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Since the utilization of anthracyclines in cancer therapy, severe cardiotoxicity has become a major obstacle. The major challenge in treating cancer patients with anthracyclines is minimizing cardiotoxicity without compromising antitumor efficacy. Herein, histone deacetylase SIRT6 expression was reduced in plasma of patients treated with anthracyclines-based chemotherapy regimens. Furthermore, overexpression of SIRT6 alleviated doxorubicin-induced cytotoxicity in cardiomyocytes, and potentiated cytotoxicity of doxorubicin in multiple cancer cell lines. Moreover, SIRT6 overexpression ameliorated doxorubicin-induced cardiotoxicity and potentiated antitumor efficacy of doxorubicin in mice, suggesting that SIRT6 overexpression could be an adjunctive therapeutic strategy during doxorubicin treatment. Mechanistically, doxorubicin-impaired mitochondria led to decreased mitochondrial respiration and ATP production. And SIRT6 enhanced mitochondrial biogenesis and mitophagy by deacetylating and inhibiting Sgk1. Thus, SIRT6 overexpression coordinated metabolic remodeling from glycolysis to mitochondrial respiration during doxorubicin treatment, which was more conducive to cardiomyocyte metabolism, thus protecting cardiomyocytes but not cancer cells against doxorubicin-induced energy deficiency. In addition, ellagic acid, a natural compound that activates SIRT6, alleviated doxorubicin-induced cardiotoxicity and enhanced doxorubicin-mediated tumor regression in tumor-bearing mice. These findings provide a preclinical rationale for preventing cardiotoxicity by activating SIRT6 in cancer patients undergoing chemotherapy, but also advancing the understanding of the crucial role of SIRT6 in mitochondrial homeostasis.
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Objective@#To evaluate the early and long-term outcomes cardiac surgery of patients with Ebstein anomaly.@*Methods@#The clinic data of 237 patients with Ebstein anomaly received surgical procedures from March 2004 to December 2017 at Department of Cardiac Surgery, First Hospital of Tsinghua University was analyzed retrospectively. There were 105 male and 132 female patients with age of (19.4±16.7) years (ranging from 3 months to 64 years). The surgical procedures include anatomical repair in 188 patients, one and a half ventricle repair in 37 patients, tricuspid valve repair in 4 patients, tricuspid valve replacement in 10 patients, and Fontan procedure in 3 patients (total cavopulmonary connection in 2 patients; Glenn procedure in 1 patient).@*Results@#The early mortality was 2.1% (n=5). One case of atrioventricular (0.4%) newly occurred. There were 228 patients available to follow-up. The range of follow-up duration was 3 to 168 months. Late survival was 99.1% (2 cases of late death) at 10 years. Three patients received reoperation (1.3%), including tricuspid valve repair of 1 patient and one and a half ventricle repair of 2 patients). Indication of tricuspid valve regurgitation improved from 3.6±0.3 to 1.5±0.4. Survival rate at 5 and 10 years was 98.6% and 98.2%, respectively.@*Conclusions@#The principle of the techniques is to reconstruct the tricuspid valve and right ventricle anatomically. For most cases, the anatomical repair was demonstrated with low mortality, less complications and excellent durability at long-term follow-up. If the tricuspid valve is severely hypoplastic, one and a half ventricle repair and valve replacement may be alternatie.
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Objective To prospectively evaluate the mid-term results of mitral annuloplasty using autologous pericardium for mitral valve insufficiency.Methods From April 2004 to December 2011,48 patients underwent mitral annuloplasty using autologous pericardium,the average length of pericardial strips was (51.9 ±2.8)cm.Carpentier classification was class Ⅰ in 5 cases,class Ⅱ in 41 cases,and class Ⅲ in 2 cases.The mitral valve repair techniques included quadrangular resection in 30 cases,valve repair in 7 cases,chordae transposition in 4 cases,edge to edge technique in 2cases,and artificial chordae tendineae in 3 cases.Concomitant procedures included one case arotic valve replacement,11 cases tricuspid valve repair,9 cases coronary artery bypass grafting,1 case coronary artery muscle bridge resection,and 1 case permanent pacemaker implant.Datum on long-term outcomes were obtained by questionnaires and by phone interview [average follow-up time (62.2 ± 21.3) months].Results Compared with preoperative datum,the diameters of left ventricular end diastolic diameter (LVDD) and left atrial diameter (LAD) examined by echocardiography show significant reduction in postoperative [(58.6 ± 1.7) mm vs (45.1 ± 1.3) ram,t =12.85,P ＜0.01 ; (50.6 ± 1.6)mm vs (38.0 ± 1.4)ram,t =9.58,P ＜0.01].There was early postoperative death in one case,cerebral infarction in one case,but none of patients died in late postoperative period.One patient had moderate mitral valve regurgitation in long-term follow-up.None of patients had redo operation and hemolytic complications.Conclusions Mitral annuloplasty using an autologous pericardium was an acceptable technique with low anticoagulation complications,permanent,well left ventricular function maintenance,and an economic method.
