Caveolin-1 in renal cell carcinoma promotes tumour cell invasion, and in co-operation with pERK predicts metastases in patients with clinically confined disease

Background: Up to 40% of patients initially diagnosed with clinically-confined renal cell carcinoma (RCC) and who undergo curative surgery will nevertheless relapse with metastatic disease (mRCC) associated with poor long term survival. The discovery of novel prognostic/predictive biomarkers and drug targets is needed and in this context the aim of the current study was to investigate a putative caveolin-1/ERK signalling axis in clinically confined RCC, and to examine in a panel of RCC cell lines the effects of caveolin-1 (Cav-1) on pathological processes (invasion and growth) and select signalling pathways. Methods: Using immunohistochemistry we assessed the expression of both Cav-1 and phosphorylated-ERK (pERK) in 176 patients with clinically confined RCC, their correlation with histological parameters and their impact upon disease-free survival. Using a panel of RCC cell lines we explored the functional effects of Cav-1 knockdown upon cell growth, cell invasion and VEGF-A secretion, as well Cav-1 regulation by cognate cell signalling pathways. Results: We found a significant correlation (P = 0.03) between Cav-1 and pERK in a cohort of patients with clinically confined disease which represented a prognostic biomarker combination (HR = 4.2) that effectively stratified patients into low, intermediate and high risk groups with respect to relapse, even if the patients’ tumours displayed low grade and/or low stage disease. In RCC cell lines Cav-1 knockdown unequivocally reduced cell invasive capacity while also displaying both pro-and anti-proliferative effects; targeted knockdown of Cav-1 also partially suppressed VEGF-A secretion in VHL-negative RCC cells. The actions of Cav-1 in the RCC cell lines appeared independent of both ERK and AKT/mTOR signalling pathways. Conclusion: The combined expression of Cav-1 and pERK serves as an independent biomarker signature with potential merit in RCC surveillance strategies able to predict those patients with clinically confined disease who will eventually relapse. In a panel of in-vitro RCC cells Cav-1 promotes cell invasion with variable effects on cell growth and VEGF-A secretion. Cav-1 has potential as a therapeutic target for the prevention and treatment of mRCC

Is it possible to predict improved diabetes outcomes following diabetes self-management education : a mixed-methods longitudinal design

Objective: To predict the diabetes-related outcomes of people undertaking a type 2 Diabetes Self-Management Education (DSME) programme from their baseline data. Design: A mixed-methods longitudinal experimental study. 6 practice nurses and 2 clinical academics undertook blind assessments of all baseline and process data to predict clinical, behavioural and psychological outcomes at 6 months post-DSME programme. Setting Primary care. Participants: –31 people with type 2 diabetes who had not previously undertaken DSME. Intervention: All participants undertook the Diabetes Manual 1:1 self-directed learning 12-week DSME programme supported by practice nurses trained as Diabetes Manual facilitators. Outcome variables: Glycated haemoglobin (HbA1c), diabetes knowledge, physical activity, waist circumference, self-efficacy, diabetes distress, anxiety, depression, demographics, change talk and treatment satisfaction. These variables were chosen because they are known to influence self-management behaviour or to have been influenced by a DSME programme in empirical evidence. Results: Baseline and 6-month follow-up data were available for 27 participants of which 13 (48%) were male, 22 (82%) white British, mean age 59 years and mean duration of type 2 diabetes 9.1 years. Significant reductions were found in HbA1c t(26)=2.35, p=0.03, and diabetes distress t(26)=2.30, p=0.03, and a significant increase in knowledge t(26)=−2.06, p=0.05 between baseline and 6 months. No significant changes were found in waist circumference, physical activity, anxiety, depression or self-efficacy. Accuracy of predictions varied little between clinical academics and practice nurses but greatly between outcome (0–100%). The median and mode accuracy of predicted outcome was 66.67%. Accuracy of prediction for the key outcome of HbA1c was 44.44%. Diabetes distress had the highest prediction accuracy (81.48%). Conclusions: Clinicians in this small study were unable to identify individuals likely to achieve improvement in outcomes from DSME. DSME should be promoted to all patients with diabetes according to guidelines

Developing urban futures

The Urban Age turns its ‘reflexive lens’ to Africa after a series of international conferences that have allowed us to assess selected cities in hotspots of urban growth and change across the world. For 15 years, the Urban Age project has conducted a worldwide investigation into the future of cities, holding conferences, generating research, curating exhibitions, publishing books (most recently Shaping Cities in an Urban Age) and producing newspapers like this one to explore the relationship between the design of cities – how we live, move and work – and how they can be better governed and managed to tackle the challenges of, for example, uncontrolled sprawl, inequality and climate change. The risks associated with steep and unmanaged urban growth are high. The essays in this publication provide context and perspective on the challenges faced by developing cities: from fragmented urbanisation and economic inefficiency, to environmental damage and limited democratic accountability. As the location for the 17th Urban Age conference, Addis Ababa, with its distinctive model of urban transformation in Africa, is explored in greater detail as a basis to frame questions around our shared urban future

Changes in cognitive flexibility and hypothesis search across human life history from childhood to adolescence to adulthood

