IBIS - Instituto de Biomedicina de Sevilla (Andalucía)

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12105/16958

El Instituto de Biomedicina de Sevilla (IBIS), fue creado el 24 de marzo de 2006 en virtud de un convenio firmado por la Consejería de Salud de la Junta de Andalucía, la Consejería de Innovación, Ciencia y Empresa de la Junta de Andalucía, el Servicio Andaluz de Salud, la Universidad de Sevilla, y el Consejo Superior de Investigaciones Científicas. El IBIS representa la continuidad de un proyecto iniciado con la creación en el año 2000 del Laboratorio de Investigaciones Biomédicas (LIB), mediante acuerdo entre la Consejería de Salud de la Junta de Andalucía, el Servicio Andaluz de Salud, y la Universidad de Sevilla. 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 208

Regulation of anti-phage defense mechanisms by using cinnamaldehyde as a quorum sensing inhibitor
(Frontiers Media, 2024) Barrio-Pujante, Antonio; Bleriot, Inés; Blasco, Lucía; Fernández-García, Laura; Pacios, Olga; Ortiz-Cartagena, Concha; Cuenca, Felipe Fernández; Oteo-Iglesias, Jesus; Tomás, María; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica; Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas); Xunta de Galicia (España)
Background: Multidrug-resistant bacteria and the shortage of new antibiotics constitute a serious health problem. This problem has led to increased interest in the use of bacteriophages, which have great potential as antimicrobial agents but also carry the risk of inducing resistance. The objective of the present study was to minimize the development of phage resistance in Klebsiella pneumoniae strains by inhibiting quorum sensing (QS) and thus demonstrate the role of QS in regulating defense mechanisms. Results: Cinnamaldehyde (CAD) was added to K. pneumoniae cultures to inhibit QS and thus demonstrate the role of the signaling system in regulating the anti-phage defense mechanism. The QS inhibitory activity of CAD in K. pneumoniae was confirmed by a reduction in the quantitative expression of the lsrB gene (AI-2 pathway) and by proteomic analysis. The infection assays showed that the phage was able to infect a previously resistant K. pneumoniae strain in the cultures to which CAD was added. The results were confirmed using proteomic analysis. Thus, anti-phage defense-related proteins from different systems, such as cyclic oligonucleotide-based bacterial anti-phage signaling systems (CBASS), restriction-modification (R-M) systems, clustered regularly interspaced short palindromic repeat-Cas (CRISPR-Cas) system, and bacteriophage control infection (BCI), were present in the cultures with phage but not in the cultures with phage and CAD. When the QS and anti-phage defense systems were inhibited by the combined treatment, proteins related to phage infection and proliferation, such as the tail fiber protein, the cell division protein DamX, and the outer membrane channel protein TolC, were detected. Conclusion: Inhibition of QS reduces phage resistance in K. pneumoniae, resulting in the infection of a previously resistant strain by phage, with a significant increase in phage proliferation and a significant reduction in bacterial growth. QS inhibitors could be considered for therapeutic application by including them in phage cocktails or in phage-antibiotic combinations to enhance synergistic effects and reduce the emergence of antimicrobial resistance.
