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Search Results: 1 - 10 of 222112 matches for " Helen C Hurst "
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Update on HER-2 as a target for cancer therapy: The ERBB2 promoter and its exploitation for cancer treatment
Helen C Hurst
Breast Cancer Research , 2001, DOI: 10.1186/bcr329
Abstract: Over-expression of ERBB2 (HER-2/neu) is an adverse prognostic factor in human breast cancer, and may predict resistance to both chemotherapy and endocrine therapy (for review [1]). This over-expression was originally attributed solely to amplification of the ERBB2 gene (usually 2- to 10-fold), which frequently occurs both in tumours and in derived cell lines. It became clear, however, that over-expression can also be observed from a single copy gene [2]. Moreover, in all of the cell lines examined that exhibit gene amplification, an elevation in ERBB2 mRNA levels per gene copy was also observed [2]. This indicated that over-expression of the gene precedes and increases the likelihood of gene amplification, suggesting that further research into the transcriptional regulation of ERBB2 would be informative.Consequently, a number of groups have used nuclear run-on assays to measure gene transcription rates, and these have shown an increase in transcription rate sufficient to account for the degree of over-expression in a number of breast tumour derived cell lines that over-express ERBB2 (for review [3]). Subsequent studies therefore sought to identify the gene sequences that are required to mediate this increase in transcription rate. This was largely done by examining the activity of reporter constructs that contain the major transcription initiation site plus various extents of the ERBB2 5'-flanking sequence, and hence comparing promoter activity in breast tumour lines with low and high levels of expression. The results of those experiments are summarized here, and attempts either to target promoter function or to exploit the differential activity of the ERBB2 promoter for use in genetic therapies are reviewed.The human ERBB2 proximal promoter contains typical TATA and CCAAT boxes, at -22 to -26 bp and -71 to -75 bp, respectively (Fig. 1); it should be noted that the TATA box is not conserved in the rodent neu gene, making it difficult to compare studies across specie
Alternative TFAP2A isoforms have distinct activities in breast cancer
Chiara Berlato, KaYi V Chan, Anna M Price, Monica Canosa, Angelo G Scibetta, Helen C Hurst
Breast Cancer Research , 2011, DOI: 10.1186/bcr2838
Abstract: Expression levels of four TFAP2A isoforms were assayed at the level of RNA and protein (via the generation of isoform-specific antibodies) in a panel of breast tumour cell lines and in tissue from normal breast and primary tumour samples. Expression constructs for each isoform were used in reporter assays with synthetic and natural promoters (cyclin D3 and ERBB2) to compare the activation and repression activity of the isoforms.We demonstrate that the two isoforms AP-2α 1b and AP-2α 1c, in addition to the originally cloned, AP-2α 1a, are conserved throughout evolution in vertebrates. Moreover, we show that isoform 1c in particular is expressed at levels at least on a par with the 1a isoform in breast epithelial lines and tissues and may be more highly expressed in tamoxifen resistant tumours. The isoforms share a similar transactivation mechanism involving the recruitment of the adaptors CITED2 or 4 and the transactivators p300 or CBP. However, isoform 1b and 1c are stronger transactivators of the ERBB2 promoter than isoform 1a. In contrast, AP-2α 1a is the only isoform able to act as a repressor, an activity that requires an intact sumoylation motif present within the N-terminus of the protein, and which the other two isoforms lack.Our findings suggest that TFAP2A isoforms may be differentially regulated during breast tumourigenesis and this, coupled with differences in their transcriptional activity, may impact on tumour responses to tamoxifen therapy. These data also have implications for the interpretation of tumour studies that seek to correlate outcomes with TFAP2A expression level.AP-2α belongs to the AP-2 family of transcription factors with four other members, AP-2β, γ, δ and ε [1], which have all been implicated in the regulation of proliferation and differentiation in specific tissues. In particular, AP-2α is expressed in the developing and adult mammary gland [2,3]. In breast cancer, lower AP-2α expression levels are found in invasive cancer compared to
