Cellular model systems to study the tumor biological role of kallikrein-related peptidases in ovarian and prostate cancer

Since the identification of the gene family of kallikrein related peptidases (KLKs), their function has been robustly studied at the biochemical level. In vitro biochemical studies have shown that KLK proteases are involved in a number of extracellular processes that initiate intracellular signaling pathways by hydrolysis, as reviewed in Chapters 8, 9, and 15, Volume 1. These events have been associated with more invasive phenotypes of ovarian, prostate, and other cancers. Concomitantly, aberrant expression of KLKs has been associated with poor prognosis of patients with ovarian and prostate cancer (Borgoño and Diamandis, 2004; Clements et al., 2004; Yousef and Diamandis, 2009), with prostate-specific antigen (PSA, KLK3) being a long standing, clinically employed biomarker for prostate cancer (Lilja et al., 2008). Data generated from patient samples in clinical studies, alongwith biochemical activity, suggests that KLKs function in the development and progression of these diseases. To bridge the gap between their function at the molecular level and the clinical need for efficacious treatment and prognostic biomarkers, functional assessment at the in vitro cellular level, using various culture models, is increasing, particularly in a three-dimensional (3D) context (Abbott, 2003; Bissell and Radisky, 2001; Pampaloni et al., 2007; Yamada and Cukierman, 2007).

Nutritional status and dietary intake of acute care patients : results from the Nutrition Care Day Survey 2010

Background & aims: One aim of the Australasian Nutrition Care Day Survey was to determine the nutritional status and dietary intake of acute care hospital patients. Methods: Dietitians from 56 hospitals in Australia and New Zealand completed a 24-h survey of nutritional status and dietary intake of adult hospitalised patients. Nutritional risk was evaluated using the Malnutrition Screening Tool. Participants ‘at risk’ underwent nutritional assessment using Subjective Global Assessment. Based on the International Classification of Diseases (Australian modification), participants were also deemed malnourished if their body mass index was <18.5 kg/m2. Dietitians recorded participants’ dietary intake at each main meal and snacks as 0%, 25%, 50%, 75%, or 100% of that offered. Results: 3122 patients (mean age: 64.6 ± 18 years) participated in the study. Forty-one percent of the participants were “at risk” of malnutrition. Overall malnutrition prevalence was 32%. Fifty-five percent of malnourished participants and 35% of well-nourished participants consumed ≤50% of the food during the 24-h audit. “Not hungry” was the most common reason for not consuming everything offered during the audit. Conclusion: Malnutrition and sub-optimal food intake is prevalent in acute care patients across hospitals in Australia and New Zealand and warrants appropriate interventions.

Paclitaxel resistance and multicellular spheroid formation are induced by kallikrein-related peptidase 4 in serous ovarian cancer cells in an ascites mimicking microenvironment

High tumor kallikrein-related-peptidase 4 (KLK4) levels are associated with a poor outcome for women with serous epithelial ovarian cancer (EOC), for which peritoneal dissemination and chemoresistance are key events. To determine the role of KLK4 in these events, we examined KLK4-transfected SKOV-3 and endogenous KLK4 expressing OVCA432 cells in 3-dimensional (3D) suspension culture to mimic the ascites microenvironment. KLK4-SKOV-3 cells formed multicellular aggregates (MCAs) as seen in ascites, as did SKOV-3 cells treated with active KLK4. MCA formation was reduced by treatment with a KLK4 blocking antibody or the selective active site KLK4 sunflower trypsin inhibitor (SFTI-FCQR). KLK4-MCAs formed larger cancer cell foci in mesothelial cell monolayers than those formed by vector and native SKOV-3 cells, suggesting KLK4-MCAs are highly invasive in the peritoneal microenvironment. A high level of KLK4 is expressed by ascitic EOC cells compared to matched primary tumor cells, further supporting its role in the ascitic microenvironment. Interestingly, KLK4 transfected SKOV-3 cells expressed high levels of the KLK4 substrate, urokinase plasminogen activator (uPA), particularly in 3D-suspension, and high levels of both KLK4 and uPA were observed in patient cells taken from ascites. Importantly, the KLK4-MCAs were paclitaxel resistant which was reversed by SFTI-FCQR and to a lesser degree by the general serine protease inhibitor, Aprotinin, suggesting that in addition to uPA, other as yet unidentified substrates of KLK4 must be involved. Nonetheless, these data suggest that KLK4 inhibition, in conjunction with paclitaxel, may improve the outcome for women with serous epithelial ovarian cancer and high KLK4 levels in their tumors.

