Collaborative Engineering: An Airbus Case Study

AbstractThis document introduces the main concepts of Collaborative Engineering as a new methodology, procedures and tools to design and develop an aircraft, as Airbus Military is implementing.Airbus designs and industrializes aircrafts under Concurrent Engineering techniques since decades with success. The introduction of new PLM methodologies, procedures and tools, mainly in the industrialization areas, and the need to reduce time-to-market conducted Airbus Military to push the engineering teams to do things in a different way.Traditional Engineering works sequentially, Concurrent Engineering basically overlaps tasks between teams using maturity states and taking assuming risks. Collaborative Engineering promotes a single team to develop product, processes and resources from the conceptual phase to the start of the serial production. The deliverable of the team is an iDMU (industrial DMU), a complete definition and verification of the virtual manufacturing of the product

Implementation of the iDMU for an Aerostructure Industrialization in AIRBUS

AbstractAIRBUS Military has undertaken a project to implement the industrial Digital Mock-Up (iDMU) concept to support the industrialization process of a medium size aerostructure. Within the framework of a collaborative engineering strategy, such project is part of the efforts to deploy Digital Manufacturing as a key technology for the industrialization of aircrafts assembly lines. The project has confirmed the potential of the iDMU to improve the industrial design process in a collaborative engineering environment. This communication presents the main project objectives, the key methodological points, the main project achievements and the next additional developments to increase the scope and benefits of the iDMU concept

El carlismo frente a Cánovas del Castillo: el patrocinio del retraimiento electoral en el diario nocedalista «El Siglo Futuro» entre los comicios de 1876 y 1884

The confusion that followed the defeat of Carlos VII and his supporters in the second Carlist campaign, during the rise of Canovism, was attempted to be halted by the former neo-Catholic minister Cándido Nocedal, who founded the newspaper El Siglo Futuro (1875-1936). Unlike what happened after 1868, those who emerged as leaders of Carlist politics and unconditional supporters of Pius IX's Syllabus of Errors recommended not to field traditionalist candidates in the elections. This exclusive position, among other issues, led to contentious disagreements within the Catholic-Monarchical Communion, which was not very homogeneous and was further polarized by Nocedal’s appointment as Chief-Delegate of Don Carlos in 1879. The purpose of this text is to analyze the perspective of El Siglo Futuro before several elections that took place during the reign of Alfonso XII.El desconcierto inaugurado por la derrota de Carlos VII y sus partidarios en la segunda carlistada durante el ascenso del canovismo trató de ser atajado por el antaño ministro neocatólico Cándido Nocedal mediante la fundación del diario El Siglo Futuro (1875-1936). Al contrario de lo que había ocurrido a partir de 1868, quienes pasaron a erigirse en directores de la política carlista y adictos incondicionales al Syllabus de Errores de Pío IX, recomendaron en todo momento la no presentación de candidatos tradicionalistas a las elecciones. Esta postura exclusivista, entre otras cuestiones, dio paso a desencuentros conflictivos en el seno de la poco homogénea Comunión Católico-Monárquica que se agrandarían con la designación de Cándido Nocedal en 1879 como Jefe-Delegado de don Carlos. La pretensión de este texto es examinar el punto de vista de El Siglo Futuro ante varios de los comicios que se sucedieron durante el reinado de Alfonso XII

Challenges and Opportunities for Spark Plasma Sintering: A Key Technology for a New Generation of Materials

This is an open access article distributed under the terms of the Creative Commons Attribution License.-- et al.Peer reviewe

Role of the E2g phonon in the superconductivity of MgB2: a Raman scattering study

Temperature dependent Raman scattering studies in polycrystalline MgB2(10<T<300 K)reveal that the E2g phonon does not experience any self energy renormalization effect across the superconducting critical temperature Tc ~ 40 K. In contrast, most of the current theoretical models rely on the role of the E2g phonon in the electron-phonon coupling mechanism of superconductivity in MgB2. According to these models, a hardening of 12% is expected below Tc at the Gamma point of the Brillouim zone. In the presence of our results, those models must be reviewed. The analysis of the temperature dependence of the E2g phonon frequency yields to a isobaric Gruneisen parameter of -1.2< gama(E2g)< 0.2, smaller than the value of 3.9 obtained from isothermal Raman experiments under pressure. It is suggested that this apparent disagreement can be explained in terms of pressure induced changes of the topology of the Fermi surface. Finally we notice that the phonon linewidth presents the expected two-phonon anharmonic decay as a function of T and no anomalous temperature dependence of the linewidth is observed near Tc.Comment: Published in Solid State Comm. 125, 499 (2003

