Enhancing [ 177 Lu]Lu-DOTA-TATE therapeutic efficacy in vitro by combining it with metronomic chemotherapeutics

Background: Peptide receptor radionuclide therapy (PRRT) uses [177Lu]Lu-[DOTA0-Tyr3]octreotate ([177Lu]Lu-DOTA-TATE) to treat patients with neuroendocrine tumours (NETs) overexpressing the somatostatin receptor 2A (SSTR2A). It has shown significant short-term improvements in survival and symptom alleviation, but there remains room for improvement. Here, we investigated whether combining [177Lu]Lu-DOTA-TATE with chemotherapeutics enhanced the in vitro therapeutic efficacy of [177Lu]Lu-DOTA-TATE. Results: Transfected human osteosarcoma (U2OS + SSTR2A, high SSTR2A expression) and pancreatic NET (BON1 + STTR2A, medium SSTR2A expression) cells were subjected to hydroxyurea, gemcitabine or triapine for 24 h at 37oC and 5% CO2. Cells were then recovered for 4 h prior to a 24-hour incubation with 0.7–1.03 MBq [177Lu]Lu-DOTA-TATE (25 nM) for uptake and metabolic viability studies. Incubation of U2OS + SSTR2A cells with hydroxyurea, gemcitabine, and triapine enhanced uptake of [177Lu]Lu-DOTA-TATE from 0.2 ± 0.1 in untreated cells to 0.4 ± 0.1, 1.1 ± 0.2, and 0.9 ± 0.2 Bq/cell in U2OS + SSTR2A cells, respectively. Cell viability post treatment with [177Lu]Lu-DOTA-TATE in cells pre-treated with chemotherapeutics was decreased compared to cells treated with [177Lu]Lu-DOTA-TATE monotherapy. For example, the viability of U2OS + SSTR2A cells incubated with [177Lu]Lu-DOTA-TATE decreased from 59.5 ± 22.3% to 18.8 ± 5.2% when pre-treated with hydroxyurea. Control conditions showed no reduced metabolic viability. Cells were also harvested to assess cell cycle progression, SSTR2A expression, and cell size by flow cytometry. Chemotherapeutics increased SSTR2A expression and cell size in U2OS + SSTR2A and BON1 + STTR2A cells. The S-phase sub-population of asynchronous U2OS + SSTR2A cell cultures was increased from 45.5 ± 3.3% to 84.8 ± 2.5%, 85.9 ± 1.9%, and 86.6 ± 2.2% when treated with hydroxyurea, gemcitabine, and triapine, respectively. Conclusions: Hydroxyurea, gemcitabine and triapine all increased cell size, SSTR2A expression, and [177Lu]Lu-DOTA-TATE uptake, whilst reducing cell metabolic viability in U2OS + SSTR2A cells when compared to [177Lu]Lu-DOTA-TATE monotherapy. Further investigations could transform patient care and positively increase outcomes for patients treated with [177Lu]Lu-DOTA-TATE

Public engagement with marine climate change issues: (Re)framings, understandings and responses

Climate change impacts on marine environments have been somewhat neglected in climate change research, particularly with regard to their social dimensions and implications. This paper contributes to addressing this gap through presenting a UK focused mixed-method study of how publics frame, understand and respond to marine climate change-related issues. It draws on data from a large national survey of UK publics (N = 1,001), undertaken in January 2011 as part of a wider European survey, in conjunction with in-depth qualitative insights from a citizens’ panel with participants from the East Anglia region, UK. This reveals that discrete marine climate change impacts, as often framed in technical or institutional terms, were not the most immediate or significant issues for most respondents. Study participants tended to view these climate impacts ‘in context’, in situated ways, and as entangled with other issues relating to marine environments and their everyday lives. Whilst making connections with scientific knowledge on the subject, public understandings of marine climate impacts were mainly shaped by personal experience, the visibility and proximity of impacts, sense of personal risk and moral or equity-based arguments. In terms of responses, study participants prioritised climate change mitigation measures over adaptation, even in high-risk areas. We consider the implications of these insights for research and practices of public engagement on marine climate impacts specifically, and climate change more generally

English language skills requirements for internationally educated nurses working in the care industry: barriers to UK registration or institutionalised discrimination?