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Objective To investigate the effect of PDGF-A on cardiac allograft vasculopathy and myocardial fibrosis in rats.Methods By using inbred Wistar rats as donors,and Sprague Dawley (SD)rats as recipients,heterotopic heart transplantation model was established,Four groups,each having 8 animals,were used.In normal heart group,Wistar rat hearts as blank control;In no rejection group,inbred Wistar rats as donors and recipients without immunosuppressive drugs,and grafts were removed on the day 60;In acute rejection group and chronic rejection group,Wistar rats as donors,SD rats as recipients,and the grafts were harvested on the day 5 without immunosuppresslve drugs in acute rejection group;In chronic rejectlon group,the graits were Immunohistochemistry was used for macrophages(CD68 positive cells)and reverse transcriptionpolymerase chain reaction(RT-PCR)assay for expression of PDGF-A mRNA in cardiac allografts.Results Macrophage infiltration was not found in normal heart group and no rejection group.In acute rejection group and chronic rejection group,macrophage infiltration was found around coronary vessels and in myocardial interstitium,especially in myocardial fibrosis area in chronic rejection allografts.The relative content of PDGF-A mRNA in normal heart group,no rejection group,acute rejection group,and chronic rejection group was 0.26±0.06,0.31±0.04,0.88±0.12,0.94±0.11respectively.PDGF-A mRNA was increased in chronic rejection group and acute rejection group significantly as compared with that in normal heart group and no rejection group(P＜0.01).Conclusion Macrophage infiltration and expression of PDGF-A are associated with cardiac allograft vasculopathy and myocardial fibrosis.
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Objective To investigate the mechanism of albtrans retinoic acid (atRA)attenuating cardiac allograft vasculopathy and myocardial fibrosis. Methods With inbred Wistar rats as donors and Sprague Dawley (SD) rats as recipients, heterotopic heart transplantation model was rejection group received same doses of cyclosporine A for 60 days. Grafts were removed on the day 60 post-transplant. Paraffin-embedded sections of cardiac allograft were stained with Masson's trichrome and Van Gieson for examination of myocardial fibrosis and vascular stenosis. Immunohistochemistry was performed to observe CD68 positive cell infiltration. Platelet-derived growth factor-A (PDGF-A)mRNA was detected by using reverse transcription-polymerase chain reaction (RT-PCR). Results The index of fibrosis in chronic rejection group and atRA-treated group was 64. 0 ± 11.9 and 34. 7 ±6. 3 respectively with the significant difference (P<0. 01). Chronic rejection all,grafts showed severe vessel disease. The luminal occlusion index of coronary arteries in chronic rejection group was 62. 9 4± 17. 2, and 40. 1± 8. 2 in atRA-treated group with significant difference (P<0. 01). CD68-positive cell count in atRA-treated group and chronic rejection group was 17. 6 4± 4. 2 and 32. 1 ± 9. 3 with significant difference (P<0. 01). The relative expression levels of PDGF-A mRNA in atRA-treated group and chronic rejection group were 0. 46 ± 0. 08 and 0. 94 4±0. 11 respectively with significant difference (P<0. 01). Conclusion AtRA attenuates cardiac all,graft vasculopathy and myocardial fibrosis. The effects might be induced by inhibition of CD68 positive cell infiltration and PDGF-A mRNA expression.
