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 need for informed analyses of health policy is now greater than ever. The twelve essays in this volume show that public debates routinely bypass complex ethical, sociocultural, historical, and political questions about how we should address ideals of justice and equality in health care. Integrating perspectives from the humanities, social sciences, medicine, and public health, this volume illuminates the relationships between justice and health inequalities to enrich debates. Understanding Health Inequalities and Justice explores three questions: How do scholars approach (...) relations between health inequalities and ideals of justice? When do justice considerations inform solutions to health inequalities, and how do specific health inequalities affect perceptions of injustice? And how can diverse scholarly approaches contribute to better health policy? From addressing patient agency in an inequitable health care environment to examining how scholars of social justice and health care amass evidence, this volume promotes a richer understanding of health and justice and how to achieve both. -/- The contributors are Judith C. Barker, Paula Braveman, Paul Brodwin, Jami Suki Chang, Debra DeBruin, Leslie A. Dubbin, Sarah Horton, Carla C. Keirns, J. Paul Kelleher, Nicholas B. King, Eva Feder Kittay, Joan Liaschenko, Anne Drapkin Lyerly, Mary Faith Marshall, Carolyn Moxley Rouse, Jennifer Prah Ruger, and Janet K. Shim. (shrink)

One dark and rainy night, Yuso sexually assaults and tortures Zelan. In escaping from the scene of his crime, he falls heavily and becomes an impotent paraplegic. Instead of treating his fate as divine retribution for his wicked acts, Yuso sees it as sheer bad luck. He shows no remorse for what he has done, and vainly hopes that he will recover his powers, which he now treats as involuntarily hoarded resources to be used on less rainy days. In the (...) presence of others, he pretends that he has turned over a new leaf. He asks for religious and educational books, hoping to make up for his poor education and deprived social background. But he immediately discards them when he is alone in favor of the pornographic magazines which he has bribed a nurse to smuggle in for him. His deception and various obscene acts committed in the hospital are exposed; by the time he comes up for trial, everyone knows that he is still a lustful, sadistic, and unrepentant man. Most retributivists have a sufficient justification for punishing Yuso independently of the social consequences of his punishment. Two features of the case might cause some difficulties. First, Yuso has already experienced considerable suffering and deprivation both before and after his crime, and retributivists might disagree about the relevance of the suffering to his punishment. Secondly, Yuso is unrepentant, and it is unlikely that punishment will change him. This might, as we shall see, create a problem for those who think that the justifying aim of punishment is the moral reform of the offender. (shrink)

Constitutionalism and the Rule of Law are related ideas about how the powers of government and of state officials are to be limited. The two ideas are sometimes equated. But constitutionalism, generally understood, usually refers to various constitutional devices and procedures, such as the separation of powers between the legislature, the executive and the judiciary, the independence of the judiciary, due process or fair hearings for those charged with criminal offences, and respect for individual rights, which are partly constitutive of (...) a liberal democratic system of government. The Rule of Law, on the other hand, embodies certain standards that define the characteristic virtues of a legal system as such. (shrink)

The purpose of this essay is to study the problem of inherent obscurity of the criterion for maximal utility in utilitarianism. For the sake of convenience of analysis, situations of moral actions are classified into four categories. It is shown that morality is flexible, especially in the positive sense, in that a virtuous action can be taken in various ways and/or to various degrees. For some situations it is inherently unclear what the moral requirement is, and whether it is a (...) maximum or a minimum. It is concluded that the schism of the principle of utility between the principle of the good and the principle of the right seems to be inevitable, and the interpretation of the ultimate criterion for maximal utility should be relaxed or interpreted separately and differently according to the situation of action. (shrink)

John Stuart Mill's essay On Liberty, published in 1859, has had a powerful impact on philosophical and political debates ever since its first appearance. This volume of essays covers the whole range of problems raised in and by the essay, including the concept of liberty, the toleration of diversity, freedom of expression, the value of allowing 'experiments in living', the basis of individual liberty, multiculturalism and the claims of minority cultural groups. Mill's views have been fiercely contested, and they are (...) at the centre of many contemporary debates. The essays are by leading scholars, who systematically and eloquently explore Mill's views from various perspectives. The volume will appeal to a wide range of readers including those interested in political philosophy and the history of ideas. (shrink)

What ecological advantages do animals gain by being able to detect, extract and exploit wavelength information? What are the advantages of representing that information as hue qualities? The benefits of adding chromatic to achromatic vision, marginal in object detection, become apparent in object recognition and receiving biological signals. It is argued that this improved performance is a direct consequence of the fact that many animals' visual systems reduce wavelength information to combinations of four basic hues. This engenders a simple categorical (...) scheme that permits a rich amount of sensory information to be rapidly and efficiently employed by cognitive machinery of limited capacity. (shrink)

At 8 a.m. I get in my car and set off for work. At 7:59 a.m., before I started it, my car was at rest; at 8:01 a.m. it is in motion. When a thing is not in motion, it is at rest, and when it is not at rest, it is in motion. But what was the state of the car at 8:00 a.m., as I was starting it? It would be inaccurate to say that it was in motion (...) but it would be inaccurate, also, to say that it was at rest: it was “just starting.” But, if whenever a thing is not in motion it is at rest, the state of “just starting”—or, of course, the comparable state of “just stopping”—must be either a state of motion or a state of rest. Which? (shrink)

This detailed and sympathetic, but not uncritical, study of On Liberty' argues for the general consistency and coherence of Mill's defence of individual liberty, but maintains that there are significant non-utilitarian elements in his arguments.

Organisational change is one of the most frequently recurring organisational phenomena of our time, yet despite this, organisations are not succeeding in instituting change processes effectively; dismal "change success rates" are recorded. Van Tonder and Van Vuuren (2004) have argued that the adoption of an ethical framework from within which change practices are to be approached and "managed", would significantly reduce the negative consequences of change initiatives. As a first step in this direction, the current study set out to establish (...) the meaning that employees attribute to "ethical" and "unethical" change. Data obtained from a sample of 111 respondents from seven companies were subjected to basic content analysis and key themes extracted. The results indicate a limited understanding of ethics concepts among employees. A clear need for both intensified education and research is indicated. (shrink)