Hypoxic-stabilized EPAS1 proteins transactivate DNMT1 and cause promoter hypermethylation and transcription inhibition of EPAS1 in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality globally. Although cigarette smoking is by far the most important risk factor for lung cancer, the aberrant expression of oncogenes and tumor suppressor genes contributes a great deal to tumorigenesis. Here, we reveal that aberrant expression of endothelial PAS domain-containing protein 1 ( EPAS1) gene, which encodes hypoxia inducible factor 2α, has a critical role in NSCLC. Our results showed EPAS1 mRNA was down-regulated in 82.5% of NSCLC tissues, and a new region of EPAS1 promoter was found to be highly methylated in lung cancer cell lines and NSCLC tissues. Moreover, the methylation rates were negatively correlated to EPAS1 mRNA expression in lung tissues. Further, demethylation analysis demonstrated EPAS1 was regulated by DNA methyltransferases (DNMTs) in NSCLC. In contrast, DNMT1 was verified as an EPAS1 target gene by chromatin immunoprecipitation assay and could be transactivated by stabilized EPAS1 proteins in hypoxic lung cells, thereby decreasing EPAS1 mRNA expression by methylation regulation. Collectively, our study suggests there might be a mechanism of negative-feedback regulation for EPAS1 in NSCLC. That is, hypoxic-stabilized EPAS1 proteins transactivated DNMT1, which further promoted the hypermethylation of EPAS1 promoter and decreased EPAS1 mRNA expression levels in NSCLC.-Xu, X.-H., Bao, Y., Wang, X., Yan, F., Guo, S., Ma, Y., Xu, D., Jin, L., Xu, J., Wang, J. Hypoxic-stabilized EPAS1 proteins transactivate DNMT1 and cause promoter hypermethylation and transcription inhibition of EPAS1 in non-small cell lung cancer.

YKL-40 is highly expressed in the epicardial adipose tissue of patients with atrial fibrillation and associated with atrial fibrosis.

BACKGROUND: YKL-40 (CHI3L1) is a novel biomarker for inflammation, tissue remodeling, and fibrosis, as well as cardiovascular diseases. We investigated the association between YKL-40 expression in epicardial adipose tissue (EAT) and atrial fibrosis in patients with atrial fibrillation (AF). METHODS: Blood samples, subcutaneous adipose tissue (SAT), paracardial adipose tissue (PAT), EAT, and adjacent atrial myocardium were acquired from patients receiving coronary artery bypass grafts. The patients were divided into the AF group (n = 28) and the sinus rhythm (SR) group (n = 36). RESULTS: We did not detect a significant difference in the serum YKL-40 levels in the SR and AF groups (P = 0.145). Quantitative real-time PCR showed that YKL-40 (CHI3L1) mRNA levels in the EAT were significantly higher than in the SAT or PAT of AF patients, or the EAT of SR patients (All P < 0.001). We found similar results for YKL-40 protein levels by immunohistochemistry. Masson staining showed significantly more fibrosis in AF patients than in SR patients (P < 0.001). Western blotting indicated that AF patients had significantly higher expression of collagen I (P = 0.039). We found a linear relationship between YKL-40 mRNA expression and the collagen volume fraction of the atrial myocardium (y = 3.576x + 26.205, P < 0.001). Multivariate linear regression analysis revealed that body mass index is an independent risk factor for YKL-40 expression in EAT (ß = 0.328, P = 0.011). CONCLUSIONS: YKL-40, which is highly expressed in the EAT of patients with AF, is affected by body mass index and associated with atrial fibrosis, which may contribute to the development of AF.

DACH1 inhibits the proliferation and invasion of lung adenocarcinoma through the downregulation of peroxiredoxin 3.

In this study, we found the expression of Dachshund 1 (DACH1) is downregulated while peroxiredoxin 3 (PRX3) upregulated in both lung adenocarcinoma tissues and cells. Transfection of DACH1 can significantly downregulate PRX3 expression in targeting lung adenocarcinoma cells. Further experimental results demonstrated the evidence that overexpression of DACH1 resulted in significant retardation of in vitro proliferation and invasion of lung adenocarcinoma cells. Direct upregulation of PRX3 by co-transfection of PRX3 messenger RNA (mRNA) can prevent the above alteration caused by DACH1 transfection. Besides, lower DACH1 expression significantly correlated with tumor diameter and tumor invasion in all the 36 patients diagnosed with lung adenocarcinoma in our hospital during the past months. In conclusion, DACH1 can inhibit the proliferation and invasion of lung adenocarcinoma through the downregulation of PRX3. Decreased expression of DACH1 is involved in the initiation and development of lung cancer, which might be an adverse prognostic factor of lung adenocarcinoma.

