© 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)

This special issue of Science, Technology, & Human Values assembles papers that consider relations among science, ethics, and justice. The papers are drawn from a 2011 National Science Foundation-sponsored workshop that brought together interdisciplinary scholars to consider, incorporate, and attend to the meanings, uses, and social consequences of ethical questions and justice ideals in technoscientific projects. The papers included in this special issue examine key areas that emerged from this workshop, including public participation, the production of knowledge, what counts as (...) consent, ownership of biomaterials, and others. Together, the papers raise questions about new directions and articulations of power, justice, and inequalities in science and technology studies. (shrink)

The gaps, fissures, and lapses of attention in a life—what I call “ordinary oblivions”—are fertile fragilities that present a compelling source for ethics. Plato, not Aristotle, is the ancient philosopher specially poised to speak to this feature of human life. Drawing upon poet C. K. Williams's idea that forgetting is a “looking away” that makes possible “beginning again,” I present a Platonic approach to ethics as an alternative to Aristotelian or virtue ethics. Plato's Phaedrus is a key source text for (...) this alternate picture; from it I suggest how we might construe Iris Murdoch's “task of seeing” in terms of the engagement with written form. Poetry is a central locale for such engagement, and thus suggests a kind of ethical praxis that arises from the theoretical emphases of my examination of forgetting, the unmoored self, remade other-regard, and sacred sources. (shrink)

Consecutive measurements performed on the same quantum system can reveal fundamental insights into quantum theory’s causal structure, and probe different aspects of the quantum measurement problem. According to the Copenhagen interpretation, measurements affect the quantum system in such a way that the quantum superposition collapses after each measurement, erasing any memory of the prior state. We show here that counter to this view, un-amplified measurements have coherent ancilla density matrices that encode the memory of the entire set of quantum measurements (...) that came before, and that the chain of this entire set is therefore non-Markovian. In contrast, sequences of amplified measurements are equivalent to a quantum Markov chain. We argue that the non-Markovian nature of quantum measurement has empirical consequences that are incompatible with the assumption of wave function collapse, thus elevating the collapse assumption into a testable hypothesis. Finally, we find that all of the information necessary to reconstruct an arbitrary non-Markovian quantum chain of measurements is encoded on the boundary of that chain, reminiscent of the holographic principle. (shrink)

In the current era of accountability, standardization has become the norm. From state mandated standards to district scripted curriculum, the individual child has been lost at the hands of removed politicians and administrators. Teachers have lost the freedom to individualize their classrooms to meet the needs of their students, and instead they contribute daily to the mass production line that we call "American education." As a result of No Child Left Behind, education now lacks the element of personalization necessary to (...) create meaningful learning experiences for students. There is currently a dire need for reform that revisits a child-centered approach to teaching and learning, as suggested by philosopher John .. (shrink)

Professional sport in the United States has widely adopted biometric technologies, dramatically expanding the monitoring of players’ biodata. These technologies have the potential to prevent injuries, improve performance, and extend athletes’ careers; they also risk compromising players’ privacy and autonomy, the confidentiality of their data, and their careers. The use of these technologies in professional sport and the consumer sector remains largely unregulated and unexamined. We seek to provide guidance for their adoption by examining five areas of concern: validity and (...) interpretation of data; increased surveillance and threats to privacy; risks to confidentiality and concerns regarding data security; conflicts of interest; and coercion. Our analysis uses professional sport as a case study; however, these concerns extend to other domains where their use is expanding, including the consumer sector, collegiate and high school sport, the military, and commercial sectors where monitori... (shrink)

The rapid expansion of research on Brain-Computer Interfaces is not only due to the promising solutions offered for persons with physical impairments. There is also a heightened need for understanding BCIs due to the challenges regarding ethics presented by new technology, especially in its impact on the relationship between man and machine. Here we endeavor to present a scoping review of current studies in the field to gain insight into the complexity of BCI use. By examining studies related to BCIs (...) that employ social research methods, we seek to demonstrate the multitude of approaches and concerns from various angles in considering the social and human impact of BCI technology. For this scoping review of research on BCIs’ social and ethical implications, we systematically analyzed six databases, encompassing the fields of medicine, psychology, and the social sciences, in order to identify empirical studies on BCIs. The search yielded 73 publications that employ quantitative, qualitative, or mixed methods. Of the 73 publications, 71 studies address the user perspective. Some studies extend to consideration of other BCI stakeholders such as medical technology experts, caregivers, or health care professionals. The majority of the studies employ quantitative methods. Recurring themes across the studies examined were general user opinion towards BCI, central technical or social issues reported, requests/demands made by users of the technology, the potential/future of BCIs, and ethical aspects of BCIs. Our findings indicate that while technical aspects of BCIs such as usability or feasibility are being studied extensively, comparatively little in-depth research has been done on the self-image and self-experience of the BCI user. In general there is also a lack of focus or examination of the caregiver’s perspective. (shrink)