Functional Analysis of a Breast Cancer-Associated FGFR2 Single Nucleotide Polymorphism Using Zinc Finger Mediated Genome Editing
Luisa J. Robbez-Masson, Csaba B?d?r, J. Louise Jones, Helen C. Hurst, Jude Fitzgibbon, Ian R. Hart, Richard P. Grose
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0078839
Abstract: Genome wide association studies have identified single nucleotide polymorphisms (SNP) within fibroblast growth factor receptor 2 (FGFR2) as one of the highest ranking risk alleles in terms of development of breast cancer. The potential effect of these SNPs, in intron two, was postulated to be due to the differential binding of cis-regulatory elements, such as transcription factors, since all the SNPs in linkage disequilibrium were located in a regulatory DNA region. A Runx2 binding site was reported to be functional only in the minor, disease associated allele of rs2981578, resulting in increased expression of FGFR2 in cancers from patients homozygous for that allele. Moreover, the increased risk conferred by the minor FGFR2 allele associates most strongly in oestrogen receptor alpha positive (ERα) breast tumours, suggesting a potential interaction between ERα and FGFR signalling. Here, we have developed a human cell line model system to study the effect of the putative functional SNP, rs2981578, on cell behaviour. MCF7 cells, an ERα positive breast cancer cell line homozygous for the wild-type allele were edited using a Zinc Finger Nuclease approach. Unexpectedly, the acquisition of a single risk allele in MCF7 clones failed to affect proliferation or cell cycle progression. Binding of Runx2 to the risk allele was not observed. However FOXA1 binding, an important ERα partner, appeared decreased at the rs2981578 locus in the risk allele cells. Differences in allele specific expression (ASE) of FGFR2 were not observed in a panel of 72 ERα positive breast cancer samples. Thus, the apparent increased risk of developing ERα positive breast cancer seems not to be caused by rs2981578 alone. Rather, the observed increased risk of developing breast cancer might be the result of a coordinated effect of multiple SNPs forming a risk haplotype in the second intron of FGFR2.
Constrained Dynamics for Quantum Mechanics I. Restricting a Particle to a Surface
Hendrik Grundling,C. A. Hurst
Mathematics , 1997, DOI: 10.1063/1.532241
Abstract: We analyze constrained quantum systems where the dynamics do not preserve the constraints. This is done in particular for the restriction of a quantum particle in Euclidean n-space to a curved submanifold, and we propose a method of constraining and dynamics adjustment which produces the right Hamiltonian on the submanifold when tested on known examples. This method we hope will become the germ of a full Dirac algorithm for quantum constraints. We take a first step in generalising it to the situation where the constraint is a general selfadjoint operator with some additional structures.
Prognostic factors for short-term improvement in acute and persistent musculoskeletal pain consulters in primary care
Jennifer E Bolton, Hugh C Hurst
Chiropractic & Manual Therapies , 2011, DOI: 10.1186/2045-709x-19-27
Abstract: Consecutive patients with a new episode of musculoskeletal pain completed self-report questionnaires at baseline, and then again at the 4/5th treatment visit, and if they were still consulting, at the 10th visit. The outcome was defined as patient self-report improvement sufficient to make a meaningful difference. Independent predictors of outcome were identified using multivariate regression analyses.Acute (<7 weeks) patients, on average, had more severe conditions in terms of pain, disability, anxiety and work fear-avoidance behaviour than patients with persistent (≥7 weeks) pain, but were more likely to be better by the 4/5th visit. Several variables at baseline were associated with improvement at the 4/5th visit, but the predictive models were weak and unable to discriminate between patients who were improved and those who were not. In contrast, it was possible to elicit a predictive model for improvement later on at the 10th visit, but only in patients with persistent pain. Being employed, reporting a decline in work fear-avoidance behaviour at the 4/5th visit, and being better by the 4/5th visit, were all independently associated with improvement. This model accounted for 34.3% (p < 0.001) of the variation in observed improvement, and had good discriminative ability (the area under receiver operating characteristic (ROC) curve was 0.80 (95%CI 0.73 to 0.86)) and approximate balance in correctly identifying improved and non-improved cases (79.0% and 68% respectively).We were unable to identify baseline characteristics that predicted early outcome in musculoskeletal pain patients. However, early self-reported improvement and decline in work fear-avoidance behaviour as predictors of later improvement highlighted the importance of speedy recovery in persistent musculoskeletal pain consulters. Our findings reinforce the elusive nature of baseline predictors, and the need for more emphasis on early changes as prognostic predictors in musculoskeletal conditions.Muscul
