Disturbance of suprachiasmatic nucleus function improves cardiac repair after myocardial infarction by IGF2-mediated macrophage transition.

Suprachiasmatic nucleus (SCN) in mammals functions as the master circadian pacemaker that coordinates temporal organization of physiological processes with the environmental light/dark cycles. But the causative links between SCN and cardiovascular diseases, specifically the reparative responses after myocardial infarction (MI), remain largely unknown. In this study we disrupted mouse SCN function to investigate the role of SCN in cardiac dysfunction post-MI. Bilateral ablation of the SCN (SCNx) was generated in mice by electrical lesion; myocardial infarction was induced via ligation of the mid-left anterior descending artery (LAD); cardiac function was assessed using echocardiography. We showed that SCN ablation significantly alleviated MI-induced cardiac dysfunction and cardiac fibrosis, and promoted angiogenesis. RNA sequencing revealed differentially expressed genes in the heart of SCNx mice from D0 to D3 post-MI, which were functionally associated with the inflammatory response and cytokine-cytokine receptor interaction. Notably, the expression levels of insulin-like growth factor 2 (Igf2) in the heart and serum IGF2 concentration were significantly elevated in SCNx mice on D3 post-MI. Stimulation of murine peritoneal macrophages in vitro with serum isolated from SCNx mice on D3 post-MI accelerated the transition of anti-inflammatory macrophages, while antibody-mediated neutralization of IGF2 receptor blocked the macrophage transition toward the anti-inflammatory phenotype in vitro as well as the corresponding cardioprotective effects observed in SCNx mice post-MI. In addition, disruption of mouse SCN function by exposure to a desynchronizing condition (constant light) caused similar protective effects accompanied by elevated IGF2 expression on D3 post-MI. Finally, mice deficient in the circadian core clock genes (Ckm-cre; Bmal1f/f mice or Per1/2 double knockout) did not lead to increased serum IGF2 concentration and showed no protective roles in post-MI, suggesting that the cardioprotective effect observed in this study was mediated particularly by the SCN itself, but not by self-sustained molecular clock. Together, we demonstrate that inhibition of SCN function promotes Igf2 expression, which leads to macrophage transition and improves cardiac repair post-MI.

Mitral early-diastolic inflow peak velocity (E)-to-left atrial strain ratio as a novel index for predicting elevated left ventricular filling pressures in patients with preserved left ventricular ejection fraction.

OBJECTIVES: We sought to explore the relationship between an index of left ventricular diastolic function parameters combined with left atrial strain and the diastolic function of patients with preserved ejection fraction. METHODS: We prospectively enrolled 388 patients with left ventricular ejection fraction (LVEF) ≥ 50%, 49 of whom underwent left heart catherization. Transthoracic echocardiography was performed within 12 h before or after the procedure. Left atrial (LA) strain was obtained by speckle tracking echocardiography. These patients served as the test group. The remaining patients (n = 339) were used to validate the diagnostic performance of the mitral early-diastolic inflow peak velocity (E)-to-left atrial reservoir strain ratio (E/LASr) in left ventricular diastolic dysfunction. RESULTS: Invasive measurements of LV end-diastolic pressure (LVEDP) demonstrated that the E/LASr ratio was increased in patients with elevated LVEDP [ 2.0 (1.8-2.2) vs 3.0 (2.6-4.0), p < 0.001] in the test group (n = 49). After adjusting for age, mitral A, E/e' ratio and ß-blocker use, the E/LASr ratio was an independent predictor of elevated LVEDP and showed good diagnostic performance in determining elevated LVEDP [area under the curve (AUC) 0.903, cutoff value 2.7, sensitivity 74.2%, specificity 94.4%]. In the validation group (n = 339), the E/LASr ratio also performed well in diagnosing elevated left atrial pressure (LAP) (AUC 0.904, cutoff value 3.2, sensitivity 76.5%, specificity 89.0%), while with a cut-off value of 2.7, the E/LASr ratio showed high accuracy in discriminating elevated LAP. In addition, E/LASr was a good index of excellent diagnostic utility (AUC: 0.899 to 0.996) in the categorization of diastolic dysfunction grades. Regarding the clinical relevance of this index, the E/LASr ratio could accurately diagnose HF with preserved ejection fraction (HFpEF) (0.781), especially in patients with "indeterminate" status (AUC: 0.829). Furthermore, an elevated E/LASr ratio was significantly associated with the risk of rehospitalization due to major adverse cardiac events (MACEs) within one year (odds ratio: 1.183, 95% confidence interval: 1.067, 1.312). CONCLUSIONS: In patients with EF preservation, the E/LASr ratio is a novel index for assessing elevated left ventricular filling pressure with high accuracy.

