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Item Open Access Standard setting in Australian medical schools(BioMed Central, 2018) Ward, H.M.; Chiavaroli, N.; Fraser, J.; Mansfield, K.; Starmer, D.; Surmon, L.; Veysey, M.; O'Mara, D.Background: Standard setting of assessment is critical in quality assurance of medical programs. The aims of this study were to identify and compare the impact of methods used to establish the passing standard by the 13 medical schools who participated in the 2014 Australian Medical Schools Assessment Collaboration (AMSAC). Methods: A survey was conducted to identify the standard setting procedures used by participating schools. Schools standard setting data was collated for the 49 multiple choice items used for benchmarking by AMSAC in 2014. Analyses were conducted for nine schools by their method of standard setting and key characteristics of 28 panel members from four schools. Results: Substantial differences were identified between AMSAC schools that participated in the study, in both the standard setting methods and how particular techniques were implemented. The correlation between the item standard settings data by school ranged from − 0.116 to 0.632. A trend was identified for panel members to underestimate the difficulty level of hard items and overestimate the difficulty level of easy items for all methods. The median derived cut-score standard across schools was 55% for the 49 benchmarking questions. Although, no significant differences were found according to panel member standard setting experience or clinicians versus scientists, panel members with a high curriculum engagement generally had significantly lower expectations of borderline candidates (p = 0.044). Conclusion: This study used a robust assessment framework to demonstrate that several standard setting techniques are used by Australian medical schools, which in some cases use different techniques for different stages of their program. The implementation of the most common method, the Modified Angoff standard setting approach was found to vary markedly. The method of standard setting used had an impact on the distribution of expected minimally competent student performance by item and overall, with the passing standard varying by up to 10%. This difference can be attributed to the method of standard setting because the ASMSAC items have been shown over time to have consistent performance levels reflecting similar cohort ability. There is a need for more consistency in the method of standard setting used by medical schools in Australia.Item Metadata only Obesity related FTO gene polymorphism and the risk of adverse pregnancy outcomes(Elsevier, 2015) Andraweera, P.; Dekker, G.; Leemaqz, S.; McCowan, L.; Roberts, C.; Annual Conference of the International Federation of Placental Associations (IFPA) : Brisbane, Australia)Abstract not availableItem Metadata only Novel twists in hormone-mediated carcinogenesis(Bioscientifica, 2016) Tilley, W.D.Item Open Access Comprehensive assessment of estrogen receptor beta antibodies in cancer cell line models and tissue reveals critical limitations in reagent specificity(Elsevier, 2017) Nelson, A.; Groen, A.; Miller, J.; Warren, A.; Holmes, K.; Tarulli, G.; Tilley, W.; Katzenellenbogen, B.; Hawse, J.; Gnanapragasam, V.; Carroll, J.Abstract not availableItem Metadata only Renewed interest in the progesterone receptor in breast cancer(Nature Publishing Group, 2016) Lim, E.; Palmieri, C.; Tilley, W.D.Item Metadata only Androgen and estrogen receptors in breast cancer coregulate human UDP-glucuronosyltransferases 2B15 and 2B17(American Association for Cancer Research, 2016) Hu, D.; Selth, L.; Tarulli, G.; Meech, R.; Wijayakumara, D.; Chanawong, A.; Russell, R.; Caldas, C.; Robinson, J.; Carroll, J.; Tilley, W.; Mackenzie, P.; Hickey, T.Glucuronidation is an enzymatic process that terminally inactivates steroid hormones, including estrogens and androgens, thereby influencing carcinogenesis in hormone-dependent cancers. While estrogens drive breast carcinogenesis via the estrogen receptor alpha (ERα), androgens play a critical role as prohormones for estrogen biosynthesis and ligands for the androgen receptor (AR). In this study, the expression and regulation of two androgen-inactivating enzymes, the UDP-glucuronosyltransferases UGT2B15 and UGT2B17, was assessed in breast cancer. In large clinical