991 resultados para Androgen Levels
Resumo:
The evaluation of satisfaction levels related to performance is an important aspect in increasing market share, improving profitability and enlarging opportunities for repeat business and can lead to the determination of areas to be improved, improving harmonious working relationships and conflict avoidance. In the construction industry, this can also result in improved project quality, enhanced reputation and increased competitiveness. Many conceptual models have been developed to measure satisfaction levels - typically to gauge client satisfaction, customer satisfaction and home buyer satisfaction - but limited empirical research has been carried out, especially in investigating the satisfaction of construction contractors. In addressing this, this paper provides a unique conceptual model or framework for contractor satisfaction based on attributes identified by interviews with practitioners in Malaysia. In addition to progressing research in this topic and being of potential benefit to Malaysian contractors, it is anticipated that the framework will also be useful for other parties - clients, designers, subcontractors and suppliers - in enhancing the quality of products and/or services generally.
Resumo:
The extent of poor project outcomes is a recurring issue for construction industries worldwide. One of the main causes of these and project failure seems to be the inability of contractors to provide a high level of service quality to the project team. In Malaysia, design failures have also been identified as a further contributory factor. To overcome this, different types of subjective performance measurement have been progressively developed. These approaches are typically concerned with client satisfaction, customer satisfaction, home buyer satisfaction and occupant satisfaction, but very seldom consider contractor satisfaction. This paper examines the implications of this, and what is involved in developing satisfaction measures based on contractor perception instead of the typical sole concern with client performance. As a result, other attributes such as participants’ performance, business performance, project performance, external factors and contractor characteristics are also examined. Several potential attributes are derived from interviews among Malaysian contractors, namely: performance (direct attributes) and contractor characteristics (indirect attributes) that possibly influence contractor satisfaction levels. These attributes are then developed to improve the existing conceptual framework. The developed framework is expected to help the project team in performing projects more efficiently, maintaining service quality and improving relationships between participants. In addition, the findings of the paper should assist contractors enhance competitiveness, improve their image and create more job opportunities in the future.
Resumo:
Children with early and continuously treated phenylketonuria (ECT-PKU) remain at risk of developing executive function (EF) deficits. There is some evidence that a high phenylalanine to tyrosine ratio (phe:tyr) is more strongly associated with impaired EF development than high phenylalanine alone. This study examined EF in a sample of 11 adolescents against concurrent and historical levels of phenylalanine, phe:tyr, and tyrosine. Lifetime measures of phe:tyr were more strongly associated with EF than phenylalanine-only measures. Children with a lifetime phe:tyr less than 6 demonstrated normal EF, whereas children who had a lifetime phe:tyr above 6, on average, demonstrated clinically impaired EF.
Resumo:
Objective: To assess the effect of graded increases in exercised-induced energy expenditure (EE) on appetite, energy intake (EI), total daily EE and body weight in men living in their normal environment and consuming their usual diets. Design: Within-subject, repeated measures design. Six men (mean (s.d.) age 31.0 (5.0) y; weight 75.1 (15.96) kg; height 1.79 (0.10) m; body mass index (BMI) 23.3(2.4) kg/m2), were each studied three times during a 9 day protocol, corresponding to prescriptions of no exercise, (control) (Nex; 0 MJ/day), medium exercise level (Mex; ~1.6 MJ/day) and high exercise level (Hex; ~3.2 MJ/day). On days 1-2 subjects were given a medium fat (MF) maintenance diet (1.6 ´ resting metabolic rate (RMR)). Measurements: On days 3-9 subjects self-recorded dietary intake using a food diary and self-weighed intake. EE was assessed by continual heart rate monitoring, using the modified FLEX method. Subjects' HR (heart rate) was individually calibrated against submaximal VO2 during incremental exercise tests at the beginning and end of each 9 day study period. Respiratory exchange was measured by indirect calorimetry. Subjects completed hourly hunger ratings during waking hours to record subjective sensations of hunger and appetite. Body weight was measured daily. Results: EE amounted to 11.7, 12.9 and 16.8 MJ/day (F(2,10)=48.26; P<0.001 (s.e.d=0.55)) on the Nex, Mex and Hex treatments, respectively. The corresponding values for EI were 11.6, 11.8 and 11.8 MJ/day (F(2,10)=0.10; P=0.910 (s.e.d.=0.10)), respectively. There were no treatment effects on hunger, appetite or body weight, but there was evidence of weight loss on the Hex treatment. Conclusion: Increasing EE did not lead to compensation of EI over 7 days. However, total daily EE tended to decrease over time on the two exercise treatments. Lean men appear able to tolerate a considerable negative energy balance, induced by exercise, over 7 days without invoking compensatory increases in EI.