Support for multiple classes of local expression clusters in Drosophila melanogaster, but no evidence for gene order conservation
Claudia C Weber, Laurence D Hurst
Genome Biology , 2011, DOI: 10.1186/gb-2011-12-3-r23
Abstract: We show that D. melanogaster has at least three classes of expression clusters: first, as observed in mammals, large clusters of functionally unrelated housekeeping genes; second, small clusters of functionally related highly co-expressed genes; and finally, as previously defined by Spellman and Rubin, larger domains of co-expressed but functionally unrelated genes. The latter are, however, not independent of the small co-expression clusters and likely reflect a methodological artifact. While the small co-expression and housekeeping/essential gene clusters resemble those observed in yeast, in contrast to yeast, we see no evidence that any of the three cluster types are preserved as synteny blocks. If anything, adjacent co-expressed genes are more likely to become rearranged than expected. Again in contrast to yeast, in D. melanogaster, gene pairs with short intergene distance or in divergent orientations tend to have higher rearrangement rates. These findings are consistent with co-expression being partly due to shared chromatin environment.We conclude that, while similar in terms of cluster types, gene order evolution has strikingly different patterns in yeasts and in D. melanogaster, although recombination is associated with gene order rearrangement in both.In all well studied eukaryotic genomes gene order is known not to be random, with genes with similar expression profiles tending to cluster (see, for example, [1-4]). The model organisms used for work on gene order evolution are the yeasts, for which we have high-resolution gene order rearrangement data across a group of species, as well as excellent data on numerous additional parameters (for example, gene expression, and recombination rates) for one focal species, Saccharomyces cerevisiae. In S. cerevisiae we observe pairs or triplets of adjacent genes that are functionally related and very highly co-expressed [5-7]. Similarly, we find stretches of up to about 10 to 15 genes enriched for essential genes that
Losing the desire: selection can promote obligate asexuality
Kayla C King, Gregory DD Hurst
BMC Biology , 2010, DOI: 10.1186/1741-7007-8-101
Abstract: See research article http://www.biomedcentral.com/1471-2148/10/229 webciteAlthough sexual reproduction is costly, it is extremely widespread and is the dominant and ancestral mode of reproduction of eukaryotic organisms [1]. It is thus clear that sex must confer great benefits, and parthenogenesis (a type of asexual reproduction) is disadvantageous [2]. Despite their low evolutionary potential, parthenogenetic lineages do 'spin off' from sexual ancestors in a broad range of animals [3]. Several vertebrate and invertebrate species are composed of both sexual and asexual lineages. Stouthamer et al. [4] have now published a model of how obligate asexuality could evolve in parasitoid wasps with the help of a symbiont.There are several evolutionary routes to parthenogenesis in animals [3] (Box 1). One of the more remarkable recent experiments on the origin of asexuality demonstrated that certain haplodiploid taxa could be 'cured' of asexuality when treated with antibiotics [5]. Haplodiploid taxa, which include many social insects such as termites and wasps, produce males from unfertilized eggs and females from fertilized eggs. This demonstration [5] was explained by the fact that parthenogenesis can arise from manipulation by endosymbionts.This system is now one in which the forces driving the establishment of asexual lineages are well known. Bacterial symbionts (such as Wolbachia, Cardinium and Rickettsia) can be transmitted only through the cytoplasm of eggs, from a female to her offspring. Males are essentially 'dead ends', and symbiont fitness is thus maximized by converting male progeny to female development. In arrhenotokous haplodiploid taxa (such as the parasitoid wasps studied by Stouthamer et al. [4,5]), this can be achieved by the parasite taking haploid unfertilized eggs that would develop into males and diploidizing their genome, such that they develop as females. At the start of this process, symbiont-infected females do mate with males, and fertilized eggs
