PPARγ-independent induction of growth arrest and apoptosis in prostate and bladder carcinoma

Background Although PPARγ antagonists have shown considerable pre-clinical efficacy, recent studies suggest PPARγ ligands induce PPARγ-independent effects. There is a need to better define such effects to permit rational utilization of these agents. Methods We have studied the effects of a range of endogenous and synthetic PPARγ ligands on proliferation, growth arrest (FACS analysis) and apoptosis (caspase-3/7 activation and DNA fragmentation) in multiple prostate carcinoma cell lines (DU145, PC-3 and LNCaP) and in a series of cell lines modelling metastatic transitional cell carcinoma of the bladder (TSU-Pr1, TSU-Pr1-B1 and TSU-Pr1-B2). Results 15-deoxy-prostaglandin J2 (15dPGJ2), troglitazone (TGZ) and to a lesser extent ciglitazone exhibited inhibitory effects on cell number; the selective PPARγ antagonist GW9662 did not reverse these effects. Rosiglitazone and pioglitazone had no effect on proliferation. In addition, TGZ induced G0/G1 growth arrest whilst 15dPGJ2 induced apoptosis. Conclusion Troglitazone and 15dPGJ2 inhibit growth of prostate and bladder carcinoma cell lines through different mechanisms and the effects of both agents are PPARγ-independent.

Antisense-mediated suppression of hyaluronan synthase 2 inhibits the tumorigenesis and progression of breast cancer

The progression of several cancers is correlated with the increased synthesis of the glycosaminoglycan, hyaluronan. Hyaluronan is synthesized at the plasma membrane by various isoforms of hyaluronan synthases (HAS). The importance of HAS2 expression in highly invasive breast cancer was characterized by the antisense inhibition of HAS2 (ASHAS2). The effect of HAS2 inhibition on cell proliferation, migration, hyaluronan metabolism, and receptor status was characterized in vitro, whereas the effect on tumorigenicity and metastasis was established in vivo. HAS2 inhibition resulted in a 24-hour lag in proliferation that was concomitant to transient arrest of 79% of the cell population in G 0-G1. Inhibition of HAS2 did not alter the expression of the other HAS isoforms, whereas hyaluronidase (HYAL2) and the hyaluronan receptor, CD44, were significantly down-regulated. ASHAS2 cells accumulated greater amounts of high molecular weight hyaluronan (>10,000 kDa) in the culture medium, whereas mock and parental cells liberated less hyaluronan of three distinct molecular weights (100, 400, and 3,000 kDa). The inhibition of HAS2 in the highly invasive MDA-MB-231 breast cancer cell line inhibited the initiation and progression of primary and secondary tumor formation following s.c. and intracardiac inoculation into nude mice, whereas controls readily established both primary and secondary tumors. The lack of primary and secondary tumor formation was manifested by increased survival times where ASHAS2 animals survived 172% longer than the control animals. Collectively, these unique results strongly implicate the central role of HAS2 in the initiation and progression of breast cancer, potentially highlighting the codependency between HAS2, CD44, and HYAL2 expression. ©2005 American Association for Cancer Research.

Promoting physical activity to older adults : a preliminary evaluation of three general practice-based strategies

The aim of this study was to explore the feasibility of an exercise scientist (ES) working in general practice to promote physical activity (PA) to 55 to 70 year old adults. Participants were randomised into one of three groups: either brief verbal and written advice from a general practitioner (GP) (G1, N=9); or individualised counselling and follow-up telephone calls from an ES, either with (G3, N=8) or without a pedometer (G2, N=11). PA levels were assessed at week 1, after the 12-wk intervention and again at 24 weeks. After the 12-wk intervention, the average increase in PA was 116 (SD=237) min/wk; N=28, p < 0.001. Although there were no statistically significant between-group differences, the average increases in PA among G2 and G3 participants were 195 (SD=207) and 138 (SD=315) min/wk respectively, compared with no change (0.36, SD=157) in G1. After 24 weeks, average PA levels remained 56 (SD=129) min/wk higher than in week 1. The small numbers of participants in this feasibility study limit the power to detect significant differences between groups, but it would appear that individualised counselling and follow-up contact from an ES, with or without a pedometer, can result in substantial changes in PA levels. A larger study is now planned to confirm these findings.

Gender dimensions of resource extraction : the place of women

This chapter examines two core dimensions of women’s gendered experiences of mining in Australia and more specifically in Western Australia (WA). First, the chapter explores what has been and continues to be women’s principal relationship to mining encapsulated in the social and cultural identity of the ‘mining wife’ and, more recently, ‘fly-in/fly-out (FIFO) wife’. Second, the chapter addresses the fraught emergence of women as mineworkers. As the research presented in this chapter makes clear, the human cost of developmentalism was and continues to be deeply gendered.

