Artículos (Instituto de Biomedicina de Sevilla (IBIS))

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Circulating miRNA Signatures Associated with Atherosclerosis and Cardiometabolic Comorbidities in People with HIV
(MDPI, 2026-02-12) Martinez-Velasco, Marina; Sánchez-Herrero, José Francisco; Ibañez, Laura; Muñoz-López, Francisco Manuel; Cairó, Mireia; López Cortés, Luis Fernando; Dalmau, David; HUMT and CoRIS Cohorts; Medicina; Instituto de Biomedicina de Sevilla (IBIS)
Background: People with HIV (PWH) experience increased cardiovascular disease driven by chronic inflammation despite suppressive antiretroviral therapy. Circulating microRNAs (miRNAs) have emerged as potential biomarkers of cardiometabolic dysfunction, yet their relevance to HIV-associated atherosclerosis remains unclear. Methods: We analyzed PWH PBMC-derived miRNAs in two independent cohorts: the HUMT cohort (N = 185), characterized by carotid ultrasound assessment of atheroma plaque and carotid intima-media thickness (cIMT), and the CoRIS cohort (N = 119), stratified by cardiometabolic comorbidity burden (≥3 comorbidities vs none). An exploratory miRNA microarray comparing individuals with and without atheroma plaque (AP+ vs. AP-, N = 72) identified candidate miRNAs, a subset of which was selected for validation by RT-qPCR. Associations with atherosclerosis, cardiometabolic comorbidities and the HIV-adapted COMVIH-CoR clinical cardiovascular risk score were examined. Results: Forty-four miRNAs were differentially expressed in AP+ vs. AP- in the microarray. RT-qPCR validation showed sex-specific miRNA association with miR-638 was consistently downregulated in AP+ and pathological cIMT among men, while reduced expression of miR-27b-5p and miR-3613-5p was observed in women. Associations between miRNAs and cardiometabolic comorbidities differed by cohort: in HUMT, miR-638 was reduced in diabetes and obesity, while miR-140-5p and miR-27b-5p were decreased in smokers and individuals with low HDL. CoRIS participants with multiple comorbidities showed a generalized miRNAs upregulation. Notably, miR-140-5p was consistently elevated in individuals with high COMVIH-CoR scores across both cohorts. Conclusions: PBMC-derived miRNAs capture heterogeneous, context-dependent dimensions of cardiovascular risk in PWH, likely reflecting cumulative immune-metabolic stress rather than universal diagnostic markers of subclinical atherosclerosis and supporting a phenotype-specific role.
Genetic variation in the TLL1 gene is not associated with fibrosis in patients with metabolic associated fatty liver disease
(Public Library of Science (PLoS), 2020-12-11) Bayoumi, Ali; Jalil, Ismail; Metwally, Mayada; Adams, Leon A.; Aller, Rocío; García-Monzón, Carmelo; Gallego Durán, Rocío; Romero Gómez, Manuel; Eslam, Mohammed; Medicina; Instituto de Biomedicina de Sevilla (IBIS)
Metabolic associated fatty liver disease (MAFLD) is the most prevalent liver disease in Western nations, with high heritability. A recent study of Japanese patients with the disease suggested that TLL1 rs17047200 is associated with fibrosis; whether a similar association is observed in Caucasian patients with MAFLD is unknown. We investigated the association of the TLL1 rs17047200 polymorphism with liver fibrosis in a cohort of Caucasian patients with MAFLD (n = 728). We also investigated whether TLL1 expression is altered during liver injury in humans, in murine models of fibrosis, and in in-vitro. While TLL1 expression is upregulated in the liver of humans with MAFLD and in mice, the rs17047200 variant was not associated with fibrosis or any other histological features, or with hepatic TLL1 expression. In conclusion, the TLL1 rs17047200 variant is not a risk variant for fibrosis in Caucasian patients with MAFLD. However, TLL1 could be involved in the pathogenesis of liver fibrosis.
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.