A novel functional polymorphism of GSTM3 reduces clear cell renal cell carcinoma risk through enhancing its expression by interfering miR-556 binding.

Dysregulation of glutathione-S-transferase M3 (GSTM3) has been related to clear cell renal cell carcinoma (ccRCC) in our former study. GSTM3 plays a pivotal role of detoxification and clearance of reactive oxygen species (ROS) in tumour tissues. This study aimed to examine: (1) the associations between GSTM3 single nucleotide polymorphisms (SNPs) and risk of ccRCC, and (2) the potential molecular mechanism accounting for its effects. 5 SNPs in 3'UTR of GSTM3 were initially genotyped in 329 cases and 420 healthy controls. A SNP-rs1055259 was found to be significantly associated with the susceptibility of ccRCC (OR = 0.59, 95% CI = 0.41-0.92; P = .019). The minor allele of rs1055259 (G allele) was associated with RCC risk. This SNP was predicted to affect microRNA (miR)-556 binding to 3'UTR of GSTM3 mRNA. To determine the functional impact, plasmid constructs carrying different alleles of rs1055259 were created. Compared to rs1055259 A-allele constructs, cells transfected with rs1055259 G-allele construct had higher transcriptional activity and were less responsive to miR-556 changes and gene expression. Elevated GSTM3 expression in G-allele cells was associated with ROS activity and ccRCC development. Taken together, this study indicated that a functional polymorphism of GSTM3 -rs1055259 reduced susceptibility of RCC in the Chinese population. It influenced GSTM3 protein synthesis by interfering miR-556 binding, subsequently suppressed ROS activity and ccRCC progression.

Theory-based pharmacokinetics and pharmacodynamics of S- and R-warfarin and effects on international normalized ratio: influence of body size, composition and genotype in cardiac surgery patients.

AIMS: The aims of this study are to apply a theory-based mechanistic model to describe the pharmacokinetics (PK) and pharmacodynamics (PD) of S- and R-warfarin. METHODS: Clinical data were obtained from 264 patients. Total concentrations for S- and R-warfarin were measured by ultra-high performance liquid tandem mass spectrometry. Genotypes were measured using pyrosequencing. A sequential population PK parameter with data method was used to describe the international normalized ratio (INR) time course. Data were analyzed with NONMEM. Model evaluation was based on parameter plausibility and prediction-corrected visual predictive checks. RESULTS: Warfarin PK was described using a one-compartment model. CYP2C9 *1/*3 genotype had reduced clearance for S-warfarin, but increased clearance for R-warfarin. The in vitro parameters for the relationship between prothrombin complex activity (PCA) and INR were markedly different (A = 0.560, B = 0.386) from the theory-based values (A = 1, B = 0). There was a small difference between healthy subjects and patients. A sigmoid Emax PD model inhibiting PCA synthesis as a function of S-warfarin concentration predicted INR. Small R-warfarin effects was described by competitive antagonism of S-warfarin inhibition. Patients with VKORC1 AA and CYP4F2 CC or CT genotypes had lower C50 for S-warfarin. CONCLUSION: A theory-based PKPD model describes warfarin concentrations and clinical response. Expected PK and PD genotype effects were confirmed. The role of predicted fat free mass with theory-based allometric scaling of PK parameters was identified. R-warfarin had a minor effect compared with S-warfarin on PCA synthesis. INR is predictable from 1/PCA in vivo.