The influence of neighbourhood disadvantage on smoking cessation and its contribution to inequalities in smoking status

Introduction and aims: Individual smokers from disadvantaged backgrounds are less likely to quit, which contributes to widening inequalities in smoking. Residents of disadvantaged neighbourhoods are more likely to smoke, and neighbourhood inequalities in smoking may also be widening because of neighbourhood differences in rates of cessation. This study examined the association between neighbourhood disadvantage and smoking cessation and its relationship with neighbourhood inequalities in smoking. Design and methods: A multilevel longitudinal study of mid-aged (40-67 years) residents (n=6915) of Brisbane, Australia, who lived in the same neighbourhoods (n=200) in 2007 and 2009. Neighbourhood inequalities in cessation and smoking were analysed using multilevel logistic regression and Markov chain Monte Carlo simulation. Results: After adjustment for individual-level socioeconomic factors, the probability of quitting smoking between 2007 and 2009 was lower for residents of disadvantaged neighbourhoods (9.0%-12.8%) than their counterparts in more advantaged neighbourhoods (20.7%-22.5%). These inequalities in cessation manifested in widening inequalities in smoking: in 2007 the between-neighbourhood variance in rates of smoking was 0.242 (p≤0.001) and in 2009 it was 0.260 (p≤0.001). In 2007, residents of the most disadvantaged neighbourhoods were 88% (OR 1.88, 95% CrI 1.41-2.49) more likely to smoke than residents in the least disadvantaged neighbourhoods: the corresponding difference in 2009 was 98% (OR 1.98 95% CrI 1.48-2.66). Conclusion: Fundamentally, social and economic inequalities at the neighbourhood and individual-levels cause smoking and cessation inequalities. Reducing these inequalities will require comprehensive, well-funded, and targeted tobacco control efforts and equity based policies that address the social and economic determinants of smoking.

Private health insurance status and utilisation of dental services in Australia

This article focuses on the relationship between private insurance status and dental service utilisation in Australia using data between 1995 and 2001. This article employs joint maximum likelihood to estimate models of time since last dental visit treating private ancillary health insurance (PAHI) as endogenous. The sensitivity of results to the choice between two different but related types of instrumental variables is examined. We find robust evidence in both 1995 and 2001 that individuals with a PAHI policy make significantly more frequent dental consultations relative to those without such coverage. A comparison of the 1995 and 2001 results, however, suggests that there has been an increasing role of PAHI in terms of the frequency of dental consultations over time. This seems intuitive given the trends in the price of unsubsidised private dental consultations. In terms of policy, our results suggest that while government measures to increase private health insurance coverage in Australia has been successful to a significant degree, it may have come at some cost in terms of socio-economic inequality as the privately insured are provided much better access to care and financial protection.

Combined expression of KLK4, KLK5, KLK6, and KLK7 by ovarian cancer cells leads to decreased adhesion and paclitaxel-induced chemoresistance.

OBJECTIVE: Chemoresistance is a critical feature of advanced ovarian cancer with only 30% of patients surviving longer than 5 years. We have previously shown that four kallikrein-related (KLK) peptidases, KLK4, KLK5, KLK6 and KLK7 (KLK4-7), are implicated in peritoneal invasion and tumour growth, but underlying mechanisms were not identified. We also reported that KLK7 overexpression confers chemoresistance to paclitaxel, and cell survival via integrins. In this study, we further explored the functional consequenses of overexpression of all four KLKs (KLK4-7) simultaneously in the ovarian cancer cell line, OV-MZ-6, and its impact on integrin expression and signalling, cell adhesion and survival as contributors to chemoresistance and metastatic progression. METHODS: Quantitative gene and protein expression analyses, confocal microscopy, cell adhesion and chemosensitivity assays were performed. RESULTS: Expression of α5β1/αvβ3 integrins was downregulated upon combined stable KLK4-7 overexpression in OV-MZ-6 cells. Accordingly, the adhesion of these cells to vitronectin and fibronectin, the extracellular matrix binding proteins of α5β1/αvβ3 integrins and two predominant proteins of the peritoneal matrix, was decreased. KLK4-7-transfected cells were more resistant to paclitaxel (10-100 nmol/L: 38-54%), but not to carboplatin, which was associated with decreased apoptotic stimuli. However, the KLK4-7-induced paclitaxel resistance was not blocked by the MEK1/2 inhibitor, U0126. CONCLUSIONS: This study demonstrates that combined KLK4-7 expression by ovarian cancer cells promotes reduced integrin expression with consequently less cell-matrix attachment, and insensitivity to paclitaxel mediated by complex integrin and MAPK independent interactions, indicative of a malignant phenotype and disease progression suggesting a role for these KLKs in this process.

