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Background: Previous studies show that the spleen and bone marrow can serve as leukemia microenvironments in which macrophages play a significant role in immune evasion and chemoresistance. We hypothesized that the macrophage driven tolerogenic process of efferocytosis is a major contributor to the immunosuppressive leukemia microenvironment and that this was driven by aberrant phosphatidylserine expression from cell turnover and cell membrane dysregulation. Methods: Since MerTK is the prototypic efferocytosis receptor, we assessed whether the MerTK inhibitor MRX2843, which is currently in clinical trials, would reverse immune evasion and enhance immune-mediated clearance of leukemia cells. Results: We found that inhibition of MerTK decreased leukemia-associated macrophage expression of M2 markers PD-L1, PD-L2, Tim-3, CD163 and Arginase-1 compared to vehicle-treated controls. Additionally, MerTK inhibition led to M1 macrophage repolarization including elevated CD86 and HLA-DR expression, and increased production of T cell activating cytokines, including IFN-β, IL-18, and IL-1β through activation of NF-κB. Collectively, this macrophage repolarization had downstream effects on T cells within the leukemia microenvironment, including decreased PD-1+Tim-3+ and LAG3+ checkpoint expression, and increased CD69+CD107a+ expression. Discussion: These results demonstrate that MerTK inhibition using MRX2843 altered the leukemia microenvironment from tumor-permissive toward immune responsiveness to leukemia and culminated in improved immune-mediated clearance of AML.

Leonardo Polo answers the following questions posed to him by the editor of the Anuario Filosófico: 1) What is the present state of philosophy? 2) What kind of philosophy can be cultivated nowadays? 3) How does one philosophize?

La profusión de teorías contemporáneas que, sobre la interpretación, se cruzan actualmente en la mesa de un investigador, pueden ocultar el hecho de que los autores tardomedievales o iniciadores de la modernidad, en el Siglo de Oro, también estaban preocupados por lograr correctamente la aplicación de la ley a los casos concretos o de compaginar las distintas leyes entre sí. Y que se debatían entre doctrinas dispares y, al igual que hoy, con gran carga polémica. ¿Quién no tiene todavía presentes los cánones que Friedrich Karl von Savigny (fundador de la escuela histórica alemana del derecho) propuso en el siglo XIX para lograr una interpretación plausible? Él habló de los fines de la interpretación, como también antes lo hicieron, aunque de manera diferente, los hombres del Siglo de Oro. También comentó los varios aspectos o canales de acercamiento al hecho interpretado: el gramatical, el histórico, el sistemático y el teleológico; muchos de estos aspectos ya habían sido objeto de disputa antes incluso del Siglo de Oro. Hasta la expresión “interpretación auténtica” viene de los antiguos glosadores, comentaristas y teólogos que enseñaron en legendarias universidades, como las de Salamanca y Coimbra. El trabajo que aquí presento no pretende abrir un diálogo con las teorías modernas de la interpretación; se limita a perfilar el esfuerzo que uno de aquellos autores, Juan de Salas, hizo para aglutinar los aspectos filosóficos y jurídicos de la interpretación que a principios del siglo XVII eran discutidos en España y que no debiéramos hacerlos desaparecer de nuestra memoria.

For a Medieval thinker, in addition to positive law, there is another more fundamental law which is known by analyzing our own rational nature and our ultimate end. In this monographic issue, the nature and reach of the natural law will be studied in various medieval authors (St. Augustine, Alcuin of York, Philip the Chancellor, William of Auxerre, St. Bonaventure, St. Thomas Aquinas, John Duns Scotus and William of Ockham).

The practical reinterpretation of positive law in the light of its originating principle, oriented to the common good, need neither be a dispensation from the law, nor a discrediting of the legislator, nor a judgment on the law itself, nor an interpretation of said law, but rather it is a virtue, i.e. that of epieikeia. This is made necessary by the fact that a law cannot refer rightly to all cases; in some cases it will fail, and thus the legislator writes the law to cover what occurs in the majority of the cases, without ignoring the fact that in certain cases there will be a failure of the law to apply. This is, according to St. Thomas, that which is contemplated by the epieikeia in order to reinterpret positive law in the light of natural law.

Cicero’s main philosophical interest is in practical philosophy. This interest stemmed from his legal career and from his political activity. As a result of his philosophy, Greek moral philosophy was received in Latin culture. Cicero is, in his life and his works, the refusal of the moral, anthropological and political nihilism. His ideas, very present in the moral and political philosophy of the Middle Ages, continue being a key for contemporary world views.

Western thought has maintained a permanent attention by the problem of «habere»; even the modern as Marcel and Sartre have taken care of this category. But the contemporary nihilism has put in evidence the necessity to think the dwelling of the concrete existence of the man and its relationship with areas that offer a support to him. There are so many ways to «havere» as potentiality forms, in one of which it express the «habere» like determinadon ordered to the space in which the man is.

This starting point of the deontological argument as formulated by Millán- Puelles is the absolute imperative of duty on conscience, and its terminus or culmination is God as an Absolute Person. The proof departs from the commanded conscience to the Conscience that commands. An imperative is not only a demand directed toward a free willl, but likewise the demand that one will be directed by another. Each imperative is a dialogue betwen wills. Thence the need that the imperative be imposed ultimately by a person.