Aim: To compare the efficacy, safety, and tolerability of abemaciclib plus endocrine therapy (ET) versus ET alone in postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) from China, Brazil, India, and South Africa. Methods: This randomized, double-blind, phase III study was conducted between 9 December 2016 and 29 March 2019. Postmenopausal women with HR-positive, HER2-negative ABC with no prior systemic therapy in an advanced setting (cohort A) or progression on prior ET (cohort B) received abemaciclib (150 mg twice daily) or placebo plus: anastrozole (1 mg/day) or letrozole (2.5 mg/day) (cohort A) or fulvestrant (500 mg per label) (cohort B). The primary endpoint was progression-free survival (PFS) in cohort A, analyzed using the stratified log-rank test. Secondary endpoints were PFS in cohort B (key secondary endpoint), objective response rate (ORR), and safety. This interim analysis was planned after 119 PFS events in cohort A. Results: In cohort A, 207 patients were randomly assigned to the abemaciclib arm and 99 to the placebo arm. Abemaciclib significantly improved PFS versus placebo (median: not reached versus 14.7 months; hazard ratio 0.499; 95% confidence intervals (CI) 0.346–0.719; p = 0.0001). ORR was 65.9% in the abemaciclib arm and 36.1% in the placebo arm ( p < 0.0001, measurable disease population). In cohort B, 104 patients were randomly assigned to the abemaciclib arm and 53 to the placebo arm. Abemaciclib significantly improved PFS versus placebo (median: 11.5 versus 5.6 months; hazard ratio 0.376; 95% CI 0.240–0.588; p < 0.0001). ORR was 50.0% in the abemaciclib arm and 10.5% in the placebo arm ( p < 0.0001, measurable disease population). The most frequent grade ⩾3 adverse events in the abemaciclib arms were neutropenia, leukopenia, and anemia (both cohorts), and lymphocytopenia (cohort B). Conclusion: The addition of abemaciclib to ET demonstrated significant and clinically meaningful improvement in PFS and ORR, without new safety signals observed in this population. Trial Registration: ClinicalTrials.gov identifier: NCT02763566.

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Oxidized low-density lipoprotein (ox-LdL)-mediated endothelial cell injury has an important role in the vascular complications of type 2 diabetes. Astragaloside IV (ASV) is an active component of Radix Astragali, which has been demonstrated to exert protective effects against endothelial damage. The present study explored whether microRNAs (miRNAs) are involved in mediating the protective effects of ASV on ox-LdL-induced damage in human umbilical vein endothelial cells (HUVEcs). RNA sequencing and reverse transcription-quantitative PcR analyses revealed that ox-LdL treatment significantly downregulated miR-140-3p expression in HUVECs. miR-140-3p overexpression promoted cell proliferation and inhibited apoptosis in ox-LdL-induced HUVEcs. However, inhibition of miR-140-3p expression could reverse the effects of ASV on ox-LdL-induced HUVEcs and reactivate ASV-inhibited PI3K/Akt signaling in ox-LdL-induced HUVECs. In addition, Krüppel-like factor 4 (KLF4) was identified as a target of miR-140-3p in ox-LDL-treated HUVECs. Subsequent experiments revealed that KLF4 overexpression partially counteracted the protective effects of miR-140-3p or ASV treatment in ox-LdL-induced HUVEcs. Taken together, the current findings demonstrated that the protective effects of ASV on HUVECs were dependent on miR-140-3p upregulation and subsequent inhibition of KLF4 expression, which in turn suppressed the PI3K/Akt signaling pathway. The present results shed light to the molecular mechanism by which ASV alleviated ox-LdL-induced endothelial cell damage.

Long non-coding RNA (lncRNA) plays a critical role in male germline development. Atrazine (AZ) as an environmental endocrine disrupting chemical (EDCs) can induce male reproductive toxicity in amphibians. Our previous studies demonstrated that AZ can alter gene and circular RNA (cir-cRNA) expression of damaged testes in Xenopus laevis (X. laevis). We furthered to investigate the lncRNA expression profiling in the testis of X. laevis. Over 3559 lncRNAs were detected by lncRNA sequencing. AZ induced 40 upregulated and 46 downregulated differentially expressed lncRNAs. KEGG analysis showed that AZ-affected lncRNAs mainly involve in 19 pathways among which 12 pathways are found in circRNA analysis. This study for the first time demonstrated that AZ can alter lncRNAs which may play a role in testicular degeneration through regulating expressions of functional genes in X. laevis. Our data may provide more insights on the mechanism about male reproductive toxicity of EDCs. K E Y W O R D S ceRNA, frog, herbicide, lncRNA, reproductive toxicology