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.

Objective To analyze the expression level of kinesin family member 26B(KIF26B)in bladder cancer based on the pub-lic database,and to investigate the effect of silencing KIF26B on the proliferation,invasion and migration of bladder cancer cells.Methods The expression of KIF26B in bladder cancer and its relationship with survival and prognosis were analyzed based on GEO and UaLcan databases.Real-time quantitative polymerase chain reaction(RT-qPCR)and Western blot were used to detect the expression of KIF26B in bladder cancer cell lines(T24,J82)and normal bladder epithelial cells SV-HUV-1.si-KIF26B and si-NC fragments were transfected into T24 cells,and the effects of silencing KIF26B on the proliferation,invasion and migration of T24 cells were detected by methyl thiazolyl tetrazolium(MTT)assay,Transwell assay and scratch assay.Western blot was used to detect the expression levels of p-MEK,MEK,ERK and p-ERK proteins after the silencing of KIF26B.Results KIF26B was highly expressed in bladder cancer tis-sues,and the prognosis of patients with high expression of KIF26B was worse(P＜0.05).The expression level of KIF26B in bladder cancer cell lines T24 and J82 was significantly higher than that in normal bladder epithelial cells SV-HUV-1(P＜0.05).After the si-lencing of KIF26B gene,MTT,Transwell and scratch assay Results showed that the proliferation,invasion and migration ability of T24 cells were significantly decreased(P＜0.05);After silencing KIF26B,the expression of p-MEK and p-ERK proteins in T24 cells was down-regulated(P＜0.05),while MEK and ERK proteins had no significant changes(P＞0.05).Conclusion KIF26B is highly ex-pressed in bladder cancer tissues and cells,which is associated with poor prognosis of patients.Silencing KIF26B can inhibit the prolifera-tion,invasion and migration of bladder cancer cells,and the mechanism may play a role through the MEK/ERK pathway.

Objective Endothelial injury plays a crucial role in forming deep vein thrombosis.This study aims to compare the effectiveness of various methods for creating rabbit femoral vein thrombotic models after the endothelial injuryso as to provide a solid experimental foundation for further research on the endothelial injury and deep vein thrombosis.Methods Forty-five rabbits were randomly divided into three groups(A,B,C),with 15 cases in each group and subjected to the endothelial injury using the methods of simple clamping,combined complete ligation,and combined incomplete ligation,respectively.The intravascular ultrasonic manifestations and local endothelial pathological changes were compared at 1,3,and 7 days after modeling.Results Significant differences in vascular diameter and Young's modulus values were observed after 7 days of modeling(P<0.05).In pairwise comparisons between the groups,the Young's modulus values in group C were significantly higher than those in groups A and B after 7 days of modeling(P<0.05).Pathological examination confirmed the presence of fibr-inoid thrombus in the blood vessels of group C on the seventh day of modeling.Conclusion Combining simple clam-ping and incomplete ligation can produce a relatively stable endothelial injury and thrombus formation.This method provides a robust experimental model for further investigation into deep vein thrombosis after the endothelial injury.

Objective:To investigate the current status of the teaching methods used in the integrated basic and clinical courses and the approaches for improving such teaching methods, and to improve the teaching quality of the integrated basic and clinical courses for "4+4" Medical Doctor Program in Peking Union Medical College.Methods:Students in the Class 2020 of "4+4" Medical Doctor Program who completed the integrated courses from September 2020 to August 2021 were enrolled as subjects. Questionnaire surveys and interviews were performed for the subjects in terms of class hours, integration effect, and self-learning methods. R4.0.0 software was used to perform a statistical analysis of data.Results:The mean weekly class hours of existing modules were (27.59±2.61) hours per week, which was higher than the expectation of students. There was a negative linear correlation between weekly class hours and mean satisfaction score of each module ( r=-0.71, P=0.022). The integration of basic and clinical medical courses had a mean satisfaction score of 2.652. The median preview time for case-based learning/problem-based learning was 30 minutes. Conclusions:In the reform of the integration of basic and clinical medical courses, it is crucial to select and apply proper teaching methods. In order to further improve teaching effect, it is advised to reduce the class hours of theoretical lectures and carefully design and prepare learning materials, and the teaching contents should be organized according to the internal logic of knowledge and the association between clinical knowledge and the knowledge learned during the stage of basic medicine.

