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Background: This study aimed to evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) for patients with partially platinum-sensitive, platinum-resistant, or platinum-refractory ovarian cancer., Methods: Patients with partially platinum-sensitive, platinum-resistant, or platinum-refractory ovarian cancer were recruited in this prospective, open-label, single-arm, multicenter study. Eligible patients were given 4-6 cycles of PLD (40 mg/m2 on day 1, every 4 weeks). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), quality of life, and safety. Exploratory endpoints included the change trend of CA125 and platinum-free interval., Results: Between June 2017 and November 2020, 167 eligible patients were included in the full analysis set. The median PFS and OS were 6.8 months (95% CI, 4.4-9.3 months) and 19.1 months (95% CI, 15.0-23.3 months), respectively. The ORR and DCR were 32.3% and 60.5%, respectively. The ORR (62.3 vs 22.5%) and DCR (84.9 vs 60.7%) of patients with a CA125 decrease after the first cycle were significantly higher than those without a CA125 decrease (all P < .05). Grade ≥ 3 and serious adverse events were reported in 9.9% and 3.9% of patients, respectively. No treatment-related death was observed., Conclusion: PLD showed promising efficacy and manageable tolerability in patients with partially platinum-sensitive, platinum-resistant, or platinum-refractory ovarian cancer.ClinicalTrials.gov Identifier: Chinese Clinical Trial Registry, ChiCTR1900022962., (© The Author(s) 2024. Published by Oxford University Press.)

The major antioxidant L-ascorbic acid (AsA) plays important roles in plant growth, development, and stress responses. However, the importance of AsA concentration and the regulation of AsA metabolism in plant reproduction remain unclear. In Arabidopsis (Arabidopsis thaliana) anthers, the tapetum monolayer undergoes cell differentiation to support pollen development. Here, we report that a transcription factor, DEFECTIVE IN TAPETAL DEVELOPMENT AND FUNCTION 1 (TDF1), inhibits tapetal cell division leading to cell differentiation. We identified SKEWED5-SIMILAR 18 (SKS18) as a downstream target of TDF1. Enzymatic assays showed that SKS18, annotated as a multicopper oxidase-like protein, has ascorbate oxidase activity, leading to AsA oxidation. We also show that VITAMIN C DEFECTIVE1 (VTC1), an AsA biosynthetic enzyme, is negatively controlled by TDF1 to maintain proper AsA contents. Consistently, either knockout of SKS18 or VTC1 overexpression raised AsA concentrations, resulting in extra tapetal cells, while SKS18 overexpression in tdf1 or the vtc1-3 tdf1 double mutant mitigated their defective tapetum. We observed that high AsA concentrations caused lower accumulation of reactive oxygen species (ROS) in tapetal cells. Overexpression of ROS scavenging genes in tapetum restored excess cell divisions. Thus, our findings demonstrate that TDF1-regulated AsA balances cell division and cell differentiation in the tapetum through governing ROS homeostasis., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Society of Plant Biologists.)

DNA G4-structures from human c-MYC promoter and telomere are considered as important drug targets; however, the developing of small-molecule-based fluorescent binding ligands that are highly selective in targeting these G4-structures over other types of nucleic acids is challenging. We herein report a new approach of designing small molecules based on a non-selective thiazole orange scaffold to provide two-directional and multi-site interactions with flanking residues and loops of the G4-motif for better selectivity. The ligands are designed to establish multi-site interactions in the G4-binding pocket. This structural feature may render the molecules higher selectivity toward c-MYC G4s than other structures. The ligand-G4 interaction studied with 1H NMR may suggest a stacking interaction with the terminal G-tetrad. Moreover, the intracellular co-localization study with BG4 and cellular competition experiments with BRACO-19 may suggest that the binding targets of the ligands in cells are most probably G4-structures. Furthermore, the ligands that either preferentially bind to c-MYC promoter or telomeric G4s are able to downregulate markedly the c-MYC and hTERT gene expression in MCF-7 cells, and induce senescence and DNA damage to cancer cells. The in vivo antitumor activity of the ligands in MCF-7 tumor-bearing mice is also demonstrated., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

c-MYC is an important oncogene that is considered as an effective target for anticancer therapy. Regulation of this gene's transcription is one avenue for c-MYC-targeting drug design. Direct binding to a transcription factor and generating the intervention of a transcriptional programme appears to be an effective way to modulate gene transcription. NM23-H2 is a transcription factor for c-MYC and is proven to be related to the secondary structures in the promoter. Here, we first screened our small-molecule library for NM23-H2 binders and then sifted through the inhibitors that could target and interfere with the interaction process between NM23-H2 and the guanine-rich promoter sequence of c-MYC. As a result, a quinazolone derivative, SYSU-ID-01: , showed a significant interference effect towards NM23-H2 binding to the guanine-rich promoter DNA sequence. Further analyses of the compound-protein interaction and the protein-DNA interaction provided insight into the mode of action for SYSU-ID-01: . Cellular evaluation results showed that SYSU-ID-01: could abrogate NM23-H2 binding to the c-MYC promoter, resulting in downregulation of c-MYC transcription and dramatically suppressed HeLa cell growth. These findings provide a new way of c-MYC transcriptional control through interfering with NM23-H2 binding to guanine-rich promoter sequences by small molecules., (© Oxford University Press OR Nucleic Acids Research 2015.)