T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematologic malignancy with a poor prognosis, despite advancements in treatment. Many patients struggle with relapse or refractory disease. Investigating the role of the super-enhancer (SE) regulated gene ubiquitin-specific protease 20 (USP20) in T-ALL could enhance targeted therapies and improve clinical outcomes. Analysis of histone H3 lysine 27 acetylation (H3K27ac) chromatin immunoprecipitation sequencing (ChIP-seq) data from six T-ALL cell lines and seven pediatric samples identified USP20 as an SE-regulated driver gene. Utilizing the Cancer Cell Line Encyclopedia (CCLE) and BloodSpot databases, it was found that USP20 is specifically highly expressed in T-ALL. Knocking down USP20 with short hairpin RNA (shRNA) increased apoptosis and inhibited proliferation in T-ALL cells. In vivo studies showed that USP20 knockdown reduced tumor growth and improved survival. The USP20 inhibitor GSK2643943A demonstrated similar anti-tumor effects. Mass spectrometry, RNA-Seq, and immunoprecipitation revealed that USP20 interacted with hypoxia-inducible factor 1 subunit alpha (HIF1A) and stabilized it by deubiquitination. Cleavage under targets and tagmentation (CUT&Tag) results indicated that USP20 co-localized with HIF1A, jointly modulating target genes in T-ALL. This study identifies USP20 as a therapeutic target in T-ALL and suggests GSK2643943A as a potential treatment strategy.

OBJECTIVES: To investigate the structural changes of rat thoracic aorta and changes in expression levels of Bmal1 and cyclins in thoracic aorta endothelial cells following heat stress. METHODS: Twenty male SD rats were randomized equally into control group and heat stress group. After exposure to 32 ℃ for 2 weeks in the latter group, the rats were examined for histopathological changes and Bmal1 expression in the thoracic aorta using HE staining and immunohistochemistry. In the cell experiments, cultured rat thoracic aortic endothelial cells (RTAECs) were incubated at 40 ℃ for 12 h with or without prior transfection with a Bmal1-specific small interfering RNA (si-Bmal1) or a negative sequence. In both rat thoracic aorta and RTAECs, the expressions of Bmal1, the cell cycle proteins CDK1, CDK4, CDK6, and cyclin B1, and apoptosis-related proteins Bax and Bcl-2 were detected using Western blotting. TUNEL staining was used to detect cell apoptosis in rat thoracic aorta, and the changes in cell cycle distribution and apoptosis in RTAECs were analyzed with flow cytometry. RESULTS: Compared with the control rats, the rats exposed to heat stress showed significantly increased blood pressures and lowered heart rate with elastic fiber disruption and increased expressions of Bmal1, cyclin B1 and CDK1 in the thoracic aorta (P<0.05). In cultured RTAECs, heat stress caused significant increase of Bmal1, cyclin B1 and CDK1 protein expression levels, which were obviously lowered in cells with prior si-Bmal1 transfection. Bmal1 knockdown also inhibited heat stress-induced increase of apoptosis in RTAECs as evidenced by decreased expression of Bax and increased expression of Bcl-2. CONCLUSIONS Heat stress upregulates Bmal1 expression and causes alterations in expressions of cyclins to trigger apoptosis of rat thoracic aorta endothelial cells, which can be partly alleviated by suppressing Bmal1 expression.
Animals ; ARNTL Transcription Factors/genetics* ; Male ; Aorta, Thoracic/metabolism* ; Rats ; Rats, Sprague-Dawley ; Endothelial Cells/metabolism* ; Apoptosis ; Cells, Cultured ; Heat-Shock Response ; Cyclin B1/metabolism* ; CDC2 Protein Kinase/metabolism* ; Cyclins/metabolism* ; RNA, Small Interfering ; bcl-2-Associated X Protein/metabolism*

