CYP2D6 gene variants: association with breast cancer specific survival in a cohort of breast cancer patients from the United Kingdom treated with adjuvant tamoxifen.

INTRODUCTION: Tamoxifen is one of the most effective adjuvant breast cancer therapies available. Its metabolism involves the phase I enzyme, cytochrome P4502D6 (CYP2D6), encoded by the highly polymorphic CYP2D6 gene. CYP2D6 variants resulting in poor metabolism of tamoxifen are hypothesised to reduce its efficacy. An FDA-approved pre-treatment CYP2D6 gene testing assay is available. However, evidence from published studies evaluating CYP2D6 variants as predictive factors of tamoxifen efficacy and clinical outcome are conflicting, querying the clinical utility of CYP2D6 testing. We investigated the association of CYP2D6 variants with breast cancer specific survival (BCSS) in breast cancer patients receiving tamoxifen. METHODS: This was a population based case-cohort study. We genotyped known functional variants (n = 7; minor allele frequency (MAF) > 0.01) and single nucleotide polymorphisms (SNPs) (n = 5; MAF > 0.05) tagging all known common variants (tagSNPs), in CYP2D6 in 6640 DNA samples from patients with invasive breast cancer from SEARCH (Studies of Epidemiology and Risk factors in Cancer Heredity); 3155 cases had received tamoxifen therapy. There were 312 deaths from breast cancer, in the tamoxifen treated patients, with over 18000 years of cumulative follow-up. The association between genotype and BCSS was evaluated using Cox proportional hazards regression analysis. RESULTS: In tamoxifen treated patients, there was weak evidence that the poor-metaboliser variant, CYP2D6*6 (MAF = 0.01), was associated with decreased BCSS (P = 0.02; HR = 1.95; 95% CI = 1.12-3.40). No other variants, including CYP2D6*4 (MAF = 0.20), previously reported to be associated with poorer clinical outcomes, were associated with differences in BCSS, in either the tamoxifen or non-tamoxifen groups. CONCLUSIONS: CYP2D6*6 may affect BCSS in tamoxifen-treated patients. However, the absence of an association with survival in more frequent variants, including CYP2D6*4, questions the validity of the reported association between CYP2D6 genotype and treatment response in breast cancer. Until larger, prospective studies confirming any associations are available, routine CYP2D6 genetic testing should not be used in the clinical setting.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

FcRn Affinity-Pharmacokinetic Relationship of Five Human IgG4 Antibodies Engineered for Improved In Vitro FcRn Binding Properties in Cynomolgus Monkeys

ABSTRACT: Th

Hand distance modulates the electrophysiological correlates of target selection during a tactile search task

This study investigated whether the N140cc ERP component, described as a possible electrophysiological marker of target selection in touch, was modulated by body posture. Participants performed a tactile search task in which they had to localize a tactile target, presented to the left or right hand, while a simultaneous distractor was delivered to the opposite hand. Importantly, the distance between target and distractor (hands separation) was manipulated in different experimental conditions (near vs. far hands). Results showed reduced errors and enhanced amplitudes of the late N140cc when the hands were far apart than in close proximity. This suggests that the competition between target and distractor is stronger when the hands are close together in the near condition, resulting in a degraded selection process. These findings confirm that the N140cc reflects target selection during the simultaneous presentation of competing stimuli and demonstrate for the first time that the attentional mechanisms indexed by this ERP component are based at least in part on postural representations of the body

Motorized recreation sounds influence nature scene evaluations: The role of attitude moderators

Soundscape assessment takes many forms, including letting the consequences of the soundscape be an indicator of soundscape quality or value. As a result, much social science research has been conducted to better quantify problem soundscapes and the subsequent effects on humans exposed to them. Visual evaluations of natural environments are one area where research has consistently shown detrimental effects of noisy or anthropogenic soundscapes (e.g., those containing noise from motorized recreation), but the potential moderating role of individual attitudes toward elements within the soundscape has not been sufficiently explored. This study demonstrates that both pro-motorized recreation and pro-motorized recreation management attitudes can alter the effect of motorized recreation noise on scenic evaluations in opposing directions. Pro-recreation attitudes lessen the effect of the soundscape, while pro-management attitudes heighten the negative effect of anthropogenic sounds on scenic evaluation. The implications for other areas of soundscape research, especially with regard to soundscape quality assessment through experienced outcomes, are discussed, including possible strategies for prioritizing known or relevant moderating variables

Collaboration and knowledge exchange between scholars in Britain and the empire, 1830–1914

In recent years there has been a growing interest among historians in the British Empire as a space of knowledge production and circulation. Much of this work assumes that scholarly cooperation and collaboration between individuals and institutions within the Empire had the effect (and often also the aim) of strengthening both imperial ties and the idea of empire. This chapter argues, however, that many examples of scholarly travel, exchange, and collaboration were undertaken with very different goals in mind. In particular, it highlights the continuing importance of an ideal of scientific internationalism, which stressed the benefits of scholarship for the whole of humanity and prioritized the needs and goals of individual academic and scientific disciplines. As the chapter shows, some scholars even went on to develop nuanced critiques of the imperial project while using the very structures of empire to further their own individual, disciplinary and institutional goals