Objective To investigate the efficacy of negative pressure combined ureteroscopy combined with flexible ureteroscopy holmium laser lithotripsy in the treatment of renal calculi or upper ureteral calculi with a maximum diameter of 2-4cm.Methods The data of patients with renal calculi or upper ureteral calculi with a maximum diameter of 2-4cm who were hospitalized inAffiliated Hospital of Youjiang Medical University for Nationalities from March 2023 to March 2024 were collected and divided into observation group(n=40)and control group(n=40).The observation group was treated with negative pressure combined ureteroscopy combined with flexible ureteroscopy for holmium laser lithotripsy,and control group was treated with nephroscope for percutaneous nephrolithotomy(PCNL).The operation time,postoperative hospital stay,changes of blood routine white blood cell(WBC)before and after operation,changes of urine routine WBC before and after operation,postoperative visual analogue score(VAS),one-stage stone clearance rate and postoperative complications were compared between two groups.Results The postoperative hospitalization time and VAS of observation group were significantly lower than those of control group(P＜0.05).There was no significant difference in operation time,stone clearance rate,postoperative blood routine WBC and postoperative urine routine WBC between two groups(P＞0.05).However,the blood routine WBC of two groups after operation was higher than that before operation(P＜0.05).The overall stone clearance rate of two surgical methods was 86.25％,of which the stone clearance rate of observation group was 82.5％,and control group was 90％.There was no significant difference between two groups(P＞0.05).Conclusion It is safe and effective to treat renal calculi;or upper ureteral calculi with a maximum diameter of 2-4cm by negative pressure combined ureteroscopy combined with flexible ureteroscopy holmium laser lithotripsy.It is expected to partially replace PCNL and become another safe and reliable operation for the treatment of renal calculi or upper ureteral calculi with a maximum diameter of 2-4cm.

Objective:To investigate the value of the extrahepatic bile duct and main pancreatic duct segment patterns on magnetic resonance cholangiopancreatography (MRCP) for differentiating the periampullary carcinoma (PAC).Methods:The clinicopathologic data of 125 patients with PAC who were admitted to Wuxi No.2 People’s Hospital from June 2013 to December 2021 were retrospectively analyzed, including 72 males and 53 females, aged (64.9±8.6) years. According to its anatomy, the extrahepatic bile duct (B) was divided into suprapancreatic and intrapancreatic (including ampullary) segments, and the main pancreatic duct (P) was divided into tail-body and head segments. MRCP patterns: i. the extrahepatic bile duct or main pancreatic duct visible without dilatation, ii. cutoff of the distal extrahepatic bile duct or main pancreatic duct with upstream dilatation, iii. cutoff of the intrapancreatic or head segment with upstream dilatation and remnant intrapancreatic or head segments invisible, iv. cutoff of the intrapancreatic or head segment with upstream dilatation and nondilated remnant intrapancreatic or head segments, were represented as 0, 1, 2, and 3, respectively. Segment patterns of B1/P0+ B1/P1, B0/P2+ B0/P3+ B2/P2+ B2/P3+ B3/P3, B3/P0, and B0/P0+ B2/P0 on MRCP were compared in PAC patients.Results:Of the 125 patients, there were 57 (45.6%) with pancreatic head carcinoma, 36 (28.8%) with ampullary carcinoma, 20 (16.0%) with distal cholangiocarcinoma, and 12 (9.6%) with periampullary duodenal carcinoma. Segment patterns of B0/P2+ B0/P3+ B2/P2+ B2/P3+ B3/P3 were found in 52 patients with pancreatic head carcinoma (91.2%, 52/57), with a significant difference between PAC (χ 2=110.66, P<0.001). Segment patterns of B1/P0+ B1/P1were found in 36 patients with ampullary carcinoma (100.0%, 36/36), fallowed by 11 (91.7%, 11/12) with periampullary duodenal carcinoma, with a significant difference between PAC (χ 2=129.95, P<0.001). Segment pattern of B3/P0 presented in 16 patients with distal cholangiocarcinoma (80.0%, 16/20), with a significant difference between PAC (χ 2=62.45, P<0.001). The segment patterns of B0/P0+ B2/P0 were only seen in 3 of 57(5.3%) patients with pancreatic head carcinoma. Conclusion:On MRCP, cutoff of the head segment with upstream dilatation and remnant head segment invisible or nondilated indicates the pancreatic head carcinoma. Cutoff of the intrapancreatic segment with upstream dilatation, remnant intrapancreatic segment visible, and main pancreatic duct nondilated, indicates the distal cholangiocarcinoma. And cutoff of the distal extrahepatic segment with upstream dilatation and main pancreatic duct dilatation or not, indicates the ampullary or periampullary duodenal carcinoma.