Control of cell cycle progression by phosphorylation of cyclin-dependent kinase (CDK) substrates

The eukaryotic cell cycle is a fundamental evolutionarily conserved process that regulates cell division from simple unicellular organisms, such as yeast, through to higher multicellular organisms, such as humans. The cell cycle comprises several phases, including the S-phase (DNA synthesis phase) and M-phase (mitotic phase). During S-phase, the genetic material is replicated, and is then segregated into two identical daughter cells following mitotic M-phase and cytokinesis. The S- and M-phases are separated by two gap phases (G1 and G2) that govern the readiness of cells to enter S- or M-phase. Genetic and biochemical studies demonstrate that cell division in eukaryotes is mediated by CDKs (cyclin-dependent kinases). Active CDKs comprise a protein kinase subunit whose catalytic activity is dependent on association with a regulatory cyclin subunit. Cell-cycle-stage-dependent accumulation and proteolytic degradation of different cyclin subunits regulates their association with CDKs to control different stages of cell division. CDKs promote cell cycle progression by phosphorylating critical downstream substrates to alter their activity. Here, we will review some of the well-characterized CDK substrates to provide mechanistic insights into how these kinases control different stages of cell division.

Offspring of mothers fed a high fat diet display hepatic cell cycle inhibition and associated changes in gene expression and DNA methylation

The association between an adverse early life environment and increased susceptibility to later-life metabolic disorders such as obesity, type 2 diabetes and cardiovascular disease is described by the developmental origins of health and disease hypothesis. Employing a rat model of maternal high fat (MHF) nutrition, we recently reported that offspring born to MHF mothers are small at birth and develop a postnatal phenotype that closely resembles that of the human metabolic syndrome. Livers of offspring born to MHF mothers also display a fatty phenotype reflecting hepatic steatosis and characteristics of non-alcoholic fatty liver disease. In the present study we hypothesised that a MHF diet leads to altered regulation of liver development in offspring; a derangement that may be detectable during early postnatal life. Livers were collected at postnatal days 2 (P2) and 27 (P27) from male offspring of control and MHF mothers (n = 8 per group). Cell cycle dynamics, measured by flow cytometry, revealed significant G0/G1 arrest in the livers of P2 offspring born to MHF mothers, associated with an increased expression of the hepatic cell cycle inhibitor Cdkn1a. In P2 livers, Cdkn1a was hypomethylated at specific CpG dinucleotides and first exon in offspring of MHF mothers and was shown to correlate with a demonstrable increase in mRNA expression levels. These modifications at P2 preceded observable reductions in liver weight and liver:brain weight ratio at P27, but there were no persistent changes in cell cycle dynamics or DNA methylation in MHF offspring at this time. Since Cdkn1a up-regulation has been associated with hepatocyte growth in pathologic states, our data may be suggestive of early hepatic dysfunction in neonates born to high fat fed mothers. It is likely that these offspring are predisposed to long-term hepatic dysfunction.

Iron(II) spin transition complexes with dendritic ligands, Part I

The ligands G1- and G2-oligo (benzyl ether) (PBE) dendrons and their iron(II) complexes [Fe(Gn-PBE)3]A2·xH2O (with n = 1, 2 and A = triflate, tosylate) were prepared. The magnetic properties of the complexes were investigated by a SQUID magnetometer. All complexes exhibit gradual spin transition below room temperature. At very low temperatures the magnetic behaviour reflects zero-field splitting (ZFS) effects. 57Fe-Mössbauer spectroscopy was performed to distinguish between ZFS of high spin species and spin state conversion into the low spin state. Further characterisation was carried out by thermogravimetric analysis (TGA) and FT-IR spectroscopy. Structural features have been determined by powder XRD measurements.

