IBIMA-Plataforma BIONAND - Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina (Andalucía)

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12105/16927

El Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina (IBIMA Plataforma BIONAND) es un Instituto Sanitario de Investigación creado en julio de 2010, a partir de un acuerdo entre la Consejería de Salud de la Junta de Andalucía y la Universidad de Málaga, que ratificaron su compromiso para el afianzamiento de IBIMA como centro de vanguardia y excelencia en biomedicina. Es uno de los más de 30 institutos acreditados en España para la investigación sanitaria, siendo un espacio de investigación multidisciplinar en el que trabajan científicos procedentes del ámbito universitario y sanitario para la mejora de la salud de los ciudadanos y el desarrollo social y económico de la provincia de Málaga. El órgano de gestión de IBIMA Plataforma BIONAND es la Fundación Pública Andaluza para la Investigación de Málaga en Biomedicina y Salud (FIMABIS). Acreditado por el Instituto de Salud Carlos III como Instituto de Investigación Sanitaria en 2015, y renovando esta acreditación cada 5 años, forma parte así del total de 34 Institutos de Investigación Sanitaria acreditados existentes en la actualidad.

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Phase IV adaptive randomised clinical trials evaluating efficacy and cost-efficacy of pre-emptive pharmacogenetic genotyping strategies in the Spanish National Health System: iPHARMGx Master Protocol and PREVESTATGx nested clinical trial
(BMJ Publishing Group, 2024-11-07) Stewart, Stefan; Seco-Meseguer, Enrique; Diago-Sempere, Elena; Marín-Candón, Alicia; Carmona, Montserrat; Estébanez, Miriam; López-Fernández, Luis A; Imaz-Iglesia, Iñaki; Del Mar García Saiz, María; Laserna-Mendieta, Emilio J; Peiró, Ana M; Farré, Magí; Rodriguez-Jimenez, Consuelo; Saiz-Rodriguez, Miriam; Sanabria-Cabrera, Judith; Rosas-Alonso, Rocío; Abad-Santos, Francisco; Pedrosa-Pérez, Lucía; Carcas, Antonio J; García García, Irene; Borobia, Alberto M; iPHARMGx study group; Instituto de Salud Carlos III; Unión Europea. Comisión Europea. NextGenerationEU
Introduction: Genetic variations impact drug response, driving the need for personalised medicine through pre-emptive pharmacogenetic testing. However, the adoption of pre-emptive pharmacogenetic testing for commonly prescribed drugs, such as statins, outside of tertiary hospitals is limited due to a lack of pharmacoeconomic evidence to support widespread implementation by healthcare policy-makers. The Spanish Consortium for the Implementation of Pharmacogenetics (iPHARMGx Consortium) addresses this by developing a clinical trial master protocol that will govern multiple nested adaptive clinical trials that compare genotype-guided treatments to standard care in specific drug-gene-population triads, asses their cost-efficacy and identify novel biomarkers through advanced sequencing techniques. The first of these studies aims to assess whether a pre-emptive statin therapy genotyping scheme reduces the incidence of statin-associated muscle symptoms (SAMS) in a population at risk of cardiovascular disease susceptible of receiving high-intensity or moderate-intensity doses of statins: The PREVESTATGx trial. Methods and analysis: the PREVESTATGX trial is a multicentre, adaptive randomised controlled pragmatic phase IV clinical trial nested to the iPHARMGx master protocol with two parallel arms, aiming for superiority. Randomisation will be conducted on an individual basis with a centralised approach and stratification by centre. After inclusion in the trial and genotyping has been performed, subjects will be randomly allocated to experimental group (pharmacogenetic genotype-guided statin prescription) or standard-of-care statin prescription (as deemed by attending physician). The main objective is to assess the efficacy of a statin pre-emptive genotyping strategy in reducing the incidence of SAMS. A total of 225 subjects will be recruited among the 10 participating centres if no futility/efficacy boundary is reached in the prespecified interim analyses. Recruitment will be carried out during a 12-month period and subjects will be followed for a 9-month period. Ethics and dissemination: The PREVESTATGx trial received ethical approval on 24 April 2024. Results will be disseminated via publication in peer-reviewed journals as well as presentation at international conferences. Trial results will be submitted for publication in an open-access peer-reviewed medical speciality-specific publication. Trial registration number: EU CT number: 2023-509418-12-00/Clinical trial Identifier (ClinicalTrials.gov): NCT06262685. Protocol version 1.2 12 April 2024 (includes non-substantial modification number 14 June 2024). Trial registration of this study can be located at both the EU Clinical Trials Register available from https:// euclinicaltrials.eu/search-for-clinical-trials/?lang=en and https://clinicaltrials.gov. Registration on both websites was done before the enrolment of the first patient complying with European regulations. EU Clinical Trials Register is a primary registry according to the WHO.
