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

Insufficient alveolar bone thickness increases the risk of periodontal dehiscence and fenestration, especially in orthodontic tooth movement. Abaloparatide (ABL), a synthetic analog of human PTHrP (1-34) and a clinical medication for treating osteoporosis, has recently demonstrated its potential in enhancing craniofacial bone formation. Herein, we show that intraoral submucosal injection of ABL, when combined with mechanical force, promotes in situ alveolar bone thickening. The newly formed bone is primarily located outside the original compact bone, implying its origin from the periosteum. RNA sequencing of the alveolar bone tissue revealed that the focal adhesion (FA) pathway potentially mediates this bioprocess. Local injection of ABL alone enhances cell proliferation, collagen synthesis, and phosphorylation of focal adhesion kinase (FAK) in the alveolar periosteum; when ABL is combined with mechanical force, the FAK expression is upregulated, in line with the accomplishment of the ossification. In vitro, ABL enhances proliferation, migration, and FAK phosphorylation in periosteal stem cells. Furthermore, the pro-osteogenic effects of ABL on alveolar bone are entirely blocked when FAK activity is inhibited by a specific inhibitor. In summary, abaloparatide combined with mechanical force promotes alveolar bone formation via FAK-mediated periosteal osteogenesis. Thus, we have introduced a promising therapeutic approach for drug-induced in situ alveolar bone augmentation, which may prevent or repair the detrimental periodontal dehiscence, holding significant potential in dentistry.
Osteogenesis/drug effects* ; Periosteum/cytology* ; Parathyroid Hormone-Related Protein/administration & dosage* ; Animals ; Focal Adhesion Protein-Tyrosine Kinases/metabolism* ; Alveolar Process/drug effects* ; Cell Proliferation/drug effects* ; Phosphorylation ; Rats ; Male ; Humans ; Focal Adhesion Kinase 1/metabolism* ; Cell Movement/drug effects*

Objective:To analyze the research literature related to end tuberculosis (TB) using bibliometric methods, so as to provide researchers with insights into current research trends and hotspots in this field.Methods:A search was conducted using the Web of Science core collection data base on March 5, 2024. The research was limited to articles and reviews published between 2014 and 2023. The results were visualized with VOSviewer, and an analysis was performed on the involved national, international research cooperation networks and keyword clustering.Results:A total of 1 092 articles related to end TB research were retrieved and screened, with a total citation counts of 14 871 and an average citation counts of 13.62 per article. The United States of America had the highest number of publications (328 articles, 30.04%), while China ranked seventh (100 articles, 9.16%). International scientific collaboration network analysis indicated that countries primarily included the United Kindom, the United States of America, Switzerland, South Africa, the Netherlands, Australia, and India, which had formed close cooperation in the field of end TB research. Keyword clustering analysis suggested that current research hotspots in end TB field included cost analysis related to TB, management of latent TB individuals, strategies for TB prevention and control, key technologies in TB elimination, and TB epidemiology and associated risk factors.Conclusions:Over the past decade, the number of publications and citations in the field of end TB is relatively high. International research collaboration has been extensive, and the research content covers multiple dimensions, including the management and cost analysis of different disease stages, technological innovations, considerations for comprehensive control strategy, and epidemiology.

Lenvatinib, a second-generation multi-receptor tyrosine kinase inhibitor approved by the FDA for first-line treatment of advanced liver cancer, facing limitations due to drug resistance. Here, we applied a multidimensional, high-throughput screening platform comprising patient-derived resistant liver tumor cells (PDCs), organoids (PDOs), and xenografts (PDXs) to identify drug susceptibilities for conquering lenvatinib resistance in clinically relevant settings. Expansion and passaging of PDCs and PDOs from resistant patient liver tumors retained functional fidelity to lenvatinib treatment, expediting drug repurposing screens. Pharmacological screening identified romidepsin, YM155, apitolisib, NVP-TAE684 and dasatinib as potential antitumor agents in lenvatinib-resistant PDC and PDO models. Notably, romidepsin treatment enhanced antitumor response in syngeneic mouse models by triggering immunogenic tumor cell death and blocking the EGFR signaling pathway. A combination of romidepsin and immunotherapy achieved robust and synergistic antitumor effects against lenvatinib resistance in humanized immunocompetent PDX models. Collectively, our findings suggest that patient-derived liver cancer models effectively recapitulate lenvatinib resistance observed in clinical settings and expedite drug discovery for advanced liver cancer, providing a feasible multidimensional platform for personalized medicine.

