Desk based prompts to replace workplace sitting with stair climbing; a pilot study of acceptability, effects on behaviour and disease risk factors.

BACKGROUND: Prolonged sitting is associated with increased risk of obesity, type 2 diabetes and cardiovascular disease. Occupational sitting accounts for up to 50 h/week for employees. This pilot study assessed the acceptability of stair climbing as an interruption to sitting throughout working hours, and provided preliminary data of the effects on glucose and lipid profiles. METHODS: A quasi-experimental design was conducted involving 16 sedentary office workers (five females and 11 males) for intervention (n = 8) and control groups (n = 8) with mean age of 36.38 (5.58). For the eight-week intervention, a continuous four-floor stair climb and descent was performed eight times/day spread evenly over the working day. A prompt to climb was presented on the participant's computer eight times/day. Participants in the experimental group recorded daily floors climbed and steps (measured using pedometers) in a weekly log sheet. Blood samples were collected pre and post intervention to test effects on fasting glucose and 2 h plasma glucose, triglycerides, and total (TC), LDL and HDL cholesterol. Experimental participants were interviewed at the end of the study. The Wilcoxon signed rank test was used to compare the median changes (pre-post) of the dependent variables. RESULTS: On average, the experimental group climbed 121 floors/week when prompted. There were significant reductions in fasting blood glucose, TC and LDL, as well as the derived measures of 'bad' cholesterol and the TC/HDL ratio in the experimental group. Post-experimental interviews indicated that the interruption to sitting was well tolerated. CONCLUSION: Prompted stair climbing activity had impacts on health outcomes and was found acceptable to employees at work. TRIAL REGISTRATION: Ethics for this study was approved by Science, Technology, Engineering and Mathematics Ethical Review Committee, University of Birmingham with ethics reference number ERN_15_0491.

Improved Simulation of Edaphic and Manure Phosphorus Loss in SWAT.

Watershed models such as the Soil Water Assessment Tool (SWAT) and the Agricultural Policy Environmental EXtender (APEX) are widely used to assess the fate and transport of agricultural nutrient management practices on soluble and particulate phosphorus (P) loss in runoff. Soil P-cycling routines used in SWAT2012 revision 586, however, do not simulate the short-term effects of applying a concentrated source of soluble P, such as manure, to the soil surface where it is most vulnerable to runoff. We added a new set of soil P routines to SWAT2012 revision 586 to simulate surface-applied manure at field and subwatershed scales within Mahantango Creek watershed in south-central Pennsylvania. We corroborated the new P routines and standard P routines in two versions of SWAT (conventional SWAT, and a topographically driven variation called TopoSWAT) for a total of four modeling "treatments". All modeling treatments included 5 yr of measured data under field-specific, historical management information. Short-term "wash off" processes resulting from precipitation immediately following surface application of manures were captured with the new P routine whereas the standard routines resulted in losses regardless of manure application. The new routines improved sensitivity to key factors in nutrient management (i.e., timing, rate, method, and form of P application). Only the new P routines indicated decreases in soluble P losses for dairy manure applications at 1, 5, and 10 d before a storm event. The new P routines also resulted in more variable P losses when applying manure versus commercial fertilizer and represented increases in total P losses, as compared with standard P routines, with rate increases in dairy manure application (56,000 to 84,000 L ha). The new P routines exhibited greater than 50% variation among proportions of organic, particulate, and soluble P corresponding to spreading method. In contrast, proportions of P forms under the standard P routines varied less than 20%. Results suggest similar revisions to other agroecosystem watershed models would be appropriate.

Personality Science in the Digital Age: The Promises and Challenges of Psychological Targeting for Personalized Behavior-Change Interventions at Scale.

With the rapidly growing availability of scalable psychological assessments, personality science holds great promise for the scientific study and applied use of customized behavior-change interventions. To facilitate this development, we propose a classification system that divides psychological targeting into two approaches that differ in the process by which interventions are designed: audience-to-content matching or content-to-audience matching. This system is both integrative and generative: It allows us to (a) integrate existing research on personalized interventions from different psychological subdisciplines (e.g., political, educational, organizational, consumer, and clinical and health psychology) and to (b) articulate open questions that generate promising new avenues for future research. Our objective is to infuse personality science into intervention research and encourage cross-disciplinary collaborations within and outside of psychology. To ensure the development of personality-customized interventions aligns with the broader interests of individuals (and society at large), we also address important ethical considerations for the use of psychological targeting (e.g., privacy, self-determination, and equity) and offer concrete guidelines for researchers and practitioners.

