Chemical Inhibition of Wild-Type p53-Induced Phosphatase 1 (WIP1/PPM1D) by GSK2830371 Potentiates the Sensitivity to MDM2 Inhibitors in a p53-Dependent Manner

Sensitivity to MDM2 inhibitors is widely different among responsive TP53 wild-type cell lines and tumors. Understanding the determinants of MDM2 inhibitor sensitivity is pertinent for their optimal clinical application. Wild-type p53-inducible phosphatase-1 (WIP1) encoded by PPM1D, is activated, gained/amplified in a range of TP53 wild-type malignancies, and is involved in p53 stress response homeostasis. We investigated cellular growth/proliferation of TP53 wild-type and matched mutant/null cell line pairs, differing in PPM1D genetic status, in response to Nutlin-3/RG7388 ± a highly selective WIP1 inhibitor, GSK2830371. We also assessed the effects of GSK2830371 on MDM2 inhibitor-induced p53Ser15 phosphorylation, p53-mediated global transcriptional activity, and apoptosis. The investigated cell line pairs were relatively insensitive to single-agent GSK2830371. However, a non–growth-inhibitory dose of GSK2830371 markedly potentiated the response to MDM2 inhibitors in TP53 wild-type cell lines, most notably in those harboring PPM1D-activating mutations or copy number gain (up to 5.8-fold decrease in GI50). Potentiation also correlated with significant increase in MDM2 inhibitor–induced cell death endpoints that were preceded by a marked increase in a WIP1 negatively regulated substrate, phosphorylated p53Ser15, known to increase p53 transcriptional activity. Microarray-based gene expression analysis showed that the combination treatment increases the subset of early RG7388-induced p53 transcriptional target genes. These findings demonstrate that potent and selective WIP1 inhibition potentiates the response to MDM2 inhibitors in TP53 wild-type cells, particularly those with PPM1D activation or gain, while highlighting the mechanistic importance of p53Ser15 and its potential use as a biomarker for response to this combination regimen. Mol Cancer Ther; 15(3); 379–91. ©2016 AACR

Creating scenarios of the impact of copd and their relationship to copd assessment test (CAT™) scores

Background: The COPD Assessment Test (CAT™) is a new short health status measure for routine use. New questionnaires require reference points so that users can understand the scores; descriptive scenarios are one way of doing this. A novel method of creating scenarios is described. Methods: A Bland and Altman plot showed a consistent relationship between CAT scores and scores obtained with the St George’s Respiratory Questionnaire for COPD (SGRQ-C) permitting a direct mapping process between CAT and SGRQ items. The severity associated with each CAT item was calculated using a probabilistic model and expressed in logits (log odds of a patient of given severity affirming that item 50% of the time). Severity estimates for SGRQ-C items in logits were also available, allowing direct comparisons with CAT items. CAT scores were categorised into Low, Medium, High and Very High Impact. SGRQ items of corresponding severity were used to create scenarios associated with each category. Results: Each CAT category was associated with a scenario comprising 12 to 16 SGRQ-C items. A severity ‘ladder’ associating CAT scores with exemplar health status effects was also created. Items associated with ‘Low’ and ‘Medium’ Impact appeared to be subjectively quite severe in terms of their effect on daily life. Conclusions: These scenarios provide users of the CAT with a good sense of the health impact associated with different scores. More generally they provide a surprising insight into the severity of the effects of COPD, even in patients with apparently mild-moderate health status impact

Socio-cultural influences on the behaviour of South Asian women with diabetes in pregnancy: qualitative study using a multi-level theoretical approach