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In the age of globalisation dominated by mass communication, the flow of information contributes to a big extent to the worldviews of its "global citizens". From this point of view the mass media can be seen as one of the most salient sources of cross-cultural communication. This study investigates mass communication across cultures, focusing on South East Asia (Malaysia and Singapore), Australia and Germany. The centre of attention is the Western media coverage of South East Asia and vice versa. In this context a content analysis of newspapers of the three regions has been conducted. In addition, working practices and conditions of Western foreign correspondents in South East Asia have been examined. Apart from the investigation of inter-cultural media coverage, another focus of attention will be the examination of two levels of communication: The business level, concentrating on issues like e.g. the Asian business etiquette; and the private level, looking into the transition to a different culture from the perspective of Australian and German expatriates. Apart from investigating mass communication across cultures and to provide a written analysis of the findings, a series of radio documentaries in English and in German has been produced. They cover the following issues: Foreign correspondents in South East Asia, the expatriate-lifestyle of Australians and Germans in South East Asia, business etiquette in Asia, student exchange Germany-Asia, image and prejudices East-West and Tourism.
Resumo:
This study focused on a group of primary school teachers as they implemented a variety of intervention actions within their class programs aimed towards supporting the reduction of high levels of communication apprehension (CA) among students.Six teachers and nine students, located across three primary schools, four year levels,and six classes, participated in this study. For reasons of confidentiality the schools,principals, parents, teachers, teacher assistants, and students who were involved in this study were given fictitious names. The following research question was explored in this study: What intervention actions can primary school teachers implement within their class programs that support the reduction of high CA levels among students? Throughout this study the term CA referred to "an individual's level of fear or anxiety associated with either real or anticipated (oral) communication with another person or persons" (McCroskey, 1984, p. 13). The sources of CA were explained with reference to McCroskey's state-trait continuum. The distinctions between high and appropriate levels of CA were determined conceptually and empirically. The education system within which this study was conducted promoted the philosophy of inclusion and the practices of inclusive schooling. Teachers employed in this system were encouraged to create class programs inclusive of and successful for all students. Consequently the conceptual framework within which this study was conducted was based around the notion of inclusion. Action research and case study research were the methodologies used in the study. Case studies described teachers' action research as they responded to the challenge of executing intervention actions within their class programs directed towards supporting the reduction of high CA levels among students. Consequently the teachers and not the researcher were the central characters in each of the case studies. Three principal data collection instruments were used in this study: Personal Report of Communication Fear (PRCF) scale, semistructured interviews, and dialogue journals. The PRCF scale was the screening tool used to identify a pool of students eligible for the study. Data relevant to the students involved in the study were gathered during semistructured interviews and throughout the dialogue journaling process. Dialogue journaling provided the opportunity for regular contact between teachers and the researcher, a sequence to teacher and student intervention behaviours, and a permanent record of teacher and student growth and development. The majority of teachers involved in this study endeavoured to develop class programs inclusive of all students.These teachers acknowledged the importance of modifying aspects of their class programs in response to the diverse and often multiple needs of individual students with high levels of CA. Numerous conclusions were drawn regarding practical ways that the teachers in this study supported the reduction of high CA levels among students. What this study has shown is that teachers can incorporate intervention actions within their class programs aimed towards supporting students lower their high levels of CA. Whilst no teacher developed an identical approach to intervention, similarities and differences were evident among teachers regarding their selection, interpretation, and implementation of intervention actions. Actions that teachers enacted within their class programs emerged from numerous fields of research including CA, inclusion, social skills, behaviour teaching, co-operative learning, and quality schools. Each teacher's knowledge of and familiarity with these research fields influenced their preference for and commitment to particular intervention actions. Additional factors including each teacher's paradigm of inclusion and exclusion contributed towards their choice of intervention actions. Possible implications of these conclusions were noted with reference to teachers,school administrators, support personnel, system personnel, teacher educators, parents, and researchers.
