Notch and NOXA-related pathways in melanoma cells

Notch receptor-mediated intracellular events represent an ancient cell signaling system, and alterations in Notch expression are associated with various malignancies in which Notch may function as an oncogene or less commonly as a tumor suppressor. Notch signaling regulates cell fate decisions in the epidermis, including influencing stem cell dynamics and growth/differentiation control of cells in skin. Because of increasing evidence that the Notch signaling network is deregulated in human malignancies, Notch receptors have become attractive targets for selective killing of malignant cells. Compared with proliferating normal human melanocytes, melanoma cell lines are characterized by markedly enhanced levels of activated Notch-1 receptor. By using a small molecule gamma-secretase inhibitor (GSI) consisting of a tripeptide aldehyde, N-benzyloxycarbonyl-Leu-Leu-Nle-CHO, which can block processing and activation of all four different Notch receptors, we identified a specific apoptotic vulnerability in melanoma cells. GSI triggers apoptosis in melanoma cells, but only G2/M growth arrest in melanocytes without subsequent cell death. Moreover, GSI treatment induced a pro-apoptotic BH3-only protein, NOXA, in melanoma cells but not in normal melanocytes. The use of GSI to induce NOXA induction overcomes the apoptotic resistance of melanoma cells, which commonly express numerous cell survival proteins such as Mcl-1, Bcl-2, and survivin. Taken together, these results highlight the concept of synthetic lethality in which exposure to GSI, in combination with melanoma cells overexpressing activated Notch receptors, has lethal consequences, producing selective killing of melanoma cells, while sparing normal melanocytes. By identifying signaling pathways that contribute to the transformation of melanoma cells (e.g. Notch signaling), and anti-cancer agents that achieve tumor selectivity (e.g., GSI-induced NOXA), this experimental approach provides a useful framework for future therapeutic strategies in cutaneous oncology.

Teaching tribology and maintenance-related subjects : a hands-on focus

In this paper different aspects of teaching tribology and maintenance-related subjects with a hands-on focus at Queensland University of Technology (QUT) are presented and discussed. As part of the study, a combination of data from core units, such as engineering design units, and elective units, was used, in addition to laboratory experiments, real-life projects, interactive software packages and industry visits. The mechanical engineering curriculum structure used at QUT, consisting of the main specialization (first major) and the second specialization (second major), is also discussed with specific emphasis on the teaching of tribology and maintenance-related subjects. To evaluate students' satisfaction with the novel teaching approaches used, tailored questionnaires were used as well as QUT's online learning experience survey (LEX). Statistical results of these sureveys are presented and discussed. In summary, these showed that students overwhelmingly support the hands-on and practical focus in teaching tribology and maintenance-related subjects and that the teaching approaches used shorten the learning curve and make students better prepared for integration in the workplace.

Associations between perception of wellness and health-related quality of life, comorbidities, modifiable lifestyle factors and demographics in older Australians

Aim: The associations between perceived wellness and health-related quality of life, comorbidities and modifiable lifestyle factors in older adults were explored. Methods: Self-administered questionnaires including the Perceived Wellness Survey and the 36-Item Short Form of the Medical Outcomes Study version two were distributed to 328 community-living adults aged 65 years and over. Results: Results showed positive associations between perception of wellness and health-related quality of life. General health (r(249) = 0.66, P < 0.01), vitality (r(249) = 0.59, P < 0.01) and mental health (r(249) = 0.52, P < 0.01) had the strongest association; and social functioning (r(249) = 0.3, P < 0.01) and pain (r(249) = 0.36, P < 0.01) the lowest. Perceived wellness was influenced by hearing, mobility, memory, chronic disease, exercise, gambling and single status. Conclusion: The study identified that perceived wellness in older adults is a multidimensional construct.

Dose response relationships between physical activity, walking and health-related quality of life in mid-age and older women

Background Although physical activity is associated with health-related quality of life (HRQL), the nature of the dose-response relationship remains unclear. This study examined the concurrent and prospective dose-response relationships between total physical activity (TPA) and (only) walking with HRQL in two age cohorts of women. Methods Participants were 10,698 women born in 1946-1951 and 7,646 born in 1921-1926, who completed three mailed surveys for the Australian Longitudinal Study on Women's Health. They reported weekly TPA minutes (sum of walking, moderate, and vigorous minutes). HRQL was measured with the Medical Outcomes Study Short-Form 36 Health Status Survey (SF-36). Linear mixed models, adjusted for socio-demographic and health-related variables, were used to examine associations between TPA level (none, very low, low, intermediate, sufficient, high, and very high) and SF-36 scores. For women who reported walking as their only physical activity, associations between walking and SF-36 scores were also examined. Results Curvilinear trends were observed between TPA and walking with SF-36 scores. Concurrently, HRQL scores increased significantly with increasing TPA and walking, in both cohorts, with increases less marked above sufficient activity levels. Prospectively, associations were attenuated although significant and meaningful improvements in physical functioning and vitality were observed across most TPA and walking categories above the low category. Conclusion For women in their 50s-80s without clinical depression, greater amounts of TPA are associated with better current and future HRQL, particularly physical functioning and vitality. Even if walking is their only activity, women, particularly those in their 70s-80s, have better health-related quality of life.

