SAS - Hospital Universitario Virgen de las Nieves
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Publication Revisión sistemática sobre el uso de peces para el control vectorial de las enfermedades transmitidas por mosquitos(Ministerio de Sanidad y Consumo, 2025-06-05) Tortosa-La Osa, Silvia; Esteo Alcalá, María Victoria; Martín-Ruiz, Eva; Olry de Labry-Lima, Antonio; [Martín-Ruiz,E] Departamento de Enfermería; Facultad de Enfermería, Fisioterapia y Podología; Universidad de Sevilla. Sevilla. España.; [Martín-Ruiz,E] Escuela Andaluza de Salud Pública. Granada. España.; [Olry de Labry-Lima,A] Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública; Instituto de Salud Carlos III. Madrid. España.; [Olry de Labry-Lima,A] Centro Andaluz de Documentación e Información de Medicamentos (CADIME). Granada. España.FUNDAMENTOS // Se estima que un 80% de la población mundial está en riesgo de contraer una enfermedad de transmisión vectorial, siendo los mosquitos los responsables de una mayor carga de enfermedad. Dado que el control biológico es una opción más natural que otras intervenciones disponibles y que el uso de peces está muy extendido, el objetivo de esta revisión fue analizar la eficacia de las intervenciones con peces para el control de las enfermedades transmitidas por mosquitos. MÉTODOS // Se llevó a cabo una búsqueda bibliográfica a través de PubMed, Embase, Cochrane, LILACS, WOS-Core Collection y CAB Abstracts de estudios observacionales o experimentales publicados en inglés, español o portugués hasta diciembre de 2023. Las variables de resultados de interés eran indicadores entomológicos y epidemiológicos. RESULTADOS // De las 2.227 referencias identificadas, siete artículos fueron finalmente incluidos. Todos los estudios midieron el impacto usando indicadores entomológicos, mientras que solo dos usaron, además, epidemiológicos. Las intervenciones se basaron en la liberación de peces en recipientes de agua domésticos, en campos de arroz y en excavaciones y pozos vinculados a la construcción de un canal. En todos los estudios se observó una reducción significativa de los indicadores entomológicos y epidemiológicos. La reducción larvaria osciló entre el 80% y el 100%, mientras que la reducción de casos clínicos llegó a un 99,87%. CONCLUSIONES // La liberación de peces conlleva una reducción relevante tanto de los indicadores larvarios como de los casos clínicos. No obstante, es necesario analizar si la liberación de peces a mayor escala es factible, sostenible, coste-efectiva y suficiente para lograr el control vectorial, además de considerar el potencial impacto negativo de su introducción en un determinado ecosistema.Publication Vol. 30, nº 18. Sistema de alertas en salud pública: alertas epidemiológicas del años 2024.(Consejería de Salud y Consumo, 2025-05-16) Servicio de Vigilancia y Salud LaboralEnfermedades de Declaración Obligatoria por provincias. Semana 19/2025 y acumulado desde la semana 01/2025. Datos provisionales. Incluye además el artículo titulado “Sistema de alertas en salud pública: alertas epidemiológicas del años 2024”, de “Carla Torralba Suárez, Juan Carlos Carmona Lagares”.Publication Vol. 30, nº 16. Vigilancia de sarampión en atención primaria: análisis de un estudio de contactos en el distrito Granada-Metropolitano.(Consejería de Salud y Consumo, 2025-04-25) Servicio de Vigilancia y Salud LaboralEnfermedades de Declaración Obligatoria por provincias. Semana 16/2025 y acumulado desde la semana 01/2025. Datos provisionales. Incluye además el artículo titulado “Vigilancia de sarampión en atención primaria: análisis de un estudio de contactos en el distrito Granada-Metropolitano”, de “José Antonio Marín Rodríguez, Laura Leyva Valverde, Andrea Luque Martínez, Diego Almagro Nievas, Begoña López Hernández, Manuel Carlos del Moral Campaña”.Publication Surgical treatment for infective endocarditis in elderly patients(Elsevier, 2011-06-06) Ramirez-Duque, N.; García-Cabrera, Emilio; Ivanova-Georgieva, R.; Noureddine, Mariam; Lomas, J. M.; Hidalgo-Tenorio, Carmen; Plata, A.; Gálvez-Acebal, Juan; Ruiz-Morales, J.; de la Torre-Lima, J.; Reguera-Iglesias, José María; Martinez-Marcos, F. J.; de Alarcón, Arístides; [Ramirez-Duque,N; Garcia-Cabrera,E; Alarcon,A] Hospital Virgen del Rocio, Sevilla, Spain.; [Ivanova-Georgieva,R; Ruiz-Morales;J;] Hospital