Most cancers are currently incurable, partly due to abnormal post-translational modifications (PTMs). In this study, we initially used multiple myeloma (MM) as a working model and found that SUMOylation activating enzyme subunit 1 (SAE1) promotes the malignancy of MM. Through proteome microarray analysis, SAE1 was identified as a potential target for bioactive colcemid or its derivative colchicine. Elevated levels of SAE1 were associated with poor clinical survival and increased MM proliferation in vitro and in vivo. Additionally, SAE1 directly SUMOylated and upregulated the total protein expression of p27, leading to LLPS-mediated nuclear export of p27. Our study also demonstrated the involvement of SAE1 in other types of cancer cells, and provided the first monomer crystal structure of SAE1 and its key binding model with colchicine. Colchicine also showed promising results in the Patient-Derived Tumor Xenograft (PDX) model. Furthermore, a controlled clinical trial with 56 MM patients demonstrated the clinical efficacy of colchicine. Our findings reveal a novel mechanism by which tumor cells evade p27-induced cellular growth arrest through p27 SUMOylation-mediated nuclear export. SAE1 may serve as a promising therapeutic target, and colchicine may be a potential treatment option for multiple types of cancer in clinical settings.

Objective To explore the application value of serum cystatin C(CysC)and cluster of differentiation 147(CD147)in predicting restenosis after intracranial artery stenosis stenting(ICASS)in patients with acute ischemic stroke(AIS).Methods A total of 151 AIS patients who received ICASS were selected as the study group,and 112 healthy individuals who underwent physical examinations during the same period were chosen as the control group.The study group was further divided into the restenosis group(30 cases)and the non-stenosis group(121 cases)based on the restenosis status within 6 months after ICASS.The serum CysC levels of the subjects were detected by immunoturbidimetry,and the serum CD147 levels were measured by enzyme-linked immunosorbent assay.Multivariate Logistic regression analysis was conducted to identify factors influencing restenosis after ICASS in AIS patients.The receiver operating characteristic(ROC)curve was used to evaluate the application efficacy of serum CysC and CD147 levels in predicting restenosis after ICASS in AIS patients.Results Serum levels of CysC and CD147 were higher in the study group than those in the control group(P＜0.01).The proportion of patients with stenosis degree>75%and serum levels of CysC and CD147 were higher in the restenosis group than those in the non-stenosis group(P＜0.01).The degree of stenosis>75%and the increased serum levels of CysC and CD147 were risk factors for restenosis after ICASS in AIS patients(P＜0.01).ROC curve analysis showed that serum CysC and CD147 levels independently predicted the AUC of AIS patients with restenosis after ICASS were 0.845 and 0.850,respectively,and the combined predicted AUC was 0.942.The combined prediction efficiency was significantly better than that of single indicator prediction(P＜0.05).Conclusion The increased levels of serum CysC and CD147 in AIS patients are risk factors for restenosis after ICASS,and the combination of the two is more effective in predicting intracranial artery restenosis after ICASS in AIS patients.

Objective To explore the application value of serum cystatin C(CysC)and cluster of differentiation 147(CD147)in predicting restenosis after intracranial artery stenosis stenting(ICASS)in patients with acute ischemic stroke(AIS).Methods A total of 151 AIS patients who received ICASS were selected as the study group,and 112 healthy individuals who underwent physical examinations during the same period were chosen as the control group.The study group was further divided into the restenosis group(30 cases)and the non-stenosis group(121 cases)based on the restenosis status within 6 months after ICASS.The serum CysC levels of the subjects were detected by immunoturbidimetry,and the serum CD147 levels were measured by enzyme-linked immunosorbent assay.Multivariate Logistic regression analysis was conducted to identify factors influencing restenosis after ICASS in AIS patients.The receiver operating characteristic(ROC)curve was used to evaluate the application efficacy of serum CysC and CD147 levels in predicting restenosis after ICASS in AIS patients.Results Serum levels of CysC and CD147 were higher in the study group than those in the control group(P＜0.01).The proportion of patients with stenosis degree>75%and serum levels of CysC and CD147 were higher in the restenosis group than those in the non-stenosis group(P＜0.01).The degree of stenosis>75%and the increased serum levels of CysC and CD147 were risk factors for restenosis after ICASS in AIS patients(P＜0.01).ROC curve analysis showed that serum CysC and CD147 levels independently predicted the AUC of AIS patients with restenosis after ICASS were 0.845 and 0.850,respectively,and the combined predicted AUC was 0.942.The combined prediction efficiency was significantly better than that of single indicator prediction(P＜0.05).Conclusion The increased levels of serum CysC and CD147 in AIS patients are risk factors for restenosis after ICASS,and the combination of the two is more effective in predicting intracranial artery restenosis after ICASS in AIS patients.

