Background/Aims: Ubiquitination is widely involved in the progression of hepatocellular carcinoma (HCC) by regulating various cellular processes. However, systematic strategies for screening core ubiquitin-related genes, clarifying their functions and mechanisms, and ultimately developing potential therapeutics for patients with HCC are still lacking. Methods: Cox and LASSO regression analyses were performed to construct a ubiquitin-related gene prediction model for HCC. Loss- and gain-of-function studies, transcriptomic and metabolomics analysis were used to explore the function and mechanism of UBE2S on HCC cell glycolysis and growth. Results: Based on 1,423 ubiquitin-related genes, a four-gene signature was successfully constructed to evaluate the prognosis of patients with HCC. UBE2S was identified in this signature with the potential to predict the survival of patients with HCC. E2F2 transcriptionally upregulated UBE2S expression by directly binding to its promoter. UBE2S positively regulated glycolysis in a HIF-1α-dependent manner, thus promoting the proliferation of HCC cells. Mechanistically, UBE2S enhanced K11-linkage polyubiquitination at lysine residues 171 and 196 of VHL independent of E3 ligase, thereby indirectly stabilizing HIF-1α protein levels by mediating the degradation of VHL by the proteasome. In particular, the combination of cephalomannine, a small molecule compound that inhibits the expression of UBE2S, and PX-478, an inhibitor of HIF-1α, significantly improved the anti-tumor efficacy. Conclusions UBE2S is identified as a key biomarker in HCC among the thousands of ubiquitin-related genes and promotes glycolysis by E3 enzyme-independent ubiquitination, thus serving as a therapeutic target for the treatment of HCC.

Objective     To analyze the echocardiographic characteristics of above grade 3+ mitral regurgitation (MR) patients by 3D transesophageal echocardiography (3D-TEE) in transcatheter edge-to-edge repair (TEER) and compare the intervention rate of TEER treatment in patients with different risk stratification. Methods     We retrospectively analyzed the clinical data of 91 patients with above grade 3+ MR in Anzhen Hospital between June 2021 and April 2022. There were 45 males and 46 females aged 66.5±15.9 years. According to pathogenesis, the patients were divided into different anatomical groups and risk stratification groups. There were 34 patients in a simple degenerative group (simple DMR group), 28 patietns in a complex disease group (Complex group), 14 patients in a simple ventricular  functional reflux group (simple VFMR group), 9 patients in a simple atrial functional reflux group (simple AFMR group), and 6 patients in a mixed functional reflux group (mixed FMR group). All patients were examined with a unified standard of transthoracic echocardiography (TTE) and 3D-TEE to compare the characteristic three-dimensional structural changes of the mitral valve in each group. According to the three partition strategy of preoperative anatomical evaluation of TEER, the risk stratification was conducted for the enrolled patients, which was divided into three regions from light to heavy: green area, yellow area, and red area. TEER treatment intervention rate of patients with different risk stratification was calculated. Results     Ant leaf angle and post leaf angle were negative in the simple DMR and Complex groups, and non-planar angle, prolapse height and prolapse volume were higher than those of the other groups (P=0.000). Ant leaf angle and post leaf angle were positive in the VFMR group and the mixed FMR group. Anterior and posterior (AP) diameter of valve ring (P=0.036), tenting height and tenting volume were higher than those of other groups (P=0.000).  AP diameter, tenting height and tenting volume were changed mildly in patients with simple AFMR. MR patients in red and yellow zone achieved a 28.1% TEER intervention rate. Conclusion     Standardized TTE and TEE examinations are crucial for the qualitative and quantitative diagnosis of MR in the echo core-lab. 3D-TEE mitral valve parameter can help determine the exact pathogenesis of MR and to improve the interventional rate of challenging MR patients.

Aortic stenosis (AS) is the most common primary valve lesion requiring surgery or transcatheter intervention in modern era. Its prevalence is rising rapidly as a consequence of the aging population. Transcatheter aortic valve replacement (TAVR) as a therapy option for older high-risk symptomatic severe AS patients has emerged and is currently extending its indications towards surgery intermediate- and low-risk subjects. Considering the common characteristics of frailty and high comorbidity among AS patients, cardiac rehabilitation (CR) has been proven to improve not only survival but also quality of life in previous reports. CR as a classⅠ recommendation in guidelines for the prevention and treatment of cardiovascular disease has been widely used in clinical practice. The purpose of this article is to sort out the current CR programs for TAVR patients in global medical management, and explore the CR optimization program fit for China medical model in post COVID-19 pandemic era.