Pulmonary expression of CYP2A13 and ABCB1 is regulated by FOXA2, and their genetic interaction is associated with lung cancer.

Inhaled xenobiotics such as tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone are mainly metabolized by phase I oxidase cytochrome P450, family 2, subfamily A, polypeptide 13 (CYP2A13), phase II conjugate UDP glucuronosyltransferase 2 family, polypeptide B17 (UGT2B17), and phase III transporter ATP-binding cassette, subfamily B (MDR/TAP), member 1 (ABCB1), with genetic polymorphisms implicated in lung cancer. Their genetic interaction and pulmonary expression regulation are largely unknown. We analyzed joint association for CYP2A13 and ABCB1 polymorphisms in 2 independent lung cancer case populations (669 and 566 patients) and 1 common control population (749 subjects), and characterized the trans-acting function of the lung development-related transcription factor forkhead box A2 (FOXA2). We undertook FOXA2 overexpression and down-regulation in lung epithelial cell lines, analyzed functional impact on the transactivation of CYP2A13, UGT2B17, and ABCB1, and measured correlation for their expressions in lung tissues. We found a substantial reduction in cancer risk (OR 0.39; 95% CI 0.25-0.61; Pinteraction = 0.029) associated with combined genotypes for CYP2A13 R257C and a functionary regulatory variant in the cis element of ABCB1 synergistically targeted by GATA binding protein 6 and FOXA2. Genetic manipulation of FOXA2 consistently influenced its binding to and transactivation of the promoters of CYP2A13, UGT2B17, and ABCB1, whose mRNA and protein expressions were all consistently correlated with those of FOXA2 in both tumorous and normal lung tissues. We therefore establish FOXA2 as a core transcriptional modulator for pulmonary xenobiotic metabolic pathways and uncover an etiologically relevant interaction between CYP2A13 and ABCB1, furthering our understanding of expression and function of the xenobiotic metabolism system.

Effects of MIAVS on Early Postoperative ELWI and Respiratory Mechanics.

BACKGROUND: The effects of minimally invasive aortic valve surgery (MIAVS) on the early postoperative extravascular lung water index (ELWI) and respiratory mechanics have rarely been studied. MATERIAL/METHODS: A total of 90 patients were divided into 3 groups: a conventional full sternotomy (CS) group (n=30), an upper ministernotomy (US) group (n=30), and a right anterior thoracotomy (RT) group (n=30). Hemodynamic and respiratory mechanics parameters were recorded at perioperative time points, including before skin incision (T(-1)); at sternum closing (T0); and 4 h (T4), 8 h (T8), 12 h (T12), and 24 h (T24) after the operation. The ventilator support time, ICU length of stay, and postoperative hospitalization time, as well as the thoracic drainage volume and blood transfusion volume, were recorded. RESULTS: The ELWI and pulmonary vascular permeability index (PVPI) increased at T4, and the values were significantly lower in the US group than in the RT group and CS group (P<0.05). At T8, the ELWI and PVPI in the US group and RT group were significantly lower than in the CS group. At T12, there were no significant differences among the 3 groups. In addition, at T4 static lung compliance decreased, plateau airway pressure increased, and airway resistance changed non-significantly. There were no significant differences between the US group and the RT group, but both groups showed better results than the CS group did. CONCLUSIONS: The ELWI and PVPI may transiently increase after aortic valve surgery with cardiopulmonary bypass. Compared with the 12 h required to recover from a conventional sternotomy operation, it may only take 8 h to recover from MIAVS.

An Adjusted Calculation Model of Reduced Heparin Doses in Cardiopulmonary Bypass Surgery in a Chinese Population.

