PGRMC1 phosphorylation affects cell shape, motility, glycolysis, mitochondrial form and function, and tumor growth.

BACKGROUND: Progesterone Receptor Membrane Component 1 (PGRMC1) is expressed in many cancer cells, where it is associated with detrimental patient outcomes. It contains phosphorylated tyrosines which evolutionarily preceded deuterostome gastrulation and tissue differentiation mechanisms. RESULTS: We demonstrate that manipulating PGRMC1 phosphorylation status in MIA PaCa-2 (MP) cells imposes broad pleiotropic effects. Relative to parental cells over-expressing hemagglutinin-tagged wild-type (WT) PGRMC1-HA, cells expressing a PGRMC1-HA-S57A/S181A double mutant (DM) exhibited reduced levels of proteins involved in energy metabolism and mitochondrial function, and altered glucose metabolism suggesting modulation of the Warburg effect. This was associated with increased PI3K/AKT activity, altered cell shape, actin cytoskeleton, motility, and mitochondrial properties. An S57A/Y180F/S181A triple mutant (TM) indicated the involvement of Y180 in PI3K/AKT activation. Mutation of Y180F strongly attenuated subcutaneous xenograft tumor growth in NOD-SCID gamma mice. Elsewhere we demonstrate altered metabolism, mutation incidence, and epigenetic status in these cells. CONCLUSIONS: Altogether, these results indicate that mutational manipulation of PGRMC1 phosphorylation status exerts broad pleiotropic effects relevant to cancer and other cell biology.

National project seeking to improve pain management in the emergency department setting: findings from the NHMRC-NICS National Pain Management Initiative.

OBJECTIVES: The National Pain Management Initiative was established by the National Institute of Clinical Studies to improve analgesic practice across Australian EDs. METHODS: A barrier analysis provided information to better implement changes in analgesic practice. A working party was established and developed a multifaceted intervention strategy and clinical indicators. An online data collection system was developed and sites collected data at three monthly intervals for 18 months. A stepped-wedge design was chosen to manage the number of hospitals involved. Clinical indicators included documentation of pain score, time to analgesia, appropriate use of parenteral narcotics and effectiveness of analgesia for severe pain. RESULTS: A total of 16,627 patient datasets were entered from 45 metropolitan and regional hospitals. There was an increase from 41% to 64% in documented pain score (difference in proportions 23%, 95% confidence interval: 20-26) and median time to analgesia fell from 61 min (interquartile range: 23-122) to 41 min (interquartile range: 15-95). Appropriate parenteral narcotic use was over 90% for all time points combined. For all patients with severe pain there was no significant change in the proportion with a documented reduction of pain within 1 h of presentation. CONCLUSION: Significant improvements in documentation of pain score and time to analgesia were demonstrated through a national project of targeted improvement. Parenteral narcotic use has a high level of adherence to recommended practice. An improvement in the effectiveness of analgesia in severe pain has not been clearly demonstrated in this study.