How was the evolution of our unique biological life history related to distinctive human developments in cognition and culture? We suggest that the extended human childhood and adolescence allows a balance between exploration and exploitation, between wider and narrower hypothesis search, and between innovation and imitation in cultural learning. In particular, different developmental periods may be associated with different learning strategies. This relation between biology and culture was probably coevolutionary and bidirectional: life-history changes allowed changes in learning, which in turn both allowed and rewarded extended life histories. In two studies, we test how easily people learn an unusual physical or social causal relation from a pattern of evidence. We track the development of this ability from early childhood through adolescence and adulthood. In the physical domain, preschoolers, counterintuitively, perform better than school-aged children, who in turn perform better than adolescents and adults. As they grow older learners are less flexible: they are less likely to adopt an initially unfamiliar hypothesis that is consistent with new evidence. Instead, learners prefer a familiar hypothesis that is less consistent with the evidence. In the social domain, both preschoolers and adolescents are actually the most flexible learners, adopting an unusual hypothesis more easily than either 6-y-olds or adults. There may be important developmental transitions in flexibility at the entry into middle childhood and in adolescence, which differ across domains

The Active Brains Digital Intervention to Reduce Cognitive Decline in Older Adults: Protocol for a Feasibility Randomized Controlled Trial.

BACKGROUND: Increasing physical activity, improving diet, and performing brain training exercises are associated with reduced cognitive decline in older adults. OBJECTIVE: In this paper, we describe a feasibility trial of the Active Brains intervention, a web-based digital intervention developed to support older adults to make these 3 healthy behavior changes associated with improved cognitive health. The Active Brains trial is a randomized feasibility trial that will test how accessible, acceptable, and feasible the Active Brains intervention is and the effectiveness of the study procedures that we intend to use in the larger, main trial. METHODS: In the randomized controlled trial (RCT), we use a parallel design. We will be conducting the intervention with 2 populations recruited through GP practices (family practices) in England from 2018 to 2019: older adults with signs of cognitive decline and older adults without any cognitive decline. Trial participants were randomly allocated to 1 of 3 study groups: usual care, the Active Brains intervention, or the Active Brains website plus brief support from a trained coach (over the phone or by email). The main outcomes are performance on cognitive tasks, quality of life (using EuroQol-5D 5 level), Instrumental Activities of Daily Living, and diagnoses of dementia. Secondary outcomes (including depression, enablement, and health care costs) and process measures (including qualitative interviews with participants and supporters) will also be collected. The trial has been approved by the National Health Service Research Ethics Committee (reference 17/SC/0463). RESULTS: Results will be published in peer-reviewed journals, presented at conferences, and shared at public engagement events. Data collection was completed in May 2020, and the results will be reported in 2021. CONCLUSIONS: The findings of this study will help us to identify and make important changes to the website, the support received, or the study procedures before we progress to our main randomized phase III trial. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number 23758980; http://www.isrctn.com/ISRCTN23758980. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/18929

Long-lasting blood pressure lowering effects of nitrite are NO-independent and mediated by hydrogen peroxide, persulfides, and oxidation of protein kinase G1α redox signalling

Aims Under hypoxic conditions, nitrite (NO2-) can be reduced to nitric oxide (NO) eliciting vasorelaxation. However, nitrite also exerts vasorelaxant effects of potential therapeutic relevance under normal physiological conditions via undetermined mechanisms. We, therefore, sought to investigate the mechanism(s) by which nitrite regulates the vascular system in normoxia and, specifically, whether the biological effects are a result of NO generation (as in hypoxia) or mediated via alternative mechanisms involving classical downstream targets of NO [e.g. effects on protein kinase G1 alpha (PKG1 alpha)]. Methods and results Ex vivo myography revealed that, unlike in thoracic aorta (conduit vessels), the vasorelaxant effects of nitrite in mesenteric resistance vessels from wild-type (WT) mice were NO-independent. Oxidants such as H2O2 promote disulfide formation of PKG1 alpha, resulting in NO- cyclic guanosine monophosphate (cGMP) independent kinase activation. To explore whether the microvascular effects of nitrite were associated with PKG1 alpha oxidation, we used a Cys42Ser PKG1 alpha knock-in (C42S PKG1 alpha KI; 'redox-dead') mouse that cannot transduce oxidant signals. Resistance vessels from these C42S PKG1 alpha KI mice were markedly less responsive to nitrite-induced vasodilation. Intraperitoneal (i.p.) bolus application of nitrite in conscious WT mice induced a rapid yet transient increase in plasma nitrite and cGMP concentrations followed by prolonged hypotensive effects, as assessed using in vivo telemetry. In the C42S PKG1 alpha KI mice, the blood pressure lowering effects of nitrite were lower compared to WT. Increased H2O2 concentrations were detected in WT resistance vessel tissue challenged with nitrite. Consistent with this, increased cysteine and glutathione persulfide levels were detected in these vessels by mass spectrometry, matching the temporal profile of nitrite's effects on H2O2 and blood pressure. Conclusion Under physiological conditions, nitrite induces a delayed and long-lasting blood pressure lowering effect, which is NO-independent and occurs via a new redox mechanism involving H2O2, persulfides, and PKG1 alpha oxidation/activation. Targeting this novel pathway may provide new prospects for anti-hypertensive therapy