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MAPK inhibitors dynamically affect melanoma release of immune NKG2D-ligands, as soluble protein and extracellular vesicle-associated
Get PDFMetastatic melanoma presents, in many cases, oncogenic mutations in BRAF, a MAPK involved in proliferation of tumour cells. BRAF inhibitors, used as therapy in patients with these mutations, often lead to tumour resistance and, thus, the use of MEK inhibitors was introduced in clinics. BRAFi/MEKi, a combination that has modestly increased overall survival in patients, has been proven to differentially affect immune ligands, such as NKG2D-ligands, in drug-sensitive vs. drug-resistant cells. However, the fact that NKG2D-ligands can be released as soluble molecules or in extracellular vesicles represents an additional level of complexity that has not been explored. Here we demonstrate that inhibition of MAPK using MEKi, and the combination of BRAFi with MEKi in vitro, modulates NKG2D-ligands in BRAF-mutant and WT melanoma cells, together with other NK activating ligands. These observations reinforce a role of the immune system in the generation of resistance to directed therapies and support the potential benefit of MAPK inhibition in combination with immunotherapies. Both soluble and EV-associated NKG2D-ligands, generally decreased in BRAF-mutant melanoma cell supernatants after MAPKi in vitro, replicating cell surface expression. Because potential NKG2D-ligand fluctuation during MAPKi treatment could have different consequences for the immune response, a pilot study to measure NKG2D-ligand variation in plasma or serum from metastatic melanoma patients, at different time points during MAPKi treatment, was performed. Not all NKG2D-ligands were equally detected. Further, EV detection did not parallel soluble protein. Altogether, our data confirm the heterogeneity between melanoma lesions, and suggest testing several NKG2D-ligands and other melanoma antigens in serum, both as soluble or vesicle-released proteins, to help classifying immune competence of patients
La judía de Toledo o Alfonso VIII d’Eusebio Asquerino: la modernité contrastée d’une réécriture légendaire
No full textCódigo de conduta. Prevenção da introdução e dispersão de flora e fauna exótica invasora: agentes ambientais
Get PDFDe forma intencional ou involuntária, o ser humano transporta espécies entre locais desde tempos imemoriais. No entanto, nos últimos 50 anos, o ritmo de introdução de espécies exóticas no meio natural acelerou de forma alarmante, tornando-se numa das principais causas de perda de biodiversidade. A globalização, juntamente com as alterações climáticas, a destruição de habitats, o aumento do trânsito de pessoas e o comércio, são hoje os principais responsáveis pela perda de biodiversidade a nível global, acarretando também graves prejuízos para a economia e a saúde humana
de Vicente Algueró, F. J. (2022). De la ley al aula. Crónica de la educación en España 1977-2022. Madrid, Editorial Círculo Rojo, 322 pp. [RECENSIÓN]
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Poesía de sátira política y clandestina del Siglo de Oro. Antología esencial. Volumen I. Reinados de Felipe III y Felipe IV
Get PDFEn el marco del proyecto de investigación "La burla como diversión y arma social en el Siglo de Oro (II). Poesía política y clandestina. Recuperación patrimonial y contexto histórico y cultural" (AEI/FEDER, UE, PID2020-116009GB-I00), del Ministerio de Ciencia e Innovación (MICINN) del Gobierno de España, este volumen aborda el corpus correspondiente a los reinados de Felipe III y Felipe IV, ampliando sustancialmente el material disponible hasta el momento del abundante repertorio de la poesía clandestina y de sátira política del Siglo de Oro. Incluye esta entrega 381 poemas procedentes de numerosos manuscritos, acompañados de un aparato de notas que intenta aclarar las claves complejas de sus alusiones satíricas y precedidos de un estudio introductorio en el que, además de establecerse el estado de la cuestión sobre la materia, se ofrecen reflexiones teóricas sobre los criterios y retos de edición de este difícil y fascinante corpus de enorme interés literario, histórico, social y cultural
Cobimetinib Alone and Plus Venetoclax With/Without Atezolizumab in Patients With Relapsed/Refractory Multiple Myeloma
