[Show abstract][Hide abstract] ABSTRACT: Background
To validate the expression of a urine-based bladder cancer associated diagnostic signature comprised of 10 targets; ANG, CA9, MMP9, MMP10, SERPINA1, APOE, SDC1, VEGFA, SERPINE1 and IL8 in bladder tumor tissues.Methods
Immunohistochemical analyses were performed on tumor specimens from 213 bladder cancer patients (transitional cell carcinoma only) and 74 controls. Staining patterns were digitally captured and quantitated (Aperio, Vista, CA), and expression was correlated with tumor stage, tumor grade and outcome measures.ResultsWe revealed a positive association of 9 of the 10 proteins (excluding VEGF) in bladder cancer. Relative to control cases, a reduction in SDC1 and overexpression of MMP9, MMP10, SERPINE1, IL8, APOE, SERPINA1, ANG were associated with high stage bladder cancer. Reduced VEGF and increased SERPINA1 were associated with high-grade bladder cancer. Disease-specific survival was significantly reduced in tumors with high expression of SERPINE1 and/or IL8.Conclusions
These findings confirm that the proteins in a urine-based diagnostic signature are aberrantly expressed in bladder tumor tissues, and support the potential additional utility of selected biomarkers for the clinicopathological evaluation of excised tissue or biopsy material.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_200.
[Show abstract][Hide abstract] ABSTRACT: As molecular profiling data continues to accumulate, the design of integrative computational analyses that can provide insights into the dynamic aspects of cancer progression becomes feasible. Here, we present a novel computational method for the construction of cancer progression models based on the analysis of static tumor samples. We demonstrate the reliability of the method with simulated data, and describe the application to breast cancer data. Our findings support a linear, branching model for breast cancer progression. An interactive model facilitates the identification of key molecular events in the advance of disease to malignancy.
[Show abstract][Hide abstract] ABSTRACT: Background: Due to the faltering sensitivity and/or specificity, urine-based assays currently have a limited role in the management of patients with bladder cancer (BCa). The aim of this study was to externally validate our previously reported protein biomarker panel from multiple sites in the US and Europe. Methods: This multicenter external validation study included a total of 320 subjects (BCa = 183). The 10 biomarkers (IL8, MMP9, MMP10, SERPINA1, VEGFA, ANG, CA9, APOE, SDC1 and SERPINE1) were measured using commercial ELISA assays in an external laboratory. The diagnostic performance of the biomarker panel was assessed using receiver operator curves (ROC) and descriptive statistical values. Results: Utilizing the combination of all 10 biomarkers, the AUROC for the diagnostic panel was noted to be 0.847 [95% CI: 0.796 - 0.899], outperforming any single biomarker. The multiplex assay at optimal cutoff value achieved an overall sensitivity of 0.79, specificity of 0.79, PPV of 0.73 and NPV of 0.84 for BCa classification. Sensitivity values of the diagnostic panel for high-grade BCa, low-grade BCa, MIBC and NMIBC were 0.81, 0.90, 0.95 and 0.77, respectively. Conclusions: Urinary levels of the biomarker panel enabled discrimination of BCa patients and controls, and the levels of biomarker subsets were associated with advancing tumor grade and stage. Impact: If proven to be reliable, urinary diagnostic biomarker assays can detect BCa in a timely manner such that the patient can expect improvements in overall survival and quality of life. -
The Journal of Urology 06/2014; 191(4). · 3.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Intravesical Bacillus Calmette-Guérin (BCG) has been shown to induce a specific immunologic response (i.e., activation of IL-2 and effector T-cells), while preclinical studies using ALT-803 (mutated IL-15 analogue combined with IL-15Rα-Fc fusion) have shown promising results by prolonging the agent's half-life and stimulating CD8+ T-cells. Based on these results, we hypothesized that the intravesical administration of ALT-803 along with BCG will generate an immunologic response leading to significant bladder tumor burden reduction. Using a well-established carcinogen induced rat non-muscle invasive bladder cancer (NMIBC) model, we studied the effects of intravesical ALT-803 with and without BCG. Rat tissues were evaluated to document treatment response. Intravesical ALT-803 was safe and well tolerated alone and in combination with BCG. As a single treatment agent, ALT-803 reduced tumor burden by 35% compared to control whereas BCG alone only reduced tumor burden by 15%. However, the combination of ALT-803 plus BCG reduced tumor burden by 46% compared to control. Immune monitoring suggested that the antitumor response was linked to the production and secretion of IL-1α, IL-1β and RANTES, which in turn, induced the proliferation and activation of NK cells. Lastly, tumoral responses of the combinational treatment were associated with 76% reduction in angiogenesis, which is significantly higher than when assessed with either agent alone. The enhanced therapeutic index seen with this duplet provides justification for the development of this regimen for future clinical trials.
