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)

Nelson, L. The impossibility of the "Theory of knowledge."--Moore, G. E. Four forms of skepticism.--Lehrer, K. Skepticism & conceptual change.--Quine, W. V. Epistemology naturalized.--Rozeboom, W. W. Why I know so much more than you do.--Price, H. H. Belief and evidence.--Lewis, C. I. The bases of empirical knowledge.--Malcolm, N. The verification argument.--Firth, R. The anatomy of certainty.--Chisholm, R. M. On the nature of empirical evidence.--Meinong, A. Toward an epistemological assessment of memory.--Brandt, R. The epistemological status of memory beliefs.--Malcolm, N. A definition (...) of factual memory.--Martin, C. B. and Deutscher, M. Remembering.--Ayer, A. J. Basic propositions.--Reichenbach, H. Are phenomenal reports absolutely certain?--Goodman, N. Sense and certainty.--Lewis, C. I. The given element in empirical knowledge.--Alston, W. Varieties of privileged access.--Schlick, M. The foundation of knowledge.--Russell, B. Epistemological premisses, basic propositions, and factual premisses.--Firth, R. Coherence, certainty, and epistemic priority.--Sellars, W. Empiricism and the philosophy of mind.--Quinton, A. The foundations of knowledge. (shrink)

Introduction to Philosophy, Fourth Edition, is the most comprehensive topically organized collection of classical and contemporary philosophy available. Building on the exceptionally successful tradition of previous editions, this edition for the first time incorporates the insights of a new coeditor, John Martin Fischer, and has been updated and revised to make it more accessible. Ideal for introductory philosophy courses, the text includes sections on the meaning of life, God and evil, knowledge and reality, the philosophy of science, the mind/body (...) problem, freedom of will, consciousness, ethics, and philosophical puzzles and paradoxes. It presents seventy substantial--and in some cases complete--selections from the best and most influential works in philosophy, offering a unique balance between classical and contemporary material. An extensive glossary of philosophical terms is also included. The fourth edition features fifteen new readings, including work by Albert Camus, Roderick M. Chisholm, Daniel Dennett, Harry G. Frankfurt, William Paley, Derek Parfit, John Perry, Richard Taylor, Peter Van Inwagen, Bernard Williams, and Susan Wolf. Part III, Knowledge and Reality, has been restructured and now includes Plato's Thaetetus, selections by Edmund L. Gettier and Robert Nozick, and an essay by Christopher Grau that explores the philosophical concepts presented in the popular film The Matrix. Two new ethics puzzles--"The Trolley Problem" and "Ducking Harm and Sacrificing Others"--are also included. This edition incorporates Study Questions after each reading and is accompanied by an Instructor's CD and a Student Companion Website, both containing helpful resources. (shrink)

Online supplement, "Mulsow: Additions to Notes drawn from the 2002 edition of Moderne aus dem Untergrund" full versions of nearly 300 notes that were truncated in the print edition. Hosted on H. C. Erik Midelfort's website. Martin Mulsow's seismic reinterpretation of the origins of the Enlightenment in Germany won awards and renown in its original German edition, and now H. C. Erik Midelfort's translation makes this sensational book available to English-speaking readers. In Enlightenment Underground, Mulsow shows that even in (...) the late seventeenth century some thinkers in Germany ventured to express extremely dangerous ideas, but did so as part of a secret underground. Scouring manuscript collections across northern Europe, Mulsow studied the writings of countless hitherto unknown radical jurists, theologians, historians, and dissident students who pushed for the secularization of legal, political, social, and religious knowledge. Often their works circulated in manuscript, anonymously, or as clandestinely published books. Working as a philosophical microhistorian, Mulsow has discovered the identities of several covert radicals and linked them to circles of young German scholars, many of whom were connected with the vibrant radical cultures of the Netherlands, England, and Denmark. The author reveals how radical ideas and contributions to intellectual doubt came from Socinians and Jews, church historians and biblical scholars, political theorists, and unemployed university students. He shows that misreadings of humorous or ironic works sometimes gave rise to unintended skeptical thoughts or corrosively political interpretations of Christianity. This landmark book overturns stereotypical views of the early Enlightenment in Germany as cautious, conservative, and moderate, and replaces them with a new portrait that reveals a movement far more radical, unintended, and puzzling than previously suspected. (shrink)

We first introduce the intuitive idea of a relation of grounding between facts . Then we propose a definition of this idea, based on a certain theory of the structure of facts . Finally we consider the idea of proofs of a special kind, namely proofs which follow the grounds of what is proved.