OBJECTIVE: To investigate the safety and efficacy of an adjusted regimen of heparin infusion in cardiopulmonary bypass (CPB) surgery in a Chinese population. DESIGN: Prospective, single-center, observational study. SETTING: University teaching hospital. PARTICIPANTS: Patients having cardiac surgery with CPB were selected for this study using the following criteria: 18 to 75 years of age, undergoing first-time cardiac surgery with conventional median sternotomy, aortic clamping time between 40 and 120 minutes, and preoperative routine blood tests showing normal liver, renal, and coagulation functions. The exclusion criteria include salvage cases, a history of coagulopathy in the family, and long-term use of anticoagulation or antiplatelet drugs. INTERVENTIONS: Sixty patients were divided randomly into a control group (n = 30) receiving a traditional heparin regimen and an experimental group (n = 30) receiving an adjusted regimen. MEASUREMENTS AND MAIN RESULTS: Activated coagulation time (ACT) was monitored at different time points, ACT>480 seconds was set as the safety threshold of CPB. Heparin doses (initial dose, added dose, and total dose), protamine doses (initial dose, added dose, and total dose), CPB time, aortic clamping time, assisted circulation time, sternal closure time, blood transfusion volume, and drainage volume 24 hours after surgery were recorded. There was no significant difference in achieving target ACT after the initial dose of heparin between the 2 groups; CPB time, aortic clamping time, assisted circulation time, postoperative complication rate, and drainage volume between the 2 groups were not significantly different (p>0.05). However, initial and total dosage of heparin, initial and total dosage of protamine, sternal closure time, and intraoperative blood transfusion volume in the experimental group were significantly lower (p< 0.05). CONCLUSIONS: Adjusted regimen of heparin infusion could be used safely and effectively in Chinese CPB patients, which might reduce the initial and total dosage of heparin and protamine as well as sternal closure time and intraoperative blood transfusion volume.

Hydrogen Sulfide Attenuates Myocardial Hypoxia-Reoxygenation Injury by Inhibiting Autophagy via mTOR Activation.

BACKGROUND: Autophagy plays a significant role in myocardial ischemia reperfusion (IR) injury. Hydrogen sulfide (H2S) has been demonstrated to protect cardiomyocytes against IR injury, while whether it has anti-autophagy effect has not been known. The aim of this study was to investigate whether H2S regulates autophagy during IR injury and its possible mechanism. METHODS AND RESULTS: The cardiomyocytes of neonatal rats were randomized into Con, hypoxia-reoxygenation (HR) and H2S protection groups. The severity of cell injury was evaluated by cell vitality (MTT) and lactate dehydrogenase (LDH) release assays, and autophagy level was evaluated by flow cytometry and the assessment of autophagy-related gene (Atg) expression, such as that of Beclin1 and LC3-II. In response to H2S, Beclin1 and LC3-II protein were found to be down-regulated and p-mTOR protein was found to be up-regulated, together with an increase in cell vitality and a decrease in LDH. Furthermore, to find out whether mTOR was involved in the protective effect of H2S, rapamycin, inhibiter of mTOR, was used with or without applying NaHS and HR. It was found that rapamycin attenuated the myocardiocyte protective effect of H2S. To demonstrate the effect of autophagy during HR injury, the cardiomyocytes were pre-treated with 3-MA, which is an autophagy inhibitor, cell injury was attenuated by 3-MA. CONCLUSIONS: H2S plays a myocardial protective role against IR injury by regulating autophagy via mTOR activation.

Hypermethylation reduces expression of tumor-suppressor PLZF and regulates proliferation and apoptosis in non-small-cell lung cancers.

Deregulation of promyelocytic leukemia zinc finger protein (PLZF), a tumor suppressor gene, was reported in different types of solid tumors. This study for the first time explored the reduced expression of PLZF and its effects in non-small-cell lung cancer (NSCLC) carcinogenesis. PLZF was found to be down-regulated by 62.8% in 87.1% of 154 paired NSCLC samples by quantitative real-time PCR, and its expression was found to be associated with the sex of the patient (P=0.02). Further analysis showed that down-regulation of PLZF in 35.6% NSCLC samples (31 out of 87) was triggered by hypermethylation in the promoter region. This was validated by demethylation analysis using the A549 cell line. Dual-luciferase reporter assay indicated that CTCF binding to the promoter region could activate PLZF transcription. Overexpression of PLZF in both A549 and LTEP lung cancer cell lines was found to inhibit proliferation and increase apoptosis. Therefore, reduced expression of PLZF was found to be common in NSCLC. PLZF down-regulation was partially correlated with hypermethylation in the promoter region. Decreased levels of PLZF expression may contribute to the pathogenesis of NSCLC by promoting cell survival. Therefore, the restoration of PLZF expression may serve as a new strategy for NSCLC therapy.

