Discovery of Molecular DNA Methylation-Based Biomarkers through Genome-Wide Analysis of Response Patterns to BCG for Bladder Cancer

Background: Bacillus Calmette-Guérin (BCG) immunotherapy, the standard adjuvant intravesical therapy for some intermediate and most high-risk non-muscle invasive bladder cancers (NMIBCs), suffers from a heterogenous response rate. Molecular markers to help guide responses are scarce and currently not used in the clinical setting. Methods: To identify novel biomarkers and pathways involved in response to BCG immunotherapy, we performed a genome-wide DNA methylation analysis of NMIBCs before BCG therapy. Genome-wide DNA methylation profiles of DNA isolated from tumors of 26 BCG responders and 27 failures were obtained using the Infinium MethylationEPIC BeadChip. Results: Distinct DNA methylation patterns were found by genome-wide analysis in the two groups. Differentially methylated CpG sites were predominantly located in gene promoters and gene bodies associated with bacterial invasion of epithelial cells, chemokine signaling, endocytosis, and focal adhesion. In total, 40 genomic regions with a significant difference in methylation between responders and failures were detected. The differential methylation state of six of these regions, localized in the promoters of the genes GPR158, KLF8, C12orf42, WDR44, FLT1, and CHST11, were internally validated by bisulfite-sequencing. GPR158 promoter hypermethylation was the best predictor of BCG failure with an AUC of 0.809 (p-value < 0.001). Conclusions: Tumors from BCG responders and BCG failures harbor distinct DNA methylation profiles. Differentially methylated DNA regions were detected in genes related to pathways involved in bacterial invasion of cells or focal adhesion. We identified candidate DNA methylation biomarkers that may help to predict patient prognosis after external validation in larger, well-designed cohorts

BIFI:a Taverna plugin for a simplified and user-friendly workflow platform

BACKGROUND: Heterogeneity in the features, input-output behaviour and user interface for available bioinformatics tools and services is still a bottleneck for both expert and non-expert users. Advancement in providing common interfaces over such tools and services are gaining interest among researchers. However, the lack of (meta-) information about input-output data and parameter prevents to provide automated and standardized solutions, which can assist users in setting the appropriate parameters. These limitations must be resolved especially in the workflow-based solution in order to ease the integration of software. FINDINGS: We report a Taverna Workbench plugin: the XworX BIFI (Beautiful Interfaces for Inputs) implemented as a solution for the aforementioned issues. BIFI provides a Graphical User Interface (GUI) definition language used to layout the user interface and to define parameter options for Taverna workflows. BIFI is also able to submit GUI Definition Files (GDF) directly or discover appropriate instances from a configured repository. In the absence of a GDF, BIFI generates a default interface. CONCLUSION: The Taverna Workbench is an open source software providing the ability to combine various services within a workflow. Nevertheless, users can supply input data to the workflow via a simple user interface providing only a text area to enter the input in text form. The workflow may contain meta-information in human readable form such as description text for the port and an example value. However, not all workflow ports are documented so well or have all the required information. BIFI uses custom user interface components for ports which give users feedback on the parameter data type or structure to be used for service execution and enables client-side data validations. Moreover, BIFI offers user interfaces that allow users to interactively construct workflow views and share them with the community, thus significantly increasing usability of heterogeneous, distributed service consumption. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1756-0500-7-740) contains supplementary material, which is available to authorized users

Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005.

The First International Symposium on Pheochromocytoma, held in October 2005, included discussions about developments concerning these rare catecholamine-producing tumors. Recommendations were made during the symposium for biochemical diagnosis, localization, genetics, and treatment. Measurement of plasma or urinary fractionated metanephrines, the most accurate screening approach, was recommended as the first-line test for diagnosis; reference intervals should favor sensitivity over specificity. Localization studies should only follow reasonable clinical evidence of a tumor. Preoperative pharmacologic blockade of circulatory responses to catecholamines is mandatory. Because approximately a quarter of tumors develop secondary to germ-line mutations in any one of five genes, mutation testing should be considered; however, it is not currently cost effective to test every gene in every patient. Consideration of tumor location, presence of multiple tumors, presence of metastases, and type of catecholamine produced is useful in deciding which genes to test. Inadequate methods to distinguish malignant from benign tumors and a lack of effective treatments for malignancy are important problems requiring further resolution