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Differential Genetic Diagnosis between Leiomyoma and Leiomyosarcoma
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Alba Machado-Lopez, Aymara Mas
Unfortunately, the available “omics” profiles for LMS have been limited due to its rare incidence of 1 in 350 women undergoing hysterectomy or myomectomy for presumed benign LM (23,52–55). Moreover, nucleic acids are difficult to extract from FFPE tissue because of the need to remove paraffin and neutralize the covalent protein–DNA interactions resulting from the fixation process. In addition, tissue preparation (i.e., fixation, paraffin embedding, and archival storage) contributes to fragmentation, cross-linking, and chemical modification of FFPE tissue-derived nucleic acids. Consequently, these changes may result in identification of false positive SNVs or indels due to deamination and depurination processes, which also affect gene expression (56).
The Emerging Field of RNA Nanotechnology
Published in Lajos P. Balogh, Nano-Enabled Medical Applications, 2020
Cell endosome escape is an important consideration for in vivo delivery. Therapeutic particles are initially recognized by cell surface receptor(s) and then delivered through entry into the cellular endosome. The pH within the endosome ranges from 4.3 to 5.8 [32], where RNA is more stable than DNA (Table 5.1). In acidic environments [33], the protonation of DNA purine bases leads to depurination and the resulting apurinic DNA is susceptible to cleavage. The higher stability of RNA in acidic environments is especially useful in therapy since RNA will survive in the endosome after cell entry, and disperse throughout the cell during endocytosis.
DNA Repair and Carcinogenesis
Published in Philip L. Grover, Chemical Carcinogens and DNA, 2019
Evidence has recently been obtained in E. coli,49 for two forms of glycosylase which can break the glycosyl bond between the sugar and a damaged base, and cause the loss of a single base (depurination or depyrimidination). Chemical rather than enzymatic depurination can bring about a similar result. Such DNA is then susceptible to an endonuclease which has been shown to attack DNA specifically at such apurinic or apyrimidinic sites, introducing a single-strand break. This incision is followed by a limited amount of excision and repolymerization using the opposite strand as template.49-52 Whether this is the same process as the “short repair” observed in mammalian cells is not known, but it can be expected to restore DNA to its undamaged state if an intact template is available for accurate repolymerizing of the excised region. Of course, if the particular segment on the opposite DNA strand itself contains damaged, noninstructive bases, (e.g., a pyrimidine dimer as shown in Figure 1E), then none of these excision-repair replication processes can be expected to function properly in their usual “error-free” manner. Therefore, in these particular instances, mutations might be introduced by as yet unidentified processes which the cell uses to take care of such special situations.
The WHO claims estrogens are ‘carcinogenic’: is this true?
Published in Climacteric, 2023
The 4-hydroxy estrogens can stimulate growth of human breast cancer cells [63,64]. Relatively unstable, they can be transformed into highly reactive quinones with the formation of semiquinones as an intermediate stage [69] (Figure 2(a,b)) (see later section ‘Additive oxidative cell stress’). Adducts of DNA with 4-hydroxy estrogen quinones are unstable DNA compounds, which lead to destruction via depurination. DNA adducts with 2-hydroxy estrogen are more stable, and are reversible without DNA destruction [69,70]. Elevated 4-hydroxylase enzyme activity and 4-hydroxyestradiol were found in high concentrations in human breast cancer tissues [63,71,72]. Concentrations of quinones were higher in the cancer tissue compared to control [72]. Animal experiments clearly showed a mutagenic effect of 4-hydroxyestradiol quinones [73].
Future challenges with DNA-encoded chemical libraries in the drug discovery domain
Published in Expert Opinion on Drug Discovery, 2019
Guixian Zhao, Yiran Huang, Yu Zhou, Yizhou Li, Xiaoyu Li
In-solution DEL-compatible reactions are usually mild in an aqueous condition for solubility reason with neutral or slightly basic condition to avoid depurination. The in-solution DEL chemistry also started from peptide synthesis but has been expanded to become a diverse reaction toolbox, which has already been comprehensively reviewed in several literature reports [26,27,46,82,86]. Recently, many new reactions have been added to the toolbox. Fan et al. disclosed a ring opening reaction of on-DNA epoxides with amines assisted by zirconium tetrakis, thereby providing a new chemistry for using the abundantly available amines in DEL synthesis [87]. Lu and co-workers reported a ruthenium-promoted on-DNA ring-closing metathesis; by incorporating two olefins at different positions in a linear structure, this method provides a feasible way to access constrained macrocycles [88]. Brønsted acid catalysts, coinage transition metals, and oxidants furnish diverse drug-like structures from easily accessible BBs; however, these conditions were rarely considered as DEL-compatible because they may cause unacceptable DNA damage. To overcome this limitation, by using hexathymidine oligonucleotide adapter, Brunschweiger and co-workers developed acid- and gold-catalyzed reactions on DNA, which has been exploited to build the scaffold diversity at the initial step of library synthesis through cycloaddition [89] and three-component reactions [90]. Very recently, the same group also reported a Yb(III)-mediated Castagnoli-Cushman reaction for the synthesis of isoquinolones and an Ag(I)-mediated cycloaddition for the synthesis highly substituted pyrrolidines [91]. In addition, Schreiber and co-workers have developed an elegant method to build DNA-conjugated polycyclic isoxazolidines via [3 + 2] nitrone–olefin cycloaddition [92]. These reactions, although still limited by the BB availability, have reflected a trend in DEL-compatible chemistry research: development of reactions that can build drug-like core structures ‘in situ’ during the library synthesis, rather than preparing them ‘off-line’ and then conjugating to the DNA.