Scientists know that human activities, primarily fossil fuel combustion, are causing Earth’s temperature to increase. Yet in 2021, only 60% of the US population understood that human activities are the primary cause of global warming. We experimentally test whether information about the human causes of global warming influences Americans’ beliefs and concerns about global warming and support for climate policies. We find that communicating information about the human-causes of global warming increases public understanding that global warming is human-caused. This information, (...) both alone and with additional information about climate impacts and policy solutions, also increases public concern about global warming and support for climate policies, although the effects on climate concern and policy support are smaller. Importantly, the treatment effects are consistent across political party, with no backlash effects among Republicans. This suggests that when informed about climate change causes, impacts and solutions, most Americans can update their own climate change beliefs, risk perceptions, and policy support. (shrink)

The National Institute of Mental Health (Bethesda, MD) reports that approximately 5.2 million Americans experience post-traumatic stress disorder (PTSD) each year. PTSD can be severely debilitating and diminish quality of life for patients and those who care for them. Studies have indicated that propranolol, a beta-blocker, reduces consolidation of emotional memory. When administered immediately after a psychic trauma, it is efficacious as a prophylactic for PTSD. Use of such memory-altering drugs raises important ethical concerns, including some futuristic dystopias put forth (...) by the President's Council on Bioethics. We think that adequate informed consent should facilitate ethical research using propranolol and, if it proves efficacious, routine treatment. Clinical evidence from studies should certainly continue to evaluate realistic concerns about possible ill effects of diminishing memory. If memory-attenuating drugs prove effective, we believe that the most immediate social concern is the over-medicalization of bad memories, and its subsequent exploitation by the pharmaceutical industry. (shrink)

New pharmacological therapies, often dubbed `lifestyle drugs', demonstrate the enactment of yet another interface between technologies and bodies that promises a re-fashioning of the body with transformative, life-enhancing results. This article analyzes the emergence of one lifestyle drug, Viagra, from a technoscience studies perspective, conceptualizing Viagra as a new medical technology of the body. Through an analysis of promotional materials for Viagra, we argue that this pharmaceutical device performs ideological work through its discursive scripts that serves to reinforce and augment (...) dominant cultural narratives in relation to material bodies, particularly those of hegemonic masculinity and male (and female) sexuality. We conclude that Viagra carries the potential to reify and reinforce these dominant and hegemonic narratives, while at the same time, through ensuring an open market for heterogeneous users, it provides spaces for alternatives to these normative ideals and assumptions. (shrink)

This article examines the question: How do local organizations deal with competing temporal dynamics when building and implementing base/bottom of the pyramid initiatives? Time has been neglected in the BoP literature to date, yet, addressing poverty in a developing country requires a complex perspective of time. An analysis of 21 semi-structured interviews with locally based organizations implementing BoP initiatives in the Philippines revealed that the organizations had an ambitemporal perspective. In particular, we discover that they harmonize multiple temporal pacers by (...) making strategic decisions about the best mechanism of entrainment to utilize to move their community and any stakeholders to a long-term temporal horizon. We find that organizations manage this process by generating what we term a “third time” via a process of push-and-pull entrainment between the communities, the business, and the different temporal pacers. This article develops a conceptual framework for helping organizations to harmonize competing temporal dynamics to generate a bespoke “third time” for each community they work with. (shrink)

The National Institute of Mental Health reports that approximately 5.2 million Americans experience post-traumatic stress disorder each year. PTSD can be severely debilitating and diminish quality of life for patients and those who care for them. Studies have indicated that propranolol, a beta-blocker, reduces consolidation of emotional memory. When administered immediately after a psychic trauma, it is efficacious as a prophylactic for PTSD. Use of such memory-altering drugs raises important ethical concerns, including some futuristic dystopias put forth by the President's (...) Council on Bioethics. We think that adequate informed consent should facilitate ethical research using propranolol and, if it proves efficacious, routine treatment. Clinical evidence from studies should certainly continue to evaluate realistic concerns about possible ill effects of diminishing memory. If memory-attenuating drugs prove effective, we believe that the most immediate social concern is the over-medicalization of bad memories, and its subsequent exploitation by the pharmaceutical industry. (shrink)

Since the late 1980s, the human genetics and genomics research community has been promising to usher in a “new paradigm for health care”—one that uses molecular profiling to identify human genetic variants implicated in multifactorial health risks. After the completion of the Human Genome Project in 2003, a wide range of stakeholders became committed to this “paradigm shift,” creating a confluence of investment, advocacy, and enthusiasm that bears all the marks of a “scientific/intellectual social movement” within biomedicine. Proponents of this (...) movement usually offer four ways in which their approach to medical diagnosis and health care improves upon current practices, arguing that it is more “personalized,” “predictive,” “preventive,” and “participatory” than the medical status quo. Initially, it was personalization that seemed to best sum up the movement's appeal. By 2012, however, powerful opinion leaders were abandoning “personalized medicine” in favor of a new label: “precision medicine.” The new label received a decisive seal of approval when, in January 2015, President Obama unveiled plans for a national “precision medicine initiative” to promote the development and use of genomic tools in health care. (shrink)