Targeted phage hunting to specific clinical isolates is an efficient antibiotic resistance and infection control strategy
(American Society for Microbiology (ASM), 2024-10-03) Ferriol-González, Celia; Concha-Eloko, Robby; Bernabéu-Gimeno, Mireia; Fernández-Cuenca, Felipe; Cañada-Garcia, Javier Enrique; García-Cobos, Silvia; Sanjuán, Rafael; Domingo-Calap, Pilar; European Society of Clinical Microbiology and Infectious Diseases; Agencia Estatal de Investigación (España); Generalitat Valenciana (España); University of Valencia (España); Comunidad de Madrid (España); Ministerio de Ciencia e Innovación (España)
Klebsiella pneumoniae is one of the most threatening multi-drug-resistant pathogens today, with phage therapy being a promising alternative for personalized treatments. However, the intrinsic capsule diversity in Klebsiella spp. poses a substantial barrier to the phage host range, complicating the development of broad-spectrum phage-based treatments. Here, we have isolated and genomically characterized phages capable of infecting each of the acquired 77 reference serotypes of Klebsiella spp., including capsular types widespread among high-risk K. pneumoniae clones causing nosocomial infections. We demonstrated the possibility of isolating phages for all capsular types in the collection, revealing high capsular specificity among taxonomically related phages, in contrast to a few phages that exhibited broad-spectrum infection capabilities. To decipher the determinants of the specificity of these phages, we focused on their receptor-binding proteins, with particular attention to depolymerases. We also explored the possibility of designing a broad-spectrum phage cocktail based on phages isolated in reference capsular-type strains and determining the ability to lyse relevant clinical isolates. A combination of 12 phages capable of infecting 55% of the reference Klebsiella spp. serotypes was tested on a panel of carbapenem-resistant K. pneumoniae clinical isolates. Thirty-one percent of isolates were susceptible to the phage cocktail. However, our results suggest that in a highly variable encapsulated bacterial host, phage hunting must be directed to the specific Klebsiella isolates. This work is a step forward in the understanding of the complexity of phage-host interactions and highlights the importance of implementing precise and phage-specific strategies to treat K. pneumoniae infections worldwide.IMPORTANCEThe emergence of resistant bacteria is a serious global health problem. In the absence of effective treatments, phages are a personalized and effective therapeutic alternative. However, little is still known about phage-host interactions, which are key to implementing effective strategies. Here, we focus on the study of Klebsiella pneumoniae, a highly pathogenic encapsulated bacterium. The complexity and variability of the capsule, where in most cases phage receptors are found, make it difficult for phage-based treatments. Here, we isolated a large collection of Klebsiella phages against all the reference strains and in a cohort of clinical isolates. Our results suggest that clinical isolates represent a challenge, especially high-risk clones. Thus, we propose targeted phage hunting as an effective strategy to implement phage-derived therapies. Our results are a step forward for new phage-based strategies to control K. pneumoniae infections, highlighting the importance of understanding phage-host interactions to design personalized treatments against Klebsiella spp.
Mitomycin C as an Anti-Persister Strategy against Klebsiella pneumoniae: Toxicity and Synergy Studies
(Multidisciplinary Digital Publishing Institute (MDPI), 2024-08-28) Pacios, Olga; Herrera-Espejo, Soraya; Armán, Lucía; Ibarguren-Quiles, Clara; Blasco, Lucía; Bleriot, Inés; Fernández-García, Laura; Ortiz-Cartagena, Concha; Paniagua, María; Barrio-Pujante, Antonio; Aracil, Belen; Cisneros, José Miguel; Pachón-Ibáñez, María Eugenia; Tomás, María; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); RETICS-Investigación en Patología Infecciosa (REIPI-ISCIII) (España); Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas); Ministerio de Ciencia e Innovación (España); Unión Europea. Comisión Europea. NextGenerationEU; Xunta de Galicia (España); Fulbright Program (Estados Unidos); Plan Estatal de Investigación Científica y Técnica y de Innovación
The combination of several therapeutic strategies is often seen as a good way to decrease resistance rates, since bacteria can more easily overcome single-drug treatments than multi-drug ones. This strategy is especially attractive when several targets and subpopulations are affected, as it is the case of Klebsiella pneumoniae persister cells, a subpopulation of bacteria able to transiently survive antibiotic exposures. This work aims to evaluate the potential of a repurposed anticancer drug, mitomycin C, combined with the K. pneumoniae lytic phage vB_KpnM-VAC13 in vitro and its safety in an in vivo murine model against two clinical isolates of this pathogen, one of them exhibiting an imipenem-persister phenotype. At the same time, we verified the absence of toxicity of mitomycin C at the concentration using the human chondrocyte cell line T/C28a2. The viability of these human cells was checked using both cytotoxicity assays and flow cytometry.