Resumo:
Prostrate Cancer(PCa)is the most common cause of cancer death amongst Western males. PCa occurs in two distinct stages. In its early stage, growth and development is dependent primarily on male sex hormones (androgens) such as testosterone, although other growth factors have roles maintaining PCa cell survival in this stage. In the later stage of PCa development, growth and.maintenance is independent of androgen stimulation and growth factors including Insulin-like Growth Factor -1 (IGf.:·l) and Epidermal Growth Factor (EGF) are thought to have more crucial roles in cell survival and PCa progression. PCa, in its late stages, is highly aggressive and metastatic, that is, tumorigenic cells migrate from the primary site of the body (prostate) and travel via the systemic and lymphatic circulation, residing and colonising in the bone, lymph node, lung, and in more rare cases, the brain. Metastasis involves both cell migration and tissue degradation activities. The degradation of the extracellular matrix (ECM), the tissue surrounding the organ, is mediated in part by members of a family of 26 proteins called the Matrix Metalloproteases (MMPs), whilst ceil adhesion molecules, of which proteins known as Integrins are included, mediate ce11 migration. A family of proteins known as the ADAMs (A Disintegrin . And Metalloprotease domain) were a recently characterised family at the commencement of this study and now comprise 34 members. Because of their dual nature, possessing an active metaiioprotease domain, homologous to that of the MMPs, and an integrin-binding domain capable of regulating cell-cell and cell-ECM contacts, it was thought likely that members of the ADAMs family may have implications for the progression of aggressive cancers such as those ofthe prostate. This study focussed on two particular ADAMs -9 and -10. ADAM-9 has an active metalloprotease domain, which has been shown to degrade constituents of the ECM, including fibronectin, in vitro. It also has an integrin-binding capacity through association with key integrins involved in PCa progression, such as a6~1. ADAM-10 has no such integrin binding activities, but its bovine orthologue, MADM, is able to degrade coHagen type IV, a major component of basement membranes. It is likely human ADAM-10 has the same activity. It is also known to cleave Ll -a protein involved in cell anchorage activities - and collagen type XVII - which is a principal component of the hemidesmosomes of cellular tight junctions. The cleavage of these proteins enables the cell to be released from the surrounding environment and commence migratory activities, as required in metastasis. Previous studies in this laboratory showed the mRNA expression of the five ADAMs -9,- 10, -11, -15 and -17 in PCa cell lines, characteristic of androgen-dependent and androgen independent disease. These studies were furthered by the characterisation of AD AM-9, -10 and -17 mRNA regulation by Dihydrotestosterone (DHT) in the androgen-responsive cell line (LNCaP). ADAM-9 and -10 mRNA levels were elevated in response to DHT stimulation. Further to these observations, the expression of ADAM-9 and -10 was shown in primary prostate biopsies from patients with PCa. ADAM-1 0 was expressed in the cytoplasm and on the ceH membrane in epithelial and basal cells ofbenign prostate glands, but in high-grade PCa glands, ADAM-I 0 expression was localised to the nucleus and its expression levels appeared to be elevated when compared to low-grade PCa glands. These studies provided a strong background for the hypothesis that ADAM-9 and -10 have key roles in the development ofPCa and provided a basis for further studies.The aims of this study were to: 1) characterise the expression, localisation and levels, of ADAM-9 and -10 mRNA and protein in cell models representing characteristics of normal through androgen-dependent to androgen-independent PCa, as well as to expand the primary PCa biopsy data for ADAM-9 and ADAM-10 to encompass PCa bone metastases 2) establish an in vitro cell system, which could express elevated levels of ADAM-1 0 so that functional cell-based assays such as cell migration, invasion and attachment could be carried out, and 3) to extend the previous hormonal regulation data, to fully characterise the response of ADAM-9 and -10 mRNA and protein levels to DHT, IGF-1, DHT plus IGF-1 and EGF in the hormonal/growth factor responsive cell line LNCaP. For aim 1 (expression of ADAM-9 and -10 mRNA and protein), ADAM-9 and -10 mRNA were characterised by R T -PCR, while their protein products were analysed by Western blot. Both