The language of “participant-driven research,” “crowdsourcing” and “citizen science” is increasingly being used to encourage the public to become involved in research ventures as both subjects and scientists. Originally, these labels were invoked by volunteer research efforts propelled by amateurs outside of traditional research institutions and aimed at appealing to those looking for more “democratic,” “patient-centric,” or “lay” alternatives to the professional science establishment. As mainstream translational biomedical research requires increasingly larger participant pools, however, corporate, academic and governmental research programs (...) are embracing this populist rhetoric to encourage wider public participation. We examine the ethical and social implications of this recruitment strategy. We begin by surveying examples of “citizen science” outside of biomedicine, as paradigmatic of the aspirations this democratizing rhetoric was originally meant to embody. Next, we discuss the ways these aspirations become articulated in the biomedical context, with a view to drawing out the multiple and potentially conflicting meanings of “public engagement” when citizens are also the subjects of the science. We then illustrate two uses of public engagement rhetoric to gain public support for national biomedical research efforts: its post-hoc use in the “care.data” project of the National Health Service in England, and its proactive uses in the “Precision Medicine Initiative” of the United States White House. These examples will serve as the basis for a normative analysis, discussing the potential ethical and social ramifications of this rhetoric. We pay particular attention to the implications of government strategies that cultivate the idea that members of the public have a civic duty to participate in government-sponsored research initiatives. We argue that such initiatives should draw from policy frameworks that support normative analysis of the role of citizenry. And, we conclude it is imperative to make visible and clear the full spectrum of meanings of “citizen science,” the contexts in which it is used, and its demands with respect to participation, engagement, and governance. (shrink)

With over three billion people currently living below the poverty line, finding better ways to lift people out of poverty is a concern of scholars from a range of disciplines. Within Management Studies, the focus is on developing market-based solutions to poverty alleviation through Bottom/Base-of-the-Pyramid initiatives. To date, these have enjoyed limited success, sometimes even exacerbating the problems they attempt to solve. As a result, there is a growing academic and practitioner push for a third iteration—BoP 3.0—that moves closer to (...) a sustainable development model of poverty alleviation. Through a grounded theory study of 21 Philippines-based organizations implementing poverty alleviation initiatives at the community level, this paper seeks to add to the existing suite of tools and guidance in the BoP field. It does so by questioning how these organizations approach the development and implementation of market-based approaches to poverty alleviation. Our results suggest that these organizations adopt a more community-centric approach, focusing on the creation of a self-reliant community before all else. We find this to be the result of a deeper understanding of the drivers of poverty in the communities they work with. Through the extrapolation of key themes and issues in our data, we propose a new conceptual model for building BoP 3.0 initiatives. This model consists of three intertwined theoretical dimensions: understanding issues as matters of concern; identifying limitations; and navigating time. These elements are linked by three active phases that allowed the organizations to move from one dimension to the next: sensemaking; entrainment; and investment. (shrink)

With over three billion people currently living below the poverty line, finding better ways to lift people out of poverty is a concern of scholars from a range of disciplines. Within Management Studies, the focus is on developing market-based solutions to poverty alleviation through Bottom/Base-of-the-Pyramid initiatives. To date, these have enjoyed limited success, sometimes even exacerbating the problems they attempt to solve. As a result, there is a growing academic and practitioner push for a third iteration—BoP 3.0—that moves closer to (...) a sustainable development model of poverty alleviation. Through a grounded theory study of 21 Philippines-based organizations implementing poverty alleviation initiatives at the community level, this paper seeks to add to the existing suite of tools and guidance in the BoP field. It does so by questioning how these organizations approach the development and implementation of market-based approaches to poverty alleviation. Our results suggest that these organizations adopt a more community-centric approach, focusing on the creation of a self-reliant community before all else. We find this to be the result of a deeper understanding of the drivers of poverty in the communities they work with. Through the extrapolation of key themes and issues in our data, we propose a new conceptual model for building BoP 3.0 initiatives. This model consists of three intertwined theoretical dimensions: understanding issues as matters of concern; identifying limitations; and navigating time. These elements are linked by three active phases that allowed the organizations to move from one dimension to the next: sensemaking; entrainment; and investment. (shrink)

Personalized medicine aims to tailor disease prevention, diagnosis, and treatment to individuals on the basis of their genes, lifestyle and environments. Patient and interest organizations may potentially play an important role in the realization of PM. This paper investigates the views and perspectives on PM of a variety of PIOs. Semi-structured telephone interviews were conducted among leading representatives of 13 PIOs located in Europe and North-America. The data collected were analysed using a conventional content analysis approach. The PIO representatives supported (...) the realization of PM but feared that many financial, structural and organizational challenges may delay its realization. They encouraged strategies to modernize drug licencing mechanisms, develop research and data sharing infrastructures, and educate patients and health care professionals in PM. Notably, they emphasized the importance of developing PM in an equitable way and taking into consideration the patients’ needs, values and personal situation. Despite varying levels of awareness regarding PM, the PIO representatives expressed willingness to engage in the PM agenda and recommended that PIOs work closely with policy-makers to design PM in a way that truly addresses the needs and concerns of patients. PIOs have the potential to become central drivers of the PM agenda. Collaborations should be further developed between PIOs, researchers, drug developers and health care authorities. (shrink)