[Efficacy of subgroup mouse bone mesenchymal stem cells on mobilizing autologous cardiac stem cells and repairing ischemic myocardial tissue].

OBJECTIVE: To search for the bone mesenchymal stem cell (MSC) subgroup which might be more effective on repairing myocardial damage. METHODS: In this experiment, four MSC subgroups were defined based on the surface differentiation antigen detection of mouse bone mesenchymal stem cells (mBMSCs): SCA-1(+)/CD45(+)/CD31(+), SCA-1(+)/CD45(+)/CD31(-), SCA-1(+)/CD45(-)/CD31(-) and SCA-1(+)/CD45(-)/CD31(+). These subgroup cells and unselected mBMSCs were injected into infarcted mouse via tail vein. Echocardiographic heart function measurement and in vivo DiR-labeled stem cells imaging were performed at 48 h after injection. In situ C-kit (a flag antigen of cardiac stem cells) and cardiac-specific differentiation antigen immunohistochemistry detection was made in the infarcted myocardium. RESULTS: The capacity of the SCA-1(+)/CD45(+)/CD31(+) cells on improving heart function was significantly higher than other cell groups (all P < 0.05). In vivo imaging showed that the mean fluorescence intensity of the SCA-1(+)/CD45(+)/CD31(+) cells was also higher than other cell groups (all P < 0.05). Number of cardiac stem cells in the infracted myocardium was significantly increased after the injection of all subgroup cells and unsorted mBMSCs cells for 48 h compared untreated infracted myocardium. The capacity of mobilizing cardiac stem cells is as follows: SCA-1(+)/CD45(+)/CD31(+) >SCA-1(+)/CD45(-)/CD31(+) >SCA-1(+)/CD45(-)/CD31(-) >SCA-1(+)/CD45(+)/CD31(-). CONCLUSION: The SCA-1(+)/CD45(+)/CD31(+) subgroups of mBMSCs exhibites the highest capacity to improve cardiac function after myocardial infarction and to mobilize autologous cardiac stem cells compared with other mBMSCs subgroups and unsorted mBMSCs cells.

PEBP4 gene expression and its significance in invasion and metastasis of non-small cell lung cancer.

The goal of this study was to investigate the function of phosphatidylethanolamine-binding protein 4 (PEBP4) in invasion and metastasis of non-small cell lung cancer (NSCLC). PEBP4 mRNA and protein expression in 56 cases of NSCLC tissues were detected using RT-PCR and Western blot, and the relationship between PEBP4 expression and invasion and metastasis of NSCLC was analyzed. The change in the invasive ability of human NSCLC cell line HCC827 was observed after knocking down PEBP4 expression using RNA interference. PEBP4 mRNA and protein expression in cancer tissues of patients with lymph node metastasis were significantly higher than those in patients without lymph node metastasis (p < 0.05). PEBP4 expression significantly decreased in HCC827 cells after transfection with PEBP4 siRNA (p < 0.01), and the number of HCC827 cells that migrated through Transwell chambers was significantly lower than that of non-transfected control and transfected control cells (p < 0.01). PEBP4 over-expression may promote the invasion and metastasis of NSCLC.

The relationship between EGFR gene mutation status and ERCC1 in lung adenocarcinoma of Chinese patients receiving platinum-based neoadjuvant chemotherapy.

