Amplification of the receptor tyrosine kinase ErbB-2 has been linked to the proliferation of breast cancer cells.1,2 Trastuzumab targets the extracellular domain of ErbB-2, leading to growth inhibition of approximately 15% of the breast cancers with genomic amplification of the ERBB2 gene.3 Clinical studies have demonstrated its efficacy in both early4 and metastatic breast cancers. 5,6 However, many tumors with ERBB2 amplification are not responsive to treatment.7 Moreover, the ones that initially respond, eventually progress and acquire drug resistance.8 An in vitro model for this acquired resistance was established by Chan & al.9 The breast cancer cell line, BT474, containing amplified ERBB2, was grown in the presence of trastuzumab for several months until subclones outgrew. Gene expression profiling was performed on these clones to determine differentially expressed genes between the parental and resistant cells. DARPP-32 (Dopamine and cAMP regulated phosphoprotein of 32kDa) was, by far, the most overexpressed transcript. DARPP-32 is coamplified with ERBB2 on the same amplicon of chromosome 17.10 This protein has been mostly described in neurobiology, but DARPP-32 overexpression was recently reported in gastrointestinal, esophageal, prostate and breast cancer.11 Therefore, we suggest that overexpression of DARPP-32 can cause acquired resistance of breast cancer cells to trastuzumab. The in vitro knockout of DARPP-32, using stable shRNA transfection, abolishes the resistance to trastuzumab in the clones, while overexpression of DARPP-32 in the parental cells results in de novo resistance. Overall, our results suggest that DARPP-32 may be a potential therapeutic target in breast cancer patients who develop acquired trastuzumab resistance.

While there has been research on development of multiplicative reasoning, and how to teach multiplication facts, there is little research on how children consider they learn these. This study explores the children's learning as they consider how they commit their multiplication facts to memory, discover calculation strategies and develop multiplicative thinking. A group of eleven Year 4 children (8 years old) participated in a series of 13 lessons where they became coresearchers in the exploration of their learning. A contextually based thematic approach was provided through 'Crocodilian Studies'. The mixed-method approach to this study included formal assessment, participant observation, individual interviews, the children's written ideas, and individual case studies. The most significant finding of this study was the powerful influence of peer learning. The children enriched and directed each other's learning as they shared ideas and reflected on their own mathematical learning as they observed and critiqued the thinking of peers. As the children were involved in thinking about how they learn they were able to identify gaps and construct their own learning pathways. A significant finding was that children can develop their multiplicative strategies while they commit their multiplication facts to memory, in a relatively short time provided that the learning process facilitates strategy development and understanding. By exposing the children to multiplication facts in sequenced clusters provided them with a manageable number of facts to be learnt at one time. Another finding related to how children develop calculation strategies through lesson activities rather than being explicitly taught them. The children considered practice important for memorisation. Parental support was significant in enriching the children's learning.

本研究旨在探討大學生目的感、學生學習投入與自我調整學習之間的差異與相關。首先，以性別、年級、就讀學校性質及學校區域等因素瞭解現今大學生的目的感現況，並探討不同目的感之大學生，其在學習投入與自我調整學習之間的差異情況，最後，分析目的感層面、學生學習投入與自我調整學習三者之間的關係。 研究對象為臺灣北、中、南、東四個地區449位大學生，研究工具包含「大學生目的感量表」、「學生學習投入量表」及「自我調整學習」三部分，並以描述性統計、單因子變異數分析(ANOVA)、多變量變異數分析(MANOVA)及路徑分析(Path analysis)等研究方法進行統計分析。 主要研究結果如下： 1. 臺灣大學生之目的感以「疏離者」居多，而「有目的感者」次之，「三分鐘熱度者」最少。 2. 大學生目的感中，具有「宗教信仰」、「常參與宗教信仰的活動」、「家庭管教態度為開明權威」或「常參加社團活動」的學生具有較強烈的目的感。 3. 在大學生的學習投入程度中，以「有目的感者」表現做好，「疏離者」表現最差。不同目的感取向的大學生，在學習投入方面也有所不同；在「學習投入」總量表、「合作共學」分量表及「反思與整合學習」分量表中，「三分鐘熱度者」及「空有夢想者」表現較「疏離者」好。另外，在「自我學習策略」分量表之中，也呈現「三分鐘熱度者」表現較「疏離者」佳。 4. 大學生之自我調整學習狀況，以「有目的感者」表現最好，「疏離者」表現最差。此外，不同目的感取向的大學生，在自我調整學習方面也有所不同。在「自我調整學習」總量表、「努力堅持策略」分量表及「環境建構策略」分量表中，「三分鐘熱度者」的表現較「疏離者」良好；而在「自我調整學習」總量表、「努力堅持策略」分量表、「表現目標導向策略」分量表及「時間管理策略」分量表中，「空有夢想者」的表現較「疏離者」良好。 5. 學校環境越支持程度越高者，其學生就越具有明確的目的感。而目的感越高的學生，也會更投入於學習之中。此外，學生參與同儕合作程度越高者，監控自我的學習歷程的意願也就越高。 最後，本研究將針對上述研究結果進行討論，並提出具體之建議，以做為目前實務工作及未來研究之參考。

