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1.  Influencing factors on the NMP-22 urine assay: an experimental model 
BMC Urology  2012;12:23.
Background
The commercial NMP-22 urine assays for bladder cancer (BCa) detect nuclear mitotic apparatus protein 1 (NUMA1) using monoclonal antibodies. It remains unclear whether these assays are monitoring a tumor antigen or some other phenomenon associated with the disease state. In this study, we investigated the influence of urinary cellular and protein concentration, and hematuria on the performance of the NMP-22 tests in an experimental model.
Methods
Pooled urine from healthy subjects were spiked with varying concentrations of benign (UROtsa) cells, cancer cells (RT4, T24, KU-7 and UM-UC-14), whole blood or serum, prior to analysis with both NMP22® Bladder Cancer ELISA test and the NMP22® BladderChek® point-of-care test.
Results
Urines from control subjects were negative for NMP-22. The addition of whole blood at 50ul/10 ml, but not serum, resulted in a false-positive result. Furthermore, the addition of a high concentration of benign urothelial cells (106) or the cell lysate from these cells (306 μg protein) resulted in a false-positive result. High concentrations of pooled-cancer cells (106) or cell lysate (30.6 μg and above) resulted in a positive NMP-22 assay. Concordance between the NMP-22 ELISA assay and the NMP-22 point of care assay was >90%.
Conclusions
Rather than detecting a specific tumor antigen, urinary NMP-22 assays may be measuring the cellularity or amount of cell turnover that may be introduced into the urine by a variety of conditions, including surface shedding from bladder tumors. The absence of significant urinary cellularity in some cases due to lesion characteristics or the timing of sampling may result in false-negative NMP-2 assays.
doi:10.1186/1471-2490-12-23
PMCID: PMC3480828  PMID: 22928931
Bladder cancer; Urine; NMP-22
2.  PAI-1 Leads to G1-phase Cell Cycle Progression through Cyclin D3/CDK4/6 Up-regulation 
Molecular cancer research : MCR  2014;12(3):322-334.
The canonical function of Plasminogen activator inhibitor-1 (PAI-1/SERPINE1) is as an inhibitor of uPA for blood clot maintenance, but it is now also considered a pleiotropic factor that can exert diverse cellular and tumorigenic effects. However, the mechanism controlling its pleiotropic effects is far from being understood. To elucidate the tumorigenic role of PAI-1, we tested the effects of PAI-1 after manipulation of its expression or through the use of a small molecule inhibitor, tiplaxtinin. Down-regulation of PAI-1 significantly reduced cellular proliferation through an inability to progress from the G0/G1-phase of the cell cycle. Accordingly, overexpression of PAI-1 augmented proliferation by encouraging S-phase entry. Biochemically, cell cycle arrest was associated with the depletion of the G1-phase transition complexes, Cyclin D3/CDK4/6 and Cyclin E/CDK2, in parallel with the up-regulation of the cell cycle inhibitors p53, p21Cip1/Waf1 and p27Kip1. PAI-1 depletion significantly decreased the tumor size of urothelial T24 and UM-UC-14 xenografts and overexpression of PAI-1 substantially increased the tumor size of HeLa xenografts. Lastly, immunohistochemical analysis of human bladder and cervical tumor tissue microarrays revealed increased expression of PAI-1 in cancerous tissue, specifically in aggressive tumors, supporting the relevance of this molecule in human tumor biology.
doi:10.1158/1541-7786.MCR-13-0543
PMCID: PMC4064567  PMID: 24464915
cancer; cell cycle arrest; cyclin D3; plasminogen activator inhibitor -1; p21/27
3.  Investigation of CCL18 and A1AT as potential urinary biomarkers for bladder cancer detection 
BMC Urology  2013;13:42.
Background
In this study, we further investigated the association of two biomarkers, CCL18 and A1AT, with bladder cancer (BCa) and evaluated the influence of potentially confounding factors in an experimental model.
Methods
In a cohort of 308 subjects (102 with BCa), urinary concentrations of CCL18 and A1AT were assessed by enzyme-linked immunosorbent assay (ELISA). In an experimental model, benign or cancerous cells, in addition to blood, were added to urines from healthy controls and analyzed by ELISA. Lastly, immunohistochemical staining for CCL18 and A1AT in human bladder tumors was performed.
Results
Median urinary protein concentrations of CCL18 (52.84 pg/ml vs. 11.13 pg/ml, p < 0.0001) and A1AT (606.4 ng/ml vs. 120.0 ng/ml, p < 0.0001) were significantly elevated in BCa subjects compared to controls. Furthermore, the addition of whole blood to pooled normal urine resulted in a significant increase in both CCL18 and A1AT. IHC staining of bladder tumors revealed CCL18 immunoreactivity in inflammatory cells only, and there was no significant increase in these immunoreactive cells within benign and cancerous tissue and no association with BCa grade nor stage was noted. A1AT immunoreactivity was observed in the cytoplasm of epithelia cells and intensity of immunostaining increased with tumor grade, but not tumor stage.
Conclusions
Further development of A1AT as a diagnostic biomarker for BCa is warranted.
doi:10.1186/1471-2490-13-42
PMCID: PMC3846766  PMID: 24011266
Biomarkers; Bladder cancer; Specificity; Urine

Results 1-3 (3)