Review Essay

Book reviewed: Christopher C. Sellers, The Trials of Developing the ‘Social’ With the ‘Science’: A Review Essay of Hazards of the Job: From Industrial Disease to Environmental Health Science     

Carfilzomib Promotes the Unfolded Protein Response and Apoptosis in Cetuximab-Resistant Colorectal Cancer

Cetuximab is a common treatment option for patients with wild-type K-Ras colorectal carcinoma. However, patients often display intrinsic resistance or acquire resistance to cetuximab following treatment. Here we generate two human CRC cells with acquired resistance to cetuximab that are derived from cetuximab-sensitive parental cell lines. These cetuximab-resistant cells display greater in vitro proliferation, colony formation and migration, and in vivo tumour growth compared with their parental counterparts. To evaluate potential alternative therapeutics to cetuximab-acquired-resistant cells, we tested the efficacy of 38 current FDA-approved agents against our cetuximab-acquired-resistant clones. We identified carfilzomib, a selective proteosome inhibitor to be most effective against our cell lines. Carfilzomib displayed potent antiproliferative effects, induced the unfolded protein response as determined by enhanced CHOP expression and ATF6 activity, and enhanced apoptosis as determined by enhanced caspase-3/7 activity. Overall, our results indicate a potentially novel indication for carfilzomib: that of a potential alternative agent to treat cetuximab-resistant colorectal cancer.     

EPLIN,a Putative Tumour Suppressor in Colorectal Cancer,Implications in Drug Resistance

Colorectal cancer is a serious threat to human health. Poor prognosis and frequently reported drug resistance urges research into novel biomarkers and mechanisms to aid in the understanding of the development and progression of colorectal cancer and to optimise therapeutic strategies. In the current study, we investigated the roles of a putative tumour suppressor, EPLIN, in colorectal cancer. Our clinical colorectal cancer cohort and online databases revealed a downregulation of EPLIN in colorectal cancer tissues compared with normal tissues. The reduced expression of EPLIN was associated with poor clinical outcomes of patients. In vitro cellular function assays showed that EPLIN elicited an inhibitory effect on cellular growth, adhesion, migration and invasion. Utilising a protein microarray on protein samples from normal and tumour patient tissues suggested HSP60, Her2 and other signalling events were novel potential interacting partners of EPLIN. It was further revealed that EPLIN and HSP60 were negative regulators of Her2 in colorectal cancer cells. The clinical cohort also demonstrated that expression of HSP60 and Her2 affected clinical outcomes, but most interestingly the combination of EPLIN, HSP60 and Her2 was able to identify patients with the most unfavourable clinical outcome by independently predicting patient overall survival and disease free survival. Furthermore, EPLIN and HSP60 exhibited potential to regulate cellular response to chemotherapeutic and EGFR/Her2 targeted therapeutic agents. In conclusion, EPLIN is an important prognostic factor for patients with colon cancer and reduced EPLIN in CRC contributes to aggressive traits of CRC cells and their responses to chemotherapeutic drugs. Collectively, EPLIN is a pivotal factor for the development and progression of colorectal cancer and has important clinical and therapeutic values in this cancer type.     

Systems engineering methodologies, tacit knowledge and communities of practice

In the context of technology development and systems engineering, knowledge is typically treated as a complex information structure. In this view, knowledge can be stored in highly sophisticated data systems and processed by explicitly intelligent, software-based technologies. This paper argues that the current emphasis upon knowledge as information (or even data) is based upon a form of rationalism which is inappropriate for any comprehensive treatment of knowledge in the context of human-centred systems thinking. A human-centred perspective requires us to treat knowledge in human terms. The paper sets out the particular importance of tacit knowledge in this regard. It sets out two case studies which reveal the critical importance of a careful treatment of tacit knowledge for success in two complex, technology-driven projects.

