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 investigate the mechanism of argon-helium cryotherapy in regulating the tyrosine-protein kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)path-way,thereby inhibiting the inflammatory response in rats with atherosclerotic occlusive disease(ASO)of the lower extremities.Methods Forty rats were randomly divided into sham group,lower extremity ASO group,Ar-He Cryo group and Ar-He Cryo+p-JAK group,with 10 rats in each group.The average blood flow velocity of the lower extremity artery,lipid profile and inflammation levels were measured in each group.Hematoxylin-eosin(HE)staining was used to examine histopathologi-cal changes in arterial vessel tissues.Western blotting was performed to detect the expression levels of JAK2,p-JAK2,STAT3,p-STAT3 and suppressor of cytokine signaling 3(SOCS3)proteins in arterial vessel tissues.Results The average blood flow velocity of the lower extremity artery in the lower extremity ASO group was significantly lower than that in the sham group(P＜0.05).The average blood flow velocity in the Ar-He Cryo group was significantly higher than that in the ASO group(P＜0.05).The average blood flow velocity in the Ar-He Cryo+p-JAK group was significantly lower than that in the Ar-He Cryo group(P＜0.05).Serum total cholesterol(TC),triglyceride(TG),low-density lipoprotein cholesterol(LDL-C)levels,tumor necrosis factor-alpha(TNF-α),interleukin-1 β(IL-1β),interleukin-6(IL-6)levels and endothelin-1(ET-1)content in the lower extremity ASO group were significantly higher than those in the sham group,while serum high-densi-ty lipoprotein cholesterol(HDL-C)levels and nitric oxide(NO)content were significantly lower than those in the sham group(P＜0.05).In the Ar-He Cryo group,serum TC,TG,LDL-C levels as well as TNF-α,IL-1β,IL-6 levels and ET-1 content were significantly lower than those in the lower extremity ASO group,while serum HDL-C levels and NO content were significantly higher(P＜0.05).In the Ar-He Cryo+p-JAK group,serum TC,TG,LDL-C levels as well as TNF-α,IL-1 β,IL-6 levels and ET-1 content were significantly higher than those in the Ar-He Cryo group,while HDL-C levels and NO content were significantly lower(P＜0.05).Compared with the sham group,the lower extremity venous vessels in the lower extremity ASO group showed significant steno-sis;compared with the lower extremity ASO group,the degree of stenosis in the lower extremity ve-nous vessels was significantly reduced in the Ar-He Cryo group;the degree of stenosis in the lower extremity venous vessels in the Ar-He Cryo+p-JAK group was similar to that in the lower extremity ASO group and significantly more severe than that in the Ar-He Cryo group.The ratios of p-JAK2/JAK2 and p-STAT3/STAT3 in arterial vessel tissues of the lower extremity ASO group were signifi-cantly higher than those in the sham group,and SOCS3 protein expression was significantly lower than that in the sham group(P＜0.05).In the Ar-He Cryo group,p-JAK2/JAK2 and p-STAT3/STAT3 in arterial vessel tissues were significantly lower than those in the lower extremity ASO group,and SOCS3 protein expression was significantly higher than that in the lower extremity ASO group(P＜0.05).In the Ar-He Cryo+p-JAK group,p-JAK2/JAK2 and p-STAT3/STAT3 in arte-rial vessel tissues were significantly higher than those in the Ar-He Cryo group,and SOCS3 protein expression was significantly lower than that in the Ar-He Cryo group(P＜0.05).Conclusion Ar-gon-helium cryotherapy can reduce lipid deposition in the arteries of rats with lower extremity ASO,inhibit inflammatory responses,and its mechanism may be related to the inhibition of activation of JAK2/STAT3 signaling pathway.

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.

【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.

