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Blokzijl, F.

Publications and source records attributed to Blokzijl, F..

3 recordsLinked to original sources

VIBE: An R-package for advanced RNA-seq data exploration, disease stratification and therapeutic targeting

BackgroundDevelopment of therapies e.g. antibody-based treatments, rely on several factors, including the specificity of target expression and characterization of downstream signaling pathways. While existing tools for analyzing and visualizing RNA-seq data offer evaluation of individual gene-level expression, they lack a comprehensive assessment of pathway-guided analysis, relevant for single- and dual-targeting therapeutics. Here, we introduce VIBE (VIsualization of Bulk RNA Expression data), an R package which provides a thorough exploration of both individual and combined gene expression, supplemented by pathway-guided analyses. VIBEs versatility proves pivotal for disease stratification and therapeutic targeting in cancer, immune, metabolic, and other disorders. ResultsVIBE offers a wide array of functions that streamline the visualization and analysis of transcriptomics data for single- and dual-targeting therapies such as antibodies. Its intuitive interface allows users to evaluate the expression of target genes and their associated pathways across various indications, aiding in target and disease prioritization. Metadata, such as specific treatment or number of prior lines of therapy, can be easily incorporated to refine the identification of patient cohorts hypothesized to derive benefit from a given drug. Through real-world scenario representations using simulated data, we demonstrate how VIBE can be used to assist in indication selection for several user cases. VIBE integrates statistics in all graphics, enabling data-informed decision-making. Its enhanced user experience features include boxplot sorting and group genes either individually or averaged based on pathways, ensuring custom visuals for insightful decisions. For a deeper dive into its extensive functionalities, please review the vignettes on the GitHub repository (https://github.com/genmab/VIBE). ConclusionsVIBE facilitates detailed visualization of individual and cohort-level summaries such as concordant or discordant expression of two genes or pathways. Such analyses can help to prioritize disease indications that are amenable to treatment strategies like bispecific antibody therapies or pathway-guided monoclonal antibody therapies. By using this tool, researchers can enhance the indication selection and potentially accelerate the development of novel targeted therapies with the end goal of precision, personalization, and ensuring treatments align perfectly with individual patient needs across a spectrum of medical domains.

bioinformatics↗

Early divergence of mutational mechanisms drives genetic heterogeneity of fetal tissues

A developing human fetus needs to balance rapid cellular expansion with maintaining genomic stability. Here, we accurately quantified and characterized somatic mutation accumulation in fetal tissues by analyzing individual stem cells from human fetal liver and intestine. Fetal mutation rates were ~5-fold higher than in tissue-matched adult stem cells. The mutational landscape of fetal intestinal stem cells resembled that of adult intestinal stem cells, while the mutation spectrum of fetal liver stem cells is distinct from stem cells of the fetal intestine and the adult liver. Our analyses indicate that variation in mutational mechanisms, including oxidative stress and spontaneous deamination of methylated cytosines, contribute to the observed divergence in mutation accumulation patterns and drive genetic mosaicism in humans.\n\nOne Sentence SummaryLiver and intestinal cells accumulate elevated amounts and diverged types of somatic DNA mutations during early human fetal development

genomics↗

Deficiency of global genome nucleotide excision repair explains mutational signature observed in cancer

Nucleotide excision repair (NER) is one of the main DNA repair pathways that protect cells against genomic damage. Disruption of this pathway can contribute to the development of cancer and accelerate aging. Tumors deficient in NER are more sensitive to cisplatin treatment. Characterization of the mutational consequences of NER-deficiency may therefore provide important diagnostic opportunities. Here, we analyzed the somatic mutational profiles of adult stem cells (ASCs) from NER-deficient Ercc1-/{Delta} mice, using whole-genome sequencing analysis of clonally derived organoid cultures. Our results indicate that NER-deficiency increases the base substitution load in liver, but not in small intestinal ASCs, which coincides with a tissue-specific aging-pathology observed in these mice. The mutational landscape changes as a result of NER-deficiency in ASCs of both tissues and shows an increased contribution of Signature 8 mutations, which is a pattern with unknown etiology that is recurrently observed in various cancer types. The scattered genomic distribution of the acquired base substitutions indicates that deficiency of global-genome NER (GG-NER) is responsible for the altered mutational landscape. In line with this, we observed increased Signature 8 mutations in a GG-NER-deficient human organoid culture in which XPC was deleted using CRISPR-Cas9 gene-editing. Furthermore, genomes of NER-deficient breast tumors show an increased contribution of Signature 8 mutations compared with NER-proficient tumors. Elevated levels of Signature 8 mutations may therefore serve as a biomarker for NER-deficiency and could improve personalized cancer treatment strategies.

molecular biology↗