Objective To explore the impact of macrophage-to-myofibroblast transition(MMT)on pulmonary fibro-sis induced by acute lung injury by LPS.Methods Totally 21 male mice were randomly classified into 7 groups:control group,model group(LPS-PF)at different time points and intervention group of clodronate-liposomes(CL-LIP)treatement at different time points(n=3).Pulmonary fibrosis was identified by HE and Masson staining microscopy.The immuno-fluorescence technology was used for the evaluation of numbers of macrophage-to-myofi-broblast transition cells(MMT cell which co-expressed CD68 and α-SMA).Bone marrow-derived macrophages(BMDMs)were randomly classified into two group:control(Ctrl)group and TGF-β1-treated group induced by transforming growthfactor-β1.α-SMA,FN and Col1 were detected by RT-qPCR.The expression of α-SMA,Smad3 and p-Smad3 protein was evaluated by Western blot.Results At day 7,the Ashcroft score of lung tissue in LPS-PF mouse model was significantly increased when compared with the Ctrl group(P＜0.01);While the score signifi-cantly declined when the model was pretreated with CL-LIP(P＜0.05).As detected by immuno-fluorescence stai-ning,in CL-LIP group the number of CD68-positive cells co-labeled with α-SMA was obviously less then that of LPS-PF group of the corresponding time point(P＜0.01).When the BMDMs were stimulated by TGF-β1 at 24 h,48 h and 96 h respectively,a higher expression of α-SMA,FN,Col1,were found in TGF-β1-treated group than that in Ctrl group at the corresponding time point(P＜0.01).The expression of Smad3,p-Smad3 significantly higher in LPS-PF group(at both day 7 and day 10)and TGF-β1-treated group(at both 48 h and 96 h)as compared to cor-responding control group(P＜0.01).Conclusions MMT promotes pulmonary fibrosis induced by ALI via LPS.Smad3 is proved to be involved in the MMT process.

Objective:To analyze the clinical characteristics and prognosis of patients with myelodysplastic syndrome (MDS) with a bone marrow nucleated erythroid cell proportion of greater than or equal to 50% (MDS-E) .Methods:The clinical characteristics and prognostic factors of patients with MDS-E were retrospectively analyzed by collecting the case data of 1 436 newly treated patients with MDS diagnosed in the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences from May 2014 to June 2023.Results:A total of 1 436 newly diagnosed patients with complete data were included in the study, of which 337 (23.5%) patients with MDS-E had a younger age of onset and lower neutrophil and platelet counts compared with those in patients with an erythroid cell proportion of less than 50% (MDS-NE) (all P<0.05). The proportion of MDS cases with ring sideroblasts (MDS-RS) was higher in the MDS-E group than in the MDS-NE group, and multi-hit TP53 mutations were more enriched in the MDS-E group than in the MDS-NE group (all P<0.05). Among patients with MDS-RS, the frequency of complex karyotypes and the TP53 mutation rate were significantly lower in the MDS-E group than in the MDS-NE group (0 vs 11.9%, P=0.048 and 2.4% vs 15.1%, P=0.053, respectively). Among patients with TP53 mutations, the frequencies of complex karyotypes and multi-hit TP53 mutations were significantly higher in the MDS-E group than in the MDS-NE group (87.5% vs 64.6%, P=0.003 and 84.0% vs 54.2%, P<0.001, respectively). Survival analysis of patients with MDS-RS found that the overall survival (OS) in the MDS-E group was better than that in the MDS-NE group [not reached vs 63 (95% CI 53.3-72.7) months, P=0.029]. Among patients with TP53 mutations and excess blasts, the OS in the MDS-E group was worse than that in the MDS-NE group [6 (95% CI 2.2-9.8) months vs 12 (95% CI 8.9-15.1) months, P=0.022]. Multivariate analysis showed that age of ≥65 years ( HR=2.47, 95% CI 1.43-4.26, P=0.001), mean corpuscular volume (MCV) of ≤100 fl ( HR=2.62, 95% CI 1.54-4.47, P<0.001), and TP53 mutation ( HR=2.31, 95% CI 1.29-4.12, P=0.005) were poor prognostic factors independent of the Revised International Prognostic Scoring System (IPSS-R) prognosis stratification in patients with MDS-E. Conclusion:Among patients with MDS-RS, MDS-E was strongly associated with a lower proportion of complex karyotypes and TP53 mutations, and the OS in the MDS-E group was longer than that in the MDS-NE group. Among patients with TP53 mutations, MDS-E was strongly associated with complex karyotypes and multi-hit TP53 mutations, and among TP53-mutated patients with excess blasts, the OS in the MDS-E group was shorter than that in the MDS-NE group. Age of ≥65 years, MCV of ≤100 fl, and TP53 mutation were independent adverse prognostic factors affecting OS in patients with MDS-E.

