Activation of Cell Cycle Arrest and Apoptosis by the Proto-Oncogene Pim-2

Potent survival effects have been ascribed to the serine/threonine kinase proto-oncogene PIM-2. Elevated levels of PIM-2 are associated with various malignancies. In human cells, a single Pim-2 transcript gives rise mainly to two protein isoforms (34, 41 kDa) that share an identical catalytic site but differ at their N-terminus, due to in-frame alternative translation initiation sites. In this study we observed that the 34 kDa PIM-2 isoform has differential nuclear and cytoplasmic forms in all tested cell lines, suggesting a possible role for the balance between these forms for PIM-2's function. To further study the cellular role of the 34 kDa isoform of PIM-2, an N-terminally HA-tagged form of this isoform was transiently expressed in HeLa cells. Surprisingly, this resulted in increased level of G1 arrested cells, as well as of apoptotic cells. These effects could not be obtained by a Flag-tagged form of the 41 kDa isoform. The G1 arrest and apoptotic effects were associated with an increase in T14/Y15 phosphorylation of CDK2 and proteasom-dependent down-regulation of CDC25A, as well as with up-regulation of p57, E2F-1, and p73. No such effects were obtained upon over-expression of a kinase-dead form of the HA-tagged 34 kDa PIM-2. By either using a dominant negative form of p73, or by over-expressing the 34 kDa PIM-2 in p73-silenced cells, we demonstrated that these effects were p73-dependent. These results demonstrate that while PIM-2 can function as a potent survival factor, it can, under certain circumstances, exhibit pro-apoptotic effects as well

Cardiac response and complications during endovascular repair of abdominal aortic aneurysms: A concurrent comparison with open surgery

AbstractPurpose: The purpose of this study was to assess and to compare perioperative changes in left ventricular function and the incidence of adverse cardiac events in two groups of patients with abdominal aortic aneurysms, one during endovascular aneurysm repair (EAR) and the other during open aneurysm repair (OAR). Methods: One hundred twenty consecutive patients who underwent EAR (49 patients) or OAR (71 patients) were prospectively studied. During the operation, the left ventricular function was assessed by the recording of the left ventricle stroke work index (SWI) and the cardiac index (CI) with a pulmonary artery catheter. Measurements were performed before, during, and after stent-graft deployment or aortic cross-clamping. Both maneuvers were defined as aortic occlusion (AO). Transesophageal echocardiography was performed to identify signs of wall motion abnormalities of the left ventricular wall, which indicated myocardial ischemia. Six-lead electrocardiograph monitoring was maintained until discharge from the intensive care unit. Postoperative cardiac complications were diagnosed by clinical observation, 12-lead ECG analysis at 1, 3, and 7 days after the operation, transthoracic echocardiography at 1 month, and measurement of cardiac enzymes. Results: The two study groups were comparable with regard to most clinical aspects. The baseline myocardial performance was worse in patients who underwent EAR compared with patients who underwent OAR, as indicated by a reduced SWI (33.1 and 37.4, respectively; P =.03). During AO there was a comparable increase of the CI in both groups. However, after AO the rise in CI was higher in patients who underwent OAR compared with patients who underwent EAR (0.7 and 0.2, respectively; P <.01), representing a more pronounced hyperdynamic state. In addition, the SWI demonstrated a decrease in patients who underwent OAR compared with an increase in patients who underwent EAR during AO (–1.4 and +1.9, respectively; P =.04) and after AO (–0.9 and +2.6, respectively; P =.01). These findings represent more severe myocardial stress in patients who underwent OAR. The incidence of postoperative clinical cardiac adverse events was comparable in the two study groups. However, myocardial ischemia, as indicated by electrocardiography and transesophageal echocardiography, had a higher incidence in patients who underwent open surgery as compared with patients whose condition was managed endovascularly (57% and 33%, respectively; P =.01). Conclusion: Hemodynamic alterations during endovascular repair were not as severe as those in patients with open surgery and indicated less myocardial stress in the former category. These findings may explain a lower incidence of myocardial ischemia that was observed during endovascular repair. A lower frequency of clinical perioperative cardiac events in patients undergoing endovascular treatment may ultimately be expected. (J Vasc Surg 2001;33:353-60.

Five-year results of a randomized clinical trial of conventional surgery, endovenous laser ablation and ultrasound-guided foam sclerotherapy in patients with great saphenous varicose veins

BackgroundA variety of techniques exist for the treatment of patients with great saphenous vein (GSV) varicosities. Few data exist on the long-term outcomes of these interventions. MethodsPatients undergoing conventional surgery, endovenous laser ablation (EVLA) and ultrasound-guided foam sclerotherapy (UGFS) for GSV varicose veins were followed up for 5years. Primary outcome was obliteration or absence of the treated GSV segment; secondary outcomes were absence of GSV reflux, and change in Chronic Venous Insufficiency quality-of-life Questionnaire (CIVIQ) and EuroQol-5D (EQ-5D) scores. ResultsA total of 224 legs were included (69 conventional surgery, 78 EVLA, 77 UGFS), 193 (862 per cent) of which were evaluated at final follow-up. At 5years, Kaplan-Meier estimates of obliteration or absence of the GSV were 85 (95 per cent c.i. 75 to 92), 77 (66 to 86) and 23 (14 to 33) per cent in the conventional surgery, EVLA and UGFS groups respectively. Absence of above-knee GSV reflux was found in 85 (73 to 92), 82 (72 to 90) and 41 (30 to 53) per cent respectively. CIVIQ scores deteriorated over time in patients in the UGFS group (098 increase per year, 95 per cent c.i. 016 to 179), and were significantly worse than those in the EVLA group (-044 decrease per year, 95 per cent c.i. -122 to 035) (P=0013). CIVIQ scores for the conventional surgery group did not differ from those in the EVLA and UGFS groups (044 increase per year, 95 per cent c.i. -041 to 129). EQ-5D scores improved equally in all groups. ConclusionEVLA and conventional surgery were more effective than UGFS in obliterating the GSV 5years after intervention. UGFS was associated with substantial rates of GSV reflux and inferior CIVIQ scores compared with EVLA and conventional surgery. Registration number: NCT00529672 (http://www.clinicaltrials.gov)