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The long-term maintenance of leukaemia stem cells (LSCs) is responsible for the high degree of malignancy in MLL(mixed-lineage leukaemia) rearranged acute myeloid leukaemia (AML). The DNA damage response (DDR) and DOT1L/H3K79me pathways are required to maintain LSCs in MLLr-AML, but little is known about their interplay. This study revealed that the DDR enzyme ATM regulates the maintenance of LSCs in MLLr-AML with a sequential protein-posttranslational-modification manner via CBP-DOT1L. We identified the phosphorylation of CBP by ATM, which confers the stability of CBP by preventing its proteasomal degradation, and characterised the acetylation of DOT1L by CBP, which mediates the high level of H3K79me2 for the expression of leukaemia genes in MLLr-AML. In addition, we revealed that the regulation of CBP-DOT1L axis in MLLr-AML by ATM was independent of DNA damage activation. Our findings provide insight into the signalling pathways involoved in MLLr-AML and broaden the understanding of the role of DDR enzymes beyond processing DNA damage, as well as identigying them as potent cancer targets.

Vessels encapsulating tumor clusters (VETC) is a novel vascular pattern distinct from microvascular invasion that is significantly associated with poor prognosis in patients with hepatocellular carcinoma (HCC). This study aimed to predict the VETC pattern and prognosis of patients with HCC based on preoperative gadolinium-ethoxybenzyl-diethylenetriaminepentaacetic acid (Gd-EOB-DTPA) magnetic resonance imaging (MRI).

ABSTRACTBackgroundAlthough cardiac disorder-related adverse events (AEs) have been reported in patients treated with aryl hydrocarbon receptor (AHR) agonists, their safety profiles remain unknown. Here, we identified significant cardiac disorders associated with AHR agonists and further evaluated their relevance.Research design and methodsDatabase queries were performed using OpenVigil 2.1 and AEs voluntarily submitted to Food and Drug Administration Adverse Event Reporting System (FAERS) between 2004 and 2020 were included. This study based on the Medical Dictionary for Regulatory Activities and the standardized MedDRA Queries to define the preferred terms, and we used reporting odd ratio to detect signals.ResultsIn the FAERS database, 14,078 cardiac disorder-related AEs were identified in patients receiving AHR agonists. Among all AHR agonists, the number of cardiac disorder-related PTs with positive signals for AHR agonists was 93. Peripheral swelling (n = 1572) and atrial fibrillation (n = 1277) were the most reported cardiac disorder-related AEs among AHR agonists in disproportionately reported PTs. Moreover, several AHR agonists were highly associated with tachyarrhythmia.ConclusionsBy mining the FAERS database, we provided more information on the association between AHR agonist use and cardiac disorder-related AEs.

Biothiols are biomolecules found in a higher content in cancer cells compared to normal cells, marking them useful cancer biomarkers. Chemiluminescence is widely used in biological imaging due to its excellent sensitivity and signal-to-noise ratio (SNR). In this study, we designed and prepared a chemiluminescent probe that is activated by a thiol–chromene “click” nucleophilic reaction. This probe is initially chemiluminescent but turned off and releases extremely strong chemiluminescence in the presence of thiols. It has high selectivity to thiol compared with other analytes. Real-time imaging of mice tumor sites showed significant chemiluminescence after the probe was injected, and the chemiluminescence of osteosarcoma tissues was also significantly stronger than that in adjacent tissues. We conclude that this chemiluminescent probe has potential to detect thiol, diagnose cancer, especially in its early stages, and aid in the development of related cancer drugs.