SYSTEMS BIOLOGY APPROACH TO UNRAVEL THE MOLECULAR MECHANISMS INVOLVED IN T-CELL ACUTE LYMPHOBLASTIC LEUKAEMIA

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Publications

StemCellNet: an interactive platform for network-oriented investigations in stem cell biology

Publication . Pinto, Jose P.; Kalathur, Ravi Kiran Reddy; Machado, Rui; JM Xavier; Bragança, José; Futschik, Matthias E.

Stem cells are characterized by their potential for self-renewal and their capacity to differentiate into mature cells. These two key features emerge through the interplay of various factors within complex molecular networks. To provide researchers with a dedicated tool to investigate these networks, we have developed StemCellNet, a versatile web server for interactive network analysis and visualization. It rapidly generates focused networks based on a large collection of physical and regulatory interactions identified in human and murine stem cells. The StemCellNet web-interface has various easy-to-use tools for selection and prioritization of network components, as well as for integration of expression data provided by the user. As a unique feature, the networks generated can be screened against a compendium of stemness-associated genes. StemCellNet can also indicate novel candidate genes by evaluating their connectivity patterns. Finally, an optional dataset of generic interactions, which provides large coverage of the human and mouse proteome, extends the versatility of StemCellNet to other biomedical research areas in which stem cells play important roles, such as in degenerative diseases or cancer. The StemCellNet web server is freely accessible at http://stemcellnet.sysbiolab.eu.

2014-07Journal article

Open Access

TRIB2 as a biomarker for diagnosis and progression of melanoma

Publication . Hill, Richard; Kalathur, Ravi Kiran Reddy; Colaco, Laura; Brandao, Ricardo; Ugurel, Selma; Futschik, Matthias; Link, Wolfgang

Malignant melanoma is the most deadly form of skin cancer. There is a critical need to identify the patients that could be successfully treated by surgery alone and those that require adjuvant treatment. In this study, we demonstrate that the expression of tribbles2 (TRIB2) strongly correlates with both the presence and progression of melanocyte-derived malignancies. We examined the expression of TRIB2 in addition to 12 previously described melanoma biomarkers across three independent full genome microarray studies. TRIB2 expression was consistently and significantly increased in benign nevi and melanoma, and was highest in samples from patients with metastatic melanoma. The expression profiles for the 12 biomarkers were poorly conserved throughout these studies with only TYR, S100B and SPP1 showing consistently elevated expression in metastatic melanoma versus normal skin. Strikingly we confirmed these findings in 20 freshly obtained primary melanoma tissue samples from metastatic lesions where the expression of these biomarkers were evaluated revealing that TRIB2 expression correlated with disease stage and clinical prognosis. Our results suggest that TRIB2 is a meaningful biomarker reflecting diagnosis and progression of melanoma, as well as predicting clinical response to chemotherapy.

2015-04Journal article

Open Access

HDNetDB: A Molecular Interaction Database for Network-Oriented Investigations into Huntington's Disease

Publication . Reddy Kalathur, Ravi Kiran; Pinto, Jose Pedro; Sahoo, Biswanath; Chaurasia, Gautam; Futschik, Matthias E.

Huntington's disease (HD) is a progressive and fatal neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene. Although HD is monogenic, its molecular manifestation appears highly complex and involves multiple cellular processes. The recent application of high throughput platforms such as microarrays and mass-spectrometry has indicated multiple pathogenic routes. The massive data generated by these techniques together with the complexity of the pathogenesis, however, pose considerable challenges to researchers. Network-based methods can provide valuable tools to consolidate newly generated data with existing knowledge, and to decipher the interwoven molecular mechanisms underlying HD. To facilitate research on HD in a network-oriented manner, we have developed HDNetDB, a database that integrates molecular interactions with many HD-relevant datasets. It allows users to obtain, visualize and prioritize molecular interaction networks using HD-relevant gene expression, phenotypic and other types of data obtained from human samples or model organisms. We illustrated several HDNetDB functionalities through a case study and identified proteins that constitute potential cross-talk between HD and the unfolded protein response (UPR). HDNetDB is publicly accessible at http://hdnetdb.sysbiolab.eu.

2017-07Journal article

Open Access

StemChecker: a web-based tool to discover and explore stemness signatures in gene sets

Publication . Pinto, Jose P.; Kalathur, Ravi Kiran Reddy; Oliveira, Daniel V.; Barata, Tania; Machado, Rui; Machado, Susana; Pacheco-Leyva, Ivette; Duarte, Isabel; Futschik, Matthias E.

Stem cells present unique regenerative abilities, offering great potential for treatment of prevalent pathologies such as diabetes, neurodegenerative and heart diseases. Various research groups dedicated significant effort to identify sets of genes-so-called stemness signatures-considered essential to define stem cells. However, their usage has been hindered by the lack of comprehensive resources and easy-to-use tools. For this we developed StemChecker, a novel stemness analysis tool, based on the curation of nearly fifty published stemness signatures defined by gene expression, RNAi screens, Transcription Factor (TF) binding sites, literature reviews and computational approaches. StemChecker allows researchers to explore the presence of stemness signatures in user-defined gene sets, without carrying-out lengthy literature curation or data processing. To assist in exploring underlying regulatory mechanisms, we collected over 80 target gene sets of TFs associated with pluri- or multipotency. StemChecker presents an intuitive graphical display, as well as detailed statistical results in table format, which helps revealing transcriptionally regulatory programs, indicating the putative involvement of stemness-associated processes in diseases like cancer. Overall, StemChecker substantially expands the available repertoire of online tools, designed to assist the stem cell biology, developmental biology, regenerative medicine and human disease research community. StemChecker is freely accessible at http://stemchecker.sysbiolab.eu.

2015-07Journal article

Open Access

UniHI 7: an enhanced database for retrieval and interactive analysis of human molecular interaction networks

Publication . Kalathur, Ravi Kiran Reddy; Pinto, Jose Pedro; Hernandez-Prieto, Miguel A.; Machado, Rui; Almeida, Dulce; Chaurasia, Gautam; Futschik, Matthias E.

Unified Human Interactome (UniHI) (http://www.unihi.org) is a database for retrieval, analysis and visualization of human molecular interaction networks. Its primary aim is to provide a comprehensive and easy-to-use platform for network-based investigations to a wide community of researchers in biology and medicine. Here, we describe a major update (version 7) of the database previously featured in NAR Database Issue. UniHI 7 currently includes almost 350 000 molecular interactions between genes, proteins and drugs, as well as numerous other types of data such as gene expression and functional annotation. Multiple options for interactive filtering and highlighting of proteins can be employed to obtain more reliable and specific network structures. Expression and other genomic data can be uploaded by the user to examine local network structures. Additional built-in tools enable ready identification of known drug targets, as well as of biological processes, phenotypes and pathways enriched with network proteins. A distinctive feature of UniHI 7 is its user-friendly interface designed to be utilized in an intuitive manner, enabling researchers less acquainted with network analysis to perform state-of-the-art network-based investigations.

2014-01Journal article

Open Access