In recent years, point of care ultrasound (POCUS) has developed rapidly in the fields of anesthesia and critical care. POCUS is widely used in clinic to monitor the function of human tissues and organs such as the heart, lungs, and diaphragm due to its visual, non-invasive, portable, and repeatable characters at the bedside. Diaphragm is an important structure to maintain respiratory function. Diaphragm paralysis or dysfunction can cause a significant decrease in inspiratory function. The patient's diaphragm function can be assessed through monitoring diaphragm thickness and activity by POCUS, and combined with other clinical indicators, the patient's recovery of respiratory function can be comprehensively evaluated, and rapidly identify the pathological conditions, such as diaphragm paralysis, diaphragm atrophy, diaphragmatic hypoplasia and amyotrophic lateral sclerosis. Dynamic evaluation of the process from diaphragmatic dysfunction to recovery can provide guidance for weaning and extubation, and real-time feedback on the treatment effect. This article reviews the ultrasound evaluation methods and clinical applications to the diaphragm, in order to guide clinicians to use relevant indicators to comprehensively evaluate the structure and function of the diaphragm, and then diagnose and treat diaphragm dysfunction, which may help making clinical decision.

The outbreak of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 has rapidly spread globally. Cancer patients are at a higher risk of being infected with the coronavirus and are more likely to develop severe complications, as compared to the general population. The increasing spread of COVID-19 presents challenges for the clinical care of patients with gynecological malignancies. Concerted efforts should be put into managing gynecological malignancies in an orderly manner by strictly implementing the measures that are specifically developed for controlling the spread of COVID-19. We have drafted Recommendations on Management of Gynecological Malignancies during the COVID-19 Pandemic based on our experience on controlling COVID-19 pandemic in China. We recommend that patients with gynecological malignancies should be managed in hierarchical and individualized manners in combination with local conditions related to COVID-19. Medical care decision should be balanced between controlling COVID-19 pandemic spread and timely diagnosis and treatment for gynecologic oncology patients.

Macrophages play critical roles in renal fibrosis. However, macrophages exhibit ontogenic and functional heterogeneities, and which population of macrophages contributes to renal fibrosis and the underlying mechanisms remain unclear. In this study, we genetically targeted Notch signaling by disrupting the transcription factor recombination signal binding protein-Jκ (RBP-J), to reveal its role in regulation of macrophages during the unilateral ureteral obstruction (UUO)-induced murine renal fibrosis. Myeloid-specific disruption of RBP-J attenuated renal fibrosis with reduced extracellular matrix deposition and myofibroblast activation, as well as attenuated epithelial-mesenchymal transition, likely owing to the reduced expression of TGF-β. Meanwhile, RBP-J deletion significantly hampered macrophage infiltration and activation in fibrotic kidney, although their proliferation appeared unaltered. By using macrophage clearance experiment, we found that kidney resident macrophages made negligible contribution, but bone marrow (BM)-derived macrophages played a major role in renal fibrogenesis. Further mechanistic analyses showed that Notch blockade reduced monocyte emigration from BM by down-regulating CCR2 expression. Finally, we found that myeloid-specific Notch activation aggravated renal fibrosis, which was mediated by CCR2 macrophages infiltration. In summary, our data have unveiled that myeloid-specific targeting of Notch could ameliorate renal fibrosis by regulating BM-derived macrophages recruitment and activation, providing a novel strategy for intervention of this disease.