cohorts, high UGT2B15 and UGT2B17 levels positively influenced disease-specific survival in distinct molecular subgroups. Expression of these genes was highest in cases positive for ERα. In cell line models, ERα, AR, and the transcription factor FOXA1 cooperated to increase transcription via tandem binding events at their proximal promoters. ERα activity was dependent on FOXA1, facilitated by AR activation, and potently stimulated by estradiol as well as estrogenic metabolites of 5α-dihydrotestosterone. AR activity was mediated via binding to an estrogen receptor half-site 3′ to the FOXA1 and ERα-binding sites. Although AR and FOXA1 bound the UGT promoters in AR-positive/ERα-negative breast cancer cell lines, androgen treatment did not influence basal transcription levels. Ex vivo culture of human breast tissue and ERα+ tumors provided evidence for upregulation of UGT2B15 and UGT2B17 by estrogen or androgen treatment. ERα binding was evident at the promoters of these genes in a small cohort of primary tumors and distant metastases. Collectively, these data provide insight into sex steroid receptor-mediated regulation of androgen-inactivating enzymes in ERα+ breast cancer, which may have subtype-specific consequences for disease progression and outcomes.Item Metadata only A ZEB1-miR-375-YAP1 pathway regulates epithelial plasticity in prostate cancer(Nature Publishing Group, 2017) Selth, L.; Das, R.; Townley, S.; Coutinho, I.; Hanson, A.; Centenera, M.; Stylianou, N.; Sweeney, K.; Soekmadji, C.; Jovanovic, L.; Nelson, C.; Zoubeidi, A.; Butler, L.; Goodall, G.; Hollier, B.; Gregory, P.; Tilley, W.MicroRNA-375 (miR-375) is frequently elevated in prostate tumors and cell-free fractions of patient blood, but its role in genesis and progression of prostate cancer is poorly understood. In this study, we demonstrated that miR-375 is inversely correlated with epithelial–mesenchymal transition signatures (EMT) in clinical samples and can drive mesenchymal–epithelial transition (MET) in model systems. Indeed, miR-375 potently inhibited invasion and migration of multiple prostate cancer lines. The transcription factor YAP1 was found to be a direct target of miR-375 in prostate cancer. Knockdown of YAP1 phenocopied miR-375 overexpression, and overexpression of YAP1 rescued anti-invasive effects mediated by miR-375. Furthermore, transcription of the miR-375 gene was shown to be directly repressed by the EMT transcription factor, ZEB1. Analysis of multiple patient cohorts provided evidence for this ZEB1-miR-375-YAP1 regulatory circuit in clinical samples. Despite its anti-invasive and anti-EMT capacities, plasma miR-375 was found to be correlated with circulating tumor cells in men with metastatic disease. Collectively, this study provides new insight into the function of miR-375 in prostate cancer, and more broadly identifies a novel pathway controlling epithelial plasticity and tumor cell invasion in this disease.Item Open Access Genomic agonism and phenotypic antagonism between estrogen and progesterone receptors in breast cancer(American Association for the Advancement of Science, 2016) Singhal, H.; Greene, M.; Tarulli, G.; Zarnke, A.; Bourgo, R.; Laine, M.; Chang, Y.-F.; Ma, S.; Dembo, A.; Raj, G.; Hickey, T.; Tilley, W.; Greene, G.The functional role of progesterone receptor (PR) and its impact on estrogen signaling in breast cancer remain controversial. In primary ER+ (estrogen receptor–positive)/PR+ human tumors, we report that PR reprograms estrogen signaling as a genomic agonist and a phenotypic antagonist. In isolation, estrogen and progestin act as genomic agonists by regulating the expression of common target genes in similar directions, but at different levels. Similarly, in isolation, progestin is also a weak phenotypic agonist of estrogen action. However, in the presence of both hormones, progestin behaves as a phenotypic estrogen antagonist. PR remodels nucleosomes to noncompetitively redirect ER genomic binding to distal enhancers enriched for BRCA1 binding motifs and sites that link PR and ER/PR complexes. When both hormones are present, progestin modulates estrogen action, such that responsive transcriptomes, cellular processes, and ER/PR recruitment to genomic sites correlate with those observed with PR alone, but not ER alone. Despite this overall correlation, the transcriptome patterns modulated by dual treatment are