Get PDFThis phase IB/II trial evaluated safety and efficacy of cobimetinib alone and in novel combinations with veneto-clax with/without atezolizumab in patients with relapsed/refractory multiple myeloma. Forty-nine patients were enrolled. Cobimetinib alone and in combination with venetoclax with/without atezolizumab was determined to be safe and tolerable; anti-tumor activity was moderate overall but higher in patients with translocation t(11;14). Introduction: Mitogen-activated protein kinase pathway mutations are present in > 50% of patients with relapsed/refractory (R/R) multiple myeloma (MM). MEK inhibitors show limited single-agent activity in R/R MM; combi-nation with B-cell lymphoma-2 (BCL-2) and programmed death-ligand 1 inhibition may improve efficacy. This phase Ib/II trial (NCT03312530) evaluated safety and efficacy of cobimetinib (cobi) alone and in combination with veneto-clax (ven) with/without atezolizumab (atezo) in patients with R/R MM. Patients and Methods: Forty-nine patients were randomized 1:2:2 to cobi 60 mg/day on days 1-21 (n = 6), cobi 40 mg/day on days 1-21 + ven 800 mg/day on days 1-28 with/without atezo 840 mg on days 1 and 15 of 28-day cycles (cobi-ven, n = 22; cobi-ven-atezo, n = 21). Safety run-in cohorts evaluated cobi-ven and cobi-ven-atezo dose levels. Results: Any-grade common adverse events (AEs) with cobi, cobi-ven, and cobi-ven-atezo, respectively, included diarrhea (33.3%, 81.8%, 90.5%) and nausea (16.7%, 50.0%, 66.7%); common grade >= 3 AEs included anemia (0%, 22.7%, 23.8%), neutropenia (0%, 13.6%, 38.1%), and thrombocytopenia (0%, 18.2%, 23.8%). The overall response rate for all-comers was 0% (cobi), 27.3% (cobi-ven), and 28.6% (cobi-ven-atezo), and 0%, 50.0%, and 100%, respectively, in patients with t(11;14) + . Biomarker analysis demon-strated non-t(11;14) patient selection with NRAS /KRAS /BRAF mutation or high BCL-2/BCL-2-L1 ratio ( > 52% of the study population) could enrich for responders to the cobi-ven combination. Conclusions: Cobi-ven and cobi-ven-atezo demonstrated manageable safety with moderate activity in all-comers, and higher activity in patients with t(11;14) + MM, supporting a biomar ker-dr iven approach for ven in MM
Factors associated with a post-procedure spontaneous pregnancy after a hysterosapingo-foam-sonography (HyFoSy): results from a multicenter observational study
Get PDFBackground: Tubal patency testing constitutes an essential part of infertility work-up. Hysterosalpingo-foam-sonography (HyFoSy) is currently one of the best tests for assessing tubal patency. The objective of our study was to evaluate the post-procedure rate of spontaneous pregnancy among infertile women submitted for an HyFoSy exam with ExEm((R)) foam and the factors associated with this. Methods: Multicenter, prospective, observational study performed at six Spanish centers for gynecologic sonography and human reproduction. From December 2015 to June 2021, 799 infertile women underwent HyFoSy registration consecutively. The patients' information was collected from their medical records. Multivariable regression analyses were performed, controlling for age, etiology, and time of sterility. The main outcome was to measure post-procedure spontaneous pregnancy rates and the factors associated with the achievement of pregnancy. Results: 201 (26.5%) women got spontaneous conception (SC group), whereas 557 (73.5%) women did not get pregnant (non-spontaneous conception group, NSC). The median time for reaching SC after HyFoSy was 4 months (CI 95% 3.1-4.9), 18.9% of them occurring the same month of the procedure. Couples with less than 18 months of infertility were 93% more likely to get pregnant after HyFoSy (OR 1.93, 95% CI 1.34-2.81; p < 0.001); SC were two times more frequent in women under 35 years with unexplained infertility (OR 2.22, 95% CI 1.07-4.65; P0.033). Conclusion: After HyFoSy, one in four patients got pregnant within the next twelve months. Couples with shorter infertility time, unexplained infertility, and women under 35 years are more likely to achieve SC after HyFoSy
The relationship competencies guiding tool: a development, content validation and implementation study
Get PDFAim: The aims of this paper are (1) to present the results of the development, content validation and imple-mentation study of the Relationship Competencies Guiding Tool; (2) to provide examples of how each item in the tool is reflected in clinical narratives written by nurses and justify the corresponding scores after the evaluation; (3) to present how the language and content of the narratives are interpreted with the tool and to describe an exemplar; and (4) to present barriers to and facilitators of the application of the tool. Background: From a person-centered care approach, the fostering of authentic relationships with patients is key to achieving therapeutic benefits. Therefore, it is essential to help nurses establish meaningful relationships with patients and help them acquire these abilities. Clinical narratives can be used as a way to promote reflective practice and professional competency development among nurses. A tool to evaluate