Survivin is an inhibitor of apoptosis protein (IAP) that is markedly overexpressed in most cancers. We identified two novel functionally divergent splice variants, i.e. non-antiapoptotic survivin-2B and antiapoptotic survivin-deltaEx3. Because survivin-2B might be a naturally occurring antagonist of antiapoptotic survivin variants, we analyzed the subcellular distribution of these proteins. PSORT II analysis predicted a preferential cytoplasmic localization of survivin and survivin-2B, but a preferential nuclear localization of survivin-deltaEx3. GFP-tagged survivin variants confirmed the predicted subcellular localization and additionally revealed a cell cycle-dependent nuclear accumulation of survivin-deltaEx3. Moreover, a bipartite nuclear localization signal found exclusively in survivin-deltaEx3 may support cytoplasmic clearance of survivin-deltaEx3. In contrast to the known association between survivin and microtubules or centromeres during mitosis, no corresponding co-localization became evident for survivin-deltaEx3 or survivin-2B. In conclusion, our study provided data on a differential subcellular localization of functionally divergent survivin variants, suggesting that survivin isoforms may perform different functions in distinct subcellular compartments and distinct phases of the cell cycle.

Survivin, a novel member of the inhibitor of apoptosis protein (IAP) family, reduces the susceptibility of tumor cells to proapoptotic stimuli, thereby promoting tumor cell survival during tumor progression and treatment with anticancer drugs. Recently, we identified 2 novel alternative splice variants of survivin, survivin-2B and survivin-⌬Ex3, which differ in their antiapoptotic properties. Survivin-2B has lost its antiapoptotic potential and may act as a naturally occurring antagonist of antiapoptotic survivin and survivin-⌬Ex3. Because the in vivo expression of these splice variants in human cancer has not been analyzed so far, 57 renal cell carcinomas (RCCs) were explored using quantitative reverse transcriptase polymerase chain reaction. We found that all RCCs express survivin-⌬Ex3, survivin-2B and survivin, the latter being the dominant transcript. When we compared early and intermediate stages with late stages of clear cell RCCs, no significant changes in the expression levels of survivin and survivin-⌬Ex3 became evident. However, a significant decrease was observed for the mRNA ratio between survivin-2B and survivin in late tumor stages (p ‫؍‬ 0.036). Chromophilic/papillary RCCs, which are known to be less aggressive than clear cell RCCs, did not show significantly lower expression levels of antiapoptotic survivin and survivin⌬Ex3, compared with stage-adjusted clear cell RCCs. Our study demonstrates for the first time in vivo expression of functionally different survivin variants and suggests a role of these survivin splice variants in the progression and clinical behavior of human RCCs.

In a prospective study, the clinical value of transoesophageal two-dimensional echocardiography (TOE) as compared with transthoracic two-dimensional echocardiography (TTE) was determined in patients with suspected infective endocarditis. Ninety-six patients were studied consecutively with an electronic sector scanner using 2.25 and 3.5 MHz probes for TTE and a 3.5 MHz probe embedded in tip of a flexible 12 mm gastroscope for TOE. Results of surgery and autopsy were available for 20 of the 96 patients with infective endocarditis and echocardiographically demonstrated vegetations and 70 control patients with valvular heart disease without infective endocarditis and no signs of vegetations, who were studied preoperatively with TTE and TOE. For TTE and TOE, the measured sensitivity was 63% and 100%, specificity 98% and 98%, positive predictive accuracy 92% and 95%, and negative predictive accuracy 91% and 100%, respectively. In 39 patients who had positive blood cultures, vegetations were found by TOE in 32 patients (82%), but in only 27 patients (69%) by TTE. Image quality was the main factor contributing to the superiority of TOE over TTE: it was reduced in 11/20 patients (55%) in whom vegetations were not detected by TTE. Another important factor was the size of vegetations. Only 6/24 vegetations (25%) of less than 5 mm but 9/13 vegetations of 6-10 mm, and 14/14 vegetations of greater than 11 mm detected by TOE were also observed with TTE. The clinical importance of detecting vegetations was demonstrated by the rate of embolism. In patients with vegetations embolism was 25% when blood cultures were positive and 21% when they were negative. In patients without echocardiographically detectable vegetations signs of embolism were seen in no patient with positive and 7% of the patients with negative blood cultures. Evidence of vegetations was found on the aortic valve in 14 patients and on the mitral valve in seven patients in whom valvular incompetence was not present, indicating that the valve had not yet been damaged significantly. TOE is superior to TTE in detecting vegetations in suspected infective endocarditis because of better image quality, particularly when vegetations are small. TOE seems to be indicated in patients with suspected endocarditis and reduced image quality or negative TTE results. Early detection of vegetations on valves may help confirm the diagnosis of infective endocarditis at an early stage and hopefully lead to an improved prognosis by reducing delay in instituting appropriate therapy.

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