Disruption of pro-oxidant and antioxidant systems with elevated expression of the ubiquitin proteosome system in the cachectic heart muscle of nude mice.

BACKGROUND: Current research into the mechanisms of organ atrophy associated with cancer cachexia have centred on the loss of skeletal muscle, as it is one of the most profound physical changes of the disease. However, many patients with cancer cachexia also experience significant atrophy of the heart. The mechanisms causing cardiac tissue wastage in cancer cachexia are largely unknown. However, it is believed to involve a number of molecular interactions between the tumour and host. Increased levels of oxidative stress have been found in cancer cachectic skeletal muscle and has been linked to the activation of the ubiquitin proteosome system (UPS). The aim of the current study was to examine the role of oxidative stress and the UPS in the hearts of mice with cancer cachexia. METHODS: Oxidative damage to DNA (8-OH-2dG), mRNA levels of the ROS-producing enzymes NADPH oxidase (NOX), and xanthine oxidase (XDH), the antioxidant enzyme superoxide dismutase (SOD) and key components of the UPS was measured in the heart of mice with cancer cachexia. Protein expression levels of NOX enzyme subunits and SOD enzyme activity was also measured in the same heart samples. RESULTS: 8-OH-2dG levels were 1.5-fold higher in the heart of mice with cancer cachexia, and this was associated with a 1.7-fold lower level of NOX2 mRNA and twofold higher XDH mRNA in the same hearts. Cancer cachexia was also associated with a 1.5-fold lower level of SOD activity in the heart. Accompanying these pro- and antioxidant differences was a significantly higher level of mRNA for the key UPS elements MURF-1 (4.3=fold) and MAFbx (3.8-fold) in the hearts of mice with cancer cachexia. CONCLUSIONS: The current study demonstrated that cardiac atrophy of cachectic mice is associated with oxidative damage to DNA in the myocardium. The higher levels of XDH mRNA in cachectic hearts suggest that xanthine oxidase may have an important role to play in producing oxidative stress. It appears that the combination of higher XDH expression and lower SOD enzyme activity are key contributors to oxidative stress and cardiac tissue damage in cancer-induced cardiac atrophy. Oxidative stress in the myocardium as with skeletal muscle may also induce increased expression of the E3 ligases MURF-1 and MAFbx as seen in this study.

Marine polyunsaturated fatty acids and cancer therapy.

Polyunsaturated fatty acids (PUFAs) derived from marine sources, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are widely consumed as supplements within the community. However, the use of marine PUFAs in a therapeutic context is also increasing in patients receiving treatment for a range of cancer types. On balance, the literature suggests that marine PUFAs have potential as an effective adjuvant to chemotherapy treatment, may have direct anticancer effects, and may help ameliorate some of the secondary complications associated with cancer. Although a range of doses have been trialled, it would appear that supplementation of fish oil (>3 g per day) or EPA/DHA (>1 g EPA and >0.8 g DHA per day) is associated with positive clinical outcomes. However, further research is still required to determine the mechanisms via which marine PUFAs are mediating their effects. This review summarises our current understanding of marine PUFAs and cancer therapy.

A method for defining competency in Pediatrics.

In 1972 the American Board of Pediatrics (ABP) initiated studies leading to a report which identifies the important components of competency needed in the practice of pediatrics. The development of the report involved a group process engaging ABP board members and examiners. The outcome has been (a) the delineation of a process for establishing definitions of competency in a medical discipline; (b) the development of a framework for specifying the abilities needed to perform the tasks required of pediatricians; (c) an elaboration of samples of pediatric subjects to which these abilities and tasks are relevant; and (d) the development of a basis for choice of methods to use for purposes of certification.