Anti-oestrogen therapy switches off tumour suppressors and proapoptotic genes in breast cancer and reveals a new therapeutic opportunity

Background Previous studies in the Tenovus Centre have demonstrated that the development of antioestrogen resistance in vitro is accompanied by unfavourable changes in the breast cancer phenotype leading to increase tumour cell growth rate. Here evidence is presented to suggest that this is in part due to antihormones causing the epigenetic silencing of oestrogen-induced genes involved in the negative regulation of cell growth. Importantly, we show that reversal of this process using the demethylation agent 5-azacytidine (5AZA) allows oestrogen-induced cell kill by a previously unrecognised mechanism. Methods The breast cancer cell lines used in this study were MCF7, MCF7-derived tamoxifen-resistant variant (TamR) and TamR sublines that had been withdrawn from tamoxifen (TamRwd) for up to 6 months. Cells were challenged by oestradiol (E2), antihormones and 5AZA. Cell growth responses were assessed by anchorage-dependent growth assays and alterations in expression/activity of oestrogen receptor (ER) and ER-regulated genes were analysed by real-time PCR, western blotting and/or immunocytochemistry. Results Compared with the parental MCF7 cells, TamR cells showed a significant upregulated basal rate of growth that was maintained on tamoxifen withdrawal for 6 months. Following the tamoxifen withdrawal, the cells remained ER-positive and showed a slight growth response to E2. In contrast, they showed no growth inhibitory response to tamoxifen. Examination of the methylation status of the promoters of two classically ER-regulated genes switched off in TamR and TamRwd cells, pS2 and progesterone receptor (PR), confirmed their increased methylation and that 5AZA was able to reverse this process, allowing the re-expression of pS2 and PR on E2 treatment. Although pS2 and PR are not thought to play a role in the regulation of cell growth, these data provide proof of principal that gene silencing occurs in TamR cells and that it can be reinstated by 5AZA plus E2. To determine whether tamoxifen was capable of inducing the methylation of ER-regulated genes involved in cell growth, TamRwd cells pretreated with 5AZA were subject to an E2 dose–response challenge. In contrast to TamRwd cells treated with E2, which promoted a growth response, E2 in combination with 5AZA was strongly inhibitory at physiological doses of the steroid (10-9 M), with this action being reversed by tamoxifen. An Affymetrix analysis of the TamR cells has revealed multiple E2-regulated genes that are switched off in the resistant cells whose ontology indicates tumour suppressor/proapoptotic functions. Conclusion Our data suggest that antihormone resistance may be associated with the epigenetic silencing of growth inhibitory genes leading to enhanced growth rates. We propose that reinstatement of the expression of such genes using demethylation agents in combination with E2 may provide a previously unrecognised therapeutic opportunity in breast cancer

Stick-Slip Motion and Phase Transition in a Block-Spring System

We study numerically stick slip motions in a model of blocks and springs being pulled slowly. The sliding friction is assumed to change dynamically with a state variable. The transition from steady sliding to stick-slip is subcritical in a single block and spring system. However, we find that the transition is continuous in a long chain of blocks and springs. The size distribution of stick-slip motions exhibits a power law at the critical point.Comment: 8 figure