Virgen de la Victoria, Málaga, Spain.; [Noureddine,M; de la Torre-Lima,J;] Hospital Costa del Sol, Marbella, Spain.; [Lomas,JM; Martinez-Marcos,FJ] Hospital Juan Ramón Jiménez, Huelva, Spain.; [Hidalgo-Tenorio,C] Hospital Virgen de las Nieves, Granada, Spain.; [Plata,A; Reguera,JM] Hospital Carlos Haya, Malaga, Spain.; Ministerio de Sanidad y Consumo; Instituto de Salud Carlos III; Spanish Network for the Research in Infectious Diseases; Grupo para el Estudio de las Infecciones Cardiovasculares de la Sociedad Andaluza de Enfermedades Infecciosas (SAEI)Objectives: We evaluate the clinical, echographic and prognostic characteristics of infective endocarditis (IE) in a large population of elderly patients, and the results of surgical approach.Methods: Multicentric, prospective, observational cohort study with 961 consecutive left-sided IE: ;356 patients aged >= 65 years were compared with 605 younger. Indications for cardiac surgery, potential surgical risk, time and outcome, were compared.Results: Hospital-acquired endocarditis, comorbidity, renal failure and septic shock were more frequent in elderly, but embolisms were less. Intracardiac destruction and ventricular failure were similar in both groups, but significantly fewer elderly patients underwent cardiac surgery (36% vs 51%; p < 0.01), and this group showed a worse outcome (43.2% of mortality vs 27% in younger; p < 0.01), resulting age as an independent predictor of mortality (OR: 1.02 CI95%: 1.01-1.03). Compared with medical treatment, surgery showed lower percentages ofmortality compared with medical treatment (23.3% vs 31.3%; p = 0.03) in younger group, but a high mortality was observed with both procedures (47.6% vs 40.3%; p = 0.1) in the elderly.Conclusions: Although similar percentages of heart failure and intracardiac complications, increasing age is associated with higher mortality in IE. Lower rates of surgical treatment and a worse outcome after operation are common features in elderly patients.Item LncRNA-mRNA Co-Expression Analysis Identifies AL133346.1/CCN2 as Biomarkers in Pediatric B-Cell Acute Lymphoblastic Leukemia.(MDPI, 2020-12-17) Cuadros, Marta; Garcia, Daniel J; Andrades, Alvaro; Arenas, Alberto M; Coira, Isabel F; Baliñas-Gavira, Carlos; Peinado, Paola; Rodriguez, Maria I; Alvarez-Perez, Juan Carlos; Ruiz-Cabello, Francisco; Camos, Mireia; Jimenez-Velasco, Antonio; Medina, Pedro P; Aula de Investigación sobre la Leucemia infantil: Héroes contra la Leucemia; Ministry of Economy of Spain; Junta de Andalucía; University of Granada; Spanish Association for Cancer Research (LAB-AECC); “Fundación Benéfica Anticáncer Santa Cándida y San Francisco Javier”; Spanish Ministry of Education, Culture and Sports FPUPediatric acute B-cell lymphoblastic leukemia (B-ALL) constitutes a heterogeneous and aggressive neoplasia in which new targeted therapies are required. Long non-coding RNAs have recently emerged as promising disease-specific biomarkers for the clinic. Here, we identified pediatric B-ALL-specific lncRNAs and associated mRNAs by comparing the transcriptomic signatures of tumoral and non-tumoral samples. We identified 48 lncRNAs that were differentially expressed between pediatric B-ALL and healthy bone marrow samples. The most relevant lncRNA/mRNA pair was AL133346.1/CCN2 (previously known as RP11-69I8.3/CTGF), whose expression was positively correlated and increased in B-ALL samples. Their differential expression pattern and their strong correlation were validated in external B-ALL datasets (Therapeutically Applicable Research to Generate Effective Treatments, Cancer Cell Line Encyclopedia). Survival curve analysis demonstrated that patients with "high" expression levels of CCN2 had higher overall survival than those with "low" levels (p = 0.042), and this gene might be an independent prognostic biomarker in pediatric B-ALL. These findings provide one of the first detailed descriptions of lncRNA expression profiles in pediatric B-ALL and indicate that these potential biomarkers could help in the classification of leukemia subtypes and that CCN2 expression could predict the survival outcome of pediatric B-cell acute lymphoblastic leukemia patients.Item Cross-Resistance to Abiraterone and Enzalutamide in Castration Resistance Prostate Cancer Cellular Models Is Mediated by AR Transcriptional Reactivation.