Shayna Stein, Rui Zhao, Hiroshi Haeno, Igor Vivanco, and Franziska Michor. 1/2/2018. “Mathematical modeling identifies optimum lapatinib dosing schedules for the treatment of glioblastoma patients .” Plos Computational Biology, 14, 1. Publisher's VersionAbstract

Human primary glioblastomas (GBM) often harbor mutations within the epidermal growth factor receptor (EGFR). Treatment of EGFR-mutant GBM cell lines with the EGFR/HER2 tyrosine kinase inhibitor lapatinib can effectively induce cell death in these models. How- ever, EGFR inhibitors have shown little efficacy in the clinic, partly because of inappropriate dosing. Here, we developed a computational approach to model the in vitro cellular dynam- ics of the EGFR-mutant cell line SF268 in response to different lapatinib concentrations and dosing schedules. We then used this approach to identify an effective treatment strategy within the clinical toxicity limits of lapatinib, and developed a partial differential equation modeling approach to study the in vivo GBM treatment response by taking into account the heterogeneous and diffusive nature of the disease. Despite the inability of lapatinib to induce tumor regressions with a continuous daily schedule, our modeling approach consistently predicts that continuous dosing remains the best clinically feasible strategy for slowing down tumor growth and lowering overall tumor burden, compared to pulsatile schedules cur- rently known to be tolerated, even when considering drug resistance, reduced lapatinib tumor concentrations due to the blood brain barrier, and the phenotypic switch from prolifer- ative to migratory cell phenotypes that occurs in hypoxic microenvironments. Our mathe- matical modeling and statistical analysis platform provides a rational method for comparing treatment schedules in search for optimal dosing strategies for glioblastoma and other can- cer types. 

Chao Fang, Huanzi Zhong, Yuxiang Lin, Bin Chen, Mo Han, Huahui Ren, Haorong Lu, Jacob Mayne Luber, Min Xia, Wangsheng Li, Shayna Stein, Xun Xu, Wenwei Zhang, Radoje Drmanac, Jian Wang, Huanming Yang, Lennart Hammarström, Aleksandar David Kostic, Karsten Kristiansen, and Junhua Li. 12/23/2017. “Assessment of the cPAS-based BGISEQ-500 platform for metagenomic sequencing .” GigaScience. Publisher's Version
Shayna Stein, Zhixiang Lu, Emad Bahrami-Samani, Juw Won Park, and Yi Xing. 12/15/2015. “Discover hidden splicing variations by mapping personal transcriptomes to personal genomes.” Nucleic Acids Research, 43, 22, Pp. 10612–10622. Publisher's VersionAbstract

RNA-seq has become a popular technology for studying genetic variation of pre-mRNA alternative splicing. Commonly used RNA-seq aligners rely on the consensus splice site dinucleotide motifs to map reads across splice junctions. Consequently, genomic variants that create novel splice site dinucleotides may produce splice junction RNA-seq reads that cannot be mapped to the reference genome. We developed and evaluated an approach to identify ‘hidden’ splicing variations in personal transcriptomes, by mapping personal RNA-seq data to personal genomes. Computational analysis and experimental validation indicate that this approach identifies personal specific splice junctions at a low false positive rate. Applying this approach to an RNA-seq data set of 75 individuals, we identified 506 personal specific splice junctions, among which 437 were novel splice junctions not documented in current human transcript annotations. 94 splice junctions had splice site SNPs associated with GWAS signals of human traits and diseases. These involve genes whose splicing variations have been implicated in diseases (such as OAS1), as well as novel associations between alternative splicing and diseases (such as ICA1). Collectively, our work demonstrates that the personal genome approach to RNA-seq read alignment enables the discovery of a large but previously unknown catalog of splicing variations in human populations.