El encuentro entre Husserl y Heidegger. El giro de la fenomenología

El presente trabajo trata de explicar las raíces filosóficas de Heidegger en su comprensión por el ser distinta a la tradición positivista. Se investiga la admiración y crítica de este a Husserl, sus puntos de encuentro, la inevitable evolución de Heidegger, y la explicación esquemática de por qué sigue ese camino. En este sentido, no se dejará de tratar del ser en la concepción de ambos autores y de la diferencia entre la etapa temprana de Heidegger y la fenomenología de Husserl. Se abordará también la etapa posterior de Heidegger solo en relación a lo que concierne a la fenomenología husserliana. En general, el trabajo pretende establecer una relación clara entre Husserl y Heidegger, la interpretación que el primero hace del segundo que fue posteriormente discutida, y la inspiración que Heidegger recibe de Husserl, especialmente en su doctrina del Dasein, la cual está fuertemente influenciada por el giro que él mismo hace a partir de la fenomenología de Husserl. También se pretende trazar un debate entre las dos doctrinas, a saber: la postura de Husserl en la que la fenomenología se centra en investigar las experiencias de la conciencia y la postura de Heidegger, la cual no depende solo de las experiencias, sino también del ser que las vive y puede hablar de ellas, y que tiene el poder de generar fenómenos de lo existente. En este debate, se pretende tocar un tema muy importante en la discusión entre ambos filósofos, a saber, el foco en el que se centra la investigación de cada autor. Para Husserl, que viene de una fuerte influencia idealista donde los fenómenos de la conciencia eran más importantes que el tema del ser, es evidente que las experiencias de la conciencia son como tal lo que debe investigarse. En cambio, para Heidegger es más necesario conocer el sustento de dichas experiencias, lo que las posibilita, volviendo a una ontología que se había olvidado en el positivismo e idealismo. En este sentido, Heidegger recupera el ser de una manera peculiar, pues él es influenciado también por la doctrina moderna de la filosofía de Nietzsche. También por el propio Husserl, al que le dará un giro en el que mezclará distintos elementos que harán de Heidegger uno de los filósofos más interesantes del siglo XX. Con todo, el trabajo se centra en explicar un giro que marca un antes y un después tanto en la tradición fenomenológica como en la filosofía continental, con sus detalles más relevantes y un debate (Husserl-Heidegger) que sigue teniendo importancia en la actualidad, y es por eso por lo que su interés será desarrollado en el trabajo

Diccionario vasco-castellano y método para enseñar el castellano a los vascongados

Dialecto : texto en euskera central -- guipuzcoanoS. XIX -- Periodo : primer euskera modernoEuskalkia : erdialdekoa -- gipuzkeraXIX. md. -- Aroa : lehen euskara modernoaDigitalización. Vitoria-Gasteiz : Fundación Sancho el Sabio, 200

Guía-manual del lenguaje para uso de los viajeros en el País Vasco

Digitalización. Vitoria-Gasteiz : Archivos y Bibliotecas, Mayo 199

Palafox y los Jesuitas

Copia digital. Valladolid : Junta de Castilla y León. Consejería de Cultura y Turismo, 2012-2013SignaturizadoAntep

Diccionario manual o vocabulario vasco-castellano para el uso de los vascongados que quieran aprender el castellano

Contiene: primera parte del método práctico para enseñar el castellano en las escuelas vascongada

Diccionario-manual castellano-vasco

Dialecto : texto en euskera central -- guipuzcoanoS. XIX -- Periodo : primer euskera modernoEuskalkia : erdialdekoa -- gipuzkeraXIX. md. -- Aroa : lehen euskara modernoaDiccionario vasco-castellano y método para enseñar el castellano a los vascongados / por Juan María de EgurenDigitalización. Vitoria-Gasteiz : Archivos y Bibliotecas, Junio 1994Carton

Soluble CD137 as a dynamic biomarker to monitor agonist CD137 immunotherapies

Background On the basis of efficacy in mouse tumor models, multiple CD137 (4-1BB) agonist agents are being preclinically and clinically developed. The costimulatory molecule CD137 is inducibly expressed as a transmembrane or as a soluble protein (sCD137). Moreover, the CD137 cytoplasmic signaling domain is a key part in approved chimeric antigen receptors (CARs). Reliable pharmacodynamic biomarkers for CD137 ligation and costimulation of T cells will facilitate clinical development of CD137 agonists in the clinic. Methods We used human and mouse CD8 T cells undergoing activation to measure CD137 transcription and protein expression levels determining both the membrane-bound and soluble forms. In tumor-bearing mice plasma sCD137 concentrations were monitored on treatment with agonist anti-CD137 monoclonal antibodies (mAbs). Human CD137 knock-in mice were treated with clinical-grade agonist anti-human CD137 mAb (Urelumab). Sequential plasma samples were collected from the first patients intratumorally treated with Urelumab in the INTRUST clinical trial. Anti-mesothelin CD137-encompassing CAR-transduced T cells were stimulated with mesothelin coated microbeads. sCD137 was measured by sandwich ELISA and Luminex. Flow cytometry was used to monitor CD137 surface expression. Results CD137 costimulation upregulates transcription and protein expression of CD137 itself including sCD137 in human and mouse CD8 T cells. Immunotherapy with anti-CD137 agonist mAb resulted in increased plasma sCD137 in mice bearing syngeneic tumors. sCD137 induction is also observed in human CD137 knock-in mice treated with Urelumab and in mice transiently humanized with T cells undergoing CD137 costimulation inside subcutaneously implanted Matrigel plugs. The CD137 signaling domain-containing CAR T cells readily released sCD137 and acquired CD137 surface expression on antigen recognition. Patients treated intratumorally with low dose Urelumab showed increased plasma concentrations of sCD137. Conclusion sCD137 in plasma and CD137 surface expression can be used as quantitative parameters dynamically reflecting therapeutic costimulatory activity elicited by agonist CD137-targeted agents

