Modified Sandwich-graft Technique Employing Aorfix and Viabahn Stent-grafts to Preserve Hypogastric Flow in Cases of Complex Aortoiliac and Isolated Common Iliac Artery Aneurysms Including the Internal Iliac Artery Ostium.

OBJECTIVE: The aim was to assess the early and mid-term safety and clinical outcomes of a modified sandwich-graft technique (MSGT) that employed the Aorfix and Viabahn stent-grafts to preserve hypogastric flow in cases of complex aortoiliac and isolated common iliac artery (CIA) aneurysms including internal iliac artery (IIA) ostium who were not suitable for an iliac branch device (IBD). METHODS: A review of prospective collected data of all consecutive cases of treatment of complex aortoiliac or isolated CIA aneurysms including IIA ostium using the MSGT to preserve the hypogastric flow in three European centres between April 1, 2010, and December 31, 2013, was performed. All patients included were unfit for open repair and not suitable for an IBD. RESULTS: During the study period, 21 patients met the study criteria and had 25 MSGTs. The mean follow-up duration was 17.2 months. The technical success rate was 100%, with no perioperative mortality and stent-graft or MSGT-treated IIA occlusions. There were two cases with Type Ib endoleaks and one Type III endoleaks intraoperatively that were successfully managed. There was also no reported early and late pelvic ischaemia. The primary patency rate was 90.5%, and two cases of MGST treated IIA occlusions with no reported symptoms of pelvic ischaemia during follow-up. CONCLUSIONS: MSGT was a safe and feasible strategy to preserve hypogastric flow in cases of complex aortoiliac and isolated CIA aneurysms including IIA ostium and who were not suitable for IBD, with encouraging early and mid-term outcomes.

Lovastatin and simvastatin are modulators of the proteasome.

Lovastatin and simvastatin are HMG-CoA reductase inhibitors widely used as antihyperlipidemic drugs, which also display antiproliferative properties. In the present paper, we provide evidence that both lovastatin and simvastatin are modulators of the purified bovine pituitary 20 S proteasome, since they mildly stimulate the chymotrypsin-like activity and inhibit the peptidylglutamylpeptide hydrolyzing activity without interfering with the trypsin-like activity. However, those effects are only observed when the closed ring forms of the drugs are used, while the opened ring form of lovastatin acts as a mild inhibitor of the chymotrypsin like activity. The closed ring form of lovastatin is much more potent as a cytotoxic agent on the Colon-26 (C-26) colon carcinoma cell line than the opened ring form, which is only mildly cytostatic. Moreover, neither the cytotoxic effects nor the effects on 20 S proteasome activities are prevented by mevalonate, which by itself inhibits the trypsin-like activity of the proteasome. Neither the opened ring nor the closed ring form of lovastatin induces an accumulation of ubiquitin-protein conjugates, which is observed after treatment with lactacystin, a selective proteasome inhibitor. In contrast with the opened ring form of lovastatin, the closed ring form induces the disappearance of detectable p27(kip1) from C-26 cells. Altogether, our results indicate that the closed ring form of lovastatin induces cytotoxic effects independent of its HMG-CoA inhibiting activity, however, those effects are mediated by a complex modulation of proteasome activity rather than by inhibition of the 20 S proteasome.

Effects of proteasome inhibitor PSI on neoplastic and non-transformed cell lines.

In this study we compared the sensitivity of different human and murine cell lines varying in the stage of transformation to dose- and time-dependent cytostatic and/or cytotoxic effects of PSI (a selective proteasome inhibitor), measured by a standard MTT assay. It was found that intensively proliferating cell lines were more sensitive to very small doses of PSI after 24 h incubation than the slow proliferating ones. Non-transformed cell lines showed no sensitivity to PSI, as there was no difference in cell viability in comparison with the control group even after 72 h incubation.

Effects of the combination of a proteasome inhibitor (PSI) and an inhibitor of ubiquitin-ligases (Leu-Ala) on the ultrastructure of human leukemic U937 cells.

