E regulation of apoptosis mitotic cell cycle spindle assembly checkpoint regulation of mitotic metaphase/anaphase transition62.81 2.mesenchymal cell differentiation somatic cell DNA recombination somatic diversification of BMS5 biological activity immune receptors2.carboxylic acid metabolic process cellular ketone metabolic process1.establishment of RNA localization RNA transport1.Glycolysis hexose catabolic process111.73 1.embryonic epithelial tube formation somatic recombination of immunoglobulin gene segments production of molecular mediator of immune response1.provirus integration DNA integration1.natural killer cell mediated cytotoxicity leukocyte mediated cytotoxicity1.regulation of caspase activity regulation of peptidase activity1.somatic recombination of immunoglobulin genes during immune response immunoglobulin production during immune response*Enrichment Score is the -log10 of the average p-value of the terms in the cluster. Fold change is the ratio of the proportion of genes in the tested list versus the Human Gene Reference database. doi:10.1371/journal.pone.0055975.tWentzensen et al., developed methods to detect p16 protein in cell lysates of cervix exudates using ELISA. The sensitivity of this ELISA method for the identification of high-risk lesions was 84 , and the specificity was 87 [52]. In agreement with these data, the specificity of CDKN2A mRNA detection, which encodes p16, in screening for CIN2+ was very close (93 , Table 4). Two new markers identified in this work (CDKN3 and NUSAP1), along with CDKN2A, showed a high specificity (93 ) and PPV (93.4 ); therefore, they might be good candidates to use with HC2 as a first-line strategy in a screening program. The scope of this study was to perform a feasibility evaluation to Potassium clavulanate web ascertain whether determining the mRNA levels of novel genes in cervical samples would allow for the identification of high-grade CIN or invasive lesions with high sensitivity and specificity. However, the potential sensitivities reported in this analysis are most likely overestimated compared to those likely to be found in clinical practice, as those with CIN2+ have a higher proportion of cervicalcancer (which is easy to identify) than that expected in any screening setting. In contrast, the specificity seems to be underestimated, given that a large proportion of CIN1- had CIN1. Therefore, we did not expect to obtain conclusive data on the sensitivity, specificity or predictive values of the assays. Further studies are needed to determine the levels of CDKN3, NUSAP1, and CDC20 mRNA or protein in cervical samples from a screening population to obtain information about the predictive values and to define the optimal trade-off between sensitivity and specificity for the detection of CIN2+. PRC1, CCNB2, and SYCP2 are markers exclusively associated with invasive cervical cancer. Together with NUSAP1, CDKN3, and CDC20, these genes represent potential specific targets for the treatment of advanced CC, particularly CDKN3, which was found to be associated with poor survival. These genes encode proteins involved in the cell cycle, specifically in the M phase (mitosis and cytokinesis). According to the IH data, approximately 30 ofMitosis as Source of Biomarkers in Cervical CancerTable 6. DAVID functional annotation cluster analysis at the highest stringency of the 100 genes most deregulated in cervical cancer compared with normal cervical epithelium*.ClusterEnrichment Score 13.Biological Process Mitosis ?nuclear division M phase o.E regulation of apoptosis mitotic cell cycle spindle assembly checkpoint regulation of mitotic metaphase/anaphase transition62.81 2.mesenchymal cell differentiation somatic cell DNA recombination somatic diversification of immune receptors2.carboxylic acid metabolic process cellular ketone metabolic process1.establishment of RNA localization RNA transport1.Glycolysis hexose catabolic process111.73 1.embryonic epithelial tube formation somatic recombination of immunoglobulin gene segments production of molecular mediator of immune response1.provirus integration DNA integration1.natural killer cell mediated cytotoxicity leukocyte mediated cytotoxicity1.regulation of caspase activity regulation of peptidase activity1.somatic recombination of immunoglobulin genes during immune response immunoglobulin production during immune response*Enrichment Score is the -log10 of the average p-value of the terms in the cluster. Fold change is the ratio of the proportion of genes in the tested list versus the Human Gene Reference database. doi:10.1371/journal.pone.0055975.tWentzensen et al., developed methods to detect p16 protein in cell lysates of cervix exudates using ELISA. The sensitivity of this ELISA method for the identification of high-risk lesions was 84 , and the specificity was 87 [52]. In agreement with these data, the specificity of CDKN2A mRNA detection, which encodes p16, in screening for CIN2+ was very close (93 , Table 4). Two new markers identified in this work (CDKN3 and NUSAP1), along with CDKN2A, showed a high specificity (93 ) and PPV (93.4 ); therefore, they might be good candidates to use with HC2 as a first-line strategy in a screening program. The scope of this study was to perform a feasibility evaluation to ascertain whether determining the mRNA levels of novel genes in cervical samples would allow for the identification of high-grade CIN or invasive lesions with high sensitivity and specificity. However, the potential sensitivities reported in this analysis are most likely overestimated compared to those likely to be found in clinical practice, as those with CIN2+ have a higher proportion of cervicalcancer (which is easy to identify) than that expected in any screening setting. In contrast, the specificity seems to be underestimated, given that a large proportion of CIN1- had CIN1. Therefore, we did not expect to obtain conclusive data on the sensitivity, specificity or predictive values of the assays. Further studies are needed to determine the levels of CDKN3, NUSAP1, and CDC20 mRNA or protein in cervical samples from a screening population to obtain information about the predictive values and to define the optimal trade-off between sensitivity and specificity for the detection of CIN2+. PRC1, CCNB2, and SYCP2 are markers exclusively associated with invasive cervical cancer. Together with NUSAP1, CDKN3, and CDC20, these genes represent potential specific targets for the treatment of advanced CC, particularly CDKN3, which was found to be associated with poor survival. These genes encode proteins involved in the cell cycle, specifically in the M phase (mitosis and cytokinesis). According to the IH data, approximately 30 ofMitosis as Source of Biomarkers in Cervical CancerTable 6. DAVID functional annotation cluster analysis at the highest stringency of the 100 genes most deregulated in cervical cancer compared with normal cervical epithelium*.ClusterEnrichment Score 13.Biological Process Mitosis ?nuclear division M phase o.
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