Genome-Wide Network-Based Analysis of Colorectal Cancer Identifies Novel Prognostic Factors and an Integrative Prognostic Index

Background/Aims: Colorectal cancer (CRC) is one of leading cancers in both incidence and mortality rate. The 5-year survival rate varies considerably depending on the pathological stage of the tumor. Although prominent progress has been made through screening for survival-associated factors from a certain type of genetic or epigenetic modifications, few attempts have been made to apply a network-based approach in prognostic factor identification, which could prove valuable for a complex, multi-faceted disease such as CRC. Methods: In this study, a TCGA dataset of 379 CRC patients was subjected to a network-based analysis strategy consisting of multivariate regression, co-expression network and gene regulatory network analyses, and survival analyses. Both genetic and epigenetic aberrations, including those in gene expression and DNA methylation at specific sites, were screened for significant association with patient survival. A prognostic index (PI) integrating all potential prognostic factors was subsequently validated for its prognostic value. Results: A collection of six miRNAs, eleven mRNAs, and nine DNA methylation sites were identified as potential prognostic factors. The low- and high-risk patient groups assigned based on PI level showed significant difference in overall survival (hazard ratio = 1.32, 95% confidence interval 1.29-1.36, p < 0.0001). Patients in the low- and high-risk groups can be further divided into a total of four subgroups, based on pathological staging. In the two high-risk subgroups (PI > 0), there was significant different (Cox p < 0.0001) in OS between the earlier (stages I/II) and later stages (stages III/IV). However, in the two low-risk subgroups (PI < 0), earlier (stages I/II) and later stages (stages III/IV) showed no significant difference in OS (Cox p = 0.185). On the other hand, there were significant differences in OS between the low- and high-risk subgroups when both subgroups were of earlier stages (Cox p < 0.001) or of later stages (Cox p < 0.0001). Conclusion: The novel network-based, integrative analysis adopted in this study was efficient in screening for prognostic predictors. Along with PI, the set of 6 miRNAs, 11 mRNAs, and 9 DNA methylation sites could serve as the basis for improved prognosis estimation for CRC patients in future clinical practice

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Zircon U-Pb dating for the granite prophyries in Hongshan prophry copper deposit and Tongkenzhang porphyry molybdenum deposits in East Jiangxi Province and their significance

The Tongkengzhang molybdenum deposit and Hongshan copper deposit are two important porphyry deposits in the Wuyishan metallogenic belt in Southeast China. After performance of LA-ICP-MS zircon U-Pb dating, we obtained 138 ± 1Ma for the granite-prophyry in Tongkengzhang porphyry Mo deposit, and 99Ma and 49Ma for the granite prophyry in Hongshan porphyry Cu mine. The LA-ICP-MS zircon U-Pb dating of the granite prophyry in Hongshan deposit gives two distinguishing ages, which possibly represent the granite porphyry crystallization and disturb of post-mineralization thermal event, respectively. The data show the ages of the granite porphyry are consistent with those molybdenite Re-Os dating achieved by previous studies, which reflects the Cretaceous rock- and oreforming event. Based on compiled data from previous researches, we suggest that the Tongkengzhang Mo porphyry and the Hongshan Cu porphyry occurred in the extensional belt of the continental back arc and in the extensional faulted basins trigged by lithospheric thinning, respectively

Identification of three antiviral inhibitors against Japanese encephalitis virus from library of pharmacologically active compounds 1280.

Japanese encephalitis virus (JEV) can cause severe central nervous disease with a high mortality rate. There is no antiviral drug available for JEV-specific treatment. In this study, a cytopathic-effect-based, high-throughput screening assay was developed and applied to screen JEV inhibitors from Library of Pharmacologically Active Compounds 1280. The antiviral effects of three hit compounds including FGIN-1-27, cilnidipine, and niclosamide were evaluated in cells by western blotting, indirect immunofluorescence assay, and plaque reduction assay. A time-of-addition assay proved that all three compounds inhibited JEV at the stage of replication. The EC50s of FGIN-1-27, cilnidipine, and niclosamide were 3.21, 6.52, and 5.80 µM, respectively, while the selectivity indexes were 38.79, 30.67, and 7.49. FGIN-1-27 and cilnidipine have high efficiency and selectivity against JEV. This study provided two JEV antiviral inhibitors as candidates for treatment of JEV infection

