A key barrier to the realization of personalized medicine for cancer is the identification of biomarkers. Here we describe a two-stage strategy for the discovery of serum biomarker signatures corresponding to specific cancer-causing mutations and its application to prostate cancer (PCa) in the context of the commonly occurring phosphatase and tensin homolog (PTEN) tumor-suppressor gene inactivation. In the first stage of our approach, we identified 775 N-linked glycoproteins from sera and prostate tissue of wild-type and Pten-null mice. Using label-free quantitative proteomics, we showed that Pten inactivation leads to measurable perturbations in the murine prostate and serum glycoproteome. Following bioinformatic prioritization, in a second stage we applied targeted proteomics to detect and quantify 39 human ortholog candidate biomarkers in the sera of PCa patients and control individuals. The resulting proteomic profiles were analyzed by machine learning to build predictive regression models for tissue PTEN status and diagnosis and grading of PCa. Our approach suggests a general path to rational cancer biomarker discovery and initial validation guided by cancer genetics and based on the integration of experimental mouse models, proteomics-based technologies, and computational modeling.serum biomarkers | mass spectrometry | Pten conditional knockout mouse model

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The artificial urinary sphincter should be long enough to prevent strangulation effects of the urethral tissue and short enough to avoid the improper dissection of the surrounding tissue. To optimize the sphincter length, the empirical three-parameter urethra compression model is proposed based on the mechanical properties of the urethra: wall pressure, tissue response rim force and sphincter periphery length. In vitro studies using explanted animal or human urethras and different artificial sphincters demonstrate its applicability. The pressure of the sphincter to close the urethra is shown to be a linear function of the bladder pressure. The force to close the urethra depends on the sphincter length linearly. Human urethras display the same dependences as the urethras of pig, dog, sheep and calf. Quantitatively, however, sow urethras resemble best the human ones. For the human urethras, the mean wall pressure corresponds to (-12.6 +/- 0.9) cmH2O and (-8.7 +/- 1.1) cmH2O, the rim length to (3.0 +/- 0.3) mm and (5.1 +/- 0.3) mm and the rim force to (60 +/- 20) mN and (100 +/- 20) mN for urethra opening and closing, respectively. Assuming an intravesical pressure of 40 cmH2O, and an external pressure on the urethra of 60 cmH2O, the model leads to the optimized sphincter length of (17.3 +/- 3.8) mm.