ADAM-9 and -10 mRNA and protein were expressed at readily detectable levels across progressively metastatic PCa cell lines model that represent characteristics of low-grade,. androgen-dependent (LNCaP and C4) to high-grade, androgen-independent (C4-2 and C4-2B) PCa. When the non-tumorigenic prostate cell line RWPE-1 was compared with the metastatic PCa cell line PC-3, differential expression patterns were seen by Western blot analysis. For ADAM-9, the active form was expressed at higher levels in RWPE-1, whilst subcellular fractionation showed that the active form of ADAM-9 was predominantly located in the cell nucleus. For ADAM-I 0, in both of the cell Jines, a nuclear specific isoform of the mature, catalytically active ADAM-I 0 was found. This isoforrn differed by -2 kDa in Mr (smaller) than the cytoplasmic specific isoform. Unprocessed ADAM-I 0 was readily detected in R WPE-1 cell lines but only occasionally detected in PC-3 cell lines. Immunocytochemistry using ADAM-9 and -10 specific antibodies confirmed nuclear, cytoplasmic and membrane expression of both ADAMs in these two cell lines. To examine the possibility of ADAM-9 and -10 being shed into the extracellular environment, membrane vesicles that are constitutively shed from the cell surface and contain membrane-associated proteins were collected from the media of the prostate cell lines RWPE-1, LNCaP and PC-3. ADAM-9 was readily detectable in RWPE- 1 and LNCaP cell membrane vesicles by Western blot analysis, but not in PC-3 cells, whilst the expression of ADAM-I 0 was detected in shed vesicles from each of these prostate cell lines. By Laser Capture Microdissection (LCM), secretory epithelial cells of primary prostate gland biopsies were isolated from benign and malignant glands. These secretory cells, by Western blot analysis, expressed similar Mr bands for ADAM-9 and -10 that were found in PCa cell lines in vitro, indicating that the nuclear specific isoforrn of ADAM-I 0 was present in PCa primary tumours and may represent the predominantly nuclear form of ADAM-I 0 expression, previously shown in high-grade PCa by immunohistochemistry (IHC). ADAM-9 and -10 were also examined by IHC in bone metastases taken from PCa patients at biopsy. Both ADAMs could be detected at levels similar to those shown for Prostate Specific Antigen (PSA) in these biopsies. Furthermore, both ADAM-9 and -10 were predominantly membrane- bound with occasional nuclear expression. For aim 2, to establish a cell system that over-expressed levels of ADAM-10, two fulllength ADAM-I 0 mammalian expression vectors were constructed; ADAM-I 0 was cloned into pcDNA3.1, which contains a CMV promoter, and into pMEP4, containing an inducible metallothionine promoter, whose activity is stimulated by the addition of CdC}z. The efficiency of these two constructs was tested by way of transient transfection in the PCa cell line PC-3, whilst the pcDNA3.1 construct was also tested in the RWPE-1 prostate cell line. Resultant Western blot analysis for all transient transfection assays showed that levels of ADAM-I 0 were not significantly elevated in any case, when compared to levels of the housekeeping gene ~-Tubulin, despite testing various levels of vector DNA, and, for pMEP4, the induction of the transfected cell system with different degrees of stimulation with CdCh to activate the metallothionine promoter post-transfection. Another study in this laboratory found similar results when the same full length ADAM-10 sequence was cloned into a Green Fluorescent Protein (GFP) expressing vector, as no fluorescence was observed by means of transient tran sfection in the same, and other, PCa cell lines. It was hypothesised that the Kozak sequence included in the full-length construct (human ADAMI 0 naturally occurring sequence) is not strong enough to initiate translation in an artificial system, in cells, which, as described in Aim 1, are already expressing readily detectable levels of endogenous ADAM-10. As a result, time constraints prevented any further progress with Aim 2 and functional studies including cell attachment, invasion and migration were unable to be explored. For Aim 3, to characterise the response of ADAM-9 and -10 mRNA and protein levels to DHT, IGF-1, DHT plus IGF-1 and EGF in LNCaP cells, the levels of ADAM-9 and -10 mRNA were not stimulated by DHT or IGF-I alone, despite our previous observations that initially characterised ADAM-9 and -10 mRNA as being responsive to DHT. However, IGF-1 in synergy with DHT did significantly elevate mRNA levels ofboth ADAMs. In the case of ADAM-9 and -10 protein, the