Objective:To investigate the changes of left atrial structure and function in patients with apical hypertrophic cardiomyopathy (ApHCM) by three-dimensional (3D) echocardiography.Methods:From September 2020 to December 2022, 112 patients with ApHCM(ApHCM group) diagnosed at Tongji Hospital Tongji Medical College, Huazhong University of Science and Technology and 41 age- and sex-matched normal controls(control group) were finally enrolled. In 'pure’ ApHCM patients, cardiac hypertrophy was confined to the apical segment below the papillary muscle. The wall thickness of apical and intermediate segments in 'mixed’ ApHCM patients increased, but the wall thickness of apical segment was the largest. Two-dimensional(2D) and 3D volume and strain parameters of left atrium were compared between control group and ApHCM group, 'pure’ and 'mixed’ ApHCM patients.The correlations between 2D and 3D volume and strain parameters of left atrium and intraclass correlation coefficient (ICC) of those parameters were analyzed. The ROC curve was performed to determine the cutoff values of 3D left atrial volume abnormalities in all subjects. Logistics regression analysis was performed to analyze the impact factors of the left atrial enlargement in patients with ApHCM.Results:Compared with the control group, 2D left atrial maximum volume index (2D LAVimax), 2D left atrial minimum volume index (2D LAVimin), 3D left atrial maximum volume index (3D LAVimax), 3D left atrial minimum volume index (3D LAVimin), and 3D left atrial presystolic volume index (3D LAVipreA) significantly increased in ApHCM group( Z=-6.54, -6.38, -6.98, -7.40, -6.96; all P<0.001). However, 2D left atrial ejection fraction (2D LAEF) ( Z=-3.75, P<0.001), 2D left atrial expansion index (2D LAEI) ( t=-4.15, P<0.001), 3D left atrial ejection fraction (3D LAEF) ( Z=-5.09, P<0.001), 3D left atrial expansion index (3D LAEI) ( t=-5.49, P<0.001), 2D left atrial reservoir strain (2D LASr) ( t=-12.03, P<0.001), 2D left atrial conduit strain (2D LAScd) ( t=7.91, P<0.001), 2D left atrial contractile strain (2D LASct) ( t=6.06, P<0.001), 3D left atrial reservoir strain (3D LASr) ( t=-9.23, P<0.001), 3D left atrial conduit strain (3D LAScd) ( t=7.12, P<0.001) and 3D left atrial contractile strain (3D LASct) ( t=4.78, P<0.001) significantly decreased in ApHCM group. Compared with the 'pure’ ApHCM group, 2D LAVimax, 3D LAVimax, 2D LAVimin, 3D LAVimin, 3D LAVipreA in patients with mixed ApHCM increased more significantly, while 2D LAEF, 2D LAEI and 2D LASr decreased more significantly. The measurements of left atrial volume and strain by 3D echocardiography were significantly correlated with 2D measurements ( P<0.05). The correlations between 2D LAVimax and 3D LAVimax, 2D LAVimin and 3D LAVimin, 2D LAEF and 3D LAEF, 2D LASr and 3D LASr, 2D LAEI and 3D LAEI ( r=0.91, 0.93, 0.72, 0.76, 0.57; all P<0.05) were more than moderate. The repeatability of 3D left atrial strain was lower than 2D results, while the repeatability of 3D left atrial volume was higher than 2D results. ROC curve analysis showed that 3D echocardiography parameters could identify left atrial volume abnormality in all subjects. The cutoff values of 3D LAVimax, 3D LAVimin, 3D LAVipreA in all subjects were 36 ml/m 2, 18 ml/m 2 and 27 ml/m 2, respectively. Multivariate binary logistic regression analyses showed that ratio of LV systolic obliteration to cavity was independent factor affecting left atrial enlargement in ApHCM patients( OR=1.20, P<0.001). Conclusions:Three-dimensional echocardiography is significant for the accurate evaluation of left atrial structural changes in patients with ApHCM. Ratio of left ventricular systolic obliteration to cavity was an independent impact factor of left atrial enlargement in ApHCM patients.