OBJECTIVE: This study aimed to explore the association between body mass index (BMI) and mortality based on the 10-year population-based multicenter prospective study. METHODS: A general population-based multicenter prospective study was conducted at four sites in rural China between 2013 and 2023. Multivariate Cox proportional hazards models and restricted cubic spline analyses were used to assess the association between BMI and mortality. Stratified analyses were performed based on the individual characteristics of the participants. RESULTS: Overall, 19,107 participants with a sum of 163,095 person-years were included and 1,910 participants died. The underweight (< 18.5 kg/m ²) presented an increase in all-cause mortality (adjusted hazards ratio [ aHR] = 2.00, 95% confidence interval [ CI]: 1.66-2.41), while overweight (≥ 24.0 to < 28.0 kg/m ²) and obesity (≥ 28.0 kg/m ²) presented a decrease with an aHR of 0.61 (95% CI: 0.52-0.73) and 0.51 (95% CI: 0.37-0.70), respectively. Overweight ( aHR = 0.76, 95% CI: 0.67-0.86) and mild obesity ( aHR = 0.72, 95% CI: 0.59-0.87) had a positive impact on mortality in people older than 60 years. All-cause mortality decreased rapidly until reaching a BMI of 25.7 kg/m ² ( aHR = 0.95, 95% CI: 0.92-0.98) and increased slightly above that value, indicating a U-shaped association. The beneficial impact of being overweight on mortality was robust in most subgroups and sensitivity analyses. CONCLUSION This study provides additional evidence that overweight and mild obesity may be inversely related to the risk of death in individuals older than 60 years. Therefore, it is essential to consider age differences when formulating health and weight management strategies.
Humans ; Body Mass Index ; China/epidemiology* ; Male ; Female ; Middle Aged ; Prospective Studies ; Rural Population/statistics & numerical data* ; Aged ; Follow-Up Studies ; Adult ; Mortality ; Cause of Death ; Obesity/mortality* ; Overweight/mortality*

Intermittent theta burst stimulation (iTBS), a time-saving and cost-effective repetitive transcranial magnetic stimulation regime, has been shown to improve cognition in patients with Alzheimer's disease (AD). However, the specific mechanism underlying iTBS-induced cognitive enhancement remains unknown. Previous studies suggested that mitochondrial functions are modulated by magnetic stimulation. Here, we showed that iTBS upregulates the expression of iron-sulfur cluster assembly 1 (ISCA1, an essential regulatory factor for mitochondrial respiration) in the brain of APP/PS1 mice. In vivo and in vitro studies revealed that iTBS modulates mitochondrial iron-sulfur cluster assembly to facilitate mitochondrial respiration and function, which is required for ISCA1. Moreover, iTBS rescues cognitive decline and attenuates AD-type pathologies in APP/PS1 mice. The present study uncovers a novel mechanism by which iTBS modulates mitochondrial respiration and function via ISCA1-mediated iron-sulfur cluster assembly to alleviate cognitive impairments and pathologies in AD. We provide the mechanistic target of iTBS that warrants its therapeutic potential for AD patients.
Humans ; Mice ; Animals ; Transcranial Magnetic Stimulation ; Alzheimer Disease/therapy* ; Cognitive Dysfunction/therapy* ; Cognition ; Sulfur ; Iron ; Iron-Sulfur Proteins ; Mitochondrial Proteins

Objective Tissue uptake and distribution of nano-/microplastics was studied at a single high dose by gavage in vivo.Methods Fluorescent microspheres (100 nm, 3 μm, and 10 μm) were given once at a dose of 200 mg/(kg·body weight). The fluorescence intensity (FI) in observed organs was measured using the IVIS Spectrum at 0.5, 1, 2, and 4 h after administration. Histopathology was performed to corroborate these findings.Results In the 100 nm group, the FI of the stomach and small intestine were highest at 0.5 h, and the FI of the large intestine, excrement, lung, kidney, liver, and skeletal muscles were highest at 4 h compared with the control group (P < 0.05). In the 3 μm group, the FI only increased in the lung at 2 h (P < 0.05). In the 10 μm group, the FI increased in the large intestine and excrement at 2 h, and in the kidney at 4 h (P < 0.05). The presence of nano-/microplastics in tissues was further verified by histopathology. The peak time of nanoplastic absorption in blood was confirmed.Conclusion Nanoplastics translocated rapidly to observed organs/tissues through blood circulation;however, only small amounts of MPs could penetrate the organs.

