The Adverse Outcome Pathway (AOP) concept is a knowledge assembly and communication tool to facilitate the transparent translation of mechanistic information into outcomes meaningful to the regulatory assessment of chemicals. The AOP framework and associated knowledgebases (KBs) have received significant attention and use in the regulatory toxicology community. However, it is increasingly apparent that the potential stakeholder community for the AOP concept and AOP KBs is broader than scientists and regulators directly involved in chemical safety assessment. In this paper we (...) identify and describe those stakeholders who currently—or in the future—could benefit from the application of the AOP framework and knowledge to specific problems. We also summarize the challenges faced in implementing pathway-based approaches such as the AOP framework in biological sciences, and provide a series of recommendations to meet critical needs to ensure further progression of the framework as a useful, sustainable and dependable tool supporting assessments of both human health and the environment. Although the AOP concept has the potential to significantly impact the organization and interpretation of biological information in a variety of disciplines/applications, this promise can only be fully realized through the active engagement of, and input from multiple stakeholders, requiring multi-pronged substantive long-term planning and strategies. (shrink)

© Copyright 2015, Mary Ann Liebert, Inc..Signal transducer and activator of transcription factor 3 is hyperactivated in head and neck squamous cell carcinomas. Cumulative evidence indicates that IL-6 production by HNSCC cells and/or stromal cells in the tumor microenvironment activates STAT3 and contributes to tumor progression and drug resistance. A library of 94,491 compounds from the Molecular Library Screening Center Network was screened for the ability to inhibit interleukin-6 -induced pSTAT3 activation. For contractual reasons, the primary high-content screening campaign was (...) conducted over several months in 3 distinct phases; 1,068 primary HCS actives remained after cytotoxic or fluorescent outliers were eliminated. One thousand one hundred eighty-seven compounds were cherry-picked for confirmation; actives identified in the primary HCS and compounds selected by a structural similarity search of the remaining MLSCN library using hits identified in phases I and II of the screen. Actives were confirmed in pSTAT3 IC50 assays, and an IFNγ-induced pSTAT1 activation assay was used to prioritize selective inhibitors of STAT3 activation that would not inhibit STAT1 tumor suppressor functions. Two hundred three concentration-dependent inhibitors of IL-6-induced pSTAT3 activation were identified and 89 of these also produced IC50s against IFN-γ-induced pSTAT1 activation. Forty-nine compounds met our hit criteria: they reproducibly inhibited IL-6-induced pSTAT3 activation by ≥70% at 20 μM; their pSTAT3 activation IC50s were ≤25 μM; they were ≥2-fold selective for pSTAT3 inhibition over pSTAT1 inhibition; a cross target query of PubChem indicated that they were not biologically promiscuous; and they were ≥90% pure. Twenty-six chemically tractable hits that passed filters for nuisance compounds and had acceptable drug-like and ADME-Tox properties by computational evaluation were purchased for characterization. The hit structures were distributed among 5 clusters and 8 singletons. Twenty-four compounds inhibited IL-6-induced pSTAT3 activation with IC50s ≤20 μM and 13 were ≥3-fold selective versus inhibition of pSTAT1 activation. Eighteen hits inhibited the growth of HNSCC cell lines with average IC50s ≤ 20 μM. Four chemical series were progressed into lead optimization: the guanidinoquinazolines, the triazolothiadiazines, the amino alcohols, and an oxazole-piperazine singleton. (shrink)

Розкрито сутність поняття «рейтинг». Доведено значущість рейтингової оцінки для суб’єктів фінансового ринку, зокрема для страхових компаній, потенційних страхувальників, інвесторів та кредиторів.

This collection addresses two different audiences: 1) historians and philosophers of the life sciences reflecting on collaborations across disciplines, especially as regards defining and addressing Grand Challenges; 2) researchers and other stakeholders involved in cross-disciplinary collaborations aimed at tackling Grand Challenges in the life and medical sciences. The essays collected here offer ideas and resources both for the study and for the practice of goal-driven cross-disciplinary research in the life and medical sciences. We organise this introduction in three sections. The (...) first section provides some background and context. The second motivates our take on this topic and then outlines the central ideas of each paper. The third section highlights the specificity and significance of this approach by considering: a) how this collection departs from existing literature on inter- and trans-disciplinarity, b) what is characteristic about this approach, and c) what role this suggests for the history and philosophy of the life sciences in addressing Grand Challenges. (shrink)

