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Tyrosine kinase inhibitors (TKIs) discontinuation is the standard option for patients with chronic myeloid leukaemia (CML) in deep molecular response (MR) with imatinib. This study aimed to evaluate the efficacy and safety of one year consolidation with ponatinib on treatment-free remission (TFR) rate. This was a multicenter open-label, single-arm, phase II, exploratory clinical trial including patients with CML treated ≥4 years with imatinib therapy, and MR4.0 ≥12 months. Patients entered the TFR phase after receiving ponatinib at 15 mg/day for one year. Twenty three patients received ponatinib and 19 completed consolidation. Among the patients with detectable BCR::ABL1, 70% deepened response. The 48-weeks MR4.0 rate was 68.4% (95%CI: 43.4-87.4). The 48-week TFR rate as classically defined was 73.7% (95% CI: 8 56.3-96.4). Five restarted TKIs and all regained MR. The most frequent adverse events (AEs) were constipation (34.8%), asthenia (30.4%) and myalgia (21.7%). Patients who remained relapse-free one year after ponatinib discontinuation exhibited higher levels of NK and NKT-like cells with degranulation capacity. Consolidation with ponatinib showed a high TFR rate and adequate safety, granting further research.

HIV-1 infection may produce a detrimental effect on the immune response. Early start of antiretroviral therapy (ART) is recommended to preserve the integrity of the immune system. In fact, people with HIV (PWH) and normal CD4/CD8 ratio appear not to be more susceptible to severe forms of COVID-19 than the general population and they usually present a good seroconversion rate in response to vaccination against SARS-CoV-2. However, few studies have fully characterized the development of cytotoxic immune populations in response to COVID-19 vaccination in these individuals. In this study, we recruited PWH with median time of HIV-1 infection of 6 years, median CD4/CD8 ratio of 1.0, good adherence to ART, persistently undetectable viral load, and negative serology against SARS-CoV-2, who then received the complete vaccination schedule against COVID-19. Blood samples were taken before vaccination against COVID-19 and one month after receiving the complete vaccination schedule. PWH produced high levels of IgG against SARS-CoV-2 in response to vaccination that were comparable to healthy donors, with a significantly higher neutralization capacity. Interestingly, the cytotoxic activity of PBMCs from PWH against SARS-CoV-2-infected cells was higher than healthy donors before receiving the vaccination schedule, pointing out the pre-existence of activated cell populations with likely unspecific antiviral activity. The characterization of these cytotoxic cell populations revealed high levels of Tgd cells with degranulation capacity against SARS-CoV-2-infected cells. In response to vaccination, the degranulation capacity of CD8+ T cells also increased in PWH but not in healthy donors. The full vaccination schedule against COVID-19 did not modify the ability to respond against HIV-1-infected cells in PWH and these individuals did not show more susceptibility to breakthrough infection with SARS-CoV-2 than healthy donors after 12 months of follow-up. These results revealed the development of protective cell populations with broad-spectrum antiviral activity in PWH with normal CD4/CD8 ratio and confirmed the importance of early ART and treatment adherence to avoid immune dysfunctions.

HIV-1 infection cannot be cured due to long-lived viral reservoirs formed by latently infected CD4 + T cells. “Shock and Kill” strategy has been considered to eliminate the viral reservoir and achieve a functional cure but the stimulation of cytotoxic immunity is necessary. Ponatinib is a tyrosine kinase inhibitor (TKI) clinically used against chronic myeloid leukemia (CML) that has demonstrated to be effective against HIV-1 infection in vitro . Several TKIs may induce a potent cytotoxic response against cancer cells that makes possible to discontinue treatment in people with CML who present long-term deep molecular response. In this longitudinal study, we analyzed the capacity of ponatinib to induce an antiviral response against HIV-1 infection in peripheral blood mononuclear cells (PBMCs) obtained from people with CML previously treated with imatinib for a median of 10 years who changed to ponatinib for 12 months to boost the anticancer response before discontinuing any TKI as part of the clinical trial NCT04043676. Participants were followed-up for an additional 12 months in the absence of treatment. PBMCs were obtained at different time points and then infected in vitro with HIV-1. The rate of infection was determined by quantifying the intracellular levels of p24-gag in CD4 + T cells. The levels of p24-gag+ CD4 + T−cells were lower when these cells were obtained during and after treatment with ponatinib in comparison with those obtained during treatment with imatinib. Cytotoxicity of PBMCs against HIV-infected target cells was significantly higher during treatment with ponatinib than during treatment with imatinib, and it was maintained at least 12 months after discontinuation. There was a significant negative correlation between the lower levels of p24-gag+ CD4 + T−cells and the higher cytotoxicity induced by PBMCs when cells were obtained during and after treatment with ponatinib. This cytotoxic immunity was mostly based on higher levels of Natural Killer and Tγδ cells seemingly boosted by ponatinib. In conclusion, transient treatment with immunomodulators like ponatinib along with ART could be explored to boost the antiviral activity of cytotoxic cells and contribute to the elimination of HIV-1 reservoir.