Measurement of ventilation and cardiac related impedance changes with electrical impedance tomography

Introduction Electrical impedance tomography (EIT) has been shown to be able to distinguish both ventilation and perfusion. With adequate filtering the regional distributions of both ventilation and perfusion and their relationships could be analysed. Several methods of separation have been suggested previously, including breath holding, electrocardiograph (ECG) gating and frequency filtering. Many of these methods require interventions inappropriate in a clinical setting. This study therefore aims to extend a previously reported frequency filtering technique to a spontaneously breathing cohort and assess the regional distributions of ventilation and perfusion and their relationship. Methods Ten healthy adults were measured during a breath hold and while spontaneously breathing in supine, prone, left and right lateral positions. EIT data were analysed with and without filtering at the respiratory and heart rate. Profiles of ventilation, perfusion and ventilation/perfusion related impedance change were generated and regions of ventilation and pulmonary perfusion were identified and compared. Results Analysis of the filtration technique demonstrated its ability to separate the ventilation and cardiac related impedance signals without negative impact. It was, therefore, deemed suitable for use in this spontaneously breathing cohort. Regional distributions of ventilation, perfusion and the combined ΔZV/ΔZQ were calculated along the gravity axis and anatomically in each position. Along the gravity axis, gravity dependence was seen only in the lateral positions in ventilation distribution, with the dependent lung being better ventilated regardless of position. This gravity dependence was not seen in perfusion. When looking anatomically, differences were only apparent in the lateral positions. The lateral position ventilation distributions showed a difference in the left lung, with the right lung maintaining a similar distribution in both lateral positions. This is likely caused by more pronounced anatomical changes in the left lung when changing positions. Conclusions The modified filtration technique was demonstrated to be effective in separating the ventilation and perfusion signals in spontaneously breathing subjects. Gravity dependence was seen only in ventilation distribution in the left lung in lateral positions, suggesting gravity based shifts in anatomical structures. Gravity dependence was not seen in any perfusion distributions.

Effects of speeding and headway related variable message signs on driver behaviour and attitudes

This research project examined objective measures of driver behaviour and road users' perceptions on the usefulness and effectiveness of three specific VMS (Variable Message Signs) interventions to improve speeding and headway behaviours. The interventions addressed speeding behaviour alone (intervention 1), headway behaviour alone (intervention 2) and a combination of speeding and headway behaviour (intervention 3). Six VMS were installed along a segment of the Bruce Highway, with a series of three signs for each of the northbound and southbound traffic. Speeds and headway distances were measured with loop detectors installed before and after each VMS. Messages addressing speeding and headway were devised for display on the VMS. A driver could receive a message if they were detected as exceeding the posted speed limit (of 90km/hr) or if the distance to the vehicle in front was less than 2.0s. In addition to the on-road objective measurement of speeding and headway behaviours, the research project elicited self-reported responses to the speeding and headway messages from a sample of drivers via a community-based survey. The survey sought to examine the drivers' beliefs about the effectiveness of the signs and messages, and their views about the role, use, and effectiveness of VMS more generally.

Patient expectations, outcomes and satisfaction : related, relevant or redundant?

Abstract Study design: A prospective investigation of patients undergoing lumbar spine surgery. Objective: Is there a correlation between patient’s expectations before lumbar surgery, postoperative outcomes and satisfaction levels? Methods: A prospective study of 145 patients undergoing primary, single-level surgery for degenerative lumbar conditions was conducted. Oswestry Disability Index (ODI), back visual analogue scale (VAS) and leg VAS were assessed pre-operatively and at 6 weeks and 6 months post-surgery. Patients’ expectations were measured pre-operatively by asking them to score the level of pain and disability that would be least acceptable for them to undergo surgery and be satisfied. Satisfaction was assessed six weeks post-operatively with a Likert scale. Differences in patient expectations between actual and expected improvements were quantified. Results: Most patients had a clinically relevant improvement, but only about half achieved their expectation. Satisfaction did not correlate with pre-operative pain or disability, or with patient expectation of improvement. Instead, satisfaction correlated with positive outcomes. Conclusions Patient expectations have little bearing on final outcome and satisfaction.