Objective:To study the distribution of TCM constitutions in maintenance hemodialysis (MHD) patients.Methods:This is a multicenter cross-sectional study. The general clinical data, dialysis-related parameters and physical and chemical examination data of MHD patients from 6 dialysis centers in Sichuan were collected. At the same time, DS01-A tongue and facial pulse information collection system was used for TCM constitution discrimination.Results:A total of 232 MHD patients were enrolled , and 417 kinds of TCM constitutions were detected, including 59 patients (25.43%) with moderate constitution and 173 patients (74.57%) with biased constitution. Phlegm-dampness was the most common type of solid constitution 47 patients (20.26%). The most common deficiency constitution was qi deficiency 86 patients (37.07%). There were certain differences in the physical distribution of patients with different gender, age, dialysis age, BMI, and whether they had diabetes, hypertension or anemia.Conclusions:The TCM constitutions of MHD patients are mainly biased constitution. Gender, age, BMI, diabetes or hypertension have a certain impact on the distribution of TCM constitutions. At the same time, different constitutions may have an impact on the anemia of MHD patients. The intervention of TCM constitutions on MHD patients may be beneficial to the prognosis of MHD patients.

Objective:To analyze the effect of recombinant human thrombopoietin(rhTPO)on platelet(PLT)reconstitution after autologous peripheral blood stem cell transplantation(APBSCT)in patients with multiple myeloma(MM).Methods:The clinical data of 147 MM patients who were diagnosed in the First Affiliated Hospital of Soochow University and received APBSCT as the first-line therapy were retrospectively analyzed.According to whether rhTPO was used during APBSCT,the patients were divided into rhTPO group(80 cases)and control group(67 cases).The time of PLT engraftment,blood product infusion requirements,the proportion of patients with PLT recovery to ≥ 50 × 109/L and ≥ 100 × 109/L at+14 days and+100 days after transplantation,and adverse reactions including the incidence of bleeding were compared between the two groups.Results:There were no significant differences between the two groups in sex,age,M protein type,PLT count at the initial diagnosis,median duration of induction therapy before APBSCT,and number of CD34+cells reinfused(all P＞0.05).The median time of PLT engraftment in the rhTPO group was 10(6-14)days,which was shorter than 11(8-23)days in the control group(P＜0.001).The median PLT transfusion requirement in the rhTPO group during APBSCT was 15(0-50)U,which was less than 20(0-80)U in the control group(P=0.001).At+14 days after transplantation,the proportions of patients with PLT 2 50 × 109/L in the rhTPO group and the control group were 66.3％and 52.2％,while the proportions of patients with PLT ≥ 100 × 109/L were 23.8％and 11.9％,respectively,with no significant differences(all P＞0.05).At+100 days after transplantation,the proportion of patients with PLT ≥ 50 × 109/L in rhTPO group and control group was 96.3％and 89.6％,respectively(P＞0.05),but the proportion of patients with PLT ≥ 100 × 109/L in rhTPO group was higher than that in control group(75.0％vs 55.2％,P=0.012).There was no difference in the overall incidence of bleeding events in different locations during period of low PLT level of patients between the two groups.In rhTPO group,the rhTPO administration was well tolerated,and the incidences of abnormal liver and kidney function and infection were similar to those in the control group.Conclusion:When MM patients undergo first-line APBSCT,subcutaneous injection of rhTPO can shorten the time of platelet engraftment,reduce the transfusion volume of blood products,and be well tolerated,moreover,more patients have achieve a high level of PLT recovery after transplantation,which is very important for ensuring the safety of APBSCT and maintenance therapy.

Objective:To analyze the factors affecting overall survival(OS)of adult patients with core-binding factor acute myeloid leukemia(CBF-AML)and establish a prediction model.Methods:A total of 216 newly diagnosed patients with CBF-AML in the First Affiliated Hospital of Zhengzhou University from May 2015 to July 2021 were retrospectively analyzed.The 216 CBF-AML patients were divided into the training and the validation cohort at 7:3 ratio.The Cox regression model was used to analyze the clinical factors affecting OS.Stepwise regression was used to establish the optimal model and the nomogram.Receiver operating characteristic(ROC)curve,calibration curve and decision curve analysis(DCA)were used to evaluate the model performance.Results:Age(≥ 55 years old),peripheral blood blast(≥80％),fusion gene(AML1-ETO),KIT mutations were identified as independent adverse factors for OS.The area under the ROC curve at 3-year was 0.772 and 0.722 in the training cohort and validation cohort,respectively.The predicted value of the calibration curve is in good agreement with the measured value.DCA shows that this model performs better than a single factor.Conclusion:This prediction model is simple and feasible,and can effectively predict the OS of CBF-AML,and provide a basis for treatment decision.