BRG1 overexpression in smooth muscle cells promotes the development of thoracic aortic dissection.

BACKGROUND: Here we investigated Brahma-related gene 1 (BRG1) expression in aortic smooth muscle cells (SMCs) and its role in the regulation of the pathological changes in aortic SMCs of thoracic arotic dissection (TAD). METHODS: BRG1, matrix metalloproteinase 2 (MMP2), and MMP9 mRNA and protein expression in human aortic specimens were examined by qPCR and western blot, respectively. The percentage of apoptotic and contractile SMCs in aortic specimens were determined by TUNEL assay and α-SMA immunohistochemical staining, respectively. The role of BRG1 in MMP2 and MMP9 expression, cell apoptosis, and phenotype transition in aortic SMCs were investigated using a human aortic SMC line via adenovirus mediated gene transfer. MMPs mRNA and protein levels were analyzed by qPCR and western blot, respectively. The percentage of apoptotic and contractile cells were determined through flow cytometry analysis. RESULTS: The expression level of BRG1 in the aortic walls (adventitia-removed) was significantly higher in the TAD than the normal group. BRG1 expression was positively correlated to expression of MMP2 and MMP9 and SMC apoptosis, but was negatively correlated to the percentage of contractile aortic SMCs in TAD specimens. In human aortic SMC line, BRG1 transfection led to significant upregulation of MMP2 and MMP9 expression and a concomitant increase in SMC apoptosis as well as a decrease in the percentage of contractile phenotype of cells. CONCLUSIONS: BRG1 is significantly upregulated in the aortic SMCs of TAD, and its overexpression might promote the development of TAD by increasing MMP2 and MMP9 expression, inducing SMC apoptosis and the transition from contractile to synthetic phenotype.

The use of intra-aortic balloon pump in patients undergoing heart valve replacement: outcome and risk analysis.

BACKGROUND AND AIM OF THE STUDY: Intra-aortic balloon pump (IABP) in heart valve surgical patients is associated with a higher mortality than coronary artery bypass grafting (CABG). The study aim was to analyze the early outcome of heart valve surgical patients requiring IABP support, and to assess the risk factors for early mortality. METHODS: Among a cohort of 5,786 patients undergoing heart valve replacement without CABG, 81 (1.4%) required IABP support. Data from these latter patients were collected and analyzed retrospectively, and univariate and multivariate logistic regression were applied to identify risk factors for early mortality in patients requiring IABP support. RESULTS: IABP was inserted in 30 patients intraoperatively, and in 51 patients postoperatively. The overall mortality was 50.6%. Mortality in the intraoperative IABP subgroup was significantly lower than in the postoperative IABP subgroup (26.7% versus 64.7%, p = 0.001). The independent risk factors for early mortality were: age increasing by 10 years (OR 1.906, 95% CI: 1.165-3.116, p = 0.010) and pulmonary hypertension (OR 4.153, 95% CI: 1.380-12.499, p = 0.011). Intraoperative IABP insertion (OR 0.297, 95% CI: 0.100-0.876, p = 0.028) was identified as a protective factor compared to postoperative insertion. CONCLUSION: The mortality of patients requiring IABP support after heart valve replacement was high. The efficacy of intraoperative IABP insertion was better than a postoperative mandatory use. Clearly, more attention should be paid to older patients or those with pulmonary hypertension, who may benefit less from IABP.

Comparison of six risk scores for in-hospital mortality in Chinese patients undergoing heart valve surgery.