Effectiveness of catch-up and at-birth nirsevimab immunisation against RSV hospital admission in the first year of life: a population-based case-control study, Spain, 2023/24 season
(European Centre for Disease Prevention and Control (ECDC), 2025-02) Nuñez, Olivier; Olmedo, Carmen; Moreno-Perez, David; Lorusso, Nicola; Fernández Martínez, Sergio; Pastor Villalba, Pedro Eliseo; Gutierrez, Ángeles; Alonso Garcia, Marcos; Latasa, Pello; Sancho, Rosa; Mendioroz, Jacobo; Martinez-Marcos, Montserrat; Muñoz Platón, Enriqueta; García Rivera, María Victoria; Pérez-Martínez, Olaia; Álvarez-Gil, Rosa; Rivas Wagner, Eva; López González-Coviella, Nieves; Zornoza, Matilde; Barranco Boada, María Isabel; Pacheco, M Del Carmen; Álvarez Río, Virginia; Fiol Jaume, Miguel; Morey Arance, Roxana; Adiego Sancho, Begoña; Mendez Diaz, Manuel; Batalla, Noa; Andreu, Cristina; Castilla, Jesús; Garcia-Cenoz, Manuel; Fernández Ibáñez, Ana; Huerta Huerta, Marta; Ibáñez Pérez, Ana Carmen; Berradre-Sáenz, Belén; Lamas, Joaquín; Hermoso, Luisa; Casado Cobo, Susana; Galán Cuesta, Manuel; Montenegro, Sara; Domínguez, María; Jarrin Vera, Inmaculada; Limia, Aurora; Pastor-Barriuso, Roberto; Monge Corella, Susana; Nirsevimab Effectiveness Study Collaborators; Instituto de Salud Carlos III
Background: Respiratory syncytial virus (RSV) causes substantial morbidity in infants < 1 year. In October 2023, Spain recommended the monoclonal antibody nirsevimab to all children born since 1 April 2023, at birth or as catch-up if born before October 2023.AimWe estimated nirsevimab effectiveness in preventing RSV hospitalisations during the 2023/24 season. Methods: We conducted a nationwide population-based matched case-control study. Cases were children hospitalised for lower respiratory tract infection who were RSV PCR-positive. For each case, we selected four population density controls born in the same province and date (±2 days). We defined at-birth immunisation as receiving nirsevimab during the first 2 weeks of life, and catch-up immunisation within 30 days from campaign onset. Causal intention-to-treat (ITT) and per-protocol (PP) effectiveness was estimated using inverse-probability-of-immunisation weighted conditional logistic regression. Results: We included 406 cases and 1,623 controls in catch-up and 546 cases and 2,182 controls in at-birth immunisation studies. Effectiveness in preventing RSV hospitalisations for catch-up immunisation was 71% (95% confidence interval (CI): 65-76) by ITT and 80% (95% CI: 75-84) PP. Effectiveness for at-birth immunisation was 78% (95% CI: 73-82) by ITT and 83% (95% CI: 79-87) PP. Effectiveness was similar for ICU admission, need of mechanical ventilation, and RSV viral subgroups A and B. Children born pre-term or with birthweight < 2,500 g showed lower PP effectiveness of 60-70%. Conclusions: Population-level nirsevimab immunoprophylaxis in children in their first RSV season was very effective in preventing RSV hospitalisations, ICU admission and mechanical ventilation, with reduced but still high effectiveness for pre-term and low-birthweight children.
Gestational breast cancer: distinctive molecular and clinico-epidemiological features
(Springer, 2024-11-08) de la Haba-Rodríguez, J R; Mínguez, P; Rojo, F; Martín, M; Alba, E; Servitja, S; Prat, A; Pérez-Fidalgo, Jose Alejandro; Gavilá, J; Morales, C; Rodriguez-Lescure, A; Herrero, C; Peña-Enriquez, R; Herranz, J; Hernando, C; Hernández-Blanquisett, A; Guil-Luna, S; Martinez, M T; Blanch, S; Caballero, R; Martín, N; Pollan-Santamaria, Marina; Guerrero-Zotano, Ángel; Bermejo, B; Instituto de Salud Carlos III; University of Córdoba (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
Gestational breast cancer (GBC), defined as breast cancer (BC) diagnosed during pregnancy or the first-year post-partum, accounts for 6-15% of BC cases in women aged 20-44 years. GBC has worse prognosis than non-GBC, but reasons behind are not clear. The GEICAM/2012-03 Study (Molecular Characterization of Gestational Breast Cancer) is a multicenter prospective/retrospective observational registry of patients diagnosed with GBC. From November 2014 to June 2015 seventy patients diagnosed with GBC were included in the study, 30 diagnosed during pregnancy and 40 after delivery. Our current study was aimed to explore differences in epidemiological, clinico-pathological and gene expression features of GBC tumors, from the GEICAM/2012-03 Study, compared to non-GBC tumors from patients of similar age (< 43 years) from six different GEICAM studies, used as non- GBC control population. As per the main objective, the study found multiple differences showing GBC tumors as a different biological entity. GBC showed a more aggressive biology, with higher Ki67 levels, higher incidence of breast and/or ovarian cancer family history, and germline deleterious BRCA1/2 mutations, and are enriched in basal-like intrinsic subtype. GBC patients showed a lower number of tumor infiltrating lymphocytes, while specific genetic signatures highlight differences in GBC´s distinctive transcriptome. Our study shows that GBC is potentially a clinically and molecularly different entity, with specific epidemiological, clinical, and histological features, as well as a distinctive altered immune state and genetic signature. Nevertheless, further studies are needed to better understand the biology of GBC and to identify new targets against which develop new, more effective, targeted therapies.