CD5 expression by dendritic cells directs T cell immunity and sustains immunotherapy responses.

The induction of proinflammatory T cells by dendritic cell (DC) subtypes is critical for antitumor responses and effective immune checkpoint blockade (ICB) therapy. Here, we show that human CD1c+CD5+ DCs are reduced in melanoma-affected lymph nodes, with CD5 expression on DCs correlating with patient survival. Activating CD5 on DCs enhanced T cell priming and improved survival after ICB therapy. CD5+ DC numbers increased during ICB therapy, and low interleukin-6 (IL-6) concentrations promoted their de novo differentiation. Mechanistically, CD5 expression by DCs was required to generate optimally protective CD5hi T helper and CD8+ T cells; further, deletion of CD5 from T cells dampened tumor elimination in response to ICB therapy in vivo. Thus, CD5+ DCs are an essential component of optimal ICB therapy.

Using systems medicine to identify a therapeutic agent with potential for repurposing in inflammatory bowel disease.

Inflammatory bowel diseases (IBDs) cause significant morbidity and mortality. Aberrant NF-κB signalling is strongly associated with these conditions, and several established drugs influence the NF-κB signalling network to exert their effect. This study aimed to identify drugs that alter NF-κB signalling and could be repositioned for use in IBD. The SysmedIBD Consortium established a novel drug-repurposing pipeline based on a combination of in silico drug discovery and biological assays targeted at demonstrating an impact on NF-κB signalling, and a murine model of IBD. The drug discovery algorithm identified several drugs already established in IBD, including corticosteroids. The highest-ranked drug was the macrolide antibiotic clarithromycin, which has previously been reported to have anti-inflammatory effects in aseptic conditions. The effects of clarithromycin effects were validated in several experiments: it influenced NF-κB-mediated transcription in murine peritoneal macrophages and intestinal enteroids; it suppressed NF-κB protein shuttling in murine reporter enteroids; it suppressed NF-κB (p65) DNA binding in the small intestine of mice exposed to lipopolysaccharide; and it reduced the severity of dextran sulphate sodium-induced colitis in C57BL/6 mice. Clarithromycin also suppressed NF-κB (p65) nuclear translocation in human intestinal enteroids. These findings demonstrate that in silico drug repositioning algorithms can viably be allied to laboratory validation assays in the context of IBD, and that further clinical assessment of clarithromycin in the management of IBD is required.This article has an associated First Person interview with the joint first authors of the paper.

P53 apoptosis mediator PERP: localization, function and caspase activation in uveal melanoma.

p53 apoptosis effector related to PMP-22 (PERP) is a transcriptional target gene of p53 tumour suppressor that is specifically induced during apoptosis and not during cell cycle arrest. In primary uveal melanoma (UM), the most common intraocular malignancy in adults that has a reportedly unaffected signalling pathway upstream of and including p53, PERP expression is down-regulated in the metastatic monosomy 3-type tumours, compared with the less aggressive disomy 3-type tumours. Here, we demonstrate experimentally, by the use of full-length PERP-green fluorescent protein (GFP) fusions and real-time confocal microscopy, the intracellular targeting and plasma membrane localization of PERP in living UM cells and show that expression of PERP induces caspase-mediated apoptosis in UM cells. Induction of PERP expression in GFP-PERP-transfected UM cells leads to increased levels of cleaved caspase-8 forms, as well as to reduction of its full-length substrate Bid, but not to detectable processing of caspase-9. The levels of mature caspase-8, -9 and -3 proteins significantly correlate with PERP expression levels in primary UMs. Transcriptional profiling of PERP and caspase-8 in tumour specimens indicates that the positive association of PERP and caspase-8 proteins is a consequence of post-translational processing, most likely at the level of caspase-8 cleavage, and not of increased transcription of pro-caspase-8. We conclude that PERP expression leads to activation of an extrinsic receptor-mediated apoptotic pathway, with a possible subsequent engagement of the intrinsic apoptotic pathway. The findings underline the apoptotic pathway mediated by PERP as a critical mechanism employed by UM tumours to modulate susceptibility to apoptosis.

Human TNF-Luc reporter mouse: A new model to quantify inflammatory responses.

