, José Luis; Beltrán, Paola; Delso, Cristina; Freixa-Pamias, Román; Moliner, Pedro; Corbella, Xavier; Comín-Colet, Josep; HERMeS trial investigators group
The role of non-invasive telemedicine (TM) combining telemonitoring and teleintervention by videoconference (VC) in patients recently admitted due to heart failure (HF) ('vulnerable phase' HF patients) is not well established. The aim of the Heart failure Events reduction with Remote Monitoring and eHealth Support (HERMeS) trial is to assess the impact on clinical outcomes of implementing a TM service based on mobile health (mHealth), which includes remote daily monitoring of biometric data and symptom reporting (telemonitoring) combined with VC structured, nurse-based follow-up (teleintervention). The results will be compared with those of the comprehensive HF usual care (UC) strategy based on face-to-face on-site visits at the vulnerable post-discharge phase. We designed a 24 week nationwide, multicentre, randomized, controlled, open-label, blinded endpoint adjudication trial to assess the effect on cardiovascular (CV) mortality and non-fatal HF events of a TM-based comprehensive management programme, based on mHealth, for patients with chronic HF. Approximately 508 patients with a recent hospital admission due to HF decompensation will be randomized (1:1) to either structured follow-up based on face-to-face appointments (UC group) or the delivery of health care using TM. The primary outcome will be a composite of death from CV causes or non-fatal HF events (first and recurrent) at the end of a 6 month follow-up period. Key secondary endpoints will include components of the primary event analysis, recurrent event analysis, and patient-reported outcomes. The HERMeS trial will assess the efficacy of a TM-based follow-up strategy for real-world 'vulnerable phase' HF patients combining telemonitoring and teleintervention.
Genome-wide profiling of non-smoking-related lung cancer cells reveals common RB1 rearrangements associated with histopathologic transformation in EGFR-mutant tumors
(Elsevier, 2020-02) Pros, E; Saigi, M; Alameda, D; Gomez-Mariano, Gema Maria; Martinez-Delgado, Beatriz; Alburquerque-Bejar, J J; Carretero, J; Tonda, R; Esteve-Codina, A; Catala, I; Palmero, R; Jove, M; Lazaro, C; Patiño-García, Ana; Gil-Bazo, I; Verdura, S; Teulé, A; Torres-Lanzas, J; Sidransky, D; Reguart, N; Pio, R; Juan-Vidal, O; Nadal, E; Felip, E; Montuenga, L M; Sanchez-Cespedes, M; Asociación Española Contra el Cáncer; Ministerio de Economía y Competitividad (España); Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Gobierno de Navarra (España); Fundación Ramón Areces
Background: The etiology and the molecular basis of lung adenocarcinomas (LuADs) in nonsmokers are currently unknown. Furthermore, the scarcity of available primary cultures continues to hamper our biological understanding of non-smoking-related lung adenocarcinomas (NSK-LuADs). Patients and methods: We established patient-derived cancer cell (PDC) cultures from metastatic NSK-LuADs, including two pairs of matched EGFR-mutant PDCs before and after resistance to tyrosine kinase inhibitors (TKIs), and then performed whole-exome and RNA sequencing to delineate their genomic architecture. For validation, we analyzed independent cohorts of primary LuADs. Results: In addition to known non-smoker-associated alterations (e.g. RET, ALK, EGFR, and ERBB2), we discovered novel fusions and recurrently mutated genes, including ATF7IP, a regulator of gene expression, that was inactivated in 5% of primary LuAD cases. We also found germline mutations at dominant familiar-cancer genes, highlighting the importance of genetic predisposition in the origin of a subset of NSK-LuADs. Furthermore, there was an over-representation of inactivating alterations at RB1, mostly through complex intragenic rearrangements, in treatment-naive EGFR-mutant LuADs. Three EGFR-mutant and one EGFR-wild-type tumors acquired resistance to EGFR-TKIs and chemotherapy, respectively, and histology on re-biopsies revealed the development of small-cell lung cancer/squamous cell carcinoma (SCLC/LuSCC) transformation. These features were consistent with RB1 inactivation and acquired EGFR-T790M mutation or FGFR3-TACC3 fusion in EGFR-mutant tumors. Conclusions: We found recurrent alterations in LuADs that deserve further exploration. Our work also demonstrates that a subset of NSK-LuADs arises within cancer-predisposition syndromes. The preferential occurrence of RB1 inactivation, via complex rearrangements, found in EGFR-mutant tumors appears to favor SCLC/LuSCC transformation under growth-inhibition pressures. Thus RB1 inactivation may predict the risk of LuAD transformation to a more aggressive type of lung cancer, and may need to be considered as a part of the clinical management of NSK-LuADs patients.
Pyrazolones metabolites are relevant for identifying selective anaphylaxis to metamizole.
(2016-03-31) Ariza, Adriana; García-Martín, Elena; Salas, María; Montañez, María I; Mayorga, Cristobalina; Blanca-Lopez, Natalia; Andreu, Inmaculada; Perkins, James; Blanca, Miguel; Agúndez, José A G; Torres, María J
Non-steroidal anti-inflammatory drugs (NSAIDs) are the most common cause of hypersensitivity reactions, with pyrazolones the most frequent drugs inducing selective reactions. Immediate selective hypersensitivity to pyrazolones is thought to be mediated by specific-IgE. Sensitivity of in vitro diagnostic tests is low and this may be due to the incomplete characterization of the structures involved. Here we investigated whether main metabolites of metamizole (dipyrone) in human could be involved in the immune response using the basophil activation test (BAT). We studied subjects with confirmed selective immediate hypersensitivity to metamizole and performed BAT with metamizole and its metabolites: 4-methylamino-antipyrine (MAA), 4-aminoantipyrine (AA), 4-acetylamino-antipyrine (AAA) and 4-formylamino-antipyrine (FAA). BAT results showed an increase of positive results from 37.5% to 62.5% using metamizole plus metabolites as compared with the BAT carried out only with the parent drug, demonstrating that metamizole metabolites have a role in the reaction and can induce specific basophil activation in patients with immediate hypersensitivity to this drug. Our findings indicate that pyrazolone metabolites are useful for improving the in vitro diagnosis of allergic reactions to metamizole.

Browse

Recent Submissions