The value of the left atrial appendage orifice perimeter of 3D model based on 3D TEE data in the choice of device size of LAmbre™ occluder.

Preoperative optimal selection of the occluder size is crucial in percutaneous left atrial appendage (LAA) occlusion, and the maximal width of the LAA orifice is the main reference index, however it can not fully meet the practical operation requirements. We retrospectively analyzed three-dimensional (3D) transesophageal echocardiography (TEE) and computed tomography (CT) imaging dataset of the 41 patients who underwent LAA occlusion with LAmbre™ system. The LAA orifice parameters were overall evaluated to determine their role in device size selection. Eight LAA 3D models of the four cases who had been replaced their device during the procedure based on TEE and CT were printed out to verify the optimal parameter decision strategy. There was a significant concordance of the results between 3D TEE and CT in the LAA orifice evaluation. The correlations between the perimeter and maximal width measurements by 3D TEE and the closure disk of the device were stronger than that between the area measurements and the closure disk (r = 0.93, 0.95, 0.86, respectively and p < 0.001 all), and the result was similar to that by CT (r = 0.92, 0.93, 0.84, respectively and p < 0.001 all). The ratios of the maximal width to the minimal width of the four cases were all > 1.4, however the rest 37 cases were all ≤ 1.4. Based on the comprehensive assessment of the LAA orifice perimeter and maximal width of the 3D printed models, the experiments were all succeed just for one try. The LAA orifice perimeter of 3D printed model based on 3D TEE may help in choosing the optimal device size of LAmbre™, especially for the LAA with flater ostial shape.

Ultrasound combined with targeted cationic microbubble-mediated angiogenesis gene transfection improves ischemic heart function.

The present study aimed to construct targeted cationic microbubbles (TCMBs) by synthesizing cationic microbubbles conjugated to an intercellular adhesion molecule-1 (ICAM-1) antibody, and then to use the TCMBs to deliver the angiopoietin-1 (Ang-1) gene into infarcted heart tissue using ultrasound-mediated microbubble destruction. It was hypothesized that the TCMBs would accumulate in higher numbers than non-targeted cationic microbubbles (CMBs) in the infarcted heart, and would therefore increase the efficiency of targeted Ang-1 gene transfection and promote angiogenesis. The results of the study demonstrated that the ability of TCMBs to target inflammatory endothelial cells was 18.4-fold higher than that of the CMBs in vitro. The accumulation of TCMBs was greater than that of CMBs in TNF-α-stimulated human umbilical cord veins, indicated by a 212% higher acoustic intensity. In vivo, the TCMBs specifically accumulated in the myocardial infarct area in a rabbit model. Three days after ultrasound microbubble-mediated gene transfection, Ang-1 protein expression in the TCMB group was 2.7-fold higher than that of the CMB group. Angiogenesis, the thickness of the infarct region and the heart function of the TCMB group were all significantly improved compared with those in the CMB and control groups at 4 weeks following gene transfection (all P<0.01). Therefore, the results of the current study demonstrate that ultrasound-mediated TCMB destruction effectively delivered the Ang-1 gene to the infarcted myocardium, resulting in improved cardiac morphology and function in the animal model. Ultrasound-mediated TCMB destruction is a promising strategy for improving gene therapy in the future.

Improving the efficacy of therapeutic angiogenesis by UTMD-mediated Ang-1 gene delivery to the infarcted myocardium.

This study aimed to verify the feasibility and efficacy of ultrasound-targeted microbubble destruction (UTMD)-mediated angiopoietin-1 (Ang-1) gene delivery into the infarcted myocardium. Microbubbles carrying anti-intercellular adhesion molecule-1 (ICAM-1) antibody were prepared and identified. The microbubbles carrying anti-ICAM-1 antibody selectively adhered to the interleukin (IL)-1ß-stimulated ECV304 cells and to the ischemic vascular endothelium, and the infarct area was examined to evaluate the targeting ability of ICAM-1 microbubbles in vitro and in vivo. The intravenous administration of the Ang-1 gene was carried out by UTMD in rabbits with acute myocardial infarction (AMI). The rabbits were divided into the control (no treatment), non-targeted microbubble destruction (non-TMB) and the ICAM-1 TMB (TMB) group. Gene delivery by direct intramyocardial injection (IMI) served as a reference. Two weeks later, regional myocardial perfusion and cardiac function were evaluated by echocardiography, and Ang-1 gene-mediated angiogenesis was assessed histologically and biochemically. The results revealed that the ICAM-1-targeted microbubbles selectively adhered to the IL-1ß-stimulated ECV304 cells in vitro and to the ischemic vascular endothelium in the infarct area of the rabbits with AMI. Two weeks after the delivery of the Ang-1 gene, compared with the non-TMB group, left ventricular function and myocardial perfusion at the infarct area had improved in the TMB and IMI group (p<0.01). Ang-1 gene expression was detectable in the non-TMB, TMB and IMI group, while its expression was higher in the latter 2 groups (all p<0.01). The microvascular density (MVD) of the infarct area in the non-TMB, TMB and IMI group was 65.6 ± 4.4, 96.7 ± 2.1 and 100.7 ± 3.6, respectively (p<0.01). The findings of our study indicate that UTMD-mediated gene delivery may be used to successfully deliver the Ang-1 gene to the infarcted myocardium, thus improving the efficacy of therapeutic angiogenesis. This may provide a novel strategy for future gene therapy.

[Expression of Smad4 and Smad7 of BMP signaling pathway in oral squamous cell carcinoma].

PURPOSE: To observe the changes of the expressions of Smad4 and Smad7 in oral squamous cell carcinoma and adjacent normal tissue, and to investigate the effects of Smad4 and Smad7 on occurrence and development of oral squamous cell carcinoma (OSCC). METHODS: Seventy-two cases with OSCC which were pathologically confirmed were included in the study. Cancer tissue and adjacent normal tissue were taken to make slices. SP immunohistochemical method was used to detect the expression of Smad4 and Smad7 in oral squamous cell carcinoma and adjacent normal tissue. SPSS11.5 software package was used for statistical analysis. RESULTS: The positive expression rate of Smad4 protein was 69.44% in adjacent normal tissues, and it was 45.83% in oral squamous cell carcinoma(P<0.05). The positive expression rate of Smad4 was lower when the degree of differentiation decreased; The positive expression rate of Smad4 with lymph node metastasis was 22.50%, while it was 65.63% without lymph node metastasis(P<0.05). The positive expression rate of Smad7 protein in adjacent normal tissues was 19.44%, and it was 83.33% (P<0.05) in oral squamous cell carcinoma, the positive expression rate of Smad7 was higher when the degree of differentiation decreased. The positive expression rate of Smad7 with lymph node metastasis was 92.50%, while it was 68.75%(P<0.05) without lymph node metastasis. CONCLUSIONS: The expression of Smad4 is significantly reduced in cancer tissues and the expression is lower when the degree of differentiation decreased; the expression rate of Smad4 with lymph node metastasis is lower compared with those without lymph node metastasis. Smad7 has the opposite effect. Loss of expression of Smad4 may contribute to the development and metastasis of oral squamous cell carcinoma. Over-expression of Smad7 may promote the development and metastasis of oral squamous cell carcinoma. The inhibition of BMP/Smads signaling pathway may result in the occurrence and development of oral squamous cell carcinoma continually. Supported by Science and Technology Development Plan (2010GSF10239) of Shandong Province and Science and Technology Special Project of Shandong Province (2012G0021852).