Bone marrow MSC from pediatric patients with B-ALL highly immunosuppress T-cell responses but do not compromise CD19-CAR T-cell activity

Altres ajuts Funding Financial support for this work was obtained from the Obra Social La Caixa (LCF/PR/HR19/52160011), the Leo Messi Foundation, and the 'Heroes hasta la médula' initiative to PM. SRZ was supported by a Marie Sklodowska Curie Fellowship (GA 795833). MV is supported by a Juan de la Cierva fellowship from the MINECO. PM is an investigator of the Spanish Cell Therapy cooperative network (TERCEL).Background Although adoptive transfer of CD19-directed chimeric antigen receptor (CAR) T-cells (CD19-CAR T-cells) achieves high rates of complete response in patients with B-cell acute lymphoblastic leukemia (B-ALL), relapse is common. Bone marrow (BM) mesenchymal stem/stromal cells (BM-MSC) are key components of the hematopoietic niche and are implicated in B-ALL pathogenesis and therapy resistance. MSC exert an immunosuppressive effect on T-cells; however, their impact on CD19-CAR T-cell activity is understudied. Methods We performed a detailed characterization of BM-MSC from pediatric patients with B-ALL (B-ALL BM-MSC), evaluated their immunomodulatory properties and their impact on CD19-CAR T-cell activity in vitro using microscopy, qRT-PCR, ELISA, flow cytometry analysis and in vivo using a preclinical model of severe colitis and a B-ALL xenograft model. Results While B-ALL BM-MSC were less proliferative than those from age-matched healthy donors (HD), the morphology, immunophenotype, differentiation potential and chemoprotection was very similar. Likewise, both BM-MSC populations were equally immunosuppressive in vitro and anti-inflammatory in an in vivo model of severe colitis. Interestingly, BM-MSC failed to impair CD19-CAR T-cell cytotoxicity or cytokine production in vitro using B-ALL cell lines and primary B-ALL cells. Finally, the growth of NALM6 cells was controlled in vivo by CD19-CAR T-cells irrespective of the absence/presence of BM-MSC. Conclusions Collectively, our data demonstrate that pediatric B-ALL and HD BM-MSC equally immunosuppress T-cell responses but do not compromise CD19-CAR T-cell activity

NG2 antigen is a therapeutic target for MLL-rearranged B-cell acute lymphoblastic leukemia

Altres ajuts: This work has been supported by the Asociación Española Contra el Cáncer (AECC), Beca FERO, and OM are supported by postdoctoral fellowships from the AECC scientific foundation and the Catalunya Government (Beatriu de Pinos, BP00048), respectively. PM also acknowledges the financial support from the Obra Social La Caixa-Fundaciò Josep Carreras and "Premio Miguelín".B cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer, with cure rates of ∼80%. MLL-rearranged (MLLr) B-ALL (MLLr-B-ALL) has, however, an unfavorable prognosis with common therapy refractoriness and early relapse, and therefore new therapeutic targets are needed for relapsed/refractory MLLr-B-ALL. MLLr leukemias are characterized by the specific expression of chondroitin sulfate proteoglycan-4, also known as neuron-glial antigen-2 (NG2). NG2 was recently shown involved in leukemia invasiveness and central nervous system infiltration in MLLr-B-ALL, and correlated with lower event-free survival (EFS). We here hypothesized that blocking NG2 may synergize with established induction therapy for B-ALL based on vincristine, glucocorticoids, and l-asparaginase (VxL). Using robust patient-derived xenograft (PDX) models, we found that NG2 is crucial for MLLr-B-ALL engraftment upon intravenous (i.v.) transplantation. In vivo blockade of NG2 using either chondroitinase-ABC or an anti-NG2-specific monoclonal antibody (MoAb) resulted in a significant mobilization of MLLr-B-ALL blasts from bone marrow (BM) to peripheral blood (PB) as demonstrated by cytometric and 3D confocal imaging analysis. When combined with either NG2 antagonist, VxL treatment achieved higher rates of complete remission, and consequently higher EFS and delayed time to relapse. Mechanistically, anti-NG2 MoAb induces neither antibody-dependent cell-mediated not complement-dependent cytotoxicity. NG2 blockade rather overrides BM stroma-mediated chemoprotection through PB mobilization of MLLr-B-ALL blasts, thus becoming more accessible to chemotherapy. We provide a proof of concept for NG2 as a therapeutic target for MLLr-B-ALL