same trends of stimulation as found at the rnRNA level were shown by Western blot analysis when ADAM-9 and -10 signal intensity was normalised with the housekeeping protein ~-Tubulin. For EGF treatment, both ADAM-9 and -10 mRNA and protein levels were significantly elevated, and further investigation vm found this to be the case for each of these ADAMs proteins in the nuclear fractions of LNCaP cells. These studies are the first to describe extensively, the expression and hormonal/growth factor regulation of two members of the ADAMs family ( -9 and -1 0) in PCa. These observations imply that the expression of ADAM-9 and -10 have varied roles in PCa whilst it develops from androgen-sensitive (early stage disease), through to an androgeninsensitive (late-stage), metastatic disease. Further studies are now required to investigate the several key areas of focus that this research has revealed, including: • Investigation of the cellular mechanisms that are involved in actively transporting the ADAMs to the cell's nuclear compartment and the ADAMs functional roles in the cell nucleus. • The construction of a full-length human ADAM-10 mammalian expression construct with the introduction of a new Kozak sequence, that elevates ADAM-I 0 expression in an in vitro cell system are required, so that functional assays such as cell invasion, migration and attachment may be carried out to fmd the functional consequences of ADAM expression on cellular behaviour. • The regulation studies also need to be extended by confirming the preliminary observations that the nuclear levels of ADAMs may also be elevated by hormones and growth factors such as DHT, IGF-1 and EGF, as well as the regulation of levels of plasma membrany vesicle associated ADAM expression. Given the data presented in this study, it is likely the ADAMs have differential roles throughout the development of PCa due to their differential cellular localisation and synergistic growth-factor regulation. These observations, along with those further studies outlined above, are necessary in identifying these specific components ofPCa metastasis to which the ADAMs may contribute.
Resumo:
Prostate cancer is an important male health issue. The strategies used to diagnose and treat prostate cancer underscore the cell and molecular interactions that promote disease progression. Prostate cancer is histologically defined by increasingly undifferentiated tumour cells and therapeutically targeted by androgen ablation. Even as the normal glandular architecture of the adult prostate is lost, prostate cancer cells remain dependent on the androgen receptor (AR) for growth and survival. This project focused on androgen-regulated gene expression, altered cellular differentiation, and the nexus between these two concepts. The AR controls prostate development, homeostasis and cancer progression by regulating the expression of downstream genes. Kallikrein-related serine peptidases are prominent transcriptional targets of AR in the adult prostate. Kallikrein 3 (KLK3), which is commonly referred to as prostate-specific antigen, is the current serum biomarker for prostate cancer. Other kallikreins are potential adjunct biomarkers. As secreted proteases, kallikreins act through enzyme cascades that may modulate the prostate cancer microenvironment. Both as a panel of biomarkers and cascade of proteases, the roles of kallikreins are interconnected. Yet the expression and regulation of different kallikreins in prostate cancer has not been compared. In this study, a spectrum of prostate cell lines was used to evaluate the expression profile of all 15 members of the kallikrein family. A cluster of genes was co-ordinately expressed in androgenresponsive cell lines. This group of kallikreins included KLK2, 3, 4 and 15, which are located adjacent to one another at the centromeric end of the kallikrein locus. KLK14 was also of interest, because it was ubiquitously expressed among the prostate cell lines. Immunohistochemistry showed that these 5 kallikreins are co-expressed in benign and malignant prostate tissue. The androgen-regulated expression of KLK2 and KLK3 is well-characterised, but has not been compared with other kallikreins. Therefore, KLK2, 3, 4, 14 and 15 expression were all measured in time course and dose response experiments with androgens, AR-antagonist treatments, hormone deprivation experiments and cells transfected with AR siRNA. Collectively, these experiments demonstrated that prostatic kallikreins are specifically and directly regulated by the AR. The data also revealed that kallikrein genes are