Objective: To investigate the early intervention effects of metoprolol on connexin 43(Cx43) and phosphorylated Cx43 (p-Cx43) expression in rabbits with post myocardial infarction. Methods: A total of 24 adult male New Zealand white rabbits were divided into sham group (n=6), early treatment group(n=6), routine treatment group(n=6), and myocardial infarction group(n=6) with a randomized block design blocked by weight. Myocardial infarction was induced by left anterior descending coronary artery (LAD) ligation. Rabbits in sham group received similar surgical procedure without LAD ligation. Metoprolol (12.5 mg/kg dissolved in 2 ml distilled water) was applied to rabbits in early treatment group and routine treatment group per gavage immediately after recovery from anesthesia and at 24 hours after myocardial infarction, respectively, then treated daily for 40 days. Rabbits in sham group and myocardial infarction group received 2 ml distilled water per gavage daily for 40 days. Plasma lactate dehydrogenase (LDH) and creatine kinase (CK) level were detected by automatic biochemistry analyzer after 6 hours in all rabbits. Ventricular fibrillation threshold (VFT) was measured in vivo by bipolar pacing electrodes at 40 days. Cx43 and p-Cx43 distribution in ventricular tissue was detected by immunofluorescence analyses. Cx43 and p-Cx43 protein level in ventricular tissue was determined by Western blot. Results: (1) Plasma LDH ((851.7±85.9)U/L vs. (332.3±39.6)U/L, P<0.01) and CK ((1 192.7±105.3)U/L vs. (462.3±65.6)U/L, P<0.01) were significantly higher in myocardial infarction group than in sham group (both P<0.01). (2) VFT was significantly lower in myocardial infarction group than that in sham group ((470.0±91.0) beats per minute vs. (683.3±60.9) beats per minute, P<0.05), and VFT was significantly higher in early treatment group ((633.3±43.2) beats per minute) and routine treatment group ((645.0±30.8) beats per minute) than in the myocardial infarction group (both P<0.05). (3) Immunofluorescence analyses showed that Cx43 was mainly localized in the intercalated disk, which was perpendicular to the cell long axis with linear arrangement, and less lateral distribution in sham group, early treatment group and routine treatment group, which was significantly different as the case in the myocardial infarction group. The expression of p-Cx43 in myocardial infarction group was less than in sham group, which was significantly upregulated in in early treatment group and routine treatment group when compared with myocardial infarction group, and expression of p-Cx43 was significantly higher in early treatment group than in routine treatment group. (4)The p-Cx43/Cx43 ratio of protein was significantly lower in myocardial infarction group than in sham group (0.165±0.011 vs. 0.363±0.046, P<0.05), and significantly higher in early treatment group (0.720±0.063) and routine treatment group (0.364±0.030) than in myocardial infarction group (both P<0.05), and this ratio was significantly higher in early treatment group than in routine treatment group (P<0.05). Conclusion Metoprolol treatment, especially the early metoprolol treatment (within 24 hours after LAD ligation), could significantly improve VFT by ameliorating the distribution and dephosphorylation of myocardial Cx43 in rabbits with experimental myocardial infarction.

Objective: To assess the efficacy and safety of thrombolytic treatment with reteplase in patients with intermediate-risk acute pulmonary embolism. Methods: Ten consecutive patients with intermediate-risk acute pulmonary embolism who received thrombolytic treatment with reteplase at Thrombosis and Vascular Medicine Center, Fuwai Hospital from March to November in 2016 were included.Vital signs, right ventricular diameter, systolic pulmonary artery pressure, and biochemical markers were assessed before and after thrombolytic therapy with reteplase, and bleeding complications were also observed during 3 months follow up. Results: (1) For the efficacy outcomes: at 48 hours after thrombolytic treatment with reteplase, echocardiography-derived diameter of right ventricular was significant reduced from (27.9±3.8) mm to (24.8±2.6) mm (P=0.03), systolic pulmonary artery pressure decreased from (63.9±21.6) mmHg(1 mmHg=0.133 kPa) to (34.4±19.8) mmHg (P=0.02). Heart rate and breathing rate were also decreased significantly (both P<0.05), blood pressure remained unchanged post therapy.Hypoxemia was quickly corrected with an significant elevation of PaO₂ and SaO₂ ((65.2±14.3) mmHg vs. (80.0±9.6) mmHg, P=0.006; (90.8±3.5)% vs. (95.2 ±1.6)%, P=0.002 respectively). PaCO₂ was also increased significantly (P<0.05). Serum NT-proBNP and cTnI were decreased significantly (both P<0.05). There was no recurrent pulmonary embolism or deep-vein thrombosis during the 3 months follow-up. (2) For the safety outcomes: a thrombolytic relevant hemoptysis (about 70 ml) occurred in 1 patient, and was controlled by PCC therapy.No other clinically relevant events were observed during thrombolytic treatment. Eight patients were followed more than 3 months, there was no major bleeding complication or death during the follow up period. Conclusion Treatment of intermediate-risk acute pulmonary embolism with reteplase is effective and safe and there are no obvious side effects.

