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 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.

The technology of three-dimensional(3D)printing emerged in the late 1970s and has since undergone considerable development to find numerous applications in mechanical engineering,industrial design,and biomedicine.In biomedical science,several studies have initially found that 3D printing technology can play an important role in the treatment of diseases in hepatopancreatobiliary surgery.For example,3D printing technology has been applied to create detailed anatomical models of disease organs for preoperative personalized surgical strategies,surgical simulation,intraoperative navigation,medical training,and patient education.Moreover,cancer models have been created using 3D printing technology for the research and selection of chemotherapy drugs.With the aim to clarify the development and application of 3D printing technology in hepatopancreatobiliary surgery,we introduce seven common types of 3D printing technology and review the status of research and application of 3D printing technology in the field of hepatopancreatobiliary surgery.

Objective To compare the efficacy of intravenous thrombolysis combined with intravascular therapy for patients with acute ischemic stroke(AIS)from different treatment opportunities and its impact on prognosis.Methods A total of 180 AIS patients admitted to Wenzhou Central Hospital from July 2021 to September 2023 were selected as study objects,and divided into group A(thrombolysis within 2h),Group B(thrombolysis within 2-3h),group C(thrombolysis within 3-4.5h),group D(thrombolysis within 4.5-6h)and group E(thrombolysis within 6-9h)according to different thrombolysis times after owset.There were 36 cases in each group.All patients received alteplase intravenous thrombolysis combined with intravascular therapy.Vascular recanalization,neurological function,prognosis,ability of daily living and complications were compared among all groups.Results Vascular recanalization rate of five groups had statistical significance(χ2=11.500,P=0.022).Vascular recanalization rate of group E was significantly lower than that of other four groups(P<0.05),and vascular recanalization rate of group D was significantly lower than that of groups A,B and C(P<0.05).After thrombolysis,National Institutes of Health stroke scale(NIHSS)score and modified Rankin scale(mRS)score of patients in all groups were significantly decreased with the extension of time(P<0.05).At different time after thrombolysis,NIHSS score and mRS score in group E were significantly higher than those in other four groups,and NIHSS score and mRS score in group D were significantly higher than those in groups A,B and C(P<0.05).After thrombolysis,Barthel index(BI)of all groups increased significantly with the extension of time(P<0.05).At different time after thrombolysis,BI score of group E were significantly lower than those of other four groups,and BI score of group D were significantly lower than those of groups A,B and C(P<0.05).Within 90 days after thrombolysis,there was no significant difference in the incidence of intracranial hemorrhage,oral hemorrhage,nosocomial infection and cerebral hernia among five groups(χ2=1.356,P=0.852).Conclusion Alteplase intravenous thrombolysis combined with intravascular therapy in AIS patients within 4.5h has better clinical efficacy and better prognosis.

Ischemic stroke has a high rate of disability and mortality and is often accompanied by white matter injury(WMI).WMI patients often have cognitive disorders,emotional disorders,sensorimotor disorders,urinary incontinence and other symptoms,which seriously affect daily life.WMI can be detected early through imaging techniques,but there is a lack of appropriate intervention and specific treatment.Studying the pathological mechanism of WMI after ischemic stroke is helpful to prevent the occurrence of WMI,delay its progression,and contribute to the development of effective drugs or specific treatments.This article reviewed the research progress of WMI mechanism after ischemic stroke in order to provide scientific basis for clinical prevention and treatment.

Objective:To investigate the diagnostic efficacy of MRI-based or CT-based measurements and the combined evaluation methods for preoperative bone quality assessment in patients with cervical degenerative diseases.Methods:Patients who underwent spine surgery for cervical degenerative diseases at the Department of Orthopedics, Huashan Hospital, Fudan University from September 2020 to March 2022 with available preoperative X-ray, CT, MRI and dule energy X-Ray absorptiometry (DEXA) data were included in this study. Vertebral bone quality score (VBQ) based on MRI T1-weightedimages and CT Hounsfiled unit (HU) values of the cervical spine were measured, and a combined diagnostic formula based on the binary logistic regression was constructed. The patients were divided into normal bone mass (T≥-1.0) and osteopenia/osteoporosis groups (T<-1.0). The student's t-test and Chi-square test were performed for comparisons between groups. The Pearson correlation coefficient was also used to investigate the correlation between DEXA-T scores, cervical VBQ and CT HU values. In addition, receiver operating characteristic curve (ROC) were plotted to explore the diagnostic efficacy of VBQ, CT HU and their combined diagnosis. Meanwhile, the corresponding sensitivity and specificity were obtained. Results:A total of 71 patients were included in this study (17 in the normal group and 54 in the osteopenia/osteoporosis group). The student's t-test showed that VBQ (2.90±0.70 vs. 3.83±0.83, t=4.23, P<0.001) and CT HU values (370.26±85.38 vs. 295.20±67.96, t=3.73, P=0.002) were significantly different between the two groups. The area under the ROC curve (AUC) for VBQ and CT values of the cervical spine were 0.81 and 0.75, respectively, and the AUC for the combined diagnostic value constructed on the basis of both was 0.85. Applying VBQ scores alone had a diagnostic sensitivity of 80% and a specificity of 70%, and the combined diagnosis with VBQ and CT HU had a sensitivity of 90% and a specificity of 75%. Person correlation analysis showed a significant correlation between DEXA T value, cervical VBQ value and CT HU value. The detailed formula was: DEXA T score=-0.63×cervical VBQ+0.64 ( r=-0.55, P<0.001), CT HU value=-40.20×cervical VBQ+458.40 ( r=-0.45, P<0.001), DEXA T score=0.006×CT HU-3.47 ( r=0.45, P<0.001). Conclusion:This study confirmed the feasibility of using cervical VBQ values, CT HU values and combined diagnostics for preoperative bone density screening in patients with degenerative cervical spine diseases. This method allows surgeons to perform an initial preoperative bone density screening based on the patient's existing imaging data, and thus could aid in confirming the indication and scheme of surgery. The method could be a powerful tool for preoperative bone density assessment screening in patients with cervical degenerative diseases.