The specific aim of this study was to assess the relationship between the mutation status of the epidermal growth factor receptor (EGFR) gene and excision repair cross-complementation group 1 (ERCC1) in lung adenocarcinoma of patients that received platinum-based neoadjuvant chemotherapy. One hundred and seven primary lung adenocarcinoma patients with 22 stage IIa, 61 stage IIb, and 24 stage IIIa (TNM staging 2009) were included in this study. EGFR genetic mutations including exon 19 and 21 were detected by direct polymerase chain reaction (PCR) sequencing and compared with various clinical/pathologic features. Immunohistochemistry was performed to detect the expression of ERCC1 compared to EGFR mutation status in tumors. The frequency of EGFR mutations before and after chemotherapy was 64.3% (61/107) and 73.2% (70/107), respectively. The mutation frequency of exon 19 and 21 were 60.7% (37/61) and 39.3% (24/61) prior to chemotherapy, compared to 58.6% (41/70) and 41.4% (29/70) after chemotherapy. Mutations in EGFR were significantly different in females (prechemo: p = 0.003 vs. postchemo: p = 0.012) and nonsmokers (prechemo: p = 0.007 vs. postchemo: p = 0.000). Positive expression of ERCC1 was higher in patients with unchanged EGFR mutation status (28.4%, 25/88) than that in patients with altered mutation status (26.3%, 5/19) (p = 0.021). Log rank analysis indicated that disease-free survival was influenced by EGFR mutation status. Patients with an unchanged EGFR mutational status after chemotherapy were more likely to express ERCC1, and this change may serve as a clinical indicator of therapy response.

[The application of triple branches aortic arch stent-graft placement in the surgical treatment of acute Stanford type A aortic dissection].

OBJECTIVE: To sum up the experience of performing ascending aorta replacement combined triple-branched stent graft implantation for acute Stanford type A aortic dissection. METHODS: From January 2010 to December 2010, 14 patients with acute Stanford type A aortic dissection underwent the procedure of performing ascending aorta replacement combined triple-branched stent graft implantation. Right axillary artery cannulation was used for cardiopulmonary bypass and selected cerebral perfusion. When the body temperature drops below 18°C, the ascending aorta was transected near the base of the innominate artery. From the incision, the triple-branched stent graft was implanted into the true lumen of the arch, descending aorta and the aorta bifurcation vessel. The transected stump of the ascending aorta was anastomosis to the proximal of the branched blood vessel prosthesis. RESULTS: Cardiopulmonary bypass time was (186 ± 38) min, cross clamp time was (101 ± 27) min, and average selective cerebral perfusion and lower body arrest time was (39 ± 11) min. The in-hospital mortality was zero. One patient of transient postoperative neurologic dysfunction, one of acute renal failure, one of transient limbs disturbance, one of secondary thoracotomy operation, one of gastrointestinal hemorrhage and one of postoperative chylothorax were observed. CT angiography rechecked showed the position of the vascular stent were satisfactory and the blood flow of arterial branches stents were lucid. The false lumen of the aortic arch and descending aorta closed with thrombus or shrinked. CONCLUSIONS: The patients required aortic arch to be reconstructed which had no main tearing of intima in the arch may be best candidates for this technique. Open triple-branched stent graft placement combined ascending aorta replacement is an effective means for aortic arch reconstruction in acute Stanford type A aortic dissection.

Prognostic impact of vascular endothelial growth factor-A and E-cadherin expression in completely resected pathologic stage I non-small cell lung cancer.

OBJECTIVE: The purpose of this study was to evaluate the value of vascular endothelial growth factor-A and E-cadherin expression as well as other confirmed prognostic factors in predicting the clinical outcome after definitive surgery of pathologic stage I non-small cell lung cancer. METHODS: One hundred and eighty-five consecutive and non-selected patients who underwent definitive surgery for stage I non-small cell lung cancer in our institute were included in this study. Formalin-fixed paraffin-embedded specimens were stained for vascular endothelial growth factor-A and E-cadherin and the correlation between the staining, its clinicopathological parameters and its prognostic power were analyzed statistically. RESULTS: Of the 185 patients studied, 92 cases (49.7%) were strongly positive for vascular endothelial growth factor-A. Vascular endothelial growth factor-A expression was only related to visceral pleural involvement (P < 0.001). A total of 95 carcinomas (51.4%) were E-cadherin-negative tumors. E-cadherin expression correlated with histology (P < 0.001), tumor size (P = 0.001) and visceral pleural involvement (P < 0.001). In univariate analysis by log-rank test, gender, tumor size, lymphovascular invasion, visceral pleural involvement, vascular endothelial growth factor-A expression and E-cadherin expression were significant prognostic factors (P = 0.003, 0.042, 0.026, 0.035, 0.008 and 0.006, respectively). In multivariate analysis, gender, vascular endothelial growth factor-A and E-cadherin expression maintained its independent prognostic influence on overall survival (P = 0.013, <0.001 and 0.036, respectively). CONCLUSIONS: Expression of vascular endothelial growth factor-A is related to visceral pleural involvement, and E-cadherin expression correlates with histology, tumor size and visceral pleural involvement. Multivariate analysis confirmed gender, vascular endothelial growth factor-A and E-cadherin expression were significant predictive factors for overall survival in completely resected pathologic stage I non-small cell lung cancer.