Cyclophilin A (CypA) is found to be highly expressed in different kinds of tumor cells,which could regulate the occurrence and development of many kinds of tumor through multiple signal transduction pathways such as inducing the formation of inflammatory carcinoma,accelerating the transcription cycle of tumor cells,promoting the invasion and metastasis of tumor cells,inhibiting the apoptosis of tumor cells and reducing the sensitivity of tumor cells to chemotherapy drugs.It suggests that CypA might be considered as a kind of oncogene,which is expected to be a novel target for tumor treatment.

Objective To assess the cardiopulmonary exercise testing (CPET) derived performance of oxygen uptake and ventilation efficiency parameters,including oxygen uptake efficiency plateau (OUEP),oxygen uptake efficiency slope (OUES),(V)E/(V)CO2 slope and lowest (V)E/(V)CO2,in patients with end-stage chronic heart failure(CHF) and evaluate their clinical value on monitoring cardiac function and hemodynamic status.Methods A total of 26 end-stage CHF patients considered for heart transplantation were enrolled in this study.CPET,echocardiography and invasive hemodynamic examinations with Swan-Ganz flowing balloon catheter were performed.Correlation analysis was made between oxygen uptake and ventilation efficiency parameters from CPET and echocardiographic and hemodynamic parameters.Results OUEP and OUES showed good correlation with peak oxygen consumption (peak (V)O2) (r =0.535,P ＜ 0.01 ; r =0.840,P ＜ 0.001).In end-stage CHF patients,the slope of OUEP with respect to peak (V)O2 is about 32,but the slope of OUES with respect to peak (V)O2 is only about 2.The difference was 16 times.The change of OUEP was more sensitive and significant than those of OUES and peak (V)O2 (P ＜ 0.05).OUEP,peak (V)O2 (％ pred),(V)E/(V)CO2 slope and lowest (V)E/(V)CO2 were all correlated well with non-invasive hemodynamic parameters peak cardiac output (r=0.535,P＜0.01; r=0.652,P＜0.001; r=-0.640,P＜0.001 ; r=-0.606,P=0.001 respectively) and peak cardiac index (r =0.556,P＜0.01;r =0.772,P ＜0.001; r =-0.641,P ＜ 0.001 ; r =-0.620,P ＜ 0.001 respectively) derived from CPET,but not correlated with invasive hemodynamic parameters cardiac output and cardiac index at rest (P ＞0.05).Both peak (V)O2 (％ pred) and (V)E/(V)CO2 slope were significantly correlated with invasive hemodynamic parameters systolic pulmonary arterial pressure (r =-0.424,P ＜ 0.05 ; r =0.509,P ＜ 0.01) and mean pulmonary arterial pressure (r=-0.479,P＜0.05; r=0.405,P＜0.05).Peak (V)O2(％pred)was also significantly correlated with pulmonary capillary wedge pressure (r =-0.415,P ＜ 0.05),and (V)E/(V)CO2 slope was significantly correlated with pulmonary vascular resistance (r =0.429,P ＜ 0.05).Conclusions The oxygen uptake and ventilation efficiency parameters derived from CPET,including peak (V)O2,OUEP,lowest (V)E/(V)CO2 and (V)E/(V)CO2 slope etc,are objectively monitoring and evaluating cardiac function and hemodynamic status.And they are useful for optimizing clinical management of patients with end-stage CHF.

Objective To assess peak oxygen consumption (peak (V)O2) derived from cardiopulmonary exercise testing (CPET),concentrations of NT-proBNP and echocardiographic changes in patients with chronic heart failure (CHF) and reduced left ventricular ejection fraction (LVEF,＜ 40％).Methods Seventy patients were included and divided into two groups according to the New York Heart Association (NYHA) classification:NYHA Ⅱ group (17 cases) and NYHA Ⅲ-Ⅳ group (53 cases).The basic clinical information,plasma concentration of NT-proBNP at rest,echocardiographic parameters and peak (V)O2 from CPET were compared between two groups.Correlation among peak (V)O2,NT-proBNP and echocardiographic parameters in this patient cohort was assessed and their abilities to discriminate the NYHA Ⅲ-Ⅳ grade were analyzed through c-Statistic.Results Left atrial diameter ((51.3 ±7.2) mm vs.(44.0 ±7.4) mm,P ＜0.001) was larger,plasma concentration of NT-proBNP (1 379-4 399 pmol/L vs.1 109-2 356 pmol/L,P ＜ 0.01) was higher and peak (V)O2 ((13.4 ± 3.5) ml · kg-1 · min 1 vs.(18.2 ± 3.7) ml · kg-1 · min-1,P ＜ 0.001) were significantly lower in NYHA Ⅲ-Ⅳ group than those in NYHA Ⅱ group.However,left ventricular end-diastolic diameter (LVEDD) and LVEF were similar between two groups.Peak (V)O2 correlated significantly with NT-proBNP (r =-0.311,P ＜ 0.01),but neither peak (V)O2 nor NT-proBNP correlated with echocardiographic parameters (LA,LVEDD and LVEF).ROC analysis showed that peak (V)O2 had the strongest discriminatory power for detecting NYHA Ⅲ-Ⅳ grade patients (AUC =0.835,P ＜0.001),followed by the NT-proBNP (AUC =0.723,P ＜0.01).Conclusion Peak (V)O2 is a more sensitive parameter to detect the disease aggravation (NYHA Ⅲ-Ⅳ grade) of the CHF patients with reduced LVEF compared to plasma NT-proBNP and echocardiographic parameters (LA,LVEDD,LVEF).