High 4E-BP1 expression associates with chromosome 8 gain and CDK4/6 sensitivity in Ewing sarcoma
(Amer soc clinical investigation inc, 2025-10-16) Funk, Cornelius M.; Ehlers, Anna C.; Orth, Martin F.; Aljakouch, Karim; Li, Jing; Hölting, Tilman Lb; Romero Pérez, Laura; Musa, Julian; Anatomía y Embriología Humana; Instituto de Biomedicina de Sevilla (IBIS); Asociación Candela Riera al laboratorio de JA; Asociación Todos somos Ivn al laboratorio de JA; Subvenciones de la Ayuda Alemana contra el Cáncer; Beca de ayuda alemana contra el cánce; Beca de la Fundación Heinrich F.C. Behr; Instituto de Salud Carlos III; CTS1035: Patología Molecular del Cáncer Sólido
Chromosome 8 (chr8) gains are common in cancer, but their contribution to tumor heterogeneity is largely unexplored. Ewing sarcoma (EwS) is defined by FET::ETS fusions with few other recurrent mutations to explain clinical diversity. In EwS, chr8 gains are the second most frequent alteration, making it an ideal model to study the relevance of chr8 gains in an otherwise silent genomic context. We report that chr8 gain-driven expression patterns correlate with poor overall survival of patients with EwS. This effect is mainly mediated by increased expression of the translation initiation factor binding protein 4E-BP1, encoded by EIF4EBP1 on chr8. Among all chr8-encoded genes, EIF4EBP1 expression showed the strongest association with poor survival and correlated with chr8 gains in EwS tumors. Similar findings emerged across multiple cancer entities in The Cancer Genome Atlas. Multiomics profiling revealed that 4E-BP1 orchestrates a pro-proliferative proteomic network. Silencing 4E-BP1 reduced proliferation, clonogenicity, spheroidal growth in vitro, and tumor growth in vivo. Drug screens demonstrated that high 4E-BP1 expression sensitizes EwS to pharmacological CDK4/6-inhibition. Chr8 gains and elevated 4E-BP1 emerge as prognostic biomarkers in EwS, with poor outcomes driven by 4E-BP1-mediated pro-proliferative networks that sensitize tumors to CDK4/6 inhibitors. Testing for chr8 gains may enhance risk stratification and therapy in EwS and other cancers.
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
Unveiling balanced prenatal microbial colonization in amniotic fluid through an integrated culture and sequencing approach
(Springer Nature, 2026-01-09) González Rovira, María; Sáinz Bueno, José Antonio; García Díaz, Lutgardo; Martínez-Pancorbo, C.; Sánchez, J.; Gutiérrez Pozo, Gabriel; Magoutas, K.; Mesías-Pérez, A.; Mellado Durán, María Encarnación; Payne, M.; Sousa Martín, Carolina; Moreno Amador, María de Lourdes; Microbiología y Parasitología; Cirugía; Genética; Ministerio de Ciencia, Innovación y Universidades (MICIU). España; Federación de Asociaciones de Celíacos de España (FACE); Universidad de Sevilla
Background The evidence of a low-biomass microbial community in the amniotic fluid (AF) is challenging the traditional concept of a sterile womb. To clarify microbial presence and host responses, a comprehensive, multi-methodological approach is required. Methods We designed an optimized culturing strategy that maximized microorganism recovery by implementing differential centrifugation and concentration of AF samples, followed by plating onto four distinct selective media types and incubation under both stringent aerobic (up to two weeks) and prolonged anaerobic (up to four weeks) conditions, including an initial pre-enrichment step in Brain Heart Infusion (BHI) broth for low-abundance organisms. These results were combined with PacBio 16S rRNA gene sequencing, Illumina shotgun metagenomics, and antimicrobial peptides (AMP) detection. Using this approach, we characterized microbial presence in 154 AF samples across gestational stages. Data normality was assessed with the Shapiro-Wilk test, guiding the selection of both parametric and non-parametric tests, and a p-value of < 0.05 was considered statistically significant. Results We detected culturable microorganisms in 33.1% of samples, with a higher proportion in elective caesarean Sect. (55.0%) compared to amniocentesis (29.5%), suggesting increased microbial load toward term. We applied stringent contamination controls, and repeatedly recovered viable microorganisms Bacillus, Cutibacterium, Micrococcus, and Staphylococcus, with Cutibacterium acnes and Staphylococcus epidermidis common. Both sequencing methods revealed a low-biomass, low-diversity microbial community with high inter-individual variability. Notably, striking microbial discordance in diamniotic twin pregnancies, challenged intrauterine homogeneity. Higher Human Beta Defensin (HBD) -1 levels correlated with absence of culturable bacteria or microbial DNA, while levels of HBD-1, HBD-3, and LL-37 were reduced in Staphylococcus-positive samples, suggesting a dynamic interplay between specific bacteria and host defences. Conclusions Our findings indicate that viable bacteria and/or DNA can transiently access the prenatal environment microbial balance. We propose a novel perspective of a potential regulatory axis between microorganisms and AMP.