BACKGROUND: To compare six risk scores with regard to their validity to predict in-hospital mortality after heart valve surgery in a single-centre patient population of China. METHODS: From January 2006 to December 2011, 3479 consecutive patients who underwent heart valve surgery at our centre were collected and scored according to the EuroSCORE II, VA risk score, NNE risk score, Ambler risk score, NYC risk score, and STS risk score. Calibration of the six risk scores was assessed by the Hosmer-Lemeshow (H-L) test. Discrimination was tested by calculating the area under the receiver operating characteristic (ROC) curve. RESULTS: Observed mortality was 3.32% overall. The STS score showed good calibration in predicting in-hospital mortality (H-L: P = 0.126). The EuroSCORE II, VA score, NNE score, and NYC score underpredicted observed mortality (H-L: P < 0.0001, P < 0.0001, P = 0.001, and P < 0.0001, respectively) and the Ambler score overpredicted observed mortality (H-L: P = 0.005). The discriminative power (i.e. the area under the ROC curve) for in-hospital mortality was highest for the STS score (0.706), followed by the EuroSCORE II model (0.693), NNE score (0.684), NYC score (0.682), Ambler score (0.677) and VA score (0.643). CONCLUSION: Compared with the EuroSCORE II, VA score, NNE score, NYC score, and the Ambler score, the STS score gives an accurate prediction for individual operative risk in patients undergoing heart valve surgery at our centre. Therefore, the use of the STS score for risk evaluation maybe suitable in patients undergoing heart valve surgery at our centre in the future.

Case report: Resection of a giant right ventricular myxoma.

Myxoma constitutes the main subtype of all benign cardiac tumors, tending to be more common in women and occurring mostly in the left and right atria. Its classic clinical presentations are intracardiac obstruction, embolization, and systemic or constitutional symptoms, such as fever, in decreasing order. Several imaging techniques such as echocardiography, computed tomography, and angiocardiography contribute to the diagnosis of myxoma, ruling out significant coronary diseases, and assessment of myocardial invasion and tumor involvement of adjacent structures. Surgical resection is the only effective therapeutic option for patients with cardiac myxoma. Here, we report a unique case of a middle-aged man who presented with a giant myxoma and a 3-day history of chest tightness and shortness of breath after physical activity. Subsequently, transthoracic echocardiography revealed a mass of solid echodensity located within the right ventricle, complicated by abnormal hemodynamics. A cardiac computed tomographic angiography showed a large homogeneous density filling defect consuming most parts of the right ventricle and protruding from beat to beat. A surgical resection and histological study later successfully confirmed the diagnosis, and the patient's postoperative recovery course was found to be uneventful.

Risk model of prolonged intensive care unit stay in Chinese patients undergoing heart valve surgery.

BACKGROUND: The aim of this study was to develop a preoperative risk prediction model and an scorecard for prolonged intensive care unit length of stay (PrlICULOS) in adult patients undergoing heart valve surgery. METHODS: This is a retrospective observational study of collected data on 3925 consecutive patients older than 18 years, who had undergone heart valve surgery between January 2000 and December 2010. Data were randomly split into a development dataset (n=2401) and a validation dataset (n=1524). A multivariate logistic regression analysis was undertaken using the development dataset to identify independent risk factors for PrlICULOS. Performance of the model was then assessed by observed and expected rates of PrlICULOS on the development and validation dataset. Model calibration and discriminatory ability were analysed by the Hosmer-Lemeshow goodness-of-fit statistic and the area under the receiver operating characteristic (ROC) curve, respectively. RESULTS: There were 491 patients that required PrlICULOS (12.5%). Preoperative independent predictors of PrlICULOS are shown with odds ratio as follows: (1) age, 1.4; (2) chronic obstructive pulmonary disease (COPD), 1.8; (3) atrial fibrillation, 1.4; (4) left bundle branch block, 2.7; (5) ejection fraction, 1.4; (6) left ventricle weight, 1.5; (7) New York Heart Association class III-IV, 1.8; (8) critical preoperative state, 2.0; (9) perivalvular leakage, 6.4; (10) tricuspid valve replacement, 3.8; (11) concurrent CABG, 2.8; and (12) concurrent other cardiac surgery, 1.8. The Hosmer-Lemeshow goodness-of-fit statistic was not statistically significant in both development and validation dataset (P=0.365 vs P=0.310). The ROC curve for the prediction of PrlICULOS in development and validation dataset was 0.717 and 0.700, respectively. CONCLUSION: We developed and validated a local risk prediction model for PrlICULOS after adult heart valve surgery. This model can be used to calculate patient-specific risk with an equivalent predicted risk at our centre in future clinical practice.