The idea of personalised medicine (PM) has gathered momentum recently, attracting funding and generating hopes as well as scepticism. As PM gives rise to differing interpretations, there have been several attempts to clarify the concept. In an influential paper published in this journal, Schleidgen and colleagues have proposed a precise and narrow definition of PM on the basis of a systematic literature review. Given that their conclusion is at odds with those of other recent attempts to understand PM, we consider (...) whether their systematic review gives them an edge over competing interpretations. We have found some methodological weaknesses and questionable assumptions in Schleidgen and colleagues’ attempt to provide a more specific definition of PM. Our perplexities concern the lack of criteria for assessing the epistemic strength of the definitions that they consider, as well as the logical principles used to extract a more precise definition, the narrowness of the pool from which they have drawn their empirical data, and finally their overlooking the fact that definitions depend on the context of use. We are also worried that their ethical assumption that only patients’ interests are legitimate is too simplistic and drives all other stakeholders’ interests—including those that are justifiable—underground, thus compromising any hope of a transparent and fair negotiation among a plurality of actors and interests. As an alternative to the shortcomings of attempting a semantic disciplining of the concept we propose a pragmatic approach. Rather than considering PM to be a scientific concept in need of precise demarcation, we look at it as an open and negotiable concept used in a variety of contexts including at the level of orienting research goals and policy objectives. We believe that since PM is still more an ideal than an achieved reality, a plurality of visions is to be expected and we need to pay attention to the people, reasons and interests behind these alternative conceptions. In other words, the logic and politics of PM cannot be disentangled and disagreements need to be tackled addressing the normative and strategic conflicts behind them. (shrink)

According to Thomas Reid, the development of natural sciences following the model of Newton's Principia and Optics would provide further evidence for the belief in a provident God. This project was still supported by his student, Dugald Stewart, in the early nineteenth century. John Fearn , an early critic of the Scottish common sense school, thought that the rise of ‘infidelity’ in the wake of scientific progress had shown that the apologetic project of Reid and Stewart had failed. In reaction (...) to Reid and Stewart, he proposed an idealist philosophy that would dispense with the existence of matter, and would thus cut at the root what he thought was the main source of modern atheism. In this paper, I consider Fearn's critique of Reid and Stewart in his main works: First Lines of the Human Mind and Manual of the Physiology of Mind . I also consider Fearn's arguments against Hume and in favour of a renewed apologetics in An Essay on the Philosophy of Faith and the Economy of Revelatio.. (shrink)

Both a significant body of literature and the case study presented here show that digital knowledge repositories struggle to attract the needed level of data and knowledge contribution that they need to be successful. This happens also to high profile and prestigious initiatives. The paper argues that the reluctance of researchers to contribute can only be understood in light of the highly competitive context in which research careers need to be built nowadays and how this affects researchers’ quality of life. (...) Competition and managerialism limit the discretion of researchers in sharing their results and in donating their working time. A growing corpus of research shows that academic researchers are increasingly overworked and highly stressed. This corroborates the point that the room for undertaking additional tasks with future and uncertain benefits is very limited. The paper thus recommends that promoters of digital knowledge repositories focus on the needs of the researchers who are expected to contribute their knowledge. In order to treat them fairly and to ensure the success of the repositories, knowledge sharing needs to be rewarded so as to improve the working conditions of contributors. In order to help implementing this researcher-centred approach, the paper proposes the idea of expediential trust: rewards for contributing should be such that rational, self-interested researchers would freely decide to contribute their knowledge and effort trusting that this would make them better off. (shrink)

The paper discusses the possibility that the benefits of pharmacogenomics will not be distributed equally and will create orphan populations. I argue that since these inequalities are not substantially different from those produced by ‘traditional’ drugs and are not generated with the intention to discriminate, their production needs not be unethical. Still, the final result is going against deep-seated moral feelings and intuitions, as well as broadly accepted principles of just distribution of health outcomes and healthcare. I thus propose two (...) provisos that would prevent the most offensive outcomes and moderate the scope of the produced inequalities. The first proviso rejects pharmacogenomics innovations that worsen existing group inequalities and aggravate the disadvantage of communities with a history of discrimination. The second proviso requires that there is a strategy in place to even out as much as possible the distribution of benefits in the future and that a system of compensations is in place for pharmacogenomic orphans. Given that only one moral problem generated by pharmacogenomics has been tackled, the list of provisos might be expanded when other issues are considered. (shrink)

The paper uses two historical examples, public health (1840-1880) and town planning (1945-1975) in Britain, to analyse the challenges faced by goal-driven research, an increasingly important trend in science policy, as exemplified by the prominence of calls for addressing Grand Challenges. Two key points are argued. (1) Given that the aim of research addressing social or global problems is to contribute to improving things, this research should include all the steps necessary to bring science and technology to fruition. This need (...) is captured by the idea of practical integration, which brings this type of research under the umbrella of collective practical reason rather than under the aegis of science. Achieving practical integration is difficult for many reasons: the complexity of social needs, the plurality of values at stake, the limitation of our knowledge, the elusive nature of the skills needed to deal with uncertainty, incomplete information and asymmetries of power. Nevertheless, drawing from the lessons of the case studies, it is argued that (2) practical integration needs a proper balance between values, institutions and knowledge: i.e. a combination of mutual support and mutual limitation. Pursuing such a balance provides a flexible strategy for approximating practical integration. (shrink)