PLoS ONE 06/2014; 9(6):e96705. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cancer invasion and metastasis develops through a series of steps that involve the loss of cell to cell and cell to matrix adhesion, degradation of extracellular matrix and induction of angiogenesis. Different protease systems (e.g., matrix metalloproteinases, MMPs) are involved in these steps. MMP-10, one of the lesser studied MMPs, is limited to epithelial cells and can facilitate tumor cell invasion by targeting collagen, elastin and laminin. Enhanced MMP-10 expression has been linked to poor clinical prognosis in some cancers, however, mechanisms underlying a role for MMP-10 in tumorigenesis and progression remain largely unknown. Here, we report that MMP-10 expression is positively correlated with the invasiveness of human cervical and bladder cancers.
BMC Cancer 05/2014; 14(1):310. · 3.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Up to 70% of patients with non-muscle invasive bladder cancer (NMIBC) experience disease recurrence, making it one of the most prevalent cancers in the US. The purpose of this study was to test the performance of a multiplex urinary biomarker assay for the monitoring of voided urine for recurrent bladder cancer (BCa). Methods: This retrospective, multicenter study included a total of 125 subjects with a history of BCa. Voided urine specimens were collected prior to procedure from these subjects (53 with confirmed tumor recurrence and 72 with confirmed non-tumor recurrence) for analysis. A prediction rule consistent of single parameter's results sum of 10 urine-based biomarkers (IL8, MMP9, MMP10, SERPINA1, VEGFA, ANG, CA9, APOE, SERPINE1, SDC1) was measured using enzyme-linked immunosorbent assays. The diagnostic performance of the biomarker panel was assessed using receiver operator curves (ROC) and descriptive statistical values (e.g., sensitivity and specificity). Results: The combination of all 10 biomarkers outperformed any single biomarker with a calculated AUROC for the diagnostic panel of 0.904 [95% CI: 0.853 - 0.956]. The multiplex assay achieved an overall sensitivity of 79% and specificity of 88% for recurrent BCa, and significantly outperformed the Urovysion cytogenetic assay (sensitivity 42%, specificity 94%) and voided urinary cytology (sensitivity 33%, specificity 90%). Conclusions: A diagnostic panel of 10 urinary biomarkers that accurately detects primary BCa also performs well for the detection of recurrent BCa. Impact: The identification of a reliable urine-based surveillance and detection assay would be of benefit to both patients and the healthcare system.
Cancer Epidemiology Biomarkers & Prevention 04/2014; · 4.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The ability to accurately measure multiple proteins simultaneously in a single assay has the potential to markedly improve the efficiency of a myriad of clinical assays. Here, we tested the performance of a new, multiplex protein array platform to quantitate three bladder cancer-associated proteins in urine samples. The following analytes, interleukin 8 (IL8), matrix metallopeptidase 9 (MMP9), and vascular endothelial growth factor A (VEGFA) were monitored using Q-plex, a customized multiplex ELISA system from Quansys Biosciences, and individual target commercial ELISA kits. The performance of the two approaches was compared by evaluating the diagnostic accuracy of the biomarker assays in samples from a cohort of 73 subjects of known bladder cancer status.