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.
Challenging the Top Player: A Preliminary Study on Testosterone Response to An Official Chess Tournament.
(2020-02-13) Mendoza, Guillermo; Jiménez, Manuel; García-Romero, Jerónimo; García-Bastida, Jorge; Rivilla, Iván; de Albornoz-Gil, Margarita Carrillo; Baron-Lopez, Francisco Javier; Benítez-Porres, Javier; Alvero-Cruz, José Ramón
According to the Challenge Hypothesis, high levels of testosterone (T) are associated with status-seeking behaviors, especially in competitive situations. However, there have not been many studies about rivals' social status and pre-competition neuroendocrine responses. The aim of this study was to analyze whether the participants in a chess tournament showed different pre-match testosterone and cortisol levels depending on differences in ELO (i.e., the International Chess Federation rating to rank the competitive potential and social status between players). The sample was six male participants (mean ± SD) aged 25.5 ± 8.4 years with experience in official tournaments of 16.33 ± 5.72 years and an average ELO rating of 2217.67 ± 112.67. Saliva samples were collected before each round for hormonal determination when participants competed against a rival with a different ELO rating. After five competition rounds per participant, higher rival pre-competition T concentrations were shown when playing against the best-rated participant, but there were no differences in cortisol (C). The multilevel model confirmed rises in rivals' precompetitive T levels modulated by the difference in the opponent´s ELO rating. No significant changes were observed in C. The results suggest that the rival´s status can determine the opponent´s anticipatory neuroendocrine responses to an official chess tournament.
Effects of Long-Term Alcohol Drinking on the Dopamine D2 Receptor: Gene Expression and Heteroreceptor Complexes in the Striatum in Rats.
(2018-01-24) Feltmann, Kristin; Borroto-Escuela, Dasiel Oscar; Rüegg, Joëlle; Pinton, Luca; de Oliveira Sergio, Thatiane; Narváez, Manuel; Jimenez-Beristain, Antonio; Ekström, Tomas J; Fuxe, Kjell; Steensland, Pia
Background: Reduced dopamine D2 receptor (D2R) ligand binding has repeatedly been demonstrated in the striatum of humans with alcohol use disorder (AUD). The attenuated D2R binding has been suggested to reflect a reduced D2R density, which in turn has been proposed to drive craving and relapse. However, results from rodent studies addressing the effects of alcohol drinking on D2R density have been inconsistent. Methods: A validated alcohol drinking model (intermittent access to 20% alcohol) in Wistar rats was used to study the effects of voluntary alcohol drinking (at least 12 weeks) on the D2R in the striatum compared to age-matched alcohol-naïve control rats. Reverse transcriptase quantitative PCR was used to quantify isoform-specific Drd2 gene expression levels. Using bisulfite pyrosequencing, DNA methylation levels of a regulatory region of the Drd2 gene were determined. In situ proximity ligation assay was used to measure densities of D2R receptor complexes: D2R-D2R, adenosine A2A receptor (A2AR)-D2R, and sigma1 receptor (sigma1R)-D2R. Results: Long-term voluntary alcohol drinking significantly reduced mRNA levels of the long D2R isoform in the nucleus accumbens (NAc) but did not alter CpG methylation levels in the analyzed sequence of the Drd2 gene. Alcohol drinking also reduced the striatal density of D2R-D2R homoreceptor complexes, increased the density of A2AR-D2R heteroreceptor complexes in the NAc shell and the dorsal striatum, and decreased the density of sigma1R-D2R heteroreceptor complexes in the dorsal striatum. Conclusions: The present results on long-term alcohol drinking might reflect reduced D2R levels through reductions in D2R-D2R homoreceptor complexes and gene expression. Furthermore, based on antagonistic interactions between A2AR and D2R, an increased density of A2AR-D2R heteroreceptor complexes might indicate a reduced affinity and signaling of the D2R population within the complex. Hence, both reduced striatal D2R levels and reduced D2R protomer affinity within the striatal A2AR-D2R complex might underlie reduced D2R radioligand binding in humans with AUD. This supports the hypothesis of a hypodopaminergic system in AUD and suggests the A2AR-D2R heteroreceptor complex as a potential novel treatment target.
A Novel Integrative Mechanism in Anxiolytic Behavior Induced by Galanin 2/Neuropeptide Y Y1 Receptor Interactions on Medial Paracapsular Intercalated Amygdala in Rats.
