An Eight-Gene Blood Expression Profile Predicts the Response to Infliximab in Rheumatoid Arthritis

BACKGROUND: TNF alpha blockade agents like infliximab are actually the treatment of choice for those rheumatoid arthritis (RA) patients who fail standard therapy. However, a considerable percentage of anti-TNF alpha treated patients do not show a significant clinical response. Given that new therapies for treatment of RA have been recently approved, there is a pressing need to find a system that reliably predicts treatment response. We hypothesized that the analysis of whole blood gene expression profiles of RA patients could be used to build a robust predictor to infliximab therapy. METHODS AND FINDINGS: We performed microarray gene expression analysis on whole blood RNA samples from RA patients starting infliximab therapy (n = 44). The clinical response to infliximab was determined at week 14 using the EULAR criteria. Blood cell populations were determined using flow cytometry at baseline, week 2 and week 14 of treatment. Using complete cross-validation and repeated random sampling we identified a robust 8-gene predictor model (96.6% Leave One Out prediction accuracy, P = 0.0001). Applying this model to an independent validation set of RA patients, we estimated an 85.7% prediction accuracy (75-100%, 95% CI). In parallel, we also observed a significantly higher number of CD4+CD25+ cells (i.e. regulatory T cells) in the responder group compared to the non responder group at baseline (P = 0.0009). CONCLUSIONS: The present 8-gene model obtained from whole blood expression efficiently predicts response to infliximab in RA patients. The application of the present system in the clinical setting could assist the clinician in the selection of the optimal treatment strategy in RA

Co-culture of primary CLL cells with bone marrow mesenchymal cells, CD40 ligand and CpG ODN promotes proliferation of chemoresistant CLL cells phenotypically comparable to those proliferating in vivo

Chronic lymphocytic leukemia (CLL) cells residing in the bone marrow (BM) and in secondary lymphoid tissues receive survival and proliferative signals from the microenvironment, resulting in persistence of residual disease after treatment. In this study, we characterized primary CLL cells cultured with BM stromal cells, CD40 ligand and CpG ODN to partially mimic the microenvironment in the proliferative centers. This co-culture system induced proliferation and chemoresistance in primary CLL cells. Importantly, co-cultured primary CLL cells shared many phenotypical features with circulating proliferative CLL cells, such as upregulation of ZAP-70 and CD38 and higher CD49d and CD62L expression. This indicates aggressiveness and capability to interact with surrounding cells, respectively. In addition, levels of CXCR4 were decreased due to CXCR4 internalization after CXCL12 stimulation by BM stromal cells. We suggest that this co-culture system can be used to test drugs and their combinations that target the proliferative and drug resistant CLL cells

Anàlisi, disseny i implementació d'una eina de simulació per a l'estudi de la interoperabilitat mitjançant conversió d'atributs en entorns multi-domini

El present projecte part d'un estudi sobre el tractament de situacions d'emergència, on es considera que una infraestructura de comunicació, sobre aquest tipus d'escenaris, ha d'implementar la interoperabilitat i el control d'accés, entre els diferents elements que hi participen, utilitzant la conversió d'atributs. Per tal de materialitzar aquest estudi s'ha realitzat un anàlisi de les necessitats de l'aplicació i un disseny detallat dels mòduls que el formen. S'ha implementat d'aquesta manera una eina de simulació per entorns multi-domini. Finalment s'han realitzat un conjunt de proves per comprovar la seva fiabilitat respecte l'estudi original.El presente proyecto parte de un estudio sobre el tratamiento de situaciones de emergencia, donde se considera que una infraestructura de comunicación, sobre este tipo de escenarios, tiene que implementar la interoperabilidad y el control de acceso, entre los diferentes elementos que participan, utilizando la conversión de atributos. Con tal de materializar este estudio se ha realizado un análisis de las necesidades de la aplicación y un diseño detallado de los módulos que lo forman. Se ha implementado de esta manera una herramienta de simulación para entornos multi-dominio. Finalmente se han realizado un conjunto de pruebas para comprobar su fiabilidad respecto al estudio original.The present project departs from a study on the treatment of emergency situations, where it says that an infrastructure of communication, on this type of scenes, has to implement the interoperability and the control of access, between the different elements that take part on it, using the conversion of attributes. So to materialize this study there has been realized an analysis of the needs of the application and a detailed design of the modules that they form it. A tool of simulation for environments multi-domain has been implemented. Finally a set of tests have been realized to verify his reliability with regard to the original study

