Antitumor immunity induced by antibody-based natural killer cell engager therapeutics armed with not-alpha IL-2 variant.

Harnessing innate immunity is emerging as a promising therapeutic approach in cancer. We report here the design of tetraspecific molecules engaging natural killer (NK) cell-activating receptors NKp46 and CD16a, the ß-chain of the interleukin-2 receptor (IL-2R), and a tumor-associated antigen (TAA). In vitro, these tetraspecific antibody-based natural killer cell engager therapeutics (ANKETs) induce a preferential activation and proliferation of NK cells, and the binding to the targeted TAA triggers NK cell cytotoxicity and cytokine and chemokine production. In vivo, tetraspecific ANKETs induce NK cell proliferation and their accumulation at the tumor bed, as well as the control of local and disseminated tumors. Treatment of non-human primates with CD20-directed tetraspecific ANKET leads to CD20+ circulating B cell depletion, with minimal systemic cytokine release and no sign of toxicity. Tetraspecific ANKETs, thus, constitute a technological platform for harnessing NK cells as next-generation cancer immunotherapies.

Lipocalin-2 Regulates Epidermal Growth Factor Receptor Intracellular Trafficking.

Epidermal growth factor receptor (EGFR) activation and lipocalin-2 (Lcn2) expression are frequently observed in the same pathological contexts, such as cancers or chronic kidney disease (CKD). However, the significance of this association is unknown. Here, we describe the role of Lcn2 in regulating EGFR trafficking. We show that Lcn2 increases EGFR cell surface abundance and is required for transforming growth factor α (TGF-α)-induced EGFR recycling to the plasma membrane and sustained activation. Lcn2 binds to the intracellular domain of EGFR in late endosomal compartments and inhibits its lysosomal degradation. Consistently, Lcn2 enhances EGFR-induced cell migration after TGF-α stimulation. In vivo, Lcn2 gene inactivation prevents EGFR recycling to the plasma membrane in an experimental model of CKD. Remarkably, this is associated with a dramatic decrease of renal lesions. Together, our data identify Lcn2 as a key mediator of EGFR trafficking processes. Hence, therapeutic inhibition of Lcn2 may counteract the deleterious effect of EGFR activation.

Endoplasmic reticulum stress drives proteinuria-induced kidney lesions via Lipocalin 2.

In chronic kidney disease (CKD), proteinuria results in severe tubulointerstitial lesions, which ultimately lead to end-stage renal disease. Here we identify 4-phenylbutyric acid (PBA), a chemical chaperone already used in humans, as a novel therapeutic strategy capable to counteract the toxic effect of proteinuria. Mechanistically, we show that albumin induces tubular unfolded protein response via cytosolic calcium rise, which leads to tubular apoptosis by Lipocalin 2 (LCN2) modulation through ATF4. Consistent with the key role of LCN2 in CKD progression, Lcn2 gene inactivation decreases ER stress-induced apoptosis, tubulointerstitial lesions and mortality in proteinuric mice. More importantly, the inhibition of this pathway by PBA protects kidneys from morphological and functional degradation in proteinuric mice. These results are relevant to human CKD, as LCN2 is increased in proteinuric patients. In conclusion, our study identifies a therapeutic strategy susceptible to improve the benefit of RAS inhibitors in proteinuria-induced CKD progression.

Caracterización psicosocial de deportistas y reconocimiento de la importancia del psicólogo deportivo / Psychosocial Characterization of Athletes and the Importance of Sports Psychologists / Caracterização psicossocial de atletas e reconhecimento da importância do psicólogo esportivo

Resumen Objetivo. Desarrollar la caracterización psicosocial de un grupo de deportistas del departamento del Huila (Colombia), e identificar su percepción acerca de la labor del psicólogo deportivo. Método. Investigación descriptiva, transversal, en la que participaron 817 deportistas (72.3% hombres, edad promedio 17.26 años [DE = 4.28]). La información fue obtenida mediante un instrumento ad hoc de autorreporte, validado por expertos, guardando las consideraciones éticas del caso. Resultados. Se evidenciaron asociaciones significativas (p < 0.05) entre los factores psicológicos emocionales (principalmente ansiedad y estrés) y cognitivos (atención, concentración, cohesión, motivación, autoconfianza y cohesión), con las variables sexo, sometimiento a cirugías, trabajo actual, asociación a club deportivo, participación en competencias y acompañamiento con psicólogo deportivo. Muchos de los encuestados no tenían acceso a los profesionales en psicología deportiva, pero resaltaron su importancia para el mejoramiento del rendimiento deportivo. Conclusión. El estudio permitió tener una panorámica general de las condiciones sociodemográficas de los deportistas y de sus necesidades psicosociales. No obstante, se deben llevar a cabo ejercicios más rigurosos que permitan no solo establecer relaciones estadísticas entre las variables reportadas, sino también realizar intervenciones efectivas.