WGS characterization of MDR Enterobacterales with different ceftolozane/tazobactam susceptibility profiles during the SUPERIOR surveillance study in Spain
(Oxford University Press, 2020-10-22) Hernández García, Marta; García Fernández, Sergio; García-Castillo, M.; Bou, Germán; Cercenado, Emilia; Delgado Valverde, María Mercedes; Mulet, Xavier; Pitart, Cristina; Rodríguez-Lozano, Jesús; Cantón, Rafael; Microbiología; Instituto de Salud Carlos III; Ministerio de Economía y Competitividad (MINECO). España; European Union (UE)
Objectives: To analyse by WGS the ceftolozane/tazobactam (C/T) resistance mechanisms in Escherichia coli and Klebsiella spp. isolates recovered from complicated intra-abdominal and urinary tract infections in patients from Spanish ICUs (SUPERIOR surveillance study, 2016–17). Methods: The clonal relatedness, the resistome and the virulome of 45 E. coli and 43 Klebsiella spp. isolates with different C/T susceptibility profiles were characterized. Results: In E. coli, two (C/T susceptible) carbapenemase producers (VIM-2-CC23, OXA-48-ST38) were detected. The most relevant clone was ST131-B2-O25:H4-H30 (17/45), particularly the CTX-M-15-ST131-H30-Rx sublineage (15/17). ST131 strains were mainly C/T susceptible (15/17) and showed an extensive virulome. In non-ST131 strains (28/45), CTX-M enzymes [CTX-M-14 (8/24); CTX-M-15 (6/24); CTX-M-1 (3/24); CTX-M-32 (2/24)] were found in different clones. C/T resistance was detected in non-clonal E. coli isolates (13%, 6/45) with ESBL (4/6) and non-ESBL (2/6) genotypes. Among Klebsiella spp., Klebsiella pneumoniae (42/43) and Klebsiella michiganensis (1/43) species were identified; 42% (18/43) were carbapenemase producers and 58% showed a C/T resistance phenotype (25/43). OXA-48-ST11 (12/18), OXA-48-ST392 (2/18), OXA-48-ST15 (2/18), NDM-1-ST101 (1/18) and OXA-48!VIM-2-ST15 (1/18) isolates were found, all C/T resistant. Correlation between carbapenemase detection and resistance to C/T was demonstrated (P , 0.001). In non-carbapenemase-producing K. pneumoniae (25/43), C/T resistance (28%, 7/25) was detected in ESBL (3/7) and AmpC (2/7) producers. Overall, an extensive virulome was found and was correlated with carbapenemase carriage (P , 0.001) and C/T resistance (P , 0.05), particularly in OXA-48-ST11 strains (P , 0.05). Conclusions: Prediction of antimicrobial susceptibility profiles using WGS is challenging. Carbapenemaseencoding genes are associated with C/T resistance in K. pneumoniae, but other resistance mechanisms might be additionally involved.
Infecciones en pacientes colonizados con bacterias gramnegativas resistentes a carbapenémicos en una ciudad media española
(Sociedad española de quimioterapia, 2021-06-08) Soria Segarra, Carmen; Delgado Valverde, María Mercedes; Serrano García, María Luisa; López Hernández, Inmaculada; Navarro Marí, José María; Gutiérrez-Fernández, José; Microbiología
Objetivo. Debido a que existen pocos estudios sobre las implicaciones clínicas de la colonización por bacterias gramnegativas resistentes a carbapenémicos (BRC) se analizó ésta en frotis rectales (FR) y faríngeos (FF) y su relación con la capacidad de predecir infección/colonización. Material y métodos. Se realizó un estudio transversal, retrospectivo de los pacientes adultos hospitalizados entre enero del 2016 y diciembre del 2019. Los aislamientos fueron caracterizados mediante MicroScan y espectrometría de masas, aplicando los puntos de corte EUCAST 2018. La detección de carbapenemasas se realizó mediante PCR y secuenciación Sanger; se asignó el secuenciotipo mediante MLST. La relación genética entre los aislados se hizo mediante electroforesis de campo pulsado usando las enzimas Xbal, Spel o Apal. Resultados. Se detectaron 308 (86,03 %) FR y 50 (13,97%) FF positivos, teniendo el FR una sensibilidad del 85%, especificidad del 100%, VPP 100% y VPN 97%. En los FR se aislaron: 44% (n=135) Acinetobacter baumannii, 26% (n=80) Enterobacterales (20 KPC, 29 OXA-48, 22 VIM, 2 IMP, 7 NDM), 17% (n=53) Pseudomonas aeruginosa y 13% (n=40) Stenotrophomonas maltophilia. En los FF se aislaron un 44% (n=22) S. maltophilia, 40% (n=20) A. baumannii, 8% (n=4) P. aeruginosa y 8% (n=4) Enterobacterales (3 VIM, 1 OXA). De los pacientes con tomas simultáneas de FR y FF, 41 (40,6%) tuvieron positividad en ambos frotis, 45 (44,6%) sólo en FR y 15 (14,9%) sólo en FF. En el 81,3% (n=13) de los episodios la colonización precedió a la infección, existiendo asociación entre infección y colonización (p<0,001;X2) y en todos en los que se conservó la información del pulsotipo los aislados de las muestras clínicas y de los frotis fueron similares. Conclusiones. La probabilidad de predecir la infección a través del colonizado por BRC en diferentes muestras clínicas es factible, teniendo el FR una mayor sensibilidad para detectar colonización.
