PubMed · 8886895
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C E Ng, G P Raaphorst. Time-temperature parameters and scheduling protocols.. https://pubmed.ncbi.nlm.nih.gov/8886895/
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Drug response differs substantially in cancer patients due to inter- and intra-tumor heterogeneity. Particularly, transcriptome context, especially tumor microenvironment, has been shown playing a significant role in shaping the actual treatment outcome. In this study, we develop a deep variational autoencoder (VAE) model to compress thousands of genes into latent vectors in a low-dimensional space. We then demonstrate that these encoded vectors could accurately impute drug response, outperform standard signature-gene based approaches, and appropriately control the overfitting problem. We apply rigorous quality assessment and validation, including assessing the impact of cell line lineage, cross-validation, cross-panel evaluation, and application in independent clinical data sets, to warrant the accuracy of the imputed drug response in both cell lines and cancer samples. Specifically, the expression-regulated component (EReX) of the observed drug response achieves high correlation across panels. Using the well-trained models, we impute drug response of The Cancer Genome Atlas data and investigate the features and signatures associated with the imputed drug response, including cell line origins, somatic mutations and tumor mutation burdens, tumor microenvironment, and confounding factors. In summary, our deep learning method and the results are useful for the study of signatures and markers of drug response.
[reaction: see text] (-)-Doliculide, a potent antitumor agent, is synthesized stereoselectively in a convergent manner. The key strategy involves a stereoselective synthesis of the polyketide unit and synthesis of the D-tyrosine derivative, followed by assembly of the fragments by an esterification and cycloamidation reaction sequence. The synthesis of the polyketide fragment was achieved by an iterative asymmetric synthesis to install stereoselectively both 1,3-dimethyl groups and the 1,3-diol unit by utilizing asymmetric cyclopropanations and Sharpless asymmetric epoxidations as the key steps.
The activation of ErbB tyrosine kinase receptors (ErbB1, -2, -3, and -4) by ligand-induced homo- or heterodimerization regulates cell growth, death, and differentiation. AG1478 and PD153035 (also know as AG1517) have been adopted as specific ErbB1 inhibitors based on their high specificity for ErbB1 as compared to ErbB2 in in vitro kinase assays. We compared their ability to inhibit ErbB receptor signaling in intact cells to that of a novel ErbB receptor kinase inhibitor, BIBX1382BS. Neither AG1478 nor PD153035 displayed any specificity for ErbB1-mediated signaling induced by transforming growth factor alpha (TGF-alpha) as compared to signaling initiated through the other ErbB kinases. In contrast, BIBX1382BS was more potent at inhibiting signaling induced by TGF-alpha than that induced by neuregulin1-beta1 or anti-ErbB2 agonist antibodies. Interestingly, this compound blocked antibody-induced ErbB4 homodimer activation at even lower concentrations than ErbB1-triggered signaling. Thus, BIBX1382BS, but not AG1478 and PD153035, can be employed to differentiate between the ErbB kinases in intact cells when used at appropriate concentrations.