Impact of a novel nurse-led prechemotherapy education intervention (ChemoEd) on patient distress, symptom burden, and treatment-related information and support needs : results from a randomised, controlled trial

Background: High levels of distress and need for self-care information by patients commencing chemotherapy suggest that current prechemotherapy education is suboptimal. We conducted a randomised, controlled trial of a prechemotherapy education intervention (ChemoEd) to assess impact on patient distress, treatment-related concerns, and the prevalence and severity of and bother caused by six chemotherapy side-effects. Patients and methods: One hundred and ninety-two breast, gastrointestinal, and haematologic cancer patients were recruited before the trial closing prematurely (original target 352). ChemoEd patients received a DVD, question-prompt list, self-care information, an education consultation ≥24 h before first treatment (intervention 1), telephone follow-up 48 h after first treatment (intervention 2), and a face-to-face review immediately before second treatment (intervention 3). Patient outcomes were measured at baseline (T1: pre-education) and immediately preceding treatment cycles 1 (T2) and 3 (T3). Results: ChemoEd did not significantly reduce patient distress. However, a significant decrease in sensory/psychological (P = 0.027) and procedural (P = 0.03) concerns, as well as prevalence and severity of and bother due to vomiting (all P = 0.001), were observed at T3. In addition, subgroup analysis of patients with elevated distress at T1 indicated a significant decrease (P = 0.035) at T2 but not at T3 (P = 0.055) in ChemoEd patients. Conclusions: ChemoEd holds promise to improve patient treatment-related concerns and some physical/psychological outcomes; however, further research is required on more diverse patient populations to ensure generalisability.

The human tissue kallikrein and kallikrein-related peptidase family

The human kallikrein-related peptidases are a subgroup of trypsin and chymotrypsin-like serine peptidases that are characterized by their homology to tissue kallikrein or kallikrein 1 (KLK1) encoded by the KLK1 gene (reviewed in[1-4]). The human KLK locus spans an approximately 320 kb region on chromosome 19q13.3-13.4 and contains fifteen genes encoding KLK1 and fourteen other kallikrein-related peptidases, KLK2-KLK15, which have been named contiguously in the locus in the order of their discovery [5-8] (Figure 606.1). It is the largest contiguous cluster of serine protease encoding genes in the human genome which has evolved from gene duplication of KLK1 and then subsequent reduplication of the newly evolved KLK genes [2]. The high conservation noted for KLK1-KLK3 (62-77%) reflects the proposed duplication of the KLK1 gene that produced the KLK2 gene which further generated the KLK3 gene. In contrast, the newer KLK4-KLK15 proteases share much less similarity, from 24-66%, although strong homology between KLK4 and KLK5, KLK9 and KLK11, and KLK10 and KLK12 suggests these genes are duplications of each other [2]...

Making Arrangements : Remote proposal sequences and attendant structural phenomena in social interaction

In this thesis, I contribute to the study of how arrangements are made in social interaction. Using conversation analysis, I examine a corpus of 375 telephone calls between employees and clients of three Community Home Care (CHC) service agencies in metropolitan Adelaide, South Australia. My analysis of the CHC data corpus draws upon existing empirical findings within conversation analysis in order to generate novel findings about how people make arrangements with one another, and some of the attendant considerations that parties to such an activity can engage in: Prospective informings as remote proposals for a future arrangement – Focusing on how employees make arrangements with clients, I show how the employees in the CHC data corpus use ‘prospective informings’ to detail a future course of action that will involve the recipient of that informing. These informings routinely occasion a double-paired sequence, where informers pursue a response to their informing. This pursuit often occurs even after recipients have provided an initial response. This practice for making arrangements has been previously described by Houtkoop (1987) as ‘remote proposing.’ I develop Houtkoop’s analysis to show how an informing of a future arrangement can be recompleted, with response solicitation, as a proposal that is contingent upon a recipient’s acceptance. Participants’ understanding of references to non-present third parties – In the process of making arrangements, references are routinely made to non-present third parties. In the CHC data corpus, these third parties are usually care workers. Prior research (e.g., Sacks & Schegloff, 1979; Schegloff, 1996b) explains how the use of ‘recognitional references’ (such as the bare name ‘Kerry’), conveys to recipients that they should be able to locate the referent from amongst their acquaintances. Conversely, the use of ‘non-recognitional references’ (such as the description ‘a lady called Kerry’), conveys that recipients are unacquainted with the referent. I examine instances where the selection of a recognitional or non-recognitional reference form is followed by a recipient initiating repair on that reference. My analysis provides further evidence thatthe existing analytic account of these references corresponds to the way in which participants themselves make sense of them. My analysis also advances an understanding of how repair can be used, by recipients, to indicate the inappositeness of a prior turn. Post-possible-completion accounts – In a case study of a problematic interaction, I examine a misunderstanding that is not resolved within the repair space, the usual defence of intersubjectivity in interaction (cf. Schegloff, 1992b). Rather, I explore how the source of trouble is addressed, outside of the sequence of its production, with a ‘post-possible-completion account.’ This account specifies the basis of a misunderstanding and yet, unlike repair, does so without occasioning a revised response to a trouble-source turn. By considering various aspects of making arrangements in social interaction, I highlight some of the rich order that underpins the maintenance of human relationships across time. In the concluding section of this thesis I review this order, while also discussing practical implications of this analysis for CHC practice.