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1. The importance of the RET gene in thyroid cancer and therapeutic implications. Nature, 2021 May,17:296–306.

2. To Bud or not to Bud: The RET perspective in CAKUT. Pediatr Nephrol. 2014 Apr; 29(4): 597–608.

3. RET Aberrations in Diverse Cancers. Clin Cancer Res; 23(8) April 15, 2017,1988-1997.

4. Curigliano G, et al. 2021 ASCO, Poster 9089.

5.Öйú·ÇСϸ°û·Î°© RET »ùÒòÈÚºÏÁÙ´²¼ì²âר¼Ò¹²Ê¶. Öлª²¡ÀíѧÔÓÖ¾, 2021, 50(6): 583-591.

6. RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies. Journal of Thoracic Oncology Vol. 2020.15 No. 4: 541-549.

7. Pre-clinical characterization of potent and selective next-generation RET inhibitors. Loxo Oncology at Lilly. Presented at: AACR Annual Meeting 2021.

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