Background: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ~4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC. Patients and methods: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies. Results: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 ( P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02–2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to –), 5.4 (4.6–7.0), 3.8 (3.3–4.6), 3.2 (2.9–3.7) and 2.3 (2.1–2.6) years. Conclusion: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.

ObjectiveTo evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival.Patients and MethodsWe conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and December 31, 2014, including 2865 high-grade serous ovarian carcinomas (HGSOCs), with more than 12,000 person-years of follow-up time. Tissue microarrays were stained for MyD88 and TLR4, and staining intensity was classified using a 2-tiered system for each marker (weak vs strong).ResultsExpression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P<.001 for both). In HGSOC, strong MyD88 expression was modestly associated with shortened overall survival (hazard ratio [HR], 1.13; 95% CI, 1.01–1.26; P=.04) but was also associated with advanced stage (P<.001). The expression of TLR4 was not associated with survival. In low-grade serous ovarian cancer (LGSOC), strong expression of both MyD88 and TLR4 was associated with favorable survival (HR [95% CI], 0.49 [0.29–0.84] and 0.44 [0.21–0.89], respectively; P=.009 and P=.02, respectively).ConclusionResults are consistent with an association between strong MyD88 staining and advanced stage and poorer survival in HGSOC and demonstrate correlation between strong MyD88 and TLR4 staining and improved survival in LGSOC, highlighting the biological differences between the 2 serous histotypes.

Alexander BN, Fewell JE. Metyrapone restores the febrile response to Escherichia coli LPS in pregnant rats. Am J Physiol Regul Integr Comp Physiol 300: R1588 -R1595, 2011. First published April 13, 2011 doi:10.1152 doi:10. /ajpregu.00785.2010 an important component of the host's defense response to immune challenge, is absent or attenuated in rats near the term of pregnancy. The present experiments were carried out to determine the role of endogenous glucocorticoids in mediating the altered core temperature (Tc) response to exogenous pyrogen (i.e., Escherichia coli LPS). For the experiments, metyrapone-a glucocorticoid synthesis inhibitor-was administered to near-term pregnant rats prior to an EC100 dose of E. coli LPS. Administration of LPS following vehicle elicited a significant corticosterone response and resulted in a decrease in Tc (i.e., hypothermia). Prior administration of metyrapone, however, which abolished the corticosterone response and altered the pyrogenic/ cryogenic cytokine response to LPS, eliminated hypothermia and restored the febrile response. Our results provide evidence that endogenous glucocorticoids play a role in mediating the altered febrile response to immune stimuli observed in rats near the term of pregnancy.glucocorticoids; hypothermia; infection NUMEROUS PHYSIOLOGICAL CHANGES accompany the maternal adaptation to pregnancy in rats, including reversible changes in blood hormone concentrations (e.g., corticosterone) and basal thermoregulatory control, as well as the cytokine, prostanoid, and Tc responses to immune challenge (4,17,19,21,34). For example, Fofie and Fewell (21) observed that Tc responses to intraperitoneal administration of 160 g/kg Escherichia coli LPS (EC 100 in nonpregnant rats) are different in pregnant rats as early as day 10 of the 21-day gestational period compared with nonpregnant oophorectomized rats. In nonpregnant rats, 160 g/kg E. coli LPS elicits an increase in Tc (i.e., a fever) with a latency, magnitude, and duration of 1.5 h, 1.9°C, and at least 4.5 h, respectively (21). Accompanying the febrile response are significant increases in plasma IL-1␤, IL-6, TNF-␣, and IL-1ra (22). In pregnant rats, however, 160 g/kg E. coli LPS elicits a "regulated" decrease in Tc (i.e., hypothermia)-the magnitude and duration of which increase with increasing LPS dose and gestation-before a modest increase in Tc above baseline is recorded (21, 52); accompanying the hypothermia are significant increases in plasma TNF-␣, and IL-ra, but not IL-1␤ and IL-6 (22). The mechanism and consequences for the mother and fetus of this altered thermoregulatory component of the acute phase response remain largely unknown.It has long been known that glucocorticoids have an antipyretic action on natural fevers in man (27), and Coelho et al.(13) and Morrow et al. (38) have shown that endogenous glucocorticoids modulate bacterial pyrogen-induced fever in male rats. Furthermore, Moore and Fewell (36) have recently shown that oral administration of mifepristone (RU38486)-a progesterone and gl...