The combination biomarker panel analyses revealed an AUROC value of 0.9476 for the Q-plex assay, and 0.9119 for the combination of the single-target ELISA assays. The Q-plex assay achieved an overall diagnostic sensitivity of 0.93 and specificity of 0.81, and the individual target ELISA assays achieved an overall sensitivity of 0.77 and specificity of 0.91.
Based on these encouraging preliminary data, we believe that the Q-Plex technology is a viable platform that can be exploited as an efficient, highly accurate tool to quantitate multiplex panels of diagnostic proteins in biologic specimens.
[Show abstract][Hide abstract] ABSTRACT: Tumor angiogenesis is essential for tumor growth and metastasis and is dependent on key angiogenic factors. Angiogenin (ANG), a 14.2-kDa polypeptide member of the RNase A superfamily, is an angiogenic protein that has been reported to be upregulated and associated with poor prognosis in some human cancers. The mechanisms through which aberrant ANG levels promote specific steps in tumor progression are unknown. Here, we show that ANG expression in human tissues is strongly correlated with an invasive cancer phenotype. We also show that ANG induces cellular survival, proliferation, endothelial tube formation and xenograft angiogenesis and growth. Novel mechanistic investigations revealed that ANG expression stimulated matrix metallopeptidase-2 (MMP2) expression through the phosphorylation of ERK1/2. Targeting ANG in vivo with N65828, a small-molecule inhibitor of the ribonucleolytic activity of human ANG, resulted in the diminution of xenograft tumoral growth through the inhibition of angiogenesis. Our findings support an unrecognized interplay between ANG, ERK1/2 and MMP2 that can impact tumor growth and progression. The targeting of ANG and associated factors could provide a novel strategy to inhibit tumor establishment and growth.Oncogene advance online publication, 24 February 2014; doi:10.1038/onc.2014.2.
[Show abstract][Hide abstract] ABSTRACT: To determine the diagnostic and prognostic capability of urinary and tumoral syndecan-1 (SDC-1) levels in patients with cancer of the urinary bladder.
SDC-1 levels were quantitated by enzyme-linked immunosorbent assay (ELISA) in 308 subjects (102 cancer subjects and 206 non-cancer subjects) to assess its diagnostic capabilities in voided urine. The performance of SDC-1 was evaluated using the area under the curve of a receiver operating characteristic curve. In addition, immunohistochemical (IHC) staining assessed SDC-1 protein expression in 193 bladder specimens (185 cancer subjects and 8 non-cancer subjects). Outcomes were correlated to SDC-1 levels.
Mean urinary levels of SDC-1 did not differ between the cancer subjects and the non-cancer subjects, however, the mean urinary levels of SDC-1 were reduced in high-grade compared to low-grade disease (p < 0.0001), and in muscle invasive bladder cancer (MIBC) compared to non-muscle invasive bladder cancer (NMIBC) (p = 0.005). Correspondingly, preliminary data note a shift from a membranous cellular localization of SDC-1 in normal tissue, low-grade tumors and NMIBC, to a distinctly cytoplasmic localization in high-grade tumors and MIBC was observed in tissue specimens.
Alone urinary SDC-1 may not be a diagnostic biomarker for bladder cancer, but its urinary levels and cellular localization were associated with the differentiation status of patients with bladder tumors. Further studies are warranted to define the potential role for SDC-1 in bladder cancer progression.
BMC Cancer 02/2014; 14(1):86. · 3.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: While significant progress continues to be made in the early detection and therapeutic management of primary tumors, the incidence of metastatic disease remains the major cause of mortality. Accordingly, the development of novel effective therapies that can ameliorate dissemination and secondary tumor growth are a clinical priority. The identification of genetic and functional alterations in cancer cells that affect factors implicated in the metastatic process is critical for designing preventive and therapeutic strategies. Evidence implicating the protein deleted in liver cancer-1 (DLC1), a Rho GTPase activator, in metastasis has accumulated to a point where DLC1 may be considered as a metastasis suppressor gene. This review presents evidence supporting an anti-metastatic role for DLC1 in several human cancers and discusses the mechanisms contributing to its inhibitory effects. In addition, promising opportunities for therapeutic interventions based on DLC1 function and downstream pathways involved in the metastatic process are considered.