sufficiently different from individual treatments, such that antagonism of oncogenic processes is both predicted and observed. Combination therapies using the selective PR modulator/antagonist (SPRM) CDB4124 in combination with tamoxifen elicited 70% cytotoxic tumor regression of T47D tumor xenografts, whereas individual therapies inhibited tumor growth without net regression. Our findings demonstrate that PR redirects ER chromatin binding to antagonize estrogen signaling and that SPRMs can potentiate responses to antiestrogens, suggesting that cotargeting of ER and PR in ER+/PR+ breast cancers should be explored.Item Metadata only Brain responses to mechanical rectal stimuli in patients with faecal incontinence: an fMRI study(Wiley, 2017) Mirbagheri, N.; Hatton, S.; Ng, K.; Lagopoulos, J.; GLADMAN, M.AIM: Continence is dependent on anorectal/brain interactions. Consequently, aberrations of the brain-gut axis may be important in the pathophysiology of faecal incontinence (FI) in certain patients. The aim of this study was to assess the feasibility of recording brain responses to rectal mechanical stimuli in patients with FI using functional Magnetic Resonance Imaging (fMRI). METHOD: A prospective, cohort pilot study was performed to assess brain responses during rectal stimulation in 14 patients (4 male, mean [SD] age 62 [15] years). Blood oxygen level-dependent (BOLD) signals were measured by fMRI during rest and mechanical distension, involving random repetitions of isobaric phasic rectal distensions at fixed (15 & 45 mmHg) and variable (10% above sensory perception threshold) pressures. RESULTS: Increases in BOLD signals in response to high-pressure rectal distension (45mmHg) and maximum toleration were observed in the cingulate gyrus, thalamus, insular cortex, inferior frontal gyrus, cerebellum, caudate nucleus, supramarginal gyrus, putamen and amygdala. Additionally, activation of the supplementary motor cortex and caudate nucleus with inconsistent activity in the frontal lobe was observed. CONCLUSIONS: This study has demonstrated the feasibility of recording brain responses to rectal mechanical stimulation using fMRI in patients with FI, revealing activity in widespread areas of the brain involved in visceral sensory processing. The observed activity in the supplementary motor cortex and caudate nucleus, with relative paucity of activity in the frontal lobes, warrants investigation in future studies to determine whether aberrations in cerebral processing of rectal stimuli play a role in the pathogenesis of FI. This article is protected by copyright. All rights reserved.Item Open Access Educating for interprofessional practice: moving from knowing to being, is it the final piece of the puzzle?(BioMed Central, 2017) Ward, H.; Gum, L.; Attrill, S.; Bramwell, D.; Lindemann, I.; Lawn, S.; Sweet, L.Background: Professional socialisation and identity arise from interactions occurring within university-based interprofessional education, and workplace-based interprofessional practice experience. However, it is unclear how closely language and concepts of academic learning situations align with workplace contexts for interprofessional learning. This paper reports on a study that brought together university-based educators responsible for teaching health professional students and health service-based practitioners who supervise students in the field. Methods: Interviews and focus groups with university-based educators and health service-base practitioners were used to explore perceptions of capabilities required for interprofessional practice. The qualitative data were then examined to explore similarities and differences in the language used by these groups. Results: This analysis identified that there were language differences between the university-based educators and health service based practitioners involved in the project. The former demonstrated a curriculum lens, focusing on educational activities, student support and supervision. Conversely, health service-based practitioners presented a client-centred lens, with a focus on communication, professional disposition, attitude towards clients and co-workers, and authenticity of practice. Conclusions: Building on these insights, we theorise about the need for students to develop the self in order to be an interprofessional practitioner. The implications for health professional