Dissection of TBK1 signaling via phosphoproteomics in lung cancer cells

TANK-binding kinase 1 (TBK1) has emerged as a novel therapeutic target for unspecified subset of lung cancers. TBK1 reportedly mediates prosurvival signaling by activating NF-κB and AKT. However, we observed that TBK1 knockdown also decreased viability of cells expressing constitutively active NF-κB and interferon regulatory factor 3. Basal phospho-AKT level was not reduced after TBK1 knockdown in TBK1-sensitive lung cancer cells, implicating that TBK1 mediates unknown survival mechanisms. To gain better insight into TBK1 survival signaling, we searched for altered phosphoproteins using mass spectrometry following RNAi-mediated TBK1 knockdown. In total, we identified 2,080 phosphoproteins (4,621 peptides), of which 385 proteins (477 peptides) were affected after TBK1 knockdown. A view of the altered network identified a central role of Polo-like kinase 1 (PLK1) and known PLK1 targets. We found that TBK1 directly phosphorylated PLK1 in vitro. TBK1 phosphorylation was induced at mitosis, and loss of TBK1 impaired mitotic phosphorylation of PLK1 in TBK1-sensitive lung cancer cells. Furthermore, lung cancer cell sensitivity to TBK1 was highly correlated with sensitivity to pharmacological PLK inhibition. We additionally found that TBK1 knockdown decreased metadherin phosphorylation at Ser-568. Metadherin was associated with poor outcome in lung cancer, and loss of metadherin caused growth inhibition and apoptosis in TBK1-sensitive lung cancer cells. These results collectively revealed TBK1 as a mitosis regulator through activation of PLK1 and also suggested metadherin as a putative TBK1 downstream effector involved in lung cancer cell survival.     

Protocol in managing oral surgical patients taking dabigatran

New anticoagulants are being introduced into the market. These drugs are orally administered, have predictable pharmacokinetics and dose response, do not require monitoring and have an acceptable safety profile when used appropriately, and so avoid many of the disadvantages and possible complications of warfarin and heparin. Dabigatran is the most widely used, and has been approved by the Therapeutic Goods Administration. The use of dabigatran will likely increase in the coming years, and so it is important for dentists to be aware of its mechanism of action, the possible complications, and how to reverse the bleeding if it occurs. This review discusses dabigatran and reports on our experience of five cases, and provides practical clinical advice on how to manage patients on dabigatran who require dental treatment, particularly extractions.     

Abdominal compartment syndrome caused by tension pneumoperitoneum in a scuba diver

Abdominal compartment syndrome is a surgical emergency caused by a raised intra-abdominal pressure, which may lead to respiratory, cardiovascular and renal compromise. It is most commonly seen in post-operative and trauma patients and it has a variety of causes. Tension pneumoperitoneum (TP) is a rare cause of abdominal compartment syndrome most often seen after gastrointestinal endoscopy with perforation.We present the case of a fit 52-year-old experienced female diver who developed TP and shock following a routine training dive to 27m. Following accidental inhalation of water, she had an unstaged ascent and, on reaching the surface, developed severe acute abdominal pain and distension. She was brought to our emergency department by air ambulance for assessment. Clinical and radiological examination revealed a shocked patient with dramatic free intra-abdominal gas and signs of abdominal compartment syndrome, which was treated with needle decompression. Symptoms and signs resolved quickly with no need for further surgical intervention. TP is a surgical emergency where surgery can be avoided with prompt diagnosis and treatment.