Tumour-specific HMG-CoAR is an independent predictor of recurrence free survival in epithelial ovarian cancer

<p>Abstract</p> <p>Background</p> <p>Our group previously reported that tumour-specific expression of the rate-limiting enzyme in the mevalonate pathway, 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR) is associated with more favourable tumour parameters and a good prognosis in breast cancer. In the present study, the prognostic value of HMG-CoAR expression was examined in tumours from a cohort of patients with primary epithelial ovarian cancer.</p> <p>Methods</p> <p>HMG-CoAR expression was assessed using immunohistochemistry (IHC) on tissue microarrays (TMA) consisting of 76 ovarian cancer cases, analysed using automated algorithms to develop a quantitative scoring model. Kaplan Meier analysis and Cox proportional hazards modelling were used to estimate the risk of recurrence free survival (RFS).</p> <p>Results</p> <p>Seventy-two tumours were suitable for analysis. Cytoplasmic HMG-CoAR expression was present in 65% (n = 46) of tumours. No relationship was seen between HMG-CoAR and age, histological subtype, grade, disease stage, estrogen receptor or Ki-67 status. Patients with tumours expressing HMG-CoAR had a significantly prolonged RFS (p = 0.012). Multivariate Cox regression analysis revealed that HMG-CoAR expression was an independent predictor of improved RFS (RR = 0.49, 95% CI (0.25-0.93); p = 0.03) when adjusted for established prognostic factors such as residual disease, tumour stage and grade.</p> <p>Conclusion</p> <p>HMG-CoAR expression is an independent predictor of prolonged RFS in primary ovarian cancer. As HMG-CoAR inhibitors, also known as statins, have demonstrated anti-neoplastic effects <it>in vitro</it>, further studies are required to evaluate HMG-CoAR expression as a surrogate marker of response to statin treatment, especially in conjunction with current chemotherapeutic regimens.</p

Identification of a myometrial molecular profile for dystocic labor

<p>Abstract</p> <p>Background</p> <p>The most common indication for cesarean section (CS) in nulliparous women is dystocia secondary to ineffective myometrial contractility. The aim of this study was to identify a molecular profile in myometrium associated with dystocic labor.</p> <p>Methods</p> <p>Myometrial biopsies were obtained from the upper incisional margins of nulliparous women undergoing lower segment CS for dystocia (n = 4) and control women undergoing CS in the second stage who had demonstrated efficient uterine action during the first stage of labor (n = 4). All patients were in spontaneous (non-induced) labor and had received intrapartum oxytocin to accelerate labor. RNA was extracted from biopsies and hybridized to Affymetrix HuGene U133A Plus 2 microarrays. Internal validation was performed using quantitative SYBR Green Real-Time PCR.</p> <p>Results</p> <p>Seventy genes were differentially expressed between the two groups. 58 genes were down-regulated in the dystocia group. Gene ontology analysis revealed 12 of the 58 down-regulated genes were involved in the immune response. These included (ERAP2, (8.67 fold change (FC)) HLA-DQB1 (7.88 FC) CD28 (2.60 FC), LILRA3 (2.87 FC) and TGFBR3 (2.1 FC)) Hierarchical clustering demonstrated a difference in global gene expression patterns between the samples from dystocic and non-dystocic labours. RT-PCR validation was performed on 4 genes ERAP2, CD28, LILRA3 and TGFBR3</p> <p>Conclusion</p> <p>These findings suggest an underlying molecular basis for dystocia in nulliparous women in spontaneous labor. Differentially expressed genes suggest an important role for the immune response in dystocic labor and may provide important indicators for new diagnostic assays and potential intrapartum therapeutic targets.</p

Maternal plasma vascular endothelial growth factor concentrations in normal and hypertensive pregnancies and their relationship to peripheral vascular resistance

Objective: The aim of this study was to measure maternal plasma vascular endothelial growth factor concentrations during normal and hypertensive pregnancies and examine their relationship with maternal total peripheral resistance values.Study Design: Plasma concentrations of total immunoreactive vascular endothelial growth factor and total peripheral resistances were measured serially throughout pregnancy in 20 women with preeclampsia, 24 women with gestational hypertension, and 26 normotensive control women. One-way analysis of variance and a regression model were used to analyze the vascular endothelial growth factor levels in the groups and the relationship between vascular endothelial growth factor concentration and total peripheral resistance.Results: At 10 to 14 weeks’ gestation plasma vascular endothelial growth factor concentrations in all subjects were 4 to 5 times greater than the levels measured post partum (P &lt; .0001). Mean vascular endothelial growth factor concentrations were similar in the control and gestational hypertension groups; in both groups levels remained stable until 34 to 36 weeks’ gestation, when levels increased a further 1.3-fold (P &lt; .01). In comparison, vascular endothelial growth factor concentrations in subjects in the preeclampsia group were greater at 28 to 32 weeks’ gestation (P = .002) and at 34 to 36 weeks’ gestation (P &lt; .001). Vascular endothelial growth factor concentrations were also increased during the 4 weeks that preceded the diagnosis of preeclampsia (P &lt; .05). Vascular endothelial growth factor concentrations were associated with the elevated total peripheral resistance observed during the clinical disorder in the preeclampsia group but not in the other groups.Conclusion: Maternal plasma vascular endothelial growth factor concentrations increased before the clinical onset of preeclampsia and were further elevated during the vasoconstricted state observed in this disorder. We speculate that the hyperdynamic circulation that characterizes the latent phase of preeclampsia causes vascular shear stress, which in turn increases the levels of circulating vascular endothelial growth factor. Because vascular endothelial growth factor normally acts as a vasodilator, its increase may represent an unsuccessful vascular rescue response

The transcription factor Sox11 is a prognostic factor for improved recurrence-free survival in epithelial ovarian cancer

Abstract Background: Current prognostic molecular markers for epithelial ovarian cancer (EOC) are insufficient. The aim of the current study was to investigate the role of Sox11 in EOC Methods: Using an in silico transcriptomic screen Sox11 was identified as a potential EOC biomarker. Sox11 protein expression was evaluated using immunohistochemistry (IHC) in 76 EOC cases, which were analyzed using automated algorithms to develop a quantitative scoring model. Results: Sox11 mRNA expression was up-regulated in EOC compared to normal tissues. Automated analysis of Sox11 in the EOC cohort revealed high expression of Sox11, in 40% of tumours, who had an improved recurrence free survival (RFS) (p= 0.002). Multivariate analysis confirmed Sox11 was an independent predictor of improved RFS after controlling for stage and grade. Conclusions: These data suggest that Sox11 is a new prognostic marker in EOC. Loss of SOX 11 is associated with a decreased RFS and a more aggressive phenotype