Epidemiological and clinical characterization of community, healthcare-associated and nosocomial colonization and infection due to carbapenemase-producing Klebsiella pneumoniae and Escherichia coli in Spain
(Springer, 2024-12) Salamanca-Rivera, Elena; Palacios-Baena, Zaira R; Cañada-Garcia, Javier Enrique; Moure García, Zaira; Perez-Vazquez, Maria; Calvo-Montes, Jorge; Martínez-Martínez, Luis; Cantón, Rafael; Ruiz Carrascoso, Guillermo; Pitart, Cristina; Navarro, Ferran; Bou, Germán; Mulet, Xavier; González-López, Juan José; Sivianes, Fran; Delgado-Valverde, Mercedes; Pascual, Álvaro; Oteo-Iglesias, Jesus; Rodríguez-Baño, Jesús; GEMARA/GEIRAS-SEIMC/REIPI CARB-ES-19 Study Group; Instituto de Salud Carlos III; Ministerio de Ciencia e Innovación (España); Unión Europea. Comisión Europea. NextGenerationEU; Plan Nacional de I+D+i (España); Ministerio de Economía y Competitividad (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas)
Background: Community-acquired (CA) and healthcare-associated (HCA) infections caused by carbapenemase-producing Enterobacterales (CPE) are not well characterized. The objective was to provide detailed information about the clinical and molecular epidemiological features of nosocomial, HCA and CA infections caused by carbapenemase-producing Klebsiella pneumoniae (CP-Kp) and Escherichia coli (CP-Ec). Methods: A prospective cohort study was performed in 59 Spanish hospitals from February to March 2019, including the first 10 consecutive patients from whom CP-Kp or CP-Ec were isolated. Patients were stratified according to acquisition type. A multivariate analysis was performed to identify the impact of acquisition type in 30-day mortality. Results: Overall, 386 patients were included (363 [94%] with CP-Kp and 23 [6%] CP-Ec); in 296 patients (76.3%), the CPE was causing an infection. Acquisition was CA in 31 (8.0%) patients, HCA in 183 (47.4%) and nosocomial in 172 (48.3%). Among patients with a HCA acquisition, 100 (54.6%) had been previously admitted to hospital and 71 (38.8%) were nursing home residents. Urinary tract infections accounted for 19/23 (82.6%), 89/130 (68.5%) and 42/143 (29.4%) of CA, HCA and nosocomial infections, respectively. Overall, 68 infections (23%) were bacteremia (8.7%, 17.7% and 30.1% of CA, HCA and nosocomial, respectively). Mortality in infections was 28% (13%, 14.6% and 42.7% of CA, HCA and nosocomial, respectively). Nosocomial bloodstream infections were associated with increased odds for mortality (adjusted OR, 4.00; 95%CI 1.21-13.19). Conclusions: HCA and CA infections caused by CPE are frequent and clinically significant. This information may be useful for a better understanding of the epidemiology of CPE.
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.
The persistence of low CD4/CD8 ratio in chronic HIV-infection, despite ART suppression and normal CD4 levels, is associated with pre-therapy values of inflammation and thymic function.
(Elsevier, 2024-12) Garrido-Rodríguez, Vanesa; Bulnes-Ramos, Ángel; Olivas-Martínez, Israel; Pozo-Balado, María Del Mar; Álvarez-Ríos, Ana Isabel; Gutiérrez, Félix; Izquierdo Miguel, Rebeca; García, Federico; Tiraboschi, Juan Manuel; Vera-Méndez, Francisco; Peraire, Joaquim; Rull, Anna; Pacheco, Yolanda María; CoRIS Cohort; Instituto de Salud Carlos III; Ministerio de Ciencia, Innovación y Universidades (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Regional Government of Andalusia (España); Centro de Investigación Biomédica en Red - CIBERBBN (Bioingeniería, Biomateriales y Nanomedicina); Ministerio de Ciencia e Innovación (España); Unión Europea. Comisión Europea. NextGenerationEU; Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas)
Background: Persistence of a low CD4/CD8 ratio is associated with an increased morbimortality in people living with HIV (PLWH) under effective antiretroviral therapy. We aimed to explore the immunological significance of a persistently low CD4/CD8 ratio, even despite normal CD4 levels, and assess whether these features vary from those associated to a low nadir-CD4, another well-established predictor of disease progression. Methods: CD4-recovered PLWH were classified by CD4/CD8 ratio after three-years of ART (viral suppression, CD4≥500; R < 0.8, n = 24 and R > 1.2, n = 28). sj/β-TRECs ratio and inflammatory-related markers were quantified. PBMCs were immunophenotyped by CyTOF and functionally characterized by ELISPOT. Subjects were also reclassified depending on nadir-CD4 (N ≤ 350/N > 350). Results: R < 0.8 showed a differential inflammatory profile compared to R > 1.2 (increased β2-microglobulin, D-dimers and IP-10 before ART). R < 0.8 presented lower baseline thymic function, being inversely correlated with post-ART inflammation. R < 0.8 at follow-up showed most alterations in CD8 subsets (increasing frequency and exhibiting a senescent phenotype [e.g., CD57+, CD95+]) and enhanced T-cell IFNγ/IL-2 secretion. However, comparing N ≤ 350 to N > 350, the main features were altered functional markers in CD4 T-cells, despite no differences in maturational subsets, together with a restricted T-cell cytokine secretion pattern. Conclusion: Persistence of low CD4/CD8 ratio in successfully-treated PLWH, with normal CD4 counts, is associated with baseline inflammation and low thymic function, and it features post-therapy alterations specific to CD8 T-cells. Differently, subjects recovered from low nadir-CD4 in this setting feature post-therapy alterations on CD4 T-cells. Hence, different mechanisms of disease progression could underlie these biomarkers, potentially requiring different clinical approaches.