Histological severity and hepatic outcomes in patients with metabolic dysfunction-associated steatotic liver disease and discrepant FIB-4 and liver stiffness measurement
(Korean Association for the Study of the Liver, 2026) Rabbat, Joseph; Yang, Boyu; Lee, Hye Won; Lin, Huapeng; Tsochatzis, Emmanuel A.; Petta, Salvatore; Gallego Durán, Rocío; Romero Gómez, Manuel; Yip, Terry Cheuk-Fung; Medicina; Instituto de Biomedicina de Sevilla (IBIS)
Background/Aims: Current guidelines recommend a 2-step approach for identifying advanced fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD), using Fibrosis-4 index (FIB-4) followed by liver stiffness measurement (LSM) via vibration-controlled transient elastography (VCTE). However, some patients may exhibit discordant results. This study evaluates the histological severity and outcomes in patients with discordant FIB-4 and LSM results. Methods: This secondary analysis of the VCTE-Prognosis study included 12,950 patients evaluated for MASLD at 16 tertiary centers, of whom 2,915 underwent liver biopsy. Patients were categorized into four groups based on established FIB-4 (1.3) and LSM (8 kPa) cutoffs. Results: F3–F4 fibrosis was observed in 6.4%, 13.7%, 30.6%, and 62.4% in low-FIB-4-low-LSM (n=6,403), high-FIB-4-low-LSM (n=3,017), low-FIB-4-high-LSM (n=1,363), and high-FIB-4-high-LSM (n=2,167) groups, respectively. During a median follow-up of 47.4 months, 248 patients experienced hepatic decompensation, hepatocellular carcinoma, liver transplantation, or liver-related death. The incidence rates of liver-related events (LREs) were 0.67, 1.19, 2.58, and 21.30 per 1,000 person-years, respectively. Compared to low-FIB-4-low-LSM patients, those with low-FIB-4-high-LSM (adjusted subdistribution hazard ratio [aSHR] 4.12) and high-FIB-4-high-LSM (aSHR 21.38) had a significantly higher risk of LREs, while high-FIB-4-low-LSM patients did not. Similar findings were observed when hepatic decompensation and hepatocellular carcinoma were analyzed separately. Conclusions: Approximately 30% of patients in tertiary centers exhibit discordant FIB-4 and LSM results, with LSM more likely reflecting true severity. While some patients with discordant results may have advanced fibrosis, the overall incidence of LREs remains low.
NO-immune privilege for hematopoietic stem cells
(Inst biochemistry & Cell biology; Springer nature, 2025-02-28) Chédeville, Agathe L.; Méndez-Ferrer, Simón; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS); Ministerio de Ciencia, Innovación y Universidades (España)
Evaluation of bone metabolism in children with cystic fibrosis
(Elsevier, 2021-03-16) Mora Vallellano, Josefa; Delgado Pecellín, Carmen; Delgado Pecellín, Isabel; Quintana Gallego, Esther; López-Campos Bodineau, José Luis; Farmacología, Pediatría y Radiología; Medicina; Instituto de Biomedicina de Sevilla (IBIS)
Background Cystic fibrosis (CF) bone disease (CFBD) has attracted considerable recent interest from researchers, although several aspects of CFBD pathophysiology remain poorly understood. The objective of this research was to investigate CFBD in children with CF and its relation to clinical and bone metabolism markers. Methods In a prospective observational study of 68 patients with CF and 63 healthy controls, we studied bone turnover biomarkers and bone mineral density (BMD). The biomarkers included osteocalcin, total-alkaline phosphatase, bone-alkaline phosphatase, N-terminal propeptide of type-1-procollagen, osteoprotegerin (OPG), interleukine-6, tumor necrosis factor alpha (TNF-α), type-1-collagen cross-linked C-telopeptide (CTX), parathormone (PTH), 25-vitamin D, 1,25-vitamin D, calcium and phosphorus. BMD was examined in lumbar spine, comparing two healthy Spanish populations. Two regression analyses were applied to any significant associations to evaluate predictors of BMD and of CF, expressed as odds ratios (OR) with 95% confidence intervals. Results After adjusting for age, sex, and height Z-score, gains in BMD LS in children and adolescents (6–16 years) with CF were not less than in healthy reference population. Patients with CF showed significant associations with different bone turnover biomarkers. Age, gender, body mass index, PTH, CTX and OPG were significant predictors of BMD (R2 = 0.866, p < 0,001). Moreover, we found that PTH (OR = 1.070; 95% CI 1.019–1.123), and TNFα (OR = 2.173; 95% CI 1.514–3.118) were significantly linked to CF, and calcium (OR = 0.115; 95% CI 0.025–0.524), 1,25-vitamin D (OR = 0.979; 95% CI 0.962 0.996) and OPG (OR = 0.189; 95% CI 0.073–0.489) were significant reduced. Conclusion A normal bone mineral density along with altered remodeling was found in CF patients with a normal nutritional status and without acute lung disease.
