FUNCTIONAL GENOMICS IN PRIMARY T CELLS AND MONOCYTES IDENTIFIES MECHANISMS BY WHICH GENETIC SUSCEPTIBILITY LOCI INFLUENCE SYSTEMIC SCLEROSIS RISK.

Congresos y Conferencias: Comunicación de congreso- Conferencia invitada.Winner of EULAR 2022 Abstract Award in the category of Basic Scienc

Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis

Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals.MCIN/AEI by "ERDF A way of making Europe" RTI2018101332-B-100Red de Investigacion en Inflamacion y Enfermedades Reumaticas (RIER) from Instituto de Salud Carlos III RD16/0012/0013Innovative Medicines Initiative 1 & 2 Joint Undertaking (JU) 115565 831434European Union's FP7 and Horizon 2020 research and innovation programsEFPIAJuan de la Cierva Incorporacion program - MCIN/AEI IJC2018-035131-

The Effect of Body Fat Distribution on Systemic Sclerosis

Obesity contributes to a chronic proinflammatory state, which is a known risk factor to develop immune-mediated diseases. However, its role in systemic sclerosis (SSc) remains to be elucidated. Therefore, we conducted a two-sample mendelian randomization (2SMR) study to analyze the effect of three body fat distribution parameters in SSc. As instrumental variables, we used the allele effects described for single nucleotide polymorphisms (SNPs) in different genomewide association studies (GWAS) for SSc, body mass index (BMI), waist-to-hip ratio (WHR) and WHR adjusted for BMI (WHRadjBMI). We performed local (pHESS) and genome-wide (LDSC) genetic correlation analyses between each of the traits and SSc and we applied several Mendelian randomization (MR) methods (i.e., random effects inverse-variance weight, MR-Egger regression, MR pleiotropy residual sum and outlier method and a multivariable model). Our results show no genetic correlation or causal relationship between any of these traits and SSc. Nevertheless, we observed a negative causal association between WHRadjBMI and SSc, which might be due to the effect of gastrointestinal complications suffered by the majority of SSc patients. In conclusion, reverse causality might be an especially difficult confounding factor to define the effect of obesity in the onset of SSc.MCIN/AEI RTI2018101332-B-100 IJC2018-038026-I IJC2019-040080-I PRE2019-087586"ERDF A way of making Europe" - European UnionRed de Investigacion en Inflamacion y Enfermedades Reumaticas (RIER) from Instituto de Salud Carlos III RD16/0012/0013ESF Investing in your futur

FUNDAMENTOS EMPÍRICOS Y METODOLÓGICOS DE UNA BASE DE DATOS LÉXICA DE LA MORFOLOGÍA DERIVATIVA DEL INGLÉS ANTIGUO

[EN] This article lays the empirical and methodological basis for the development of a lexical database that analyses the dervative morphology of Old English. After revising the state of the art, the working hypotheses are established and the descriptive principles for the analysis of trnasparent as well as opaque derivation are established. Finally, a step is taken in the explanatory direction by defining the paramenters of the analysis of the bases and adjunts of derivation that are relevant for explanation.[ES] Este trabajo sienta las bases empíricas y metodológicas para la creación de una base de datos léxica que analice la morfología derivativa del inglés antiguo. Se revisa el estado de la cuestión, se formulan las hipótesis de partida, se proponen los principios descriptivos para el análisis de la derivación transparente y opaca y se avanza en la dirección explicativa al establecer los parámetros de análisis de las bases y de los adjuntos de las derivaciones que son relevantes para las explicaciones.La investigación de la que se da cuenta en este trabajo se ha financiado con cargo al proyecto HUM2005-07651-C02-02/FILOTorre Alonso, R.; Martín Arista, J.; Ibáñez Moreno, A.; González Torres, E.; Caballero González, L. (2008). FUNDAMENTOS EMPÍRICOS Y METODOLÓGICOS DE UNA BASE DE DATOS LÉXICA DE LA MORFOLOGÍA DERIVATIVA DEL INGLÉS ANTIGUO. Revista de Lingüística y Lenguas Aplicadas. 3:129-144. doi:10.4995/rlyla.2008.696SWORD129144