Objective: To explore influence of long-term oral valsartan-angiotensin II type 1 receptor blocker on ventricular arrhythmia after myocardial infarction (MI) in rabbits and its possible mechanism. Methods: A total of 24 New Zealand rabbits were randomly divided into sham operation group (n=8), MI group (n=8) and valsartan group (n=8) according to number table. Sham operation group only received thoracotomy without ligation of anterior descending branch of left coronary artery (LAD), while MI group and valsartan group received ligation of anterior descending branch of LAD. Valsartan group received valsartan gavage (10 mg•kg-1•d-1) since the second day after operation, three groups all were fed for 12 weeks. Mono active potential (MAP) of left ventricular myocardial cells of subendocardial myocardium（inner layer myocardium）, subepicardial myocardium（outer layer myocardium）and middle layer myocardium were recorded before MI and 12 weeks after MI, and times of provocative malignant arrhythmias were recorded on 12 weeks after MI in three groups. Results: 1. Ventricular tachycardia or fibrillation (VT/ VF) episodes were markedly decreased in VAL group than that in MI group on 12 weeks after MI [(3.1±0.8) vs. (12.7±1.5), P＜0.05]; 2. After MI 12 w, the action potential duration to 90% repolarization (APD90) of three-layer ventricular myocytes in MI group was prolonged than that before MI [（259.2±22.1）ms,（288.0±25.8）ms,（244.6±22.6）ms vs.（230.1±23.2）ms,（244.2±23.4）ms,（229.0±21.7）ms, P＜0.05 or＜0.01]；but there were no significant difference in APD90 of three layers ventricular myocytes between before and after MI in valsartan group (P>0.05 all); Compared with sham operation group and valsartan group, there was significant prolonged in transmural dispersion of repolarization (TDR) [(18.8±6.2) vs. (23.9±7.7) vs. (37.2±10.2), P<0.05 or＜0.01] in MI group; There was no significant difference in TDR between valsartan group and sham operation group (P>0.05). Conclusions: Long-term oral valsartan can significantly reduce malignant ventricular arrhythmia incidence in rabbits after MI, which may be related to improving TDR in rabbits after MI.

Before 131I-HAb18F(ab')2 administration, 24 cases of mid-term or advanced hepatocellular carcinoma(HCC) were given Lugol's Liquid to block the thyroid gland, and submitted to hepatic colloid imaging. The cases were randomly divided into 3 groups. Then 131I-HAb18F(ab')2 was injected into the target hepatic artery with doses of 0.5, 0.75, 1.0 mCi/kg, respectively. At the followed 10, 48, 96 and 192 hours, 131I-HAb18F(ab')2 distribution in human body was acquired by whole body dynamic image with Single photon emission computed tomography(SPECT). The results showsed that 131I-HAb18F(ab')2 in tumor tissue was significantly higher than that in normal liver tissue and other organs. This difference became obvious as time passed. 131I-HAb18F(ab')2 is stable in human body and it can combine with HCC tissue specifically. So it is a new medicine deserving further research for the treatment of HCC.
Adult ; Aged ; Antibodies, Monoclonal ; administration & dosage ; pharmacokinetics ; Carcinoma, Hepatocellular ; radiotherapy ; Female ; Humans ; Immunoglobulin Fab Fragments ; administration & dosage ; metabolism ; Iodine Radioisotopes ; administration & dosage ; pharmacokinetics ; Liver Neoplasms ; radiotherapy ; Male ; Middle Aged ; Radioimmunotherapy ; Radiopharmaceuticals ; administration & dosage ; pharmacokinetics ; Tissue Distribution