A Model of Continuous Improvement Programme Management

The aim of this study is to identify key management decisions that enable the sustainment of a continuous improvement (CI) initiative. To accomplish this aim, we examine the procedures and practices used by two manufacturing companies for the management of their CI initiatives; one that is successfully sustaining the effectiveness of its CI initiative and another failing to do the same. This research makes two contributions to the conceptual understanding of CI programme management. First, we identify five CI programme management factors that enable the sustainment of a CI initiative. Second, the five factors are incorporated into a new CI programme management model. The model details a ‘bottom-up’ procedure for the generation of manufacturing performance improvement ideas and the management of their implementation

CD137 (4-1BB) requires physically associated cIAPs for signal transduction and antitumor effects

CD137 (4-1BB) is a member of the TNFR family that mediates potent T cell costimulatory signals upon ligation by CD137L or agonist monoclonal antibodies (mAbs). CD137 agonists attain immunotherapeutic antitumor effects in cancer mouse models, and multiple agents of this kind are undergoing clinical trials. We show that cIAP1 and cIAP2 are physically associated with the CD137 signaling complex. Moreover, cIAPs are required for CD137 signaling toward the NF-κB and MAPK pathways and for costimulation of human and mouse T lymphocytes. Functional evidence was substantiated with SMAC mimetics that trigger cIAP degradation and by transfecting cIAP dominant-negative variants. Antitumor effects of agonist anti-CD137 mAbs are critically dependent on the integrity of cIAPs in cancer mouse models, and cIAPs are also required for signaling from CARs encompassing CD137’s cytoplasmic tail.I.M. has been granted with PID2020-112892RB funded by MICIN/AEI/10.13039/501100011033 and SAF2017-83267-C2-1-R funded by MICIN/AEI/10.13039/501100011033/ and by FEDER “Una manera de hacer Europa,” (HR21-00083) the Fundación La Caixa, “MINCITH. Metabolic requirements for immune INfiltration in effective Cancer ImmunoTHerapy” “AYUDAS FUNDACIÓN BBVA A EQUIPOS DE INVESTIGACIÓN CIENTÍFICA 2019” Fundación BBVA, the Instituto de Salud Carlos III (PI20/00002 and PI19/01128), cofinanced by the Fondos FEDER “A way to make Europe” and Joint Translational Call for Proposals 2015 (JTC 2015), TRANSCAN456 2 (code TRS-2016-00000371), and the Gobierno de Navarra Proyecto LINTERNA (reference 0011-1411-2020-000075). Funding was also received from B. J. Baselga (Fundación FERO) and the T2-EVOLVE project from the EU. I.M. and M.A. receive grant funding from Pharmamar and Highlight Therapeutics. M.A. is supported by AECC (INVES1904ALVA). J.M.Z. has been granted with PID2019-110405RB-I00 funded by MICIN/AEI/10.13039/501100011033 and with P2022/BMD-7225 funded by Consortium in Biomedicine of Comunidad de Madrid.Peer reviewe

Heterogenous presence of neutrophil extracellular traps in human solid tumours is partially dependent on IL-8

Neutrophil extracellular traps (NETs) are webs of extracellular nuclear DNA extruded by dying neutrophils infiltrating tissue. NETs constitute a defence mechanism to entrap and kill fungi and bacteria. Tumours induce the formation of NETs to the advantage of the malignancy via a variety of mechanisms shown in mouse models. Here, we investigated the presence of NETs in a variety of human solid tumours and their association with IL-8 (CXCL8) protein expression and CD8+ T-cell density in the tumour microenvironment. Multiplex immunofluorescence panels were developed to identify NETs in human cancer tissues by co-staining with the granulocyte marker CD15, the neutrophil marker myeloperoxidase and citrullinated histone H3 (H3Cit), as well as IL-8 protein and CD8+ T cells. Three ELISA methods to detect and quantify circulating NETs in serum were optimised and utilised. Whole tumour sections and tissue microarrays from patients with non-small cell lung cancer (NSCLC; n = 14), bladder cancer (n = 14), melanoma (n = 11), breast cancer (n = 31), colorectal cancer (n = 20) and mesothelioma (n = 61) were studied. Also, serum samples collected retrospectively from patients with metastatic melanoma (n = 12) and NSCLC (n = 34) were ELISA assayed to quantify circulating NETs and IL-8. NETs were detected in six different human cancer types with wide individual variation in terms of tissue density and distribution. At least in NSCLC, bladder cancer and metastatic melanoma, NET density positively correlated with IL-8 protein expression and inversely correlated with CD8+ T-cell densities. In a series of serum samples from melanoma and NSCLC patients, a positive correlation between circulating NETs and IL-8 was found. In conclusion, NETs are detectable in formalin-fixed human biopsy samples from solid tumours and in the circulation of cancer patients with a considerable degree of individual variation. NETs show a positive association with IL-8 and a trend towards a negative association with CD8+ tumour-infiltrating lymphocytes