We have used the dipeptide Leu-Ala in an attempt to prevent the formation of ubiquitin-protein conjugates in U937 cells by inhibition of cellular E3 enzymes (ubiquitin ligases). Proteasome inhibitors induce the formation of perinuclear aggregates of ubiquitinated proteins and proteasomes (aggresomes) in the area of the proteolytic center of the cell. Leu-Ala did not prevent the forrmation of those aggregates under the action of PSI (peptidyl aldehyde, selective inhibitor of the chymotrypsin-like activity of the proteasome), however it induced an accumulation of lipid droplets in treated cells, suggesting a previously unknown involvement of Leu-Ala in lipid metabolism. We conclude, that either Leu-Ala is not able to completely inhibit the cellular E3 enzymes or some of those enzymes are insensitive to this dipeptide, allowing therefore the build-up of ubiquitin-conjugates in the proteolytic centre of the cell.

Effects of an inhibitor of tripeptidyl peptidase II (Ala-Ala-Phe-chloromethylketone) and its combination with an inhibitor of the chymotrypsin-like activity of the proteasome (PSI) on apoptosis, cell cycle and proteasome activity in U937 cells.

AAF-AMC is not a specific TPP II substrate, since it is also hydrolyzed by purified proteasomes. Moreover, AAF-cmk, claimed to be a specific TPP II inhibitor, also inhibits the chymotrypsin-like activity of the proteasome. While AAF-cmk itself is mildly cytostatic to U-937 cells and induces cell cycle block in G1, its combination with PSI does not induce an increase in the cytostatic/cytotoxic effects. This suggests that TPP II is possibly less important for cell metabolism than it was previously believed and it is less probable that it can be able to fully compensate for the loss of the proteasome function.

A series of 15 patients with extracranial carotid artery aneurysms: surgical and endovascular treatment.

OBJECTIVES: This is a retrospective review of 15 patients with primary and secondary aneurysms of extracranial carotid arteries treated surgically and endoluminally over 20 years in one centre. PATIENTS AND METHODS: Fifteen aneurysms of extracranial carotid arteries were noticed in the same number of patients: five atherosclerotic, two after previous carotid surgery, six post-traumatic, one inflammatory, one of unknown etiology. All of them were symptomatic. RESULTS: In the group treated surgically some complications occurred in the perioperative time: one haematoma, two transient neurological deficits, one fatal stroke. In the endovascular group of patients no complications occurred after the treatment. One fatal stroke occurred during operation-the patient died on the 43rd postoperative day due to respiratory insufficiency. Two other deaths occurred during the follow-up: one caused by myocardial infarction 10 years after the aneurysm resection, and the second due to a fatal stroke 3 years after aneurysmorraphy. One patient refused treatment and died 9 months after being diagnosed. CONCLUSION: Neurological deficits in patients after neck injuries should arouse the suspicion of the presence of a carotid artery aneurysm. Open repair remains the method of choice in treating carotid artery aneurysms but endovascular procedures create the possibility of treating extracranial aneurysms in selected cases when open surgery is not recommended.

Increased local vascular endothelial growth factor expression associated with antitumor activity of proteasome inhibitor.

Inhibition of the proteasome, a multicatalytic proteinase complex, is an attractive approach to cancer therapy. Here we report that a selective inhibitor of the chymotrypsin-like activity of the proteasome, PSI (N-benzyloxycarbonyl-Ile-Glu(O-t-butyl)-Ala-leucinal) may inhibit growth of solid tumors not only through apoptosis induction, but also indirectly--through inhibition of angiogenesis. Two murine tumors: colon adenocarcinoma (C-26) and Lewis lung carcinoma (3LL) were chosen to study the antitumor effect of PSI. In an in vivo model of local tumor growth, PSI exerted significant antitumor effects against C-26 colon carcinoma, but not against 3LL lung carcinoma. Retardation of tumor growth was observed in mice treated with both 10 nmoles and 100 nmoles doses of PSI and in the latter group prolongation of the survival time of tumor-bearing mice was observed. PSI inhibited angiogenesis in the C-26 growing tumors with no such effect in 3LL tumors. Unexpectedly, that activity was associated with upregulation of vascular endothelial growth factor (VEGF) at the level of mRNA expression and protein production in C-26 tumors treated with PSI. C-26 cells treated with PSI produced increased amounts of VEGF in vitro in a dose- and time-dependent manner. We demonstrated that in C-26 colon adenocarcionoma higher VEGF production may render endothelial cells susceptible to the proapoptotic activity of PSI and is associated with inhibition of tumor growth.