MicroRNA-134-5p Regulates Media Degeneration through Inhibiting VSMC Phenotypic Switch and Migration in Thoracic Aortic Dissection.

Abnormal phenotypic switch, migration, and proliferation of vascular smooth muscle cells (VSMCs) are hallmarks for pathogenesis of thoracic aortic dissection (TAD). In the current study, we identified miR-134-5p as a critical regulator controlling human VSMC phenotypic switch and migration to investigate whether miR-134-5p affects human VSMC functions and development of TAD. Using miRNA microarray of aorta specimens from 12 TAD and 12 controls, we identified miR-134-5p, which was significantly downregulated in TAD tissues. With qPCR detection, we found that miR-134-5p was also evidently decreased in human AoSMCs. Ectopic expression of miR-134-5p obviously promoted VSMC differentiation and expression of contractile markers, such as α-SMA, SM22α, and MYH11. miR-134-5p potently inhibited PDGF-BB-induced VSMC phenotypic switch and migration. We further identified STAT5B and ITGB1 as downstream targets of miR-134-5p in human VSMCs and proved them to be mediators in VSMC phenotypic switch and progression of TAD. Finally, Ad-miR-134-5p obviously suppressed the aorta dilatation and vascular media degeneration by 39% in TAD mice after vascular injury induced by Ang II. Our findings revealed that miR-134-5p was a novel regulator in vascular remodeling and pathological progress of TAD via targeting STAT5B/ITGB1 expression. Targeting miR-134-5p or its downstream molecules in VSMCs might develop new avenues in clinical treatment of TAD.

The Application of Induced Pluripotent Stem Cells in Pathogenesis Study and Gene Therapy for Vascular Disorders: Current Progress and Future Challenges.

Vascular disorders are complex diseases with high morbidity and mortality. Among them, the dilated macrovascular diseases (MVD), such as aortic aneurysm and aortic dissection, have presented a huge threat to human health. The pathogenesis of vascular diseases is mostly associated with property alteration of vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs). Studies have confirmed that induced pluripotent stem cells (iPSCs) can be proliferated and differentiated into other somatic cells, such as VECs and VSMCs. And patient-specific cells could provide detailed human-associated information in regard to pathogenesis or drug responses. In addition, differentiated ECs from iPSC have been widely used in disease modeling as a cell therapy. In this review, we mainly discussed the application of hiPSCs in investigating the pathological mechanism of different inherited vascular diseases and provide a comprehensive understanding of hiPSCs in the field of clinical diagnosis and gene therapy.

[Association between CYP2C9 and VKORC1 genetic polymorphism and warfarin dose requirements].

OBJECTIVE: To assess the contribution of vitamin K epoxide reductase complex 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) genotype, age, body size, height, and weight to warfarin dose requirement. METHODS: Blood samples were collected from 191 patients receiving warfarin therapy. Patients's age, gender, height, and weight were registered. PCR-RFLP method was used for the detection of VKORC1-1639G > A and CYP2C9 genotype. RESULTS: VKORC1-1639G > A genotyping showed that 159 patients were homozygous AA, 31 were heterozygous GA, and 1 was homozygous GG genotype. CYP2C9 genotyping showed that 176 patients were *1/*1, 15 patients were heterozygous *1/*3. Patients with VKORC1-1639 (G > A) GG + GA genotype required a significantly higher warfarin dose than those with AA genotype [(3.36 +/- 0.97) mg/d vs. (1.75 +/- 0.56) mg/d, P < 0.01], and patients with CYP2C9*1/*1 genotype also required a higher warfarin dose than those with CYP2C9*1/*3 genotype [(2.06 +/- 0.83) mg/d vs. (1.55 +/- 1.32) mg/d, P < 0.05]. The multiple linear regression model for warfarin dose indicated age, weight and VKORC1 genotype could explain the inter-individual variation in dose requirement of 9.3%, 7.4%, 51.9% patients, respectively; age, weight, CYP2C9 and VKORC1 genotype together could explain the inter-individual variation in dose requirement of 64.1% patients. CONCLUSION: This study showed that age, weight and VKORC1 and CYP2C9 polymorphism had significant influences on warfarin dose requirements and should be considered on dosing regimens modification to improve the safety of warfarin therapy.