Seeking a Balance: Helping Pre-Service Teachers Develop Positive Attitudes towards Mathematics as They Develop Competency  [PDF]
Chris Hurst, Audrey Cooke
Open Journal of Social Sciences (JSS) , 2014, DOI: 10.4236/jss.2014.24022
Abstract: Mathematical competence of teachers continues to be an issue of great interest to mathematics educators within tertiary institutions and it is often thought of simultaneously with the notion of mathematics anxiety. While there has been considerable recent research into the latter, no clear conclusions have been able to be drawn about many aspects of the phenomenon and how it is linked to mathematical competence. Most recently, international studies have highlighted notable differences in the standards of teacher preparation in different countries and in Australia new standards for accreditation of teacher education programs have been drafted. This paper reports on a part of on-going research into mathematics anxiety and competence of pre-service teachers. It uses two small samples of pre-service teachers from different cohorts of a Bachelor of Education course and attempts to identify factors that may help develop positive attitudes towards mathematics as they seek to develop their competency in mathematics. In addition, as a response to greater reported levels of anxiety regarding cognitive and knowledge traits, the paper identifies targeted professional learning and social constructivist teaching as key factors as well as the need to identify personal knowledge of mathematics as a prelude to seeking to become more competent.
A Groenewold-Van Hove Theorem for S^2
Mark J. Gotay,Hendrik Grundling,C. A. Hurst
Physics , 1995,
Abstract: We prove that there does not exist a nontrivial quantization of the Poisson algebra of the symplectic manifold S^2 which is irreducible on the subalgebra generated by the components {S_1,S_2,S_3} of the spin vector. We also show that there does not exist such a quantization of the Poisson subalgebra P consisting of polynomials in {S_1,S_2,S_3}. Furthermore, we show that the maximal Poisson subalgebra of P containing {1,S_1,S_2,S_3} that can be so quantized is just that generated by {1,S_1,S_2,S_3}.
Addressing the Issue of Chronic, Inappropriate Benzodiazepine Use: How Can Pharmacists Play a Role?
Helen C. Gallagher
Pharmacy , 2013, DOI: 10.3390/pharmacy1020065
Abstract: Prescribing guidelines do not recommend the long-term use of benzodiazepines since their effectiveness with chronic use is out-weighed by risks including dependence, memory and cognitive impairment, hip fractures and traffic accidents. Despite these guidelines, historical data points to an increasing proportion of inappropriate, repeat prescribing of benzodiazepines in Ireland and elsewhere, with up to 33% of patients who use these drugs doing so long-term. The typical long-term benzodiazepine user is an older, socio-economically disadvantaged patient who has been prescribed these medicines by their general practitioner (GP) and dispensed them by their community pharmacist. Misuse of benzodiazepines in nursing homes and psychiatric institutions is also of concern, with one Irish study indicating that almost half of all admissions to a psychiatric hospital were prescribed these drugs, usually despite a lack of clear clinical need. Discontinuation of benzodiazepines has proven to be of benefit, as it is followed by improvements in cognitive and psychomotor function, particularly in elderly patients. It is obvious that an inter-professional effort, focusing on the primary care setting, is required to address benzodiazepine misuse and to ensure appropriate pharmaceutical care. Pharmacists must be an integral part of this inter-professional effort, not least because they are uniquely positioned as the health professional with most frequent patient contact. There is already some supporting evidence that pharmacists’ involvement in interventions to reduce benzodiazepine use can have positive effects on patient outcomes. Here, this evidence is reviewed and the potential for pharmacists to play an expanded role in ensuring the appropriate use of benzodiazepines is discussed.
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