The integrated stress response (ISR) is a key determinant of tumorigenesis in response to oncogenic forms of stress like genotoxic, proteotoxic and metabolic stress. ISR relies on the phosphorylation of the translation initiation factor eIF2 to promote the translational and transcriptional reprogramming of gene expression in stressed cells. While ISR promotes tumor survival under stress, its hyperactivation above a level of tolerance can also cause tumor death. The tumorigenic function of ISR has been recently demonstrated for lung adenocarcinomas (LUAD) with (...) KRAS mutations. ISR mediates the translational repression of the dual‐specificity phosphatase DUSP6 to stimulate ERK activity and LUAD growth. The significance of this finding is highlighted by the strong anti‐tumor responses of ISR inhibitors in pre‐clinical LUAD models. Elucidation of the mechanisms of ISR action in LUAD progression via cell‐autonomous and immune regulatory mechanisms will provide a better understanding of its tumorigenic role to fully exploit its therapeutic potential in the treatment of a deadly form of cancer. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:176 HUME ON PROMISES AND THEIR OBLIGATION This discussion of Hume's account of promises pursues certain issues raised by William Vitek in his paper "The Humean Promise: Whence Comes Its Obligation?" The question I consider first is what, for Hume, it is for someone to make a promise. I then go on to consider Hume's view of promisekeeping as an artificial virtue and the distinction which Hume makes between (...) two kinds of obligation in relation to promises: a natural and an artificial obligation. The issue with which I am principally concerned is how far Hume succeeds in explaining our recognition of the obligation to keep promises. The Humean Promise There is implicit in Hume's "Of the Obligation of Promises" an account of what it is for someone to make a promise, i.e., of the conditions which are at least necessary for this to occur. It is worthwhile making these conditions explicit in order to bring out points of similarity with the celebrated account of promises provided in recent 4 philosophy by John Searle. We find in both Hume and Searle a recognition that promising is a social institution which depends upon certain conventions, and that the conditions for promising reflect these conventions. Among the conditions which appear to be common to their different accounts are the following: 1.That a certain form of words is used (typically, of the form ' I promise...'). 2.That these words are understood by the speaker. 177 3.That they predicate an act of the speaker which will be performed for the interest or advantage of another. 4.That the action is not one which the speaker would undertake in the normal course of events. 5.That the speaker's utterance expresses a serious intention or resolution. 6.That in making this utterance the speaker wills the obligation to act accordingly. Let me comment briefly on these conditions. 1.The condition that a certain form of words is used in effect acknowledges that promising involves a distinctive type of speech act: namely, one which can, in itself, bind the speaker to the performance of an action (T 522). Presumably, however, this does not necessarily require the actual use of the words · I promise' — the context may determine that a promise has been made, even without the use of these words. We should note that language itself is, for Hume, the product of a convention (T 490); so also, therefore, must be the institution of promisemaking and promise-keeping. 2.The condition that these words are understood by the speaker is implicit in Hume's comment that while "the expression makes on most occasions the whole of the promise," someone who makes use of the expression without understanding its meaning "wou'd not certainly be bound by it" (T 523). It is a condition which relates to what Searle describes as the normal 'input' and 'output' conditions, i.e., the conditions which govern "serious and literal linguistic communication." It is presupposed, for example, that the speaker (and perhaps also the hearer) knows how to speak 178 the language, that he is not play-acting or speaking in jest, and so on. 3.The condition that these words predicate an act of the speaker for the interest or advantage of another is obviously implicit, at least, in Hume's account of promise-keeping as an artificial virtue (of which I will say more later). But it should be emphasised that a promise is not simply an undertaking to act in a certain way towards another person: it is a matter of undertaking to do something for that person. 4.That the action is not one which the speaker would normally undertake, again, is a condition for which Hume caters: indeed, it is an essential part of his account that an action which a person promises to perform is not one which would occur in accordance with his natural passions or inclinations (T 519). There may, nevertheless, be possible exceptions to this, as where someone promises to do something which self-interest would incline him to do anyway. But in this kind of case promising has for Hume the special function of increasing the... (shrink)

David Brink’s new book, Fair Opportunity and Responsibility delivers an important and erudite contribution to the under theorised notion of ‘fair opportunity’ in our culpability determinations. Bri...