Urolithin A shows anti-atherosclerotic activity via activation of class B scavenger receptor and activation of Nef2 signaling pathway.

BACKGROUND: This study investigates the therapeutic potential of urothelin A in attenuating atherosclerotic lesion in wistar rat models and explore the role of Scavenger receptor-class B type I (SR-BI) and activation of Nrf-2 singling pathway. METHODS: Wistar rats (n=48) were feed with high cholesterol diet supplemented with Vitamin D3 and subjected to balloon injury of the aorta. Three days prior to the aortal injury, rats (n=16) were administered urothelin A (3mg/kg/d; po). Positive control were rats receiving high cholesterol diet and balloon injury of the aorta (n=16). The sham group (n=16) consisted of rats fed on basal diet. After twelve weeks blood was collected from all animals for estimation of lipid and angiotensin II (Ang II) levels along, subsequently all animals were sacrificed and morphologic analysis of the aorta was performed. Expression of SR-BI and phosphorylated extracellular signal regulated kinase 1/2 (p-ERK1/2) protein were evaluated by Western blot. RESULTS: After twelve weeks of treatment with urolithin A, there was a significant decrease in the plasma lipid and Ang II levels and improvement of aortic lesion compared with the sham group. There was an increased expression of SR-BI and inhibition of p-ERK1/2 (p<0.05). The expression of SR-BI was inversely correlated with levels of Ang II. CONCLUSION: From the results it can be safely concluded that administration of urolithin A attenuates atherosclerosis via upregulation of SR-BI expression and inhibition of p-ERK1/2 levels.

Functional polymorphisms of the neuropilin 1 gene are associated with the risk of tetralogy of Fallot in a Chinese Han population.

Tetralogy of Fallot (TOF) is one of the most severe forms of cyanotic congenital heart disease (CHD) and is also the most common. Previous genome-wide association study (GWAS) and replication studies have suggested that a polymorphism in the neuropilin 1 (NRP1) gene is significantly associated with the risk of TOF. To further confirm the association between the NRP1 polymorphism and the risk of TOF and to identify additional positive functional single-nucleotide polymorphisms (SNPs) for TOF risk, we systematically screened for functional polymorphisms throughout the regulatory and coding regions of the NRP1 gene. A total of 11 functional SNPs in 747 Chinese Han individuals, including 314 TOF patients and 433 healthy controls, were genotyped using the MassARRAY system and GeneScan. The results revealed that the allelic and genotypic frequencies of the NRP1 polymorphism rs2228638 were strongly associated with the risk of TOF (p = 0.002 and 0.001, respectively). To increase the robustness of rs2228638 as a TOF risk SNP, we conducted a meta-analysis that combined published studies and our current case-control study. The meta-analysis showed that the T allele of the NRP1 polymorphism rs2228638 was significantly associated with an increased risk of TOF in the combined population, which included European and Chinese Han individuals [combined p < 0.00001, odds ratio (OR) = 1.53, 95% confidence interval (95% CI) = 1.35-1.73]. In addition, the association analysis suggested for the first time that there is a strong association between the allele distribution of rs10080 and susceptibility to TOF (p = 0.001). Our data provide further evidence of the association between NRP1 polymorphisms and TOF risk, and suggest that rs2228638 may be an excellent marker for TOF risk in European and Chinese Han populations.