(2021-03-23) Simon, Iris; Perales, Sonia; Casado-Medina, Laura; Rodríguez-Martínez, Alba; Garrido-Navas, Maria Del Carmen; Puche-Sanz, Ignacio; Diaz-Mochon, Juan J; Alaminos, Clara; Lupiañez, Pablo; Lorente, Jose A; Serrano, María J; Real, Pedro JAndrogen deprivation therapy (ADT) and novel hormonal agents (NHAs) (Abiraterone and Enzalutamide) are the goal standard for metastatic prostate cancer (PCa) treatment. Although ADT is initially effective, a subsequent castration resistance status (CRPC) is commonly developed. The expression of androgen receptor (AR) alternative splicing isoforms (AR-V7 and AR-V9) has been associated to CRPC. However, resistance mechanisms to novel NHAs are not yet well understood. Androgen-dependent PCa cell lines were used to generate resistant models to ADT only or in combination with Abiraterone and/or Enzalutamide (concomitant models). Functional and genetic analyses were performed for each resistance model by real-time cell monitoring assays, flow cytometry and RT-qPCR. In androgen-dependent PCa cells, the administration of Abiraterone and/or Enzalutamide as first-line treatment involved a critical inhibition of AR activity associated with a significant cell growth inhibition. Genetic analyses on ADT-resistant PCa cell lines showed that the CRPC phenotype was accompanied by overexpression of AR full-length and AR target genes, but not necessarily AR-V7 and/or AR-V9 isoforms. These ADT resistant cell lines showed higher proliferation rates, migration and invasion abilities. Importantly, ADT resistance induced cross-resistance to Abiraterone and/or Enzalutamide. Similarly, concomitant models possessed an elevated expression of AR full-length and proliferation rates and acquired cross-resistance to its alternative NHA as second-line treatment.Item A Systematic Review on the Association of Acquired Human Cytomegalovirus Infection with Hearing Loss.(2020-12-11) Martinez-Gomez, Estrella; Perez-Carpena, Patricia; Flook, Marisa; Lopez-Escamez, José ACongenital cytomegalovirus (CMV) infection induces a clinical syndrome usually associated with hearing loss. However, the effect of acquired CVM infection in adults and children has not been clearly defined. The objective of this review is to critically appraise scientific evidence regarding the association of acquired CMV infection with postnatal hearing loss or tinnitus. A systematic review of records reporting sensorineural hearing loss (SNHL) or tinnitus and acquired CMV infection including articles published in English was performed. Search strategy was limited to human studies with acquired CMV infection. After screening and quality assessment, nine studies involving 1528 individuals fulfilled the inclusion criteria. A total of 14% of patients with SNHL showed evidence of previous exposure to CMV, while in individuals without SNHL (controls) the percentage rose up to 19.3%. SNHL was reported as unilateral or bilateral in 15.3%, and not specified in 84.7% of cases. The degree of SNHL ranged from mild to profound for both children and adults. None of the records reported tinnitus. The prevalence of children or adults with acquired SNHL with a confirmed acquired CMV infection by Polymerase Chain Reaction (PCR) or IgM anti-CMV antibodies is low. Phenotyping of patients with acquired CMV infection was limited to hearing loss by pure tone audiometry and no additional audiological testing was performed in most of the studies. Additional symptoms deserve more attention, including episodic vertigo or tinnitus, since some patients with the clinical spectrum of Meniere Disease could result from a CMV latent infection.Item Sex-Dependent Aggregation of Tinnitus in Swedish Families.