Ins and outs of HSCs and VEGF-induced vascular remodeling: Toward improved HSC mobilization and engraftment
(Cell press; Elsevier BV, 2025-07-08) Caduc, Madeline J.; Méndez-Ferrer, Simón; Fisiología Médica y Biofísica; Instituto de Biomedicina de Sevilla (IBIS); Servicio Alemán de Intercambio Académico (DAAD); Programa de Becas Mildred Scheel para la Investigación del Cáncer; Plan de Investigación Científica, Técnica y de Innovación, Ministerio de Ciencia, Innovación y Universidades, Gobierno de España
High leptin levels independent of body mass index are associated with inflammation and poorer treatment response in patients with diffuse large B-cell lymphoma
(Elsevier, 2026-02) Hontecillas-Prieto, Lourdes; García-Domínguez, Daniel J.; Jiménez Cortegana, Carlos; Nogales-Fernández, Esteban; Palazón-Carrión, Natalia; García Sancho, Alejandro Martín; Ríos Herranz, Eduardo; Cruz Merino, Luis de la; Sánchez Margalet, Víctor; Instituto de Biomedicina de Sevilla (IBIS); Medicina; Instituto de Biomedicina de Sevilla (IBIS); Clinical Trial Unit, Hospital Universitario Virgen del Rocío, Spanish Clinical Research and Clinical Trial Platform (CTU-HUVR); Biobank Nodo Hospital Virgen Macarena (Biobanco del Sistema Sanitario Público de Andalucía); Spanish National biobanks Networ; Instituto de Salud Carlos III; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); CTS151: Bioquímica Medica
Leptin, a protein hormone secreted mainly by adipocytes, plays a key role in modulating various physiological processes. Dysregulation of this hormone has been linked to numerous diseases, including the immunological system and cancer. In patients with diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma (NHL), elevated levels of leptin appear to contribute to the development and progression of lymphoma by modulating the immune system and creating a proinflammatory environment, where lymphoma patients have a lower survival rate compared to those with normal levels. It therefore appears that leptin plays a role in inflammation, the immune system and the development of lymphoma. However, there is a need to fully understand the mechanisms involved and to develop targeted therapies for lymphoma. Our results show that leptin levels are increased (independently of body mass index) in patients with DLBCL belonging to the R2-GDP-GOTEL phase II clinical trial, and these elevated levels are associated with a worse response to treatment and survival using lenalidomide as immunomodulator. Furthermore, a positive correlation between leptin and the inflammation marker C-reactive protein (CRP) is observed, and a multivariate analysis reveals a correlation between leptin, CRP and Monocytic Myeloid-derived suppressor cells (M-MDSC) levels in patients with worse response to treatment. Taken together, these data indicate that leptin could be a promising and predictive response biomarker of treatment efficacy in patients with lymphoma. Our findings on leptin in patients with R/R DLBCL could also arouse great interest given its potential applications as a target of treatment.
Extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae from human carriage, the human-polluted environment, and food: Molecular epidemiology of two prospective cohorts in five European metropolitan areas
(PLOS, 2026-01) Verschuuren, Tess D.; Guther, Julia; Riccio, Maria Eugenia; Martak, Daniel; Salamanca, Elena; Göpel, Siri; Tacconelli, Evelina; Rodríguez-Baño, Jesús; Kluytmans, Jan A.J.W.; Medicina; Instituto de Biomedicina de Sevilla (IBIS); Netherlands Organization for Health Research and Development (ZonMw); Swiss National Science Foundation (SNFS); German Federal Ministry of Education and Research; French Agence Nationale de la Recherche; UK Medical Research Council; Instituto de Salud Carlos III; Spanish Network for Research in Infectious Diseases; European Development Regional Fund
Objectives: For 475 ESBL-producing Escherichia coli (ESBL-Ec), and 171 ESBL-producing Klebsiella pneumoniae (ESBL-Kp) collected from human carriers, the human-polluted (hp)-environment, and food: (i) to compare the antimicrobial resistance gene (ARG) content, and (ii) to assess clonal relationships between human and non-human isolates. Materials and methods: Two prospective multicenter cohorts were assessed: colonized hospitalized index-subjects and household contacts, and long-term care facility (LTCF) residents. Additionally, linked hp-environment and food samples were collected. Presence of ARGs were assessed using pairwise comparisons and proportional similarity index (PSI). Clonal relationships were assessed using cgMLST distance visualizations and maximum likelihood phylogeny. Results: ESBL-Ec and ESBL-Kp co-occurred in 14/65 households, 3/6 LTCFs, and in 33/202 of ESBL-positive participants. Thirty-nine percent of detected ARG types were found in both species (36/93). Frequencies of beta-lactamase, ESBL, aminoglycoside, and sulfonamide ARG types from human ESBL-Ec and ESBL-Kp overlapped considerably: PSIs 0.59–0.75, and were equal or higher compared to the overlap between ESBL-Ec from humans and food isolates: PSIs 0.33–0.72. Isolates from humans and the hp-environment were frequently clonally related, indicating human contamination of the environment. Links with food isolates were observed less frequently. For ESBL-Ec both interregional and regional clonal dissemination were observed, while for ESBL-Kp clonal dissemination was mainly regional. Conclusions: ESBL-Ec and ESBL-Kp from human carriage showed considerable overlap in ARG content. Furthermore, clonal links were observed frequently between humans and hp-environment, and with lower frequency between humans and food. These findings are consistent with human-to-human transmission as an important driver of ARG spread in humans.
Imipenem-Relebactam Susceptibility in Enterobacterales Isolates Recovered from ICU Patients from Spain and Portugal (SUPERIOR and STEP Studies)
(American Society for Microbiology, 2022-08-22) Hernández-García, Marta; García-Castillo, M.; Bou, Germán; Cercenado, Emilia; Delgado Valverde, María Mercedes; Oliver, Antonio; Pitart, Cristina; Rodríguez-Lozano, Jesús; Tormo, Nuria; Cantón, Rafael; Microbiología; Instituto de Salud Carlos III; Ministerio de Economia, Industria y Competitividad (MINECO). España; European Union (UE)
Imipenem-relebactam is a novel β-lactam-β-lactamase inhibitor combination. We evaluated the in vitro activity of imipenem-relebactam and comparators against Enterobacterales clinical isolates recovered in 8 Spanish and 11 Portuguese intensive care units (ICUs) (SUPERIOR, 2016–2017; STEP, 2017–2018). Overall, 747 Enterobacterales isolates (378 Escherichia coli, 252 Klebsiella spp., 64 Enterobacter spp., and 53 other species) were prospectively collected from ICU patients with complicated intraabdominal (cIAI), complicated urinary tract (cUTI), and lower respiratory tract (LRTI) infections. MICs were determined (ISO-broth microdilution), and whole-genome sequencing (WGS) was performed in a subset of isolates displaying susceptible and resistant imipenem-relebactam MICs. Imipenem-relebactam (98.7% susceptible) showed similar activity to ceftazidime-avibactam (99.5% susceptible) and higher than ceftolozane-tazobactam (86.9% susceptible). Imipenem-relebactam was inactive against 1.3% (10/747) isolates, all of them due to carbapenemase production (9 K. pneumoniae and 1 E. cloacae). Imipenem-relebactam was active against 100% of extended-spectrum β-lactamase (ESBL)-E. coli and ESBL-Klebsiella spp. isolates and 80.4% of carbapenemase-Klebsiella spp. producers. Carbapenemase genes were confirmed by WGS in 41 Klebsiella spp.: OXA-48 (20/41), KPC-3 (14/41), OXA-181 (4/41), NDM-1 (1/41), OXA-48 + VIM-2 (1/41), and KPC-3 + VIM-2 (1/41). In Klebsiella spp. isolates, relebactam restored imipenem susceptibility in all KPC-3 producers, and resistant isolates (7/41) were mostly OXA-48 + CTX-M-15-K. pneumoniae high-risk clones (7/9). Intercountry differences were detected as follows: OXA-48 (17/21) was dominant in Spain, unlike KPC-3 (14/15) in Portugal. Imipenem-relebactam was 100% active against CTX-M-15-ST131-H30Rx-E. coli high-risk clone, predominant in both countries. Our results depict the potential role of imipenem-relebactam in ICU patients with cIAIs, cUTIs, and LRTIs due to wild-type ESBL- and carbapenemase-producing Enterobacterales, particularly KPC producers. IMPORTANCE We comparatively evaluate the in vitro activity of a drug combination consisting of a carbapenem (imipenem) and a novel inhibitor of beta-lactamases (relebactam), a mechanism that destroys beta-lactam antibiotics. We assess the activity against a collection of Enterobacterales clinical isolates recovered from difficult-to-treat infections in patients admitted to different intensive care units in Portugal and Spain. Imipenem-relebactam shows excellent activity in avoiding common resistance mechanisms in this setting, such as extended-spectrum beta-lactamases and carbapenemases widely distributed, including KPCs. We show few resistant isolates (<2%). Molecular characterization by whole-genome sequencing shows that most of the resistant isolates produced specific carbapenemase, such as OXA-48 or metalo-betalactamases. Our study updates the activity of imipenem-relebactam in light of current epidemiology in a hospital setting in which the use of this combination is needed due to the presence of infections due to multidrug-resistant isolates.