Physician-perceived utility of the EORTC QLQ-GINET21 questionnaire in the treatment of patients with gastrointestinal neuroendocrine tumours: a multicentre, cross-sectional survey (QUALINETS)
(BioMed Central (BMC), 2021-01-30) Benavent, Marta; Sastre, Javier; García Escobar, Ignacio; Segura, Angel; Capdevila, Jaume; Carmona, Alberto; Sevilla, Isabel; Alonso, Teresa; Crespo, Guillermo; García, Lourdes; Canal, Neus; de la Cruz, Guillermo; Gallego, Javier
Background and objective: Patient-reported outcome measures can provide clinicians with valuable information to improve doctor-patient communication and inform clinical decision-making. The aim of this study was to evaluate the physician-perceived utility of the QLQ-GINET21 in routine clinical practice in patients with gastrointestinal neuroendocrine tumours (GI-NETs). Secondary aims were to explore the patient, clinician, and/or centre-related variables potentially associated with perceived clinical utility. Methods: Non-interventional, cross-sectional, multicentre study conducted at 34 hospitals in Spain and Portugal (NCT02853422). Patients diagnosed with GI-NETs completed two health-related quality of life (HRQoL) questionnaires (QLQ-C30, QLQ-GINET21) during a single routine visit. Physicians completed a 14-item ad hoc survey to rate the clinical utility of QLQ-GINET21 on three dimensions: 1)therapeutic and clinical decision-making, 2)doctor-patient communication, 3)questionnaire characteristics. Results: A total of 199 patients at 34 centres were enrolled by 36 participating clinicians. The highest rated dimension on the QLQ-GINET21 was questionnaire characteristics (86.9% of responses indicating "high utility"), followed by doctor-patient communication (74.4%), and therapeutic and clinical decision-making (65.8%). One physician-related variable (GI-NET patient volume > 30 patients/year) was associated with high clinical utility and two variables (older age/less experience treating GI-NETs) with low clinical utility. Conclusions: Clinician-perceived clinical utility of QLQ-GINET21 is high. Clinicians valued the instruments' capacity to provide a better understanding of patient perspectives and to identify the factors that had the largest influence on patient HRQoL.
COVID-19 Disease Map, building a computational repository of SARS-CoV-2 virus-host interaction mechanisms.
(2020-05-05) Ostaszewski, Marek; Mazein, Alexander; Gillespie, Marc E; Kuperstein, Inna; Niarakis, Anna; Hermjakob, Henning; Pico, Alexander R; Willighagen, Egon L; Evelo, Chris T; Hasenauer, Jan; Schreiber, Falk; Dräger, Andreas; Demir, Emek; Wolkenhauer, Olaf; Furlong, Laura I; Barillot, Emmanuel; Dopazo, Joaquin; Orta-Resendiz, Aurelio; Messina, Francesco; Valencia, Alfonso; Funahashi, Akira; Kitano, Hiroaki; Auffray, Charles; Balling, Rudi; Schneider, Reinhard; Ostaszewski, Marek; Mazein, Alexander; Gillespie, Marc E; Kuperstein, Inna; Niarakis, Anna; Hermjakob, Henning; Pico, Alexander R; Willighagen, Egon L; Evelo, Chris T; Hasenauer, Jan; Schreiber, Falk; Dräger, Andreas; Demir, Emek; Wolkenhauer, Olaf; Furlong, Laura I; Barillot, Emmanuel; Dopazo, Joaquin; Orta-Resendiz, Aurelio; Messina, Francesco; Valencia, Alfonso; Funahashi, Akira; Kitano, Hiroaki; Auffray, Charles; Balling, Rudi; Schneider, Reinhard
Researchers around the world join forces to reconstruct the molecular processes of the virus-host interactions aiming to combat the cause of the ongoing pandemic.