(2020-11-25) Trpchevska, Natalia; Bulla, Jan; Prada Hellberg, Matilda; Edvall, Niklas K; Lazar, Andra; Mehraei, Golbarg; Uhlen, Inger; Schlee, Winfried; Canlon, Barbara; Gallus, Silvano; Lopez-Escamez, Jose Antonio; Cederroth, Christopher RTwin and adoption studies point towards a genetic contribution to tinnitus; however, how the genetic risk applies to different forms of tinnitus is poorly understood. Here, we perform a familial aggregation study and determine the relative recurrence risk for tinnitus in siblings (λs). Four different Swedish studies (N = 186,598) were used to estimate the prevalence of self-reported bilateral, unilateral, constant, and severe tinnitus in the general population and we defined whether these 4 different forms of tinnitus segregate in families from the Swedish Tinnitus Outreach Project (STOP, N = 2305). We implemented a percentile bootstrap approach to provide accurate estimates and confidence intervals for λs. We reveal a significant λs for all types of tinnitus, the highest found being 7.27 (95% CI (5.56-9.07)) for severe tinnitus, with a higher susceptibility in women (10.25; 95% CI (7.14-13.61)) than in men (5.03; 95% CI (3.22-7.01)), suggesting that severity may be the most genetically influenced trait in tinnitus in a sex-dependent manner. Our findings strongly support the notion that genetic factors impact on the development of tinnitus, more so for severe tinnitus. These findings highlight the importance of considering tinnitus severity and sex in the design of large genetic studies to optimize diagnostic approaches and ultimately improve therapeutic interventions.Item Association between Hyperacusis and Tinnitus.(2020-07-28) Cederroth, Christopher R; Lugo, Alessandra; Edvall, Niklas K; Lazar, Andra; Lopez-Escamez, Jose-Antonio; Bulla, Jan; Uhlen, Inger; Hoare, Derek J; Baguley, David M; Canlon, Barbara; Gallus, SilvanoMany individuals with tinnitus report experiencing hyperacusis (enhanced sensitivity to sounds). However, estimates of the association between hyperacusis and tinnitus is lacking. Here, we investigate this relationship in a Swedish study. A total of 3645 participants (1984 with tinnitus and 1661 without tinnitus) were enrolled via LifeGene, a study from the general Swedish population, aged 18-90 years, and provided information on socio-demographic characteristics, as well as presence of hyperacusis and its severity. Tinnitus presence and severity were self-reported or assessed using the Tinnitus Handicap Inventory (THI). Phenotypes of tinnitus with (n = 1388) or without (n = 1044) hyperacusis were also compared. Of 1661 participants without tinnitus, 1098 (66.1%) were women and 563 were men (33.9%), and the mean (SD) age was 45.1 (12.9). Of 1984 participants with tinnitus, 1034 (52.1%) were women and 950 (47.9%) were men, and the mean (SD) age was 47.7 (14.0) years. Hyperacusis was associated with any tinnitus [Odds ratio (OR) 3.51, 95% confidence interval (CI) 2.99-4.13], self-reported severe tinnitus (OR 7.43, 95% CI 5.06-10.9), and THI ≥ 58 (OR 12.1, 95% CI 7.06-20.6). The association with THI ≥ 58 was greater with increasing severity of hyperacusis, the ORs being 8.15 (95% CI 4.68-14.2) for moderate and 77.4 (95% CI 35.0-171.3) for severe hyperacusis. No difference between sexes was observed in the association between hyperacusis and tinnitus. The occurrence of hyperacusis in severe tinnitus is as high as 80%, showing a very tight relationship. Discriminating the pathophysiological mechanisms between the two conditions in cases of severe tinnitus will be challenging, and optimized study designs are necessary to better understand the mechanisms behind the strong relationship between hyperacusis and tinnitus.Item Circulating PTGS2, JAG1, GUCY2C and PGF mRNA in Peripheral Blood and Serum as Potential Biomarkers for Patients with Metastatic Colon Cancer.(2021-05-22) Jimenez-Luna, Cristina; González-Flores, Encarnación; Ortiz, Raul; Martínez-González, Luis J; Antúnez-Rodríguez, Alba; Expósito-Ruiz, Manuela; Melguizo, Consolación; Caba, Octavio; Prados, JoseGenes involved in the angiogenic process have been proposed for the diagnosis and therapeutic response of metastatic colorectal cancer (CRC). This study aimed to investigate the value of PTGS2, JAG1, GUCY2C and PGF-circulating RNA as biomarkers in metastatic CRC. Blood cells and serum mRNA from 59 patients with metastatic CRC and 47 healthy controls were analyzed by digital PCR. The area under the receiver operating characteristic curve (AUC) was used to estimate the diagnostic value of each mRNA alone or mRNA combinations. A significant upregulation of the JAG1, PTGS2 and GUCY2C genes in blood cells and serum samples from metastatic CRC patients was detected. Circulating mRNA levels in the serum of all genes were significantly more abundant than in blood. The highest discrimination