This complete life story of David Hume, one of Scotland’s greatest thinkers, follows the Enlightenment from its early roots to its full blossoming in 18th-century Edinburgh. Using original sources, many for the first time, this biography details every aspect of the philosopher’s life—from the lukewarm reception of his now pivotal work, Treatise of Human Nature, to the fame and near excommunication brought about by his famous Essays and History. Also detailed are the stories behind his nickname, “The Great Infidel,” the (...) numerous guests seeking an invitation to dine at his table, and his lengthy intellectual involvement with a married aristocrat. This work is a well-rounded picture of the man, the century in which he lived, his famous ideas, and above all, his humanity. (shrink)

The purpose of this book is to develop a terminological structure in which private perceptions can be discussed publicly without bringing into existence the usual unnecessary philosophical problems of confused usage of language. chisholm displays an appraisive, quasi-ethical use of language, whereby he claims that a thing has some particular sensible property is to have adequate evidence that it actually does have that property. (staff).

A Lagrangian formulation is constructed for particle interpretations of quantum mechanics, a well-known example of such an interpretation being the Bohm model. The advantages of such a description are that the equations for particle motion, field evolution and conservation laws can all be deduced from a single Lagrangian density expression. The formalism presented is Lorentz invariant. This paper follows on from a previous one which was limited to the single-particle case. The present paper treats the more general case of many (...) particles in an entangled state. It is found that describing more than one particle while maintaining a relativistic description requires the specification of final boundary conditions as well as the usual initial ones, with the experimenter’s controllable choice of the final conditions thereby exerting a backwards-in-time influence. This retrocausality then allows an important theoretical step forward to be made, namely that it becomes possible to dispense with the usual, many-dimensional description in configuration space and instead revert to a description in space–time using separate, single-particle wavefunctions. (shrink)

A simple mathematical extension of quantum theory is presented. As well as opening the possibility of alternative methods of calculation, the additional formalism implies a new physical interpretation of the standard theory by providing a picture of an external reality. The new formalism, developed first for the single-particle case, has the advantage of generalizing immediately to quantum field theory and to the description of relativistic phenomena such as particle creation and annihilation.

The moral philosophy of the first half of the twentieth century, at least in the English-speaking part of the world, has been largely devoted to problems of an ontological or epistemological nature. This concentration of effort by many acute analytical minds has not produced any general agreement with respect to the solution of these problems; it seems likely, on the contrary, that the wealth of proposed solutions, each making some claim to plausibility, has resulted in greater disagreement than ever before, (...) and in some cases disagreement about issues so fundamental that certain schools of thought now find it unrewarding, if not impossible, to communicate with one another. Moral philosophers of almost all schools seem to agree, however, that no major possibility has been neglected during this period, and that every proposed solution which can be adjudged at all plausible has been examined with considerable thoroughness. It is now common practice, for example, for the authors of books on moral philosophy to introduce their own theories by what purports to be a classification and review of all \emph{possible} solutions to the basic problems of analysis; and in many cases, indeed, the primary defense of the author's own position seems to consist in the negative argument that his own position cannot fail to be correct because none of the others which he has mentioned is satisfactory. (shrink)

This paper is concerned with the causally symmetric version of the familiar de Broglie–Bohm interpretation, this version allowing the spacelike nonlocality and the configuration space ontology of the original model to be avoided via the addition of retrocausality. Two different features of this alternative formulation are considered here. With regard to probabilities, it is shown that the model provides a derivation of the Born rule identical to that in Bohm’s original formulation. This derivation holds just as well for a many-particle, (...) entangled state as for a single particle. With regard to “certainties”, the description of a particle’s spin is examined within the model and it is seen that a statistical description is no longer necessary once final boundary conditions are specified in addition to the usual initial state, with the particle then possessing a definite value for every spin component at intermediate times. These values are consistent with being the components of a single, underlying spin vector. The case of a two-particle entangled spin state is also examined and it is found that, due to the retrocausal aspect, each particle possesses its own definite spin during the entanglement, independent of the other particle. In formulating this picture, it is demonstrated how such a realistic model can preserve Lorentz invariance in the face of Bell’s theorem and avoid the need for a preferred reference frame. (shrink)

We define a concept of truthmaker function, and prove the functional completeness, w.r.t. truthmaker functions in this sense, of a set of four-valued functions corresponding to standard connectives of the system of relevance logic known as First-Degree Entailment or Belnap–Dunn logic.

