Polipéptido quimérico fibrina-filagrina citrulinado capaz de detectar los anticuerpos generados en la artritis reumatoide

Peer reviewedConsejo Superior de Investigaciones Científicas, Fundació Clinic per a la Recerca BiomédicaT3 Traducción de patente europe

Notch1 signaling in NOTCH1-mutated mantle cell lymphoma depends on Delta-Like ligand 4 and is a potential target for specific antibody therapy.

Background NOTCH1 gene mutations in mantle cell lymphoma (MCL) have been described in about 5-10% of cases and are associated with significantly shorter survival rates. The present study aimed to investigate the biological impact of this mutation in MCL and its potential as a therapeutic target. Methods Activation of Notch1 signaling upon ligand-stimulation and inhibitory effects of the monoclonal anti-Notch1 antibody OMP-52M51 in NOTCH1-mutated and -unmutated MCL cells were assessed by Western Blot and gene expression profiling. Effects of OMP-52M51 treatment on tumor cell migration and tumor angiogenesis were evaluated with chemotaxis and HUVEC tube formation assays. The expression of Delta-like ligand 4 (DLL4) in MCL lymph nodes was analyzed by immunofluorescence staining and confocal microscopy. A MCL mouse model was used to assess the activity of OMP-52M51 in vivo. Results Notch1 expression can be effectively stimulated in NOTCH1-mutated Mino cells by DLL4, whereas in the NOTCH1-unmutated cell line JeKo-1, less effect was observed upon any ligand-stimulation. DLL4 was expressed by histiocytes in both, NOTCH1-mutated and -unmutated MCL lymph nodes. Treatment of NOTCH1-mutated MCL cells with the monoclonal anti-Notch1 antibody OMP-52M51 effectively prevented DLL4-dependent activation of Notch1 and suppressed the induction of numerous direct Notch target genes involved in lymphoid biology, lymphomagenesis and disease progression. Importantly, in lymph nodes from primary MCL cases with NOTCH1/2 mutations, we detected an upregulation of the same gene sets as observed in DLL4-stimulated Mino cells. Furthermore, DLL4 stimulation of NOTCH1-mutated Mino cells enhanced tumor cell migration and angiogenesis, which could be abolished by treatment with OMP-52M51. Importantly, the effects observed were specific for NOTCH1-mutated cells as they did not occur in the NOTCH1-wt cell line JeKo-1. Finally, we confirmed the potential activity of OMP-52M51 to inhibit DLL4-induced Notch1-Signaling in vivo in a xenograft mouse model of MCL. Conclusion DLL4 effectively stimulates Notch1 signaling in NOTCH1-mutated MCL and is expressed by the microenvironment in MCL lymph nodes. Our results indicate that specific inhibition of the Notch1-ligand-receptor interaction might provide a therapeutic alternative for a subset of MCL patients

Genetic variation associated with cardiovascular risk in autoimmune diseases

Autoimmune diseases have a higher prevalence of cardiovascular events compared to the general population. The objective of this study was to investigate the genetic basis of cardiovascular disease (CVD) risk in autoimmunity. We analyzed genome-wide genotyping data from 6,485 patients from six autoimmune diseases that are associated with a high socio-economic impact. First, for each disease, we tested the association of established CVD risk loci. Second, we analyzed the association of autoimmune disease susceptibility loci with CVD. Finally, to identify genetic patterns associated with CVD risk, we applied the cross-phenotype meta-analysis approach (CPMA) on the genome-wide data. A total of 17 established CVD risk loci were significantly associated with CVD in the autoimmune patient cohorts. From these, four loci were found to have significantly different genetic effects across autoimmune diseases. Six autoimmune susceptibility loci were also found to be associated with CVD risk. Genome-wide CPMA analysis identified 10 genetic clusters strongly associated with CVD risk across all autoimmune diseases. Two of these clusters are highly enriched in pathways previously associated with autoimmune disease etiology (TNF? and IFN? cytokine pathways). The results of this study support the presence of specific genetic variation associated with the increase of CVD risk observed in autoimmunity

Miniatures from domestic contexts in Iron age Iberia

This article reviews a set of miniatures from domestic contexts in Iron Age eastern Iberia, and interprets them in terms of their role in forging social personae. After an introduction to the historical case under consideration, the miniatures are described in terms of their typology and their contexts of provenance are outlined. Though not abundant, they tend to occur in central places in the landscape; specifically, they are often found in houses of the powerful. The vast majority are miniatures of pottery and tools, though some miniature weapons are recorded. We contend that these objects were used as a means of enculturation and for the learning of values and norms. It is no coincidence that they emerge in the archaeological record of Iron Age Iberia at the same time as the rise of a social structure based on hereditary power

Cut-offs and response criteria for the Hospital Universitario la Princesa Index (HUPI) and their comparison to widely-used indices of disease activity in rheumatoid arthritis