Tumour necrosis factor (TNF) is a key cytokine during inflammatory responses and its dysregulation is detrimental in many inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. Here, we used a bacterial artificial chromosome (BAC) construct that expresses luciferase under the control of the human TNF locus to generate a novel transgenic mouse, the hTNF.LucBAC strain. In vitro stimulation of hTNF.LucBAC cells of different origin revealed a cell specific response to stimuli demonstrating the integrated construct's ability as a proxy for inflammatory gene response. Lipopolysaccharide was the most potent luciferase inducer in macrophages, while TNF was a strong activator in intestinal organoids. Lipopolysaccharide-induced luciferase activity in macrophages was downregulated by inhibitors of NF-κB pathway, as well as by Interleukin-10, a known anti-inflammatory cytokine. Moreover, the transgene-dependent luciferase activity showed a positive correlation to the endogenous murine soluble TNF secreted to the culture medium. In conclusion, the hTNF.LucBAC strain is a valuable tool for studying and screening molecules that target TNF synthesis and will allow further functional studies of the regulatory elements of the TNF locus.

Contextual barriers to lifestyle physical activity interventions in Hong Kong.

PURPOSE: Increased lifestyle physical activity, for instance, use of active transport, is a current public health target. Active transport interventions that target stair climbing are consistently successful in English-speaking populations yet unsuccessful in Hong Kong. We report two further studies on active transport in the Hong Kong Chinese. METHODS: Pedestrians on a mass transit escalator system (study 1) and in an air-conditioned shopping mall (study 2) were encouraged to take the stairs for their cardiovascular health by point-of-choice prompts. Observers coded sex, age, and walking on the mass transit system, with the additional variables of presence of children and bags coded in the shopping mall. In the first study, a 1-wk baseline was followed by 4 wk of intervention (N = 76,710) whereas in the second study (shopping mall) a 2-wk baseline was followed by a 2-wk intervention period (N = 18,257). RESULTS: A small but significant increase in stair climbing (+0.29%) on the mass transit system contrasted with no significant changes in the shopping mall (+0.09%). The active transport of walking on the mass transit system was reduced at higher rates of humidity and temperature, with steeper slopes for the effects of climate variables in men than in women. CONCLUSIONS: These studies confirm that lifestyle physical activity interventions do not have universal application. The context in which the behavior occurs (e.g., climate) may act as a barrier to active transport.

Inhibition of Hsp90 acts synergistically with topoisomerase II poisons to increase the apoptotic killing of cells due to an increase in topoisomerase II mediated DNA damage.

Topoisomerase II plays a crucial role during chromosome condensation and segregation in mitosis and meiosis and is a highly attractive target for chemotherapeutic agents. We have identified previously topoisomerase II and heat shock protein 90 (Hsp90) as part of a complex. In this paper we demonstrate that drug combinations targeting these two enzymes cause a synergistic increase in apoptosis. The objective of our study was to identify the mode of cell killing and the mechanism behind the increase in topoisomerase II mediated DNA damage. Importantly we demonstrate that Hsp90 inhibition results in an increased topoiosmerase II activity but not degradation of topoisomerase II and it is this, in the presence of a topoisomerase II poison that causes the increase in cell death. Our results suggest a novel mechanism of action where the inhibition of Hsp90 disrupts the Hsp90-topoisomerase II interaction leading to an increase in and activation of unbound topoisomerase II, which, in the presence of a topoisomerase II poison leads to the formation of an increased number of cleavable complexes ultimately resulting in rise in DNA damage and a subsequent increase cell death.

Arts, health & wellbeing: reflections on a national seminar series and building a UK research network.

An account is provided of a UK national seminar series on Arts, Health and Wellbeing funded by the Economic and Social Research Council during 2012-13. Four seminars were organised addressing current issues and challenges facing the field. Details of the programme and its outputs are available online. A central concern of the seminar programme was to provide a foundation for creating a UK national network for researchers in the field to help promote evidence-based policy and practice. With funding from Lankelly Chase Foundation, and the support of the Royal Society for Public Health, a Special interest Group for Arts, Health and Wellbeing was launched in 2015.

Pharmacokinetics of carfilzomib in patients with advanced malignancies and varying degrees of hepatic impairment: an open-label, single-arm, phase 1 study.