This paper presents a new perspective which calls for an integration of ethics and corporate social responsibility (CSR) into the company strategy as a source of competitive advantages. The research question the authors pose is how a company can successfully carry out this integration of CSR into its strategic management, for which a model that includes three stages -- introduction, implementation and generalization of CSR -- is presented. Based on an exploratory case study within a Spanish technology-intensive firm (Indra), the authors show the way this company has developed and implemented an explicit plan for the integration of ethical values and CSR initiatives into its corporate and business strategies. It is shown that there are important factors to consider in order this process can successfully carried out, such as organizational culture, human resource practices or knowledge management systems.

The main objective of this study was to determine the influence of the cytotoxic activity of peripheral blood mononuclear cells (PBMCs) on the outcome of unvaccinated individuals with critical COVID-19 admitted to the ICU. Blood samples from 23 individuals were collected upon admission and then every 2 weeks for 13 weeks until death (Exitus group) (n = 13) or discharge (Survival group) (n = 10). We did not find significant differences between groups in sociodemographic, clinical, or biochemical data that may influence the fatal outcome. However, direct cellular cytotoxicity of PBMCs from individuals of the Exitus group against pseudotyped SARS-CoV-2-infected Vero E6 cells was significantly reduced upon admission (−2.69-fold; p = 0.0234) and after 4 weeks at the ICU (−5.58-fold; p = 0.0290), in comparison with individuals who survived, and it did not improve during hospitalization. In vitro treatment with IL-15 of these cells did not restore an effective cytotoxicity at any time point until the fatal outcome, and an increased expression of immune exhaustion markers was observed in NKT, CD4+, and CD8+ T cells. However, IL-15 treatment of PBMCs from individuals of the Survival group significantly increased cytotoxicity at Week 4 (6.18-fold; p = 0.0303). Consequently, immunomodulatory treatments that may overcome immune exhaustion and induce sustained, efficient cytotoxic activity could be essential for survival during hospitalization due to critical COVID-19.

El Grupo Parrós Obras S.L. ha destacado en los últimos años como una de las empresas más avanzadas de Castilla- La Mancha gracias al desarrollo de su estrategia de gestión del conocimiento e innovación en el sector de la construcción. Dentro de sus factores de éxito, destacan su compromiso con el desarrollo tecnológico y la expansión de actividades a partir de la exploración y explotación del conocimiento organizativo. Estudiamos el caso de éxito de esta empresa para mostrar cómo una adecuada estrategia de conocimiento en un sector como el de la construcción, apoyada en elementos de soporte organizativo tales como el liderazgo, la cultura y una estructura basada en las tecnologías de la información y la comunicación (TIC), se puede convertir en un elemento clave para lograr desarrollar procesos de desarrollo empresarial a partir de sus capacidades de innovación.

The objective of this research paper is to investigate, from a theoretical point of view, the strategic relevance of social capital. In recent years, academic literature in this field has witnessed remarkable growth, recognizing social capital as a key element for companies, due to its contribution to the creation of competitive advantages. However, it might be said that its development is still emerging, given the number of discrepancies among researchers regarding its definition, measurement, and its positive or negative impact on other variables. For this reason, a set of empirical studies that show the social capital effect on diverse types of organizational results have been reviewed, taking as a reference the definition and dimensions proposed by Nahapiet and Ghoshal (1998). Additionally, different theoretical links between social capital and four related Strategic Management approaches are presented, such as the Intellectual Capital-Based View, the Knowledge-Based View, the Resource-Based View and the Dynamic Resource-Based View. A main conclusion drawn from this review is that social capital, being a knowledge-based resource, enables access to both internal and external resources and thus a firm’s competitive advantage and, consequently, its value creation can be generated from the combination of both areas. Going in depth and clarifying this strategic linkage are thus a challenge to address in future studies.

After several decades of research on Corporate Social Responsibility (CSR), one of the main problems that literature reviews show is CSR measurement. Many of previous empirical studies on CSR have used secondary information sources from ethical stock indexes, to measure this variable. However, these indexes are not suitable to address Spanish CSR efforts, since most of companies included into these indexes are mainly from the U.S and other European countries. Therefore, in this paper a scale with twenty-three items to measure CSR as a second order construct, reflective-formative type, based on its three main dimensions (economic, social and environmental) is proposed. The main contribution of this paper is to show the validity of this measure and its applicability to firms that are not included into stock indexes, such as SMEs.