Clinical performance evaluation of the Idylla™ EGFR Mutation Test on formalin-fixed paraffin-embedded tissue of non-small cell lung cancer
(2020-04-03) Delgado-García, Mercedes; Weynand, Birgit; Gómez-Izquierdo, Lourdes; Hernández, María José; Blanco, Ángela María; Varela, Mar; Matias-Guiu, Xavier; Nadal, Ernest; Márquez-Lobo, Bélgica; Alarcão, Ana; de Álava, Enrique; Biscuola, Michele
Background: Detection of epidermal growth factor receptor (EGFR) mutations in exons 18-21 is recommended in all patients with advanced Non-small-cell lung carcinoma due to the demonstrated efficiency of the standard therapy with tyrosine kinase inhibitors in EGFR-mutated patients. Therefore, choosing a suitable technique to test EGFR mutational status is crucial to warrant a valid result in a short turnaround time using the lowest possible amount of tissue material. The Idylla™ EGFR Mutation Test is a simple, fast and reliable method designed for the detection of EGFR mutations from formalin-fixed paraffin-embedded samples. The aim of this study was the Clinical Performace Evaluation of the Idylla™ EGFR Mutation Test on the Idylla™ System. Methods: EGFR mutational status was determined on 132 archived formalin-fixed paraffin-embedded tissue sections with Idylla™ technology. Results were compared with the results previously obtained by routine method in the reference lab (Therascreen® EGFR RGQ PCR v2, Qiagen in Molecular Pathology lab, Hospital Universitario Virgen del Rocío de Sevilla). Results: The overall agreement between results obtained with the Idylla™ EGFR Mutation Test and the Comparator test method was 95.38% (with 1-sided 95% lower limit of 91.7%) showing Positive Diagnostic Agreement of 93.22% and Negative Diagnostic Agreement of 97.18%, with a Limit Of Detection ≤5%. Conclusions: The Idylla™ EGFR Mutation Test passed its clinical validity performance characteristics for accuracy.
Expression and Functionality Study of 9 Toll-Like Receptors in 33 Drug-Naïve Non-Affective First Episode Psychosis Individuals: A 3-Month Study
(2020-08-25) Juncal-Ruiz, Maria; Riesco-Davila, Laura; Vazquez-Bourgon, Javier; Ortiz-Garcia de la Foz, Victor; Mayoral-Van Son, Jacqueline; Ayesa-Arriola, Rosa; Setien-Suero, Esther; Leza, Juan Carlos; Lopez-Hoyos, Marcos; Crespo-Facorro, Benedicto
Toll-like receptors (TLRs) are a pivotal component of the innate immune system that seem to have a role in the pathogenesis of psychosis. The purpose of this work was to compare the expression and functionality of 9 TLRs in three peripheral blood mononuclear cells (PBMCs) (monocytes, B cells, and T cells) between 33 drug-naïve first-episode psychosis (FEP) individuals and 26 healthy volunteers, at baseline and after 3-month of antipsychotic treatment. The expression of TLRs 1-9 were assessed by flow cytometry. For the assessment of the TLR functionality, cells collected in sodium heparin tubes were polyclonally stimulated for 18 h, with different agonists for human TLR1-9. The results of our study highlight the role that TLR5 and TLR8 might play in the pathophysiology of psychosis. We found a lower expression of these receptors in FEP individuals, regarding healthy volunteers at baseline and after 3-month of treatment on the three PBMCs subsets. Most TLRs showed a lower functionality (especially reduced intracellular levels of TNF-α) in patients than in healthy volunteers. These results, together with previous evidence, suggest that individuals with psychosis might show a pattern of TLR expression that differs from that of healthy volunteers, which could vary according to the intensity of immune/inflammatory response.
TRPC Channels: Dysregulation and Ca2+ Mishandling in Ischemic Heart Disease.