Sushi in the United States, 1945-1970

Sushi first achieved widespread popularity in the United States in the mid-1960s. Many accounts of sushi’s US establishment foreground the role of a small number of key actors, yet underplay the role of a complex web of large-scale factors that provided the context in which sushi was able to flourish. This article critically reviews existing literature, arguing that sushi’s US popularity arose from contingent, long-term, and gradual processes. It examines US newspaper accounts of sushi during 1945–1970, which suggest the discursive context for US acceptance of sushi was considerably more propitious than generally acknowledged. Using California as a case study, the analysis also explains conducive social and material factors, and directs attention to the interplay of supply- and demand-side forces in the favorable positioning of this “new” food. The article argues that the US establishment of sushi can be understood as part of broader public acceptance of Japanese cuisine

Insomnia and its correlates in a representative sample of the Greek population

<p>Abstract</p> <p>Background</p> <p>Insomnia is a major public health concern affecting about 10% of the general population in its chronic form. Furthermore, epidemiological surveys demonstrate that poor sleep and sleep dissatisfaction are even more frequent problems (10-48%) in the community. This is the first report on the prevalence of insomnia in Greece, a southeastern European country which differs in several socio-cultural and climatic aspects from the rest of European Community members. Data obtained from a national household survey (n = 1005) were used to assess the relationship between insomnia symptoms and a variety of sociodemographic variables, life habits, and health-related factors.</p> <p>Methods</p> <p>A self-administered questionnaire with questions pertaining to general health and related issues was given to the participants. The Short Form-36 (Mental Health subscale), the Athens Insomnia Scale (AIS) as a measure of insomnia-related symptoms, and the International Physical Activity Questionnaire (IPAQ) were also used for the assessment.</p> <p>Results</p> <p>The prevalence of insomnia in the total sample was 25.3% (n = 254); insomnia was more frequent in women than men (30.7% vs. 19.5%) and increased with age. Multiple regression analysis revealed a significant association of insomnia with low socio-economical status and educational level, physical inactivity, existence of a chronic physical or mental disease and increased number of hospitalizations in the previous year.</p> <p>Conclusions</p> <p>The present study confirms most findings reported from other developed countries around the world regarding the high prevalence of insomnia problems in the general population and their association with several sociodemographic and health-related predisposing factors. These results further indicate the need for more active interventions on the part of physicians who should suspect and specifically ask about such symptoms.</p

Ontogeny-Driven rDNA Rearrangement, Methylation, and Transcription, and Paternal Influence

Gene rearrangement occurs during development in some cell types and this genome dynamics is modulated by intrinsic and extrinsic factors, including growth stimulants and nutrients. This raises a possibility that such structural change in the genome and its subsequent epigenetic modifications may also take place during mammalian ontogeny, a process undergoing finely orchestrated cell division and differentiation. We tested this hypothesis by comparing single nucleotide polymorphism-defined haplotype frequencies and DNA methylation of the rDNA multicopy gene between two mouse ontogenic stages and among three adult tissues of individual mice. Possible influences to the genetic and epigenetic dynamics by paternal exposures were also examined for Cr(III) and acid saline extrinsic factors. Variables derived from litters, individuals, and duplicate assays in large mouse populations were examined using linear mixed-effects model. We report here that active rDNA rearrangement, represented by changes of haplotype frequencies, arises during ontogenic progression from day 8 embryos to 6-week adult mice as well as in different tissue lineages and is modifiable by paternal exposures. The rDNA methylation levels were also altered in concordance with this ontogenic progression and were associated with rDNA haplotypes. Sperm showed highest level of methylation, followed by lungs and livers, and preferentially selected haplotypes that are positively associated with methylation. Livers, maintaining lower levels of rDNA methylation compared with lungs, expressed more rRNA transcript. In vitro transcription demonstrated haplotype-dependent rRNA expression. Thus, the genome is also dynamic during mammalian ontogeny and its rearrangement may trigger epigenetic changes and subsequent transcriptional controls, that are further influenced by paternal exposures

Beyond Continuity? Understanding Change in the UK Welfare State since 2010

One approach to identifying policy change stresses policy instruments, settings and policy paradigms, while another also considers the process and culmination of various shifts and consequent outcomes. This article illustrates the debate through an examination of how far developments in social security policy between the 1997–2010 New Labour and 2010–15 Coalition Governments in the UK constituted real policy shifts. It shows that, despite continuities in instruments and approach, there have been substantial changes in the impact of welfare state policies related to short-term benefits, employment and housing. The article identifies new policy directions leading to a different kind of welfare state, concerned less with living standards and equality and more with individual responsibility and paid work. It suggests that this has been achieved without the need for radical changes in instruments and their settings