Exercise referral: the public health panacea for physical activity promotion? A critical perspective of exercise referral schemes; their development and evaluation

This review critically explores the development, impact and evaluation of exercise referral schemes (ERS) in the UK. A rapid expansion in the use of such ERSs has been recorded throughout leisure and primary care settings, but the evidence underpinning their implementation has been sparse and predominantly limited to randomized control trial (RCT) research design. Consequently, understanding of exercise referral as a 'real world' intervention has been limited. Considering the increasing importance being placed on evidence-based practice and clinical effectiveness, it is no longer sufficient for service providers of exercise referral to ignore the need to evaluate schemes. The guidelines on evaluation provided by the National Quality Assurance Framework for Exercise Referral are limited, hence practitioners are often unsure of the best measures to use when assessing effectiveness. Predominantly, exercise professionals focus on the collection of physiological data but tend to ignore relevant psychological and environmental parameters. Also, few UK studies have followed participants up in the long term, to see if physical activity behaviour is sustained over time. Here, evidence from two on-going, large-scale (n = 1600/annum) evaluation studies of exercise referral schemes, based in urban localities in the northwest of England, are described. A participatory action research framework for evaluation was utilized and incorporated multi-method research approaches for the assessment of both ERS participants and health professionals involved in intervention delivery. This framework is an appropriate methodology for the evaluation and development of complex interventions, and here incorporates case study, focus groups, interviews and survey questionnaires. Included was a 12-month tracking study of a cohort of exercise referral participants (n = 342), which measured leisure-time physical activity levels (Godin leisure time score), at baseline (entry to exercise referral) and at 3 monthly intervals thereafter. Adherence to the ERS was approximately 35-45%, with the older participants more likely to complete. Physiological changes during the ERS, although statistically significant, were not of a magnitude to convey any real health benefit to an individual's health status. Although small in scale, physiological changes were all in a positive direction (e.g. reduction in blood pressure) and, if maintained over time, could bring about population-level benefits in health. Participants referred from cardiac and practice nurses had higher levels of adherence than participants referred by general practitioners. Scheme B showed that the participants who adhered (n = 103) until the end of the ERS (12 weeks) were able to sustain a small increase in physical activity at the end of 12 months (increase of 21 min moderate activity/week compared with baseline). In conclusion, this research shows that the process of exercise referral benefits certain segments of the population, but not necessarily all.     

The lantibiotic lacticin 3147 produced in a milk-based medium improves the efficacy of a bismuth-based teat seal in cattle deliberately infected with Staphylococcus aureus

A preparation of the bacteriocin lacticin 3147 (prepared from a demineralized whey protein fermentation liquor) was combined as a powder with a bismuth-based intramammary teat seal and evaluated for its potential as an antimicrobial in non-lactating cows. The lacticin/teat seal formulation enabled significant bacteriocin release from the seal without the requirement for a surfactant. Studies in vivo in lactating cows demonstrated that this formulation was effective in reducing bacterial recoveries (approximately 20-fold) from teats deliberately inoculated with Staphylococcus aureus after infusion. Moreover, this formulation also significantly reduced the numbers of Staph. aureus recovered from teats that were exposed to the challenge bacterium before the infusion of the teat seal preparation. The powdered preparation of lacticin 3147 did, however, cause some teat irritation as evidenced by associated rises in somatic cell count (SCC). However, this effect was short-lived and when the mean SCC readings pre-infusion and the final two readings post-infusion were compared, there was no significant difference in the immunological acceptance between treatments.     

Effect of selenium status and supplementation with high-selenium yeast on plasma homocysteine and B vitamin concentrations in the UK elderly

The level of plasma total homocysteine (tHcy), long known to be B vitamin dependent, has recently been shown to be inversely associated with plasma selenium (Se) concentration in human subjects. We therefore, chose to investigate the interaction between Se, tHcy and B vitamins in a double-blind, placebo-controlled trial where 501 healthy UK elderly volunteers were randomly allocated to receive 100, 200, or 300 microg Se/day as high-Se-yeast, or placebo-yeast for 6 months. Plasma Se, tHcy, folate, vitamin B-12, pyridoxal-5'-phosphate (PLP) and its catabolite, 4-pyridoxic acid, were measured in all participants at baseline and in samples from the placebo, 100 and 300 microg Se/day groups, at follow-up. At baseline, Se was inversely correlated with tHcy but only in males (p < 0.001). Before supplementation, tHcy concentration was significantly lower in the highest compared to the lowest Se tertile in males (p < 0.05), and in females when folate concentrations were also in the top tertile (p < 0.05). The effect of folate, PLP and vitamin B-12 concentrations on plasma tHcy correlated with Se concentration at baseline. After 6 months of Se supplementation, only Se concentration had changed significantly. Supplementation with Se does not affect tHcy concentration in the UK elderly population.