(2020-01-10) Falcón, Débora; Galeano-Otero, Isabel; Martín-Bórnez, Marta; Fernández-Velasco, María; Gallardo-Castillo, Isabel; Rosado, Juan A; Ordóñez, Antonio; Smani, Tarik
Transient receptor potential canonical (TRPC) channels are ubiquitously expressed in excitable and non-excitable cardiac cells where they sense and respond to a wide variety of physical and chemical stimuli. As other TRP channels, TRPC channels may form homo or heterotetrameric ion channels, and they can associate with other membrane receptors and ion channels to regulate intracellular calcium concentration. Dysfunctions of TRPC channels are involved in many types of cardiovascular diseases. Significant increase in the expression of different TRPC isoforms was observed in different animal models of heart infarcts and in vitro experimental models of ischemia and reperfusion. TRPC channel-mediated increase of the intracellular Ca2+ concentration seems to be required for the activation of the signaling pathway that plays minor roles in the healthy heart, but they are more relevant for cardiac responses to ischemia, such as the activation of different factors of transcription and cardiac hypertrophy, fibrosis, and angiogenesis. In this review, we highlight the current knowledge regarding TRPC implication in different cellular processes related to ischemia and reperfusion and to heart infarction.
Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain.
(2020-05-11) Gonzalez-Quereda, Lidia; Rodriguez, Maria Jose; Diaz-Manera, Jordi; Alonso-Perez, Jorge; Gallardo, Eduard; Nascimento, Andres; Ortez, Carlos; Natera-de Benito, Daniel; Olive, Montse; Gonzalez-Mera, Laura; Munain, Adolfo Lopez de; Zulaica, Miren; Poza, Juan Jose; Jerico, Ivonne; Torne, Laura; Riera, Pau; Milisenda, Jose; Sanchez, Aurora; Garrabou, Gloria; Llano, Isabel; Madruga-Garrido, Marcos; Gallano, Pia
The term neuromuscular disorder (NMD) includes many genetic and acquired diseases and differential diagnosis can be challenging. Next-generation sequencing (NGS) is especially useful in this setting given the large number of possible candidate genes, the clinical, pathological, and genetic heterogeneity, the absence of an established genotype-phenotype correlation, and the exceptionally large size of some causative genes such as TTN, NEB and RYR1. We evaluated the diagnostic value of a custom targeted next-generation sequencing gene panel to study the mutational spectrum of a subset of NMD patients in Spain. In an NMD cohort of 207 patients with congenital myopathies, distal myopathies, congenital and adult-onset muscular dystrophies, and congenital myasthenic syndromes, we detected causative mutations in 102 patients (49.3%), involving 42 NMD-related genes. The most common causative genes, TTN and RYR1, accounted for almost 30% of cases. Thirty-two of the 207 patients (15.4%) carried variants of uncertain significance or had an unidentified second mutation to explain the genetic cause of the disease. In the remaining 73 patients (35.3%), no candidate variant was identified. In combination with patients' clinical and myopathological data, the custom gene panel designed in our lab proved to be a powerful tool to diagnose patients with myopathies, muscular dystrophies and congenital myasthenic syndromes. Targeted NGS approaches enable a rapid and cost-effective analysis of NMD- related genes, offering reliable results in a short time and relegating invasive techniques to a second tier.
TRPC and TRPV Channels' Role in Vascular Remodeling and Disease.
(2020-08-25) Martín-Bórnez, Marta; Galeano-Otero, Isabel; Del Toro, Raquel; Smani, Tarik; Martín-Bórnez, Marta; Galeano-Otero, Isabel; Del Toro, Raquel; Smani, Tarik
Transient receptor potentials (TRPs) are non-selective cation channels that are widely expressed in vascular beds. They contribute to the Ca2+ influx evoked by a wide spectrum of chemical and physical stimuli, both in endothelial and vascular smooth muscle cells. Within the superfamily of TRP channels, different isoforms of TRPC (canonical) and TRPV (vanilloid) have emerged as important regulators of vascular tone and blood flow pressure. Additionally, several lines of evidence derived from animal models, and even from human subjects, highlighted the role of TRPC and TRPV in vascular remodeling and disease. Dysregulation in the function and/or expression of TRPC and TRPV isoforms likely regulates vascular smooth muscle cells switching from a contractile to a synthetic phenotype. This process contributes to the development and progression of vascular disorders, such as systemic and pulmonary arterial hypertension, atherosclerosis and restenosis. In this review, we provide an overview of the current knowledge on the implication of TRPC and TRPV in the physiological and pathological processes of some frequent vascular diseases.
