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)

The Church of England By Law Established, in incidental payment for secular privilege, has submitted to the bonds of established clichá, in particular to the reproach that its rulers seem more concerned with the external or practical working of Anglican faith and ritual than with their intellectual definition and justification. This intellectual looseness remained unimportant in practice as long as a forceful anti–Roman spirit blew all waves of opinion in one practical direction. In time, however, that wind gradually lost force (...) and positive cross–currents of Anglican belief came to the public surface. The legislators of the sixteenth century had formulated the positive rules of the Thirty–Nine Articles and the Prayer Book in tolerantly broad language. They left no decisive teaching authority to explain their texts and to meet the challenge of shifting ritual and speculative doubt. Time has subjected both instruments to an everwidening range of individual interpretation especially since the early nineteenth century, when the Anglican monopoly of political, social and educational institutions was disputed by fresh tides of Protestant dissenters, renascent Catholics and nascent agnostics. To–day, as Mr. Cockshut wryly comments: “to throw doubt on the Anglican formularies is itself part of the Anglican tradition”. (shrink)

The meticulous printing at a moderate price of this remarkable work is a credit to the publisher. During the past thirty years M. Gilson has been the greatest single influence upon lay readers in reviving serious interest in the clerical speculation, which for twelve hundred years conscientiously spanned the gap between the collapse of Greek science and Roman law and the late sweep of modern sciences and their secular philosophies. Preoccupation with short-term apologetics after the Reformation increased clerical aloofness from (...) professional science and philosophy and probably increased the non-scholastic’s assumption that the Christian Era was merely a dark or middle age between ancient and modern intellectual life. In fact, early and medieval thinkers gradually confronted their Christian faith and pagan science and against the basso ostinato of secular warfare developed the varied themes of scientific theology and human philosophy, which crystallized into the mature Scholasticism of the thirteenth century. Hence the seventeenth century founders of modern philosophy, as M. Gilson first found à propos of Descartes, started to philosophize from a metaphysical inheritance much richer than the original Greek patrimony, especially in the light it cast upon the reality of God, the origin of the universe in which man lives, the nature and destiny of man himself. To overlook this linking inheritance, is to make modern philosophy less intelligible; while to personally judge its value, we must return to its historical sources. This is the task to which M. Gilson has devoted his pioneering judgment; this work is probably the final synthesis of his scholarship. (shrink)