Inhibition of BCR signaling using the Syk inhibitor TAK-659 prevents stroma-mediated signaling in chronic lymphocytic leukemia cells

Altres ajuts: This work was cofinanced by the European Regional Development Fund (ERDF) and Asociación Española Contra el Cáncer (AECC, M.C). N.P. is a recipient of a PhD fellowship granted by Institut de Recerca Vall d'Hebron. C.C. is supported by a grant from Sociedad Española de Hematología y Hemoterapia (SEHH).Proliferation and survival of chronic lymphocytic leukemia (CLL) cells depend on microenvironmental signals coming from lymphoid organs. One of the key players involved in the crosstalk between CLL cells and the microenvironment is the B-cell receptor (BCR). Syk protein, a tyrosine kinase essential for BCR signaling, is therefore a rational candidate for targeted therapy in CLL. Against this background, we tested the efficacy of the highly specific Syk inhibitor TAK-659 in suppressing the favorable signaling derived from the microenvironment. To ex vivo mimic the microenvironment found in the proliferation centers, we co-cultured primary CLL cells with BM stromal cells (BMSC), CD40L and CpG ODN along with BCR stimulation. In this setting, TAK-659 inhibited the microenvironment-induced activation of Syk and downstream signaling molecules, without inhibiting the protein homologue ZAP-70 in T cells. Importantly, the pro-survival, proliferative, chemoresistant and activation effects promoted by the microenvironment were abrogated by TAK-659, which furthermore blocked CLL cell migration toward BMSC, CXCL12, and CXCL13. Combination of TAK-659 with other BCR inhibitors showed synergistic effect in inducing apoptosis, and the sequential addition of TAK-659 in ibrutinib-treated CLL cells induced significantly higher cytotoxicity. These findings provide a strong rationale for the clinical development of TAK-659 in CLL

Microenvironment regulates the expression of miR-21 and tumor suppressor genes PTEN, PIAS3 and PDCD4 through ZAP-70 in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) cells are highly dependent on microenvironment, being the BCR pathway one key player in this crosstalk. Among proteins participating, ZAP-70 enhances response to microenvironmental stimuli. MicroRNA-21 (miR-21) is overexpressed in diverse neoplasias including CLL, where it has been associated to refractoriness to fludarabine and to shorter time to progression and survival. To further elucidate the role of ZAP-70 in the biology of CLL, we studied its involvement in miR-21 regulation. MiR-21 expression was higher in CLL cells with high ZAP-70. Ectopic expression of ZAP-70 induced transcription of miR-21 via MAPK and STAT3, which subsequently induced downregulation of tumor suppressors targeted by miR-21. The co-culture of primary CLL cells mimicking the microenvironment induced ZAP-70 and miR-21 expression, as well as downregulation of miR-21 targets. Interestingly, the increase in miR-21 after co-culture was significantly impaired by ibrutinib, indicating that the BCR signaling pathway is involved in its regulation. Finally, survival of CLL cells induced by the co-culture correlated with miR-21 upregulation. In conclusion, stimuli from the microenvironment regulate miR-21 and its targeted tumor suppressor genes via a signaling pathway involving ZAP-70, thus contributing to the cytoprotection offered by the microenvironment particularly observed in CLL cells expressing ZAP-70.This work was supported by research funding from the Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias (PI14/00055, F.B. and PI13/00279, M.C.), cofinanced by the European Regional Development Fund (ERDF) and Asociación Española Contra el Cáncer (AECC Barcelona, M.C. and P.A.). M.C. holds a contract from Ministerio de Economía y Competitividad (MINECO) (RYC-2012-12018). Authors thank the Cellex Foundation for providing research facilities and equipmen

Improved adhesion and tribological properties of altin-tisin coatings deposited by dcms and hipims on nitrided tool steels