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OBJECTIVE@#To explore the effect of vascular smooth muscle alpha-actin(VSMA-alpha) on cardiac allograft vasculopathy and fibrosis.@*METHODS@#After heterotopic cardiac transplantation model was established, the rats were divided into an acute rejection group, a chronic rejection group, an isograft group, and a normal group. Van Gieson staining and Massonos trichrome staining were used to observe the cardiac allograft vasculopathy and fibrosis respectively, and immunohistochemical stainings were used to examine VSM-alpha expression.@*RESULTS@#The fibrosis score of the normal group, the isograft group, the acute rejection group and the chronic rejection group were 0.00+/-0.00, 0.63+/-0.52, 1.75+/-0.71, and 2.75+/-0.46, respectively. The fibrosis score of the chronic rejection group increased significantly as compared with that of the normal group and the isograft group (both P<0.01), the indexes of coronary arteries stenosis were 0.08+/-0.02, 0.09+/-0.04, 0.12+/-0.05, and 62.86+/-17.18, respectively. The stenosis index in the chronic rejection group increased significantly as compared with that of all the other groups (P<0.01).VSMA-alpha was abundant in the allograft myocardium in the chronic rejection group.@*CONCLUSION@#Reactivation of fetal structural genes of vascular smooth muscle alpha-actin and its ectopic expression is associated with the cardiac allograft vasculopathy and fibrosis.
Subject(s)
Animals , Male , Rats , Actins , Fibrosis , Metabolism , Graft Rejection , Metabolism , Pathology , Heart Transplantation , Muscle, Smooth, Vascular , Metabolism , Myocardium , Metabolism , Pathology , Random Allocation , Rats, Sprague-Dawley , Rats, WistarABSTRACT
Objective To investigate the relationship between apoptcsis, expressions of VEGF and clinicopathological characteris- tics, and prognosis in esophageal squamous cell carcinoma (ESCC). Methods Sixty-one surgical specimens of primary esophageal squa- mous cell carcinomas were examined for VEGF by immunohistochemical staining (S-P). Apoptcsis was determined by TUNEL (TdT media- ting dUTP-biotin nick end-labeling) method. Clinicopathologic features were examined by histopathology. The prognostic impacts of these pa- rameters were analyzed by univariate and survival analysis. Results AI and VEGF were well correlated with differentiation, TNM stage. Lower tumor differentiation and higher TNM stage were related to decreasing AI and VEGF. In addition, VEGF in the groups of invasion be- yond muscularis and lymph node metastasis is significant higher than that in invasion reaching muacularis and no lymph node metastasis (P <0.01). But there were no significant correlation between AI and invasion( P>0.05). The simple-factor analysis results showed that the decrease of AI, VEGF, lymph node metastases, lower tumor differentiation, and invasion reaching muscularis were related to decrease of sur- vival rate. However, multivariate Cox analysis demonstrated that only AI and VEGF were the significant prognostic factors. Conclusions Apoptosis and angiagenesis participate in ESCC and promote its growth. VEGF is related to angiogenesis of ESCC. The increase of VEGF may promote invasion and lymph node metastasis. AI and VEGF are significant prognostic factors in ESCC.
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Objective To investigate the expression and significance of intercellular adhesion molecule-1 (ICAM-1) in graft reperfusion injury after cardiac transplantation in rats. Methods Twenty-four Wistar rats heterotopic cardiac transplantation models were randomly divided into control group (n=6) and experimental group (n=18). In control group, the ischemic period of the grafts was 60min without reperfusion. In experimental group, the grafts were respectively reperfused for 3h, 6h and 24h after 60min ischemic period. Immunohistochemical and biochemical techniques were used to detect myocardial ICAM-1 and myeloperoxidase (MPO). Results The expression of allograft ICAM-1 after reperfusion in experimental group was significantly higher than that in control group (P
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Objective To evaluate the effect of esophagogastric intramural implantation anastomosis after esophagectomy. Methods One thousand and two hundred thirty-six patients with esophageal and cardial cancers were treated by esophagogastric intramural implantation anastomosis after esophagectomy. The mucosal layer, the esophageal and gastric muscular layers were on three different levels after the anastomosis. Results Among 1236 patients, 842 cases were esophageal cancer,and 394 cases were cardial cancer.The anastomoses were performed in different levels including 15 cases below the pharynx, 193 cases on neck,634 case above the aortic arch and 394 cases below the aortic arch. One of the patients died 24 hours after the operation due to myocardial ischemia, and two of them died of respiratory failure. Anastomotic leakage, stenosis and refluxing esophagitis did not appear in this series. Conclusions Esophagogastric intramural implantation anastomosis can decrease the incidence of anastomotic leakage, stenosis and refluxing esophagitis after esophagectomy.