Mutant epidermal growth factor receptor (EGFR) is a major driver of non-small-cell lung cancer (NSCLC). Marketed first generation inhibitors, such as erlotinib, effect a transient beneficial response in EGFR mutant NSCLC patients before resistance mechanisms render these inhibitors ineffective. Secondary oncogenic EGFR mutations account for approximately 50% of relapses, the most common being the gatekeeper T790M substitution that renders existing therapies ineffective. The discovery of PF-06459988 (1), an irreversible pyrrolopyrimidine inhibitor of EGFR T790M mutants, was recently disclosed.1 Herein, we describe our continued efforts to achieve potency across EGFR oncogenic mutations and improved kinome selectivity, resulting in the discovery of clinical candidate PF-06747775 (21), which provides potent EGFR activity against the four common mutants (exon 19 deletion (Del), L858R, and double mutants T790M/L858R and T790M/Del), selectivity over wild-type EGFR, and desirable ADME properties. Compound 21 is currently being evaluated in phase-I clinical trials of mutant EGFR driven NSCLC.
Based on business management discipline of Zhejiang A&F university, this paper elaborates on the construction of resource-sharing practical teaching system. As proposed in this paper, it is important for the construction of such a system to integrate students, discipline, universities, as well as local economic and social development in order to realize resource sharing at various levels. Only by this way can teaching be more realistic and pertinent.
IndexTerms: Practical Teaching;Resource-Sharing; Combination of teaching with product Zhejiang A&F university is an agricultural and forestry university, covering science, engineering, literature, management, agriculture, economics, law,
Thyroid cancer is the most commonly diagnosed endocrine cancer, with the incidence of 14.42 per 100,000 person-years in 2010-2013. It is important to conduct an in-depth exploration into the molecular mechanisms of thyroid cancer, providing insights into the improvements of therapy. Long non-coding RNAs (lncRNAs) act as oncogenes or tumor suppressors in thyroid cancer by sponging microRNAs (miRNAs), however, the functions of numerous lncRNAs are still unknown. In the present study, via the comprehensive analysis of microarray data derived from papillary thyroid tumors and the RNA sequencing of thyroid tumors from The Cancer Genome Atlas database, EGF like and EMI domain containing 1 (EGFEM1P) expression levels in papillary thyroid tumors and normal adjacent tissues were explored. Reverse transcription-quantitative PCR was used to detect EGFEM1P, microRNA (miR)-369-3p and T cell factor 4 (TCF4) expression levels. Western blotting was used to detect TCF4 protein and cleaved caspase-3/8 expression levels. Cell proliferative ability and apoptosis were assessed using the Cell Counting Kit-8 assay and flow cytometry, respectively. The interactions between EGFEM1P and miR-369-3p, and miR-369-3p and TCF4, were determined using the dual-luciferase reporter assay. The results demonstrated that EGFEM1P was upregulated in papillary thyroid tumors and thyroid cancer cells compared with normal adjacent tissues and human normal thyroid epithelial Nthy-ori 3-1 cell line. In the examined thyroid cancer cells, EGFEM1P was demonstrated to interact with miR-369-3p and decreased miR-369-3p expression levels. Thereafter, TCF4 was determined to be a target gene of miR-369-3p and EGFEM1P promoted TCF4 expression via regulating miR-369-3p expression levels. At last, it was found that EGFEM1P expression promoted rapid cell proliferation and inhibited cell apoptosis in thyroid cancer cells via acting as a miR-369-3p sponge. In conclusion EGFEM1P promoted thyroid cancer progression via acting as a sponge of the miR-369-3p/TCF4 axis.
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