Editoria

Integrating Omic Technologies into Aquatic Ecological Risk Assessment and Environmental Monitoring: Hurdles, Achievements, and Future Outlook

Background: In this commentary we present the findings from an international consortium on fish toxicogenomics sponsored by the U.K. Natural Environment Research Council (Fish Toxicogenomics—Moving into Regulation and Monitoring, held 21–23 April 2008 at the Pacific Environmental Science Centre, Vancouver, BC, Canada). Objectives: The consortium from government agencies, academia, and industry addressed three topics: progress in ecotoxicogenomics, regulatory perspectives on roadblocks for practical implementation of toxicogenomics into risk assessment, and dealing with variability in data sets. Discussion: Participants noted that examples of successful application of omic technologies have been identified, but critical studies are needed to relate molecular changes to ecological adverse outcome. Participants made recommendations for the management of technical and biological variation. They also stressed the need for enhanced interdisciplinary training and communication as well as considerable investment into the generation and curation of appropriate reference omic data. Conclusions: The participants concluded that, although there are hurdles to pass on the road to regulatory acceptance, omics technologies are already useful for elucidating modes of action of toxicants and can contribute to the risk assessment process as part of a weight-of-evidence approach

The desirability of transitions in demand: Incorporating behavioural and societal transformations into energy modelling

Quantitative systems modelling in support of climate policy has tended to focus more on the supply side in assessing interactions among technology, economy, environment, policy and society. By contrast, the demand side is usually underrepresented, often emphasising technological options for energy efficiency improvements. In this perspective, we argue that scientific support to climate action is not only about exploring capacity of "what", in terms of policy and outcome, but also about assessing feasibility and desirability, in terms of "when", "where" and especially for "whom". Without the necessary behavioural and societal transformations, the world faces an inadequate response to the climate crisis challenge. This could result from poor uptake of low-carbon technologies, continued high-carbon intensive lifestyles, or economy-wide rebound effects. For this reason, we propose a framing for a holistic and transdisciplinary perspective on the role of human choices and behaviours in influencing the low-carbon transition, starting from the desires of individuals and communities, and analysing how these interact with the energy and economic landscape, leading to systemic change at the macro-level. In making a case for a political ecology agenda, we expand our scope, from comprehending the role of societal acceptance and uptake of end-use technologies, to co-developing knowledge with citizens from non-mainstream and marginalised communities, and to defining the modelling requirements to assess the decarbonisation potential of shifting lifestyle patterns in climate change and action

Supporting patients to get the best from their osteoporosis treatment: a rapid realist review of what works, for whom, and in what circumstance

Systematic reviews that examine effectiveness of interventions to improve medicines optimisation do not explain how or why they work. This realist review identified that interventions which effectively optimise medicines use in osteoporosis include opportunities to address patients' perceptions of illness and treatment and/or support primary care clinician decision making. INTRODUCTION: In people with osteoporosis, adherence to medicines is poorer than other diseases and patients report follow-up is lacking, and multiple unmet information needs. We conducted a rapid realist review to understand what contextual conditions and mechanisms enable interventions to support osteoporosis medication optimisation. METHODS: A primary search identified observational or interventional studies which aimed to improve medicines adherence or optimisation; a supplementary second search identified research of any design to gain additional insights on emerging findings. Extracted data was interrogated for patterns of context-mechanism-outcome configurations, further discussed in team meetings, informed by background literature and the Practicalities and Perception Approach as an underpinning conceptual framework. RESULTS: We identified 5 contextual timepoints for the person with osteoporosis (identifying a problem; starting medicine; continuing medicine) and the practitioner and healthcare system (making a diagnosis and giving a treatment recommendation; reviewing medicine). Interventions which support patient-informed decision making appear to influence long-term commitment to treatment. Supporting patients' practical ability to adhere (e.g. by lowering treatment burden and issuing reminders) only appears to be helpful, when combined with other approaches to address patient beliefs and concerns. However, few studies explicitly addressed patients' perceptions of illness and treatment. Supporting primary care clinician decision making and integration of primary and secondary care services also appears to be important, in improving rates of treatment initiation and adherence. CONCLUSIONS: We identified a need for further research to identify a sustainable, integrated, patient-centred, and cost- and clinically effective model of long-term care for people with osteoporosis