Hard coatings, such as AlTiN-TiSiN, deposited by Physical Vapor Deposition (PVD) techniques are widely used in industrial applications to protect and increase the lifetime of industrial components, such as cutting tools, dies, and forming tools. Despite their great properties, such as high hardness and wear and oxidation resistance, they are limited in cases of severe conditions due to the poor adhesion between the coating and the substrate. Duplex treatments have commonly been used to improve the adhesive properties of PVD coatings, especially those of the cathodic arc evaporation type. The purpose of this study is to achieve coatings with the good properties of the Magnetron Sputtering processes but with higher adhesion than that achieved with these techniques, thus achieving coatings that can be used under the most severe conditions. In this work, an AlTiN-TiSiN coating was deposited by a combination of DC Magnetron Sputtering (DCMS) and High-Power Impulse Magnetron Sputtering (HiPIMS) after a gas nitriding pretreatment on 1.2379 and Vanadis 4 tool steels. Mechanical (ultra-microhardness and scratch tests) and tribological tests were carried out to study the improvement in the properties of the coating. Duplex-treated samples showed improved adhesion between the coating and the substrate, with second critical load (Lc2) values greater than 100 N. Furthermore, they showed great toughness and wear resistance. These results show that this type of coating technique could be used in the most extreme applications and that they can compete with other techniques and coatings that to date they have not been able to compete with.This research was funded in part by the Spanish Ministry of Science, Innovation and Universities through grants PGC2018-096855-B-C43 and PGC2018-096855-A-C44

Repolarization of tumor infiltrating macrophages and increased survival in mouse primary CNS lymphomas after XPO1 and BTK inhibition

Altres ajuts: This work was supported by research funding from the Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias cofinanced by the European Regional Development Fund (ERDF); Fundación Asociación Española Contra el Cáncer (M.C. and P.A.) and Gilead Fellowships (GLD16/00144, GLD18/00047, F.B). M.C. holds a contract from Ministerio de Ciencia, Innovación y Universidades. S.B. is the recipient of a postdoctoral fellowship from Fundación Alfonso Martin Escudero.Patients diagnosed with primary central nervous system lymphoma (PCNSL) often face dismal outcomes due to the limited availability of therapeutic options. PCNSL cells frequently have deregulated B-cell receptor (BCR) signaling, but clinical responses to its inhibition using ibrutinib have been brief. In this regard, blocking nuclear export by using selinexor, which covalently binds to XPO1, can also inhibit BCR signaling. Selinexor crosses the blood-brain barrier and was recently shown to have clinical activity in a patient with refractory diffuse large B-cell lymphoma in the CNS. We studied selinexor alone or in combination with ibrutinib in pre-clinical mouse models of PCNSL. Orthotopic xenograft models were established by injecting lymphoma cells into the brain parenchyma of athymic mice. Tumor growth was monitored by bioluminescence. Malignant cells and macrophages were studied by immunohistochemistry and flow cytometry. Selinexor blocked tumor growth and prolonged survival in a bioluminescent mouse model, while its combination with ibrutinib further increased survival. CNS lymphoma in mice was infiltrated by tumor-promoting M2-like macrophages expressing PD-1 and SIRPα. Interestingly, treatment with selinexor and ibrutinib favored an anti-tumoral immune response by shifting polarization toward inflammatory M1-like and diminishing PD-1 and SIRPα expression in the remaining tumor-promoting M2-like macrophages. These data highlight the pathogenic role of the innate immune microenvironment in PCNSL and provide pre-clinical evidence for the development of selinexor and ibrutinib as a new promising therapeutic option with cytotoxic and immunomodulatory potential. The online version of this article (10.1007/s11060-020-03580-y) contains supplementary material, which is available to authorized users

D21.3 Analysis of initial results at EuWIN@CTTC

Deliverable D21.3 del projecte europeu NEWCOM#The nature of this Deliverable of WP2.1 (“Radio interfaces for next-generation wireless systems”) is mainly descriptive and its purpose is to provide a report on the status of the different Joint Research Activities (JRAs) currently ongoing, some of them being performed on the facilities that are available at EuWInPeer ReviewedPreprin