The moral status of babies

In their controversial paper 'After-birth abortion', Alberto Giubilini and Francesca Minerva argue that there is no rational basis for allowing abortion but prohibiting infanticide ('after-birth abortion'). We ought in all consistency either to allow both or prohibit both. This paper rejects their claim, arguing that much-neglected considerations in philosophical discussions of this issue are capable of explaining why we currently permit abortion in some cases, while prohibiting infanticide.

Health status of Thai migrants in Brisbane : findings from a cross-sectional investigation

Australia is a multi-ethnic, multi-cultural country with a long history of migration. In 2006, 22% of the population was born overseas. Thai migrants accounted for 0.2% of the population at this time, with a nearly 40% increase from around 19,000 in 1996 to 30,555 in 2006.1 Despite this, little is known about the health of this migrant group. We investigated the health status and health service utilisation of a Thai community through a cross-sectional postal survey conducted from May to September 2010. Participants were members of a Brisbane Thai temple, aged 18 years and older, who self identified as being Thai. Current health status was assessed using the SF-36v22 and self-report of diagnosed medical conditions. Use of health services was assessed using questions adapted from the Welsh Health Survey.3 Socio-demographic variables included gender, age, language spoken at home, year of arrival in Australia and type of health care insurance.

The status of the Greater Flamingo in the Galapagos

The paper covers census work carried out in 1976-77 on the Greater Flamingoes on all the islands in the Galapagos Archipelago, Ecuador South America. The work was supported by funding from the World Wildlife Fund.

Vitamin D status and skin cancer risk independent of time outdoors : 11-year prospective study in and Australian community

Vitamin D may have anti-skin cancer effects, but population-based evidence is lacking. We therefore assessed associations between vitamin D status and skin cancer risk in an Australian subtropical community. We analyzed prospective skin cancer incidence for 11 years following baseline assessment of serum 25(OH)-vitamin D in 1,191 adults (average age 54 years) and used multivariable logistic regression analysis to adjust risk estimates for age, sex, detailed assessments of usual time spent outdoors, phenotypic characteristics, and other possible confounders. Participants with serum 25(OH)-vitamin D concentrations above 75 nmol  l(-1) versus those below 75 nmol  l(-1) more often developed basal cell carcinoma (odds ratio (OR)=1.51 (95% confidence interval (CI): 1.10-2.07, P=0.01) and melanoma (OR=2.71 (95% CI: 0.98-7.48, P=0.05)). Squamous cell carcinoma incidence tended to be lower in persons with serum 25(OH)-vitamin D concentrations above 75 nmol  l(-1) compared with those below 75 nmol  l(-1) (OR=0.67 (95% CI: 0.44-1.03, P=0.07)). Vitamin D status was not associated with skin cancer incidence when participants were classified as above or below 50 nmol  l(-1) 25(OH)-vitamin D. Our findings do not indicate that the carcinogenicity of high sun exposure can be counteracted by high vitamin D status. High sun exposure is to be avoided as a means to achieve high vitamin D status.

The economics of awards, status and performance: the John Bates Clark Medal and the Fellowship of the Econometric Society

This thesis investigates whether receiving an important award in academia raises recipients’ subsequent research productivity and status compared to a synthetic control group of non-recipient scholars with similar previous research performance. It examines the case of being awarded the John Bates Clark Medal and becoming a Fellow of the Econometric Society finding evidence of positive incentive and status effects that raise both productivity and citation levels.

Exploring the ethical implications of the late discovery of adoptive and donor-insemination offspring status

Some children adopted under the now discredited period of closed adoption were never told of their adoptive status until it was revealed to them in adulthood. Yet to date, this ‘late-discovery’ experience has received little research attention. Now a new generation of ‘late discoverers’ is emerging as a result of (heterosexual couple) donor insemination (DI) practices. This study of 25 late-discovery participants of either adoptive or (heterosexual couple) DI offspring status reveals ethical concerns particular to the lateness of discovery. Most of the participants were Australian, with the remainder from the UK, USA and Canada. All were asked to give an ‘open’ account of their experience, with four themes or suggestions provided on request. These accounts were added to those available in relevant publications. The analysis employed a hermeneutic phenomenological methodology and all accounts were analysed using an ethical perspective developed by Walker (2006, 2007). The main themes that emerged were: disrupted personal autonomy, betrayal of deep levels of trust and feelings of injustice and diminished self-worth. The lack of recognition of concerns particular to late discovery has resulted in late discoverers (i) feeling unable to regain a sense of personal control, (ii) significantly disrupted relationships with those closest to them and others, including community and institutions, and (iii) feelings of diminished value and self-worth.

