Wnt addiction of genetically defined cancers reversed by PORCN inhibition.

Enhanced sensitivity to Wnts is an emerging hallmark of a subset of cancers, defined in part by mutations regulating the abundance of their receptors. Whether these mutations identify a clinical opportunity is an important question. Inhibition of Wnt secretion by blocking an essential post-translational modification, palmitoleation, provides a useful therapeutic intervention. We developed a novel potent, orally available PORCN inhibitor, ETC-1922159 (henceforth called ETC-159) that blocks the secretion and activity of all Wnts. ETC-159 is remarkably effective in treating RSPO-translocation bearing colorectal cancer (CRC) patient-derived xenografts. This is the first example of effective targeted therapy for this subset of CRC. Consistent with a central role of Wnt signaling in regulation of gene expression, inhibition of PORCN in RSPO3-translocated cancers causes a marked remodeling of the transcriptome, with loss of cell cycle, stem cell and proliferation genes, and an increase in differentiation markers. Inhibition of Wnt signaling by PORCN inhibition holds promise as differentiation therapy in genetically defined human cancers.

Improving the quality of CPR in the community.

Bystander cardiopulmonary resuscitation (CPR) is important for survival from out-of-hospital cardiac arrest (OHCA). However, recent research indicates that the quality of CPR is an important and often overlooked factor affecting survival. Individual factors, training, awareness, technique and rescuer fatigue may influence the quality of CPR. Quality components of CPR include rate, ratio, depth and ventilation-compression ratio. The new 2010 CPR guidelines advocate a ratio of compressions to ventilations of 30:2, with a rate of at least 100 compressions per minute. Depth of compression should be at least 5 cm. Rescuers should allow complete recoil of the chest. Locally, limited information is available regarding the quality of CPR being performed for OHCA. Strategies to improve the quality of CPR include research, training, education as well as incorporating appropriate technologies that measure and feedback the quality of CPR. These technologies are at the heart of recent advances, as they now make it feasible to provide routine feedback to rescuers providing CPR, through the integration of feedback devices into training equipment, defibrillators and standalone CPR assist devices.

Proposal for establishment of a National Sudden Cardiac Arrest registry.

There is a need to establish a National Sudden Cardiac Arrest registry that would track the performance and outcomes of out-of-hospital (OHCA) and in-hospital cardiac arrests (IHCA) in the country. An effective strategy to improve survival from sudden cardiac arrest in Singapore requires a multi-pronged effort targeting the community, Emergency Medical Services (EMS) and the hospitals. The establishment of such a registry is important, as it would enable the tracking of trends and effectiveness of subsequent interventions related to our national strategy for management of both OHCA and IHCA. The quality improvement process of measurement-benchmarking-feedback/change is well established. A key part of this process is data collection. A cardiac arrest registry can be a key tool for quality improvement and serves as an important foundation on which to implement and track planned improvements to cardiac arrest management both in and out of hospital. It would also aid in planning for deployment of resources, interventions and ongoing efforts to improve Singapore's EMS.

Singapore Armed Forces Medical Corps-Ministry of Health clinical practice guidelines: management of heat injury.

The Singapore Armed Forces (SAF) Medical Corps and the Ministry of Health (MOH) have published clinical practice guidelines on Management of Heat Injury to provide doctors and patients in Singapore with evidence-based guidance on the prevention and clinical management of exertional heat injuries. This article reproduces the introduction and executive summary (with recommendations from the guidelines) from the SAF Medical Corps-MOH clinical practice guidelines on Management of Heat Injury, for the information of readers of the Singapore Medical Journal. Chapters and page numbers mentioned in the reproduced extract refer to the full text of the guidelines, which are available from the Ministry of Health website: http://www.moh.gov.sg/mohcorp/publications.aspx?id=25178. The recommendations should be used with reference to the full text of the guidelines. Following this article are multiple choice questions based on the full text of the guidelines.

Compensatory caspase activation in MPP+-induced cell death in dopaminergic neurons.

Many have hypothesized that cell death in Parkinson's disease is via apoptosis and, specifically, by the mitochondrial-mediated apoptotic pathway. We tested this hypothesis using a mouse dopaminergic cell line of mesencephalic origin, MN9D, challenged with the Parkinsonism-causing neurotoxin MPP+ (1-methyl-4-phenylpyridinium ion). Apoptosis was the main mode of cell death when the cells were subjected to MPP+ treatment under serum-free conditions for 24 h. Caspase-3 and caspase-9, however, were not activated, thus indicating the existence of alternate or compensatory cell death pathway(s) in dopaminergic neuronal cells. Using caspase inhibitors, we demonstrated that these pathways involve caspase-2, -8, -6 and -7. A time-course study indicated that activation of caspase-2 and -8 occurred upstream of caspase-6 and caspase-7. Upon MPP+ challenge, the apoptosis-inducing factor was translocated from the mitochondria into the MN9D cytosol and nucleus. These results suggest the existence of alternative apoptotic pathways in dopaminergic neurons.