Epilepsy surgery in drug resistant temporal lobe epilepsy associated with neuronal antibodies

We assessed the outcome of patients with drug resistant epilepsy and neuronal antibodies who underwent epilepsy surgery. Retrospective study, information collected with a questionnaire sent to epilepsy surgery centers. Thirteen patients identified, with antibodies to GAD (8), Ma2 (2), Hu (1), LGI1 (1) or CASPR2 (1). Mean age at seizure onset: 23 years. Five patients had an encephalitic phase. Three had testicular tumors and five had autoimmune diseases. All had drug resistant temporal lobe epilepsy (median: 20 seizures/month). MRI showed unilateral temporal lobe abnormalities (mainly hippocampal sclerosis) in 9 patients, bilateral abnormalities in 3, and was normal in 1. Surgical procedures included anteromesial temporal lobectomy (10 patients), selective amygdalohippocampectomy (1), temporal pole resection (1) and radiofrequency ablation of mesial structures (1). Perivascular lymphocytic infiltrates were seen in 7/12 patients. One year outcome available in all patients, at 3 years in 9. At last visit 5/13 patients (38.5%) (with Ma2, Hu, LGI1, and 2 GAD antibodies) were in Engel's classes I or II. Epilepsy surgery may be an option for patients with drug resistant seizures associated with neuronal antibodies. Outcome seems to be worse than that expected in other etiologies, even in the presence of unilateral HS. Intracranial EEG may be required in some patients

Randomized-controlled trial of the DIALIVE liver dialysis device vs. standard of care in patients with acute-on-chronic liver failure

BACKGROUND AND AIMS: Acute on chronic liver failure (ACLF) is characterized by severe systemic inflammation, multi-organ failure and high mortality rates. Its treatment is an urgent unmet need. DIALIVE is a novel liver dialysis device that aims to exchange d ysfunctional albumin and remove damage- and pathogen-associated molecular patterns. This first-in-man randomized, controlled clinical trial was performed with the primary aim of assessing its safety in ACLF patients with secondary aims to evaluate its clinical effects, device performance and effect on pathophysiologically-relevant biomarkers. METHODS: 32 alcoholic cirrhosis patients with ACLF were included. Patients were treated with DIALIVE for up to 5-days and end points were assessed at Day-10. Safety was assessed in all patients (n=32). The secondary aims were assessed in a pre-specified subgroup that had at least 3-treatment sessions with DIALIVE (n=30). RESULTS: There were no significant differences in 28-day mortality or occurrence of serious adverse events between the groups. Significant reduction in the severity of endotoxemia and improvement in albumin function was observed in DIALIVE group, which translated into a significant reduction in the CLIF-C (Chronic Liver Failure consortium) organ failure (p=0.018) and CLIF-C ACLF scores (p=0.042) at Day-10. Time to resolution of ACLF was significantly faster in DIALIVE group (p=0.036). Biomarkers of systemic inflammation such as IL-8 (p=0.006), cell death [cytokeratin-18: M30 (p=0.005) and M65 (p=0.029)], endothelial function [asymmetric dimethylarginine (p=0.002)] and, ligands for toll-like receptor 4 (p=0.030) and inflammasome (p=0.002) improved significantly in DIALIVE group. CONCLUSIONS: These data indicate that DIALIVE appears to be safe and impacts positively on prognostic scores and pathophysiologically relevant biomarkers in patients with ACLF. Larger, adequately powered studies are warranted to further confirm its safety and efficacy. LAY SUMMARY: This is the first-in-man clinical trial which tested DIALIVE, a novel liver dialysis device for the treatment of liver cirrhosis and acute on chronic liver failure, a condition associated with severe inflammation, organ failures and a high risk of death. The study met the primary end point confirming DIALIVE system to be safe. Additionally, it reduced inflammation with improved clinical parameters. It did not, however, reduce mortality in this small study and requires further larger clinical trials to re-confirm its safety and evaluate efficacy. CLINICAL TRIAL NUMBER: NCT03065699

