PubMed · 10918248
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I H Krakoff. 2000. Predawn.. https://doi.org/10.1002/1096-911x(200008)35%3A2%3C157%3A%3Aaid-mpo20%3E3.0.co%3B2-q
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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.
Telomeres are specialized DNA/protein structures that act as protective caps to prevent end fusions. The maintenance of telomeres is essential for chromosomal stability. Telomerase is regulated by human telomerase reverse transcriptase (hTERT). c-Myc oncoprotein is also implicated in the positive regulation of hTERT expression. We show here that two clones of hTERT-transfected K562 erythroleukemia cells have elongated telomeres (22.5 and 24.0 kb), whereas telomere length of both c-Myc-transfected K562 cells and parental K562 cells is 6.5 kb. Telomerase activity and hTERT mRNA expression increased in hTERT-transfected K562 cells, while the expression levels of telomerase activity and hTERT in c-Myc-transfected K562 cells were similar to that in parental K562 cells, despite an overexpression of c-Myc. Importantly, we found that hTERT-transfected K562 cells are protected against apoptosis induced by serum deprivation and double-stranded DNA break inducing agents (ionizing irradiation, and etoposide (VP-16)), but not against DNA synthesis inhibitors (1-beta-D-arabinofuranosylcytosine and hydroxyurea). These findings suggest that overexpression of telomerase by transfecting hTERT confers telomere-elongation and resistance to double-stranded DNA break inducing agents.
A method for accurately determining the end-point, >98% conversion, of the deprotection reaction of a highly toxic 9-fluorenylmethyl (Fm) ester 1b to its corresponding carboxylate 1d in real time by FT-IR spectroscopy is reported. Advantages of this method over analysis by conventional chromatographic means include real time determination of the end-point of a reaction that is time sensitive to by-product formation, and elimination of sampling a highly toxic reaction mixture. The FT-IR method is based on monitoring, in real time, the disappearance of the Fm ester carbonyl band for 1b at 1737 cm(-1), during deprotection by piperidine, and calibration models were established by Partial Least Squares (PLS) regression analysis with high performance liquid chromatography (HPLC) as reference. The best calibration model was built with 5 PLS factors in the spectral range of 1780-1730 and 1551-1441 cm(-1) and resulted in a standard error of cross validation (SECV) of 0.63 mM 1b and a standard error of prediction (SEP) of 0.51 mM 1b in the range of 0-25 mM. This error of prediction is approximately 0.8% of the initial concentration of 1b and is well within our specifications of <2% initial concentration.