Identification of IL-6 Signalling Components as Predictors of Severity and Outcome in COVID-19
(Frontiers Media, 2022-05-13) Rodríguez Hernández, María A.; Carneros, David; Núñez Núñez, María; Coca, Ramón; Baena, Rosario; López Ruiz, Gema M.; Cano Serrano, María Elena; Martínez Tellería, Alberto; Praena Fernández, Juan Manuel; Bustos, Matilde; Biología Celular; Instituto de Salud Carlos III
IL-6 is one of the major mediators of the hyper-inflammatory responses with complex biological functions as it can signal via different modes of action. IL-6 by classical signalling has anti-inflammatory and antibacterial activities, while trans-signalling mediates pro-inflammatory effects. The net biological effect of IL-6 is established by multiple factors beyond its absolute concentration. Here, we assess the relationship between IL-6 signalling variables [IL-6, soluble IL-6R (sIL-6R) and soluble gp130 (sgp130)] and outcomes in a cohort of 366 COVID-19 patients. The potential trans-signalling was evaluated by a ratio between the pro-inflammatory binary IL-6:sIL-6R complex and the inactive ternary IL-6:sIL-6R:sgp130 complex (binary/ternary complex) and the fold molar excess of sgp130 over sIL-6R (FME). Our data provide new evidence that high levels of IL-6, sIL-6R, sgp130, binary/ternary complex ratio, and low FME are independent predictors of COVID-19 severity in survivor patients (without death), and the combination of IL-6 + sIL-6R + sgp130 exhibited the most robust classification capacity. Conversely, in a subgroup of patients with a very poor prognosis, we found that high levels of IL-6 and low levels of sIL-6R, sgp130, and binary/ternary complex ratio were predictors of death. In this context, the highest predictive capacity corresponded to the combined analysis of IL-6 + FME + lymphopenia + creatinine. Herein, we present IL-6 signalling variables as a helpful tool for the early identification and stratification of patients with clear implications for treatment and clinical decision-making.
Cis- and Trans-Regulatory Mechanisms of Gene Expression in the ASJ Sensory Neuron of Caenorhabditis elegans
(Oxford University Press, 2015-05-01) González-Barrios, María; Fierro-González, Juan Carlos; Krpelanova, Eva; Mora Lorca, José Antonio; Rafael Pedrajas, José; Peñate Salas, Xenia; Chávez de Diego, Sebastián; Swoboda, Peter; Jansen, Gert; Miranda-Vizuete, Antonio; Genética; Farmacología; Japanese Ministry of Education, Culture, Sport, Science and Technology; Junta de Andalucía
The identity of a given cell type is determined by the expression of a set of genes sharing common cis-regulatory motifs and being regulated by shared transcription factors. Here, we identify cis and trans regulatory elements that drive gene expression in the bilateral sensory neuron ASJ, located in the head of the nematode Caenorhabditis elegans. For this purpose, we have dissected the promoters of the only two genes so far reported to be exclusively expressed in ASJ, trx-1 and ssu-1. We hereby identify the ASJ motif, a functional cis-regulatory bipartite promoter region composed of two individual 6 bp elements separated by a 3 bp linker. The first element is a 6 bp CG-rich sequence that presumably binds the Sp family member zinc-finger transcription factor SPTF-1. Interestingly, within the C. elegans nervous system SPTF-1 is also found to be expressed only in ASJ neurons where it regulates expression of other genes in these neurons and ASJ cell fate. The second element of the bipartite motif is a 6 bp AT-rich sequence that is predicted to potentially bind a transcription factor of the homeobox family. Together, our findings identify a specific promoter signature and SPTF-1 as a transcription factor that functions as a terminal selector gene to regulate gene expression in C. elegans ASJ sensory neurons.