This study used a correlational design to examine the contribution of university students’ task understanding and self-efficacy to performance on a grade-bearing course assignment. Participants were 38 undergraduate students enrolled in a first-year elective course. Task understanding for explicit, implicit, and contextual task features was measured using a forced-choice task analyzer quiz and an adapted version of the Epistemological Beliefs Questionnaire (Schommer, 1990). Self-efficacy for explicit, implicit, and contextual task features was assessed on a self-efficacy for performance scale. Final grade on a major course assignment was used as a measure of task performance. Results of hierarchical regression analysis indicated that task understanding significantly predicted task performance and task understanding moderated the influence of self-efficacy on task performance. Findings may help to bridge these disparate lines of research and provide support for Winne & Hadwin’s (1998) model of self-regulated learning. Practical implications for facilitating university students’ success in their academic tasks are discussed.

The purpose of this study was to investigate the role of achievement emotions in self-regulated learning (SRL). Participants included 111 university students enrolled in a first-year course designed to teach and improve SRL. Students reported their emotional experiences while working on self-set studying goals at three times during the semester. Measures included self-reported goal attainment, intensity ratings for nine emotions, and open-ended descriptions of emotion regulation strategies. Students reported enacting a variety of strategies to regulate their emotions, often in response to boredom and anxiety. Goal attainment positively correlated with positive emotions and negatively correlated with negative emotions other than boredom. Follow-up regressions revealed that positive emotions explained more unique variance than negative emotions in goal attainment. Over time, goal attainment and emotions did not change; however, correlations between times indicated that students were reporting situation-specific emotions. Contributions of this exploratory study to theory, research, and practice are discussed.

This is a study of several contentious issues in Canadian health policy involving the interaction of public and private payers and for-profit (FP) and not-for-profit (NFP) providers; the influence of health professionals on market structure; and the role of foreign investment. A case study was used, the Ontario physiotherapy market in 2003-2005, with its complex mix of payers and providers and foreign investment opportunities. Key market features were: fragmented but substantial payer influence, effective though uncoordinated cost control across payers, constrained labour supply, and fragmented patient referral sources. These features increased the complexity of providers’ interactions with patients and payers, reducing standardization and therefore favouring local, professional-owned small business FP providers (FP/s) for ambulatory care. NFP Hospitals’ market share declined. The findings generally confirmed expected behavioural differences between FP and NFP providers but expected differences between investor-owned FP providers (FP/c) and FP/s providers were not generally found. FP/s dominated the market, and FP/c providers appeared to mimic FP/s market behaviours, competing in local sub-markets. With no single or dominant payer, cost control difficulties were expected, but all 11 payer categories (public and private) used various cost control mechanisms, resulting in significant collective but uncoordinated influence. Generally, no payer alone supported a provider’s operations. The dominant labour suppliers, regulated physiotherapists, were scarce and exerted significant pressure, affecting market structure by asserting individual preferences and professional interests. FP/s dominance resulted, supported by the traditional patient referral source, physicians in small practices. Very little foreign investment was found despite little protection for domestic providers under NAFTA. In sum, this study showed FP and NFP provider stereotypes are subject to payer pressure: FP/c organizations can adapt by mimicking FP/s, and payers can modify NFPs’ assumed community orientation. Labour shortages and historical referral patterns can make individual professionals and their preferences more influential than their collective profession without diminishing the importance of professional interests. The degree and structure of payer control can make a market unattractive to foreign investors. Finally, this market – neither a planned or standard market – had a service provision pattern more broadly influenced by professionalism and practitioner interests than policies or prices.

