Mechanisms of non-apoptotic TRAIL signalling in NSCLC

Lung cancer is one of the most common cancers worldwide and is responsible for most cancer-related deaths. 85% of lung cancer patients have non-small cell lung cancer (NSCLC). Despite the successful development of targeted anti-cancer therapies for NSCLC, the prognosis often remains poor. Novel therapies are needed and tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptor 1(R1) and TRAIL-R2 are promising therapeutic targets, as they selectively induce cell death (apoptosis) in tumour cells. Unfortunately, NSCLC cells can be resistant to TRAIL and treatment can result in tumour cell proliferation and metastasis through activation of non-canonical molecular mechanisms that are not yet fully understood. Previous research by our laboratory demonstrated that the Src kinase protein plays an important role in non-canonical TRAIL signalling. In this thesis, we further investigated the role of Src in this process, which may lead to improved therapeutic TRAIL treatment. We found that TRAIL-dependent Src activation does not result in TRAIL resistance, but influences the secretion of immune cell regulatory cytokines. Furthermore, we identified various Src binding proteins that may contribute to the undesired effects of TRAIL treatment. Additionally, we showed that 3D cultured NSCLC cells respond similarly to TRAIL treatment as the normally used 2D cultures. A new synthetic matrix was found to be suitable for use in 3D culturing. The role of Src in NSCLC in TRAIL treatment was found to be complex and to have both cell intrinsic and extrinsic effects. Further research is needed to elucidate the exact role of Src in TRAIL resistance

Queering the Carceral Cycle: Women\u27s Resistance to the Carceral State

Building upon feminist and queer scholarship that recognizes mass incarceration and the prison-industrial complex as elements of an inherently violent carceral state, Queering the Carceral Cycle excavates and analyzes twentieth-century incidents in which women resisted the state’s criminalization and/or punishment of multiply marginalized women. I argue that the state’s response to women’s acts of resistance prompted the development of new carceral strategies and technologies that expanded the carceral state’s investment in control and punishment. Moreover, by critically embracing a Foucauldian scheme known as the “carceral cycle,” I demonstrate how the state traps multiply marginalized women in a seemingly endless recurrence of criminalization, surveillance, and imprisonment. By employing the feminist methodology of intersectionality, I reveal how multiply marginalized women subverted, or queered, this cycle of entrapment by refusing to comply with the institutions that uphold the carceral state, including heteropatriarchy, capitalism, imperialism, and white supremacy. The case studies I examine vary in scope and severity, ranging from the homophobic attack on rehabilitation efforts at the Massachusetts Reformatory for Women, to the FBI surveillance and grand jury abuse used to criminalize a group of dissident lesbian college students, to the development of the first women’s high security unit, designed specifically to torture incarcerated leftist revolutionaries. Taking place in different historical and social contexts across the United States, these cases are united by women’s attempts to resist, undo, or weaken the state’s investment in carceral control, but also by the state’s capacity to find new ways to punish those who attempted, and succeeded, in undermining the state’s interests

