HDAC inhibitors increase NRF2-signaling in tumour cells and blunt the efficacy of co-adminstered cytotoxic agents

The NRF2 signalling cascade provides a primary response against electrophilic chemicals and oxidative stress. The activation of NRF2-signaling is anticipated to have adverse clinical consequences; NRF2 is activated in a number of cancers and, additionally, its pharmacological activation by one compound can reduce the toxicity or efficiency of a second agent administered concomitantly. In this work, we have analysed systematically the ability of 152 research, pre-clinical or clinically used drugs to induce an NRF2 response using the MCF7-AREc32 NRF2 reporter. Ten percent of the tested drugs induced an NRF2 response. The NRF2 activators were not restricted to classical cytotoxic alkylating agents but also included a number of emerging anticancer drugs, including an IGF1-R inhibitor (NVP-AEW541), a PIM-1 kinase inhibitor (Pim1 inhibitor 2), a PLK1 inhibitor (BI 2536) and most strikingly seven of nine tested HDAC inhibitors. These findings were further confirmed by demonstrating NRF2-dependent induction of endogenous AKR genes, biomarkers of NRF2 activity. The ability of HDAC inhibitors to stimulate NRF2-signalling did not diminish their own potency as antitumour agents. However, when used to pre-treat cells, they did reduce the efficacy of acrolein. Taken together, our data suggest that the ability of drugs to stimulate NRF2 activity is common and should be investigated as part of the drug-development process

Geodynamic setting and origin of the Oman/UAE ophiolite

The ~500km-long mid-Cretaceous Semail nappe of the Sultanate of Oman and UAE (henceforth referred to as the Oman ophiolite) is the largest and best-preserved ophiolite complex known. It is of particular importance because it is generally believed to have an internal structure and composition closely comparable to that of crust formed at the present-day East Pacific Rise (EPR), making it our only known on-land analogue for ocean lithosphere formed at a fast spreading rate. On the basis of this assumption Oman has long played a pivotal role in guiding our conceptual understanding of fast-spreading ridge processes, as modern fast-spread ocean crust is largely inaccessible

Hungry for Respect: Discrimination Among Adults Using Emergency Food Services

Objectives: We examined how adults using emergency food services report discrimination and how these reports may be associated with well-being. Methods: Data come from a survey (n=318) and from five focus groups of adults using emergency food services, conducted between 2003-2004. The survey included measures derived from the Everyday Discrimination Scale and the Centers for Epidemiologic Studies Depression Scale (CES-D). Focus groups were analyzed with content analysis. Results: The survey data suggest that everyday discrimination was associated with the CES-D, conditional on covariates. Focus group data are consistent with the survey results and suggest several avenues for future research, including how some individuals may forgo access to food and medications in order to protect their dignity in the face of discrimination. Conclusions: Qualitative and quantitative data converge into a similar theme - discrimination may be an important factor associated with well-being

The effect of visual support strategies on the quality of life of children with cerebral palsy and cerebral visual impairment/perceptual visual dysfunction in Nigeria: study protocol for a randomized controlled trial.

BACKGROUND: Cerebral visual impairment (CVI), including perceptual visual dysfunction (PVD), is common in children with cerebral palsy (CP). Inventories of questions relating to practical aspects of visual perception in everyday life, in particular the closed-ended Insight Questions Inventory (IQI), can be used to assess CVI/PVD. Studies linking responses to the inventory with specific visual support strategies, aimed at modifying the child's environment and/or behaviour to minimize the impact of the CVI/PVD, have been piloted. The IQI and tailored strategies have not been used in an African population, nor have they been tested in a controlled trial. This trial will compare the effectiveness of the IQI and linked visual support strategies versus general supportive treatments on the quality of life of children with CVI/PVD and CP through a randomized controlled trial. METHODS/DESIGN: This is a prospective, double-blind, parallel-arm, randomized controlled trial. The primary outcome is change in quality of life scores between the two arms of the trial at 6 weeks, assessed using the Paediatric Quality of Life Inventory (PedsQL) generic 4.0 and CP 3.0 module. All children will undergo baseline assessment including the Open Questions Inventory, IQI, PedsQL 3.0, PedsQL 4.0 generic, and the Strengths and Difficulties Questionnaire (SDQ). Eligible children with CP aged 4 years to < 16 years will be stratified and blocked by the age groups 4-9 and 10 to < 16 years and by Gross Motor Function Classification System (GMFCS) levels 1-3 and 4-5. Families in the intervention arm will receive tailored insight visual support strategies and telephone calls during the 6-week trial period. The control arm will receive standard treatment and the intervention after the 6-week trial period. Follow-up interviews will be performed in both arms at 6 weeks with a repeat administration of the PedsQL CP 4.0 and 3.0, the IQI and the SDQ. Secondary outcomes include a change in functional vision. DISCUSSION: This randomized controlled trial will provide evidence of the effectiveness of this intervention for children with CP in a resource-poor setting. TRIAL REGISTRATION: Pan African Clinical Trials Registration, PACTR201612001886396 . Registered on 3 December 2016

A Sterile 20 Family Kinase and Its Co-factor CCM-3 Regulate Contractile Ring Proteins on Germline Intercellular Bridges

