Chemoprevention with the metabolism modifying drugs dichloroacetate and metformin in the Li-Fraumeni Syndrome model, Trp53+/- mice

BACKGROUND: While genetic testing for familial cancer has excelled, the prevention options for those carrying high risk alleles have not. Altered bioenergetics is now acknowledged as a hallmark of cancer, and several very safe drugs are available that can target this phentoype. Dichloroacetate (DCA) inactivates pyruvate dehydrogenase kinase, resulting in activation of pyruvate dehydrogenase, reduced lactic acid production and increased mitochondrial activity. Metformin, a type 2 diabetes treatment which activates AMPK, thereby inhibiting mTOR, has unambiguously been demonstrated to reduce the risk of many cancer types in diabetics. We have tested these drugs as chemopreventive agents against the mammary tumours that occur in the BALB/c-Trp53+/- mouse spontaneous tumour model. MATERIALS and METHODS Breast cancer cell lines were examined for cell viability after DCA and/or metformin treatment in vitro (neutral red uptake assay). Four groups of female BALB/c-Trp53+/- mice were given distilled water (n=75), DCA (1.5 g/L in drinking water, ~180 mg/ kg/day, n=53), metformin (0.25 g/L in drinking water, ~30 mg/kg/day, n=61) or DCA +metformin (n=51) from 8 weeks of age, and monitored for tumour development over 78 weeks, and Kaplan-Meier survival analysis was performed. RESULTS In vitro, DCA (1-5 mM) and metformin (30-300 uM), alone or combined, significantly inhibited breast cancer cell growth. In vivo, the overall tumour-free survival curves for BALB/c-Trp53+/- mice were not significantly different between treatment groups, suggesting that metformin does not reduce cancer risk in non-diabetics. However, analysis of mammary tumours alone found that DCA reduced the number and increased their latency (28.0% vs 20.8% of mice with mean latency of 55.0 vs 63.8 weeks, untreated vs DCA respectively), whereas metformin had no effect (26.2% of mice, mean latency 54.7 weeks). DCA appeared to eliminate the early onset mammary tumours (latency <52 weeks, p=0.02), while not affecting the occurrence of longer latency tumours. In contrast, the two drug combination had worse outcomes for tumour development, (35.3% of mice, latency 48.8 weeks, p<0.02 compared to DCA alone). Preliminary western blotting results in MDA-MB-468 breast cancer cells found that DCA could block the activation of AMPK by metformin, indicating the potential for drug interactions.Supported by NHMRC Career Development Award, National Breast Cancer Foundation Novel Concept Award, and Cancer Australia

Study of transient behavior of finned coil heat exchangers

The status of research on the transient behavior of finned coil cross-flow heat exchangers using single phase fluids is reviewed. Applications with available analytical or numerical solutions are discussed. Investigation of water-to-air type cross-flow finned tube heat exchangers is examined through the use of simplified governing equations and an up-wind finite difference scheme. The degenerate case of zero air-side capacitance rate is compared with available exact solution. Generalization of the numerical model is discussed for application to multi-row multi-circuit heat exchangers

The Claims Culture: A Taxonomy of Industry Attitudes

This paper presents an analysis of a familiar aspect of construction industry culture that we have dubbed 'the claims culture'. This is a culture of contract administration that lays a strong emphasis on the planning and management of claims. The principal elements of the analysis are two sets of distinctions. The first comprises economic and occupational orders, referring to two kinds of control that are exercised over the construction process; predicated respectively on economic ownership and occupational competence. The second refers to contrasting attitudes towards relationships and problem solving within these orders: respectively 'distributive' and 'integrative'. The concepts of economic and occupational order entail further sub-categories. The various attitudes associated with these categories and sub-categories are described. They are assessed as to their consequences for change initiatives in the industry

Work placements as research-based learning – a student and employer perspective

Guest editoria

Work placements as research-based learning – a student and employer perspective

Guest editoria

Metabolomic changes in lactating multiparous naturally MAP-infected Holstein-Friesian dairy cows suggest changes in mitochondrial energy pathways

Mycobacterium avium subspecies paratuberculosis (MAP) is the causative organism of Johne's Disease, a chronic intestinal infection of ruminants. Infected cows begin shedding MAP within the asymptomatic, subclinical stage of infection before clinical signs, such as weight loss, diarrhoea and reduced milk yields develop within the clinical stages of disease. Herein, we examine the milk metabolomic profiles of naturally MAP-infected Holstein-Friesian cows. The study used biobanked milk samples which were collected 73.4 ± 3.79 (early lactation) and 143 ± 3.79 (mean ± SE) (mid-lactation) days post-calving from 5 MAP-infected and 5 control multiparous cows. The milk metabolome was assessed using flow infusion electrospray high-resolution mass spectrometry (FIE-HRMS) for sensitive, non-targeted metabolite fingerprinting. Metabolite fingerprinting assessments using partial least squares discriminate analyses (PLS-DA) indicated that lactation stage was a larger source of variation than MAP status. Examining each lactation stage separately for changes associated to MAP-infection status identified 45 metabolites, 33 in early lactation and 12 in mid-lactation, but only 6 metabolites were targeted in both stages of lactation. Pathway enrichment analysis suggested that MAP affected the malate-aspartate shuffle during early lactation. Pearson's correlation analysis indicated relationships between milk lactose concentrations in mid-lactation and 6 metabolites that were tentatively linked to MAP-infection status. The targeted metabolites were suggestive of wider changes in the bioenergetic metabolism that appear to be an acceleration of the effects of progressing lactation in healthy cows. Additionally, milk lactose concentrations suggest that MAP reduces the availability of lactose derivatives