Iron(II) spin-transition complexes with dendritic ligands, part II

The dendritic triazole-based complexes \[Fe(G1-BOC)3](triflate) 2·xH2O (1; G1-BOC = tert-butyl {3-\[3-(3-tert- butoxycarbonylaminopropyl)-5-(\[1,2,4]triazol-4-ylcarbamoyl)-phenyl]propyl} carbamate, triflate = CF3SO3-), \[Fe(G1-BOC) 3]-(tosylate)2·xH2O(2;tosylate = p-CH3PhSO3-),\[Fe(G1-DPBE)3]-(triflate) 2·xH2O {3; G1-DPBE = 3,5-bis(3,5- didodecaoxybenzyloxy)-N-\[1,2,4]triazol-4-ylbenzamide}, \[Fe(G1-DPBE) 3]-(tosylate)2·xH2O (4) and \[Fe(G1-DPBE)3](BF4)2·xH2O (5) were designed and synthesized. Magnetic and thermal properties of these novel complexes were characterized by magnetic susceptibility measurements, 57Fe Mössbauer spectroscopy and thermogravimetric analysis or differential scanning calorimetry, respectively. All dendritic complexes under study show different spin-transition behaviour with respect to the nature of different dendritic ligands and counteranions. Complexes 1 and 2 have pronounced effects of a spin-state change during the first heating process and gradual spintransition properties for further temperature treatments, whereas 3 and 4 exhibited a very sharp spin-state change in the first heating procedures. Complex 5 showed a gradual spin-transition curve. In this paper, we report how the magnetic properties of these complexes are correlated with noncoordinated water molecules and their effects on spin states.

Social Justice Impacts of the Resources Boom

Until the 1970s mining leases were issued by state governments subject to conditions that companies build or substantially finance local community infrastructure, including housing, streets, transport, schools, hospitals and recreation facilities. Townships and communities went hand in hand with mining development. However, in the past thirty years mining companies have moved progressively to an expeditionary strategy for natural resources extraction - operating a continuous production cycle of 12 hour shifts - increasingly reliant on non-resident, fly-in, fly-out or drive-in, drive-out (FIFO/DIDO) workers who typically work block rosters, reside in work camps adjacent to existing communities and travel large distances from their homes. This paper presents the key findings of our survey into the social impacts of this kind of mining development in Qld. Based on the results we argue that the social license to develop new mining projects is strong for projects requiring a 25% or less non-resident workforce, diminishes significantly thereafter and is very weak for projects planning to recruit a non-resident workforce in excess of 75%. This finding is significant because there are at least 67 new mining projects undergoing social impact assessment in Queensland, and many it appears are planning to hire significant proportions of non-resident workers. The paper considers the policy implications of this growing social justice issue concluding there is a clear need for national leadership in formulating a national policy framework for guiding socially responsible and sustainable mining development into the next millennium.

Modeling conditional correlations of asset returns : a smooth transition approach

In this paper we propose a new multivariate GARCH model with time-varying conditional correlation structure. The time-varying conditional correlations change smoothly between two extreme states of constant correlations according to a predetermined or exogenous transition variable. An LM–test is derived to test the constancy of correlations and LM- and Wald tests to test the hypothesis of partially constant correlations. Analytical expressions for the test statistics and the required derivatives are provided to make computations feasible. An empirical example based on daily return series of five frequently traded stocks in the S&P 500 stock index completes the paper.

Bang and bust: almost everything you wanted to know about sex and the mining boom (but were afraid to ask)

Recent growth and expansion of the fly-in/fly-out (FIFO) model of mining in remote rural Australia has led to concerns about the health and well-being of those employed by the mines and those in the small rural communities where they are based. A particular concern has been the potential disruption to sexual norms in mining towns and increases in sexually transmitted infections (STIs) and HIV.

An investigation into the effect of infrastructure on fly-in fly-out mining workers

Objective: To explore fly-in fly-out (FIFO) mining workers' attitudes towards the leisure time they spend in mining camps, the recreational and social aspects of mining camp culture, the camps' communal and recreational infrastructure and activities, and implications for health. Design: In-depth semistructured interviews. Setting: Individual interviews at locations convenient for each participant. Participants: A total of seven participants, one female and six males. The age group varied within 20–59 years. Marital status varied across participants. Main outcome measures: A qualitative approach was used to interview participants, with responses thematically analysed. Findings highlight how the recreational infrastructure and activities at mining camps impact participants' enjoyment of the camps and their feelings of community and social inclusion. Results: Three main areas of need were identified in the interviews, as follows: (i) on-site facilities and activities; (ii) the role of infrastructure in facilitating a sense of community; and (iii) barriers to social interaction. Conclusion: Recreational infrastructure and activities enhance the experience of FIFO workers at mining camps. The availability of quality recreational facilities helps promote social interaction, provides for greater social inclusion and improves the experience of mining camps for their temporary FIFO residents. The infrastructure also needs to allow for privacy and individual recreational activities, which participants identified as important emotional needs. Developing appropriate recreational infrastructure at mining camps would enhance social interactions among FIFO workers, improve their well-being and foster a sense of community. Introducing infrastructure to promote social and recreational activities could also reduce alcohol-related social exclusion.

