Selection, engineering, and in vivo testing of a human leukocyte antigen-independent T-cell receptor recognizing human mesothelin.

BACKGROUND: Canonical α/ß T-cell receptors (TCRs) bind to human leukocyte antigen (HLA) displaying antigenic peptides to elicit T cell-mediated cytotoxicity. TCR-engineered T-cell immunotherapies targeting cancer-specific peptide-HLA complexes (pHLA) are generating exciting clinical responses, but owing to HLA restriction they are only able to target a subset of antigen-positive patients. More recently, evidence has been published indicating that naturally occurring α/ß TCRs can target cell surface proteins other than pHLA, which would address the challenges of HLA restriction. In this proof-of-concept study, we sought to identify and engineer so-called HLA-independent TCRs (HiTs) against the tumor-associated antigen mesothelin. METHODS: Using phage display, we identified a HiT that bound well to mesothelin, which when expressed in primary T cells, caused activation and cytotoxicity. We subsequently engineered this HiT to modulate the T-cell response to varying levels of mesothelin on the cell surface. RESULTS: The isolated HiT shows cytotoxic activity and demonstrates killing of both mesothelin-expressing cell lines and patient-derived xenograft models. Additionally, we demonstrated that HiT-transduced T cells do not require CD4 or CD8 co-receptors and, unlike a TCR fusion construct, are not inhibited by soluble mesothelin. Finally, we showed that HiT-transduced T cells are highly efficacious in vivo, completely eradicating xenografted human solid tumors. CONCLUSION: HiTs can be isolated from fully human TCR-displaying phage libraries against cell surface-expressed antigens. HiTs are able to fully activate primary T cells both in vivo and in vitro. HiTs may enable the efficacy seen with pHLA-targeting TCRs in solid tumors to be translated to cell surface antigens.

Therapeutic Futility in Nursing: A Focus Group.

Introduction: The implementation of futile nursing interventions seems to be a persistent problem in adult intensive care units. Understanding this phenomenon can contribute to its prevention and all deleterious effects associated with it. Objective: To identify the perceptions of expert nurses from adult intensive care units about therapeutic futility in nursing. Methods: This study consists of a conventional content analysis. Data was collected through a focus group interview that included five expert nurses in adult intensive care, with a minimum of fifteen years of professional experience in intensive care. To analyze the information, the technique of thematic categorical analysis was used, according to Bardin. Results: Four central categories were identified for the topic under study, for which several subcategories were identified that allow a better understanding of this phenomenon. Conclusion: Adult intensive care expert nurses advocate that therapeutic futility in nursing is a reality perceived by teams and families, which should be avoided due to the risk of potentiating the implementation of ethically reprehensible care.

Conceptual Models of Nursing in Critical Care.

INTRODUCTION: Intensive care units are systems organized for the provision of care to patients in critical situations. In general, it is suggested that intensive care consists of a multidisciplinary and interprofessional specialty. Nevertheless, the predominance, relative to the professions that incorporate these units, falls on nurses. A conceptual model of nursing provides a framework for reflection, observation, and interpretation of phenomena and, specifically, it provides guidelines and guidance for aspects of clinical practice. OBJECTIVE: To understand the applicability of conceptual models of nursing in intensive care units. METHOD: Review of the literature following the Scoping Review protocol of the Joanna Briggs Institute. The research was performed in CINAHL, Cochrane, Pubmed, Scopus, and Web of Science to identify studies published prior to 2021. Fourteen studies were selected. RESULTS: There is no conceptual model of nursing universally accepted as ideal for intensive care units. However, there is unanimity in the identification of several benefits associated with the application of a conceptual model of nursing in the care of critically ill patients. CONCLUSION: For the selection of a conceptual model of nursing for these contexts, the focus should be on the person and the choice should fall on the model that is most appropriate to the patient, and not on the philosophy that supports the model. Considering the nature of care, the nursing team can select a model or a combination of models.

Fungal Glucosylceramide-Specific Camelid Single Domain Antibodies Are Characterized by Broad Spectrum Antifungal Activity.

Chemical crop protection is widely used to control plant diseases. However, the adverse effects of pesticide use on human health and environment, resistance development and the impact of regulatory requirements on the crop protection market urges the agrochemical industry to explore innovative and alternative approaches. In that context, we demonstrate here the potential of camelid single domain antibodies (VHHs) generated against fungal glucosylceramides (fGlcCer), important pathogenicity factors. To this end, llamas were immunized with purified fGlcCer and a mixture of mycelium and spores of the fungus Botrytis cinerea, one of the most important plant pathogenic fungi. The llama immune repertoire was subsequently cloned in a phage display vector to generate a library with a diversity of at least 108 different clones. This library was incubated with fGlcCer to identify phages that bind to fGlcCer, and VHHs that specifically bound fGlcCer but not mammalian or plant-derived GlcCer were selected. They were shown to inhibit the growth of B. cinerea in vitro, with VHH 41D01 having the highest antifungal activity. Moreover, VHH 41D01 could reduce disease symptoms induced by B. cinerea when sprayed on tomato leaves. Based on all these data, anti-fGlcCer VHHs show the potential to be used as an alternative approach to combat fungal plant diseases.