When a strange new test of perceptual style called the Rorschach reached the New World in the 1920s, it became almost immediately popular. Developed as a psychoana lytic "X ray" of the psyche, it succeeded because American psychologists wanted and needed it to do so, and to do so as that kind of test. Over a decade later, the MMPI was constructed as a more orthodox personality inventory geared to traditional psychiatric categories While this medical legacy was soon removed or (...) obscured, success was more gradual. After the war, clinical psychologists adopted a professional identity independent of psychiatry. Their personality assessment tools, and what counted as success, came to reflect a reclaimed disciplinary genealogy. Standardized mappings and rule-by-numbers tended to displace a trust in experience and expert Judgment. In this context, "proper" Rorschach use came to be seen as indulgent or sadly mistaken. Supporters of the MMPI were, in contrast, able to claim both science and efficiency on their side and colonized the field. The history of these tests clearly illustrates the process of co-production, of how the right tool can become very wrong as networks dissipate and professional time goes by. (shrink)

Defining technology : technology as apparatus -- Multimodal critical discourse analysis -- Analysing multimodal discourse : a toolkit approach -- Discourses of technology as progress -- Discourses of technological determinism -- Discourses of technological fetishism : (over)valuing technologies -- Discourses of technological (dis)satisfaction : consuming technologies.

Physician assistants (PAs), nurse practitioners (NPs), and medical residents constitute an increasingly significant part of the American health care workforce, yet patient assent to be seen by nonphysicians is only presumed and seldom sought. In order to assess the willingness of patients to receive medical care provided by nonphysicians, we administered provider preference surveys to a random sample of patients attending three emergency departments (EDs). Concurrently, a survey was sent to a random selection of ED residents and PAs. All respondents (...) were to assume the role of patient when presented with hypothetical clinical scenarios and standardized provider definitions. Despite presumptions to the contrary, ED patients are generally unwilling to be seen by PAs, NPs, and residents. While seldom asked in practice, 79.5% of patients fully expect to see a physician regardless of acuity or potential for cost savings by seeing another provider. Patients are more willing to see residents than nonphysicians. (shrink)

First published in 2002. Routledge is an imprint of Taylor & Francis, an informa company.

Franz Brentano developed an original theory of intrinsic value which he attempted to base on his philosophical psychology. Roderick Chisholm presents here a critical exposition of this theory and its place in Brentano's general philosophical system. He gives a detailed account of Brentano's ontology, showing how Brentano tried to secure objectivity for ethics not through a theory of practical reason, but through his theory of the intentional objects of emotions and desires. Professor Chisholm goes on to develop certain suggestions (...) about intrinsic value made by Brentano and his students, and discusses their relevance to theodicy and the problem of evil. Brentano, as the teacher of Husserl, Meinong, Twardowski, and others, stands at the origin of the phenomenological tradition and of the Polish school of philosophy that developed after World War I. He has also had considerable influence on Anglo-American philosophy. This book will interest those concerned with the origins of phenomenological value theory and more generally with the connections between ethics and philosophical psychology. (shrink)

A Lagrangian description is presented which can be used in conjunction with particle interpretations of quantum mechanics. A special example of such an interpretation is the well-known Bohm model. The Lagrangian density introduced here also contains a potential for guiding the particle. The advantages of this description are that the field equations and the particle equations of motion can both be deduced from a single Lagrangian density expression and that conservation of energy and momentum are assured. After being developed in (...) a general form, this Lagrangian formulation is then applied to the special case of the Bohm model as an example. It is thereby demonstrated that such a Lagrangian description is compatible with the predictions of quantum mechanics. (shrink)

A generalization of the familiar de Broglie-Bohm interpretation of quantum mechanics is formulated, based on relinquishing the momentum relationship p=∇S and allowing a spread of momentum values at each position. The development of this framework also provides a new perspective on the well-known question of joint distributions for quantum mechanics. It is shown that, for an extension of the original model to be physically acceptable and consistent with experiment, it is necessary to impose certain restrictions on the associated joint distribution (...) for particle positions and momenta. These requirements thereby define a new class of possible models. In pursuing this line of reasoning, the main contributions of this paper are (i) to identify the restrictions that must be imposed, (ii) to demonstrate that joint distribution expressions satisfying them do exist, and (iii) to construct a sample model based on one such joint distribution. (shrink)

This is the text of The Lindley Lecture for 1964, given by Roderick M. Chisholm (1916-1999), an American philosopher.