education in both university and workplace settings are explored.Item Metadata only Multivariate visual clustering of single nucleotide polymorphisms and clinical predictors using Chernoff faces(University of Wollongong, 2012) Lee, S.; Lee, S.; Dekker, G.; Roberts, C.; Annual Applied Statistics Education and Research Collaboration (5th : 2012 : Wollongong, New South Wales)With advanced technology, collection of health-related data in undertaken on a large scale, producing large and high-dimensional data. Visualization of such data is important and useful for further statistical analyses such as classification and clustering. However, visualizing large multivariate datasets is challenging, especially for high dimensional data, as they are often complex and confounded. Currently, visualization for Single Nucleotide Polymorphisms (SNPs) and clinical predictors of disease are assessed separately. As there is increasing evidence of genetic-environmental interactions for pregnancy complications, prediction models based solely on either clinical measurements or genetic risk factors may be inadequate. Hence, we present an example of multivariate visualization on combinations of clinical measurements and SNPs through Chernoff faces, and perform visual clustering for prediction of Preterm births (PTB). A random sample containing 100 patients (Uncomplicated pregnancy = 92, PTB=8) with 11 clinical and 4 genetic predictors are visualized into faces with various style of eyes, ears, nose and hair, showing two groups with similar face characteristics amongst Uncomplicated pregnancies and Preterm births. The faces identified as PTB appear to have either a tall hair style or no ears, which correspond to whether the mother was herself born preterm, and SNPs in TGFβ and IL1β genes.Item Metadata only Mapping of chromosomal loci associated with lipopolysaccharide synthesis and serotype specificity in Vibrio cholerae 01 by transposon mutagenesis using Tn5 and Tn2680(Springer Verlag, 1989) Ward, H.; Manning, P.Vibrio cholerae strains of the 01 serotype have been classified into three subclasses, Ogawa, Inaba and Hikojima, which are associated with the O-antigen of the lipopolysaccharide (LPS). The DNA encoding the biosynthesis of the O-antigen, the rfb locus, has been cloned and analysed (Manning et al. 1986; Ward et al. 1987). Transposon mutagenesis of the Inaba and Ogawa strains of V. cholerae, using Tn5 or Tn2680 allowed the isolation of a series of independent mutants in each of these serotypes. Some of the insertions were mapped to the rfb region by Southern hybridization using the cloned rfb DNA as a probe, confirming this location to be responsible for both O-antigen production and serotype specificity. The other insertions allowed a second region to be identified which is involved in V. cholerae LPS biosynthesis.Item Metadata only A physical map of the chromosomal region determining O-antigen biosynthesis in Vibrio cholerae 01(Elsevier, 1987) Ward, H.; Morelli, G.; Kamke, M.; Morona, R.; Yeadon, J.; Hackett, J.; Manning, P.We have previously described the cosmid cloning of the genes determining the biosynthesis of the Inaba and Ogawa O-antigens of the lipopolysaccharides of Vibrio cholerae 01 (Manning et al., 1986). By Southern hybridization analysis of chromosomal and cosmid DNA, and heteroduplex analysis between the clones we have been able to precisely define the region of contiguous chromosomal DNA in the vicinity of the O-antigen-encoding region. These data and comparison of end points of clones and of deletion derivatives demonstrate that at least 16kb of a 19-kb SstI fragment is required to encode O-antigen biosynthesis. Expression of O-antigen is independent of the orientation of this SstI fragment with respect to cloning vectors suggesting that its regulatory region has been cloned intact. No detectable differences were observed in the restriction patterns of the Inaba and Ogawa coding regions implying that only minor changes are involved when serotype conversion (Inaba to Ogawa or vice versa) occurs. Bhaskaran [Ind. J. Med. Res. 47 (1959) 253-260] originally defined this region associated with O-antigen biosynthesis oag; however, to be consistent with other organisms [Hitchcock et al., J. Bacteriol. 