Efficient elimination of primary B-ALL cells in vitro and in vivo using a novel 4-1BB-based CAR targeting a membrane-distal CD22 epitope

Altres ajuts: Funding This work was supported by the Obra Social La Caixa (LCF/PR/HR19/52160011), the Spanish Cancer Association and Leo Messi Foundation to PM.Background There are few therapeutic options available for patients with B-cell acute lymphoblastic leukemia (B-ALL) relapsing as CD19 - either after chemotherapy or CD19-targeted immunotherapies. CD22-chimeric antigen receptor (CAR) T cells represent an attractive addition to CD19-CAR T cell therapy because they will target both CD22 + CD19 - B-ALL relapses and CD19 - preleukemic cells. However, the immune escape mechanisms from CD22-CAR T cells, and the potential contribution of the epitope binding of the anti-CD22 single-chain variable fragment (scFv) remain understudied. Methods Here, we have developed and comprehensively characterized a novel CD22-CAR (clone hCD22.7) targeting a membrane-distal CD22 epitope and tested its cytotoxic effects against B-ALL cells both in in vitro and in vivo assays. Results Conformational epitope mapping, cross-blocking, and molecular docking assays revealed that the hCD22.7 scFv is a high-affinity binding antibody which specifically binds to the ESTKDGKVP sequence, located in the Ig-like V-type domain, the most distal domain of CD22. We observed efficient killing of B-ALL cells in vitro, although the kinetics were dependent on the level of CD22 expression. Importantly, we show an efficient in vivo control of patients with B-ALL derived xenografts with diverse aggressiveness, coupled to long-term hCD22.7-CAR T cell persistence. Remaining leukemic cells at sacrifice maintained full expression of CD22, ruling out CAR pressure-mediated antigen loss. Finally, the immunogenicity capacity of this hCD22.7-scFv was very similar to that of other CD22 scFv previously used in adoptive T cell therapy. Conclusions We report a novel, high-affinity hCD22.7 scFv which targets a membrane-distal epitope of CD22. 4-1BB-based hCD22.7-CAR T cells efficiently eliminate clinically relevant B- CD22 high and CD22 low ALL primary samples in vitro and in vivo. Our study supports the clinical translation of this hCD22.7-CAR as either single or tandem CD22-CD19-CAR for both naive and anti-CD19-resistant patients with B-ALL

Daratumumab displays in vitro and in vivo anti-tumor activity in models of B-cell non-Hodgkin lymphoma and improves responses to standard chemo-immunotherapy regimens

Altres ajuts: This work was carried out at the Esther Koplowitz Center, Barcelona. Genmab and Janssen pharmaceuticals funded this research. Additional grants that contributed to this work included: [...], and CIBERONC (CB16/12/00334 and CB16/12/00225).CD38 is expressed in several types of non-Hodgkin lymphoma (NHL) and constitutes a promising target for antibody-based therapy. Daratumumab (Darzalex) is a first-in-class anti-CD38 antibody approved for the treatment of relapsed/refractory (R/R) multiple myeloma (MM). It has also demonstrated clinical activity in Waldenström macroglobulinaemia and amyloidosis. Here, we have evaluated the activity and mechanism of action of daratumumab in preclinical in vitro and in vivo models of mantle cell lymphoma (MCL), follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), as monotherapy or in combination with standard chemo-immunotherapy. In vitro, daratumumab engages Fc-mediated cytotoxicity by antibody-dependent cell cytotoxicity and antibody-dependent cell phagocytosis in all lymphoma subtypes. In the presence of human serum, complement-dependent cell cytotoxicity was marginally engaged. We demonstrated by Selective Plane Illumination Microscopy that daratumumab fully penetrated a three-dimensional (3D) lymphoma organoid and decreased organoid volume. In vivo, daratumumab completely prevents tumor outgrowth in models of MCL and FL, and shows comparable activity to rituximab in a disseminated in vivo model of blastic MCL. Moreover, daratumumab improves overall survival (OS) in a mouse model of transformed CD20 FL, where rituximab showed limited activity. Daratumumab potentiates the antitumor activity of CHOP and R-CHOP in MCL and FL xenografts. Furthermore, in a patient-derived DLBCL xenograft model, daratumumab anti-tumor activity was comparable to R-CHOP and the addition of daratumumab to either CHOP or R-CHOP led to full tumor regression. In summary, daratumumab constitutes a novel therapeutic opportunity in certain scenarios and these results warrant further clinical development