Objective:To evaluate the immunogenicity of a novel influenza virus mRNA vaccine based on conserved antigens delivered by lipopolyplex (LPP) platform in a mouse model.Methods:Four copies of genes coding for extracellular domain of matrix 2 protein (M2e) and nucleoprotein (NP) of influenza A virus were synthetized after codon optimization. The fusion antigens were transcribed in vitro and delivered by LPP platform, named as LPP-4M2eNP. Expression of M2e and NP in eukaryotic cells was detected by immunofluorescence assay (IFA). BALB/c mice were inoculated intramuscularly twice with 10 μg or 30 μg LPP-4M2eNP vaccine at an interval of four weeks. Antibody response was detected by ELISA and cellular-mediated immunity (CMI) was detected by enzyme-linked immunospot assay (ELISPOT). Results:IFA showed that NP and M2e were expressed correctly in eukaryotic cells. Single dose immunization could induce significant antigen (NP, M2e)-specific CMI and antigen (NP, M2e)-specific antibody response was induced in mice with Th1 type bias after boost immunization. Moreover, NP-specific CMI was increased significantly after the second immunization, while no significant change in M2e-specific CMI was observed.Conclusions:Stronger CMI was triggered in mice by single dose of LPP-4M2eNP vaccine. Furthermore, robust humoral and cellular immune responses were induced after boost immunization. This study suggested that LPP-4M2eNP vaccine, which based on conserved antigen of influenza A and delivered by LPP platform, had great potential for development and application.

Background: Fatty acid-binding protein 4 (FABP4) has been demonstrated to be a predictor of early diabetic nephropathy. However, little is known about the relationship between FABP4 and diabetic retinopathy (DR). This study explored the value of FABP4 as a biomarker of DR in patients with type 2 diabetes mellitus (T2DM). Methods: A total of 238 subjects were enrolled, including 20 healthy controls and 218 T2DM patients. Serum FABP4 levels were measured using a sandwich enzyme-linked immunosorbent assay. The grade of DR was determined using fundus fluorescence angiography. Based on the international classification of DR, all T2DM patients were classified into the following three subgroups: non-DR group, non-proliferative diabetic retinopathy (NPDR) group, and proliferative diabetic retinopathy (PDR) group. Multivariate logistic regression analyses were employed to assess the correlation between FABP4 levels and DR severity. Results: FABP4 correlated positively with DR severity (r=0.225, P=0.001). Receiver operating characteristic curve analysis was used to assess the diagnostic potential of FABP4 in identifying DR, with an area under the curve of 0.624 (37% sensitivity, 83.6% specificity) and an optimum cut-off value of 76.4 μg/L. Multivariate logistic regression model including FABP4 as a categorized binary variable using the cut-off value of 76.4 μg/L showed that the concentration of FABP4 above the cut-off value increased the risk of NPDR (odds ratio [OR], 3.231; 95% confidence interval [CI], 1.574 to 6.632; P=0.001) and PDR (OR, 3.689; 95% CI, 1.306 to 10.424; P=0.014). Conclusion FABP4 may be used as a serum biomarker for the diagnosis of DR.

Objective To understand and analyze the effect and impact on Hospital-level Young Scholar Scientific Research Program in personal training and project promoting.Methods To review and analyze the archived documents and data materials of total 402 Young Scholar Scientific Research Program involving 339 young fellows from 2003 to 2013,compared the research input and output with general hospital level,including getting new fund,publications,Awards and patent.Results Output on researchers with Young Scholar Scientific Research Program is much higher than the general hospital level,but showing unbalanced distribution in medical disciplines.Conclusions To establishment of Young Scholar Scientific Research Program has achieved very good effect in promoting research in tertiary public hospital as well as has empowered the young fellows for conducting scientific research independently.It is proposed to go on strength the scientific management and optimize the system construction of research input,further establishing academic communication platform for young fellows.

Objective To monitor the clinical distribution of Gram-positive pathogen infection and drug-resistance situation in hospitalized children with lower respiratory tract, and guide rational application of antibiotics. Methods The isolated cultures results and drug sensitivity test result of 1 219 sputum specimens in hospitalized children with lower respiratory tract were studied. Results The 1 249 strains were isolated from 1 219 sputum specimen samples. Among which, Gram-positive pathogen was 318 strains, accounting for 25.46% (318/1 249). In 318 strains Gram-positive pathogens, staphylococcus aureus was 127 strains (39.94% ), streptococcus pneumoniae was 92 strains (28.93% ), staphylococcus epidermidis was 76 strains (23.90%), and enterococcus was 23 strains (7.23%). Then, different strains of pathogens showed totally disparate drug-resistance situations, especially towards penicillin, and the drug resistant rate was highest (89.62% , 285/318), while the drug resistant rates were also high among erythromycin, cefazolin, oxacillin, azithromycin and clindamycin: 66.67% (212/318), 52.52% (167/318), 49.06% (156/318), 49.06% (156/318) and 43.08% (137/318); meanwhile, the isolated Gram-positive pathogens showed no drug-resistance to vancomycin and linezolid. Conclusions Only using antibiotics rationally according to pathogen identification and drug sensitivity test result, can effectively control the pathogen infections.