[Show abstract][Hide abstract] ABSTRACT: 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. Implications: Targeting PAI-1 has beneficial anti-tumoral effects and should be further investigated clinically.
Molecular Cancer Research 01/2014; · 4.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chemokines, including chemokine (C-X-C motif) ligand 1 (CXCL1), may enhance tumor epithelial-stromal interactions facilitating tumor growth and invasion. Studies have linked CXCL1 expression to gastric, colon and skin cancers, however, no study to date has been reported describing CXCL1 in human prostate tumors. Herein, we set out to describe the expression pattern of CXCL1 in human prostate tumors. Utilizing a commercial tissue microarray, immunohistochemical staining was used to monitor CXCL1 protein expression in 90 primary prostate tumors and 20 benign prostate tissues. CXCL1 protein expression was noted to be predominantly in the cytoplasm of both the benign epithelia glands and cancerous epithelia glands) with >75% of benign or cancerous glands demonstrating immunoreactivity. However, staining intensity was noted to be significantly different between benign and cancerous tissue with 84% of cancerous tissue staining moderate (++) to strong (+++) compared to only 30% of benign prostate samples staining moderate (++) to strong (+++) (p<0.0001). Increased CXCL1 protein levels were associated with higher-grade tumors (Gleason≤6 vs. Gleason score 7-10, p=0.038). An increase in CXCL1 protein was present in of high-grade malignancy. Further studies are warranted to clearly define the role of CXCL1 in prostate cancer.
Pathology - Research and Practice 10/2013; · 1.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction: Recent studies suggest that infectious organisms may facilitate initiation and metastasis of many human cancers. One infectious organism of interest is Mycoplasma genitalium(Mg), a prevalent organism in humans known to cause sexually transmitted infection, as well as urethritis and prostatitis. Previous studies have demonstrated that benign, non-tumorigenic human prostate cells (BPH-1) chronically exposed to M. genitalium led to the malignant transformation of these cells as demonstrated in in vitro and in vivo models. Based on work from our laboratory, we felt this malignant transformation revolved around a specific M. genitalium’s ABC transporter (MG289) with homology to M. hyorhinis’ ABC transporter, p37. In this study, differences in M. genitalium’s ability to infect and induce a unique proteome conducive to tumoral growth were studied with engineered M. genitalium in which the p37 protein was silent. Materials and Methods: Wild-type M. genitalium (strain 431c, designated as M. genitalium WT) and MG289 deficient M. genitalium mutant (strain 260_3, designated as Mg260_3) were used for this study. We studied the infectivity potential between M. genitalium WT and Mg260_3 upon exposure to BPH-1 cells. Furthermore, we set out to identify a unique proteome in BPH-1 cells exposed to M. genitalium WT that could explain its ability to induce malignant transformation of benign cells. Validation of selected proteomic targets was carried out by Western blot analysis. Results: Both M. genitalium WT and Mg260_3 strains showed somewhat similar growth curve when absorbance at 450nm was matched at day 0. Colony forming units (CFUs) were similar for both strains at the same absorbance. However, the ability to infect BPH-1 cells was greatly reduced in Mg260_3 compared to the M. genitalium WT (p < 0.001). This was evident by infectivity assays and confocal microscopy. Proteomic analysis of BPH-1 cells infected with either M. genitalium WT or Mg260_3 for 8 hr, 24 hr and 6 days demonstrated a considerable shift in protein expression over uninfected BPH-1 cells at each time point. The preponderance of perturbed proteins regulated protein synthesis and protein processing, triggering endoplasmic reticulum stress. Conclusions: In summary, we demonstrate that Mg260_3, which is deficient of the phosphonate ABC transporter substrate-binding protein; MG289 (homologue to M. hyorhinis p37), is less effective in invading and maintaining an intracellular persistence in benign human prostate cells. In addition, deletion of MG289 resulted in altered BPH-1 responses to M. genitalium infection as evidenced by differential proteome profiling of BPH-1 infected cells.
