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Fendler, W.

Publications and source records attributed to Fendler, W..

2 recordsLinked to original sources

NormiRazor: Tool Applying GPU-accelerated Computing for Determination of Internal References in MicroRNA Transcription Studies

MotivationMulti-gene expression assays are an attractive tool in revealing complex regulatory mechanisms in living organisms. Normalization is an indispensable step of data analysis in all those studies, since it removes unwanted, non-biological variability from data. In targeted qPCR assays the normalization is typically performed with respect to prespecified reference genes, but the lack of robust strategy of their selection is reported in literature, especially in studies concerning circulating microRNAs (miRNA). ResultsPrevious studies concluded that averaged expressions of multi-miRNA combinations are more stable references than single genes. However, due to the number of such combinations the computational load is considerable and may be hindering for objective reference selection in large datasets. Existing implementations of normalization algorithms (geNorm, NormFinder and BestKeeper) have poor performance as every combination is evaluated sequentially. Thus, we designed an integrative tool which implemented those methods in a parallel manner on a graphics processing unit (GPU) using CUDA platform. We tested our approach on publicly available microRNA expression datasets. As a result the times of executions decreased 19-, 105- and 77-fold respectively for geNorm, BestKeeper and NormFinder. AvailabilityNormiRazor is available as web application at norm.btm.umed.pl. ContactWojciech Fendler, wojciech_fendler@dfci.harvard.edu.

bioinformatics

Defining and targeting adaptations to oncogenic KRASG12C inhibition using quantitative temporal proteomics

Covalent inhibitors of the KRASG12C oncoprotein have recently been developed and are being evaluated in clinical trials. Resistance to targeted therapies is common and likely to limit long-term efficacy of KRAS inhibitors (KRASi). To identify pathways of adaptation to KRASi and to predict drug combinations that circumvent resistance, we used a mass spectrometry-based quantitative temporal proteomics and bioinformatics workflow to profile the temporal proteomic response to KRASG12C inhibition in pancreatic and lung cancer 2D and 3D cellular models. We quantified 10,805 proteins across our datasets, representing the most comprehensive KRASi proteomics effort to date. Our data reveal common mechanisms of acute and long-term response between KRASG12C-driven tumors. To facilitate discovery in the cancer biology community, we generated an interactive KRASi proteome website (https://manciaslab.shinyapps.io/KRASi/). Based on these proteomic data, we identified potent combinations of KRASi with PI3K, HSP90, CDK4/6, and SHP2 inhibitors, in some instances converting a cytostatic response to KRASi monotherapy to a cytotoxic response to combination treatment. Overall, using our quantitative temporal proteomics-bioinformatics platform, we have comprehensively characterized the proteomic adaptations to KRASi and identified combinatorial regimens to induce cytotoxicity with potential therapeutic utility.

cancer biology