Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer, is growing in incidence but treatment options remain limited, particularly for late stage disease. As liver cirrhosis is the principal risk state for HCC development, markers to detect early HCC within this patient population are urgently needed. Perturbation of epigenetic marks, such as DNA methylation (5mC), is a hallmark of human cancers, including HCC. Identification of regions with consistently altered 5mC levels in circulating cell free DNA (cfDNA) during progression from cirrhosis to HCC could therefore serve as markers for development of minimally-invasive screens of early HCC diagnosis and surveillance.Methods: To discover DNA methylation derived biomarkers of HCC in the background of liver cirrhosis, we profiled genome-wide 5mC landscapes in patient cfDNA using the Infinium HumanMethylation450k BeadChip Array. We further linked these findings to primary tissue data available from TCGA and other public sources. Using biological and statistical frameworks, we selected CpGs that robustly differentiated cirrhosis from HCC in primary tissue and cfDNA followed by validation in an additional independent cohort.Results: We identified CpGs that segregate patients with cirrhosis, from patients with HCC within a cirrhotic liver background, through genome-wide analysis of cfDNA 5mC landscapes. Lasso regression analysis pinpointed a panel of probes in our discovery cohort that were validated in two independent datasets. A panel of five CpGs (cg04645914, cg06215569, cg23663760, cg13781744, and cg07610777) yielded area under the receiver operating characteristic (AUROC) curves of 0.9525, 0.9714, and 0.9528 in cfDNA discovery and tissue validation cohorts 1 and 2, respectively. Validation of a 5-marker panel created from combining hypermethylated and hypomethylated CpGs in an independent cfDNA set by bisulfite pyrosequencing yielded an AUROC of 0.956, compared to the discovery AUROC of 0.996.Conclusion: Our finding that 5mC markers derived from primary tissue did not perform well in cfDNA, compared to those identified directly from cfDNA, reveals potential advantages of starting with cfDNA to discover high performing markers for liquid biopsy development.
OBJECTIVE:Atrial fibrillation (AF) is one of the most common arrhythmias, which is caused by a number of minorring disorders caused by the heart owner's guide. It is noted in almost all organic heart disease and can also occur in non-organic heart disease,causing serious complications, such as heart failure and arterial embolism, seriously threaten people's health.Atrial fibrillation can cause serious complications, such as heart failure and arterial embolism, which seriously threaten people's health. Clinically, according to the characteristics of atrial fibrillation, atrial fibrillation is divided into paroxysmal atrial fibrillation,persistent atrial fibrillation, permanent atrial fibrillation (cannot be converted to sinus rhythm).Among them, persistent atrial fibrillation poses the greatest threat to people's health.So the main purpose of this study is to identify the differential genes in patients with permanent atrial fibrillation. MATERIALS AND METHODS:To explore potential differential genes for permanent atrial fibrillation, we analyzed three microarray datasets GSE2240 derived from the Gene Expression Omnibus (GEO) database. We used the“limma”function package of R software to screen differentially expressed genes(DEGs), and used the“pheatmap”function package to construct heatmaps for the screened differential genes.Visualization and Integration Discovery (DAVID) ,Cytoscape ,BMKcloud and String platforms were utilized for Genome Ontology (GO) analysis,Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis , PPI(protein-proteinInteraction) network analysis ,module analysis,and identification hub genes based on the selected differential genes.RESULTS:74 DEGs in total were identified, including 41 up- and 33 downregulated genes. These DEGs were mainly enriched in PI3K-Akt signaling pathway ,cGMP-PKG signaling pathway, Focal adhesion, and so on. The module analysis filtered out 12 key genes, including PRL, CREB1, AGO2, NAMPT, IGFBP2, FGF7, ANGPT2, SYT13, NRXN1, AQP4, TCEAL2, and CPLX1. 2 Hub genes were identified, including IGFBP2, and FGF7.CONCLUSIONS:IGFBP2 and FGF7 were identified as Hub genes of AF, which helped us to understand more deeply the pathophysiological mechanism of AF.
Chemotherapy has been shown to act as an immune response modifier. Many groups, incuding our own, are using chemotherapy to induce immune responses such as by using low doses of cyclophosphamide. Our previous work has demonstrated that anti-cancer agents can eliminate new/existing tumors with minimal toxicity in rat and mouse models of breast cancer. Here we demonstrate that intraductal (i.duc), but not the intravenous (IV) route of injection, of chemotherapy to mammary glands alters the tumor environment to effectively induce immune effector cells. We used the mouse HER2/neu (neu/N) transgenic, spontaneous mammary tumor model. 5-fluorouracil (5FU) was administered intraductally to the mammary glands on the left side of parous mice whereas the mammary glands on right side received no treatment (NT). The mammary tumor incidence in the 5FU treated side was significantly lower compared to mice that received NT, and IV treated group. Interestingly the incidence of mammary tumors in the untreated side of 5FU-treated mice was also significantly lower compared to the NT and IV group. We hypothesized that the protection afforded to the contralateral chain of mammary glands by ipsilateral i.duc administration of 5FU, may be mediated through an immunological mechanism. Twenty week parous mice were administered 5FU either through i.duc injection, only to left side teats, IV injection, or NT. The mice received 5FU 2 times in a 4 week interval. A week after the second treatment, the mice were sacrificed and the regional lymphnodes (RLN) of the 3rd and 4th mammary glands and spleen were removed. We isolated lymphocyte from RLN and spleen to analyze by flowcytometry. The number of CD8 T cell showed no change among the groups in the RLN but was significantly lower in the i.duc group in the spleen. The number of CD62LLOW+ T cell in 5FU treated side of RLN was significantly higher compared to the IV and NT group. On the other hand the number of CD62LLOW+ was low in the spleen. To study the population of systemic memory T cell in the peripheral blood, blood was harvested into Trucount tubes and analyzed with memory T cells surface marker. Twenty week parous mice was administered 5FU i.duc injection only to the left side, IV injection, or NT every 4weeks for a total of 3 times. Cancer cells were injected into the left side of 4th mammary gland fat pad of the mice at 16 weeks after initial procedure. One hundred μl blood was collected 5 days before and 5 days after cancer cell injection. The mice treated by i.duc 5FU showed increased numbers of CD95+/CD62L low effector memory T (TEM) cells, whereas the mice treated with IV 5FU did not recruit TEM cells significantly. There was no significant change in CD95+/CD62L high central memory T cells before and after treatment and among the groups. In summary, i.duc administration of 5FU into mammary glands effectively induced immune effector cells and prevented mammary tumor growth in neu/N transgenic mice. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-456. doi:10.1158/1538-7445.AM2011-LB-456
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