Appalachia\u27s Children: The Challenge of Mental Health

This thoughtful, compassionate book makes a major contribution to our understanding of the Southern Appalachian child—his mental disorders and his adaptive strengths. Drawing upon his extensive fieldwork as a clinical child psychiatrist in Eastern Kentucky, Dr. Looff suggests means by which these children can be helped to bridge the gap between their subculture and the mainstream of American life today. The children described in this book, the author points out, are in a real sense not “all children.” Since no child grows up in a vacuum, the children of Eastern Kentucky cannot be understood apart from the historical, geographic, and socioeconomic characteristics of the area in which they grow. Knowledge of the children requires some knowledge of the lives of parent, teachers, and the many others upon whom they are dependent. That is to say, mental disorder—or mental health—is embedded in a social matrix. Dr. Looff therefore examines the milieu of these Southern Appalachian children, their future as adults, and how they can achieve their potential—whether in their native or an urban setting. In viewing the children within their own cultural framework, Dr. Looff shows how they develop toward mental health or psychopathology, suggesting supportive techniques that build upon the strengths inherent in each child. These strengths, he suggests, rise out of the same culture that burdens the child with handicaps. Dr. Looff’s position is one of guarded optimism, based on the successes of the techniques he has used and observed in seven years of work in Appalachian field clinics. Although he details instances of mental disorder in children, and instances of failure in family functioning, he notes at the same time family strengths and sees these strengths as sources of hope. Although this book is based on fieldwork techniques within a specific area and culture, it is paradigmatically suggestive of wider application. Dr. Looff demonstrates effectively and clearly the profound need for increased concern about what is happening to the rising generation—the children of Eastern Kentucky, the children of the Southern Appalachian region, and the children of the rural south. David H. Looff, a Fellow of the American Psychiatric Association, is an associate professor of child psychiatry at the University of Kentucky.https://uknowledge.uky.edu/upk_psychology/1000/thumbnail.jp

The geometry of synchronization: quantifying the coupling direction of physiological signals of stress between individuals using inter-system recurrence networks

In the study of synchronization dynamics between interacting systems, several techniques are available to estimate coupling strength and coupling direction. Currently, there is no general ‘best’ method that will perform well in most contexts. Inter-system recurrence networks (IRN) combine auto-recurrence and cross-recurrence matrices to create a graph that represents interacting networks. The method is appealing because it is based on cross-recurrence quantification analysis, a well-developed method for studying synchronization between 2 systems, which can be expanded in the IRN framework to include N > 2 interacting networks. In this study we examine whether IRN can be used to analyze coupling dynamics between physiological variables (acceleration, blood volume pressure, electrodermal activity, heart rate and skin temperature) observed in a client in residential care with severe to profound intellectual disabilities (SPID) and their professional caregiver. Based on the cross-clustering coefficients of the IRN conclusions about the coupling direction (client or caregiver drives the interaction) can be drawn, however, deciding between bi-directional coupling or no coupling remains a challenge. Constructing the full IRN, based on the multivariate time series of five coupled processes, reveals the existence of potential feedback loops. Further study is needed to be able to determine dynamics of coupling between the different layers

Economic evaluations of pharmacogenetic and pharmacogenomic screening tests : a systematic review : second update of the literature

Objective : Due to extended application of pharmacogenetic and pharmacogenomic screening (PGx) tests it is important to assess whether they provide good value for money. This review provides an update of the literature. Methods : A literature search was performed in PubMed and papers published between August 2010 and September 2014, investigating the cost-effectiveness of PGx screening tests, were included. Papers from 2000 until July 2010 were included via two previous systematic reviews. Studies' overall quality was assessed with the Quality of Health Economic Studies (QHES) instrument. Results : We found 38 studies, which combined with the previous 42 studies resulted in a total of 80 included studies. An average QHES score of 76 was found. Since 2010, more studies were funded by pharmaceutical companies. Most recent studies performed cost-utility analysis, univariate and probabilistic sensitivity analyses, and discussed limitations of their economic evaluations. Most studies indicated favorable cost-effectiveness. Majority of evaluations did not provide information regarding the intrinsic value of the PGx test. There were considerable differences in the costs for PGx testing. Reporting of the direction and magnitude of bias on the cost-effectiveness estimates as well as motivation for the chosen economic model and perspective were frequently missing. Conclusions : Application of PGx tests was mostly found to be a cost-effective or cost-saving strategy. We found that only the minority of recent pharmacoeconomic evaluations assessed the intrinsic value of the PGx tests. There was an increase in the number of studies and in the reporting of quality associated characteristics. To improve future evaluations, scenario analysis including a broad range of PGx tests costs and equal costs of comparator drugs to assess the intrinsic value of the PGx tests, are recommended. In addition, robust clinical evidence regarding PGx tests' efficacy remains of utmost importance