the knowledge, skills, at-titudes and values necessary for developing authentic encounters with patients through clinical narratives was developed, validated and implemented.Design: An instrument-development study comprised of three steps: (1) conceptualization; (2) item generation and content validity; and (3) implementation of the tool and linguistic evaluation.Methods: This study was conducted in three major steps. Step one entailed conceptualization. Step two included the generation of items and content validation. In step three, the tool was used to independently evaluate 25 narratives. One of these narratives was also linguistically analysed to provide a comprehensive view of the interpretative strategies deployed by evaluators.Results: The Relationship Competencies Guiding Tool was developed, validated and implemented. It could help nurses work on nursing relationship-based professional competencies, guided the evaluators in the process of assigning scores to the corresponding items and helped the researchers identify certain barriers and facilitators before and during the narrative evaluation process.Conclusions: The tool has been shown to be clear, relevant and conceptually and linguistically suitable for evaluating clinical narratives. The Relationship Competencies Guiding Tool could be applied to interpret how nurses reflect professional competencies in a clinical narrative as a preliminary step in the construction of a mea-surement tool.Tweetable abstract: From a person-centered relationship-based care approach, clinical narratives can be used to promote professional competencies between nurses. The Relationship Competencies Guiding Tool may help eval-uate the knowledge, skills, attitudes and values necessary for developing authentic encounters with persons/ families, as reflected by nurses' clinical narratives
(Mis)Understandings of defence diplomacy as public diplomacy: Insights from three Spanish elites
Get PDFDefence diplomacy and public diplomacy are two diplomatic practices often treated in the literature as two disconnected realms. While the former focuses on the peaceful and cooperative use of armed forces, the latter emphasizes on the advancement of strategic communication in the international policy of actors. However, it is possible to bridge the differences between the two using the concept of soft power. By doing so, defence public diplomacy can be understood as a set of practices developed by states seeking to influence and attract third states while employing military force within these parameters. This paper contributes firstly to the conceptual debate bridging both types of diplomacies. Secondly, it selects a case study, Spain, to examine the perceptions of three different Spanish elites involved in the formulation and implementation of defence public policy: politicians, the military and defence industry managers. This paper adopts a qualitative methodology, including in-depth interviews, focus groups with experts, and manual content analysis of primary documentary sources. The results show that these elites agree on the importance of defence diplomacy for the achievement of state goals but continue to understand it fundamentally from a classical diplomatic prism. They also discuss the inclusion of new concepts, such as deterrence, as part of a defence public diplomacy
Adolescencia y Educación. Control parental y percepción de las familias sobre los riesgos en Internet
Get PDFAdolescence is a stage of constant connection to the Internet where families, in their socialising function, intervene by means of control strategies to help prevent risks. This study aims to find out their perception of the risks posed by the Internet and the parental control models they use, carrying out a qualitative study using discussion group techniques and interviews. Families consider addiction, loss of values, lack of critical thinking and bullying as the main virtual risks and preferably use controls related to punishments and control of connection time to prevent them.La adolescencia supone una etapa de conexión constante a Internet en la que las familias, en su función socializadora, intervienen mediante estrategias de control para ayudar a prevenir riesgos. Este trabajo pretende conocer a través de un estudio cualitativo, mediante técnicas de grupos de discusión y entrevistas, la percepción de los progenitores sobre los riesgos que supone Internet y los modelos de control parental que utilizan. Las familias consideran la adicción, la pérdida de valores, la ausencia de pensamiento crítico y el acoso como los principales riesgos virtuales, y utilizan preferentemente controles relacionados con castigos y con el control del tiempo de conexión para prevenirlos