ERß-dependent neuroglobin up-regulation impairs 17ß-estradiol-induced apoptosis in DLD-1 colon cancer cells upon oxidative stress injury.

Besides other mechanism(s) 17ß-estradiol (E2) facilitates neuronal survival by increasing, via estrogen receptor ß (ERß), the levels of neuroglobin (NGB) an anti-apoptotic protein. In contrast, E2 could exert protective effects in cancer cells by activating apoptosis when the ERß level prevails on that of ERα as in colon cancer cell lines. These apparently contrasting results raise the possibility that E2-induced NGB up-regulation could regulate the ERß activities shunning this receptor subtype to trigger an apoptotic cascade in neurons but not in non-neuronal cells. Here, human colorectal adenocarcinoma cell line (DLD-1) that only expresses ERß and HeLa cells transiently transfected with ERß encoding vector has been used to verify this hypothesis. In addition, neuroblastoma SK-N-BE cells were used as positive control. Surprisingly, E2 also induced NGB up-regulation, in a dose- and time-dependent manner, in DLD-1 cells. The ERß-mediated activation of p38/MAPK was necessary for this E2 effect. E2 induced NGB re-allocation in mitochondria where, subsequently to an oxidative stress injury (i.e., 100µM H2O2), NGB interacted with cytochrome c preventing its release into the cytosol and the activation of an apoptotic cascade. As a whole, these results demonstrate that E2-induced NGB up-regulation could act as an oxidative stress sensor, which does not oppose to the pro-apoptotic E2 effect in ERß-containing colon cancer cells unless a rise of oxidative stress occurs. These results support the concept that oxidative stress plays a critical role in E2-induced carcinogenesis and further open an important scenario to develop novel therapeutic strategies that target NGB against E2-related cancers.

Aortic valve re-implantation technique with Gelweave Valsalva prosthesis: safety, reproducibility and pitfalls of a geometric reconstruction.

BACKGROUND: To evaluate the safety, reproducibility and pitfalls of an aortic valve re-implantation (AVRei) technique. METHODS: From June 2005 to December 2008, 30 patients underwent aortic valve-sparing re-implantation with Gelweave Valsalva prosthesis. Mean age was 66 +/- 7 years (range 47-81). Mean aortic root diameter was 49 +/- 6 mm (range 37-70) and 12 patients had an aortic insufficiency more than 2+. All the patients were elective, except three who underwent surgery for type A aortic dissection. Two patients had Marfan syndrome and one had a bicuspid aortic valve. Isolated aortic root replacement was performed in 26 patients, whereas hemiarch extension was required in four. All the survivors underwent serial echocardiographic assessment for functional results and multi-detector computed tomography (MDCT) for aortic root morphology evaluation. RESULTS: There was one early death and one re-exploration for bleeding. Two patients suffered from a perioperative stroke and four required a pacemaker implantation because of a complete atrio-ventricular block. Mean follow-up was 12 +/- 10 months (range 1-42) with no late deaths, whereas freedom from reoperation was 100% and freedom from aortic insufficiency 2+ or more was 96.5%. MDCT aortic root reconstruction showed a pseudo-normalization of the neo-sinuses of Valsalva mimicking the human normal aortic root morphology. CONCLUSION: AVRei with Valsalva conduit is a well-tolerated procedure both in elective and emergency situations. In well-selected patients, good functional and clinical results can be achieved, regardless of the cause of the aortic root disease. Application of simple surgical manoeuvres allows durable clinical efficacy to be obtained without the risk of major complications.