ABSTRACT
PURPOSE: To compare the performance of various commercially available stethoscopes using standard acoustic engineering criteria, under recording studio conditions. MATERIALS AND METHODS: Eighteen stethoscopes (11 acoustic, 7 electronic) were analyzed using standard acoustic analysis techniques under professional recording studio conditions. An organic phantom that accurately simulated chest cavity acoustics was developed. Test sounds were played via a microphone embedded within it and auscultated at its surface by the stethoscopes. Recordings were made through each stethoscope's binaurals and/or downloaded (electronic models). Recordings were analyzed using standard studio techniques and software, including assessing ambient noise (AMB) rejection. Frequency ranges were divided into those corresponding to various standard biological sounds (cardiac, respiratory, and gastrointestinal). RESULTS: Loudness and AMB rejection: Overall, electronic stethoscopes, when set to a maximum volume, exhibited greater values of perceived loudness compared to acoustic stethoscopes. Significant variation was seen in AMB rejection capability. Frequency detection: Marked variation was also seen, with some stethoscopes performing better for different ranges (eg, cardiac) vs others (eg, gastrointestinal). CONCLUSION: The acoustic properties of stethoscopes varied considerably in loudness, AMB rejection, and frequency response. Stethoscope choice should take into account clinical conditions to be auscultated and the noise level of the environment.
ABSTRACT
The inhibition of tumor suppressor p53 protein due to its direct interaction with oncogenic murine double minute 2 (MDM2) protein, plays a central role in almost 50 % of all human tumor cells. Therefore, pharmacological inhibition of the p53-binding pocket on MDM2, leading to p53 activation, presents an important therapeutic target against these cancers expressing wild-type p53. In this context, the present study utilized an integrated virtual and experimental screening approach to screen a database of approved drugs for potential p53-MDM2 interaction inhibitors. Specifically, using an ensemble rigid-receptor docking approach with four MDM2 protein crystal structures, six drug molecules were identified as possible p53-MDM2 inhibitors. These drug molecules were then subjected to further molecular modeling investigation through flexible-receptor docking followed by Prime/MM-GBSA binding energy analysis. These studies identified fluspirilene, an approved antipsychotic drug, as a top hit with MDM2 binding mode and energy similar to that of a native MDM2 crystal ligand. The molecular dynamics simulations suggested stable binding of fluspirilene to the p53-binding pocket on MDM2 protein. The experimental testing of fluspirilene showed significant growth inhibition of human colon tumor cells in a p53-dependent manner. Fluspirilene also inhibited growth of several other human tumor cell lines in the NCI60 cell line panel. Taken together, these computational and experimental data suggest a potentially novel role of fluspirilene in inhibiting the p53-MDM2 interaction. It is noteworthy here that fluspirilene has a long history of safe human use, thus presenting immediate clinical potential as a cancer therapeutic. Furthermore, fluspirilene could also serve as a structurally-novel lead molecule for the development of more potent, small-molecule p53-MDM2 inhibitors against several types of cancer. Importantly, the combined computational and experimental screening protocol presented in this study may also prove useful for screening other commercially-available compound databases for identification of novel, small molecule p53-MDM2 inhibitors.