[Methods and results of surgical treatment for aortic root pathology due to Stanford A aortic dissection].

OBJECTIVE: To investigate the effectiveness of surgical approaches, outcomes and prognosis of aortic root pathology due to Stanford A aortic dissection. METHODS: Retrospective analysis the clinical data of 161 patients (122 male and 39 female, mean age of (44 ± 21) years) underwent surgical treatment for Stanford A aortic dissection between January 2001 and June 2011. There were 146 patients of acute aortic dissection and 15 patients of chronic aortic dissection. All the patients had aortic root pathologies that included commissural prolapsed in 140 cases, more than moderate aortic insufficiency in 75 cases, aortic sinus intima rupture in 15 cases, right and/or left coronary artery tearing in 8 cases, right and/or left coronary artery dissection in 16 cases, aortic root aneurysm in 31 cases. RESULTS: Aortic root replacement (Bentall procedures) were used in 72 cases, aortic root remodeling (including aortic valve replacement) in 80 cases, aortic root reimplantation (David procedure) in 9 cases. The cardiopulmonary bypass time was shorter in aortic root remodeling group ((193 ± 42) minutes) than the other two groups ((210 ± 61) minutes, (197 ± 34) minutes, F = 3.22, P = 0.04). The in-hospital mortality was 8.1% (13 cases), 5 cases (6.9%) in aortic root replacement group, 7 cases (8.8%) in aortic root remodeling group, 1 case in aortic root reimplantation. The cause of death included respiratory failure (4 cases), permanent neurological deficits (3 cases), multiple organ failure (4 cases), acute renal failure (2 cases). The survivors were followed up for 6 months to 6 years. There was no patient required reoperation for aortic root pathologies. There was no statistically significant difference between aortic root remodeling group and reimplantation group (P > 0.05). CONCLUSIONS: The surgical treatment for aortic root pathology due to Stanford A aortic dissection is challenging. Appropriate procedures according to the specialty of aortic root pathology can be performed with favorable functional results.

[Clinical analysis of the edge-to-edge technique for mitral regurgitation due to myxomatous degeneration].

OBJECTIVES: To explore the feature of the edge-to-edge technique and its effect for mitral regurgitation due to myxomatous degeneration. METHODS: The in-patient data and follow-up outcomes of 58 patients after the edge-to-edge technique for mitral regurgitation due to myxomatous degeneration from January 2000 to January 2009 were analyzed retrospectively. Of the 58 patients, 32 patients were male and 26 patients were female, and the age range was from 43 years to 65 years with a mean of (56 ± 6) years, and moderate mitral regurgitation was observed in 18 patients and severe regurgitation in 40 patients, and the prolapse of the anterior leaflet was observed in 50 patients and the prolapse of the bileaflet in 8 patients. The edge-to-edge technique was performed in all patients and the annuloplasty was performed in 44 patients. RESULTS: There was no perioperative death and serious complication. Postoperative transthoracic echocardiography of all the survivors indicated that the dimensions of left atrial and left ventricular were obviously decreased (P < 0.05) and mitral insufficiency was obviously improved (no regurgitation was observed in 9 patients and trace regurgitation in 30 patients and mild regurgitation in 19 patients) and there was no mitral stenosis. Totally 58 patients were followed up from 24 months to 95 months with a mean of (58 ± 20) months. During the follow-up, there were 2 deaths for noncardiac factors. Freedom from recurrent moderate or severe mitral regurgitation at 5 years after operations was 91.9%. According to undergoing combined annuloplasty or not, 58 patients were divided into the edge-to-edge technique group (14 cases) and the edge-to-edge technique + annuloplasty group (44 cases), and the survival analysis shows there was significant difference on freedom from long-term recurrent moderate or severe mitral regurgitation after operations between two groups (χ(2) = 4.034, P = 0.045) and long-term effect of the latter group was better. CONCLUSIONS: The edge-to-edge technique can be conveniently used and bring about satisfactory perioperative and long-term effects for mitral regurgitation due to myxomatous degeneration. The combination of the edge-to-edge technique and the annuloplasty can improve the long-term effect significantly.

