Dietary agents as histone deacetylase inhibitors

In cancer cells, an imbalance often exists between histone acetyltransferase (HAT) and histone deacetylase (HDAC) activities, and various drug companies are actively seeking competitive HDAC inhibitors for chemotherapeutic intervention. Cancer cells appear to be more sensitive than nontransformed cells to HDAC inhibitors, which disrupt the cell cycle and induce apoptosis via derepression of genes such as P21 and BAX. However, in the search for potent HDAC inhibitors with cancer therapeutic potential, a tendency exists to overlook or dismiss weak ligands that could prove effective in cancer prevention. Butyrate, diallyl disulfide (DADS), and sulforaphane (SFN) are three dietary agents that exhibit HDAC inhibitory activity in vitro and/or in vivo, and other such dietary agents probably will be discovered that affect HDAC activity. We make the distinction between 'pharmacologic' agents that potently derepress gene expression, during therapeutic intervention, and dietary HDAC inhibitors that, as weak ligands, might subtly regulate the expression of genes involved in cell growth and apoptosis. An important issue for future study is to determine the extent to which dietary HDAC inhibitors, by modulating genes such as p21 and Bax, enable normal, nontransformed cells to respond most effectively to external stimuli and toxic insults.     

Long-term follow-up of people who have survived cancer during childhood

Substantial improvements in survival after treatment for malignant disease in childhood are leading to a rapidly increasing number of long-term survivors, many of whom are now adults. However, late chronic adverse effects of treatment are common, and have potentially severe effects on survivors' future physical, cognitive, or psychosocial health. The aim of long-term follow-up is to facilitate timely diagnosis and appropriate management of late adverse effects, thereby reducing the frequency of severe complications. Although the delivery of long-term follow-up care varies substantially--particularly in terms of who provides it, where, and how--recognition of the importance of appropriate multidisciplinary care and cross-speciality care is increasing, especially for adolescent and adult survivors of cancer during childhood. Several models of long-term follow-up care have been developed to address this need. This review discusses the present provision of long-term follow-up, and summarises information that might facilitate design and implementation of future models of long-term follow-up care.     

Treatment of inflammatory diseases by selective eicosanoid inhibition: a double-edged sword?

Eicosanoids are generally considered to be potent pro-inflammatory mediators, and their suppression has, therefore, been a desirable therapeutic goal. However, analysis of the literature reveals that inhibition of specific eicosanoids per se is a simplistic approach because it overlooks the fact that net pathophysiological effects of these lipid mediators arise from a complex balance between eicosanoids derived from different pathways, which might exhibit both pro-and anti-inflammatory activities (depending on organs and disease stage), or which might have essential physiological roles. An alternative strategy, discussed in this review, might be to control inflammatory lipid mediators in such a way as to avoid disrupting this intricate inter-eicosanoid balance and its physiological sequelae.     

Effect of alcohol on the lactate/pyruvate ratio of recently injured adults

OBJECTIVE: To compare the ability of plasma (lactate) and the plasma lactate/pyruvate (L/P) ratio to predict shock-related outcome after injury and also to examine the influence of plasma ethanol on any relationships found. DESIGN: Prospective observational study. SETTING: Emergency departments in the UK and the Republic of South Africa. PATIENTS: Blood samples were taken at presentation from 232 adult patients 1-23 hrs (median, 3.5 hrs) after sustaining an injury or injuries deemed sufficiently severe to require inpatient care. MEASUREMENTS: Plasma concentrations of lactate, pyruvate, and ethanol, anatomical severity of injury, development of multiple organ failure, and 30-day survival were determined. RESULTS: At 90% specificity for predicting subsequent mortality and/or multiple organ failure, plasma lactate >or=3.85 mmol/L was 23% (5% to 41%) more sensitive than an L/P ratio of >or=42.76. At 90% sensitivity for ruling out morbidity, plasma lactate <1.6 mmol/L is 6% (-1% to 13%) more specific than an L/P ratio of <14.08. High L/P ratios were noted to be associated with a detectable plasma alcohol level. A post hoc regression analysis showed that alcohol-positive/-negative status was a much stronger predictor of the L/P ratio than was anatomical severity of injury, shock, or time after injury. CONCLUSIONS: Plasma lactate alone is a better predictor than the L/P ratio of shock-related outcome after injury. The interpretation of L/P ratios after injury is confounded in the presence of elevated plasma ethanol.     

Graft-versus-host disease can be separated from graft-versus-lymphoma effects by control of lymphocyte trafficking with FTY720

Graft-versus-host disease (GvHD) mediated by donor T cells recognizing host alloantigens is associated with beneficial graft-versus-tumor effects in recipients of allogeneic hematopoietic cell transplants. Since leukemias and lymphomas reside largely within the lymphohematopoietic system, we have proposed that the desired graft-versus-leukemia or graft-versus-lymphoma effect can be separated from the complication of GvHD by confinement of the graft-versus-host alloresponse to the lymphohematopoietic tissues. Since the new sphingosine-1-phosphate receptor agonist immunosuppressive drug FTY720 leads to trapping of T cells in secondary lymphoid tissues, we evaluated the possibility that this drug could diminish GvHD, a disease involving epithelial target tissues, while permitting a beneficial alloresponse to take place within the lymphohematopoietic system, leading to graft-versus-lymphoma effects. We demonstrate here that FTY720 markedly reduces GvHD in a clinically relevant, haploidentical strain combination, while permitting antitumor effects against a T cell lymphoma of unshared host MHC haplotype to proceed unhindered. These results establish a potential new immunotherapeutic approach to separating graft-versus-leukemia effects from GvHD.