(2018-05-01) Narváez, Manuel; Borroto-Escuela, Dasiel O; Santín, Luis; Millán, Carmelo; Gago, Belén; Flores-Burgess, Antonio; Barbancho, Miguel A; Pérez de la Mora, Miguel; Narváez, José; Díaz-Cabiale, Zaida; Fuxe, Kjell
Anxiety is evoked by a threatening situation and display adaptive or defensive behaviors, found similarly in animals and humans. Neuropeptide Y (NPY) Y1 receptor (NPYY1R) and Galanin (GAL) receptor 2 (GALR2) interact in several regions of the limbic system, including the amygdala. In a previous study, GALR2 enhanced NPYY1R mediated anxiolytic actions on spatiotemporal parameters in the open field and elevated plus maze, involving the formation of GALR2/NPYY1R heteroreceptor complexes in the amygdala. Moreover, the inclusion of complementary ethological parameters provides a more comprehensive profile on the anxiolytic effects of a treatment. The purpose of the current study is to evaluate the anxiolytic effects and circuit activity modifications caused by coactivation of GALR2 and NPYY1R. Ethological measurements were performed in the open field, the elevated plus-maze and the light-dark box, together with immediate early gene expression analysis within the amygdala-hypothalamus-periaqueductal gray (PAG) axis, as well as in situ proximity ligation assay (PLA) to demonstrate the formation of GALR2/NPYY1R heteroreceptor complexes. GALR2 and NPYY1R coactivation resulted in anxiolytic behaviors such as increased rearing and head-dipping, reduced stretch attend postures and freezing compared to single agonist or aCSF injection. Neuronal activity indicated by cFos expression was decreased in the dorsolateral paracapsular intercalated (ITCp-dl) subregion of the amygdala, ventromedial hypothalamic (VMH) nucleus and ventrolateral part of the periaqueductal gray (vlPAG), while increased in the perifornical nucleus of the hypothalamus (PFX) following coactivation of GALR2 and NPYY1R. Moreover, an increased density of GALR2/NPYY1R heteroreceptor complexes was explicitly observed in ITCp-dl, following GALR2 and NPYY1R coactivation. Besides, knockdown of GALR2 was found to reduce the density of complexes in ITCp-dl. Taken together, these results open up the possibility that the increased anxiolytic activity demonstrated upon coactivation of NPYY1R and GALR2 receptor was related to actions on the ITCp-dl. GALR2-NPYY1R heteroreceptor complexes may inhibit neuronal activity, by also modifying the neuronal networks of the hypothalamus and the PAG. These results indicate that GALR2/NPYY1R interactions in medial paracapsular intercalated amygdala can provide a novel integrative mechanism in anxiolytic behavior and the basis for the development of heterobivalent agonist drugs targeting GALR2/NPYY1R heteromers, especially in the ITCp-dl of the amygdala for the treatment of anxiety.
Myocardial Bmp2 gain causes ectopic EMT and promotes cardiomyocyte proliferation and immaturity.
(2018-03-14) Prados, Belén; Gómez-Apiñániz, Paula; Papoutsi, Tania; Luxán, Guillermo; Zaffran, Stephane; Pérez-Pomares, José María; de la Pompa, José Luis; Prados, Belén; Gómez-Apiñániz, Paula; Papoutsi, Tania; Luxán, Guillermo; Zaffran, Stephane; Pérez-Pomares, José María; de la Pompa, José Luis
During mammalian heart development, restricted myocardial Bmp2 expression is a key patterning signal for atrioventricular canal specification and the epithelial-mesenchyme transition that gives rise to the valves. Using a mouse transgenic line conditionally expressing Bmp2, we show that widespread Bmp2 expression in the myocardium leads to valve and chamber dysmorphogenesis and embryonic death by E15.5. Transgenic embryos show thickened valves, ventricular septal defect, enlarged trabeculae and dilated ventricles, with an endocardium able to undergo EMT both in vivo and in vitro. Gene profiling and marker analysis indicate that cellular proliferation is increased in transgenic embryos, whereas chamber maturation and patterning are impaired. Similarly, forced Bmp2 expression stimulates proliferation and blocks cardiomyocyte differentiation of embryoid bodies. These data show that widespread myocardial Bmp2 expression directs ectopic valve primordium formation and maintains ventricular myocardium and cardiac progenitors in a primitive, proliferative state, identifying the potential of Bmp2 in the expansion of immature cardiomyocytes.
Updates on the hepatocyte growth factor/c-Met axis in hepatocellular carcinoma and its therapeutic implications.
(2018) García-Vilas, Javier A; Medina, Miguel Ángel
Hepatocellular carcinoma (HCC) is the fifth most common cancer and is the second leading cause of cancer death. Since the diagnosis of HCC is difficult, in many cases patients with HCC are diagnosed advanced stage of development. Hepatocyte growth factor (HGF)/c-mesenchymal-epithelial transition receptor (c-Met) axis is a key signaling pathway in HCC, either via canonical or non-canonical pathways. Available treatments against HCC based upon HGF/c-Met inhibition can increase patient lifespan, but do not reach the expected therapeutic benefits. In HCC, c-Met monomers can bind other receptor monomers, activating several noncanonical signaling pathways, leading to increased cell proliferation, invasion, motility, and drug resistance. All of these processes are enhanced by the tumor microenvironment, with stromal cells contributing to boost tumor progression through oxidative stress, angiogenesis, lymphangiogenesis, inflammation, and fibrosis. Novel treatments against HCC are being explored to modulate other targets such as microRNAs, methyltransferases, and acetyltransferases, which are all involved in the regulation of gene expression in cancer. This review compiles basic knowledge regarding signaling pathways in HCC, and compounds already used or showing potential to be used in clinical trials.
