Search

Additional file 2. Which is entitled with Supplementary Materials and Methods, is a description about protocol revision history for study PCD-DZ650-17-001 (NCT03888092).

Additional file 6. Which is entitled with Preclinical Tissue Distribution Study, describes a preclinical tumor distribution study designed to confirm whether larotinib had a better distribution than other EGFR-TKIs in esophageal tumor tissues.

Additional file 8. Which is entitled with Treatment related adverse events occurring in 10% or more patients, is Table 3 that is cited and indicated within the submitted manuscipt. Since this table is larger than one A4, it is uploaded as an additional file.

Additional file 4. Which is entitled with Progression-free Survival and Overall Survival in Subgroups, is a supplementary table describing subgroup analyses of Progression-free Survival and Overall Survival at different dose levels.

Additional file 7. Which is entitled with Baseline characteristics, is Table 1 that is cited and indicated within the submitted manuscript. Since this table is larger than one A4, it is uploaded as an additional file.

Additional file 5. Which is entitled with Preclinical Kinase Inhibition Assays, is a report describing a preclinical study designed to make comparison of inhibitory activity on EGFR family kinases in the same batch among different first-generation EGFR-TKIs.

Additional file 1. Which is entitled with Preclinical studies on Xenografted Mice Models, is an in vivo assay reporting results regarding the evaluation of antitumor efficacy of larotinib in xenografted mice models, plasma, and tumor tissues.

Additional file 3. Which is entitled with Overall Response Assessed by Independent Radiology Review, is a supplementary table describing confirmed overall response assessed by independent radiology review.

Recent studies have indicated that side population (SP) cells, which are an enriched source of cancer stem cells (CSCs), drive and maintain many types of human malignancies. SP cells have distinguishing biological characteristics and are thought to contribute to metastasis, therapy resistance, and tumor recurrence. In the present study, the miRNA expression profiles of SP cells and non-SP cells were compared using miRNA array analysis. Both let-7 and miR-31 were significantly down-regulated in SP cells compared to non-SP cells. The results were confirmed by real-time PCR. Engineered repression of miR-31 caused marked repression of both lung cancer SP cell and non-SP cell growth in vitro. In contrast, engineered repression of let-7 caused marked promotion of both lung cancer SP and non-SP cells growth in vitro. Cell cycle studies further revealed that reduced miR-31 could inhibit SP cell proliferation by a cell cycle arrest in the G0/G1 phase, whereas reduced let-7 induced SP cell proliferation by accelerating G1/S phase transition. Notably, reduced miR-31 prevented SP cell differentiation, whereas reduced let-7 promoted SP cell differentiation under differentiation conditions. These findings indicate that reduced miR-31 and let-7 are involved in maintaining the balance between differentiation and quiescence in SP cells.