Objective:To delve deeply into the dynamic trajectories of cell subpopulations and the communication network among immune cell subgroups during the malignant progression of glioblastoma(GBM),and to endeavor to unearth key risk biomarkers in the GBM malignancy progression,so as to provide a more profound understanding for the treatment and prognosis of this disease by integrating tran-scriptomic data and clinical information of the GBM patients.Methods:Utilizing single-cell sequencing data analysis,we constructed a cell subgroup atlas during the malignant progression of GBM.The Mono-cle2 tool was employed to build dynamic progression trajectories of the tumor cell subgroups in GBM.Through gene enrichment analysis,we explored the biological processes enriched in genes that significant-ly changed with the malignancy progression of GBM tumor cell subpopulations.CellChat was used to identify the communication network between the different immune cell subgroups.Survival analysis helped in identifying risk molecular markers that impacted the patient prognosis during the malignant pro-gression of GBM.This methodological approach offered a comprehensive and detailed examination of the cellular and molecular dynamics within GBM,providing a robust framework for understanding the disease's progression and potential therapeutic targets.Results:The analysis of single-cell sequencing data identified 6 different cell types,including lymphocytes,pericytes,oligodendrocytes,macrophages,glioma cells,and microglia.The 27 151 cells in the single-cell dataset included 3 881 cells from the pa-tients with low-grade glioma(LGG),10 166 cells from the patients with newly diagnosed GBM,and 13 104 cells from the patients with recurrent glioma(rGBM).The pseudo-time analysis of the glioma cell subgroups indicated significant cellular heterogeneity during malignant progression.The cell interaction analysis of immune cell subgroups revealed the communication network among the different immune sub-groups in GBM malignancy,identifying 22 biologically significant ligand-receptor pairs across 12 key bio-logical pathways.Survival analysis had identified 8 genes related to the prognosis of the GBM patients,among which SERPINE1,COL6A1,SPP1,LTF,C1S,AEBP1,and SAA1L were high-risk genes in the GBM patients,and ABCC8 was low-risk genes in the GBM patients.These findings not only provided new theoretical bases for the treatment of GBM,but also offered fresh insights for the prognosis assessment and treatment decision-making for the GBM patients.Conclusion:This research comprehensively and pro-foundly reveals the dynamic changes in glioma cell subpopulations and the communication patterns among the immune cell subgroups during the malignant progression of GBM.These findings are of significant im-portance for understanding the complex biological processes of GBM,providing crucial new insights for precision medicine and treatment decisions in GBM.Through these studies,we hope to provide more ef-fective treatment options and more accurate prognostic assessments for the patients with GBM.

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.

To explore the efficacy and safety of immunoadsorption (IA) in removing de novo donor specific antibody (DSA) after allogeneic hematopoietic stem cell transplantation (HSCT), the relevant clinical data were retrospectively reviewed for one female patient of severe aplastic anemia (SAA). Desensitization treatment with IA after HSCT was offered for removing de novo DSA and ultimately promoting platelet engraftment at First Affiliated Hospital of Soochow University in March 2021.

Lipid homeostasis is considered to be related to intestinal metabolic balance, while its role in the pathogenesis and treatment of ulcerative colitis (UC) remains largely unexplored. The present study aimed to identify the target lipids related to the occurrence, development and treatment of UC by comparing the lipidomics of UC patients, mice and colonic organoids with the corresponding healthy controls. Here, multi-dimensional lipidomics based on LC-QTOF/MS, LC-MS/MS and iMScope systems were constructed and used to decipher the alteration of lipidomic profiles. The results indicated that UC patients and mice were often accompanied by dysregulation of lipid homeostasis, in which triglycerides and phosphatidylcholines were significantly reduced. Notably, phosphatidylcholine 34:1 (PC34:1) was characterized by high abundance and closely correlation with UC disease. Our results also revealed that down-regulation of PC synthase PCYT1α and Pemt caused by UC modeling was the main factor leading to the reduction of PC34:1, and exogenous PC34:1 could greatly enhance the fumarate level via inhibiting the transformation of glutamate to N-acetylglutamate, thus exerting an anti-UC effect. Collectively, our study not only supplies common technologies and strategies for exploring lipid metabolism in mammals, but also provides opportunities for the discovery of therapeutic agents and biomarkers of UC.

