Bemcentinib as monotherapy and in combination with low-dose cytarabine in acute myeloid leukemia patients unfit for intensive chemotherapy: a phase 1b/2a trialLoges, Heuser, Chromik
et alNat Commun (2025) 16 (1), 2846
Abstract: Beyond first line, the prognosis of relapsed/refractory (R/R) acute myeloid leukemia (AML) patients is poor with limited treatment options. Bemcentinib is an orally bioavailable, potent, highly selective inhibitor of AXL, a receptor tyrosine kinase associated with poor prognosis, chemotherapy resistance and decreased antitumor immune response. We report bemcentinib monotherapy and bemcentinib+low-dose cytarabine combination therapy arms from the completed BerGenBio-funded open-label Phase 1/2b trial NCT02488408 ( www.clinicaltrials.gov ), in patients unsuitable for intensive chemotherapy. The primary objective in the monotherapy arm was identification of maximum tolerated dose with secondary objectives to identify dose-limiting toxicities, safety and efficacy, and bemcentinib pharmacokinetic profile. In the combination arm, the primary objective was safety and tolerability, with efficacy and pharmacokinetics as secondary objectives. Safety and tolerability were based on standard clinical laboratory safety tests and Common Terminology Criteria for Adverse Events version 4. Bemcentinib monotherapy (32 R/R, 2 treatment-naïve AML and 2 myelodysplasia patients) was well-tolerated and a loading/maintenance dose of 400/200 mg was selected for combination treatment, comprising 30 R/R and 6 treatment-naïve AML patients. The most common grade 3/4 treatment-related adverse events were cytopenia, febrile neutropenia and asymptomatic QTcF prolongation, with no grade 5 events reported. In conclusion, bemcentinib+low-dose cytarabine was safe and well tolerated.© 2025. The Author(s).
A Hybrid Energy-Based and AI-Based Screening Approach for the Discovery of Novel Inhibitors of AXLLv, Kang, Chi
et alACS Med Chem Lett (2025) 16 (3), 410-419
Abstract: AXL, part of the TAM receptor tyrosine kinase family, plays a significant role in the growth and survival of various tissues and tumors, making it a critical target for cancer therapy. This study introduces a novel high-throughput virtual screening (HTVS) methodology that merges an AI-enhanced graph neural network, PLANET, with a geometric deep learning algorithm, DeepDock. Using this approach, we identified potent AXL inhibitors from our database. Notably, compound 9, with an IC50 of 9.378 nM, showed excellent inhibitory activity, suggesting its potential as a candidate for further research. We also performed molecular dynamics simulations to explore the interactions between compound 9 and AXL, providing insights for future enhancements. This hybrid screening method proves effective in finding promising AXL inhibitors, and advancing the development of new cancer therapies.© 2025 The Authors. Published by American Chemical Society.
Trimethylamine N-oxide Aggravates Thoracic Aortic Aneurysm by Inhibiting Axl to Promote Vascular Smooth Muscle Cell DysfunctionLeng, Dang, Xue
et alJ Cardiovasc Pharmacol (2025)
Abstract: Thoracic aortic aneurysm (TAA) is a life-threatening condition that currently lacks an effective therapeutic strategy. Phenotypic switching in vascular smooth muscle cells (VSMCs) and extracellular matrix (ECM) degradation are considered to be among the causes of TAA development. Trimethylamine N-oxide (TMAO) is a gut microbial metabolite that has been associated with the increased risk of cardiovascular diseases. However, its general association with TAA remains unclear. Therefore, the present study aimed to assess the possible role of TMAO in TAA development. In the mouse TAA model, TMAO exacerbates aortic dilation and degeneration, promoting the development of thoracic aortic aneurysm. Furthermore, TMAO was observed to impair murine cardiac function. In vitro, it was demonstrated that TMAO inhibited proliferation whilst promoting migration and apoptosis in VSMCs. RNA-sequence analysis of TMAO targets subsequently identified Axl and a cohort of genes associated with extracellular matrix signaling. Mechanistically, it was found that TMAO inducing a shift from a contractile to a synthetic phenotype by inhibiting Axl. Overexpressing Axl suppresses this transition. In summary, TMAO worsens TAA progression by impairing vascular smooth muscle cell function, and restoring Axl expression can counteract the phenotypic shift caused by high TMAO levels. Thus, targeting the TMAO-Axl regulatory axis could be a therapeutic strategy for TAA patients with elevated TMAO expression.Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.
Analysis of preoperative ocular optical parameters in patients with cataractXi, Liu, Ren
et alBiomed Eng Online (2025) 24 (1), 35
Abstract: This study aims to evaluate the distribution of preoperative corneal parameters obtained using the Pentacam anterior segment analyzer in Chinese male and female patients with cataracts and to investigate the correlation between these parameters and related factors. Preoperative examination data of the eyes of 1,255 patients who underwent cataract surgery were retrospectively analyzed. The Pentacam AXL was used to extract preoperative corneal measurements, and the total corneal measurement data were analyzed. The average age of the patients was 52.9 ± 21.3 years. The mean simulated keratometry values and corneal curvature of total corneal refractive power were positively correlated with age (both P < 0.01). Spearman's correlation analysis revealed a positive association between age and anterior corneal spherical aberration, posterior corneal spherical aberration, and total corneal spherical aberration changes. A negative correlation was found between age and with-the-rule astigmatism, and it was positively correlated with the ratios of against-the-rule and oblique astigmatism. A significant between-eye correlation was observed regarding spherical aberration (Z40), horizontal coma (Z31), vertical coma (Z3-1), and horizontal trefoil (Z33). The corneal curvature in females was significantly steeper than that in males (P < 0.01). Corneal curvature, corneal spherical aberration, and corneal astigmatism were found to change with age. Additionally, we found physiological differences between the sexes. Individual measurements could be taken preoperatively to facilitate the development of personalized surgical plans. By identifying age- and gender-related corneal variations, this study enables more personalized cataract surgery planning, potentially improving refractive outcomes and reducing postoperative complications through tailored surgical techniques and intraocular lens selection.© 2025. The Author(s).
膜杰作
Star Staining