Abstract Objective. To develop a psychosocial characterization of a group of athletes from the department of Huila-Colombia, and to identify their perception of the work of sports psychologists. Method. A descriptive, transversal research was conducted, in which 817 athletes (72.3% men, average age 17.26 years, [SD = 4.28]) participated. The information was obtained through an ad hoc instrument of self-reporting, validated by experts, keeping the ethical considerations of the case. Results. Significant associations (p < 0.05) exist between the psychological and emotional factors (mainly anxiety and stress) and cognitive factors (attention, concentration, cohesion, motivation, self-confidence and cohesion), with sex, surgery, current job, sports club association, participation in competitions and accompaniment with a sports psychologist as variables; even when many of the respondents do not have access to professional sports psychologists, they highlight the importance of their actions to improve performance. Conclusion. The study allows us to have a general overview of the sociodemographic conditions of athletes, as well as their psychosocial needs to be strengthened; nevertheless, more rigorous exercises must be carried out that allow establishing, not only statistical relationships between the variables reported, but also effective interventions.

Resumo Escopo. Desenvolver uma caracterização psicossocial de um grupo de atletas do departamento de Huila-Colômbia e identificar sua percepção do trabalho do psicólogo esportivo. Metodologia. Pesquisa descritiva, transversal, na que participaram 817 atletas (72,3% homens, média de idade 17.26 anos [DE = 4.28]). As informações foram obtidas por meio de um instrumento ad hoc de autorrelato, validado por especialistas, mantendo as considerações éticas do caso. Resultados. Existem associações significativas (p < 0.05) entre os fatores psicológicos emocionais (principalmente ansiedade e estresse) e cognitivos (atenção, concentração, coesão, motivação, autoconfiança e coesão), com as variáveis, sexo, cirurgia, trabalho atual, associação esportiva, participação em competições e acompanhamento com um psicólogo esportivo, e mesmo quando muitos dos entrevistados não têm acesso a profissionais em psicologia esportiva, destacam a importância de suas ações para melhorar o desempenho esportivo. Conclusão. O estudo permite uma visão geral das condições sociodemográficas dos atletas, bem como suas necessidades psicossociais a serem fortalecidas; no entanto, devem ser realizados exercícios mais rigorosos que permitam não apenas estabelecer relações estatísticas entre as variáveis relatadas, mas também realizar intervenções eficazes.

AKT2 is essential to maintain podocyte viability and function during chronic kidney disease.

In chronic kidney disease (CKD), loss of functional nephrons results in metabolic and mechanical stress in the remaining ones, resulting in further nephron loss. Here we show that Akt2 activation has an essential role in podocyte protection after nephron reduction. Glomerulosclerosis and albuminuria were substantially worsened in Akt2(-/-) but not in Akt1(-/-) mice as compared to wild-type mice. Specific deletion of Akt2 or its regulator Rictor in podocytes revealed that Akt2 has an intrinsic function in podocytes. Mechanistically, Akt2 triggers a compensatory program that involves mouse double minute 2 homolog (Mdm2), glycogen synthase kinase 3 (Gsk3) and Rac1. The defective activation of this pathway after nephron reduction leads to apoptosis and foot process effacement of the podocytes. We further show that AKT2 activation by mammalian target of rapamycin complex 2 (mTORC2) is also required for podocyte survival in human CKD. More notably, we elucidate the events underlying the adverse renal effect of sirolimus and provide a criterion for the rational use of this drug. Thus, our results disclose a new function of Akt2 and identify a potential therapeutic target for preserving glomerular function in CKD.

Priming of hepatocytes enhances in vivo liver transduction with lentiviral vectors in adult mice.

Lentiviral vectors are promising tools for liver disease gene therapy, because they can achieve protracted expression of transgenes in hepatocytes. However, the question as to whether cell division is required for optimal hepatocyte transduction has still not been completely answered. Liver gene-transfer efficiency after in vivo administration of recombinant lentiviral vectors carrying a green fluorescent protein reporter gene under the control of a liver-specific promoter in mice that were either hepatectomized or treated with cholic acid or phenobarbital was compared. Phenobarbital is known as a weak inducer of hepatocyte proliferation, whereas cholic acid has no direct effect on the cell cycle. This study shows that cholic acid is able to prime hepatocytes without mitosis induction. Both phenobarbital and cholic acid significantly increased hepatocyte transduction six- to ninefold, although cholic acid did not modify the mitotic index or cell-cycle entry. However, the effect of either compound was weaker than that observed after partial hepatectomy. In no cases was there a correlation between the expression of cell-cycle marker and transduction efficiency. We conclude that priming of hepatocytes should be considered a clinically applicable strategy to enhance in vivo liver gene therapy with lentiviral vectors.