Objective:To evaluate the efficacy and safety of immediate intraoperative transapical beating-heart septal myectomy (TA-BSM) in patients with hypertrophic obstructive cardiomyopathy (HOCM) and explored the clinical value of three-dimensional transesophageal echocardiography (3D-TEE) during the procedure of TA-BSM.Methods:One hundred and thirty-seven HOCM patients who underwent TA-BSM surgery in Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology from April 2022 to March 2023 were selected.During the operation, 3D-TEE was used to locate the position of the myocardial circumcision system and navigate the range of myocardial circumcision. The interventricular septal thickness( IVST) and peak pressure gradient of the left ventricular outflow tract (LVOT-PG) were measured, and the degree of mitral systolic anterior motion (SAM) and mitral regurgitation (MR) were evaluated in HOCM patients before and after the operation. The range of the incisal margin was measured, and the number of resection knives and the weight of the removed myocardium were recorded.Results:TA-BSM under 3D-TEE navigation was successfully performed in 137 HOCM patients. The number of resection was 7(5, 9), and the weight of the removed myocardium was 5.6(3.4, 8.9)g. During the operation, there were no adverse events such as death, aortic valve injury, and iatrogenic interventricular septal perforation. Compared with those before the operation, the wall thickness of basal and middle segments of the anterior and posterior interventricular septum decreased significantly (all P<0.001), and LVOT-PG decreased significantly ( P<0.001). After TA-BSM, the number of patients with SAM≥3 decreased from 94 cases (68.6%) to 2 cases (1.5%), and the number of patients with MR≥3+ decreased from 86 cases (62.8%) to 9 cases (6.6%)(all P<0.001). For the patients with different degrees of ventricular septal hypertrophy (mild, moderate, and severe), the postoperative IVST and LVOT-PG were significantly lower than the preoperative values, and the degree of MR and SAM signs was relieved considerably. The length of the incisal margin, the weight of excised myocardium, and the number of resection in the group with extensive septal hypertrophy in all three regions were significantly higher than those in the group with localized interventricular septal hypertrophy in single or two areas (all P<0.05). Conclusions:3D-TEE can guide and monitor the process of TA-BSM myocardial resection in real-time. By accurately evaluating the IVST and the range and hemodynamic characteristics of HOCM patients, it can effectively relieve LVOTO and significantly reduce MR to ensure the safety and effectiveness of TA-BSM in HOCM patients with different degrees and ranges of hypertrophy.

Objective:To investigate the mid-term clinical outcomes of selective column arthrodesis based on the three-column theory in the treatment of malunion of Lisfranc injury.Methods:The 28 patients with malunion of Lisfranc injury were analyzed retrospectively who had been treated by selective column arthrodesis at Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine from January 2011 to January 2020.They were 18 males and 10 females, with an average age of 37.2 years(from 18 to 65 years). Twelve left and 16 right sides were affected. According to Myerson's three-column classification, one case was medial column injury (type A), 4 ones middle column injury (type B), 7 ones medial plus middle columns injury and 16 ones three-column injury. Medial column arthrodesis was conducted in 7, middle column arthrodesis in 4 and medial plus middle columns arthrodesis in 17. The American Orthopaedic Foot and Ankle Society (AOFAS) midfoot score and visual analogue scale (VAS) were compared between preoperation and the last follow-up to evaluate the improvements in foot function and pain. The operation-related complications were recorded.Results:All patients were followed up for an average of 35.6 months (from 18 to 60 months). The AOFAS midfoot score increased from 43.1±4.1 at pre-operation to 84.1± 7.4 at the last follow-up and the VAS score decreased from 5.7±1.3 at pre-operation to 2.0±0.9 at the last follow-up (both P<0.001). The wounds healed in 28 patients, 3 of whom had postoperative wound exudation but responded to dressing change. There were no such complications as injury to the deep peroneal nerve or deep venous thrombosis. The internal fixation was removed in 5 patients at about one year after arthrodesis. Conclusion:Selective column arthrodesis based on the three-column theory can result in satisfactory med-term clinical outcomes in the treatment of malunion of Lisfranc injury.

Metformin is currently a strong candidate anti-tumor agent in multiple cancers. However, its anti-tumor effectiveness varies among different cancers or subpopulations, potentially due to tumor heterogeneity. It thus remains unclear which hepatocellular carcinoma (HCC) patient subpopulation(s) can benefit from metformin treatment. Here, through a genome-wide CRISPR-Cas9-based knockout screen, we find that DOCK1 levels determine the anti-tumor effects of metformin and that DOCK1 is a synthetic lethal target of metformin in HCC. Mechanistically, metformin promotes DOCK1 phosphorylation, which activates RAC1 to facilitate cell survival, leading to metformin resistance. The DOCK1-selective inhibitor, TBOPP, potentiates anti-tumor activity by metformin in vitro in liver cancer cell lines and patient-derived HCC organoids, and in vivo in xenografted liver cancer cells and immunocompetent mouse liver cancer models. Notably, metformin improves overall survival of HCC patients with low DOCK1 levels but not among patients with high DOCK1 expression. This study shows that metformin effectiveness depends on DOCK1 levels and that combining metformin with DOCK1 inhibition may provide a promising personalized therapeutic strategy for metformin-resistant HCC patients.
Animals ; Antineoplastic Agents/therapeutic use* ; Carcinoma, Hepatocellular/metabolism* ; Cell Line, Tumor ; Clustered Regularly Interspaced Short Palindromic Repeats ; Genome ; Humans ; Liver Neoplasms/metabolism* ; Metformin/therapeutic use* ; Mice ; Phosphorylation ; Synthetic Lethal Mutations ; Transcription Factors/metabolism* ; rac GTP-Binding Proteins/metabolism*