Vasily N. Dobrovolsky

Using error-corrected sequencing for evaluating mutagenicity of molnupiravir in humans

Page B. McKinzie, Rutu R Valapil, Emily L. Heil, James E. Polli et autres

Molnupiravir (MOV) is a prodrug of N-hydroxycytidine (NHC), an analog of the endogenous ribonucleoside cytidine that can be administered orally. MOV is used for treating patients infected by SARS-CoV-2, the coronavirus responsible for COVID-19. MOV and NHC are mutagenic in bacterial and …

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Detection of In Vivo Mutation in the Hprt and Pig-a Genes of Rat Lymphocytes

Vasily N. Dobrovolsky, Joseph G. Shaddock, Roberta A. Mittelstaedt, Daishiro Miura et autres

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Application of error-corrected sequencing technologies for in vivo regulatory mutagenicity assessment

Carole Lyn Yauk, Anthony M. Lynch, Vasily N. Dobrovolsky, Maik Schuler et autres

Error-corrected sequencing (ECS) is a transformative method for in vivo mutagenicity assessment, enabling direct, highly sensitive measurement of mutation frequency and spectrum. ECS addresses key limitations of the transgenic rodent (TGR) assay, including lack of integration into standard toxicity studies, restricted model …

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Erythrocyte PIG‐A mutant frequencies in cancer patients receiving cisplatin

Vasily N. Dobrovolsky, Omar T. Atiq, Robert H. Heflich, Mackean P. Maisha et autres

BACKGROUND: Cisplatin is a primary chemotherapy choice for various solid tumors. DNA damage caused by cisplatin results in apoptosis of tumor cells. Cisplatin-induced DNA damage, however, may also result in mutations in normal cells and the initiation of secondary malignancies. In the …

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Whole-genome high-fidelity sequencing: A novel approach to detecting and characterization of mutagenicity in vivo

Vasily N. Dobrovolsky, Tomonari Matsuda, Page B. McKinzie, J. Jaime Miranda et autres

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Unbiased whole genome detection of ultrarare off‐target mutations in genome‐edited cell populations by HiFi sequencing

Jaime A. Miranda, Kristina Fenner, Page B. McKinzie, Vasily N. Dobrovolsky et autres

Abstract DNA base editors (BEs) composed of a nuclease‐deficient Cas9 fused to a DNA‐modifying enzyme can achieve on‐target mutagenesis without creating double‐strand DNA breaks (DSBs). As a result, BEs generate far less DNA damage than traditional nuclease‐proficient Cas9 systems, which do rely …

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Roundtable “Unification Church in Japan as a Sociocultural and Political Phenomenon”

Dmitry Streltsov, K. O. Naka, V. V. Nelidov, Konstantin O. Sarkisov et autres

In the second half of 2022, the Japanese political world was shaken by a major scandal: in July 2022, former Prime Minister and a prominent member of the ruling Liberal Democratic Party Abe Shinzō was killed at an election rally. The assassin, …

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Establishment of neural stem cells from fetal monkey brain for neurotoxicity testing

Leah E. Latham, Vasily N. Dobrovolsky, Shuliang Liu, John C. Talpos et autres

Neurotoxicity assessments are generally performed using laboratory animals. However, as in vitro neurotoxicity models are continuously refined to reach adequate predicative concordance with in vivo responses, they are increasingly used for some endpoints of neurotoxicity. In this study, gestational day 80 fetal …

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Detecting N-ethyl-N-nitrosourea-induced mutation in the tissues of mice using whole-genome HiFi Sequencing

Page B. McKinzie, J. Jaime Miranda, Stephen D. Dertinger, Jeffrey C. Bemis et autres

Direct sequencing can be used for characterizing mutagenicity in complex biological models, e.g., in various tissues of mammalian species. We employed whole-genome High-Fidelity Sequencing (HiFi Sequencing) for detecting mutations induced in male CD-1 mice by N-ethyl-N-nitrosourea (ENU). Mice were treated by gavage …

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Evaluation of the mutagenic effects of Molnupiravir and N4 ‐hydroxycytidine in bacterial and mammalian cells by HiFi sequencing

Jaime A. Miranda, Page B. McKinzie, Vasily N. Dobrovolsky, Javier R. Revollo

Molnupiravir (MOV) is used to treat COVID-19. In cells, MOV is converted to the ribonucleoside analog N4-hydroxycytidine (NHC) and incorporated into the SARS-CoV-2 RNA genome during its replication, resulting in RNA mutations. The widespread accumulation of such mutations inhibits SARS-CoV-2 propagation. Although …

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Genome‐wide detection of ultralow‐frequency substitution mutations in cultures of mouse lymphoma L5178Y cells and Caenorhabditis elegans worms by PacBio sequencing

Jaime A. Miranda, Alexander W. Alund, Jian Yan, Page B. McKinzie et autres

Abstract Many conventional genetic toxicology assays require specialized cell cultures or animals and can only detect mutations that inactivate the function of a reporter gene. These limitations make such assays incompatible with many toxicological models but could be overcome by the development …

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PacBio sequencing detects genome‐wide ultra‐low‐frequency substitution mutations resulting from exposure to chemical mutagens

Javier R. Revollo, Jaime A. Miranda, Vasily N. Dobrovolsky

Abstract Genetic toxicology uses several assays to identity mutagens and protects the public. Most of these assays, however, rely on reporter genes, can only measure mutation indirectly based on phenotype, and often require specific cell lines or animal models—features that impede their …

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