BACKGROUND: Diabetes in pregnancy is common in South Asians, especially those from low-income backgrounds, and leads to short-term morbidity and longer-term metabolic programming in mother and offspring. We sought to understand the multiple influences on behaviour (hence risks to metabolic health) of South Asian mothers and their unborn child, theorise how these influences interact and build over time, and inform the design of culturally congruent, multi-level interventions. METHODS: Our sample for this qualitative study was 45 women of Bangladeshi, Indian, Sri Lankan, or Pakistani origin aged 21-45 years with a history of diabetes in pregnancy, recruited from diabetes and antenatal services in two deprived London boroughs. Overall, 17 women shared their experiences of diabetes, pregnancy, and health services in group discussions and 28 women gave individual narrative interviews, facilitated by multilingual researchers, audiotaped, translated, and transcribed. Data were analysed using the constant comparative method, drawing on sociological and narrative theories. RESULTS: Key storylines (over-arching narratives) recurred across all ethnic groups studied. Short-term storylines depicted the experience of diabetic pregnancy as stressful, difficult to control, and associated with negative symptoms, especially tiredness. Taking exercise and restricting diet often worsened these symptoms and conflicted with advice from relatives and peers. Many women believed that exercise in pregnancy would damage the fetus and drain the mother's strength, and that eating would be strength-giving for mother and fetus. These short-term storylines were nested within medium-term storylines about family life, especially the cultural, practical, and material constraints of the traditional South Asian wife and mother role and past experiences of illness and healthcare, and within longer-term storylines about genetic, cultural, and material heritage - including migration, acculturation, and family memories of food insecurity. While peer advice was familiar, meaningful, and morally resonant, health education advice from clinicians was usually unfamiliar and devoid of cultural meaning. CONCLUSIONS: 'Behaviour change' interventions aimed at preventing and managing diabetes in South Asian women before and during pregnancy are likely to be ineffective if delivered in a socio-cultural vacuum. Individual education should be supplemented with community-level interventions to address the socio-material constraints and cultural frames within which behavioural 'choices' are made

Knowledge and perceptions of diabetes in a semi-urban Omani population

<p>Abstract</p> <p>Background</p> <p>Diabetes mellitus is a major public health problem in the Sultanate of Oman. This study aimed to evaluate the knowledge and perception of diabetes in a sample of the Omani general population, and the associations between the elements of knowledge and perception, and socio-demographic factors.</p> <p>Methods</p> <p>The study was carried out in two semi-urban localities. A total of 563 adult residents were interviewed, using a questionnaire specifically designed for the present study. In addition to demographic information, the questionnaire contained questions on knowledge related to diabetes definition, symptoms, risk factors, complications and preventative measures, as well as risk perception for diabetes.</p> <p>Results</p> <p>Knowledge of diabetes was suboptimal. The percentages of correct responses to questions on diabetes definition, classical symptoms, and complications were 46.5%, 57.0%, and 55.1%, respectively. Only 29.5%, 20.8% and 16.9% identified obesity, physical inactivity and a positive family history, respectively, as risk factors for diabetes. A higher level of education, a higher household income, and the presence of a family history of diabetes were found to be positively associated with more knowledge.</p> <p>Conclusion</p> <p>This study demonstrated that there is lack of awareness of major risk factors for diabetes mellitus. Level of education is the most significant predictor of knowledge regarding risk factors, complications and the prevention of diabetes. Given that the prevalence of diabetes has increased drastically in Oman over the last decade, health promotion seems essential, along with other means to prevent and control this emerging health problem.</p

Rasch analysis of the Patient and Observer Scar Assessment Scale (POSAS) in burn scars

The Patient and Observer Scar Assessment Scale (POSAS) is a questionnaire that was developed to assess scar quality. It consists of two separate six-item scales (Observer Scale and Patient Scale), both of which are scored on a 10-point rating scale. After many years of experience with this scale in burn scar assessment, it is appropriate to examine its psychometric properties using Rasch analysis. Cross-sectional data collection from seven clinical trials resulted in a data set of 1,629 observer scores and 1,427 patient scores of burn scars. We examined the person-item map, item fit statistics, reliability, response category ordering, and dimensionality of the POSAS. The POSAS showed an adequate fit to the Rasch model, except for the item surface area. Person reliability of the Observer Scale and Patient Scale was 0.82 and 0.77, respectively. Dimensionality analysis revealed that the unexplained variance by the first contrast of both scales was 1.7 units. Spearman correlation between the Observer Scale Rasch measure and the overall opinion of the clinician was 0.75. The Rasch model demonstrated that the POSAS is a reliable and valid scale that measures the single-construct scar qualit

miR-337-3p and Its Targets STAT3 and RAP1A Modulate Taxane Sensitivity in Non-Small Cell Lung Cancers