_Educational Neuroscience_ provides an overview of the wide range of recent initiatives in educational neuroscience, examining a variety of methodological concerns, issues, and directions. Encourages interdisciplinary perspectives in educational neuroscience Contributions from leading researchers examine key issues relating to educational neuroscience and mind, brain, and education more generally Promotes a theoretical and empirical base for the subject area Explores a range of methods available to researchers Identifies agencies, organizations, and associations facilitating development in the field Reveals a variety of on-going (...) efforts to establish theories, models, methods, ethics, and a common language. (shrink)

This chapter presents emotion as a function of brain‐body interaction, as a vital part of a multi‐tiered phylogenetic set of neural mechanisms, evoked by both instinctive processes and learned appraisal systems, and argues to establish the primacy of emotion in relation to cognition. Primarily based on Damasio's somatic marker hypothesis, but also incorporating elements of Lazarus' appraisal theory, this paper presents a neuropedagogical model of emotion, the somatic appraisal model of affect. SAMA identifies quintessential components, facets, and functions of affect (...) necessary to provide a new domain, namely educational neuroscience, with a basis on which to build a dynamic model of affect serving to critique traditional cognitivist‐oriented curricula and instruction, and to inform an alternative: neuropedagogy. (shrink)

By definitively establishing that racism has broad implications for how the entire field of philosophy is practiced -- and by whom -- this powerful and ...

Common lawyers are accustomed to the presumption of innocence being described as a “golden thread” running “[t]hroughout the web” of the criminal law: “that it is the duty of the prosecution to prove the prisoner’s guilt” (Woolmington v DPP [1935] AC 462 per Viscount Sankey LC at 481). But although the language of “golden thread” is memorable and oft-quoted, the presumption of innocence must mean more than this: it is not simply a restatement of the burden of proof in a (...) criminal trial.Once this simple point is recognised, a whole host of more complex questions arise. For example: what, precisely, is the scope of the principle? Is this a matter on which consensus is possible or desirable? What role does the presumption have to play in pre-trial proceedings, in decisions by prosecutors? Does the presumption have consequences for the substantive criminal law, or can legislators blunt its impact by defining criminal offences so as to deprive the presumption of its bite? Can legislators tr. (shrink)

Although organizations can derive competitive advantage from developing and implementing information systems, they are confronted with a rising number of unethical information practices. Because end-users and computer experts are the conduit to an ethical organizational environment, their intention to report unethical IT-related practices plays a critical role in protecting intellectual property and privacy rights. Using the survey methodology, this article investigates the relationship between willingness to report intellectual property and privacy violations and Machiavellianism, gender and computer literacy in the form (...) of programming experience. We found that gender and computer expertise interact with Machiavellianism to influence individuals’ intention of reporting unethical IT practices. This study helps us to improve our understanding of the emergent ethical issues existing in the IT-enabled decision environment. (shrink)

Belief in God's being -- Belief in God's love -- Belief and God's phoenix church.

The aim of this systematic review was to summarize and assess the quality of asthma intervention health economic studies from 2002 to 2007, compare the study findings with clinical management guidelines, and suggest avenues for future improvement of asthma health economic studies. Forty of the 177 studies met our inclusion criteria. We assessed the quality of studies using The Quality of Health Economic Studies validated instrument (total score range: 0-100). Six studies (15%) had quality category 2, 26 studies (65%) achieved (...) quality category 3, and the remaining eight (20%) studies were scored as the highest quality level, category 4. Overall, the findings from this review are in line with the Global Initiative for Asthma clinical guidelines. Many asthma health economic studies lacked appropriate long term time horizons to match the chronic nature of the disease and suffered from using effectiveness measures that did not capture all disease related risks and benefits. We recommend that new asthma simulation models: be flexible to allow for long term time horizons, focus on using levels of asthma control in their structure, and estimate both long term asthma specific outcomes like well-controlled time as well as generic outcomes such as quality adjusted survival. (shrink)