BACKGROUND: Carfilzomib is approved in the United States and Europe for treatment of relapsed or refractory multiple myeloma (MM). This study evaluated pharmacokinetics (PK) and safety of carfilzomib in patients with relapsed or progressive advanced malignancies and varying degrees of impaired hepatic function. METHODS: Patients with normal hepatic function (normal) or hepatic impairment (mild, moderate, or severe) received carfilzomib infusion in 28-day cycles. The primary objective was to assess the influence of hepatic impairment on carfilzomib PK following 27 and 56 mg/m2 doses. RESULTS: The majority of patients enrolled in this study had solid tumors (n = 44) vs. MM (n = 2) since patients with multiple myeloma do not tend to have severe hepatic impairment in the same way as patients with solid tumors. A total of 11 normal and 17 mild, 14 moderate, and 4 severe hepatic impairment patients were enrolled. Compared with patients with normal hepatic function, patients with mild and moderate hepatic impairment had 44 and 26% higher carfilzomib AUC0-last, respectively (27 mg/m2 dose); increases at the 56 mg/m2 dose were 45 and 21%, respectively. Considerable PK variability (% coefficient of variation in AUC ≤100%) was discerned and no consistent trend of increasing exposure resulting from increasing hepatic impairment severity (moderate vs. mild) was seen. The observed adverse event (AE) profile in patients of mostly solid tumors was consistent with the known safety profile of carfilzomib, with the exception of an increased frequency of AEs consistent with hepatic function abnormalities. CONCLUSIONS: In this population of primarily advanced solid tumor patients, patients with mild and moderate hepatic impairment had approximately 20-50% higher carfilzomib AUC vs. normal hepatic function patients. These increases are unlikely to be clinically significant, in light of the intrinsic PK variability and exposure-response relationship of carfilzomib. Trial registration http://clinicaltrials.gov NCT01949545; date of registration: September 6, 2013.

Pharmacokinetics and safety of carfilzomib in patients with relapsed multiple myeloma and end-stage renal disease (ESRD): an open-label, single-arm, phase I study.

PURPOSE: The pharmacokinetics (PK) of carfilzomib have been previously studied in multiple myeloma patients with varying degrees of renal impairment (normal, mild, moderate, severe, and end-stage renal disease [ESRD]) at doses of 15 and 20 mg/m2. This study evaluated carfilzomib PK at higher doses of 27 and 56 mg/m2 in normal renal function and ESRD patients. METHODS: Patients received carfilzomib on two consecutive days/week for 3 weeks every 28-day cycle: 20 mg/m2 (cycle 1 day 1-2), escalated to 27 mg/m2 on cycle 1 day 8; if tolerated, 56 mg/m2 starting cycle 2 day 1. The primary objective was PK assessment with safety/tolerability and response rate as secondary and exploratory objectives, respectively. RESULTS: 26 patients were enrolled (15 normal, 11 ESRD). There was a trend toward higher area under the concentration time curve (AUC) and maximum concentration in ESRD versus normal renal function patients; however, high interpatient PK variability was discerned. Relative to patients with normal renal function, ESRD patients showed 33% higher AUC. Overall response rate was 43% for the normal renal function and 60% for the ESRD groups. Safety findings were generally similar between the two groups and consistent with the known safety profile of carfilzomib in multiple myeloma patients. CONCLUSION: There were no meaningful differences in PK between patients with normal renal function and ESRD in light of carfilzomib exposure-response relationships. These results continue to support dosing recommendation that no starting dose adjustment of carfilzomib appears warranted in patients with baseline renal impairment.

Establishing common ground in community-based arts in health.

This article originates in current research into community-based arts in health. Arts in health is now a diverse field of practice, and community-based arts in health interventions have extended the work beyond healthcare settings into public health. Examples of this work can now be found internationally in different health systems and cultural contexts. The paper argues that researchers need to understand the processes through which community-based arts in health projects evolve, and how they work holistically in their attempt to produce therapeutic and social benefits for both individuals and communities, and to connect with a cultural base in healthcare services themselves. A development model that might be adapted to assist in analysing this is the World Health Organisation Quality of Life Index (WHOQOL). Issues raised in the paper around community engagement, healthy choice and self-esteem are then illustrated in case examples of community-based arts in health practice in South Africa and England; namely the DramAide and Siyazama projects in KwaZulu-Natal, and Looking Well Healthy Living Centre in North Yorkshire. In South Africa there are arts and media projects attempting to raise awareness about HIV/AIDS through mass messaging, but they also recognize that they lack models of longer-term community engagement. Looking Well by contrast addresses health issues identified by the community itself in ways that are personal, empathic and domesticated. But there are also similarities among these projects in their aims to generate a range of social, educational and economic benefits within a community-health framework, and they are successfully regenerating traditional cultural forms to create public participation in health promotion. Process evaluation may provide a framework in which community-based arts in health projects, especially if they are networked together to share practice and thinking, can assess their ability to address health inequalities and focus better on health outcomes.

Lantern parades in the development of arts in community health.