New insights of polyamine metabolism in testicular physiology: A role of ornithine decarboxylase antizyme inhibitor 2 (AZIN2) in the modulation of testosterone levels and sperm motility.
(2018-12-19) Lambertos, Ana; Ramos-Molina, Bruno; López-Contreras, Andrés J; Cremades, Asunción; Peñafiel, Rafael
The specific role of polyamines in the testis physiology is not fully understood. Antizymes (OAZs) and antizyme inhibitors (AZINs) are modulators of ornithine decarboxylase (ODC), a key enzyme in polyamine biosynthesis and polyamine uptake. Although the three known OAZs are expressed in the testis, only OAZ3 is testis specific and has been proven to have an essential role in male fertility. Regarding the two existing AZINs, AZIN2 is the most abundantly expressed member in this gonad. Whereas previous studies suggested that AZIN2 might participate in mouse spermatogenesis, immunohistological analysis of human testicular sections revealed that AZIN2 is also detected in the steroidogenic Leydig cells but not in the germinal epithelium. In the present study, we found a close ontogenic similarity in the mRNA levels of OAZs and AZINs between mice and rats, but an opposite expression pattern of ODC activity. Further analysis of AZIN2 and OAZ3 in the testis of mice with different alterations in spermatogenesis and fertility, induced either genetically or pharmacologically, corroborated that both AZIN2 and OAZ3 are mainly expressed in the haploid germinal cells. Finally, by using transgenic mice with a truncated Azin2 gene fused to the bacterial lacZ gene, we studied the expression of Azin2 in testes, epididymides and spermatozoa. AZIN2 was detected in spermatids and spermatozoa, as well as in Leydig cells, and in epithelial epidydimal cells. Azin2 knock-out male mice were fertile; however, they showed marked decreases in testicular putrescine and plasma and testicular testosterone levels, and a dramatic reduction in the sperm motility. These results suggest an important role for AZIN2 in testicular cells by modulating polyamine concentrations, testosterone synthesis and sperm function. Overall, our data corroborate the relevance of polyamine regulation in testis functions, where both AZIN2 and OAZ3 play fundamental roles.
Role of Gut Microbiota on Cardio-Metabolic Parameters and Immunity in Coronary Artery Disease Patients with and without Type-2 Diabetes Mellitus.
(2017-10-05) Sanchez-Alcoholado, Lidia; Castellano-Castillo, Daniel; Jordán-Martínez, Laura; Moreno-Indias, Isabel; Cardila-Cruz, Pilar; Elena, Daniel; Muñoz-Garcia, Antonio J; Queipo-Ortuño, Maria I; Jimenez-Navarro, Manuel
Gut microbiota composition has been reported as a factor linking host metabolism with the development of cardiovascular diseases (CVD) and intestinal immunity. Such gut microbiota has been shown to aggravate CVD by contributing to the production of trimethylamine N-oxide (TMAO), which is a pro-atherogenic compound. Treg cells expressing the transcription factor Forkhead box protein P3 (FoxP3) play an essential role in the regulation of immune responses to commensal microbiota and have an atheroprotective role. However, the aim of this study was to analyze the role of gut microbiota on cardio-metabolic parameters and immunity in coronary artery disease (CAD) patients with and without type-2 diabetes mellitus (DM2). The study included 16 coronary CAD-DM2 patients, and 16 age, sex, and BMI matched CAD patients without DM2 (CAD-NDM2). Fecal bacterial DNA was extracted and analyzed by sequencing in a GS Junior 454 platform followed by a bioinformatic analysis (QIIME and PICRUSt). The present study indicated that the diversity and composition of gut microbiota were different between the CAD-DM2 and CAD-NDM2 patients. The abundance of phylum Bacteroidetes was lower, whereas the phyla Firmicutes and Proteobacteria were higher in CAD-DM2 patients than those in the CAD-NDM2 group. CAD-DM2 patients had significantly less beneficial or commensal bacteria (such as Faecalibacterium prausnitzii and Bacteroides fragilis) and more opportunistic pathogens (such as Enterobacteriaceae, Streptococcus, and Desulfovibrio). Additionally, CAD-DM2 patients had significantly higher levels of plasma zonulin, TMAO, and IL-1B and significantly lower levels of IL-10 and FOXP3 mRNA expression than CAD-NDM2. Moreover, in the CAD-MD2 group, the increase in Enterobacteriaceae and the decrease in Faecalibacterium prausnitzii were significantly associated with the increase in serum TMAO levels, while the decrease in the abundance of Bacteroides fragilis was associated with the reduction in the FOXP3 mRNA expression, implicated in the development and function of Treg cells. These results suggest that the presence of DM2 is related to an impaired regulation of the immune system in CAD patients, mediated in part by the gut microbiota composition and functionality and the production and effects of their gut microbiota derived molecules.