NSCLC (non-small cell lung cancer) often exhibits resistance to paclitaxel treatment. Identifying the elements regulating paclitaxel response will advance efforts to overcome such resistance in NSCLC therapy. Using in vitro approaches, we demonstrated that over-expression of the microRNA miR-337-3p sensitizes NCI-H1155 cells to paclitaxel, and that miR-337-3p mimic has a general effect on paclitaxel response in NSCLC cell lines, which may provide a novel adjuvant strategy to paclitaxel in the treatment of lung cancer. By combining in vitro and in silico approaches, we identified STAT3 and RAP1A as direct targets that mediate the effect of miR-337-3p on paclitaxel sensitivity. Further investigation showed that miR-337-3p mimic also sensitizes cells to docetaxel, another member of the taxane family, and that STAT3 levels are significantly correlated with taxane resistance in lung cancer cell lines, suggesting that endogenous STAT3 expression is a determinant of intrinsic taxane resistance in lung cancer. The identification of a miR-337-3p as a modulator of cellular response to taxanes, and STAT3 and RAP1A as regulatory targets which mediate that response, defines a novel regulatory pathway modulating paclitaxel sensitivity in lung cancer cells, which may provide novel adjuvant strategies along with paclitaxel in the treatment of lung cancer and may also provide biomarkers for predicting paclitaxel response in NSCLC

Fatty-Acid Preference Changes during Development in Drosophila melanogaster

Fatty-acids (FAs) are required in the diet of many animals throughout their life. However, the mechanisms involved in the perception of and preferences for dietary saturated and unsaturated FAs (SFAs and UFAs, respectively) remain poorly explored, especially in insects. Using the model species Drosophila melanogaster, we measured the responses of wild-type larvae and adults to pure SFAs (14, 16, and 18 carbons) and UFAs (C18 with 1, 2, or 3 double-bonds). Individual and group behavioral tests revealed different preferences in larvae and adults. Larvae preferred UFAs whereas SFAs tended to induce both a strong aversion and a persistent aggregation behavior. Adults generally preferred SFAs, and laid more eggs and had a longer life span when ingesting these substances as compared to UFAs. Our data suggest that insects can discriminate long-chain dietary FAs. The developmental change in preference shown by this species might reflect functional variation in use of FAs or stage-specific nutritional requirements, and may be fundamental for insect use of these major dietary components

Charting the course for a Blue Economy in Peru: A Research Agenda

Ocean- and coastal-based economic activities are increasingly recognised as key drivers for supporting global economies. This move towards the “blue economy” is becoming globally widespread, with the recognition that if ocean-based activities are to be sustainable, they will need to move beyond solely extractive and exploitative endeavours, aligning more closely with marine conservation and effective marine spatial planning. In this paper we define the “blue economy” as a “platform for strategic, integrated and participatory coastal and ocean development and protection that incorporates a low carbon economy, the ecosystem approach and human well-being through advancing regional industries, services and activities”. In Peru, while the seas contribute greatly to the national economy, the full potential of the blue economy has yet to be realised. This paper presents the findings of an early career scientist workshop in Lima, Peru, in March 2016. The workshop “Advancing Green Growth in Peru” brought together researchers to identify challenges and opportunities for green growth across three Peruvian economic sectors—tourism, transport and the blue economy with this paper exploring in detail the priorities generated from the “blue economy” stream. These priorities include themes such as marine spatial planning, detailed evaluations of existing maritime industries (e.g. guano collection and fisheries), development of an effective MPA network, support for sustainable coastal tourism, and better inclusion of social science disciplines in understanding societal and political support for a Peruvian blue economy. In addition, the paper discusses the research requirements associated with these priorities. While not a comprehensive list, these priorities provide a starting point for future dialogue on a co-ordinated scientific platform supporting the blue growth agenda in Peru, and in other regions working towards a successful “blue economy”

Links Between Hydrothermal Environments, Pyrophosphate, Na+, and Early Evolution

The discovery that photosynthetic bacterial membrane-bound inorganic pyrophosphatase (PPase) catalyzed light-induced phosphorylation of orthophosphate (Pi) to pyrophosphate (PPi) and the capability of PPi to drive energy requiring dark reactions supported PPi as a possible early alternative to ATP. Like the proton-pumping ATPase, the corresponding membrane-bound PPase also is a H+-pump, and like the Na+-pumping ATPase, it can be a Na+-pump, both in archaeal and bacterial membranes. We suggest that PPi and Na+ transport preceded ATP and H+ transport in association with geochemistry of the Earth at the time of the origin and early evolution of life. Life may have started in connection with early plate tectonic processes coupled to alkaline hydrothermal activity. A hydrothermal environment in which Na+ is abundant exists in sediment-starved subduction zones, like the Mariana forearc in the W Pacific Ocean. It is considered to mimic the Archean Earth. The forearc pore fluids have a pH up to 12.6, a Na+-concentration of 0.7 mol/kg seawater. PPi could have been formed during early subduction of oceanic lithosphere by dehydration of protonated orthophosphates. A key to PPi formation in these geological environments is a low local activity of water