ability between metastatic CRC patients and healthy donors was obtained with PTGS2 (AUC of 0.984) and GUCY2C (AUC of 0.896) in serum samples. Biomarker combinations did not improve the discriminatory capacity of biomarkers separately. Analyzed biomarkers showed no correlation with overall survival or progression-free survival, but GUCY2C and GUCY2C/PTGS2 expression in serum correlated significantly with the response to antiangiogenic agents. These findings demonstrate that assessment of genes involved in the angiogenic process may be a potential non-invasive diagnostic tool for metastatic CRC and its response to antiangiogenic therapy.Item Functional Genetic Variants in ATG10 Are Associated with Acute Myeloid Leukemia.(2021-03-16) Castro, Isabel; Sampaio-Marques, Belém; C Areias, Anabela; Sousa, Hugo; Fernandes, Ângela; Sanchez-Maldonado, José Manuel; Cunha, Cristina; Carvalho, Agostinho; Sainz, Juan; Ludovico, PaulaAcute myeloid leukemia (AML) is the most common acute leukemia, characterized by a heterogeneous genetic landscape contributing, among others, to the occurrence of metabolic reprogramming. Autophagy, a key player on metabolism, plays an essential role in AML. Here, we examined the association of three potentially functional genetic polymorphisms in the ATG10 gene, central for the autophagosome formation. We screened a multicenter cohort involving 309 AML patients and 356 healthy subjects for three ATG10 SNPs: rs1864182T>G, rs1864183C>T and rs3734114T>C. The functional consequences of the ATG10 SNPs in its canonical function were investigated in vitro using peripheral blood mononuclear cells from a cohort of 46 healthy individuals. Logistic regression analysis adjusted for age and gender revealed that patients carrying the ATG10rs1864182G allele showed a significantly decreased risk of developing AML (OR [odds ratio] = 0.58, p = 0.001), whereas patients carrying the homozygous ATG10rs3734114C allele had a significantly increased risk of developing AML (OR = 2.70, p = 0.004). Functional analysis showed that individuals carrying the ATG10rs1864182G allele had decreased autophagy when compared to homozygous major allele carriers. Our results uncover the potential of screening for ATG10 genetic variants in AML prevention strategies, in particular for subjects carrying other AML risk factors such as elderly individuals with clonal hematopoiesis of indeterminate potential.Item Identification of MicroRNAs as Viable Aggressiveness Biomarkers for Prostate Cancer.(2021-06-05) Martínez-González, Luis Javier; Sánchez-Conde, Victor; González-Cabezuelo, Jose María; Antunez-Rodríguez, Alba; Andrés-León, Eduardo; Robles-Fernandez, Inmaculada; Lorente, Jose Antonio; Vázquez-Alonso, Fernando; Alvarez-Cubero, María JesusMiRNAs play a relevant role in PC (prostate cancer) by the regulation in the expression of several pathways' AR (androgen receptor), cellular cycle, apoptosis, MET (mesenchymal epithelium transition), or metastasis. Here, we report the role of several miRNAs' expression patterns, such as miR-93-5p, miR-23c, miR-210-3p, miR-221-3p, miR-592, miR-141, miR-375, and miR-130b, with relevance in processes like cell proliferation and MET. Using Trizol® extraction protocol and TaqMan™ specific probes for amplification, we performed miRNAs' analysis of 159 PC fresh tissues and 60 plasmas from peripheral blood samples. We had clinical data from all samples including PSA, Gleason, TNM, and D'Amico risk. Moreover, a bioinformatic analysis in TCGA (The Cancer Genome Atlas) was included to analyze the effect of the most relevant miRNAs according to aggressiveness in an extensive cohort (n = 531). We found that miR-210-3p, miR-23c, miR-592, and miR-93-5p are the most suitable biomarkers for PC aggressiveness and diagnosis, respectively. In fact, according with our results, miR-93-5p seems the most promising non-invasive biomarker for PC. To sum up, miR-210-3p, miR-23c, miR-592, and miR-93-5p miRNAs are suggested to be potential biomarkers for PC risk stratification that could be included in non-invasive strategies such as liquid biopsy in precision medicine for PC management.Item Clinical and Functional Characterization of a Missense ELF2 Variant in a CANVAS Family.