Circadian function in patients with advanced non-small-cell lung cancer

This study aimed to evaluate whether patients with advanced non-small-cell lung cancer experience disrupted rest–activity daily rhythms, poor sleep quality, weakness, and maintain attributes that are linked to circadian function such as fatigue. This report describes the rest–activity patterns of 33 non-small-cell lung cancer patients who participated in a randomised clinical trial evaluating the benefits of melatonin. Data are reported on circadian function, health-related quality of life (QoL), subjective sleep quality, and anxiety/depression levels prior to randomisation and treatment. Actigraphy data, an objective measure of circadian function, demonstrated that patients' rest–activity circadian function differs significantly from control subjects. Our patients reported poor sleep quality and high levels of fatigue. Ferrans and Powers QoL Index instrument found a high level of dissatisfaction with health-related QoL. Data from the European Organization for Research and Treatment for Cancer reported poor capacity to fulfil the activities of daily living. Patients studied in the hospital during or near chemotherapy had significantly more abnormal circadian function than those studied in the ambulatory setting. Our data indicate that measurement of circadian sleep/activity dynamics should be accomplished in the outpatient/home setting for a minimum of 4–7 circadian cycles to assure that they are most representative of the patients' true condition. We conclude that the daily sleep/activity patterns of patients with advanced lung cancer are disturbed. These are accompanied by marked disruption of QoL and function. These data argue for investigating how much of this poor functioning and QoL are actually caused by this circadian disruption, and, whether behavioural, light-based, and or pharmacologic strategies to correct the circadian/sleep activity patterns can improve function and QoL

Evaluating government health and substance abuse programs for indigenous peoples: a comparative review

Most health and substance abuse programs for indigenous peoples in Australia are funded by the government. Over the past decade there have been calls for greater accountability in the conduct of these programs. Initial attempts focussed on the development of standardised performance indicators, an approach that has been criticised on both political and methodological grounds. Recently, some government agencies have sought to identify culturally appropriate models for the evaluation of programs for indigenous peoples. In a comparative review of the evaluation of indigenous programs in Australia and Canada, conducted for the Western Australian Aboriginal Affairs Department, the authors were not able to identify and generally applicable models. However,this literature review and our own research and experience in working with Aboriginal community organisations have identified some principles that should be an essential part of any attempts to evaluate health and substance abuse programs for indigenous peoples. Underlying these principles is the realisation that evaluation is not a politically or ideologically neutral activity.Theoretical and methodological considerations of the evaluation process must take into account the very real differences between the agenda of indigenous peoples and those who seek to evaluate programs for them

β-catenin represses expression of the tumour suppressor 15-prostaglandin dehydrogenase in the normal intestinal epithelium and colorectal tumour cells

Background: Cyclooxygenase-2 (COX-2) overexpression in colorectal cancer increases levels of its protumorigenic product prostaglandin E2 (PGE2). The recently identified colorectal tumour suppressor 15-prostaglandin dehydrogenase (15-PGDH) catalyses prostaglandin turnover and is downregulated at a very early stage in colorectal tumorigenesis; however, the mechanism responsible remains unclear. As Wnt/β-catenin signalling is also deregulated early in colorectal neoplasia, a study was undertaken to determine whether β-catenin represses 15-PGDH expression. Methods: The effect of modulating Wnt/β-catenin signalling (using β-catenin siRNA, mutant TCF4, Wnt3A or GSK3 inhibition) on 15-PGDH mRNA, protein expression and promoter activity was determined in colorectal cell lines by immunoblotting, qRT-PCR and reporter assays. The effect of β-catenin deletion in vivo was addressed by 15-PGDH immunostaining of β-catenin-/lox-villin-creERT2 mouse tissue. 15-PGDH promoter occupancy was determined using chromatin immunoprecipitation and PGE2 levels by ELISA. Results: The study shows for the first time that β-catenin knockdown upregulates 15-PGDH in colorectal adenoma and carcinoma cells without affecting COX-2 protein levels. A dominant negative mutant form of TCF4 (dnTCF4), unable to bind β-catenin, also upregulated 15-PGDH; conversely, increasing β-catenin activity using Wnt3A or GSK3 inhibition downregulated 15-PGDH. Importantly, inducible β-catenin deletion in vivo also upregulated intestinal epithelial 15-PGDH. 15-PGDH regulation occurred at the protein, mRNA and promoter activity levels and chromatin immunoprecipitation indicated β-catenin/TCF4 binding to the 15-PGDH promoter. β-catenin knockdown decreased PGE2 levels, and this was significantly rescued by 15-PGDH siRNA. Conclusion: These data suggest a novel role for β-catenin in promoting colorectal tumorigenesis through very early 15-PGDH suppression leading to increased PGE2 levels, possibly even before COX-2 upregulation

The proapoptotic BH3-only protein Bim is downregulated in a subset of colorectal cancers and is repressed by antiapoptotic COX-2/PGE2 signalling in colorectal adenoma cells

Overexpression of cyclooxygenase-2 (COX-2) and elevated levels of its enzymatic product prostaglandin E2 (PGE 2) occur in the majority of colorectal cancers and have important roles in colorectal tumorigenesis. However, despite the established prosurvival role of PGE 2 in cancer, the underlying mechanisms are not fully understood. Here, we have shown that PGE2 suppresses apoptosis via repression of the proapoptotic BH3-only protein Bim in human colorectal adenoma cells. Repression of Bim expression was dependent upon PGE 2-mediated activation of the Raf-MEK-ERK1/2 pathway, which promoted Bim phosphorylation and proteasomal degradation. Reduction of Bim expression using RNA interference reduced spontaneous apoptosis in adenoma cells and abrogated PGE 2-dependent apoptosis suppression. Treatment of COX-2-expressing colorectal carcinoma cells with COX-2-selective NSAIDs-induced Bim expression, suggesting that Bim repression via PGE2 signalling may be opposed by COX-2 inhibition. Examination of Bim expression in two established in vitro models of the adenoma-carcinoma sequence revealed that downregulation of Bim expression was associated with tumour progression towards an anchorage-independent phenotype. Finally, immunohistochemical analyses revealed that Bim expression is markedly reduced in approximately 40% of human colorectal carcinomas in vivo. These observations highlight the COX-2/PGE2 pathway as an important negative regulator of Bim expression in colorectal tumours and suggest that Bim repression may be an important step during colorectal cancer tumorigenesis. © 2010 Macmillan Publishers Limited All rights reserved