【Objective】 To investigate the situation of carbapenem-resistant Enterobacteriaceae(CRE) colonization in patients undergoing haploidentical hematopoietic stem cell transplantation (haplo-HSCT). 【Methods】 A total of 241 consecutive patients who underwent haplo-HSCT in the First Affiliated Hospital of Soochow University from June 1, 2021 to June 1, 2022 were enrolled. Anal swab screening was performed within 48 hours of admission and blood cultures were taken when the patient developed fever. Univariate and multivariate analysis were used to analyze the colonization rate, distribution, risk factors and the correlation between CRE colonization and post-transplant bloodstream infection(BSI). 【Results】 Among 241 patients with haplo-HSCT, there were 90 cases in CRE colonization positive group, with a colonization rate of 37.3% (90/241). Multivariate logistic regression analysis showed that sex (OR 2.42, 95% CI 1.38-4.22, P<0.05) and history of infection within 30 days before transplantation (OR 3.37, 95% CI 1.59-7.17, P<0.05) may be independent risk factors for CRE intestinal colonization. Of the 95 CRE strains, the top five species were carbapenem-resistant Klebsiella pneumoniae (38/95, 40.0%), carbapenem-resistant Escherichia coli (29/95, 30.5%), carbapenem-resistant Enterobacter cloacae (13/95, 13.6%), carbapenem-resistant Klebsiella acidophilus (6/95, 6.3%) and carbapenem-resistant Proteus mirabilis (3/95, 3.1%). The incidence of post-transplant BSI was 12.0% (29/241) in the CRE-colonized group and 3.3% (8/241) in the non-colonized group. In the colonization group, 100% of the pathogens of BSI were identical with those of CRE colonization. 【Conclusion】 Bacterial culture of anal swab during haplo-HSCT is helpful for detection of CRE colonization in intestinal tract, which provides some clinical basis for active monitoring of key flora, prevention and control of infection.

Enzalutamide (ENZ) is a second-generation androgen receptor (AR) antagonist used for the treatment of castration-resistant prostate cancer (CRPC) and reportedly prolongs survival time within a year of starting therapy. However, CRPC patients can develop ENZ resistance (ENZR), mainly driven by abnormal reactivation of AR signaling, involving increased expression of the full-length AR (ARfl) or dominantly active androgen receptor splice variant 7 (ARv7) and ARfl/ARv7 heterodimers. There is currently no efficient treatment for ENZR in CRPC. Herein, a small molecule LLU-206 was rationally designed based on the ENZ structure and exhibited potent inhibition of both ARfl and constitutively active ARv7 to inhibit PCa proliferation and suppress ENZR in CRPC. Mechanically, LLU-206 promoted ARfl/ARv7 protein degradation and decreased ARfl/ARv7 heterodimers through mouse double minute 2-mediated ubiquitination. Finally, LLU-206 exhibited favorable pharmacokinetic properties with poor permeability across the blood-brain barrier, leading to a lower prevalence of adverse effects, including seizure and neurotoxicity, than ENZ-based therapies. In a nutshell, our findings demonstrated that LLU-206 could effectively inhibit ARfl/ARv7-driven CRPC by dual-targeting of ARfl/ARv7 heterodimers and protein degradation, providing new insights for the design of new-generation AR inhibitors to overcome ARfl/ARv7-driven CRPC.

Stroke is considered a leading cause of mortality and neurological disability, which puts a huge burden on individuals and the community. To date, effective therapy for stroke has been limited by its complex pathological mechanisms. Autophagy refers to an intracellular degrading process with the involvement of lysosomes. Autophagy plays a critical role in maintaining the homeostasis and survival of cells by eliminating damaged or non-essential cellular constituents. Increasing evidence support that autophagy protects neuronal cells from ischemic injury. However, under certain circumstances, autophagy activation induces cell death and aggravates ischemic brain injury. Diverse naturally derived compounds have been found to modulate autophagy and exert neuroprotection against stroke. In the present work, we have reviewed recent advances in naturally derived compounds that regulate autophagy and discussed their potential application in stroke treatment.

Objective:To construct a cross-cultural nursing quality sensitive indicator system, so as to provide a basis for the hospital's cross-cultural nursing quality evaluation and monitoring.Methods:Based on the Donabedian model and the sunrise model, this study adopted the literature analysis method and the research team discussed preliminary screening indicators. From May to June 2020, 15 nursing and medical experts from a university hospital in Shanghai were selected as the subject of the consultation by using the method of convenience sampling. The Delphi method was used to conduct two rounds of expert consultations to determine the content of sensitive indicators of cross-cultural nursing quality.Results:The positive coefficients of the two rounds of consultations were 100%, and the authority coefficients were 0.883 and 0.893. The constructed cross-cultural nursing quality sensitive indicators included 3 first-level indicators and 20 second-level indicators.Conclusions:The cross-cultural nursing quality sensitive indicator constructed based on the Delphi method is scientific and representative, which can provide a reference for nursing quality evaluation and continuous quality improvement evaluation.

Chronic lymphocytic leukemia (CLL) is a highly heterogeneous disease, and combined chemotherapies symbolized by rituximab + fludarabine + cyclophosphamide have made great achievements in the era of traditional immunochemotherapy. However, for the patients with high genetic risk, relapsed and refractory patients as well as the elderly patients who cannot tolerate it, the therapeutic effect of this regimen is not good. The new drugs represented by BTK inhibitors have solved the above problems to a certain extent, and it is hopeful to move into the chemotherapy-free age of CLL treatment and bring the possibility of drug withdrawal. This article reviews the progress of CLL treatment.