BackgroundMost of the researches on continuous nursing education is from the perspective of patients， and there is a lack of studies on the impact of continuous nursing education on patient caregivers， and the care quality of caregivers is closely related to postoperative rehabilitation status of the patients. ObjectiveTo investigate the effect of continuous nursing education on anxiety relief of caregivers of patients with all-robot coronary artery bypass surgery， and to provide references for improving caregivers' anxiety and promoting patients' recovery. MethodsA total of 120 caregivers of patients with all-robot coronary artery bypass surgery at the First and Sixth Center of 301 Chinese PLA General Hospital were included from January 1， 2021 to December 31， 2022. The caregivers were randomly divided into study group and control group with 60 cases in each group by systematic random sampling method. Before the patient discharge from the hospital， all caregivers received routine nursing education. The study group received continuous nursing education for 4 weeks after patient discharged. Self-rating Anxiety Scale （SAS） was used to evaluate the two groups before and one month after discharge. ResultsOne month after discharge， SAS score in the study group was significantly lower than that in the control group ［（57.77±14.08） vs. （70.19±13.60）， t=-4.913， P<0.01］， and the proportion of SAS score above 60 in the study group was significantly lower than that in the control group （41.67% vs. 75.00%， χ²=-13.714， P<0.01）. ConclusionContinuous nursing education may help reduce the level of anxiety in caregivers of patients with all-robot coronary artery bypass surgery.

【Objective】 To investigate the correlation between early immune reconstitution and clinical outcomes in patients with acute lymphoblastic leukemia (ALL) underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). 【Methods】 The basic information and treatment data of 99 patients with ALL undering allo-HSCT from December 2018 to February 2022 were collected. The proportions of CD3⁺ T, CD3⁺CD4⁺ T, CD3⁺CD8⁺ T and CD3^-CD16⁺CD56⁺ NK cells were detected before and 30, 60 and 90 days after transplantation using flow cytometry. The correlation between early cellular immune reconstitution and neutrophil engraftment, platelet engraftment, infection, and acute and chronic graft-versus-host disease (GVHD) was analyzed. 【Results】 Among 99 ALL patients, the median time of neutrophil engraftment was day +11 (range, 8-28), and the median time of platelet engraftment was day +14 (range, 10-120). The cumulative incidence of blood stream infection (BSI) was 11.10% and the cumulative incidence of CMV within 100 days of transplantation was 40.40%. The cumulative incidence of EBV within 100 days was 7.10%. The cumulative incidence of acute graft-versus-host disease (aGVHD) was 22.30%. The cumulative incidence of chronic graft-versus-host disease (cGVHD) within 1 year of transplantation was 16.20%. 1 -year cumulative relapse rate was 13.84%. The 1 -year cumulative disease-free survival (DFS) for all patients was 80.60% and the 1-year overall survival (OS) was 90.30%. The CD4⁺/CD8⁺ ratio was positively associated with the development of aGVHD at 30 days post-transplant (OR 1.21, 95CI 1.01-1.45, P<0.05). The proportion of CD16⁺ CD56⁺ NK cell were higher in the group without BSI than that in the BSI group before and 30 days after transplantation (P < 0.05). The proportion of CD4⁺ T-cell were lower in the CMV infection group than that in the group without CMV infection at 60 and 90 days post-transplant(P<0.05). The higher level of CD4⁺ T-cells at 60 days post-transplant was a protective factor for CMV infection within 100 days (HR 0.91, 95CI 0.84-0.99, P<0.05). 【Conclusion】 Early immune reconstitution after allo-HSCT in patients with ALL is associated with aGVHD, CMV and BSI.