Objective To estimate cut-off points and to establish response criteria for the Hospital Universitario La Princesa Index (HUPI) in patients with chronic polyarthritis. Methods Two cohorts, one of early arthritis (Princesa Early Arthritis Register Longitudinal PEARL] study) and other of long-term rheumatoid arthritis (Estudio de la Morbilidad y Expresión Clínica de la Artritis Reumatoide EMECAR]) including altogether 1200 patients were used to determine cut-off values for remission, and for low, moderate and high activity through receiver operating curve (ROC) analysis. The areas under ROC (AUC) were compared to those of validated indexes (SDAI, CDAI, DAS28). ROC analysis was also applied to establish minimal and relevant clinical improvement for HUPI. Results The best cut-off points for HUPI are 2, 5 and 9, classifying RA activity as remission if =2, low disease activity if >2 and =5), moderate if >5 and <9 and high if =9. HUPI''s AUC to discriminate between low-moderate activity was 0.909 and between moderate-high activity 0.887. DAS28''s AUCs were 0.887 and 0.846, respectively; both indices had higher accuracy than SDAI (AUCs: 0.832 and 0.756) and CDAI (AUCs: 0.789 and 0.728). HUPI discriminates remission better than DAS28-ESR in early arthritis, but similarly to SDAI. The HUPI cut-off for minimal clinical improvement was established at 2 and for relevant clinical improvement at 4. Response criteria were established based on these cut-off values. Conclusions The cut-offs proposed for HUPI perform adequately in patients with either early or long term arthritis

Les col·leccions de mineralogia de la UB. Una eina d'aprenentatge i de participació dels estudiants

Les col·leccions de Mineralogia de la Universitat de Barcelona poden ser de litoteca (emprades en l'ensenyament presencial i no presencial) i sistemàtica (usades com a material de referència de recerca). Comprenen mostres de mà, làmines primes i probetes. Les col leccions de referència son controlades per estudiants, els quals comproven la identitat del mineral i en fan la catalogació. Així s'introdueix els estudiants en les tècniques de caracterització i en les tècniques de musealització

Antibodies to citrullinated human fibrinogen synthetic peptides in diagnosing rheumatoid arthritis

12 pages, 9 figures.-- PMID: 17585853 [PubMed].-- Printed version published on Jul 26, 2007.-- Supplementary information (figs. S1-S7, tables S1-S2, 25 pages) available at: http://pubs.acs.org/doi/suppl/10.1021/jm0701932/suppl_file/jm0701932si20070529_011932.pdfSince aggressive therapy given early in the rheumatoid arthritis (RA) disease course has the greatest therapeutic potential, early diagnostic tests with both high specificity and sensitivity are desirable. Rheumatoid sera were found to contain antibodies against citrullinated peptides, which are considered to be highly specific markers of RA. In the present work several analogues of the α- and β-chains of fibrin peptides containing different degrees of citrullination have been synthesized and analyzed by ELISA using 111 sera from RA patients. In addition, we have also investigated the synergistic effects of different presentation formats of the synthetic constructs. We have designed chimeric and cyclic peptides that bear different peptide sequences within the same molecule. Our results indicate that the synthesis of peptides bearing fibrinogen and filaggrin domains could be a robust method for the design of useful diagnostic strategies in RA.This work was funded by Grant 030331 from the Fundació La Marató TV3, Catalonia, Spain.Peer reviewe

Antibodies against β-fibrin synthetic peptides: A study of their association with the immunogenetic background and disease course of rheumatoid arthritis patients

Preliminary studies have shown the potential application for the diagnosis of Rheumatoid Arthritis (RA) patients with a severe disease course of an epitopic domain of β-fibrin. The aim of the present work was the analysis of the presence of antibodies against several β-fibrin synthetic peptides in relation to the immunogenetic background and disease course in a clinically well-defined RA patient cohort. Our results indicated that positive patients against anti-β-fibrin synthetic peptides have a higher percentage of HLA-DRB1 shared epitope (SE) than negative patients. We also observed that the presence of SE alleles was significantly associated with a higher level of anti-[Cit376]βfib(365–383) antibodies. When analyzing the effect of different SE alleles, we found a significant positive association between carriers of QRRAA allele and [Cit376]βfib(365–383) (Odds ratio 3.77; CI95%: 1.41–10.08). These results suggest that the anti-β-fibrin status is associated with the immunogenetic background of RA patients.This study was supported by a public grant from the Fundació Marató de TV3 (030330 and 030331), Catalonia, Spain. The statistical support of Miguel Sampayo, Carlos Iglesias and María José Bleda is gratefully acknowledged.Peer reviewe

Genetic variation associated with cardiovascular risk in autoimmune diseases

Autoimmune diseases have a higher prevalence of cardiovascular events compared to the general population. The objective of this study was to investigate the genetic basis of cardiovascular disease (CVD) risk in autoimmunity. We analyzed genome-wide genotyping data from 6,485 patients from six autoimmune diseases that are associated with a high socioeconomic impact. First, for each disease, we tested the association of established CVD risk loci. Second, we analyzed the association of autoimmune disease susceptibility loci with CVD. Finally, to identify genetic patterns associated with CVD risk, we applied the crossphenotype meta-analysis approach (CPMA) on the genome-wide data. A total of 17 established CVD risk loci were significantly associated with CVD in the autoimmune patient cohorts. From these, four loci were found to have significantly different genetic effects across autoimmune diseases. Six autoimmune susceptibility loci were also found to be associated with CVD risk. Genome-wide CPMA analysis identified 10 genetic clusters strongly associated with CVD risk across all autoimmune diseases. Two of these clusters are highly enriched in pathways previously associated with autoimmune disease etiology (TNFα and IFNγ cytokine pathways). The results of this study support the presence of specific genetic variation associated with the increase of CVD risk observed in autoimmunity