Electrical Modeling of the Growth and Differentiation of Skeletal Myoblasts Cell Cultures for Tissue Engineering.
(2020-06-02) Olmo, Alberto; Yuste, Yaiza; Serrano, Juan Alfonso; Maldonado-Jacobi, Andres; Pérez, Pablo; Huertas, Gloria; Pereira, Sheila; Yufera, Alberto; de la Portilla, Fernando
In tissue engineering, of utmost importance is the control of tissue formation, in order to form tissue constructs of clinical relevance. In this work, we present the use of an impedance spectroscopy technique for the real-time measurement of the dielectric properties of skeletal myoblast cell cultures. The processes involved in the growth and differentiation of these cell cultures in skeletal muscle are studied. A circuit based on the oscillation-based test technique was used, avoiding the use of high-performance circuitry or external input signals. The effect of electrical pulse stimulation applied to cell cultures was also studied. The technique proved useful for monitoring in real-time the processes of cell growth and estimating the fill factor of muscular stem cells. Impedance spectroscopy was also useful to study the real-time monitoring of cell differentiation, obtaining different oscillation amplitude levels for differentiated and undifferentiated cell cultures. Finally, an electrical model was implemented to better understand the physical properties of the cell culture and control the tissue formation process.
Immunomodulatory and Antioxidant Properties of Wheat Gluten Protein Hydrolysates in Human Peripheral Blood Mononuclear Cells.
(2020-06-04) Cruz-Chamorro, Ivan; Álvarez-Sánchez, Nuria; Santos-Sánchez, Guillermo; Pedroche, Justo; Fernández-Pachón, María-Soledad; Millán, Francisco; Millán-Linares, María Carmen; Lardone, Patricia Judith; Bejarano, Ignacio; Guerrero, Juan Miguel; Carrillo-Vico, Antonio
Peptides from several plant food proteins not only maintain the nutritional values of the original protein and decrease the environmental impact of animal agriculture, but also exert biological activities with significant health-beneficial effects. Wheat is the most important food grain source in the world. However, negative attention on wheat-based products has arose due to the role of gluten in celiac disease. A controlled enzymatic hydrolysis could reduce the antigenicity of wheat gluten protein hydrolysates (WGPHs). Therefore, the aims of the present study were to evaluate the effects of the in vitro administration of Alcalase-generated WGPHs on the immunological and antioxidant responses of human peripheral blood mononuclear cells (PBMCs) from 39 healthy subjects. WGPH treatment reduced cell proliferation and the production of the Type 1 T helper (Th1) and Th17 pro-inflammatory cytokines IFN-? and IL-17, respectively. WPGHs also improved the cellular anti-inflammatory microenvironment, increasing Th2/Th1 and Th2/Th17 balances. Additionally, WGPHs improved global antioxidant capacity, increased levels of the reduced form of glutathione and reduced nitric oxide production. These findings, not previously reported, highlight the beneficial capacity of these vegetable protein hydrolysates, which might represent an effective alternative in functional food generation.
Association of PET-based stages of amyloid deposition with neuropathological markers of A? pathology.
(2020-11-02) Teipel, Stefan J; Temp, Anna G M; Levin, Fedor; Dyrba, Martin; Grothe, Michel J; Alzheimer's Disease Neuroimaging Initiative
Objective: To determine if PET-based stages of regional amyloid deposition are associated with neuropathological phases of Aβ pathology. Methods: We applied data-driven regional frequency-based and a-priori striatum-based PET staging approaches to ante-mortem 18F-Florbetapir-PET scans of 30 cases from the Alzheimer's Disease Neuroimaging Initiative autopsy cohort, and used Bayesian regression analysis to study the associations of these in vivo amyloid stages with neuropathological Thal phases of regional Aβ plaque distribution and with semi-quantitative ratings of neocortical and striatal plaque densities. Results: Bayesian regression revealed extreme evidence for an association of both PET-based staging approaches with Thal phases, and these associations were about 44 times more likely for frequency-based stages and 89 times more likely for striatum-based stages than for global cortical 18F-Florbetapir-PET signal. Early (i.e., neocortical-only) PET-based amyloid stages also predicted the absence of striatal/diencephalic cored plaques. Receiver operating characteristics curves revealed highly accurate discrimination between low/high Thal phases and the presence/absence of regional plaques. The median areas under the curve were 0.99 for frequency-based staging (95% credibility interval 0.97-1.00), 0.93 for striatum-based staging (0.83-1.00), and 0.87 for global 18F-Florbetapir-PET signal (0.72-0.98). Interpretation: Our data indicate that both regional frequency- and striatum-based amyloid-PET staging approaches were superior to standard global amyloid-PET signal for differentiating between low and high degrees of regional amyloid pathology spread. Despite this, we found no evidence for the ability of either staging scheme to differentiate between low and moderate degrees of amyloid pathology which may be particularly relevant for early, preclinical stages of Alzheimer's disease.