This study investigated a number of important research questions that were prompted by the existing literature relating to the concept of responsibility for learning. Such literature has highlighted the importance of promoting personal responsibility for learning to not only students as individuals but also to the direction of education and pedagogy in general. The literature has also shown a broad concern over students’ apparent lack of responsibility as well as a lack of consensus over the precise meaning of this concept. The present study addresses gaps in the literature by exploring the following specific issues: firstly, What are students’ understandings of the concept of responsibility for learning?; secondly, How have students reported their own learning related attitudes and behaviours?; and thirdly, What are the associations between students’ understandings and their self-reports? It was also intended that data collected for the first two research questions would enable the investigation of year level and gender differences. With a methodology based on a written survey design, this study collected data from a sample of some 286 students from Australian schools in both the Primary and Secondary sectors (comprising Years 5, 7, 9 and 11). The process of data collection involved participants completing one open-ended question and two newly developed Likert-type response questionnaires that incorporated 40 individual descriptive items that were associated with six distinct subscales (i.e., Orientation Towards Schools and Learning; Active Participation in Learning Activities; Autonomy and Personal Control of Learning; Initiative; Management of Learning Resources; and Cooperation and Control of Classroom Behaviour). One scale (the SURLQ), along with the open-ended question, measured students’ understandings of Responsibility For Learning and the other scale (the SRLABQ) measured students’ perceptions of their own learning related attitudes and behaviours. The data pertaining to the first research question was analysed in two distinct ways. Firstly, students’ responses to the open-ended question were analysed qualitatively by sorting and tallying their original responses according to a determination of the themes and descriptors offered. Secondly, the responses to the SURLQ were analysed quantitatively by calculating the mean and standard deviation scores for all 40 descriptive items and hence the six subscales. Similar quantitative statistical analysis procedures were applied to the data pertaining to students’ self-reported learning attitudes and behaviours (i.e., the SRLABQ). Reliability coefficients for the SURLQ and the SRLABQ were also calculated. Descriptive data for the subscales of these two measures were cross-tabulated by year level and gender to determine whether statistically significant differences were evident. Cohen’s Effect Size calculations were applied to such differences. Statistically significant interactions between these independent variables were determined by Multivariate analysis of variance techniques. The third research question was investigated by applying correlation analysis to the mean scores of corresponding subscales and by calculating the differences between the same sets of mean scores. With respect to the first research question, it was found that according to both sets of data, students’ understandings of responsibility for learning generally supported a primarily behavioural perspective that emphasised a high degree of application to learning and relating sociably with others in the classroom. Although the SURLQ data also showed a greater acknowledgement of attitudinal components, it was noted that according to data from the two questionnaires, students did not readily associate responsible learners with being autonomous and having personal control of learning (as does the literature). With respect to the second research question, it was found that students reported themselves to be reasonably responsible learners as evidenced by the moderately high scores collected in all of the six responsibility for learning subscales. This finding led to the conclusion that the concerns expressed in the literature over students’ lack of responsibility in the classroom are not perceived by the students themselves. As the data pertaining to the third research question showed a reasonable correlation between students’ understandings of responsibility for learning and their self-reported learning attitudes and behaviours, it was concluded that students were likely to view themselves as responsible learners in a way that reflects their understandings of the concept. It was concluded that this research has important implications for all stakeholders in education. Although this study makes a major contribution to defining and describing responsibility for learning, it is evident that a lack of consensus in understanding between key stakeholders groups (i.e., researchers, educators and students) still exists. The divergence of outlook between students and various elements of the literature reinforces the need for further research to be conducted to determine the relative acceptance of behavioural compliance (and/or prudence) in the classroom versus personal control and accountability with respect to learning. It is also argued that such work would be integral to educators having a clear and unambiguous understanding of responsibility for learning so that the enhancement of this quality in students may take place in classrooms of the future.