In spite of extensive criticisms, war metaphors are still widespread in medical discourse. In the domain of public health analogies between war and infectious diseases are rooted in the similar impacts they can have on political institutions and communities. This similarity has been emphasized by the recent trend of addressing infectious disease from the point of view of national security. Nevertheless, it is here argued that the analogy cannot be used to model normative principles for treating carriers of contagious diseases (...) after the principles of ius in bello . Yet, the analogy may provide some useful practical and theoretical insights in tackling the growing problem of limiting the spread of drug-resistant pathogens: an issue that generates increasing worries and raises difficult ethical and political questions of rights, responsibilities and obligations. It is suggested that if anti-microbials and antibiotics are seen as strategic information, their misuse can be usefully compared to careless talk in times of war. (shrink)

The paper points out three serious problems in Ruud ter Meulen’s view of solidarity and of its role in healthcare ethics. First, it is not clear whether and to what extent ter Meulen expects normative concepts to be rooted in existing social practices: his criticism of liberal theories of justice seems to imply a different view on this issue than his implicit assumption that normative concepts are independent from social and historical trends. Second, it is not clear at which level (...) his notion of solidarity is meant to be applied: does it provide principles for individuals or for institutions? Nor is it clear at what level of generality it should work: is it meant for healthcare institutions or for states, for citizens or for healthcare practitioners? Third, it is not at all clear how the communitarian and the universalist aspirations in his conception of solidarity can be reconciled. In light of such difficulties it is argued that within philosophical discourse solidarity can be a useful notion only if it can be clearly distinguished from existing and commonly used ethical concepts. Three examples of such narrow and specific uses of solidarity are presented. Finally, a sceptical view of confining the work of applied philosophers to articulating normative concepts is put forward and an alternative view of blending empirical and philosophical analysis is proposed. This vision of field philosophy requires serious attention and careful understanding of the circumstances and constraints within which normative recommendations operate. It is suggested that such a modest and empirically grounded understanding of normative work is a better way of honouring the belief that philosophy is rooted in social institutions and in complex webs of relations. (shrink)

"Williams's masterful translation satisfies (at last!) a long-standing need. There are lots of good translations of Augustine's great work, but until now we have been forced to choose between those that strive to replicate in English something of the majesty and beauty of Augustine's Latin style and those that opt instead to convey the careful precision of his philosophical terminology and argumentation. Finally, Williams has succeeded in capturing both sides of Augustine's mind in a richly evocative, impeccably reliable, elegantly readable (...) presentation of one of the most impressive achievements in Western thought--Augustine's Confessions." --Scott MacDonald, Professor of Philosophy and Norma K. Regan Professor in Christian Studies, Cornell University. (shrink)

Starting from the semantic difference between the Arabic terms samāḥa or tasāmuḥ, and the Latin tolerantia, this essay proposes some observations on the Islamic notion of tolerance according to some contemporary Arabic language texts of Islamic inspiration. This literature invariably emphasises the importance of tolerance in the context of the Islamic religion and thought; and, notwithstanding some evident differences among the authors, relating to schools and to varying degrees of openness to Western thought, the discourse remains anchored in the foundational (...) literature, especially the Sunnah of the Prophet. (shrink)

kind of joke to ask what is the case if the antecedent is false—“And where are the biscuits if I don’t want any?”, “And what’s on PBS if I’m not interested?”, “And who shot Kennedy if that’s not what I’m asking?”. With normal indicative conditionals like.

This book offers a critical introduction to the work of American philosopher D. G. Leahy (1937-2014). Leahy's fundamental thinking can be characterized as an absolute creativity in which all creating is 'live' -- a happening occurring now that manifests a supersaturated polyontological actuality that is essentially created by the logic that characterizes it. Leahy leaves behind the categorial presuppositions of modern thought, eclipsing both Cartesian and Hegelian subjectivities and introducing instead an essentially new form of thinking founded in a nondual (...) logic of creation. The new thinking delineates the absolute unicity of existence as a creative interactivity beyond all traditional dichotomies (such as one vs. many, unity vs. plurality, identity vs. change): a fully "digitized" actuality that is nothing but newness, which inherently implies nothing but change. Through this new form of thinking, change itself is revealed to be the very essence of reality and mind. Any reader looking for a quantum leap beyond the thrall of modern and postmodern fixations is invited to hear and apprehend this new thinking that refuses to be conditioned by paradigms, categories, species, genera, walls, bridges, boundaries, or abstractions: an essentially free thinking that embodies creative novelty itself. (shrink)

