Targeting aberrant epigenetic networks mediated by PRMT1 and KDM4C in acute myeloid leukemia

SummaryTranscriptional deregulation plays a major role in acute myeloid leukemia, and therefore identification of epigenetic modifying enzymes essential for the maintenance of oncogenic transcription programs holds the key to better understanding of the biology and designing effective therapeutic strategies for the disease. Here we provide experimental evidence for the functional involvement and therapeutic potential of targeting PRMT1, an H4R3 methyltransferase, in various MLL and non-MLL leukemias. PRMT1 is necessary but not sufficient for leukemic transformation, which requires co-recruitment of KDM4C, an H3K9 demethylase, by chimeric transcription factors to mediate epigenetic reprogramming. Pharmacological inhibition of KDM4C/PRMT1 suppresses transcription and transformation ability of MLL fusions and MOZ-TIF2, revealing a tractable aberrant epigenetic circuitry mediated by KDM4C and PRMT1 in acute leukemia

Housing theory, housing research and housing policy

Jim Kemeny in 1992 criticised existing housing research for neglecting social theory and being overly positivist and policy focused. The result has been a strengthening of the conceptual basis of housing research in general, but also a growing schism between researchers who focus on policy relevancy and those that pursue more theoretical work. This paper challenges this schism and argues for theoretically based and policy relevant research. First the paper argues that the policy-making process is complex and can vary between different countries, situations and over time. Therefore, it is argued that many styles of research can influence policy in the right circumstances. Second, the paper challenges the idea that there can be theoretically-free housing research arguing that all research has a theoretical foundation even though in many studies it is not explicit. Finally, the paper engages with the debate about where theory for housing research should come from and what it would look like

An extension of the benefit segmentation base for the consumption of organic foods : a time perspective

Benefit segmentation is a long-standing marketing approach that emphasises the ‘what’ and ‘how’ dimensions of consumer benefits; that is, what benefits consumers perceive in product/service consumption, and how such benefits are perceived. This research proposes a fresh time-based approach to benefit segmentation – namely, focusing on the ‘when’ element or when in time benefits take effect. Drawing upon a survey of UK consumers, it explains and discusses consumption motivations through examining antecedents of temporally dominated benefits in application to organic food. Specifically, the study investigates why some consumers predominantly seek present-based benefits vis-à-vis future-based benefits or vice versa in organic food purchase and consumption behaviour. Using correlation and regression analyses, the research findings establish significant associations of level of involvement, prior knowledge level, and product usage level, and some association of time orientation with the temporally emphasised consumption benefits consumers ultimately pursue. Overall, the research highlights the added contribution of a time perspective in a benefit segmentation approach which can assist marketers in understanding better and communicating more effectively with consumers through drawing up consumer profiles based on when in time their dominantly pursued benefit for an offering is perceived to take effect

Tourist risk perceptions and revisit intention: A critical review of literature

Tourists’ perceptions of risk with travel destination are one of the key determinants of their decision-making in revisiting a destination. Despite the importance of the subject in tourism literature, a few attempts have been made to focus on the effects of tourist risk perceptions on revisit intentions. Moreover, a theoretical foundation is still lacking in current literature highlighting the relationship of the effect of tourist risk perceptions through satisfaction and attitude towards revisiting with tourist revisit intention. Taking this into account as research gap, this paper provides a critical review of the effect of tourist risk perceptions in tourism research, presenting a descriptive background, identifying the progress, develop an integrated conceptual framework, review of their theoretical propositions and methodological issues and suggesting new areas and approaches for future research. The study concludes that the area is dominated by both the quantitative and the qualitative research, and a lack of appropriate theoretical foundation is a major problem to understand the common risk dimensions and their effect on tourist revisit intention. Therefore, the integration of satisfaction and attitude towards revisit with the relationship between tourist risk perceptions and revisit intention in a single framework seems rational to provide an insight for new research approach

Hepatic STAT1-Nuclear Translocation and Interleukin 28B Polymorphisms Predict Treatment Outcomes in Hepatitis C Virus Genotype 1-Infected Patients

