Heritable clustering and pathway discovery in breast cancer integrating epigenetic and phenotypic data

BACKGROUND: In order to recapitulate tumor progression pathways using epigenetic data, we developed novel clustering and pathway reconstruction algorithms, collectively referred to as heritable clustering. This approach generates a progression model of altered DNA methylation from tumor tissues diagnosed at different developmental stages. The samples act as surrogates for natural progression in breast cancer and allow the algorithm to uncover distinct epigenotypes that describe the molecular events underlying this process. Furthermore, our likelihood-based clustering algorithm has great flexibility, allowing for incomplete epigenotype or clinical phenotype data and also permitting dependencies among variables. RESULTS: Using this heritable clustering approach, we analyzed methylation data obtained from 86 primary breast cancers to recapitulate pathways of breast tumor progression. Detailed annotation and interpretation are provided to the optimal pathway recapitulated. The result confirms the previous observation that aggressive tumors tend to exhibit higher levels of promoter hypermethylation. CONCLUSION: Our results indicate that the proposed heritable clustering algorithms are a useful tool for stratifying both methylation and clinical variables of breast cancer. The application to the breast tumor data illustrates that this approach can select meaningful progression models which may aid the interpretation of pathways having biological and clinical significance. Furthermore, the framework allows for other types of biological data, such as microarray gene expression or array CGH data, to be integrated

Puerarin Suppresses Invasion and Vascularization of Endometriosis Tissue Stimulated by 17β-Estradiol

BACKGROUND: Puerarin, a phytoestrogen with a weak estrogenic effect, binds to estrogen receptors, thereby competing with 17β-estradiol (E2) and producing an anti-estrogenic effect. This study was to investigate whether puerarin could suppress the invasion and vascularization of E2-stimulated endometriotic tissue. METHODOLOGY/PRINCIPAL FINDINGS: The endometriotic stromal cells (ESCs) were successfully established and their invasive ability under different treatments was assessed through a Transwell Assay. Simultaneously, matrix metallopeptidase 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) were detected by western blotting. Vascularization of endometriotic tissues was observed by chicken chorioallantoic membrane (CAM) assay. The staining of MMP-9, intercellular adhesion molecule 1 (ICAM-1), TIMP-1, and vascular endothelial growth factor (VEGF) in grafted endometriotic tissues was examined using immunohistochemistry analysis. The purity of ESCs in isolated cells was >95%, as determined by the fluoroimmunoassay of vimentin. E2 (10(-8) mol/L) promoted the invasiveness of ESCs by increasing MMP-9 accumulation and decreasing TIMP-1 accumulation. Interestingly, puerarin (10(-9) mol/L) significantly reversed these effects (P<0.01). The CAM assay indicated that puerarin (10(-9) mol/L) also inhibited the angiopoiesis of endometriotic tissue stimulated by the E2 (10(-8) mol/L) treatment (P<0.05). Accordingly, immunohistochemistry showed that the accumulation of MMP-9, ICAM-1, and VEGF was reduced whereas that of TIMP-1 increased in the combination treatment group compared with the E2 treatment group. CONCLUSIONS/SIGNIFICANCE: This study demonstrated that puerarin could suppress the tissue invasion by ESCs and the vascularization of ectopic endometrial tissues stimulated by E2, suggesting that puerarin may be a potential drug for the treatment of endometriosis

Estimation of regression contour clusters--an application of the excess mass approach to regression

The paper shows that the technique known as excess mass can be translated to non-parametric regression with random design in d-dimensional Euclidean space, where the regression function m is given by m(x)=E(Y|X=x),x[set membership, variant]Rd. The approach is applied to estimating regression contour clusters, which are sets where m exceeds a certain threshold value. This is accomplished without prior estimation of the regression function. Consistency of the resulting estimators is studied, and a functional central limit theorem for the excess mass is derived in the regression context.Consistency Excess mass Regression contour cluster Empirical processes Bracketing numbers Asymptotic normality

PRIM analysis

This paper analyzes a data mining/bump hunting technique known as PRIM [1]. PRIM finds regions in high-dimensional input space with large values of a real output variable. This paper provides the first thorough study of statistical properties of PRIM. Amongst others, we characterize the output regions PRIM produces, and derive rates of convergence for these regions. Since the dimension of the input variables is allowed to grow with the sample size, the presented results provide some insight about the qualitative behavior of PRIM in very high dimensions. Our investigations also reveal some shortcomings of PRIM, resulting in some proposals for modifications.Asymptotics Bump hunting Data mining Peeling + jittering VC-classes

Question-Aware Global-Local Video Understanding Network for Audio-Visual Question Answering

As a newly emerging task, audio-visual question answering (AVQA) has attracted research attention. Compared with traditional single-modality (e.g., audio or visual) QA tasks, it poses new challenges due to the higher complexity of feature extraction and fusion brought by the multimodal inputs. First, AVQA requires more comprehensive understanding of the scene which involves both audio and visual information; Second, in the presence of more information, feature extraction has to be better connected with a given question; Third, features from different modalities need to be sufficiently correlated and fused. To address this situation, this work proposes a novel framework for multimodal question answering task. It characterises an audiovisual scene at both global and local levels, and within each level, the features from different modalities are well fused. Furthermore, the given question is utilised to guide not only the feature extraction at the local level but also the final fusion of global and local features to predict the answer. Our framework provides a new perspective for audio-visual scene understanding through focusing on both general and specific representations as well as aggregating multimodalities by prioritizing question-related information. As experimentally demonstrated, our method significantly improves the existing audio-visual question answering performance, with the averaged absolute gain of 3.3% and 3.1% on MUSIC-AVQA and AVQA datasets, respectively. Moreover, the ablation study verifies the necessity and effectiveness of our design. Our code will be publicly released

Petrogenesis and geological significance of migmatitic gneiss in Mulantou area, Hainan Island

In the coastal area of Pujian to Mulantou on Hainan Island, a set of medium to deep metamorphic rocks (Mulantou complex) has been discovered, composed of migmatite, dolomite, shale, and amphibolite, with migmatite being the predominant lithology. This study selected well-developed and typical migmatitic gneisses as the research focus and conducted systematic zircon U-Pb isotope dating and petrological and geochemical studies. The results indicate that the protolith of the Mulantou migmatitic gneisses was intermediate basic volcanic rock formed around 276 Ma. These rocks exhibit geochemical characteristics of island-arc calc-alkaline basalt, suggesting a tectonic setting related to the subduction of the Paleo-Tethys Ocean. Early anatectic metamorphism occurred around 261 Ma, indicating a tectonic environment related to the collision between the South China Block and the Indochina Block. Later metamorphism took place around 248 Ma, signifying a tectonic environment associated with extension following the collision between the South China Block and the Indochina Block. Therefore, the Mulantou migmatitic gneisses preserve a comprehensive record of the tectonic evolution in Hainan Island from the Early Permian to the Early Triassic. They represent the geological consequences of events such as the closure of the Paleo-Tethys Ocean, the collision between the South China Block and the Indochina Block, and the subsequent extension. The discovery of these rocks provides new insights into the eastern extension of the Song Ma suture zone