[Strategy of dealing with left subclavian artery in total arch replacement combined with stented elephant trunk implantation for Stanford type A aortic dissection].

OBJECTIVE: To summarize the experiences of ligating left subclavian artery (LSA) in total arch replacement and stented elephant trunk implantation for Stanford type A aortic dissection patients with difficulty in exposing the LSA. METHODS: Total arch replacement and stented elephant trunk implantation were performed on 79 consecutive patients from January 2008 to June 2010. Twenty-nine cases of the cohort undertook LSA ligation due to bad exposure. There were 21 males and 8 females patients, aged from 19 to 55 years with a mean of (44 ± 12) years. There were 12 acute dissections, 4 sub-acute dissections and 13 chronic dissections. Based on thoroughly evaluation of the Willis' circle and bilateral vertebral arteries through pre-operative imaging and intra-operative circulative parameters, if the collateral circulation was considered sufficient, LSA was ligated directly and only the innominate artery and carotid artery were reconstructed; if considered insufficient, an additional bypass from ascending aorta to left axillary artery was performed. RESULTS: All the 29 operations were completed successfully. There was one patient died from pulmonary infection and the others recovered well.Blood pressure of left arms were lower than right postoperatively [(78 ± 17) mmHg vs. (126 ± 24) mmHg, 1 mmHg = 0.133 kPa, P < 0.01], but oxygen saturation, skin temperature and strength of the left hand were normal compared to the right. All the survived patients have been followed 1 - 27 months and none of them presented with any symptoms of left subclavian artery steal syndrome and ischemia of left arms. CONCLUSIONS: Ligation of LSA under strict evaluation of collateral circulation could be safe in Type A dissection patients with bad exposure due to big ascending aortic aneurysm and will simplify the procedure significantly.

A pharmacogenetics study of platinum-based chemotherapy in lung cancer: ABCG2 polymorphism and its genetic interaction with SLC31A1 are associated with response and survival.

Objective: The expression and function of platinum transporters affect drug tissue concentration and therapeutic effects. We had previously characterized functional variant of platinum intake transporter SLC31A1 gene. We aimed to investigate the association of platinum efflux transporter gene ABCG2 polymorphism and combined ABCG2 and SLC31A1 polymorphisms with clinical outcomes of NSCLC patients receiving platinum-based chemotherapy. Methods: We genotyped thirteen tagging and functional SNPs of ABCG2 in 1004 patients, and assessed their association with response, toxicity and survival using unconditional logistic regression and Cox proportional hazards regression analyses respectively. Results: Nonsynonymous rs2231142 (odds ratio [OR] 2.07; 95 % confidence interval [CI] 1.26-3.63), rs1871744 (OR 0.60; 95 % CI 0.42-0.87) and their haplotype and diplotype were associated with objective response. Rs4148157 was associated with shorter overall survival (Log-rank P = 0.002; hazard ratio [HR] 1.22; 95 % CI 1.05-1.42). Furthermore, the combined SLC31A1 rs2233914 and ABCG2 rs1871744 genotype was significantly associated with poor response (OR 0.31; 95 % CI 0.17-0.56; P interaction = 0.003). And the combined genotypes of the functional rs10759637 of SLC31A1 and the nonsynonymous rs2231142 (Log-rank P = 5.20×10-5; HR 1.47; 95 % CI 1.19-1.81; P interaction = 0.007) or linked rs4148157 of ABCG2 were significantly associated with poor survival. Conclusion: This study reveals divergent association of ABCG2 polymorphism with response and survival of NSCLC patients receiving platinum-based chemotherapy, demonstrates the combined effects of functional variants of ABCG2 and SLC31A1 on clinical outcomes, and highlights pharmacogenetic relevance of platinum transporter genes interaction.

[Surgical treatment of congenital quadricuspid aortic valve].