A functional variant of SMAD4 enhances macrophage recruitment and inflammatory response via TGF-ß signal activation in Thoracic aortic aneurysm and dissection.

Thoracic aortic aneurysm and dissection (TAAD) is the most fatal macro vascular disease. The mortality of 48h after diagnosis of dissection is up to approximately 50-68%. However, the genetic factors and potential mechanism underlying sporadic TAAD remain largely unknown. Our previous study suggested rs12455792 variant of SMAD4 gene significantly contributed to the increased risk and might participated the pathological progression of TAAD. This investigation aims to test (1) the associations between rs12455792 and MØ recruitment, inflammatory response in aggressiveness of TAAD, and (2) the molecular mechanism accounting for their effects. In TGF-ß signaling molecular detection, rs12455792 C>T variant activated the canonical and non-canonical TGF-ß mediators. It also increased the secretion of chemotactic factors of HASMCs. To confirm the impact of this change, we detected MØ recruitment and infiltration in HASMCs and aortic tissues of TAAD patients. We found that MØ recruitment in cells and tissues with rs12455792 variant genotypes was increased than that in wild type groups. Moreover, rs12455792 variant increased M1 type inflammatory response, which might contribute much to TAAD progression. To mimic the SMAD4 suppression effect of rs12455792 in vivo, we constructed the SMAD4 KD mouse. After induction with Ang II for 4w, the thoracic aorta dilatation and vascular remodeling were more serious than that of wild type group. In conclusion, rs12455792 increased MØ recruitment, M1 type inflammatory response via activated TGF-ß signaling, and further promoted vascular remodeling and pathological progress of TAAD.

A Functional Variant of SMAD4 Enhances Thoracic Aortic Aneurysm and Dissection Risk through Promoting Smooth Muscle Cell Apoptosis and Proteoglycan Degradation.

Recent studies indicate important roles for SMAD4 in SMCs proliferation, extracellular matrix maintenance, and blood vessel remodeling. However, the genetic effects of SMAD4 in the pathogenesis of thoracic aortic aneurysm and dissection (TAAD) are still largely unknown. Here we identified a functional variant of SMAD4 which might be involved in the pathological progression of TAAD. Five tagging SNPs of SMAD4 were genotyped in 202 TAAD cases and 400 controls using MALDI-TOF. rs12455792 CT or TT variant genotypes was associated with an significantly elevated TAAD risk (adjusted OR=1.58, 95%CI=1.09-2.30) under a dominant genetic model. It was located in the 5'UTR and predicted to influence transcription activity and RNA folding of SMAD4. In luciferase reporter assay, rs12455792 T allele markedly decreased luciferase activities. Accordingly, SMAD4 expression in tissues was lower in patients with CT or TT genotypes, compared with CC. Movat's pentachrome showed that rs12455792 T allele enhanced SMCs loss and fibers accumulation. With angiotensin II induction, rate of Apoptotic SMCs was significantly higher while SMAD4 silenced. Moreover, rs12455792 T allele also increased Versican degradation via ADAMTS-4. In conclusion, this variant might promote SMCs apoptosis and proteoglycans degradation, and further facilitate the progress of TAAD. Our findings identified rs12455792 as a predictor for progression of vascular media pathological changes related thoracic aortic disorders.

The combination of stem cells and tissue engineering: an advanced strategy for blood vessels regeneration and vascular disease treatment.

Over the past years, vascular diseases have continued to threaten human health and increase financial burdens worldwide. Transplantation of allogeneic and autologous blood vessels is the most convenient treatment. However, it could not be applied generally due to the scarcity of donors and the patient's condition. Developments in tissue engineering are contributing greatly with regard to this urgent need for blood vessels. Tissue engineering-derived blood vessels are promising alternatives for patients with aortic dissection/aneurysm. The aim of this review is to show the importance of advances in biomaterials development for the treatment of vascular disease. We also provide a comprehensive overview of the current status of tissue reconstruction from stem cells and transplantable cellular scaffold constructs, focusing on the combination of stem cells and tissue engineering for blood vessel regeneration and vascular disease treatment.