Microglia: Agents of the CNS Pro-Inflammatory Response.
(2020-07-17) Rodríguez-Gómez, José A; Kavanagh, Edel; Engskog-Vlachos, Pinelopi; Engskog, Mikael K R; Herrera, Antonio J; Espinosa-Oliva, Ana M; Joseph, Bertrand; Hajji, Nabil; Venero, José Luis; Burguillos, Miguel A
The pro-inflammatory immune response driven by microglia is a key contributor to the pathogenesis of several neurodegenerative diseases. Though the research of microglia spans over a century, the last two decades have increased our understanding exponentially. Here, we discuss the phenotypic transformation from homeostatic microglia towards reactive microglia, initiated by specific ligand binding to pattern recognition receptors including toll-like receptor-4 (TLR4) or triggering receptors expressed on myeloid cells-2 (TREM2), as well as pro-inflammatory signaling pathways triggered such as the caspase-mediated immune response. Additionally, new research disciplines such as epigenetics and immunometabolism have provided us with a more holistic view of how changes in DNA methylation, microRNAs, and the metabolome may influence the pro-inflammatory response. This review aimed to discuss our current knowledge of pro-inflammatory microglia from different angles, including recent research highlights such as the role of exosomes in spreading neuroinflammation and emerging techniques in microglia research including positron emission tomography (PET) scanning and the use of human microglia generated from induced pluripotent stem cells (iPSCs). Finally, we also discuss current thoughts on the impact of pro-inflammatory microglia in neurodegenerative diseases.
Role of Mitochondria in Cancer Stem Cell Resistance.
(2020-07-15) García-Heredia, José Manuel; Carnero, Amancio
Cancer stem cells (CSC) are associated with the mechanisms of chemoresistance to different cytotoxic drugs or radiotherapy, as well as with tumor relapse and a poor prognosis. Various studies have shown that mitochondria play a central role in these processes because of the ability of this organelle to modify cell metabolism, allowing survival and avoiding apoptosis clearance of cancer cells. Thus, the whole mitochondrial cycle, from its biogenesis to its death, either by mitophagy or by apoptosis, can be targeted by different drugs to reduce mitochondrial fitness, allowing for a restored or increased sensitivity to chemotherapeutic drugs. Once mitochondrial misbalance is induced by a specific drug in any of the processes of mitochondrial metabolism, two elements are commonly boosted: an increment in reactive nitrogen/oxygen species and, subsequently, activation of the intrinsic apoptotic pathway.
Targeting Cancer Stem Cells to Overcome Therapy Resistance in Ovarian Cancer.
(2020-06-04) Muñoz-Galván, Sandra; Carnero, Amancio
Ovarian cancer is the most lethal gynecological malignancy due to its late detection and high recurrence rate. Resistance to conventional platinum-based therapies and metastasis are attributed to a population of cells within tumors called cancer stem cells, which possess stem-like features and are able to recapitulate new tumors. Recent studies have deepened the understanding of the biology of ovarian cancer stem cells and their special properties and have identified multiple markers and signaling pathways responsible for their self-renewal abilities. Targeting cancer stem cells represents the most promising strategy for overcoming therapy resistance and reducing mortality in ovarian cancer, but further efforts must be made to improve our understanding of the mechanisms involved in therapy resistance. In this review, we summarize our current knowledge about ovarian cancer stem cells, their involvement in metastasis and their interactions with the tumor microenvironment; we also discuss the therapeutic approaches that are being developed to target them to prevent tumor relapse.

Browse

Recent Submissions