MSC-based VEGF gene therapy in rat myocardial infarction model using facial amphipathic bile acid-conjugated polyethyleneimine

Mesenchymal stem cells (MSCs) have attracted much attention in regenerative medicine owing to their apparent usefulness as multi-potent replacement cells. The potential of MSC therapy can be further improved by transforming MSCs with therapeutic genes that maximize the efficacy of gene therapy and their own therapeutic ability. Since most conventional transfection methodologies have shown marginal success in delivering exogenous genes into primary cultured cells, efficient gene transfer into primary MSCs is a prerequisite for the development of MSC-based gene therapy strategies to achieve repair and regeneration of damaged tissues. Herein, facially amphipathic bile acid-modified polyethyleneimine (BA-PEI) conjugates were synthesized and used to transfer hypoxia-inducible vascular endothelial growth factor gene (pHI-VEGF) in MSCs for the treatment of rat myocardial infarction. Under the optimized transfection conditions, the BA-PEI conjugates significantly increased the VEGF protein expression levels in rat MSCs, compared with traditional transfection methods such as Lipofectamine™ and branched-PEI (25 kDa). Furthermore, the prepared pHI-VEGF-engineered MSCs (VEGF-MSCs) resulted in improved cell viability, particularly during severe hypoxic exposure in vitro. The transplantation of MSCs genetically modified to overexpress VEGF by BA-PEI enhanced the capillary formation in the infarction region and eventually attenuated left ventricular remodeling after myocardial infarction in rats. This study demonstrates the applicability of the BA-PEI conjugates for the efficient transfection of therapeutic genes into MSCs and the feasibility of using the genetically engineered MSCs in regenerative medicine for myocardial infarction.     

Prognostic impact of membranous ATP-binding cassette Sub-family G member 2 expression in patients with colorectal carcinoma after surgical resection

ATP-binding cassette sub-family G member 2 (ABCG2) is a transporter protein that has been associated with multidrug resistance and poor prognosis in several types of cancers. In colorectal cancers, however, the prognostic value of ABCG2 expression is not yet clear. ABCG2 expression was analyzed by immunohistochemistry using tissue microarrays in 234 consecutive patients who underwent surgical resection. The ABCG2 expression level was defined by the composite score, determined by multiplying intensity and percentage of tumor staining scores. This was dichotomized at the median, and the association of ABCG2 expression with disease severity and patient survival was determined. ABCG2 expression in the cytoplasm and membrane was observed in 77.8% and 61.5% of the samples, respectively. High expression of ABCG2 in both the cytoplasm and membrane was found more frequently in well-differentiated lesions (P < 0.05). High expression of membranous ABCG2 was significantly associated with better overall survival (hazard ratio [HR], 0.624; 95% confidence interval [CI], 0.411–0.948; P = 0.027) and disease-specific survival (HR, 0.499; 95% CI, 0.308 - 0.808; P = 0.005) compared to low expression. However, cytoplasmic expression of ABCG2 was not significantly associated with patient survival. The expression level of membranous ABCG2 in colorectal tumors can predict post-operative patient survival, suggesting the potential for ABCG2 as a prognostic biomarker.     

Efficacy of cabazitaxel in mouse models of pediatric brain tumors

Background

There is an unmet need in the treatment of pediatric brain tumors for chemotherapy that is efficacious, avoids damage to the developing brain, and crosses the blood-brain barrier. These experiments evaluated the efficacy of cabazitaxel in mouse models of pediatric brain tumors.

Methods

The antitumor activity of cabazitaxel and docetaxel were compared in flank and orthotopic xenograft models of patient-derived atypical teratoid rhabdoid tumor (ATRT), medulloblastoma, and central nervous system primitive neuroectodermal tumor (CNS-PNET). Efficacy of cabazitaxel and docetaxel were also assessed in the Smo/Smo spontaneous mouse medulloblastoma tumor model.

Results

This study observed significant tumor growth inhibition in pediatric patient-derived flank xenograft tumor models of ATRT, medulloblastoma, and CNS-PNET after treatment with either cabazitaxel or docetaxel. Cabazitaxel, but not docetaxel, treatment resulted in sustained tumor growth inhibition in the ATRT and medulloblastoma flank xenograft models. Patient-derived orthotopic xenograft models of ATRT, medulloblastoma, and CNS-PNET showed significantly improved survival with treatment of cabazitaxel.

Conclusion

These data support further testing of cabazitaxel as a therapy for treating human pediatric brain tumors.     

Relationship between stent malapposition and incomplete neointimal coverage after drug-eluting stent implantation

Background: Using optical coherence tomography (OCT), we evaluated the relationship between malapposed and uncovered struts following implantation of drug‐eluting stents (DESs). Methods: A total of 271 patients with 306 lesions who underwent DES implantation and follow‐up OCT were included in the study. The lesions were grouped based on the presence of malapposition and then by the median value of the percentage of malapposed struts (1.3%) to produce 3 groups: lesions without malapposition (group I, n = 232) and those with percentage of malapposed struts <1.3% (group II, n = 37) or ≥1.3% (group III, n = 37). Percentages of malapposed and uncovered struts were calculated as percent ratio of malapposed or uncovered to total struts in the defined cross‐sections, respectively. We compared percentage of uncovered struts in all analyzable struts and in the residual struts without malapposed segments among the 3 groups. Results: Group III showed a significantly larger percentage of uncovered struts among all the struts (group I, 3.7 ± 6.4 vs. II, 5.5 ± 5.6 vs. III, 17.6 ± 15.9%, P < 0.001) and among residual struts without malapposed segments (3.7 ± 6.4 vs. 5.2 ± 5.7 vs. 15.0 ± 14.4%, respectively, P < 0.001). There was a significant correlation between malapposed and uncovered struts in group III (r = 0.393, P = 0.016), but not in group II (r =?0.007, P = 0.965) among residual struts without malapposed segments. Conclusion: The percentage of uncovered DES struts was quite different depending on the presence and extent of malapposed struts. (J Interven Cardiol 2012;25:270–277)