This paper describes the development of two annual lantern parades as case examples of arts in community health, which the authors define as a distinct area of activity operating mainly outside of acute healthcare settings, characterised by the use of participatory arts to promote health. The parades took place in Gateshead 1994-2006 and later in Stockton-on-Tees from 2009 to the present, and the paper reflects on the factors that made for the success of the Gateshead parade and also the problems that led to its demise. It then describes and assesses the Stockton parade, and the benefits and challenges of a workshop ethos of 'positive regard' with reference to interview data gathered from adult volunteers and school staff. It considers the potential of this annual 'tradition' to shape communal memories that identify with place, and it sets out its aspirations for future programme and research.

Inequalities, the arts and public health: Towards an international conversation.

This paper considers how participatory arts informed by thinking in public health can play a significant part internationally in addressing inequalities in health. It looks beyond national overviews of arts and health to consider what would make for meaningful international practice, citing recent initiatives of national networks in English-speaking countries and examples of influential developments in South America and the European Union. In the context of public health thinking on inequalities and social justice, the paper posits what would make for good practice and appropriate research that impacts on policy. As the arts and health movement gathers momentum, the paper urges the arts to describe their potency in the policy-making arena in the most compelling ways to articulate their social, economic and cultural values. In the process, it identifies the reflexive consideration of participatory practice - involving people routinely marginalised from decision-making processes - as a possible avenue into this work.

Arts practice and disconnected youth in Australia: Impact and domains of change.

Background: This paper describes research conducted with Big hART, Australia's most awarded participatory arts company. It considers three projects, LUCKY, GOLD and NGAPARTJI NGAPARTJI across separate sites in Tasmania, Western NSW and Northern Territory, respectively, in order to understand project impact from the perspective of project participants, Arts workers, community members and funders. Methods: Semi-structured interviews were conducted with 29 respondents. The data were coded thematically and analysed using the constant comparative method of qualitative data analysis. Results: Seven broad domains of change were identified: psychosocial health; community; agency and behavioural change; the Art; economic effect; learning and identity. Conclusions: Experiences of participatory arts are interrelated in an ecology of practice that is iterative, relational, developmental, temporal and contextually bound. This means that questions of impact are contingent, and there is no one path that participants travel or single measure that can adequately capture the richness and diversity of experience. Consequently, it is the productive tensions between the domains of change that are important and the way they are animated through Arts practice that provides sign posts towards the impact of Big hART projects.

Cell cycle phase regulates glucocorticoid receptor function.

The glucocorticoid receptor (GR) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. In contrast to many other nuclear receptors, GR is thought to be exclusively cytoplasmic in quiescent cells, and only translocate to the nucleus on ligand binding. We now demonstrate significant nuclear GR in the absence of ligand, which requires nuclear localisation signal 1 (NLS1). Live cell imaging reveals dramatic GR import into the nucleus through interphase and rapid exclusion of the GR from the nucleus at the onset of mitosis, which persists into early G(1). This suggests that the heterogeneity in GR distribution is reflective of cell cycle phase. The impact of cell cycle-driven GR trafficking on a panel of glucocorticoid actions was profiled. In G2/M-enriched cells there was marked prolongation of glucocorticoid-induced ERK activation. This was accompanied by DNA template-specific, ligand-independent GR transactivation. Using chimeric and domain-deleted receptors we demonstrate that this transactivation effect is mediated by the AF1 transactivation domain. AF-1 harbours multiple phosphorylation sites, which are consensus sequences for kinases including CDKs, whose activity changes during the cell cycle. In G2/M there was clear ligand independent induction of GR phosphorylation on residues 203 and 211, both of which are phosphorylated after ligand activation. Ligand-independent transactivation required induction of phospho-S211GR but not S203GR, thereby directly linking cell cycle driven GR modification with altered GR function. Cell cycle phase therefore regulates GR localisation and post-translational modification which selectively impacts GR activity. This suggests that cell cycle phase is an important determinant in the cellular response to Gc, and that mitotic index contributes to tissue Gc sensitivity.

Developing rat lung has a sided pacemaker region for morphogenesis-related airway peristalsis.

Prenatal airways from diverse species are capable of spontaneous peristaltic contractions in each trimester. The function of this smooth muscle activity is unknown. We demonstrate that peristalsis of the embryonic airway originates from a sided pacemaker focus, is stimulated in a calcium-dependent fashion by the pulmonary morphogen fibroblast growth factor-10 (FGF-10), and appears coupled to lung growth. Airway peristalsis may be crucial for lung development (thereby providing a physiologic role for airway smooth muscle) and play a hitherto unanticipated role in reported transgenic mutant lung phenotypes.