Nutritional status of Ugandan women living with HIV/AIDS : anthropometry and body composition assessment

Human immunodeficiency virus (HIV) that leads to acquired immune deficiency syndrome (AIDs) reduces immune function, resulting in opportunistic infections and later death. Use of antiretroviral therapy (ART) increases chances of survival, however, with some concerns regarding fat re-distribution (lipodystrophy) which may encompass subcutaneous fat loss (lipoatrophy) and/or fat accumulation (lipohypertrophy), in the same individual. This problem has been linked to Antiretroviral drugs (ARVs), majorly, in the class of protease inhibitors (PIs), in addition to older age and being female. An additional concern is that the problem exists together with the metabolic syndrome, even when nutritional status/ body composition, and lipodystrophy/metabolic syndrome are unclear in Uganda where the use of ARVs is on the increase. In line with the literature, the overall aim of the study was to assess physical characteristics of HIV-infected patients using a comprehensive anthropometric protocol and to predict body composition based on these measurements and other standardised techniques. The other aim was to establish the existence of lipodystrophy, the metabolic syndrome, andassociated risk factors. Thus, three studies were conducted on 211 (88 ART-naïve) HIV-infected, 15-49 year-old women, using a cross-sectional approach, together with a qualitative study of secondary information on patient HIV and medication status. In addition, face-to-face interviews were used to extract information concerning morphological experiences and life style. The study revealed that participants were on average 34.1±7.65 years old, had lived 4.63±4.78 years with HIV infection and had spent 2.8±1.9 years receiving ARVs. Only 8.1% of participants were receiving PIs and 26% of those receiving ART had ever changed drug regimen, 15.5% of whom changed drugs due to lipodystrophy. Study 1 hypothesised that the mean nutritional status and predicted percent body fat values of study participants was within acceptable ranges; different for participants receiving ARVs and the HIV-infected ART-naïve participants and that percent body fat estimated by anthropometric measures (BMI and skinfold thickness) and the BIA technique was not different from that predicted by the deuterium oxide dilution technique. Using the Body Mass Index (BMI), 7.1% of patients were underweight (<18.5 kg/m2) and 46.4% were overweight/obese (≥25.0 kg/m2). Based on waist circumference (WC), approximately 40% of the cohort was characterized as centrally obese. Moreover, the deuterium dilution technique showed that there was no between-group difference in the total body water (TBW), fat mass (FM) and fat-free mass (FFM). However, the technique was the only approach to predict a between-group difference in percent body fat (p = .045), but, with a very small effect (0.021). Older age (β = 0.430, se = 0.089, p = .000), time spent receiving ARVs (β = 0.972, se = 0.089, p = .006), time with the infection (β = 0.551, se = 0.089, p = .000) and receiving ARVs (β = 2.940, se = 1.441, p = .043) were independently associated with percent body fat. Older age was the greatest single predictor of body fat. Furthermore, BMI gave better information than weight alone could; in that, mean percentage body fat per unit BMI (N = 192) was significantly higher in patients receiving treatment (1.11±0.31) vs. the exposed group (0.99±0.38, p = .025). For the assessment of obesity, percent fat measures did not greatly alter the accuracy of BMI as a measure for classifying individuals into the broad categories of underweight, normal and overweight. Briefly, Study 1 revealed that there were more overweight/obese participants than in the general Ugandan population, the problem was associated with ART status and that BMI broader classification categories were maintained when compared with the gold standard technique. Study 2 hypothesized that the presence of lipodystrophy in participants receiving ARVs was not different from that of HIV-infected ART-naïve participants. Results showed that 112 (53.1%) patients had experienced at least one morphological alteration including lipohypertrophy (7.6%), lipoatrophy (10.9%), and mixed alterations (34.6%). The majority of these subjects (90%) were receiving ARVs; in fact, all patients receiving PIs reported lipodystrophy. Period spent receiving ARVs (t209 = 6.739, p = .000), being on ART (χ2 = 94.482, p = .000), receiving PIs (Fisher’s exact χ2 = 113.591, p = .000), recent T4 count (CD4 counts) (t207 = 3.694, p = .000), time with HIV (t125 = 1.915, p = .045), as well as older age (t209 = 2.013, p = .045) were independently associated with lipodystrophy. Receiving ARVs was the greatest predictor of lipodystrophy (p = .000). In other analysis, aside from skinfolds at the subscapular (p = .004), there were no differences with the rest of the skinfold sites and the circumferences between participants with lipodystrophy and those without the problem. Similarly, there was no difference in Waist: Hip ratio (WHR) (p = .186) and Waist: Height ratio (WHtR) (p = .257) among participants with lipodystrophy and those without the problem. Further examination showed that none of the 4.1% patients receiving stavudine (d4T) did experience lipoatrophy. However, 17.9% of patients receiving EFV, a non-nucleoside reverse transcriptase inhibitor (NNRTI) had lipoatrophy. Study 2 findings showed that presence of lipodystrophy in participants receiving ARVs was in fact far higher than that of HIV-infected ART-naïve participants. A final hypothesis was that the prevalence of the metabolic syndrome in participants receiving ARVs was not different from that of HIV-infected ART-naïve participants. Moreover, data showed that many patients (69.2%) lived with at least one feature of the metabolic syndrome based on International Diabetic Federation (IDF, 2006) definition. However, there was no single anthropometric predictor of components of the syndrome, thus, the best anthropometric predictor varied as the component varied. The metabolic syndrome was diagnosed in 15.2% of the subjects, lower than commonly reported in this population, and was similar between the medicated and the exposed groups (χ 21 = 0.018, p = .893). Moreover, the syndrome was associated with older age (p = .031) and percent body fat (p = .012). In addition, participants with the syndrome were heavier according to BMI (p = .000), larger at the waist (p = .000) and abdomen (p = .000), and were at central obesity risk even when hip circumference (p = .000) and height (p = .000) were accounted for. In spite of those associations, results showed that the period with disease (p = .13), CD4 counts (p = .836), receiving ART (p = .442) or PIs (p = .678) were not associated with the metabolic syndrome. While the prevalence of the syndrome was highest amongst the older, larger and fatter participants, WC was the best predictor of the metabolic syndrome (p = .001). Another novel finding was that participants with the metabolic syndrome had greater arm muscle circumference (AMC) (p = .000) and arm muscle area (AMA) (p = .000), but the former was most influential. Accordingly, the easiest and cheapest indicator to assess risk in this study sample was WC should routine laboratory services not be feasible. In addition, the final study illustrated that the prevalence of the metabolic syndrome in participants receiving ARVs was not different from that of HIV-infected ART-naïve participants.