Pharmacological Fingerprints of Contextual Uncertainty

Successful interaction with the environment requires flexible updating of our beliefs about the world. By estimating the likelihood of future events, it is possible to prepare appropriate actions in advance and execute fast, accurate motor responses. According to theoretical proposals, agents track the variability arising from changing environments by computing various forms of uncertainty. Several neuromodulators have been linked to uncertainty signalling, but comprehensive empirical characterisation of their relative contributions to perceptual belief updating, and to the selection of motor responses, is lacking. Here we assess the roles of noradrenaline, acetylcholine, and dopamine within a single, unified computational framework of uncertainty. Using pharmacological interventions in a sample of 128 healthy human volunteers and a hierarchical Bayesian learning model, we characterise the influences of noradrenergic, cholinergic, and dopaminergic receptor antagonism on individual computations of uncertainty during a probabilistic serial reaction time task. We propose that noradrenaline influences learning of uncertain events arising from unexpected changes in the environment. In contrast, acetylcholine balances attribution of uncertainty to chance fluctuations within an environmental context, defined by a stable set of probabilistic associations, or to gross environmental violations following a contextual switch. Dopamine supports the use of uncertainty representations to engender fast, adaptive responses. \ua9 2016 Marshall et al

Subcortical brain volume, regional cortical thickness, and cortical surface area across disorders: findings from the ENIGMA ADHD, ASD, and OCD Working Groups

Objective Attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. We aimed to directly compare all three disorders. The ENIGMA consortium is ideally positioned to investigate structural brain alterations across these disorders. Methods Structural T1-weighted whole-brain MRI of controls (n=5,827) and patients with ADHD (n=2,271), ASD (n=1,777), and OCD (n=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. We examined subcortical volume, cortical thickness and surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults using linear mixed-effects models adjusting for age, sex and site (and ICV for subcortical and surface area measures). Results We found no shared alterations among all three disorders, while shared alterations between any two disorders did not survive multiple comparisons correction. Children with ADHD compared to those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller ICV than controls and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared to adult controls and other clinical groups. No OCD-specific alterations across different age-groups and surface area alterations among all disorders in childhood and adulthood were observed. Conclusion Our findings suggest robust but subtle alterations across different age-groups among ADHD, ASD, and OCD. ADHD-specific ICV and hippocampal alterations in children and adolescents, and ASD-specific cortical thickness alterations in the frontal cortex in adults support previous work emphasizing neurodevelopmental alterations in these disorders

Ethical issues in collaborative action research

This article begins by raising issues around the way in which ethical approval for research is managed in university settings, where committees often base their assumptions on a principlist approach making a number of assumptions that we consider to be contestable, such as a neat separation between researcher and researched. However, collaborative action research, we argue, takes issue with the 'objectification' of research participants. It often blurs the distinction between participant and researcher, particularly when an element of self-study is included. Moreover, the collaborative nature of action research problematises the question of who is researcher and who is researched, raising issues around anonymity, the 'ownership' of findings and dissemination. In response to some of these issues, we have developed a set of eight principles we derive from our 'version' of collaborative action research and apply them in a discussion of a number of case studies from our own setting, where researchers have faced a number of dilemmas in attempting to work within the terms of reference imposed by conventional university-based ethical approval procedures. In conclusion, this article indicates some implications for university-based action researchers and makes recommendations about the forms of ethical scrutiny within the university that would be most appropriate and searching for collaborative action-based enquiry