Reading Videogames as (authorless) Literature

This article presents the outcomes of research, funded by the Arts and Humanities Research Council in England and informed by work in the fields of new literacy research, gaming studies and the socio-cultural framing of education, for which the videogame L.A. Noire (Rockstar Games, 2011) was studied within the orthodox framing of the English Literature curriculum at A Level (pre-University) and Undergraduate (degree level). There is a plethora of published research into the kinds of literacy practices evident in videogame play, virtual world engagement and related forms of digital reading and writing (Gee, 2003; Juul, 2005; Merchant, Gillen, Marsh and Davies, 2012; Apperley and Walsh, 2012; Bazalgette and Buckingham, 2012) as well as the implications of such for home / school learning (Dowdall, 2006; Jenkins, 2006; Potter, 2012) and for teachers’ own digital lives (Graham, 2012). Such studies have tended to focus on younger children and this research is also distinct from such work in the field in its exploration of the potential for certain kinds of videogame to be understood as 'digital transformations' of conventional ‘schooled’ literature. The outcomes of this project raise implications of such a conception for a further implementation of a ‘reframed’ literacy (Marsh, 2007) within the contemporary curriculum of a traditional and conservative ‘subject’. A mixed methods approach was adopted. Firstly, students contributing to a gamplay blog requiring them to discuss their in-game experience through the ‘language game’ of English Literature, culminating in answering a question constructed with the idioms of the subject’s set text ‘final examination’. Secondly, students taught their teachers to play L.A. Noire, with free choice over the context for this collaboration. Thirdly, participants returned to traditional roles in order to work through a set of study materials provided, designed to reproduce the conventions of the ‘study guide’ for literature education. Interviews were conducted after each phase and the outcomes informed a redrafting of the study materials which are now available online for teachers – this being the ‘practical’ outcome of the research (Berger and McDougall, 2012). In the act of inserting the study of L.A. Noire into the English Literature curriculum as currently framed, this research moves, through a practical ‘implementation’ beyond longstanding debates around narratology and ludology (Frasca, 2003; Juul, 2005) in the field of game studies (Leaning, 2012) through a direct connection to new literacy studies and raises epistemological questions about ‘subject identity’, informed by Bernstein (1996) and Bourdieu (1986) and the implications for digital transformations of texts for both ideas about cultural value in schooled literacy (Kendall and McDougall, 2011) and the politics of ‘expertise’ in pedagogic relations (Ranciere, 2009, Bennett, Kendall and McDougall, 2012a)

Benthic invertebrates in the headwaters of the Wye and Severn: effects of forestry and clear-felling

International audienceInvertebrate communities were recorded in three surveys between 1974 and 1994 of headwaters of the Wye and Severn at Plynlimon: the Afon Gwy (unforested), the Afon Hore (initially forested) and the Afon Hafren (forested throughout). The data cover periods before and after the clear-felling of a large area of coniferous forest in the catchment of the Hore. All three streams contained invertebrates characteristic of acidic, upland conditions and had similar species richness. Differences in assemblage composition within streams between surveys could be related to differences in method or timing of sampling. All assemblages were dominated by Insecta, particularly Plecoptera and Diptera, whereas Ephemeroptera, Moilusca, Crustacca and some families of Trichoptera (notably Hydropsychidae and Philopotamidae) were poorly represented. The forested streams (Hafren and Hore) contained similar assemblages which differed from those in the unforested stream (Gwy) in containing lower densities of Ephemeroptera and Oligochacta and much higher densities of nemourid and leuctrid Plecoptera. Clear-felling of the Hore catchment resulted in changes in physical and chemical conditions (including a reduction of stream pH, and increases in dissolved aluminium concentration and summer water temperature) but no related change in the invertebrate assemblage. The apparent failure of invertebrates to respond as expected to substantial changes in local environmental conditions may reflect either a lack of understanding of causal links between invertebrates and environmental factors, or the over-riding influence of the dynamics of recruitment to populations

Effect of oxidations on phosphorus-diffused crystalline-silicon substrates

Phosphorus diffusions are used in the fabrication process for nearly all crystalline-silicon (c-Si) photovoltaic solar cells to form the emitter of the solar cell. These phosphorous diffusions are also well known to have beneficial gettering benefits, i.e., deleterious metallic impurities are gettered from the bulk of the c-Si substrate into the phosphorous doped layer. In this study, we examined the effect of oxidations performed after the phosphorus diffusion. We were particularly interested in using the oxidation to passivate the surface of the phosphorus diffusion. Post-diffusion oxidations or moderate temperature steps in oxidizing ambients are also commonly found in commercial fabrication sequences of c-Si solar cells. we found that the bulk lifetime was degraded in Czochralski (Cz) silicon due to the post-diffusion oxidation unless there was a gettering agent present during the oxidation. Possible explanations for these results are presented at the end of the paper

“It’s like my life but more, and better!” - Playing with the Cathaby Shark Girls: MMORPGs, young people and fantasy-based social play