[Show abstract][Hide abstract] ABSTRACT: Bladder cancer is one of the most prevalent cancers worldwide. Early detection of bladder tumors is critical for improved patient outcomes. The standard method for detection and surveillance of bladder tumors is cystoscopy with urinary cytology. Limitations of cystoscopy and urinary cytology have brought to light the need for more robust diagnostic assays. Ideally, such assays would be applicable to noninvasively obtained, voided urine, and be designed not only for diagnosis, but also for monitoring disease recurrence and response to therapy. Consequently, the development of a noninvasive urine-based assay would be of tremendous benefit to both patients and healthcare systems. This article reports some of the more prominent urine-based biomarkers reported in the literature. In addition, some new technologies that have been used to identify novel urinary biomarkers are highlighted.
Biomarkers in Medicine 10/2013; 7(5):779-90. · 3.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cancers of the urinary bladder result in aggressive and highly angiogenic tumors for which standard treatments have only limited success. Patients with advanced disease have a 5-year survival rate of <20%, and no new anti-cancer agent has been successfully introduced into the clinic armamentarium for the treatment of bladder cancer in over 20 years. Investigations have identified plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor, as being highly expressed in several malignancies, including bladder cancer, in which high expression is associated with a poor prognosis. In this study, we evaluated PAI-1 as a potential therapeutic target for bladder cancer. PAI-1 expression was manipulated in a panel of cell lines and functional inhibition was achieved using the small molecule tiplaxtinin. Reduction or inhibition of PAI-1 resulted in the reduction of cellular proliferation, cell adhesion, and colony formation, and the induction of apoptosis and anoikis in vitro. Treatment of T24 xenografts with tiplaxtinin resulted in inhibition of angiogenesis and induction of apoptosis, leading to a significant reduction in tumor growth. Similar results were obtained through evaluation of the human cervical cancer HeLa cell line, showing that PAI-1 mediated effects are not restricted to tumor cells of bladder origin. Collectively, these data show that targeting PAI-1 may be beneficial and support the notion that novel drugs such as tiplaxtinin could be investigated as anti-cancer agents.
Molecular Cancer Therapeutics 09/2013; · 5.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
Further development of A1AT as a diagnostic biomarker for BCa is warranted.
[Show abstract][Hide abstract] ABSTRACT: Erythropoietin (EPO) provides an alternative to transfusion for increasing red blood cell mass and treating anemia in cancer patients. However, recent studies have reported increased adverse events and/or reduced survival in patients receiving both EPO and chemotherapy, potentially related to EPO-induced cancer progression. Additional preclinical studies that elucidate the possible mechanism underlying EPO cellular growth stimulation are needed.
Using commercial tissue microarray (TMA) of a variety of cancers and benign tissues, EPO and EPO receptor immunohistochemical staining was performed. Furthermore using a panel of human renal cells (Caki-1, 786-O, 769-P, RPTEC), in vitro and in vivo experiments were performed with the addition of EPO in normoxic and hypoxic states to note phenotypic and genotypic changes.
EPO expression score was significantly elevated in lung cancer and lymphoma (compared to benign tissues), while EPOR expression score was significantly elevated in lymphoma, thyroid, uterine, lung and prostate cancers (compared to benign tissues). EPO and EPOR expression scores in RCC and benign renal tissue were not significantly different. Experimentally, we show that exposure of human renal cells to recombinant EPO (rhEPO) induces cellular proliferation, which we report for the first time, is further enhanced in a hypoxic state. Mechanistic investigations revealed that EPO stimulates the expression of cyclin D1 while inhibiting the expression of p21cip1 and p27kip1 through the phosphorylation of JAK2 and ERK1/2, leading to a more rapid progression through the cell cycle. We also demonstrate an increase in the growth of renal cell carcinoma xenograft tumors when systemic rhEPO is administered.
In summary, we elucidated a previously unidentified mechanism by which EPO administration regulates progression through the cell cycle, and show that EPO effects are significantly enhanced under hypoxic conditions.
