Performance of a multianalyte test as an aid for the diagnosis of ovarian cancer in symptomatic women

Background: Concomitant with the development of in vitro diagnostic multivariate index assays (IVDMIAs) to improve the diagnostic efficiency of ovarian cancer detection is the need to identify appropriate biostatistical approaches to assess improvements in risk predication. In this study, we assessed the utility of three different approaches for comparing diagnostic efficiency of an ovarian cancer multivariate assay in a retrospective case control phase 2 biomarker trial. The control cohort included both disease-free women and women with benign gynecological conditions to more accurately reflect the target population of symptomatic women

Evaluation of midkine and anterior gradient 2 in a multimarker panel for the detection of ovarian cancer

The aims of this study were: to characterise and compare plasma concentrations of midkine (MDK) in normal healthy women with concentrations observed in women with ovarian cancer; and to establish and compare the performance of MDK with that of anterior gradient 2 protein (AGR2) and CA125 in the development of multi-analyte classification algorithms for ovarian cancer. Median plasma concentrations of immunoreactive MDK, AGR2 and CA125 were significantly greater in the case cohort (909 pg/ml, 765 pg/ml and 502 U/ml, respectively n = 46) than in the control cohort (383 pg/ml, 188 pg/ml and 13 U/ml, respectively n = 61) (p < 0.001). The area under the receiver operator characteristic curve (AUC) for MDK and AGR2 was not significantly different (0.734 ± 0.046 and 0.784 ± 0.049, respectively, mean ± SE) but were both significantly less than the AUC for CA125 (0.934 ± 0.030, p < 0.003). When subjected to stochastic gradient boosted logistic regression modelling, the AUC of the multi-analyte panel (MDK, AGR2 and CA125, 0.988 ± 0.010) was significantly greater than that of CA125 alone (0.934 ± 0.030, p = 0.035). The sensitivity and specificity of the multi-analyte algorithm were 95.2 and 97.7%, respectively. Within the study cohort, CA125 displayed a sensitivity and specificity of 87.0 and 94.6%, respectively. The data obtained in this study confirm that both MDK and AGR2 individually display utility as biomarkers for ovarian cancer and that in a multi-analyte panel significantly improve the diagnostic utility of CA125 in symptomatic women

Adenoviral-Directed Expression of the Type 1A Angiotensin Receptor Promotes Cardiomyocyte Hypertrophy via Transactivation of the Epidermal Growth Factor Receptor.

Angiotensin II (Ang II) may cause cardiac hypertrophy via type 1 Ang II receptors (AT1) on cardiomyocytes and through growth factors released from cardiac fibroblasts. Whereas cardiomyocyte-specific AT1 receptor expression produces cardiac hypertrophy and remodeling in vivo, delineation of the signals that mediate growth to Ang II is challenging because the prevailing in vitro model (cultured neonatal cardiomyocytes) expresses low levels of AT1 receptor and responds inconsistently to Ang II. In this study, when AT1A receptors were expressed using adenovirus in cultured neonatal cardiomyocytes, Ang II stimulated a robust hypertrophy that was not secondary to the release of cardiac fibroblast-derived factors, specifically endothelin-1. Hypertrophy was accompanied by the induction of the immediate-early response genes, c-fos and c-jun, and reexpression of atrial natriuretic peptide (ANP). Ang II-induced activation of an ANP promoter-reporter was inhibited by the dominant/negative mutants, G[alpha]qI and N17Ras, indicating that hypertrophic signaling by the AT1A receptor is via heterotrimeric G protein coupling and downstream Ras pathways. AT1A-mediated cardiomyocyte hypertrophy and mitogen-activated protein kinase (MAPK) activation were inhibited by the MAPK kinase inhibitor, PD98059, and the epidermal growth factor (EGF) receptor kinase antagonist, AG1478, but not by PKC inhibitor, bisindolylmaleimide-1. Moreover, Ang II-induced MAPK activation was prevented by treatment with a matrix metalloproteinase inhibitor, consistent with the tyrosine phosphorylation of the EGF receptor in response to AT1A receptor activation. These data unequivocally demonstrate that Ang II can directly promote cardiac myocyte growth via AT1A receptors expressed on these cells and reveal for the first time the important contribution of EGF receptor-transactivated MAPK signaling to this process

AGR2 expression in ovarian tumours: A potential biomarker for endometrioid and mucinous differentiation

Aims: To examine AGR2 expression in ovarian epithelial tumours and its potential role as a prognostic biomarker. Methods: Tissue microarray technology and immunohistochemistry were used to investigate AGR2 expression in ovarian epithelial tumours and in non-neoplastic ovarian epithelium. For the carcinomas, the expression data were correlated with clinicopathological features and disease outcome. Results: AGR2 was expressed in all benign, borderline and malignant mucinous tumours and in a high proportion of endometrioid carcinomas (89%). AGR2 was frequently expressed in benign and borderline serous tumours (76% and 95%, respectively), but less commonly expressed in serous carcinomas (19%,