Understanding the Role of GPCR Heteroreceptor Complexes in Modulating the Brain Networks in Health and Disease
(2017-02-21) Borroto-Escuela, Dasiel O; Carlsson, Jens; Ambrogini, Patricia; Narváez, Manuel; Wydra, Karolina; Tarakanov, Alexander O; Li, Xiang; Millán, Carmelo; Ferraro, Luca; Cuppini, Riccardo; Tanganelli, Sergio; Liu, Fang; Filip, Malgorzata; Diaz-Cabiale, Zaida; Fuxe, Kjell
The introduction of allosteric receptor-receptor interactions in G protein-coupled receptor (GPCR) heteroreceptor complexes of the central nervous system (CNS) gave a new dimension to brain integration and neuropsychopharmacology. The molecular basis of learning and memory was proposed to be based on the reorganization of the homo- and heteroreceptor complexes in the postjunctional membrane of synapses. Long-term memory may be created by the transformation of parts of the heteroreceptor complexes into unique transcription factors which can lead to the formation of specific adapter proteins. The observation of the GPCR heterodimer network (GPCR-HetNet) indicated that the allosteric receptor-receptor interactions dramatically increase GPCR diversity and biased recognition and signaling leading to enhanced specificity in signaling. Dysfunction of the GPCR heteroreceptor complexes can lead to brain disease. The findings of serotonin (5-HT) hetero and isoreceptor complexes in the brain over the last decade give new targets for drug development in major depression. Neuromodulation of neuronal networks in depression via 5-HT, galanin peptides and zinc involve a number of GPCR heteroreceptor complexes in the raphe-hippocampal system: GalR1-5-HT1A, GalR1-5-HT1A-GPR39, GalR1-GalR2, and putative GalR1-GalR2-5-HT1A heteroreceptor complexes. The 5-HT1A receptor protomer remains a receptor enhancing antidepressant actions through its participation in hetero- and homoreceptor complexes listed above in balance with each other. In depression, neuromodulation of neuronal networks in the raphe-hippocampal system and the cortical regions via 5-HT and fibroblast growth factor 2 involves either FGFR1-5-HT1A heteroreceptor complexes or the 5-HT isoreceptor complexes such as 5-HT1A-5-HT7 and 5-HT1A-5-HT2A. Neuromodulation of neuronal networks in cocaine use disorder via dopamine (DA) and adenosine signals involve A2AR-D2R and A2AR-D2R-Sigma1R heteroreceptor complexes in the dorsal and ventral striatum. The excitatory modulation by A2AR agonists of the ventral striato-pallidal GABA anti-reward system via targeting the A2AR-D2R and A2AR-D2R-Sigma1R heteroreceptor complex holds high promise as a new way to treat cocaine use disorders. Neuromodulation of neuronal networks in schizophrenia via DA, adenosine, glutamate, 5-HT and neurotensin peptides and oxytocin, involving A2AR-D2R, D2R-NMDAR, A2AR-D2R-mGluR5, D2R-5-HT2A and D2R-oxytocinR heteroreceptor complexes opens up a new world of D2R protomer targets in the listed heterocomplexes for treatment of positive, negative and cognitive symptoms of schizophrenia.
Drug-induced liver injury: recent advances in diagnosis and risk assessment.
(2017-03-23) Kullak-Ublick, Gerd A; Andrade, Raul J; Merz, Michael; End, Peter; Benesic, Andreas; Gerbes, Alexander L; Aithal, Guruprasad P
Idiosyncratic drug-induced liver injury (IDILI) is a rare but potentially severe adverse drug reaction that should be considered in patients who develop laboratory criteria for liver injury secondary to the administration of a potentially hepatotoxic drug. Although currently used liver parameters are sensitive in detecting DILI, they are neither specific nor able to predict the patient's subsequent clinical course. Genetic risk assessment is useful mainly due to its high negative predictive value, with several human leucocyte antigen alleles being associated with DILI. New emerging biomarkers which could be useful in assessing DILI include total keratin18 (K18) and caspase-cleaved keratin18 (ccK18), macrophage colony-stimulating factor receptor 1, high mobility group box 1 and microRNA-122. From the numerous in vitro test systems that are available, monocyte-derived hepatocytes generated from patients with DILI show promise in identifying the DILI-causing agent from among a panel of coprescribed drugs. Several computer-based algorithms are available that rely on cumulative scores of known risk factors such as the administered dose or potential liabilities such as mitochondrial toxicity, inhibition of the bile salt export pump or the formation of reactive metabolites. A novel DILI cluster score is being developed which predicts DILI from multiple complimentary cluster and classification models using absorption-distribution-metabolism-elimination-related as well as physicochemical properties, diverse substructural descriptors and known structural liabilities. The provision of more advanced scientific and regulatory guidance for liver safety assessment will depend on validating the new diagnostic markers in the ongoing DILI registries, biobanks and public-private partnerships.