Personalism is one of the philosophical perspectives which hold that the reality in person and the human person has the highest intrinsic value. This paper makes reference to Louis Janssens' eight criteria in adequate consideration of the human person but further argues that there is need to consider people as situated agents especially within gender relational perspectives. The paper identifies gender as an important social construction that shapes the consideration of the human persons within socio-spatial spheres. The main crux of (...) the paper is that there is a gender context of personalism and this has profound implications for bioethical agendas. Gender is part of the human condition, especially when we philosophically or sociologically engage the notion of equity and equality within the social system, because social realities in the relational perspective are not impartial, impersonal and equal. Gender does not determine morality but it plays a role in morality and expectations from moral agents. Women have been categorised as a sociological group because their integrity, freedom/autonomy and dignity (which are basic concerns of bioethics) are capable of being threatened. A gender perspective provides important incentives for moral theory which searches for possible conceptual imbalances or blind spots in ethical reflections. The paper refers to Sen's faces of gender inequality and expands on the notion that natality inequality is one of the fundamental levels of gender inequality, which in turn is the primary starting agenda in bioethics. The paper avers that the recognition of the fundamental importance of gender to the organization of social reality and the development of personal identities have important practical implications for bioethics. (shrink)

The need to better balance the promotion of scientific and technological innovation with risk management for consumer protection has inspired several recent reforms attempting to make regulations more flexible and adaptive. The pharmaceutical sector has a long, established regulatory tradition, as well as a long history of controversies around how to balance incentives for needed therapeutic innovations and protecting patient safety. The emergence of disruptive biotechnologies has provided the occasion for regulatory innovation in this sector. This article investigates the regulation (...) of advanced biotherapeutics in the European Union and shows that it presents several defining features of an adaptive regulation regime, notably institutionalized processes of planned adaptation that allow regulators to gather, generate, and mobilize new scientific and risk evidence about innovative products. However, our in-depth case analysis highlights that more attention needs to be paid to the consequences of the introduction of adaptive regulations, especially for critical stakeholders involved in this new regulatory ecosystem, the capacity and resource requirements placed on them to adapt, and the new tradeoffs they face. In addition, our analysis highlights a deficit in how we currently evaluate the performance and public value proposition of adaptive regulations vis-à-vis their stated goals and objectives. (shrink)

The background paper provides an introduction to the concept of pandemics and to the ethical and political issues related with pandemic preparedness.

In this article we raise a problem, and we offer two practical contributions to its solution. The problem is that academic communities interested in digital publishing do not have adequate tools to help them in choosing a publishing model that suits their needs. We believe that excessive focus on Open Access (OA) has obscured some important issues; moreover exclusive emphasis on increasing openness has contributed to an agenda and to policies that show clear practical shortcomings. We believe that academic communities (...) have different needs and priorities; therefore there cannot be a ranking of publishing models that fits all and is based on only one criterion or value. We thus believe that two things are needed. First, communities need help in working out what they want from their digital publications. Their needs and desiderata should be made explicit and their relative importance estimated. This exercise leads to the formulation and ordering of their objectives. Second, available publishing models should be assessed on the basis of these objectives, so as to choose one that satisfies them well. Accordingly we have developed a framework that assists communities in going through these two steps. The framework can be used informally, as a guide to the collection and systematic organization of the information needed to make an informed choice of publishing model. In order to do so it maps the values that should be weighed and the technical features that embed them. Building on our framework, we also offer a method to produce ordinal and cardinal scores of publishing models. When these techniques are applied the framework becomes a formal decision–making tool. Finally, the framework stresses that, while the OA movement tackles important issues in digital publishing, it cannot incorporate the whole range of values and interests that are at the core of academic publishing. Therefore the framework suggests a broader agenda that is relevant in making better policy decisions around academic publishing and OA. (shrink)

H.P. Grice is a distinguished philosopher predominantly known for his influential contributions to the philosophy of language, but that is only one strand in a rich tapestry of ideas bearing on the philosophy of mind, ethics, and metaphysics as well. Some of the essays in this collection of original papers by leading philosophers edited by Grandy and Warner develop Grice's earlier work in the philosophy of language, but most of them discuss or present his newer and less-known work. Together they (...) demonstrate the unified and powerful character of his thoughts on being, mind, meaning, and morals. An introductory essay provides some of the first overview of Grice's thought, and makes explicit some of the relations among the essays. Grice's substantial response is followed by nineteen contributed papers whose authors include Donald Davidson, Stephen Schiffer, John Searle, and P.F. Strawson. The Times Literary Supplement writes of Grice: 'the only leader of whom it is true that the level of the discipline would be raised if most philosophers took him as a model of how to think and write.' This paperback edition replaces the hardback, published March 1986. (shrink)