Prostaglandin E2 and the EP receptors in malignancy: possible therapeutic targets?

Elevated expression of COX-2 and increased levels of PGE2 are found in numerous cancers and are associated with tumour development and progression. Although epidemiological, clinical and preclinical studies have shown that the inhibition of PGE2 synthesis through the use of either non-steroidal anti-inflammatory drugs (NSAIDs) or specific COX-2 inhibitors (COXibs) has the potential to prevent and treat malignant disease, toxicities due to inhibition of COX-2 have limited their use. Thus, there is an urgent need for the development of strategies whereby COX-2 activity may be reduced without inducing any side effects. The biological effects of PGE2 are mediated by signalling through four distinct E-type prostanoid (EP) receptors - EP1 , EP2 , EP3 and EP4 . In recent years, extensive effort has gone into elucidating the function of PGE2 and the EP receptors in health and disease, with the goal of creating selective inhibitors as a means of therapy. In this review, we focus on PGE2 , and in particular on the role of the individual EP receptors and their signalling pathways in neoplastic disease. As knowledge concerning the role of the EP receptors in cancer grows, so does the potential for exploiting the EP receptors as therapeutic targets for the treatment of cancer and metastatic disease.

Donation after circulatory death.

Donation after circulatory death (DCD) describes the retrieval of organs for the purposes of transplantation that follows death confirmed using circulatory criteria. The persisting shortfall in the availability of organs for transplantation has prompted many countries to re-introduce DCD schemes not only for kidney retrieval but increasingly for other organs with a lower tolerance for warm ischaemia such as the liver, pancreas, and lungs. DCD contrasts in many important respects to the current standard model for deceased donation, namely donation after brain death. The challenge in the practice of DCD includes how to identify patients as suitable potential DCD donors, how to support and maintain the trust of bereaved families, and how to manage the consequences of warm ischaemia in a fashion that is professionally, ethically, and legally acceptable. Many of the concerns about the practice of both controlled and uncontrolled DCD are being addressed by increasing professional consensus on the ethical and legal justification for many of the interventions necessary to facilitate DCD. In some countries, DCD after the withdrawal of active treatment accounts for a substantial proportion of deceased organ donors overall. Where this occurs, there is an increased acceptance that organ and tissue donation should be considered a routine part of end-of-life care in both intensive care unit and emergency department.

Public at risk: a survey of sunbed parlour operating practices in Northern Ireland.

BACKGROUND: The International Agency for Research on Cancer has identified artificial ultraviolet (UV) radiation as a class 1 carcinogen. The contribution of sunbeds to malignant melanoma has been estimated at 100 deaths per year in the U.K. The sunbed industry is growing and claims self-regulation. OBJECTIVES: To explore the standards of operation and client protection for sunbed users. METHODS: An observational study of tanning parlour practices was conducted by Environmental Health Practitioners who made unannounced visits to the majority of known commercial tanning parlours in Northern Ireland (population 1.77 million) during July/August 2007. Descriptive statistics were produced and comparisons between groups were made using chi(2) analysis. RESULTS: All 332 premises visited cooperated with the survey. The UV type in machines was unknown in 71.2% of premises while 15.6% reported using type 4, high-dose UV devices; 36.2% of premises did not regularly service sunbeds or were unsure. Unsupervised use of sunbeds was reported in 8.6% of parlours and 3.4% provided a home sunbed service. Eye protection was available in 97.6% of premises but 34.6% charged for the service and only 79.6% sanitized these between use. Of the responders 15.9% were members of the Sunbed Association. These were more likely to have maintenance records and operating manuals but were also more likely to provide a home sunbed service. CONCLUSIONS: This study highlights the need for improved standards of regulation of the sunbed industry to protect clients from excessive and dangerous levels of UV radiation in a population where the numbers of melanomas continue to rise.

Prostaglandin E2 stimulates Fas ligand expression via the EP1 receptor in colon cancer cells.

Fas ligand (FasL/CD95L) is a member of the tumour necrosis factor superfamily that triggers apoptosis following crosslinking of the Fas receptor. Despite studies strongly implicating tumour-expressed FasL as a major inhibitor of the anti-tumour immune response, little is known about the mechanisms that regulate FasL expression in tumours. In this study, we show that the cyclooxygenase (COX) signalling pathway, and in particular prostaglandin E(2) (PGE(2)), plays a role in the upregulation of FasL expression in colon cancer. Suppression of either COX-2 or COX-1 by RNA interference in HCA-7 and HT29 colon tumour cells reduced FasL expression at both the mRNA and protein level. Conversely, stimulation with PGE(2) increased FasL expression and these cells showed increased cytotoxicity against Fas-sensitive Jurkat T cells. Prostaglandin E(2)-induced FasL expression was mediated by signalling via the EP1 receptor. Moreover, immunohistochemical analysis using serial sections of human colon adenocarcinomas revealed a strong positive correlation between COX-2 and FasL (r=0.722; P<0.0001) expression, and between EP1 receptor and FasL (r=0.740; P<0.0001) expression, in the tumour cells. Thus, these findings indicate that PGE(2) positively regulates FasL expression in colon tumour cells, adding another pro-neoplastic activity to PGE(2).

The role of immune-enhancing diets in the management of perioperative patients.

OBJECTIVE: To review the effects of immunonutrients in the perioperative patient. DATA SOURCES: Articles and published peer-review abstracts of studies reported on immune enhancing diets in patients during the perioperative period. SUMMARY OF REVIEW: Enteral nutrition is the method of choice for substrate supplementation in patients with a normal gastrointestinal tract but who are otherWise unable to eat normally. It is also a safer, more practical and less expensive alternative to the parenteral route and is now being used successfully in previously contraindicated conditions including pancreatitis and major abdominal trauma. Advances in enteral nutrition include the development of immunonutrients which have been used to attenuate the adverse effects of starvation, illness and surgery on the architecture and function of the gastrointestinal tract, implicated in the development of multiple organ dysfunction syndrome. These agents stimulate immune function and are potentially an effective strategy in improving the outcome in the peri-operative period by reducing post-operative infections and length of hospital stay. CONCLUSIONS: Immunonutrition confers an additive benefit when compared with standard enteral and parenteral nutrient preparations in the management of perioperative malnourished patients. What is less clear is at what severity of illness this benefit begins, whether there is a significant reduction in mortality and at what point the cost benefit in the reduction in complications no longer occurs.

MDMA toxicity presenting with severe hyperpyrexia: a case report.

Ingestion of even small amounts of MDMA ('ecstasy') by a small subset of the population may result in a potentially fatal clinical syndrome of severe hyperpyrexia, cardiovascular collapse, coagulopathy, rhabdomyolysis and multiple organ failure. Rapid and aggressive temperature control is of utmost importance in the management of these patients. We report a case of MDMA toxicity presenting with severe hyperpyrexia (43 degrees C) who survived after a rapid reduction in temperature to 36 degrees C within 60 minutes following active surface cooling, cooled (approximately 4 degrees C) intravenous solutions, urinary and gastric lavage solutions and replacement fluids for continuous veno-venous diafiltration.