The flip side of fly-in-fly-out : the use of 457 visas by smaller firms in the Western Australian resources sector

The focus in this article is how the extensive use of fly-in fly-out (FIFO) working arrangements in the Western Australian resources sector has an impact directly and indirectly on smaller firms and their ability to recruit workers in remote locations. We argue that the growth of FIFO working arrangements has disadvantaged smaller resource-sector firms by increasing their employment costs and decreasing their ability to attract skilled workers. As a result, smaller resource-sector firms are recruiting skilled workers on 457 visas to secure their business stability and growth, despite the complexity, costs, and risks involved.

On the effect of Reynolds number for flow past three side-by-side square cylinders for unequal gap spacings

Flow patterns and aerodynamic characteristics behind three side-by-side square cylinders has been found depending upon the unequal gap spacing (g1 = s1/d and g2 = s2/d) between the three cylinders and the Reynolds number (Re) using the Lattice Boltzmann method. The effect of Reynolds numbers on the flow behind three cylinders are numerically studied for 75 ≤ Re ≤ 175 and chosen unequal gap spacings such as (g1, g2) = (1.5, 1), (3, 4) and (7, 6). We also investigate the effect of g2 while keeping g1 fixed for Re = 150. It is found that a Reynolds number have a strong effect on the flow at small unequal gap spacing (g1, g2) = (1.5, 1.0). It is also found that the secondary cylinder interaction frequency significantly contributes for unequal gap spacing for all chosen Reynolds numbers. It is observed that at intermediate unequal gap spacing (g1, g2) = (3, 4) the primary vortex shedding frequency plays a major role and the effect of secondary cylinder interaction frequencies almost disappear. Some vortices merge near the exit and as a result small modulation found in drag and lift coefficients. This means that with the increase in the Reynolds numbers and unequal gap spacing shows weakens wakes interaction between the cylinders. At large unequal gap spacing (g1, g2) = (7, 6) the flow is fully periodic and no small modulation found in drag and lift coefficients signals. It is found that the jet flows for unequal gap spacing strongly influenced the wake interaction by varying the Reynolds number. These unequal gap spacing separate wake patterns for different Reynolds numbers: flip-flopping, in-phase and anti-phase modulation synchronized, in-phase and anti-phase synchronized. It is also observed that in case of equal gap spacing between the cylinders the effect of gap spacing is stronger than the Reynolds number. On the other hand, in case of unequal gap spacing between the cylinders the wake patterns strongly depends on both unequal gap spacing and Reynolds number. The vorticity contour visualization, time history analysis of drag and lift coefficients, power spectrum analysis of lift coefficient and force statistics are systematically discussed for all chosen unequal gap spacings and Reynolds numbers to fully understand this valuable and practical problem.

Fluidity of mica particle dispersed aluminium alloy

Cast aluminium alloy-mica particle composites were made by dispersing mica particles in a vortex produced by stirring the liquid Al-4 wt% Cu-1.5 wt% Mg alloy and then casting the melt containing the suspended particles into permanent moulds. Spiral fluidity and casting fluidity of the alloy containing mica particles in suspension were determined. Both the spiral fluidity and the casting fluidity of the base alloy were found to decrease with an increase in volume or weight percent of mica particles (of a given size), and with a decrease in particle size (for a given amount of particles). The fluidities of Al-4 wt% Cu-1.5 wt% Mg alloys containing suspended mica particles were found to correlate very well with the surface area of suspended mica particles. The regression equation for spiral fluidity Y (cm) as a function of surface area of mica particles per gram of spiral X (cm2 g–1) at 700° C was found to be Y=42.62–0.42X with a correlation coefficient of 0.9634. The regression equations for casting fluidity Yprime (cm) as a functiono of surface area of mica particles per gram of fluidity test piece Xprime (cm2 g–1) at 710 and 670° C were found to be Yprime=19.71–0.17Xprime and Yprime=13.52–0.105Xprime with correlation coefficients of 0.9194 and 0.9612 respectively. The percentage decrease in casting fluidity of composite melts containing up to 2.5 wt% mica with a drop in temperature is quite similar to the corresponding decrease in the casting fluidity of base alloy melts (without mica). The change in fluidity due to mica dispersions has been discussed in terms of changes in viscosity of the composite melts. However, the fluidities of these composite alloys containing up to 2.5 wt% mica are adequate for making a variety of simple castings including bearings for which these alloys have been developed.