OBJECTIVE: To improve the understanding of congenital quadricuspid aortic valve (QAV), explore its echocardiographic diagnostic value and summarize the methods and outcomes of surgical treatments. METHODS: The clinical data of 11 QAV patients from January 2000 to December 2008 were retrospectively analyzed. There were 9 males and 2 females with a mean operative age of (32±16) years (range: 4-55). RESULTS: In 766 patients undergoing aortic valve surgery, 11 were of congenital quadricuspid aortic valve (1.4%); cardiac pathology: infective endocarditis (n=1), left superior vena cava (n=1), aortic aneurysm (n=1), mitral prolapse (n=1) and tricuspid insufficiency (n=1). The patients of congenital QAV deformity was diagnosed by echocardiography (n=7), misdiagnosed as single valve (n=1), misdiagnosed as bicuspid valve (n=1) and misdiagnosed as rheumatic heart disease (n=2). Type B (n=7), Type A (n=2), Type F (n=1) and Type G (n=1). Eleven patients underwent the procedure of aortic valve replacement. And the concomitant procedures were aortic root broadening (n=1), ascending aortoplasty (n=1), mitral valvuloplasty (n=1) and tricuspid valvuloplasty (n=1). CONCLUSION: Quadricuspid aortic valve is rare in clinical practice. And echocardiography plays an important diagnostic role. Surgical replacement of aortic valve is the first-line therapy for these patients.

[Reoperative valve replacement in patients undergoing cardiac reoperation: a report of 104 cases].

OBJECTIVE: To review the experience of reoperative valve replacement for 104 patients. METHODS: From January 2002 to December 2009, 104 patients underwent heart valve replacement in reoperations, accounting for 2.92% of the total patient population (3557 cases) who had valve replacement during this period. In this group, 53 male and 51 female patients were included with a median age of 46 years (ranged from 13 to 72 years). The reasons of reoperation included 28 cases suffered from another valve lesion after valve replacement, 10 cases suffered from valve lesion after mitral valvuloplasty, 19 cases suffered from perivalvular leakage after valve replacement, 18 cases suffered from valve lesion after previous correction of congenital heart defect, 7 cases suffered from bioprosthetic valve decline, 10 cases suffered from prosthetic valve endocarditis, 9 cases suffered from dysfunction of machine valve, and 3 cases suffered from other causes. The re-operations were mitral and aortic valve replacement in 2 cases, mitral valve replacement in 59 cases, aortic valve replacement in 24 cases, tricuspid valve replacement in 16 cases, and Bentall's operation in 3 cases. The interval from first operation to next operation was 1 month-19 years. RESULTS: There were 8 early deaths from heart failure, renal failure and multiple organ failure (early mortality 7.69%). Major complications were intraoperative hemorrhage in 2 cases, re-exploration for mediastinal bleeding in 2 cases and sternotomy surgical site infection in 1 case. Complete follow-up (3 months-7 years and 2 months) was available for all patients. Two patients died, one patient died of intracranial hemorrhage, and another cause was unknown. CONCLUSION: Satisfactory short-term and long-term results can be obtained in reoperative valve replacement with appropriate timing of operation control, satisfactory myocardial protection, accurate surgical procedure and suitable perioperative treatment.

Association of TNFAIP3 polymorphism with rheumatic heart disease in Chinese Han population.

In a pair-matched case-control study (239 versus 478) conducted in Chinese Han population, we investigated the association between tumor necrosis factor-alpha-induced protein 3 (TNFAIP3) gene, tumor necrosis factor receptor-associated factor 1 (TRAF1) gene, complement component 5 (C5) gene, and rheumatic heart disease (RHD). We observed no association with RHD for the five tagging single nucleotide polymorphisms (tSNP) in the C5 gene, the three tSNPs in the TNFAIP3 gene, or the two tSNPs in the TRAF1 gene. However, we determined that the tSNP, rs582757, located at intron_5 of the TNFAIP3 gene, associated with RHD in Chinese Han population. Both the distribution of genotype and allele frequencies differed significantly between case and control subjects (p = 0.001 and p = 0.0004, respectively). The minor C allele reduced the risk of RHD with a per-allele odds ratio of 0.57 (0.42-0.78) for the additive model in univariate analysis (p = 0.000). Under a dominant model, CC/CT carriers had a 0.54-fold reduced risk of RHD (95% confidence interval 0.38-0.75, p = 0.000) than TT carriers. Therefore, we report a new genetic variant (rs582757) in the TNFAIP3 gene that associated with the prevalence of RHD in Chinese Han population. Further genetic and functional studies are required to identify the etiological variants in linkage disequilibrium with this polymorphism.