166 (1986) 699-705], it is suggested this be changed to rfb.Item Open Access A shuttle vector which facilitates the expression of transfected genes in Trypanosoma cruzi and Leishmania(Oxford University Press, 1992) Kelly, J.; Ward, H.; Miles, M.; Kendall, G.A Trypanosoma cruzi expression vector has been constructed using sequences derived from the flanking regions of the glyceraldehyde 3-phosphate dehydrogenase (gGAPDH) genes. The neomycln phosphotransferase (neor) gene was incorporated as a selectable marker. Using electroporatlon we have introduced this vector into both T.cruzl and Leishmania cells and conferred G418 resistance. Transformation is mediated by large extrachromosomal circular elements composed of head-to-tail tandem repeats of the vector. The transformed phenotype is stable for at least 6 months in the absence of G418 and can be maintained during passage through the T.cruzl ifecycle. Foreign genes Inserted into an expression site within the vector (pTEX) can be expressed at high levels In transformed cells. To our knowledge this paper describes the first trypanosome shuttle vector and the first vector which functions in both trypanosomes and Leishmania.Item Metadata only Improved animal production by genetic engineering of ruminal bacteria(AusBiotech, 1992) Brooker, J.; Thomson, A.; Ward, H.Ruminant production is a major focus of Australian agriculture. The ability of ruminant animals such as sheep and cattle to make productive use of low quality plant materials depends on the activity and efficiency of the anaerobic microbial population that resides in the rumen. Factors that affect ruminant production include the ability of cellulolytic microorganisms to digest plant structural polysaccharides (primarily cellulose and hemicellulose), the capacity of microorganisms to metabolise and detoxify otherwise inhibitory plant products and the efficiency of nitrogen utilisation by ruminal organisms. This review will consider some current Australian research programs aimed at improving ruminant production efficiency by genetic engineering of ruminal bacteria.Item Metadata only Low adoption of pharmacogenetic testing: an exploration and explanation of the reasons in Australia(Future Medicine, 2007) Corkindale, D.; Ward, H.; McKinnon, R.The research reported here sought to identify and illuminate the reasons for the low adoption of pharmacogenetic tests in Australia. The research initially established possible reasons and propositions drawn from previous studies and surveys on the problem in Europe and the literature on the adoption of innovations. A small-scale exploratory, qualitative study was undertaken in one state in Australia; clinicians and other stake-holders were interviewed about their use of or support for pharmacogenetic tests. The expected, quite extensive individual factors known to influence adoption and rejection of innovations were found to be present in the situations covered. The reasons for nonadoption that were found in previous surveys were also supported. Some other, possibly critical, reasons were also identified. The implications from this initial exploration are discussed and the prospects for the increased use of the tests proposed.Item Metadata only Developing an interprofessional capability framework for teaching health care students in a primary health care setting(Informa, 2013) Gum, L.; Lloyd, A.; Lawn, S.; Richards, J.; Lindemann, I.; Sweet, L.; Ward, H.; King, A.; Bramwell, D.This article is based on a partnership between a primary health service and a university whose shared goal was to prepare students and graduates for interprofessional practice (IPP). This collaborative process led to the development of consensus on an interprofessional capability framework. An action research methodology was adopted to study the development and progress of the partnership between university and health service providers. The initial aim was to understand their perceptions of IPP. Following this, the findings and draft capabilities were presented back to the groups. Finalisation of the capabilities took place with shared discussion and debate on how to implement them in the primary care setting. Several ideas and strategies were generated as to how to prepare effective interprofessional learning experiences for students in both environments (university and primary health care setting). Extensive stakeholder consultation from healthcare providers and educators has produced a framework, which incorporates the shared views and understandings, and