Human iPSC-derived APOE4/4 Alzheimer´s disease astrocytes exhibit a senescent and pro-inflammatory state that compromises neuronal support
(BioMed Central, 2025-12-12) Cáceres Palomo, Laura; Sánchez Mejías, Elisabeth; Trujillo Estrada, Laura; Pérez Moreno, Juan José; López Oliva, Elba; Lim, Tau En; DeFlitch, Leah; Vitorica Ferrández, Francisco Javier; García León, Juan Antonio; Gutiérrez, Antonia; Biología Celular; Bioquímica y Biología Molecular; Instituto de Salud Carlos III; European Union (UE)
Alzheimer´s disease (AD) is dominated by a complex cellular pathology which involves most brain cell types with glial cells increasingly recognized as playing fundamental roles in neurodegeneration. Astrocytes, which perform essential functions in preserving brain homeostasis, present a reactive phenotype in the AD brains with still unknown consequences. In this study, we generated and characterized human induced pluripotent stem cell (hiPSC)-derived astrocytes from AD patients harboring the APOE4/4 genotype, the greatest genetic risk factor for late-onset AD. Disease astrocytes showed a reactive phenotype. In addition, they showed altered mitochondrial network including perinuclear clustering of mitochondria, enhanced mitochondrial fusion and higher production of reactive oxygen species which, unexpectedly, were coincident with increased oxidative phosphorylation and glycolysis. As these mitochondrial features are related to the acquisition of cell senescence, we evaluated this at the transcriptome level and found that these AD-derived astrocytes significantly upregulated gene signatures of cellular senescence and displayed a senescence-associated secretory phenotype (SASP). To verify this finding, we observed senescence-related DNA damage response in a significant proportion of cells in the cerebral cortex of AD patients, with most of these cells being astrocytes. Finally, we confirmed that this astrocytic senescent and proinflammatory phenotype is associated with a reduced neuronal support, evidencing that APOE4/4 AD astrocytes present intrinsic features that may compromise brain homeostasis and promote neurodegeneration. Addressing the causes and consequences of this astrocytic dysfunctionality should help to elucidate novel therapeutic targets able to modify the neurodegeneration present in AD.
Neuroprotection with Bioactive Compounds
(MDPI, 2026-10-30) Río Mercado, Carmen del; Segura Carretero, Antonio; Biología Celular
Phenotype-Specific Mitochondrial Responses to Mediterranean Diet and Exercise in Elderly Obesity
(MDPI, 2026-02-01) Carrillo-Fernández, Paloma; Silva-Soto, María Ángeles; Gallego Durán, Rocío; Medina-Jiménez, Elena; Vilches-Pérez, Alberto; Mogaburo-Alba, Juan Francisco; Maya Miles, Douglas; Romero Gómez, Manuel; Bernal-López, María Rosa; Medicina; Fisiología; Instituto de Biomedicina de Sevilla (IBIS); Instituto de Salud Carlos III; Centros de Investigación En Red (CIBER); European Union (UE); Programa “Nicolás Monardes”; Junta de Andalucía; PFIS; European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER); “Acciones Individuales MSCA—Sello de Excelencia ISCIII-HEALTH 2022”; CTS1106: Enfermedades Hepáticas y Digestivas
Background/Objectives: While excessive body fat is commonly linked to metabolic disorders (metabolically unhealthy obesity, MUO), a subset of individuals remain metabolic healthy despite obesity (metabolically healthy obesity, MHO). This work aims to determine how these phenotypes influence responses to lifestyle modification (LSM) in older adults. Methods: A 12-month lifestyle modification (LSM) intervention based on the Mediterranean Diet (MedDiet) and regular physical activity (PA) was conducted in 43 older adults (70% women) classified according to World Health Organization (WHO) criteria as MHO (22 subjects) or MUO (21 subjects). Clinical, dietary, and PA parameters were assessed at baseline and follow-up. Peripheral blood mononuclear cells were analyzed for mitochondrial fusion (OPA1, MFN2), mitophagy (PINK1), biogenesis (TFAM), and the respiratory chain (COX IV) using Western blot and RT-qPCR techniques. Results: At baseline, MUO showed significant lower OPA1-L, MFN2, and TFAM along with MFN2 degradation products and PINK1 accumulation. After 12 months of LSM, MUO participants exhibited greater metabolic profile improvements, such as significantly reduced MFN2 degradation products and higher COX IV. Changes in mitochondrial proteins were associated with nutrient intake and PA and clinical parameters with phenotype-specific patterns. In MUO, protein and cholesterol intake improved MFN2 fusion (rho = 0.446, p = 0.043; rho = 0.581, p = 0.006), while carbohydrates were negatively associated with OPA1 in MHO (rho = −0.596, p = 0.025). PA was positively related to fusion proteins in both phenotypes. Clinically, significant improvements in BMI, waist circumference, and HDL were found in MUO but not in MHO. Conclusions: Older adults with obesity show phenotype-specific mitochondrial impairments that shape distinct responses to LSM, highlighting the relevance of tailoring LSM interventions by metabolic phenotype.

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