Background: Omalizumab, an anti-immunoglobulin E antibody, reduces exacerbations and symptoms in uncontrolled allergic asthma. The study objective was to estimate the costs and consequences of omalizumab compared to usual care from a US payer perspective. Methods: We estimated payer costs, quality-adjusted survival (QALYs), and the incremental cost-effectiveness ratio (ICER) of omalizumab compared to usual care using a state-transition simulation model that included sensitivity analyses. Every 2 weeks, patients could transition between chronic asthma and exacerbation health states. The best available evidence (...) informed the clinical and cost input estimates. Five years of omalizumab treatment followed by usual care was assumed to estimate a lifetime horizon. Omalizumab responders (60.5% of treated) were modeled as a separate scenario where nonresponders reverted back to usual care after 16 weeks of active treatment. Results: The mean lifetime discounted costs and QALYs were $83 400 and 13.87 for usual care and $174 500 and 14.19 for omalizumab plus usual care resulting in $287 200/QALY (95% interval: $219 300, $557 900). The ICER was $172 300/QALY when comparing omalizumab to usual care in the responder scenario. One-way sensitivity analyses indicated that the results were sensitive to the difference in treatment-specific utilities for the chronic state, exacerbation-associated mortality, omalizumab price, exacerbation rates, and response definition. Conclusions: The results suggest that adding omalizumab to usual care improves QALYs at an increase in direct medical costs. The cost-effectiveness of omalizumab is similar to other chronic disease biologics. The value increases when omalizumab response is used to guide long-term treatment. (shrink)

Tenth annual conference at the University of Manchester, 8th-10th April 1983.

The philosopher John J. McDermott comes out of the long American tradition that takes the aim of philosophical inquiry to be interpretation of the open meanings of experience, so that we might all live fuller and richer lives. Here, the authors of these nine essays explore his highly original interpretations of philosophy's various questions about our shared existence. How are we to understand the nature of American culture and to carry forward its important contributions? What is the personal importance of (...) embodiment, of living in the realization of death? How does our physical and personal environment nourish bodies and spirits? What does the deliberate pursuit of a morality offer us? How can we carry forward the fundamental tasks of education to enable those who follow us to use our shared past to address their civic and spiritual problems? What are the possibilities for community? Together, these essays offer a clear, multi-layered understanding of the compelling vision that McDermott has presented over the years. In an Afterword, McDermott responds to the authors' queries and concerns, offering a restatement of his understanding of the American philosopher's task. These essays indicate, and McDermott's response confirms, that for him philosophy is not a purely cerebral activity. Philosophy is, rather, an intellectual means of exploring the fullness of human experience, and it functions best when it operates in the context of the broad sweep of the humanities. Similarly, for McDermott the self is no given substantial entity. On the contrary, it is relational, rooted geographically and socially in its place and its fellows, and damaged when these life-giving processes fail. Further, McDermott does not accept any ultimate canopy of meaning. The human journey is a personal project within which provisional meanings must be created to sustain our advance. (shrink)

Quality and service improvement (QSI) research employs a broad range of methods to enhance the efficiency of healthcare delivery. QSI research differs from traditional healthcare research and poses unique ethical questions. Since QSI research aims to generate knowledge to enhance quality improvement efforts, should it be considered research for regulatory purposes? Is review by a research ethics committee required? Should healthcare providers be considered research participants? If participation in QSI research entails no more than minimal risk, is consent required? The (...) lack of consensus on answers to these questions highlights the need for ethical guidance. Three distinct approaches to classifying QSI research in accordance with existing ethical principles and regulations can be found in the literature. In the first approach, QSI research is viewed as distinct from other types of healthcare research and does not require regulation. In the second approach, QSI research falls within regulatory guidelines but is exempt from research ethics committee review. In the third approach, QSI research is deemed to be part of the learning healthcare system and, as such, is subject to a different set of ethical principles entirely. In this paper, we critically assess each of these views. While none of these approaches is entirely satisfactory, we argue that use of the ethical principles governing research provides the best means of addressing the numerous questions posed by QSI research. (shrink)

