Issues in public information systems development: The impact of regionalised organisational structure

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel UniversityThis thesis highlights the critical impact the effects of regionalised organisational structure and external political pressures have on the development of public sector information systems. Through the extension of a socio-technical systems (STS) model which encompasses these effects, a tool is provided for their investigation and evaluation in past and present information system (IS) developments. The foundations for this model were derived through an in-depth study of a large scale, national public IS development. Despite a large volume of research into the development and implementation of information systems, a high incidence of failure of such projects is still observed. With information systems now commonly integrated into many facets of an organisation’s business processes the costs and consequences of such failures can be far reaching. Given the additional scope and scale of many national public sector projects such consequences can be profound. While public sector IS failure has been studied in the literature, its focus is observed to be primarily that of an examination of e-government systems, neglecting the back-end (non-public facing) support systems. The focus of such studies is predominantly on the public’s interface and interaction with these systems together with their adoption and acceptance by the public. This view is a valid contribution but it does not inform the literature on the full range of unique problems that can be encountered across a complete IS development lifecycle within the public sector. Seeking to investigate these matters further, a collaboration was formed with a UK public body to facilitate the examination of the issues affecting the development and implementation of a national IS project. Onsite observations, interviews and document sampling were used across the development cycle to gather information from the perspectives of the stakeholders involved. The analysis of the data collected from this exercise highlighted a number of factors that were observed to have a significant effect on the project’s ultimate failure. Examination of this analysis from an STS perspective allowed for the extension of an existing STS model. It was extended to encompass the significant adverse effects that an organisational regionalised structure and external political pressure placed on the development of public information systems

Deficits in plasma oestradiol measurement in studies and management of breast cancer

The determination of plasma oestradiol has numerous applications in epidemiology, reproductive medicine and breast cancer management. Commercially available analytical methods, which measure the hormone levels without prior purification, have been successfully developed for measuring oestradiol in premenopausal women. The application of these methodologies to the quantification of the very low levels of oestradiol in postmenopausal women is more problematic in terms of accuracy and interpretation. The importance of using appropriate methodology is discussed and illustrated with data demonstrating the disparity in the results obtained when low levels of oestradiol were quantified using direct and indirect methods

Corporate Culture and Empathy and Excitement Labor of Service Employees inService Company, Mainly at Tokyo Disneyland

東京ディズニーランド(ディズニーシーを含むパーク)の大成功(集客と驚異的リピート率)の要因は、①「夢と魔法の王国」にふさわしいアトラクション1、②接客従業員(主に、非正社員、キャラクターを含む)のホスピタリティ・サービスが、顧客に「素晴らしい思い出に残る感動経験」を与えていることである。望ましいサービス労働のあり方は「顧客・従業員インターラクティブの共感に基づく従業員の感動労働」であるという仮説をたて、その解明を研究目的とした。①先行研究の考察、②運営会社へのインタビュー、③現場でのキャストのサービス労働の実査と簡単な質問、④顧客へのヒストリカル・インタビュー・アンケート実施という研究方法によって、接客従業員の「共感・感動労働」を実証中である。共感・感動労働の視点で、東京ディズニーランドと日本マクドナルド、スターバックスコーヒーとを比較した

Abiraterone shows alternate activity in models of endocrine resistant and sensitive disease.

Background Resistance to endocrine therapy remains a major clinical problem in the treatment of oestrogen-receptor positive (ER+) breast cancer. Studies show androgen-receptor (AR) remains present in 80-90% of metastatic breast cancers providing support for blockade of AR-signalling. However, clinical studies with abiraterone, which blocks cytochrome P450 17A1 (CYP17A1) showed limited benefit.Methods In order to address this, we assessed the impact of abiraterone on cell-viability, cell-death, ER-mediated transactivation and recruitment to target promoters. together with ligand-binding assays in a panel of ER+ breast cancer cell lines that were either oestrogen-dependent, modelling endocrine-sensitive disease, or oestrogen-independent modelling relapse on an aromatase inhibitor. The latter, harboured wild-type (wt) or naturally occurring ESR1 mutations.Results Similar to oestrogen, abiraterone showed paradoxical impact on proliferation by stimulating cell growth or death, depending on whether the cells are hormone-dependent or have undergone prolonged oestrogen-deprivation, respectively. Abiraterone increased ER-turnover, induced ER-mediated transactivation and ER-degradation via the proteasome.Conclusions Our study confirms the oestrogenic activity of abiraterone and highlights its differential impact on cells dependent on oestrogen for their proliferation vs. those that are ligand-independent and harbour wt or mutant ESR1. These properties could impact the clinical efficacy of abiraterone in breast cancer

Menstrual cycle associated changes in hormone-related gene expression in oestrogen receptor positive breast cancer.