Central infusion of the hexapeptide angiotensin IV (Ang IV) and its analogs have been demonstrated to markedly enhance memory retention and retrieval in rats using a range of learning and memory paradigms. This effect is mediated by the binding of the peptide to the specific binding site previously described as the AT4 receptor. The AT4 receptor has been isolated and identified as insulin-regulated aminopeptidase (IRAP), a type II transmembrane protein belonging to the M1 family of zinc-dependent aminopeptidases. Subsequently, AT4 receptor ligands, including Ang IV and its analogues and the unrelated peptide LVV-hemorphin-7, were demonstrated to be peptide inhibitors of IRAP. These findings suggest that AT4 ligands may exert their cognitive effects by inhibiting the catalytic activity of IRAP in the brain. Therefore, IRAP is an important target for the development of a new class of therapeutic agents for the treatment of memory loss. / To characterize IRAP at the molecular level and identify non-peptide inhibitors of IRAP for drug development, the aims of this study were to: 1) determine whether IRAP exists as a homodimer; 2) identify cysteine residue(s) involved in IRAP dimerization; 3) investigate the roles of the conserved residues of the HEXXH(X)18E Zn2+-binding motif and the GAMEN motif in substrate/inhibitor binding using site-directed mutagenesis; 4) use a molecular model of the catalytic domain of IRAP based on the crystal structure of a related M1 family metallopeptidase to: (i) identify key residues required for substrate/inhibitor binding; (ii) identify and characterize non-peptide IRAP inhibitors from a compound database by in silico virtual screening based on the homology model of IRAP. / Co-immunoprecipitation followed by Western blotting of IRAP under reducing and non-reducing conditions showed IRAP exists both as covalently- and non-covalently-bound homodimers. Serine scanning of cysteine residues potentially involved in forming inter-molecule disulfide-bonds was performed. Mutational analyses indicated that covalent homodimerization of IRAP is due to more than one cysteine residue. Limited trypsin digestion followed by co-immunoprecipitation suggests that non-covalent homodimerization of IRAP involves residues/regions within the last 130 amino acids of the protein. / The catalytic site of IRAP contains two consensus motifs, the H464EXXH468(X)18E487 Zn2+-binding motif and the G428AMEN432 motif. The role of conserved residues with these motifs was investigated using site-directed mutagenesis and pharmacological analyses. The conserved His and Glu residues of the Zn2+-binding motif were shown to be essential for IRAP catalytic activity. This was also observed for the Met and Glu residues of the GAMEN motif, while Asn mutant retained some catalytic activity. Residues important for substrate or inhibitor binding were identified as Gly, Ala and Asn. / A molecular model of the catalytic domain of IRAP based on the crystal structure of a homologous M1 metallopeptidase, leukotriene A4 hydrolase (LTA4H) was used to compare the catalytic sites of IRAP and LTA4H, and identified two amino acids at the putative substrate-binding pocket: Ala427 and Leu483 in IRAP, and the corresponding residues Tyr267 and Phe314 in LTA4H. A mutational analysis involving substitution of Ala427 and Leu483 with the corresponding residues revealed Ala427 and Leu483 characterize the enzyme S1 subsite, influencing the affinity and placement of substrates and peptide inhibitors in the catalytic site. / The molecular model of IRAP was also used for virtual screening of compound databases to identify novel non-peptide inhibitors. After two rounds of in silico screening, a family of compounds was identified and shown to be specific and competitive inhibitors of IRAP. Preliminary results suggest that one of these inhibitors, referred to as HFI 142, may possess memory-enhancing properties. The identification of non-peptide IRAP inhibitors will assist in pharmacological studies aimed at understanding the molecular mechanisms of IRAP aminopeptidase activity and physiological role of IRAP. In addition, the new inhibitors have the potential to form the basis for the development of a novel class of drugs useful for treating memory disorders.

The host immune response to parasitic helminths is usually characterized by a Th2 phenotype. As the Jagged/Notch pathway has been implicated in driving Th2 development, it was hypothesized that host macrophages and dendritic cells (DCs) could detect helminth products and mount an appropriate response via this pathway. Schistosoma mansoni soluble egg antigen (SEA) rapidly up-regulated expression of the Notch ligand, Jagged 1, in both mouse and human macrophages, as well as in conventional mouse DCs. Other factors associated with Th cell development, including the Th1-promoting factor IL-12 p40, as well as another potential Th2-promoting factor, interleukin (IL)-33, were not transcriptionally responsive to SEA in these same cell types, thus indicating the selectivity of the response. Inducible gene expression was modified by the presence of the macrophage growth factor colony-stimulating factor (CSF)-1, which inhibited Jagged 1 induction by SEA and lipopolysaccharide (LPS), but enhanced LPS-induced IL-12p40 expression. Despite the observation that SEA upregulated Jagged 1 in both macrophages and DCs, only SEA-pulsed DCs promoted IL-4 production upon T-cell activation, suggesting that Jagged 1 induction alone is insufficient for instructing Th2 development. A recombinant form of the extracellular region of Jagged 1 did, however, enhance IFN-γ production in splenocytes, thus implying that the rapid induction of Jagged 1 in macrophages and DCs can regulate T cell responses. A potential role for SEA-induced Jagged 1 in autocrine responses in macrophages was also investigated through studies with recombinant extracellular Jagged 1, as well as ectopic expression of Jagged 1 in macrophages. A comparison of the responses initiated in macrophages by SEA and the bacterial endotoxin lipopolysaccharide (LPS) revealed common activation of extracellular signal regulated kinase-1/2 (ERK-1/2) and p38 phosphorylation. However, only LPS triggered IκB degradation, phosphorylation of c-Jun N-terminal kinase (JNK) and phosphorylation of Tyr701 of signal transducer and activator of transcription 1 (STAT1). SEA robustly activated signalling in HEK293 cells expressing either Toll-like receptor 2 (TLR2) or TLR4/MD2, as well as variably in cells expressing TLR3. Jagged 1 upregulation by SEA was not abrogated in TLR4 knockout macrophages, in contrast to the LPS response. Pharmacological inhibition of the ERK-1/2 pathway impaired both SEA- and LPS-inducible Jagged 1 expression in macrophages. In conclusion, the data within this thesis suggests that Jagged 1 is an ERK-dependent target of TLR signalling that has a macrophage-specific function in the response to SEA.

Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (leaves 95-113).