(2018-03-23) Ahmad, Hena; Requena, Teresa; Frejo, Lidia; Cobo, Marien; Gallego-Martinez, Alvaro; Martin, Francisco; Lopez-Escamez, Jose A; Bronstein, Adolfo MCerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is a rare disorder with an unknown etiology. We present a British family with presumed autosomal dominant CANVAS with incomplete penetrance and variable expressivity. Exome sequencing identified a rare missense variant in the ELF2 gene at chr4:g.140058846 C > T, c.10G > A, p.A4T which segregated in all affected patients. By using transduced BE (2)-M17 cells, we found that the mutated ELF2 (mt-ELF2) gene increased ATXN2 and reduced ELOVL5 gene expression, the causal genes of type 2 and type 38 spinocerebellar ataxias. Both, western blot and confocal microscopy confirmed an increase of ataxin-2 in BE(2)-M17 cells transduced with lentivirus expressing mt-ELF2 (CEE-mt-ELF2), which was not observed in cells transduced with lentivirus expressing wt-ELF2 (CEE-wt-ELF2). Moreover, we observed a significant decrease in the number and size of lipid droplets in the CEE-mt-ELF2-transduced BE (2)-M17 cells, but not in the CEE-wt-ELF2-transduced BE (2)-M17. Furthermore, changes in the expression of ELOVL5 could be related with the reduction of lipid droplets in BE (2)-M17 cells. This work supports that ELF2 gene regulates the expression of ATXN2 and ELOVL5 genes, and defines new molecular links in the pathophysiology of cerebellar ataxias.Item Genetics of Tinnitus: Time to Biobank Phantom Sounds.(2017-09-04) Cederroth, Christopher R; Kähler, Anna K; Sullivan, Patrick F; Lopez-Escamez, Jose ATinnitus is a common phantom sensation resulting most often from sensory deprivation, and for which little knowledge on the molecular mechanisms exists. While the existing evidence for a genetic influence on the condition has been until now sparse and underpowered, recent data suggest that specific forms of tinnitus have a strong genetic component revealing that not all tinnitus percepts are alike, at least in how they are genetically driven. These new findings pave the way for a better understanding on how phantom sensations are molecularly driven and call for international biobanking efforts.Item Strategies for Isolation and Phenotypic, Genetic, and Functional Characterization of Circulating Tumor Cells.(2020-11-04) Serrano, Maria José; Lorente, Jose AFrom the medical and scientific point of view, we are witnessing important changes in the way we approach diseases, and consequently in the way we manage patients [...].Item The IS2 Element Improves Transcription Efficiency of Integration-Deficient Lentiviral Vector Episomes.(2018-08-18) Sánchez-Hernández, Sabina; Gutierrez-Guerrero, Alejandra; Martín-Guerra, Rocío; Cortijo-Gutierrez, Marina; Tristán-Manzano, María; Rodriguez-Perales, Sandra; Sanchez, Laura; Garcia-Perez, Jose Luis; Chato-Astrain, Jesus; Fernandez-Valades, Ricardo; Carrillo-Galvez, Ana Belén; Anderson, Per; Montes, Rosa; Real, Pedro J; Martin, Francisco; Benabdellah, KarimIntegration-defective lentiviral vectors (IDLVs) have become an important alternative tool for gene therapy applications and basic research. Unfortunately, IDLVs show lower transgene expression as compared to their integrating counterparts. In this study, we aimed to improve the expression levels of IDLVs by inserting the IS2 element, which harbors SARs and HS4 sequences, into their LTRs (SE-IS2-IDLVs). Contrary to our expectations, the presence of the IS2 element did not abrogate epigenetic silencing by histone deacetylases. In addition, the IS2 element reduced episome levels in IDLV-transduced cells. Interestingly, despite these negative effects, SE-IS2-IDLVs outperformed SE-IDLVs in terms of percentage and expression levels of the transgene in several cell lines, including neurons, neuronal progenitor cells, and induced pluripotent stem cells. We estimated that the IS2 element enhances the transcriptional activity of IDLV LTR circles 6- to 7-fold. The final effect the IS2 element in IDLVs will greatly depend on the target cell and the balance between the negative versus the positive effects of the IS2 element in each cell type. The better performance of SE-IS2-IDLVs was not due to improved stability or differences in the proportions of 1-LTR versus 2-LTR circles but probably to a re-positioning of IS2-episomes into transcriptionally active regions.Item Polymorphisms within the TNFSF4 and MAPKAPK2 Loci Influence the Risk of Developing Invasive Aspergillosis: A Two-Stage Case Control Study in the Context of the aspBIOmics Consortium.