BACKGROUND: T-cell lymphoblastic lymphoma/acute lymphoblastic leukemia (T-LBL/ALL) is an aggressive form of hematological malignancy associated with poor prognosis in adult patients. Histone deacetylases (HDACs) are aberrantly expressed in T-LBL/ALL and are considered potential therapeutic targets. Here, we investigated the antitumor effect of a novel HDAC inhibitor, chidamide, on T-LBL/ALL. METHODS: HDAC1, HDAC2 and HDAC3 levels in T-LBL/ALL cell lines and patient samples were compared with those in normal controls. Flow cytometry, transmission electron microscopy, and lactate dehydrogenase release assays were conducted in Jurkat and MOLT-4 cells to assess apoptosis and pyroptosis. A specific forkhead box O1 (FOXO1) inhibitor was used to rescue pyroptosis and upregulated gasdermin E (GSDME) expression caused by chidamide treatment. The role of the FOXO1 transcription factor was evaluated by dual-luciferase reporter and chromatin immunoprecipitation assays. The efficacy of chidamide in vivo was evaluated in a xenograft mouse. RESULTS: The expression of HDAC1, HDAC2 and HDAC3 was significantly upregulated in T-LBL/ALL. Cell viability was obviously inhibited after chidamide treatment. Pyroptosis, characterized by cell swelling, pore formation on the plasma membrane and lactate dehydrogenase leakage, was identified as a new mechanism of chidamide treatment. Chidamide triggered pyroptosis through caspase 3 activation and GSDME transcriptional upregulation. Chromatin immunoprecipitation assays confirmed that chidamide led to the increased transcription of GSDME through a more relaxed chromatin structure at the promoter and the upregulation of FOXO1 expression. Moreover, we identified the therapeutic effect of chidamide in vivo . CONCLUSIONS This study suggested that chidamide exerts an antitumor effect on T-LBL/ALL and promotes a more inflammatory form of cell death via the FOXO1/GSDME axis, which provides a novel choice of targeted therapy for patients with T-LBL/ALL.
Humans ; Pyroptosis/drug effects* ; Forkhead Box Protein O1/genetics* ; Aminopyridines/pharmacology* ; Animals ; Mice ; Benzamides/pharmacology* ; Cell Line, Tumor ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; Phosphate-Binding Proteins/metabolism* ; Histone Deacetylase Inhibitors/pharmacology* ; Jurkat Cells ; Histone Deacetylases/metabolism* ; Apoptosis/drug effects* ; Gasdermins

Objective:To design and develop a cone-beam CT imaging system for small animals with continuously adjustable spatial resolution.Methods:The imaging system used an X-ray source with a focal spot size of 30 μm and a flat panel detector with a pixel size of 100 μm. On this premise, a " stepping-focusing-rotating" image acquisition mode was proposed, in which the " focusing" and " stepping" systems were sequentially embedded in the " rotating" system. In this acquisition mode, the X-ray source and flat panel detector were relatively stationary to form the " focusing" system. When the " stepping" system accurately transported the object to the scanning position, the " focusing" system could achieve adjustable spatial resolution by making linear motion around the object to be scanned according to different experimental requirements. Finally the " rotating" system achieve high-quality imaging.Results:The variable spatial resolution of small animal CBCT ranges from 35.7 μm to 71.4 μm, and the FOV ranges from 39.6 mm to 108.0 mm. The conversion time for the limit spatial resolution is 19.125 s, which allowed accurate 3D reconstruction of normal mice at different resolutions with high reproducibility.Conclusions:A cone-beam CT suitable for small animals has been developed, whose spatial resolution and FOV can be adjusted arbitrarily within a certain range, which can meet the different imaging requirements in rodent experiments.

Objective:To design and develop a cone-beam CT imaging system for small animals with continuously adjustable spatial resolution.Methods:The imaging system used an X-ray source with a focal spot size of 30 μm and a flat panel detector with a pixel size of 100 μm. On this premise, a " stepping-focusing-rotating" image acquisition mode was proposed, in which the " focusing" and " stepping" systems were sequentially embedded in the " rotating" system. In this acquisition mode, the X-ray source and flat panel detector were relatively stationary to form the " focusing" system. When the " stepping" system accurately transported the object to the scanning position, the " focusing" system could achieve adjustable spatial resolution by making linear motion around the object to be scanned according to different experimental requirements. Finally the " rotating" system achieve high-quality imaging.Results:The variable spatial resolution of small animal CBCT ranges from 35.7 μm to 71.4 μm, and the FOV ranges from 39.6 mm to 108.0 mm. The conversion time for the limit spatial resolution is 19.125 s, which allowed accurate 3D reconstruction of normal mice at different resolutions with high reproducibility.Conclusions:A cone-beam CT suitable for small animals has been developed, whose spatial resolution and FOV can be adjusted arbitrarily within a certain range, which can meet the different imaging requirements in rodent experiments.

Objective To explore the changes in serum energy metabolites in patients with peripheral T-cell lymphoma,and investigate serum biomarkers for monitoring peripheral T-cell lymphoma from the perspective of energy metabolism.Methods Multiple/selected reaction monitoring(MRM/SRM)was used to detect the energy-related metabolites in the sera of 16 patients with newly diagnosed peripheral T-cell lymphoma admitted in the Hematology Medical Center of the Second Affiliated Hospital of Army Medical University from November 2020 to December 2021,as well as 10 recruited healthy volunteers.The corresponding clinical data including medical history,laboratory results and image data were collected and retrospectively analyzed.Results Significant differences were seen in the contents and expression profiles of serum energy metabolism-related products between the patients and the healthy volunteers.The patients had significantly reduced serum contents of cyclic AMP,succinate,citrate and cis-aconitate(P＜0.05),and elevated D-glucose 6-phosphate content(P＜0.05).The serum contents of citrate and succinate were negatively correlated with the risk stratification(low-,moderate-and high-risk)and clinical stage of the disease(P＜0.05).Meanwhile,there was a negative correlation between the contents of L-malic acid and citrate and the mid-term efficacy evaluation results,such as complete/partial response(CR/PR)or stable disease(SD)(P＜0.05).For patients with extranodal NK/T cell lymphoma(n=10),there were also significant reductions in the contents of cyclic AMP,succinate,citrate,isocitrate and cis-aconitate in the sera of patients compared with healthy volunteers(P＜0.05),and the contents of citrate and succinate were negatively correlated with the clinical stage(P＜0.05)and were rather correlated with mid-term efficacy evaluation results(CR/PR or SD)(P＜0.05).For patients with angioimmunoblastic T-cell lymphoma(n=6),the serum contents of cyclic AMP,citrate and succinate were significantly lower,while the content of D-glucose 6-phosphate was higher when compared with the healthy volunteers(P＜0.05),and the content of succinate was negatively correlated with both clinical stage and risk grade of the patients(P＜0.05).Conclusion There are 5 serum differential metabolites identified between patients with peripheral T-cell lymphoma and healthy controls,and succinate and citrate are expected to be serum biomarkers of peripheral T-cell lymphoma.