GSTT1 Null Genotype Significantly Increases the Susceptibility to Urinary System Cancer: Evidences from 63,876 Subjects.

GSTT1 gene plays an important role in detoxification and clearance of reactive oxygen species(ROS). A null variant in this gene has been demonstrated to confer cancer susceptibility. Although many studies have demonstrated the association between GSTT1 null polymorphism and urinary system cancer susceptibility, several publications reported opposite conclusions. For better understanding the effects of this polymorphism on the risk of urinary system cancer, a updated meta-analysis was performed with a total of 26,666 cases and 37,210 controls extracted from 117 studies, by following the latest meta-analysis guidelines (PRISMA). The results suggested that the GSTT1 null genotype was significantly associated with an increased risk of urinary system cancer (OR=1.13, 95%CI=1.05-1.22). Furthermore, stratified analyses by the type of cancer, ethnicity, source of control and quality score presented a significantly increased risk associated with GSTT1 null genotype in bladder and prostate cancer subgroup, Caucasians and Indians subgroup, population-based(PB) subgroup, medium quality and low quality subgroup. Overall, our meta-analysis suggested that GSTT1 null genotype is a potential cancer susceptibility variant. Well-designed and large-cohort studies are needed to confirm the association between GSTT1 null genotype and urinary system cancer risk.

A novel TP53 variant (rs78378222 A > C) in the polyadenylation signal is associated with increased cancer susceptibility: evidence from a meta-analysis.

Polymorphisms in TP53 are involved in the progression of different types of cancer. A rare novel TP53 variant (rs78378222 A > C allele) was found via whole-genome sequencing in 2011. This variant was shown to significantly increase the risk of glioma, colorectal adenoma and prostate cancer. Functional analysis further revealed that this variant hindered TP53 expression and its downstream effect on apoptosis. Several studies have investigated the relationship between rs78378222 and cancer susceptibility. However, the results were not consistent. We conducted the first meta-analysis to give a more credible assessment on the association about this variant and cancer risk. Our meta-analysis included 34 studies consisting of 36599 cases and 91272 controls. These studies were mostly on the basis of high-grade data from Genome-wide association studies (GWASs). The results indicated that TP53 rs78378222 was significantly associated with an increased risk of overall cancer (AC vs. AA: OR = 1.511, 95% CI = 1.285-1.777). Furthermore, stratified analyses indicated that rs78378222 increased the risk of nervous system cancer, skin cancer and other cancer. To summarize, this meta-analysis suggested that rs78378222 C allele is a potent risk factor for overall cancer.

[A pig model of myocardial infarction by intracoronary embolization with gelatin sponge].

OBJECTIVE: We produced a large-animal model of myocardial infarction induced by transcatheter embolization of the left coronary artery using a gelatin sponge. METHODS: Seven pigs underwent transcatheter embolization of the left anterior descending artery (LAD) using gelatin sponge to produce anteroapical myocardial infarction (MI). 4 weeks later, Echocardiography, Coronary angiography and Pathology was performed, and the data were compared with those of the control group (n = 6). RESULTS: The procedure mortality was 1 of 7. In the MI group, the LV end-diastolic dimension increased (control versus MI: 37.0 mm +/- 3.4 mm and 50.8 mm +/- 6.1 mm, P < 0.01), the ejection fraction (EF) decreased (control versus MI: 62.3% +/- 2.9% and 36.6% +/- 2.1%, P < 0.001). Coronary angiography revealed the LAD remained occluded. The postmortem specimen showed a transmural MI scar in the anteroseptal and apical regions in the MI group and the LV volumes at 30 mm Hg were 81.4 ml +/- 4.3 ml, the scar areas were 18.4% +/- 1.6% of total left ventricular free wall and the scar thickness was 3.5 mm +/- 0.8 mm. Histologic samples in the MI group stained with Masson's trichrome showed massive fibrosis in the border zone and patchy fibrosis in the remote region in the LV free wall, whereas the control group showed no fibrosis. CONCLUSION: This pig model of myocardial infarction is reliable, reproducible, and similar to the human condition, amenable to investigate other investigation.