The association of different genes with the three EGFR associated signa tures is likely reflective of the complexity of signaling in this pathway acro

For example, many drug targets for inflam matory diseases provide general reduction of inflamma tion, while its possible that GWAS may lead to much more disease specific targets. We HDAC inhibitor clinical trial have shown that relatively simple machine learning methods are effective at identifying potential drug repur posing opportunities, and one of our initial short listed repurposing candidates has now been approved for seriously use by the FDA. To further investigate the possible roles of reprogram ming factor diversity andor dosage in CNV instability, we generated another three sets of miPSC lines from the same donor but using different factor combinations and lowhigh dosages five miPSC lines obtained by O1. 5, ten lines obtained by OKS0. 5, and ten lines ob tained by engineered factors XYZK0. 5. Using CGH assay we compared the resulting miPSC genomes with their parental genomes and identified zero CNVs in five miPSC lines of O1. 5, 25 CNVs in ten OKS0. 5 lines, and seven CNVs in ten XYZK0. 5 lines.

In total, we screened the genomes of 41 miPSC lines and identified 63 CNVs across 24 genomic loci of the mouse genome. To investigate the potential mechanism involved in genome instability of miPSCs, we compared the CNV rates between the various methods using the same repro gramming factor combinations with altered dosages. The MannWhitney U test with the exact significance was used for single factor test and the ANOVA test was used for two factor test. By comparing the CNV numbers be tween O0. 5 and O1. 5 miPSC lines, we observed more CNVs in O0. 5 miPSCs than in O1. 5 miPSCs. This difference is sta tistically significant. Similarly comparing the number of CNVs in OKS0. 5 and OKS 1. 5 miPSC lines, although not significant does still suggest that a low dosage of reprogramming factors may induce more CNVs than a high dosage. We also com bined the CNV data in Figure 3A and 3B together based on their dosages. In the low dosage group, 49 CNVs were detected in 18 miPSC lines. while in the high dosage group, eight CNVs were detected in 13 miPSC lines. A significant difference in CNV rates was observed. which strongly supports that the dose of reprograming factors and consequently the repro gramming force can significantly affect the genome in stability during reprogramming, with higher doses and stronger reprogramming providing a protective effect. Notably, recent studies have reported that reprogram ming factor dosage can affect the epigenetic properties of iPSCs and increased levels of Oct4 and Klf4 were observed to give rise to high quality iPSCs. To further explore the roles of reprogramming force in CNV instability of miPSCs, we compared CNV rates be tween diverse factor combinations, while their total dosages remained the same. We introduced the engineered factors XYZK due to their strong promoting capability during reprogramming. The CNV rates are O0. 5, OKS0. 5 and XYZK0. 5. There is no significant dif ference between O0. 5 and OKS0. 5, however, the CNVs of XYZK0.