Phosphorylation of gH2AX as a novel prognostic biomarker for laryngoesophageal dysfunction-free survival
(2016) de Miguel-Luken, María José; Chaves-Conde, Manuel; Quintana, Begoña; Menoyo, Alicia; Tirado, Isabel; de Miguel-Luken, Verónica; Pachón, Jerónimo; Chinchón, David; Suarez, Vladimir; Carnero, Amancio
Current larynx preservation treatments have achieved an improvement of laryngoesophageal dysfunction-free survival (LDS) but lead to significant toxicities and recurrences. At present, there is no evidence to select the group of patients that may benefit from preservation approaches instead of surgery. Therefore, laryngeal biomarkers could facilitate pretreatment identification of patients who could respond to chemoradiation-based therapy. In this study, we evaluated retrospectively 53 patients with larynx cancer to determine whether gH2AX phosphorylation (pH2AX) alone or in combination with the membrane protein MAP17 (PDZK1IP1) could be used as prognostic biomarkers. We also evaluated whether the completion of cisplatin treatment and radiotherapy could predict survival in combination with pH2AX.We found that the dose of cisplatin received but not the length of the radiotherapy influenced LDS. High-pH2AX expression was associated with prolonged LDS (HR 0.26, p = 0.02) while MAP17 correlated with overall survival (OS) (HR 0.98, p = 0.05). High-MAP17 and high-pH2AX combined analysis showed improved LDS (with 61.35 months vs 32.2 months, p = 0.05) and OS (with 66.6 months vs 39.8 months, p = 0.01). Furthermore, the subgroup of high-pH2AX and optimal dose of cisplatin was also associated with OS (72 months vs 38.6 months, p = 0.03) and LDS (66.9 months vs 27 months, p = 0.017). These findings suggest that pH2AX alone or better in combination with MAP17 may become a novel and valuable prognostic biomarker for patients with laryngeal carcinoma treated with preservation approaches.
Dasatinib, a Src inhibitor, sensitizes liver metastatic colorectal carcinoma to oxaliplatin in tumors with high levels of phospho-Src
(2016-05) Perez, Marco; Lucena-Cacace, Antonio; Marín-Gómez, Luis Miguel; Padillo-Ruiz, Javier; Robles-Frias, Maria Jose; Saez, Carmen; Garcia-Carbonero, Rocio; Carnero, Amancio
Despite the development of new antineoplastic agents for the treatment of colorectal cancer (CRC), oxaliplatin and fluoropyrimidines remain the most commonly employed drugs for the treatment of both early and advanced disease. Intrinsic or acquired resistance is, however, an important limitation to pharmacological therapy, and the development of chemosensitization strategies constitute a major goal with important clinical implications. In the present work, we determined that high levels of activated Src kinase, measured as phospho-Src at the Tyr419 residue in CRC cell lines, can promote colorectal carcinoma cell resistance to oxaliplatin, but not to 5-fluorouracil (5FU), and that inhibition of this protein restores sensitivity to oxaliplatin. Similar results were observed with in vivo patient-derived xenograft (PDX) models that were orthotopically grown in murine livers. In PDX tumor lines derived from human CRC liver metastasis, dasatinib, a Src inhibitor, increases sensitivity to oxaliplatin only in tumors with high p-Src. However, dasatinib did not modify sensitivity to 5FU in any of the models. Our data suggest that chemoresistance induced by p-Src is specific to oxaliplatin, and that p-Src levels can be used to identify patients who may benefit from this combination therapy. These results are relevant for clinicians as they identify a novel biomarker of drug resistance that is suitable to pharmacological manipulation.
3D VMAT Verification Based on Monte Carlo Log File Simulation with Experimental Feedback from Film Dosimetry
(2016-11-21) Barbeiro, A R; Ureba, A; Baeza, J A; Linares, R; Perucha, M; Jiménez-Ortega, E; Velázquez, S; Mateos, J C; Leal, A
A model based on a specific phantom, called QuAArC, has been designed for the evaluation of planning and verification systems of complex radiotherapy treatments, such as volumetric modulated arc therapy (VMAT). This model uses the high accuracy provided by the Monte Carlo (MC) simulation of log files and allows the experimental feedback from the high spatial resolution of films hosted in QuAArC. This cylindrical phantom was specifically designed to host films rolled at different radial distances able to take into account the entrance fluence and the 3D dose distribution. Ionization chamber measurements are also included in the feedback process for absolute dose considerations. In this way, automated MC simulation of treatment log files is implemented to calculate the actual delivery geometries, while the monitor units are experimentally adjusted to reconstruct the dose-volume histogram (DVH) on the patient CT. Prostate and head and neck clinical cases, previously planned with Monaco and Pinnacle treatment planning systems and verified with two different commercial systems (Delta4 and COMPASS), were selected in order to test operational feasibility of the proposed model. The proper operation of the feedback procedure was proved through the achieved high agreement between reconstructed dose distributions and the film measurements (global gamma passing rates > 90% for the 2%/2 mm criteria). The necessary discretization level of the log file for dose calculation and the potential mismatching between calculated control points and detection grid in the verification process were discussed. Besides the effect of dose calculation accuracy of the analytic algorithm implemented in treatment planning systems for a dynamic technique, it was discussed the importance of the detection density level and its location in VMAT specific phantom to obtain a more reliable DVH in the patient CT. The proposed model also showed enough robustness and efficiency to be considered as a pre-treatment VMAT verification system.