[Show abstract][Hide abstract] ABSTRACT: Chemokines, including chemokine (C-X-C motif) ligand 1 (CXCL1), may regulate tumor epithelial-stromal interactions that facilitate tumor growth and invasion. Studies have linked CXCL1 expression to gastric, colon and skin cancers, but limited studies to date have described CXCL1 protein expression in human bladder cancer (BCa) tissues.
CXCL1 protein expression was examined in 152 bladder tissue specimens (142 BCa) by immunohistochemical staining. The expression of CXCL1 was scored by assigning a combined score based on the proportion of cells staining and intensity of staining. CXCL1 expression patterns were correlated with clinicopathological features and follow-up data.
CXCL1 protein expression was present in cancerous tissues, but was entirely absent in benign tissue. CXCL1 combined immunostaining score was significantly higher in high-grade tumors relative to low-grade tumors (p = 0.012). Similarly, CXCL1 combined immunostaining score was higher in high stage tumors (T2-T4) than in low-grade tumors (Ta-T1) (p < 0.0001). An increase in the combined immunostaining score of CXCL1 was also associated with reduced disease-specific survival.
To date, this is the largest study describing increased CXCL1 protein expression in more aggressive phenotypes in human BCa. Further studies are warranted to define the role CXCL1 plays in bladder carcinogenesis and progression.
BMC Cancer 07/2013; 13(1):322. · 3.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: Accurate urinary assays for bladder cancer (BCa) detection would benefit both patients and healthcare systems. Through extensive genomic and proteomic profiling of urinary components, we have previously identified a panel of eight biomarkers that can facilitate the detection of BCa in voided urine samples. Herein we set out to confirm this diagnostic molecular signature in a diverse multicenter cohort. MATERIALS AND METHODS: We performed a case-control phase II study in which voided urines from 308 subjects (102 BCa subjects and 206 subjects with varying urologic disorders) were analyzed. The urinary concentrations of eight biomarkers (IL-8, MMP-9, MMP-10, PAI-1, VEGF, ANG, CA9 and APOE) were assessed by ELISA assay. Diagnostic performance for the panel of tested biomarkers was assessed using receiver operator curves (ROC) and descriptive statistical values (e.g.,sensitivity and specificity). RESULTS: Of the eight urinary biomarkers, seven were elevated in subjects with BCa relative to subjects without BCa and were assessed in a new model. With the 7-biomarker model, the area under the ROC was noted to be 0.88 [95% CI: 0.84-0.93] with a sensitivity of 74% and specificity of 90%. By comparison, the sensitivity of voided urinary cytology (VUC) and UroVysion in this cohort was 39% and 54%, respectively. Limitations of the study include analysis performed on banked urines and lack of VUC and UroVysion data on controls. CONCLUSIONS: The study provides further evidence that the reported panel of diagnostic biomarkers can reliably achieve the non-invasive detection of BCa with higher sensitivity than currently available urine-based assays.
The Journal of urology 06/2013; · 3.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Endothelial cell growth and proliferation are critical for angiogenesis; thus, greater insight into the regulation of pathological angiogenesis is greatly needed. Previous studies have reported on chemokine (C-X-C motif) ligand 1 (CXCL1) expression in epithelial cells and that secretion of CXCL1 from these epithelial cells induces angiogenesis. However, limited reports have demonstrated CXCL1 expression in endothelial cells. In this report, we present data that expand on the role of CXCL1 in human endothelial cells inducing angiogenesis. Specifically, CXCL1 is expressed and secreted from human endothelial cells. Interference of CXCL1 function using neutralizing antibodies resulted in a reduction in endothelial cell migration and viability/proliferation, the latter associated with a decrease in levels of cyclin D and cdk4. In vitro studies revealed that CXCL1 influenced neoangiogenesis through the regulation of epidermal growth factor and ERK1/2. In a xenograft angiogenesis model, interference of CXCL1 function resulted in inhibition of angiogenesis. A better understanding of the role of CXCL1 in the interactions between the endothelial and epithelial components will provide insight into how human tissues use CXCL1 to survive and thrive in a hostile environment.Laboratory Investigation advance online publication, 3 June 2013; doi:10.1038/labinvest.2013.71.