We investigated associations between signal transducer and activator of transcription (STAT) 1 in pretreated liver tissues, interleukin (IL) 28B polymorphism and treatment response in hepatitis C virus (HCV)-infected patients treated with peginterferon and ribavirin.We performed immunostaining analysis of STAT1 in liver tissues and determined IL28B polymorphism at rs8099917. We then compared the results with treatment outcomes in HCV genotype 1 patients with high viral load who were receiving peginterferon plus ribavirin. In univariate analysis, younger age, white blood cell counts, virological responder, early virological responder (EVR), mild activity (A1) of liver inflammation grading, and lower STAT1 nuclear-stain of hepatocytes in zone 1, zone 2 and total zones of liver were associated with sustained virological responder (SVR). Multivariate analysis showed that EVR, age and hepatic STAT1 nuclear-stain in zone 2 of liver were independent predictors of SVR. It was also revealed that IL28B and STAT1-nuclear translocation in hepatocytes are independent predictors of response to treatment with peginterferon and ribavirin in chronic hepatitis C patients.Concomitant assessment of lower STAT1 nuclear-stain of hepatocytes and IL28B polymorphism is useful for prediction of SVR in HCV genotype 1 patients

Effective risk relievers for dimensional perceived risks on mail-order purchase: a case study on speciality foods in the UK

This article examines the effective risk relievers for different dimensions of perceived risk on mail-order purchase of food products. The sample comprised 1,600 active and inactive mail-order specialty food shoppers in the UK. The analysis focused on the correlation coefficients between consumers' levels of perceived risk and their weight on the importance of the risk relievers. Amongst 15 risk relievers, the results implied that there are certain risk relievers attached to higher levels of importance by consumers, who perceive higher levels of risks in certain aspects of mail-order purchase. Therefore, mail-order companies should promote the effective risk relievers to reduce specific dimensions of perceived risks

Cultural experience tourist motives dimensionality : a cross-cultural study

This empirical research of tourists&rsquo; cultural experiences aims to advance theory by developing a measurement model of tourists&rsquo; motives towards attending cultural experiences for samples of Western and Asian tourists visiting Melbourne, Australia. Drawing upon Iso-Ahola&rsquo;s (1989) seeking/avoiding dichotomy theory for tourist motivation dimensions, the hypothesized dimensions primarily included escape and seeking-related dimensions, and some hedonic dimensions because of their relevance to aesthetic products (Hirschman &amp; Holbrook, 1982; Holbrook &amp; Hirschman, 1982), which are the context for this study. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were used to crossvalidate the underlying dimensionality structure of cultural experience motives. A four-factor model was extracted from the EFA consistent with some theoretical formulations and was retained in the CFA. Specific cultural language group differences for the motive dimensions were also hypothesized between Western and Asian tourist samples, and within the Chinese- and Japanese-speaking Asian tourist samples, but not within the different cultural groups of English-speaking Western tourists. These cross-cultural hypotheses were tested for the motive dimension measurement model using invariance testing in CFA. The findings for the motive dimensions differing by cultural group were not as expected. Significant cultural differences between Western and Asian tourists were not found, but a new finding of this study was significant differences between English-speaking tourists in their motives for attending cultural experiences. Marketing implications of these findings are also presented.<br /

Methylthioadenosine reprograms macrophage activation through adenosine receptor stimulation

Regulation of inflammation is necessary to balance sufficient pathogen clearance with excessive tissue damage. Central to regulating inflammation is the switch from a pro-inflammatory pathway to an anti-inflammatory pathway. Macrophages are well-positioned to initiate this switch, and as such are the target of multiple therapeutics. One such potential therapeutic is methylthioadenosine (MTA), which inhibits TNFα production following LPS stimulation. We found that MTA could block TNFα production by multiple TLR ligands. Further, it prevented surface expression of CD69 and CD86 and reduced NF-KB signaling. We then determined that the mechanism of this action by MTA is signaling through adenosine A2 receptors. A2 receptors and TLR receptors synergized to promote an anti-inflammatory phenotype, as MTA enhanced LPS tolerance. In contrast, IL-1β production and processing was not affected by MTA exposure. Taken together, these data demonstrate that MTA reprograms TLR activation pathways via adenosine receptors to promote resolution of inflammation. © 2014 Keyel et al