(2020-12-23) Sánchez-Maldonado, Jose Manuel; Moñiz-Díez, Ana; Ter Horst, Rob; Campa, Daniele; Cabrera-Serrano, Antonio José; Martínez-Bueno, Manuel; Garrido-Collado, María Del Pilar; Hernández-Mohedo, Francisca; Fernández-Puerta, Laura; López-Nevot, Miguel Ángel; Cunha, Cristina; González-Sierra, Pedro Antonio; Springer, Jan; Lackner, Michaela; Alcazar-Fuoli, Laura; Fianchi, Luana; Aguado, José María; Pagano, Livio; López-Fernández, Elisa; Clavero, Esther; Potenza, Leonardo; Luppi, Mario; Moratalla, Lucia; Solano, Carlos; Sampedro, Antonio; Cuenca-Estrella, Manuel; Lass-Flörl, Cornelia; Pcraga Study Group,; Canzian, Federico; Loeffler, Juergen; Li, Yang; Einsele, Hermann; Netea, Mihai G; Vázquez, Lourdes; Carvalho, Agostinho; Jurado, Manuel; Sainz, JuanHere, we assessed whether 36 single nucleotide polymorphisms (SNPs) within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis (IA). We conducted a two-stage case control study including 911 high-risk patients diagnosed with hematological malignancies that were ascertained through the aspBIOmics consortium. The meta-analysis of the discovery and replication populations revealed that carriers of the TNFSF4rs7526628T/T genotype had a significantly increased risk of developing IA (p = 0.00022). We also found that carriers of the TNFSF4rs7526628T allele showed decreased serum levels of TNFSF14 protein (p = 0.0027), and that their macrophages had a decreased fungicidal activity (p = 0.048). In addition, we observed that each copy of the MAPKAPK2rs12137965G allele increased the risk of IA by 60% (p = 0.0017), whereas each copy of the MAPKAPK2rs17013271T allele was estimated to decrease the risk of developing the disease (p = 0.0029). Mechanistically, we found that carriers of the risk MAPKAPK2rs12137965G allele showed increased numbers of CD38+IgM-IgD- plasmablasts in blood (p = 0.00086), whereas those harboring two copies of the allele had decreased serum concentrations of thymic stromal lymphopoietin (p = 0.00097). Finally, we also found that carriers of the protective MAPKAPK2rs17013271T allele had decreased numbers of CD27-IgM-IgD- B cells (p = 0.00087) and significantly lower numbers of CD14+ and CD14+CD16- cells (p = 0.00018 and 0.00023). Altogether, these results suggest a role of the TNFSF4 and MAPKAPK2 genes in determining IA risk.Item The Polemic Diagnostic Role of TP53 Mutations in Liquid Biopsies from Breast, Colon and Lung Cancers.(2020-11-12) Garrido-Navas, M Carmen; García-Díaz, Abel; Molina-Vallejo, Maria Pilar; González-Martínez, Coral; Alcaide Lucena, Miriam; Cañas-García, Inés; Bayarri, Clara; Delgado, Juan Ramón; González, Encarna; Lorente, Jose Antonio; Serrano, M JoseBeing minimally invasive and thus allowing repeated measures over time, liquid biopsies are taking over traditional solid biopsies in certain circumstances such as those for unreachable tumors, very early stages or treatment monitoring. However, regarding TP53 mutation status analysis, liquid biopsies have not yet substituted tissue samples, mainly due to the lack of concordance between the two types of biopsies. This needs to be examined in a study-dependent manner, taking into account the particular type of liquid biopsy analyzed, that is, circulating tumor cells (CTCs) or cell-free DNA (cfDNA), its involvement in the tumor biology and evolution and, finally, the technology used to analyze each biopsy type. Here, we review the main studies analyzing TP53 mutations in either CTCs or cfDNA in the three more prevalent solid tumors: breast, colon and lung cancers. We evaluate the correlation for mutation status between liquid biopsies and tumor tissue, suggesting possible sources of discrepancies, as well as evaluating the clinical utility of using liquid biopsies for the analysis of TP53 mutation status and the future actions that need to be undertaken to make liquid biopsy analysis a reality for the evaluation of TP53 mutations.Item Common Genetic Polymorphisms within NFκB-Related Genes and the Risk of Developing Invasive Aspergillosis.