Germ cells in most animals are connected by intercellular bridges, actin-based rings that form stable cytoplasmic connections between cells promoting communication and coordination [1]. Moreover, these connections are required for fertility [1, 2]. Intercellular bridges are proposed to arise from stabilization of the cytokinetic ring during incomplete cytokinesis [1]. Paradoxically, proteins that promote closure of cytokinetic rings are enriched on stably open intercellular bridges [1, 3, 4]. Given this inconsistency, the mechanism of intercellular bridge stabilization is unclear. Here, we used the C. elegans germline as a model for identifying molecular mechanisms regulating intercellular bridges. We report that bridges are actually highly dynamic, changing size at precise times during germ cell development. We focused on the regulation of bridge stability by anillins, key regulators of cytokinetic rings and cytoplasmic bridges [1, 4-7]. We identified GCK-1, a conserved serine/threonine kinase [8], as a putative novel anillin interactor. GCK-1 works together with CCM-3, a known binding partner [9], to promote intercellular bridge stability and limit localization of both canonical anillin and non-muscle myosin II (NMM-II) to intercellular bridges. Additionally, we found that a shorter anillin, known to stabilize bridges [4, 7], also regulates NMM-II levels at bridges. Consistent with these results, negative regulators of NMM-II stabilize intercellular bridges in the Drosophila egg chamber [10, 11]. Together with our findings, this suggests that tuning of myosin levels is a conserved mechanism for the stabilization of intercellular bridges that can occur by diverse molecular mechanisms

Short-term serotonergic but not noradrenergic antidepressant administration reduces attentional vigilance to threat in healthy volunteers

Anxiety is associated with threat-related biases in information processing such as heightened attentional vigilance to potential threat. Such biases are an important focus of psychological treatments for anxiety disorders. Selective serotonin reuptake inhibitors (SSRIs) are effective in the treatment of a range of anxiety disorders. The aim of this study was to assess the effect of an SSRI on the processing of threat in healthy volunteers. A selective noradrenergic reuptake inhibitor (SNRI), which is not generally used in the treatment of anxiety, was used as a contrast to assess the specificity of SSRI effects on threat processing. Forty-two healthy volunteers were randomly assigned to 7 d double-blind intervention with the SSRI citalopram (20 mg/d), the SNRI reboxetine (8 mg/d), or placebo. On the final day, attentional and interpretative bias to threat was assessed using the attentional probe and the homograph primed lexical decision tasks. Citalopram reduced attentional vigilance towards fearful faces but did not affect the interpretation of ambiguous homographs as threatening. Reboxetine had no significant effect on either of these measures. Citalopram reduces attentional orienting to threatening stimuli, which is potentially relevant to its clinical use in the treatment of anxiety disorders. This finding supports a growing literature suggesting that an important mechanism through which pharmacological agents may exert their effects on mood is by reversing the cognitive biases that characterize the disorders that they treat. Future studies are needed to clarify the neural mechanisms through which these effects on threat processing are mediated

Making sense of bodily sensations: Do shared cancer narratives influence symptom appraisal?

Though new or altered bodily sensations are a common occurrence they rarely transition to biomedically defined symptoms. When they do, sensations are subject to an appraisal process that can culminate in help-seeking. The transition has particular relevance for cancer diagnoses. Studies of 'symptom appraisal' in cancer patients typically conclude that failure to regard sensations as serious or 'symptom misattribution' results in lengthier help-seeking intervals. Though multiple influences on appraisal processes are acknowledged, including the socio-cultural context, detailed description and analyses of how socio-cultural factors shape appraisal is lacking. In this paper we explore one substantial component of the sociocultural context, namely, publicly recognised shared cancer narratives, and their impact on appraisal. We undertook a secondary analysis of 24 interviews with Scottish colorectal cancer patients originally completed in 2006–2007. Our analysis showed that fear, death and severity dominated cancer narratives and were frequently restated throughout interviews. Yet, early bodily changes were often mild and vague, were commonly experienced in the context of 'feeling well' and failed to match preconceived ideas of what cancer 'feels like'. Moreover, few perceived themselves to be 'at risk' of cancer and diagnoses were characterised as 'shocking' events. Participants engaged in self-monitoring strategies and severe or painful changes prompted help-seeking. Far from misattributing symptoms, responses to bodily changes were sensible and measured; responses are particularly apt in relation to current policy rhetoric, which urges measured use of services. Our findings have resonance across healthcare settings as patients are required to negotiate a narrow and challenging space when making decisions to seek help. There is a pressing need for a more realistic approach to symptom appraisal in order to reduce help-seeking intervals. Future awareness campaigns should emphasise the importance of vague/minor bodily changes although this will necessitate discussions with health professionals on referral thresholds to achieve earlier detection

Perceived colorectal cancer candidacy and the role of candidacy in colorectal cancer screening

Screening is a well-established tool to advance earlier cancer diagnosis. We used Davison’s concept of ‘candidacy’ to explore how individuals draw on collectively constructed images of ‘typical’ colorectal cancer (CRC) sufferers, or ‘candidates’, in order to evaluate their own risk and to ascertain the impact of candidacy on screening participation in CRC. We interviewed 61 individuals who were invited to participate in the Scottish Bowel Screening Programme. Of these, 37 were screeners (17 men and 20 women) and 24 non-screeners (13 men and 11 women). To analyse these data we used a coding frame that drew on: symptoms, risk factors, and retrospective and prospective candidacy. Few participants could identify a definite bowel cancer candidate and notions of candidacy were largely predicated on luck in the sense that anyone could be a candidate for CRC and there was little evidence to support a linear relationship between feelings of risk and screening decisions. Often participants described screening as part of a wider portfolio of being healthy and referred to feeling obliged to look after themselves. Our study suggests that rather than candidates for bowel cancer, screeners viewed themselves as candidates for screening by which screening decisions pointed towards the acceptance and normalisation of the rhetoric of personal responsibility for health. These findings have related theoretical and practical implications; the moral structure that underpins the new public health can be witnessed practically in the narratives by which those who see themselves as candidates for screening embrace wider positive health practices.</p