differentially regulated by androgens; KLK2 and KLK3 were strongly up-regulated, KLK4 and KLK15 were modestly up-regulated, and KLK14 was repressed. Notably, KLK14 is located at the telomeric end of the kallikrein locus, far away from the centromeric cluster of kallikreins that are stimulated by androgens. These results show that the expression of KLK2, 3, 4, 14 and 15 is maintained in prostate cancer, but that these genes exhibit different responses to androgens. This makes the kallikrein locus an ideal model to investigate AR signalling. The increasingly dedifferentiated phenotype of aggressive prostate cancer cells is accompanied by the re-expression of signalling molecules that are usually expressed during embryogenesis and foetal tissue development. The Wnt pathway is one developmental cascade that is reactivated in prostate cancer. The canonical Wnt cascade regulates the intracellular levels of β-catenin, a potent transcriptional co-activator of T-cell factor (TCF) transcription factors. Notably, β-catenin can also bind to the AR and synergistically stimulate androgen-mediated gene expression. This is at the expense of typical Wnt/TCF target genes, because the AR:β-catenin and TCF:β-catenin interactions are mutually exclusive. The effect of β-catenin on kallikrein expression was examined to further investigate the role of β-catenin in prostate cancer. Stable knockdown of β-catenin in LNCaP prostate cancer cells attenuated the androgen-regulated expression of KLK2, 3, 4 and 15, but not KLK14. To test whether KLK14 is instead a TCF:β-catenin target gene, the endogenous levels of β-catenin were increased by inhibiting its degradation. Although KLK14 expression was up-regulated by these treatments, siRNA knockdown of β-catenin demonstrated that this effect was independent of β-catenin. These results show that β-catenin is required for maximal expression of KLK2, 3, 4 and 15, but not KLK14. Developmental cells and tumour cells express a similar repertoire of signalling molecules, which means that these different cell types are responsive to one another. Previous reports have shown that stem cells and foetal tissues can reprogram aggressive cancer cells to less aggressive phenotypes by restoring the balance to developmental signalling pathways that are highly dysregulated in cancer. To investigate this phenomenon in prostate cancer, DU145 and PC-3 prostate cancer cells were cultured on matrices pre-conditioned with human embryonic stem cells (hESCs). Soft agar assays showed that prostate cancer cells exposed to hESC conditioned matrices had reduced clonogenicity compared with cells harvested from control matrices. A recent study demonstrated that this effect was partially due to hESC-derived Lefty, an antagonist of Nodal. A member of the transforming growth factor β (TGFβ) superfamily, Nodal regulates embryogenesis and is re-expressed in cancer. The role of Nodal in prostate cancer has not previously been reported. Therefore, the expression and function of the Nodal signalling pathway in prostate cancer was investigated. Western blots confirmed that Nodal is expressed in DU145 and PC-3 cells. Immunohistochemistry revealed greater expression of Nodal in malignant versus benign glands. Notably, the Nodal inhibitor, Lefty, was not expressed at the mRNA level in any prostate cell lines tested. The Nodal signalling pathway is functionally active in prostate cancer cells. Recombinant Nodal treatments triggered downstream phosphorylation of Smad2 in DU145 and LNCaP cells, and stably-transfected Nodal increased the clonogencity of LNCaP cells. Nodal was also found to modulate AR signalling. Nodal reduced the activity of an androgen-regulated KLK3 promoter construct in luciferase assays and attenuated the endogenous expression of AR target genes including prostatic kallikreins. These results demonstrate that Nodal is a novel example of a developmental signalling molecule that is reexpressed in prostate cancer and may have a functional role in prostate cancer progression. In summary, this project clarifies the role of androgens and changing cellular differentiation in prostate cancer by characterising the expression and function of the downstream genes encoding kallikrein-related serine proteases and Nodal. Furthermore, this study emphasises the similarities between prostate cancer and early development, and the crosstalk between developmental signalling pathways and the AR axis. The outcomes of this project also affirm the utility of the kallikrein locus as a model system to monitor tumour progression and the phenotype of prostate cancer cells.