While outcomes for children with T-cell acute lymphoblastic leukemia have improved dramatically, survival rates for patients with relapsed/refractory disease remain dismal. Prior studies indicate that glucocorticoid resistance is more common than resistance to other chemotherapies at relapse. In addition, failure to clear peripheral blasts during a prednisone prophase correlates with an elevated risk of relapse in newly diagnosed patients. Here we show that intrinsic GC resistance is present at diagnosis in early thymic precursor T-ALLs as well as in a subset (...) of non-ETP T-ALLs. GC-resistant non-ETP T-ALLs are characterized by strong induction of JAK/STAT signaling in response to interleukin-7 stimulation. Removing IL7 or inhibiting JAK/STAT signaling sensitizes these T-ALLs, and a subset of ETP T-ALLs, to GCs. The combination of the GC dexamethasone and the JAK1/2 inhibitor ruxolitinib altered the balance between pro- and anti-apoptotic factors in samples with IL7-dependent GC resistance, but not in samples with IL7-independent GC resistance. Together, these data suggest that the addition of ruxolitinib or other inhibitors of IL7 receptor/JAK/STAT signaling may enhance the efficacy of GCs in a biologically defined subset of T-ALL.Leukemia advance online publication, 30 May 2017; doi:10.1038/leu.2017.136. (shrink)

Pain may appear to undermine the radically intentionalist view that the phenomenal character of any experience is entirely constituted by its representational content. That appearance is illusory. After categorizing versions of pain intentionalism along two dimensions, I argue that an 'objectivist' and 'non-mentalist' version is the most promising, if it can withstand two objections concerning what we say when in pain, and the distinctiveness of pain. I rebut these objections, in a way available to both opponents of and adherents to (...) the view that experiential content is entirely conceptual. (shrink)

The self seems to be a unitary entity remaining stable across time. Nevertheless, current theorizing conceptualizes the self as a number of interacting sub-systems involving perception, intention and action (self-model). One important function of such a self-model is to distinguish between events occurring as a result of one's own actions and events occurring as the result of somebody else's actions. We conducted an fMRI experiment that compared brain activation after an abrupt mismatch between one's own movement and its visual consequences (...) with an abrupt mismatch between one's own movement and somebody else's visually perceived hand movement. A right fronto-parietal network was selectively active during a sudden mismatch between one's own observed and performed hand action. (shrink)

This Paper Offers A New Interpretation of Phaedo 96a–103a. Plato has devoted the dialogue up to this point to a series of arguments for the claim that the soul is immortal. However, one of the characters, Cebes, insists that so far nothing more has been established than that the soul is durable, divine, and in existence before the incarnation of birth. What is needed is something more ambitious: a proof that the soul is not such as to pass out of (...) existence. According to Socrates’s initial response to Cebes at 95e8–96a1, giving such a demonstration requires a thorough investigation into “the reason for coming to be and passing away in general” (ὅλως γὰϱ δεῖ πεϱὶ γενέσεως ϰαὶ Φθοϱᾶς τὴν αἰτίαν διαπϱαγματεύσασθαι .. (shrink)

Dictionary of Viśiṣṭādvaita school in Hindu philosophy.

Jehovah's Witnesses are students of the Bible. They refuse transfusions out of obedience to the scriptural directive to abstain and keep from blood. Dr Muramoto disagrees with the Witnesses' religious beliefs in this regard. Despite this basic disagreement over the meaning of Biblical texts, Muramoto flouts the religious basis for the Witnesses' position. His proposed policy change about accepting transfusions in private not only conflicts with the Witnesses' fundamental beliefs but it promotes hypocrisy. In addition, Muramoto's arguments about pressure to (...) conform and coerced disclosure of private information misrepresent the beliefs and practices of Jehovah's Witnesses and ignore the element of individual conscience. In short, Muramoto resorts to distortion and uncorroborated assertions in his effort to portray a matter of religious faith as a matter of medical ethical debate. (shrink)

The papers in this volume bring together a number of scholars working on topics ranging from contemporary ethics to the history of philosophy. This wide scope reflects the comprehensive nature of Dietrich von Hildebrand's philosophic vision. His career includes foundational works on such subjects as ethics, philosophical method, aesthetics, and the nature of love. One struggles to imagine how Hildebrand managed to fit all this into a life that also includes extensive anti-Nazi political activism during World War II. Within this (...) broad scope of Hildebrand's work, one finds a number of important philosophical problems that beg for further development, such as his conception of personal existence, his rich and pluralistic conception of beauty, or his distinction between person and personality. In several places, however, the development of Hildebrand's thought must involve a correction or even an outright challenge to his reasoning. Each of these papers does just this, applying the insights of Hildebrand to a number of diverse philosophical problems, while also advancing and challenging his thought in various ways. Despite this wide diversity, three central issues appear again and again in these papers, and represent some of Hildebrand's most important contributions to philosophy: (i) his method of phenomenological realism, (ii) his conception of value and value-response, and (iii) his personalism. I want to provide here a brief sketch of these three areas to orient the reader before approaching the more technical details of each essay. (shrink)

In this paper, I attempt to explain one of the most controversial views attributed to the Stoic Chrysippus: that the impossible can follow from the possible. My solution finds in Chrysippus a distinction later made by the medieval logician John Buridan: that between being possible (there being a state of affairs that may occur) and being possibly-true (there being some proposition whose truth-conditions are that state of affairs). Buridan and Chrysippus have radically opposing views on the nature of propositions. What (...) their conceptions share is the conclusion that at least some propositions must be contingent beings. They argue for this while maintaining a rigorous commitment to the view that propositions are strictly bivalent. In 2. I explain the Chrysippean passage in terms of a distinction Buridan makes explicitly. In 3. I show how the distinction follows implicitly from the Stoic theory of quantification. In 4. I compare the modality with other aspects of Stoic logic. In 5. I discuss how the distinction behaves in the future tense. (shrink)

In the basic modal language and in the basic modal language with the added universal modality, first-order definability of all formulas over the class of all frames is shown. Also, it is shown that the problems of modal definability of first-order sentences over the class of all frames in the languages and are both PSPACE-complete.