This book, first published in 2006, examines the incentives at work in a wide range of institutions to see how and how well coordination is achieved by informing and motivating individual decision makers. The book examines the performance of agents hired to carry out specific tasks, from taxi drivers to CEOs. It investigates the performance of institutions, from voting schemes to kidney transplants, to see if they enhance general well being. The book examines a broad range of market transactions, from (...) auctions to labor markets, to the entire economy. The analysis is conducted using specific worked examples, lucid general theory, and illustrations drawn from news stories. Of the seventy different topics and sections, only twelve require a knowledge of calculus. The second edition offers new chapters on auctions, matching and assignment problems, and corporate governance. Boxed examples are used to highlight points of theory and are separated from the main text. (shrink)

In this research, we surveyed 214 college journalists to assess their attitudes toward a series of ethical dilemmas. Significant predictors of a nine-item index included years enrolled in college,...

Background Informed consent is an integral component of good medical practice. Many researchers have investigated measures to improve the quality of informed consent, but it is not clear which techniques work best and why. To address this problem, we propose developing a core outcome set to evaluate interventions designed to improve the consent process for surgery in adult patients with capacity. Part of this process involves reviewing existing research that has reported what is important to patients and doctors in the (...) informed consent process. Methods This qualitative synthesis comprises four phases: identification of published papers and determining their relevance; appraisal of the quality of the papers; identification and summary of the key findings from each paper while determining the definitiveness of each finding against the primary data; comparison of key themes between papers such that findings are linked across studies. Results Searches of bibliographic databases returned 11,073 titles. Of these, 16 studies met the inclusion criteria. Studies were published between 1996 and 2016 and included a total of 367 patients and 74 health care providers. Thirteen studies collected data using in-depth interviews and constant comparison was the most common means of qualitative analysis. A total of 94 findings were extracted from the primary papers and divided into 17 categories and ultimately 6 synthesised findings related to: patient characteristics, knowledge, communication, the model patient, trust and decision making. Conclusions This qualitative meta-aggregation is the first to examine the issue of informed consent for surgery. It has revealed several outcomes deemed important to capture by patients and clinicians when evaluating the quality of a consent process. Some of these outcomes have not been examined previously in research comparing methods for informed consent. This review is an important step in the development of a COS to evaluate interventions designed to improve the consent process for surgery. Registration The study protocol was registered on the international prospective register for systematic reviews. (shrink)

Dilemmas about resuscitation and life-prolonging treatment for severely compromised infants have become increasingly complex as skills in neonatal care have developed. Quality of life and resource issues necessarily influence management. Our Institute of Medical Ethics working party, on whose behalf this paper is written, recognises that the ultimate responsibility for the final decision rests with the doctor in clinical charge of the infant. However, we advocate a team approach to decision-making, emphasising the important role of parents and nurses in the (...) process. Assessing the relative burdens and benefits can be troubling, but doctors and parents need to retain a measure of discretion; legislation which would determine action in all cases is inappropriate. Caution should be exercised in involving committees in decision-making and, where they exist, their remit should remain to advise rather than to decide. Support for families who bear the consequences of their decisions is often inadequate, and facilitating access to such services is part of the wider responsibilities of the intensive care team. The authors believe that allowing death by withholding or withdrawing treatment is legitimate, where those closely involved in the care of the infant together deem the burdens to be unacceptable without compensating benefits for the infant. As part of the process accurate and careful recording is essential. (shrink)