can therefore be widely used in both settings. Development of a framework of capabilities for IPP, through a collaborative process, is a useful strategy for achieving agreement. Such a framework can guide curriculum for use in university and health service settings to assist incorporation of interprofessional capabilities into students’ learning and practice.Item Metadata only M protein of the group A streptococcus binds to the seventh short consensus repeat of human complement factor H(American Society for Microbiology, 1998) Blackmore, T.; Fischetti, V.; Sadlon, T.; Ward, H.; Gordon, D.Streptococcus pyogenes evades complement by binding the complement-regulatory protein factor H (fH) via the central conserved C-repeat region of M protein. However, the corresponding binding region within fH has not previously been precisely localized. fH is composed of 20 conserved modules called short consensus repeats (SCRs), each of which contains approximately 60 amino acids. A series of fH truncated and deletion mutants were prepared, and their interaction with M6 protein was examined. The M protein binding site was initially localized to SCRs 6 to 15 as demonstrated by ligand dot blotting, chemical cross-linking, and enzyme-linked immunosorbent assay. SCR 7 was then shown to contain the M protein binding site, as a construct consisting of the first seven SCRs bound M protein but a construct containing the first six SCRs did not bind. In addition, deletion of SCR 7 from full-length fH abolished binding to M protein. SCR 7 is known to contain a heparin binding domain, and binding of fH to M6 protein was almost totally inhibited in the presence of 400 U of heparin per ml. These results localize the M6 protein binding site of fH to SCR 7 and indicate that it is in close proximity to the heparin binding site.Item Metadata only Identification of a second heparin binding domain in human complement factor H(OXFORD UNIV PRESS, 1998) Blackmore, T.; Hellwage, J.; Sadlon, T.; Higgs, N.; Zipfel, P.; Ward, H.; Gordon, D.Complement factor H (fH) regulates activation of the alternative pathway of C, reducing the amount of C3b deposited on sialic acid-rich surfaces. Heparin binding has been used as a model for examining the sialic acid- binding characteristics of fH. We have previously shown thai of the 20 short consensus repeat (SCR) modules of fH, SCR 7 contains an important heparin binding site, but other SCRs also play a role in heparin binding. To localize the other sites, we prepared recombinant truncated and SCR deletion mutants of fH and tested them by heparin-agarose affinity chromatography. The 5 C- terminal SCRs were found to contain a heparin binding site as an SCR 7 deletion mutant of the N terminal 15 SCRs did not bind heparin, but a construct consisting of SCRs 16-20 was shown to bind heparin. Double deletion of SCRs 7 and 20 fH abrogated binding to heparin, indicating that SCR 20 contains a heparin binding site. This finding was confirmed with the observation that attachment of SCR 20 to a group of nonbinding SCRs produced a heparin-binding protein. A protein consisting of SCRs 19 and 20 did not bind heparin, whereas SCRs 18-20 did, indicating that, although SCR 20 contains a heparin binding site, at least two nonspecific adjacent SCRs are required. fH-related protein-3 (FHR-3) possesses an SCR homologous to SCR 7 of fH and bound heparin, whereas FHR-4, which lacks such an SCR, did not. Thus, fH contains two separate heparin binding sites which are located in SCRs 7 and 20.Item Metadata only Cloning and analysis of the human complement factor H gene promoter(Nature Publishing Group, 1997) Ward, H.; Higgs, N.; Blackmore, T.; Sadlon, T.The 5' flanking region of human factor H was cloned using nested polymerase chain reaction (PCR) and the promoter finder method. A total of 1.2 kb has been sequenced and a number of putative regulatory elements identified including glucocorticoid response elements, cAMP responsive element, HTF-1, and acute phase signal sequences. A 717 b.p. fragment was cloned into a CAT reporter vector and transfected into HeLa cells. A series of truncations from the 5' end of this fragment were also cloned into the CAT vector. Analysis of CAT activity of the cell lysates showed that the region from -699 to +18 is likely to contain promoter elements for the factor H gene as it was able to drive transcription of the CAT gene.