Droplet digital PCR-based circulating microRNA detection serve as a promising diagnostic method for gastric cancer

Abstract Background Novel non-invasive biomarkers for gastric cancer (GC) are needed, because the present diagnostic methods for GC are either invasive or insensitive and non-specific in clinic. The presence of stable circulating microRNAs (miRNAs) in plasma suggested a promising role as GC biomarkers. Methods Based on the quantitative droplet digital PCR (ddPCR), four miRNAs (miR-21, miR-93, miR-106a and miR-106b) related to the presence of GC were identified in plasma from a training cohort of 147 participants and a validation cohort of 28 participants. Results All circulating miRNA levels were significantly higher in the plasma of GC patients compared to healthy controls (P < 0.05). Through a combination of four miRNAs by logistic regression model, receiver operating characteristic (ROC) analyses yielded the highest AUC value of 0.887 in discriminating GC patients from healthy volunteers. Furthermore, miR-21, miR-93 and miR-106b levels were significantly related to an advanced TNM stage in GC patients. ROC analyses of the combined miRNA panel also showed the highest AUC value of 0.809 in discriminating GC patients with TNM stage I and II from stage III and IV. Through combining four miRNAs and clinical parameters, a classical random forest model was established in the training stage. In the validation cohort, it correctly discriminated 23 out of 28 samples in the blinded phase (false rate, 17.8%). Conclusions Using the ddPCR technique, circulating miR-21, miR-93, miR-106a and miR-106b could be used as diagnostic plasma biomarkers in gastric cancer patients

Quantitative Analysis of HER2 Amplification by Droplet Digital PCR in the Follow-Up of Gastric Cancer Patients Being Treated with Trastuzumab after Surgery

Background. Circulating tumor DNA (ctDNA) derived from tumors is a promising biomarker for monitoring tumor status and evaluating therapeutic effects and prognosis. We studied the plasma human epidermal growth factor receptor 2 (HER2) amplification in gastric cancer (GC) patients by droplet digital PCR (ddPCR) during therapy with trastuzumab. Methods. A total of 12 patients were recruited after surgery. All patients received FOLFOX chemotherapy combined with trastuzumab as a treatment regimen. During the 12 months of the follow-up period, using elongation factor Tu GTP binding domain containing 2 (EFTUD2) as a reference gene, plasma HER2 to EFTUD2 ratios (the HER2 ratio) were determined for each patient every 2 months by ddPCR. Results. The concordance rate of HER2 amplification examined in plasma and formalin-fixed paraffin-embedded (FFPE) samples with ddPCR was 81.4%, with a sensitivity of 76.5% and a specificity of 83.8%. Plasma HER2 ratios were correlated with the primary tumor size (p<0.01). A significant decrease in the plasma HER2 ratio was found after two months of treatment (p<0.0001). Nine patients experienced partial response, and three patients had stable disease. Seven patients had progressive disease (PD) during follow-up, and four of them had died. The median progression-free survival (PFS) was 9.8 months. For each patient who developed PD, the plasma HER2 ratio was approximately 2.3-4.1 times higher than the cut-off value at the time of PD, which was the highest during the whole follow-up period. Conclusion. Longitudinal monitoring for the plasma HER2 ratio by ddPCR in the clinical courses of GC patients holds great promise for use as an indicator of tumor progression and treatment efficacy

LIN28B promotes colon cancer migration and recurrence.

LIN28B is involved in "stemness" and tumourigenesis by negatively regulating the maturation of let-7 microRNA family members. In this study, we showed that LIN28B expression promotes migration and recurrence of colon cancer. Immunohistochemistry and reverse-transcription polymerase chain reactions were performed to detect LIN28B expression in colon cancer tissue microarrays, paraffin-embedded surgical resected tissues and cancer cells. Loss-of-function, migration and proliferation analyses were performed to delineate the potential roles of LIN28B in colon cancer. LIN28B was upregulated in colon cancer tissue compared to normal mucosa, and its overexpression correlated with reduced patient survival and increased tumour recurrence. LIN28B suppression inhibited the migration of SW480 colon cancer cells and facilitated the cytotoxicity induced by oxaliplatin in SW480 and HCT116 colon cancer cells. In conclusion, LIN28B overexpression contributes to colon tumourigenesis, and LIN28B may serve as a diagnostic tool and therapeutic target for colon cancer