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Knowledge of the molecular background of functional magnetic resonance (MR) images is required to fully exploit their potential in cancer management. We explored the prognostic impact of dynamic contrast-enhanced MR imaging (DCE-MRI) parameters in cervical cancer combined with global gene expression data to reveal their underlying molecular phenotype and construct a representative gene signature for the relevant parameter. On the basis of 78 patients with cervical cancer subjected to curative chemoradiotherapy, we identified the prognostic DCE-MRI parameter ABrix by pharmacokinetic analysis of pretreatment images based on the Brix model, in which tumors with low ABrix appeared to be most aggressive. Gene set analysis of 46 tumors with pairwise DCE-MRI and gene expression data showed a significant correlation between ABrix and the hypoxia gene sets, whereas gene sets related to other tumor phenotypes were not significant. Hypoxia gene sets specific for cervical cancer created in cell culture experiments, including both targets of the hypoxia inducible factor (HIF1α) and the unfolded protein response, were the most significant. In the remaining 32 tumors, low ABrix was associated with upregulation of HIF1α protein expression, as assessed by immunohistochemistry, consistent with increased hypoxia. On the basis of the hypoxia gene sets, a signature of 31 genes that were upregulated in tumors with low ABrix was constructed. This DCE-MRI hypoxia gene signature showed prognostic impact in an independent validation cohort of 109 patients. Our findings reveal the molecular basis of an aggressive hypoxic phenotype and suggest the use of DCE-MRI to noninvasively identify patients with hypoxia-related chemoradioresistance. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: We have applied the sensitive and specific in situ proximity ligation assay (PLA) to characterize Tyr1068 phosphorylation of the epidermal growth factor receptor (EGFR) in cervical cancer in relation to the protein level and gene dosage. Materials and methods: Pretreatment tumor biopsies from 178 patients were analyzed. EGFR protein level was determined by immunohistochemistry, and Tyr1068 phosphorylation was detected with PLA in 97 EGFR positive tumors. EGFR gene dosage was derived from array comparative genomic hybridization of 86 cases. Results: EGFR was expressed in most tumors, whereas phosphorylation was seen in about half of the EGFR positive ones. A correlation was found between the expression of EGFR and phosphorylated EGFR (p =0.016, membrane; p =0.012, cytoplasm). However, tumor regions with high protein level without phosphorylation were occasionally seen and the percentage of EGFR positive cells was higher than the phosphorylated percentage (p <0.001). Moreover, an increase in the phosphorylation in both the membrane (p =0.014) and cytoplasm (p =0.002) was seen in 11 tumors with gain of EGFR. The protein level was not correlated with gene dosage. Conclusion: In contrast to gain of the EGFR chromosomal region, high EGFR protein level may not necessarily indicate Tyr1068 phosphorylation and thereby receptor activation in cervical cancer. [Copyright &y& Elsevier]

Increasing evidence suggests that fatty acid desaturases, rate-limiting enzymes in unsaturated fatty acid biosynthesis, are important factors in the pathogenesis of lipid-induced insulin resistance. The conversion of dihomogamma linolenic acid (DGLA) into arachidonic acid (AA) in human plasma phospholipids has been shown to be regulated by insulin, suggesting a role for insulin in fatty acid desaturase 1 regulation. However insulin's role in monocyte inflammation associated with obesity and lifestyle disease development is uncertain. We therefore investigated if insulin is able to induce expression of stearoyl-CoA desaturase (SCD, ΔΔ9 desaturase), fatty acid desaturase 1 (FADS1, ΔΔ5 desaturase), and fatty acid desaturase 2 (FADS2, ΔΔ6 desaturase), as well as the sterol regulatory element binding transcription factor 1-c (SREBP-1c) in monocytes. Here, for the first time, we demonstrate that THP-1 monocytes are insulin-responsive in inducing expression of SCD, FADS1, and FADS2 in a time- and dose-dependent manner. Understanding secondary consequences of postprandial hyperinsulinemia may open up new strategies for prevention and/or treatment of obesity-related metabolic complications. [ABSTRACT FROM AUTHOR]