The tumor suppressor protein PTEN is mutated in glioblastoma multiform brain tumors, resulting in deregulated signaling through the phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB) pathway, which is critical for maintaining proliferation and survival. We have examined the relative roles of the two major phospholipid products of PI3K activity, phosphatidylinositol 3,4-biphosphate [PtdIns(3,4)P2] and phosphatidylinositol 3,4,5-triphosphate [PtdIns(3,4,5)P3], in the regulation of PKB activity in glioblastoma cells containing high levels of both of these lipids due to defective PTEN expression. Reexpression of PTEN or treatment with the PI3K inhibitor LY294002 abolished the levels of both PtdIns(3,4)P2 and PtdIns(3,4,5)P3, reduced phosphorylation of PKB on Thr308 and Ser473, and inhibited PKB activity. Overexpression of SHIP-2 abolished the levels of PtdIns(3,4,5)P3, whereas PtdIns(3,4)P2 levels remained high. However, PKB phosphorylation and activity were reduced to the same extent as they were with PTEN expression. PTEN and SHIP-2 also significantly decreased the amount of PKB associated with cell membranes. Reduction of SHIP-2 levels using antisense oligonucleotides increased PKB activity. SHIP-2 became tyrosine phosphorylated following stimulation by growth factors, but this did not significantly alter its phosphatase activity or ability to antagonize PKB activation. Finally we found that SHIP-2, like PTEN, caused a potent cell cycle arrest in G 1 in glioblastoma cells, which is associated with an increase in the stability of expression of the cell cycle inhibitor p27 KIP1 . Our results suggest that SHIP-2 plays a negative role in regulating the PI3K-PKB pathway.

Multibranched stent graft implantation eliminates aneurysm flow, preserves visceral perfusion, and avoids many of the physiologic stresses associated with other forms of repair. The results support an expanded role for this technique in the treatment of TAAA.

We conclude that outcome reports based on SAEF series extending over long time intervals do not accurately represent the results that are currently achieved with standard SAEF treatment with use of EAB plus IGR. This improved outcome is attributed to wide debridement of infected tissue beds, reduced intervals of lower body ischemia, and advances in perioperative management. To determine whether any new treatment approach actually offers improved outcome in the management of SAEF, comparison with EAB plus IGR should be limited to patients treated within the last decade at most.

The Scientific Committee confirms that the Threshold of Toxicological Concern (TTC) is a pragmatic screening and prioritisation tool for use in food safety assessment. This Guidance provides clear step-bystep instructions for use of the TTC approach. The inclusion and exclusion criteria are defined and the use of the TTC decision tree is explained. The approach can be used when the chemical structure of the substance is known, there are limited chemical-specific toxicity data and the exposure can be estimated. The TTC approach should not be used for substances for which EU food/feed legislation requires the submission of toxicity data or when sufficient data are available for a risk assessment or if the substance under consideration falls into one of the exclusion categories. For substances that have the potential to be DNA-reactive mutagens and/or carcinogens based on the weight of evidence, the relevant TTC value is 0.0025 lg/kg body weight (bw) per day. For organophosphates or carbamates, the relevant TTC value is 0.3 lg/kg bw per day. All other substances are grouped according to the Cramer classification. The TTC values for Cramer Classes I, II and III are 30 lg/kg bw per day, 9 lg/kg bw per day and 1.5 lg/kg bw per day, respectively. For substances with exposures below the TTC values, the probability that they would cause adverse health effects is low. If the estimated exposure to a substance is higher than the relevant TTC value, a non-TTC approach is required to reach a conclusion on potential adverse health effects.

Type I endoleaks represent a persistent risk of aneurysm rupture and should be treated promptly by endovascular means. Type II leaks are less dangerous and more difficult to treat, but coil embolization of feeding arteries may be warranted when leakage is associated with aneurysm enlargement.