New Analysis Framework Incorporating Mixed Mutual Information and Scalable Bayesian Networks for Multimodal High Dimensional Genomic and Epigenomic Cancer Data
- 作者列表："Xichun Wang","Sergio Branciamore","Grigoriy Gogoshin","Shuyu Ding","Andrei S. Rodin
We propose a novel two-stage analysis strategy to discover candidate genes associated with the particular cancer outcomes in large multimodal genomic cancers databases, such as The Cancer Genome Atlas (TCGA). During the first stage, we use mixed mutual information to perform variable selection; during the second stage, we use scalable Bayesian network (BN) modeling to identify candidate genes and their interactions. Two crucial features of the proposed approach are (i) the ability to handle mixed data types (continuous and discrete, genomic, epigenomic, etc.) and (ii) a flexible boundary between the variable selection and network modeling stages — the boundary that can be adjusted in accordance with the investigators’ BN software scalability and hardware implementation. These two aspects result in high generalizability of the proposed analytical framework. We apply the above strategy to three different TCGA datasets (LGG, Brain Lower Grade Glioma; HNSC, Head and Neck Squamous Cell Carcinoma; STES, Stomach and Esophageal Carcinoma), linking multimodal molecular information (SNPs, mRNA expression, DNA methylation) to two clinical outcome variables (tumor status and patient survival). We identify 11 candidate genes, of which 6 have already been directly implicated in the cancer literature. One novel LGG prognostic factor suggested by our analysis, methylation of TMPRSS11F type II transmembrane serine protease, presents intriguing direction for the follow-up studies.
我们提出了一种新的两阶段分析策略，在大型多模态基因组癌症数据库，如癌症基因组图谱 (TCGA) 中发现与特定癌症结局相关的候选基因。在第一阶段，我们使用混合互信息进行变量选择; 在第二阶段，我们使用可扩展贝叶斯网络 (BN) 建模来识别候选基因及其相互作用。所提出的方法的两个关键特征是 (i) 处理混合数据类型 (连续和离散，基因组，表观基因组等) 的能力和 (ii)变量选择和网络建模阶段之间的灵活边界-可以根据调查人员的 BN 软件可扩展性和硬件实现进行调整的边界。这两个方面导致所提出的分析框架具有很高的普遍性。我们将上述策略应用于三个不同的 TCGA 数据集 (LGG，脑低级胶质瘤; HNSC，头颈部鳞状细胞癌; STES，胃和食管癌),将多模式分子信息 (SNPs 、 mRNA 表达、 DNA 甲基化) 与两个临床结局变量 (肿瘤状态和患者生存率) 联系起来。我们确定了 11 个候选基因，其中 6 个已经直接与癌症文献有关。我们的分析提示的一个新的 LGG 预后因子，TMPRSS11F II 型跨膜丝氨酸蛋白酶的甲基化，为后续研究提供了有趣的方向。
METHODS::In colorectal cancer (CRC), hepatic arterial infusion (HAI) chemotherapy may convert primarily unresectable CRC liver metastases (CLM) into resectability, although the risk of metastatic recurrence remains high after CLM ablation. We investigated the role of antitumour immunity invoked by first-line oxaliplatin-HAI for long-term CLM outcome. In a prospective study cohort of primarily unresectable CLM, we assessed patients' fms-related tyrosine kinase 3 ligand (FLT3LG) in serum, reflecting opportune intratumoural immune activity, at baseline and following 1-3 sequences of oxaliplatin-HAI. The end points were CLM resectability and overall survival. Patients who presented an immediate twofold increment of circulating FLT3LG during the treatment and at its completion were scored as CLM resectable (16.4% with both features), were alive at final follow-up 8-12 years later. All patients experienced FLT3LG increase during the treatment course, but those who remained unresectable or had the disease converted but presented a slow and gradual FLT3LG accretion, later died of the metastatic disease. These data provide further support to our previous findings that tumour-directed immunity invoked by oxaliplatin-containing therapy predicts excellent outcome of early advanced CRC if macroscopic tumour ablation is rendered possible by the 'classic' tumour response to the cytotoxic treatment.
METHODS::Prostate cancer is one of the primary causes of death around the world. As an important drug, flutamide has been used in the clinical diagnosis of prostate cancer. However, the over dosage and improper discharge of flutamide could affect the living organism. Thus, it necessary to develop the sensor for detection of flutamide with highly sensitivity. In this paper, we report the synthesis of lanthanum cobaltite decorated halloysite nanotube (LCO/HNT) nanocomposite prepared by a facile method and evaluated for selective reduction of flutamide. The as-prepared LCO/HNT nanocomposite shows the best catalytic performance towards detection of flutamide, when compared to other bare and modified electrodes. The good electrochemical performance of the LCO/HNT nanocomposite modified electrode is ascribed to abundant active sites, large specific surface area and their synergetic effects. Furthermore, the LCO/HNT modified electrode exhibits low detection limit (0.002 μM), wide working range (0.009-145 μM) and excellent selectivity with remarkable stability. Meaningfully, the developed electrochemical sensor was applied in real environmental samples with an acceptable recovery range.
METHODS::Several studies have indicated that cancer-associated fibroblasts (CAFs) could promote cancer progression in many malignancies. However, the mechanism by which CAFs promote the growth and metastasis of lung cancer remains poorly defined. In the present study, CAFs and normal fibroblasts (NFs) were isolated from human lung cancer and adjacent tissue. The data showed that the conditional medium (CM) of CAFs could increase the proliferation, migration and invasion of lung cancer cells. Vascular cell adhesion molecule-1 (VCAM-1) showed a higher expression in CAF-CM than NF-CM, and blocking VCAM-1 in CAF-CM attenuated the proliferation and invasion of cancer cells. Further, the results showed that VCAM-1 secreted from CAFs activated AKT and MAPK signaling via receptor α4β1 integrin (very-late antigen (VLA)-4) in lung cancer cells. Moreover, CAFs promoted VCAM-1 expression and tumor growth in vivo. Additionally, bioinformatics analysis indicated a positive correlation on the CAF marker protein alpha-smooth muscle actin (α-SMA) and VCAM-1 expression, which was associated with a poor prognosis in lung cancer patients. These findings demonstrate that the VCAM-1 secreted from CAFs enhances growth and invasion by activating the AKT and MAPK signaling of lung cancer cells.