Sleepless nights : the effect of socioeconomic status, physical activity, and lifestyle factors on sleep quality in a large cohort of Australian women

The aims of this study were to examine: (1) the association between sociodemographic and lifestyle factors and sleep quality in a population-based cohort of Australian women and (2) possible influence of reproductive status and mental and physical health factors on these associations. Data on 3,655 women (mean age046.6 years, range 34.3–67.4) were obtained from the Mater Hospital University of Queensland Study of Pregnancy for this cross-sectional study. Self-rated sleep quality was assessed using the Pittsburgh Sleep Quality Index. For the purpose of this study, two cutoff points (scores 5 and 10) were used to divide women into three categories: normal (65.2 %), moderately poor (26.4 %), and very poor sleep quality (8.5 %). Other covariates were measured at 21-year follow-up as well. After adjusting for reproductive status, mental and physical health, there were significant associations between moderately poor sleep quality and education and between very poor sleep quality and unemployment, both measures of socioeconomic status. In addition, work-related exertion was associated with increased rates of moderately poor sleep quality, whereas those women undertaking moderate exercise were less likely to experience very poor sleep quality. Independent associations between sociodemographic factors and exercise with moderately poor and very poor sleep quality were identified. These findings demonstrate the dynamic nature of the association between exercise/exertion, socioeconomic status, and sleep quality and highlight the importance of taking these into consideration when dealing with issues of poor sleep quality in women.

A commentary on the current and future status of educational and developmental psychology in Australia

Educational and developmental psychology faces a number of current and future challenges and opportunities in Australia. In this commentary we consider the identity of educational and developmental psychology in terms of the features that distinguish it from other specialisations, and address issues related to training, specialist endorsement, supervision and rebating under the Australian government's Medicare system. The current status of training in Australia is considered through a review of the four university programs in educational and developmental psychology currently offered, and the employment destinations of their graduates. Although the need for traditional services in settings such as schools, hospitals, disability and community organisations will undoubtedly continue, the role of educational and developmental psychologists is being influenced and to some extent redefined by advances in technology, medicine, genetics, and neuroscience. We review some of these advances and conclude with recommendations for training and professional development that will enable Australian educational and developmental psychologists to meet the challenges ahead.