(2016-08-12) Lupiañez, Carmen B; Villaescusa, María T; Carvalho, Agostinho; Springer, Jan; Lackner, Michaela; Sánchez-Maldonado, José M; Canet, Luz M; Cunha, Cristina; Segura-Catena, Juana; Alcazar-Fuoli, Laura; Solano, Carlos; Fianchi, Luana; Pagano, Livio; Potenza, Leonardo; Aguado, José M; Luppi, Mario; Cuenca-Estrella, Manuel; Lass-Flörl, Cornelia; Einsele, Hermann; Vázquez, Lourdes; PCRAGA Study Group; Ríos-Tamayo, Rafael; Loeffler, Jurgen; Jurado, Manuel; Sainz, JuanInvasive Aspergillosis (IA) is an opportunistic infection caused by Aspergillus, a ubiquitously present airborne pathogenic mold. A growing number of studies suggest a major host genetic component in disease susceptibility. Here, we evaluated whether 14 single-nucleotide polymorphisms within NFκB1, NFκB2, RelA, RelB, Rel, and IRF4 genes influence the risk of IA in a population of 834 high-risk patients (157 IA and 677 non-IA) recruited through a collaborative effort involving the aspBIOmics consortium and four European clinical institutions. No significant overall associations between selected SNPs and the risk of IA were found in this large cohort. Although a hematopoietic stem cell transplantation (HSCT)-stratified analysis revealed that carriers of the IRF4 rs12203592T/T genotype had a six-fold increased risk of developing the infection when compared with those carrying the C allele (ORREC = 6.24, 95%CI 1.25-31.2, P = 0.026), the association of this variant with IA risk did not reach significance at experiment-wide significant threshold. In addition, we found an association of the IRF4AATC and IRF4GGTC haplotypes (not including the IRF4 rs12203592T risk allele) with a decreased risk of IA but the magnitude of the association was similar to the one observed in the single-SNP analysis, which indicated that the haplotypic effect on IA risk was likely due to the IRF4 rs12203592 SNP. Finally, no evidence of significant interactions among the genetic markers tested and the risk of IA was found. These results suggest that the SNPs on the studied genes do not have a clinically relevant impact on the risk of developing IA.Item Regulation of Fn14 Receptor and NF-κB Underlies Inflammation in Meniere's Disease.(2017-12-13) Frejo, Lidia; Requena, Teresa; Okawa, Satoshi; Gallego-Martinez, Alvaro; Martinez-Bueno, Manuel; Aran, Ismael; Batuecas-Caletrio, Angel; Benitez-Rosario, Jesus; Espinosa-Sanchez, Juan M; Fraile-Rodrigo, Jesus José; García-Arumi, Ana María; González-Aguado, Rocío; Marques, Pedro; Martin-Sanz, Eduardo; Perez-Fernandez, Nicolas; Pérez-Vázquez, Paz; Perez-Garrigues, Herminio; Santos-Perez, Sofía; Soto-Varela, Andres; Tapia, Maria C; Trinidad-Ruiz, Gabriel; Del Sol, Antonio; Alarcon Riquelme, Marta E; Lopez-Escamez, Jose AMeniere's disease (MD) is a rare disorder characterized by episodic vertigo, sensorineural hearing loss, tinnitus, and aural fullness. It is associated with a fluid imbalance between the secretion of endolymph in the cochlear duct and its reabsorption into the subarachnoid space, leading to an accumulation of endolymph in the inner ear. Epidemiological evidence, including familial aggregation, indicates a genetic contribution and a consistent association with autoimmune diseases (AD). We conducted a case-control study in two phases using an immune genotyping array in a total of 420 patients with bilateral MD and 1,630 controls. We have identified the first locus, at 6p21.33, suggesting an association with bilateral MD [meta-analysis leading signal rs4947296, OR = 2.089 (1.661-2.627); p = 1.39 × 10-09]. Gene expression profiles of homozygous genotype-selected peripheral blood mononuclear cells (PBMCs) demonstrated that this region is a trans-expression quantitative trait locus (eQTL) in PBMCs. Signaling analysis predicted several tumor necrosis factor-related pathways, the TWEAK/Fn14 pathway being the top candidate (p = 2.42 × 10-11). This pathway is involved in the modulation of inflammation in several human AD, including multiple sclerosis, systemic lupus erythematosus, or rheumatoid arthritis. In vitro studies with genotype-selected lymphoblastoid cells from patients with MD suggest that this trans-eQTL may regulate cellular proliferation in lymphoid cells through the TWEAK/Fn14 pathway by increasing the translation of NF-κB. Taken together; these findings suggest that the carriers of the risk genotype may develop an NF-κB-mediated inflammatory response in MD.