Objective To discuss the safety and clinical efficacy of modified traction method using endoloop and clip for endoscopic submucosal dissection(ESD).Methods Fifty patients who underwent ESD at Renmin Hosptial of Wuhan University between August 2016 and February 2017 were randomly divided into two groups, including 25 patients in modified ESD group and 25 patients in conventional ESD group as control. The therapeutic conditions, dissection time and incidence of complications were compared between the two groups. Results In the modified ESD group, the dissection time of submucosal exposure to the full dissection (19. 9±6. 5 min VS 26. 4±9. 2 min, P＝0. 001), total dissection time (27. 5±8. 1 min VS 35. 1± 10. 7 min, P＝0. 003), and dissection time per unit area (2. 4±1. 1 min/cm2VS 3. 3±1. 3 min/cm2, P＝0. 009) were significantly shorter compared with those in the control group. There were 1 case of delayed bleeding in the modified group and 2 cases in the control group with no significant difference ( P＝0. 248). No perforation occurred. Conclusion The modified traction method using endoloop and clip for ESD is safe and effective with a shorter operation time.

Objective To ascertain the specific activities of nigericin on inhibiting human epithelial ovarian cancer(EOC)cells,and to investigate the possible molecular mechanism of nigericin on cell migration and invasion.Methods Cell viability under different treatments of nigericin(0.312 5,0.625,1.25,2.5,5,10,20,40,80 μmol/L)on EOC A2780 and SKOV3 cell lines was examined by CCK-8 assay,with DMSO as a control.The human epithelial ovarian cancer cell lines A2780 and SKOV3 were treated with 5,10 or 20 μmol/L nigericin or with DMSO as a control.Transwell chambers was used to observe the impact of nigericin on migration and invasion of EOC cells.Western blot was used to detect the expressions of epithelial cell marker(E-cadherin),mesenchymal cell marker(Vimentin)and the epithelial-mesenchymal transition(EMT)-related transcription factors Slug,Snail,and Twist,as well as the expressions of proteins related to Wnt/β-catenin signaling pathway such as Gsk-3β,p-Gsk-3β and β-catenin under different concentration treatment of nigericin.Results CCK-8 assay showed that nigericin exhibited strong cytotoxicity on A2780 [ IC 50(16.19 ± 0.26)μmol/L,95％CI 1.077-1.341)] and SKOV3 [ IC50(11.87 ±0.21)μmol/L,95％CI 1.003-1.146] cell lines.Transwell chamber assay revealed that nigericin at different concentration(5,10,20 μmol/L)induced a remarkable reduction in the number of cells migrating through the membrane relative to the vehicle-treated controls in A2780 and SKOV3 cells [(121±9),(92±7),(59±5)/HP and(120.4±2.6),(91.8±5.5),(80.0±4.0)/HP,all P <0.05]; the invasive ability of A2780 and SKOV3 cells also inhibited [(61.2±3.7),(43.2±4.3),(23.6±2.1)/HP and(85.2±7.0),(65.2±4.6),(45.6±4.4)/HP,all P< 0.05].Western blot revealed that the increased expression of E-cadherin and decreased expression of Vimentin,Slug,Snail,Twist,p-Gsk-3β,β-catenin in EOC cells with the nigericin treatment at different concentration(5,10 and 20 μmol/L)showed concentration dependence(P < 0.05).Conclusion Nigericin may induce EMT by activating Wnt-β-catenin signaling pathway to promote the migration and invasion of EOC cells.