The major changes in hormone levels that occur through the menstrual cycle have been postulated to affect the expression of hormone-regulated and proliferation-associated genes (PAGs) in premenopausal ER+ breast cancer. Whilst previous studies have demonstrated differences in gene expression, here, we investigated if there are within patient changes in the expression of oestrogen- and progesterone-regulated genes (ERGs and PRGs) and PAGs in ER+ breast cancer during the menstrual cycle. Samples from 96 patients in two independent prospective studies of the effect of menstrual cycle on ER+ breast cancer were used. Plasma hormone measurements were used to assign tumours to one of three pre-defined menstrual cycle windows: W1 (days 27-35 and 1-6; low oestradiol and low progesterone), W2 (days 7-16; high oestradiol and low progesterone) and W3 (days 17-26; intermediate oestradiol and high progesterone). RNA expression of 50 genes, including 27 ERGs, 11 putative PRGs and seven PAGs was measured. The AvERG (geomean of PGR, GREB1, TFF1 and PDZK1) was used as a composite measure of ERG expression and showed significant changes between the three windows of the menstrual cycle increasing over 2.2-fold between W1 and W2 and decreasing between W2 and W3 and between W3 and W1. Proliferation gene expression also varied significantly, following the same pattern of changes as ERG expression, but the changes were of lower magnitude (1.4-fold increase between W1 and W2). Significant changes in the expression of eight individual ERGs, including GREB1, PGR and TFF1, and two PAGs were observed between W1 and either W2 or W3 with all genes showing higher levels in W2 or W3 (1.3-2.4-fold; FDR 0.016-0.05). The AvProg, a composite measure of PRG expression, increased significantly (1.5-fold) in W3 compared to W1 or W2 but no significant changes were observed for individual PRGs. In conclusion, we observed significant changes in ERG, PRG and PAG expression in ER+ breast tumours during the menstrual cycle that may affect the assessment and interpretation of prominent biomarkers (e.g. PgR) and commonly used multigene prognostic signatures in premenopausal ER+ breast cancer

Molecular changes in premenopausal oestrogen receptor-positive primary breast cancer in Vietnamese women after oophorectomy.

For premenopausal women with primary ER + breast cancer, oophorectomy (OvX) is an evidence-based cost-effective option and is standard treatment in many countries. However, there is virtually no data describing the effects of OvX on breast tumour biology. We therefore, characterised the endocrine and genome-wide transcriptional impact of OvX in 56 premenopausal women with ER + breast cancer for 2 weeks prior to mastectomy. Plasma estradiol concentrations decreased from 406 ± 41 to 20.7 ± 2.6 pmol/l (mean ± sem) 24 h after OvX, and to 8.1 ± 0.8 pmol/l 2 weeks later at mastectomy. Ki67 decreased in 33/36 (91.7%) tumours. The expression of 655 genes changed significantly (FDR < 1%) with an absolute mean fold-change (FC) ≥ 1.25 (257 up, 398 down). Archetypal oestrogen-regulated genes (TFF1, GREB1, PGR and PDZK1) showed large decreases in expression (FC = 0.20-0.69; p < 1e-6-1e-7). Proliferation-associated genes (e.g. TOP2A, AURKA and UBE2C) were also strongly downregulated (FC = 0.38-0.56; p < 1e-7) along with putative progesterone-regulated genes (e.g. FKBP4, MYB; FC = 0.64-0.68; p < 1e-4-1e-7). The gene expression changes did not differ according to HER2 status and correlated strongly with the changes reported previously after aromatase inhibitor (AI) treatment in postmenopausal women (rho = 0.55, p < 1e-04). However, after OvX the mean FC was significantly higher compared to AI (p < 1e-04). In conclusion, changes in tumoural gene expression after OvX were largely similar, but of a greater magnitude to those observed after AI in postmenopausal patients; however, OvX appeared to have a greater effect on progesterone-regulated genes than AI

Urinary extracellular vesicle protein profiling and endogenous lithium clearance support excessive renal sodium wasting and water reabsorption in thiazide induced hyponatremia

IntroductionThiazide diuretics are amongst the most widely used anti-hypertensive medicines worldwide. Thiazide-Induced Hyponatremia (TIH) is one of their most clinically significant adverse effects. A priori TIH must result from excessive saliuresis and/or water reabsorption. We hypothesised that pathways regulating the thiazide-sensitive NCC and the water channel AQP2 may be involved. Our aim was to assess whether patients with TIH show evidence of altered NCC and AQP2 expression in urinary extracellular vesicles (UEVs), and also whether abnormalities of renal sodium reabsorption were evident using Endogenous Lithium Clearance (ELC).MethodsBlood and urine samples were donated by patients admitted to hospital with acute symptomatic TIH, after recovery to normonatremia, and also from normonatremic controls on and off thiazides. UEVs were isolated and target proteins evaluated by Western blotting and by Nanoparticle Tracking Analysis (NTA). ELC was assessed by Inductively Coupled Plasma Mass Spectrometry.ResultsUEVs analysis by Western blotting showed that patients with acute TIH display reduced total NCC and increased phospho-NCC and AQP2 relative to appropriate control groups; smaller differences in NCC and AQP2 expression persisted after recovery from TIH. These findings were confirmed by NTA. Renal ELC was lower in acute TIH compared to controls and convalescent cases.ConclusionReduced NCC expression and increased AQP2 expression would be expected to result in saliuresis and water reabsorption in TIH patients. This study raises the possibility that UEV analysis may be of diagnostic utility in less clear cut cases of thiazide associated hyponatremia and may help identify those at risk of TIH before thiazide initiation

Relationship Between Plasma Estradiol Levels and Estrogen-Responsive Gene Expression in Estrogen Receptor–Positive Breast Cancer in Postmenopausal Women

To determine whether plasma estradiol (E2) levels are related to gene expression in estrogen receptor (ER)–positive breast cancers in postmenopausal women