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Leshchiner, Ignaty

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Leshchiner

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Ignaty

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Leshchiner, Ignaty
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    Specific temperature-induced perturbations of secondary mRNA structures are associated with the cold-adapted temperature-sensitive phenotype of influenza A virus
    (Landes Bioscience, 2012) Chursov, Andrey; Kopetzky, Sebastian J.; Leshchiner, Ignaty; Kondofersky, Ivan; Theis, Fabian J.; Frishman, Dmitrij; Shneider, Alexander
    For decades, cold-adapted, temperature-sensitive (ca/ts) strains of influenza A virus have been used as live attenuated vaccines. Due to their great public health importance it is crucial to understand the molecular mechanism(s) of cold adaptation and temperature sensitivity that are currently unknown. For instance, secondary RNA structures play important roles in influenza biology. Thus, we hypothesized that a relatively minor change in temperature (32–39°C) can lead to perturbations in influenza RNA structures and, that these structural perturbations may be different for mRNAs of the wild type (wt) and ca/ts strains. To test this hypothesis, we developed a novel in silico method that enables assessing whether two related RNA molecules would undergo (dis)similar structural perturbations upon temperature change. The proposed method allows identifying those areas within an RNA chain where dissimilarities of RNA secondary structures at two different temperatures are particularly pronounced, without knowing particular RNA shapes at either temperature. We identified such areas in the NS2, PA, PB2 and NP mRNAs. However, these areas are not identical for the wt and ca/ts mutants. Differences in temperature-induced structural changes of wt and ca/ts mRNA structures may constitute a yet unappreciated molecular mechanism of the cold adaptation/temperature sensitivity phenomena.
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    Liquid Versus Tissue Biopsy for Detecting Acquired Resistance and Tumor Heterogeneity in Gastrointestinal Cancers
    (Springer Science and Business Media LLC, 2019-09) Leshchiner, Ignaty; Elagina, Liudmila; Goyal, Lipika; Siravegna, Giulia; Livitz, Dimitri; Hanna, Megan; Wong, Alicia; Fece de la Cruz, Ferran; Giantonio, Bruce; Roeland, Eric; Ryan, David P.; Aguet, François; Hazar-Rethinam, Mehlika; Dias-Santagata, Dora; Bardelli, Alberto; Parida, Laxmi; Juric, Dejan; Getz, Gad; Corcoran, Ryan B.; Parikh, Aparna; Levovitz, Chaya; Rhrissorrakrai, Kahn; Martin, Elizabeth; Van Seventer, Emily; Slowik, Kara; Ultro, Filippo; Pinto, Christopher; Danysh, Brian; Fetter, Isobel; Shahzade, Heather; Nadres, Brandon; Allen, Jill; Blaszkowsky, Lawrence; Clark, Jeffrey; Murphy, Janet; Nipp, Ryan; Weekes, Colin; Kwan, Eunice; Faris, Jason; Wo, Jennifer; Dey-Guha, Ipsita; Ting, David; Zhu, Andrew; Hong, Theodore; Golub, Todd; Iafrate, John; Adalsteinsson, Viktor
    During cancer therapy, tumor heterogeneity can drive the evolution of multiple tumor subclones harboring unique resistance mechanisms in an individual patient1-3. Prior case reports and small case series have suggested that liquid biopsy (specifically, cell-free DNA (cfDNA)) may better capture the heterogeneity of acquired resistance4-8. However, the effectiveness of cfDNA versus standard single-lesion tumor biopsies has not been directly compared in larger scale prospective cohorts of patients following progression on targeted therapy. Here, in a prospective cohort of 42 patients with molecularly-defined gastrointestinal cancers and acquired resistance to targeted therapy, direct comparison of post-progression cfDNA versus tumor biopsy revealed that cfDNA more frequently identified clinically-relevant resistance alterations and multiple resistance mechanisms, detecting resistance alterations not found in the matched tumor biopsy in 78% of cases. Whole-exome sequencing of serial cfDNA, tumor biopsies, and rapid autopsy specimens elucidated substantial geographic and evolutionary differences across lesions. Our data suggest that acquired resistance is frequently characterized by profound tumor heterogeneity, and that the emergence of multiple resistance alterations in an individual patient may represent the “rule” rather than the “exception.” These findings have profound therapeutic implications and highlight the potential advantages of cfDNA over tissue biopsy in the setting of acquired resistance.