Priorities in Cardio-Oncology Basic and Translational Science

Despite improvements in cancer survival, cancer therapy–related cardiovascular toxicity has risen to become a prominent clinical challenge. This has led to the growth of the burgeoning field of cardio-oncology, which aims to advance the cardiovascular health of cancer patients and survivors, through actionable and translatable science. In these Global Cardio-Oncology Symposium 2023 scientific symposium proceedings, we present a focused review on the mechanisms that contribute to common cardiovascular toxicities discussed at this meeting, the ongoing international collaborative efforts to improve patient outcomes, and the bidirectional challenges of translating basic research to clinical care. We acknowledge that there are many additional therapies that are of significance but were not topics of discussion at this symposium. We hope that through this symposium-based review we can highlight the knowledge gaps and clinical priorities to inform the design of future studies that aim to prevent and mitigate cardiovascular disease in cancer patients and survivors.</p

Glyphosate detection by voltammetric techniques. A comparison between statistical methods and an artificial neural network

Glyphosate quantification methods are complex and expensive, and its control in natural water bodies is getting more important year after year. In order to find a new system that facilitates the detection of glyphosate, we present a comparison between two models to predict glyphosate concentration in aqueous dissolutions. One of them is done by an artificial neural network (ANN) embedded in a microcontroller and the other one is done by statistic methods (Partial Least Squares) in a computer. From an analytical point of view, voltammetric techniques have been selected to obtain electrochemical responses to different glyphosate concentrations. In order to get them, a voltammetry/amperometry device designed by our research group and called FraPlus has been used. In this work we have selected two sensitive electrodes (cobalt and copper), 10 different glyphosate concentrations and a train pulse made by nine different voltammetric pulses to build the models. The ANN developed model is able to properly relate data obtained by FraPlus and glyphosate concentrations and the obtained value for regression coefficient (R) is 0.9998 and the P-value is 0.0. Taking into account these results, we propose this ANN model based in voltammetric techniques working with glyphosate concentrations in a buffer as an approach to glyphosate detection in natural water bodies.Authors acknowledge financial support from the Universitat Politecnica de Valencia and its Centre de Cooperacio al Desenvolupament (Programa ADSIDEO-COOPERACIO 2010) for the research fellowship and support given by UNIJUI University & Staff during the stage of Prof. Laguarda in Ijui (RS-Brazil). We also thank MICINN (MAT2009-14564-C04-02) and GVA (PPC/2011/019) for their respective research fellowships.Laguarda-Miro, N.; Werner Ferreira, F.; Garcia-Breijo, E.; Ibáñez Civera, FJ.; Gil Sánchez, L.; Garrigues Baixauli, J. (2012). Glyphosate detection by voltammetric techniques. A comparison between statistical methods and an artificial neural network. Sensors and Actuators B: Chemical. 171-172:528-536. https://doi.org/10.1016/j.snb.2012.05.025S528536171-17

Central Pathology Review in SENTIX, a Prospective Observational International Study on Sentinel Lymph Node Biopsy in Patients with Early-Stage Cervical Cancer (ENGOT-CX2)

The quality of pathological assessment is crucial for the safety of patients with cervical cancer if pelvic lymph node dissection is to be replaced by sentinel lymph node (SLN) biopsy. Central pathology review of SLN pathological ultrastaging was conducted in the prospective SENTIX/European Network of Gynaecological Oncological Trial (ENGOT)-CX2 study. All specimens from at least two patients per site were submitted for the central review. For cases with major or critical deviations, the sites were requested to submit all samples from all additional patients for second-round assessment. From the group of 300 patients, samples from 83 cases from 37 sites were reviewed in the first round. Minor, major, critical, and no deviations were identified in 28%, 19%, 14%, and 39% of cases, respectively. Samples from 26 patients were submitted for the second-round review, with only two major deviations found. In conclusion, a high rate of major or critical deviations was identified in the first round of the central pathology review (28% of samples). This reflects a substantial heterogeneity in current practice, despite trial protocol requirements. The importance of the central review conducted prospectively at the early phase of the trial is demonstrated by a substantial improvement of SLN ultrastaging quality in the second-round review