The role of PIM1/PIM2 kinases in tumors of the male reproductive system
(2016-11-30) Jiménez-García, Manuel Pedro; Lucena-Cacace, Antonio; Robles-Frías, María José; Narlik-Grassow, Maja; Blanco-Aparicio, Carmen; Carnero, Amancio; Jiménez-García, Manuel Pedro; Lucena-Cacace, Antonio; Robles-Frías, María José; Narlik-Grassow, Maja; Blanco-Aparicio, Carmen; Carnero, Amancio
The PIM family of serine/threonine kinases has three highly conserved isoforms (PIM1, PIM2 and PIM3). PIM proteins are regulated through transcription and stability by JAK/STAT pathways and are overexpressed in hematological malignancies and solid tumors. The PIM kinases possess weak oncogenic abilities, but enhance other genes or chemical carcinogens to induce tumors. We generated conditional transgenic mice that overexpress PIM1 or PIM2 in male reproductive organs and analyzed their contribution to tumorigenesis. We found an increase in alterations of sexual organs and hyperplasia in the transgenic mice correlating with inflammation. We also found that PIM1/2 are overexpressed in a subset of human male germ cells and prostate tumors correlating with inflammatory features and stem cell markers. Our data suggest that PIM1/2 kinase overexpression is a common feature of male reproductive organs tumors, which provoke tissue alterations and a large inflammatory response that may act synergistically during the process of tumorigenesis. There is also a correlation with markers of cancer stem cells, which may contribute to the therapy resistance found in tumors overexpressing PIM kinases.
RING1B contributes to Ewing sarcoma development by repressing the NaV1.6 sodium channel and the NF-κB pathway, independently of the fusion oncoprotein
(2016) Hernandez-Muñoz, Inmaculada; Figuerola, Elisabeth; Sanchez-Molina, Sara; Rodriguez, Eva; Fernández-Mariño, Ana Isabel; Pardo-Pastor, Carlos; Bahamonde, María Isabel; Fernández-Fernández, José M; García-Domínguez, Daniel J; Hontecillas-Prieto, Lourdes; Lavarino, Cinzia; Carcaboso, Angel M; de Torres, Carmen; Tirado, Oscar M; de Álava, Enrique; Mora, Jaume
Ewing sarcoma (ES) is an aggressive tumor defined by EWSR1 gene fusions that behave as an oncogene. Here we demonstrate that RING1B is highly expressed in primary ES tumors, and its expression is independent of the fusion oncogene. RING1B-depleted ES cells display an expression profile enriched in genes functionally involved in hematological development but RING1B depletion does not induce cellular differentiation. In ES cells, RING1B directly binds the SCN8A sodium channel promoter and its depletion results in enhanced Nav1.6 expression and function. The signaling pathway most significantly modulated by RING1B is NF-κB. RING1B depletion results in enhanced p105/p50 expression, which sensitizes ES cells to apoptosis by FGFR/SHP2/STAT3 blockade. Reduced NaV1.6 function protects ES cells from apoptotic cell death by maintaining low NF-κB levels. Our findings identify RING1B as a trait of the cell-of-origin and provide a potential targetable vulnerability.
SEOM clinical guidelines for the management of germ cell testicular cancer (2016)
(2016-11-04) Aparicio, J; Terrasa, J; Durán, I; Germà-Lluch, J R; Gironés, R; González-Billalabeitia, E; Gumà, J; Maroto, P; Pinto, A; García-Del-Muro, X
Testicular cancer represents the most common malignancy in males aged 15-34 years and is considered a model of curable neoplasm. Maintaining success, reducing treatment burden, and focusing on survivorship are then key objectives. Inguinal orchiectomy is the first recommended maneuver that has both diagnostic and therapeutic aims. Most patients are diagnosed with stage I disease (confined to the testicle). Close surveillance and selective, short-course adjuvant chemotherapy are accepted alternatives for these cases. In patients with more advanced disease (stages II and III), 3-4 courses of cisplatin-based chemotherapy (according to IGCCCG risk classification) followed by the judicious surgical removal of residual masses represent the cornerstone of therapy. Poor-risk patients and those failing a first-line therapy should be referred to specialized tertiary centers. Paclitaxel-based conventional chemotherapy and high-dose chemotherapy plus autologous hematopoietic support can cure a proportion of patients with relapsing or refractory disease.
Numb-like (NumbL) downregulation increases tumorigenicity, cancer stem cell-like properties and resistance to chemotherapy
(2016) García-Heredia, José M; Verdugo Sivianes, Eva M; Lucena-Cacace, Antonio; Molina-Pinelo, Sonia; Carnero, Amancio
NumbL, or Numb-like, is a close homologue of Numb, and is part of an evolutionary conserved protein family implicated in some important cellular processes. Numb is a protein involved in cell development, in cell adhesion and migration, in asymmetric cell division, and in targeting proteins for endocytosis and ubiquitination. NumbL exhibits some overlapping functions with Numb, but its role in tumorigenesis is not fully known. Here we showed that the downregulation of NumbL alone is sufficient to increase NICD nuclear translocation and induce Notch pathway activation. Furthermore, NumbL downregulation increases epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC)-related gene transcripts and CSC-like phenotypes, including an increase in the CSC-like pool. These data suggest that NumbL can act independently as a tumor suppressor gene. Furthermore, an absence of NumbL induces chemoresistance in tumor cells. An analysis of human tumors indicates that NumbL is downregulated in a variable percentage of human tumors, with lower levels of this gene correlated with worse prognosis in colon, breast and lung tumors. Therefore, NumbL can act as an independent tumor suppressor inhibiting the Notch pathway and regulating the cancer stem cell pool.

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