This article is available open access through the publisher’s website at the link below. Copyright @ 2011 A B Academic Publishers.Digital technology has opened up a range of new on-line leisure spaces for young people. Despite their popularity, on-line games and Massive Multiplayer Online Role Playing Games in particular are still a comparatively under-researched area in the fields of both Education and more broadly Youth Studies. Drawing on a Five year ethnographic study, this paper considers the ways that young people use the virtual spaces offered by MMORPGs. This paper suggests that MMORPGs represent significant arenas within which young people act out a range of social narratives through gaming. It argues that MMORPG have become important fantasy spaces which offer young people possibilities to engage in what were formally material practices. Although this form of play is grounded in the everyday it also extends material practices and offers new and unique forms of symbolic experimentation, thus I argue that game-play narratives cannot be divorced from the everyday lives of their participants

WDR19 : An ancient, retrograde, intraflagellar ciliary protein is mutated in autosomal recessive retinitis pigmentosa and in Senior‐Loken syndrome

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99013/1/cge12196.pd

Parental cultural models and resources for understanding mathematical achievement in culturally diverse school settings

This paper proposes that the theoretical concept of cultural models can offer useful insights into parental involvement in their child’s mathematical achievement and the resources they use to go about gaining information in culturally diverse learning settings. This examination takes place within a cultural-developmental framework and draws on the notion of cultural models to explicate parental understandings of their child’s mathematics achievement and what resources are used to make sense of this. Three parental resources are scrutinized: (a) the teacher, (b) examination test results, and (c) constructions of child development. The interviews with 22 parents revealed some ambiguity around the interpretation of these resources by the parent, which was often the result of incongruent cultural models held between the home and the school. The resources mentioned are often perceived as being unambiguous but show themselves instead to be highly interpretive because of the diversity of cultural models in existence in culturally diverse settings. Parents who are in minority or marginalized positions tend to have difficulties in interpreting cultural models held by school, thereby disempowering them to be parentally involved in the way the school would like

Beyond deficit-based models of learners' cognition: Interpreting engineering students' difficulties with sense-making in terms of fine-grained epistemological and conceptual dynamics

Researchers have argued against deficit-based explanations of students' troubles with mathematical sense-making, pointing instead to factors such as epistemology: students' beliefs about knowledge and learning can hinder them from activating and integrating productive knowledge they have. In this case study of an engineering major solving problems (about content from his introductory physics course) during a clinical interview, we show that "Jim" has all the mathematical and conceptual knowledge he would need to solve a hydrostatic pressure problem that we posed to him. But he reaches and sticks with an incorrect answer that violates common sense. We argue that his lack of mathematical sense-making-specifically, translating and reconciling between mathematical and everyday/common-sense reasoning-stems in part from his epistemological views, i.e., his views about the nature of knowledge and learning. He regards mathematical equations as much more trustworthy than everyday reasoning, and he does not view mathematical equations as expressing meaning that tractably connects to common sense. For these reasons, he does not view reconciling between common sense and mathematical formalism as either necessary or plausible to accomplish. We, however, avoid a potential "deficit trap"-substituting an epistemological deficit for a concepts/skills deficit-by incorporating multiple, context-dependent epistemological stances into Jim's cognitive dynamics. We argue that Jim's epistemological stance contains productive seeds that instructors could build upon to support Jim's mathematical sense-making: He does see common-sense as connected to formalism (though not always tractably so) and in some circumstances this connection is both salient and valued.Comment: Submitted to the Journal of Engineering Educatio

LESSONS FROM THE MOTORIZED MIGRATIONS

Ten experiments have been conducted to determine if cranes can be led on migration and if those so trained will repeat migrations on their own. Results have been mixed as we have experienced the mishaps common to pilot studies. Nevertheless, we have learned many valuable lessons. Chief among these are that cranes can be led long distances behind motorized craft (air and ground), and those led over most or the entire route will return north come spring and south in fall to and from the general area of training. However, they will follow their own route. Groups transported south and flown at intervals along the route will migrate but often miss target termini. If certain protocol restrictions are followed, it is possible to make the trained cranes wild, however, the most practical way of so doing is to introduce them into a flock of wild cranes. We project that it is possible to create or restore wild migratory flocks of cranes by first leading small groups from chosen northern to southern termini