Treatment of PTEN-Null Breast Cancer by a Synthetic Lethal Approach Involving PARP1 Gene Silencing.

The loss of the phosphatase and tensin homolog (PTEN) deleted from chromosome 10 is frequently observed in a variety of human cancers and appears to be an ideal target in synthetic lethality-based treatment. In this study, the synthetic lethal interaction between PTEN loss and the gene silencing of poly [ADP-ribose] polymerase 1 (PARP1) was examined in human triple-negative breast cancer cells (PTEN-null MDA-MB-468 and PTEN-positive MDA-MB-231 cells). Polycation liposomes previously developed by us were employed to deliver the small interfering ribonucleic acid (siRNA) targeted toward PARP1 (siPARP1) into the cancer cells. The silencing of the PARP1 gene exerted a cytocidal effect on the MDA-MB-468 cells but had no effect on the MDA-MB-231 cells and the human umbilical vein endothelial cells employed as normal cells. The simultaneous knockdown of PARP1 and PTEN in the MDA-MB-231 cells resulted in the significant inhibition of cell growth. The data suggest that the effects of the PARP1 knockdown on the cells were dependent on the PTEN status. A significant increase in the DNA breaks and the extent of apoptosis, possibly due to the failure of DNA repair, was observed upon PARP1 knockdown in the MDA-MB-468 cells compared with the case in the MDA-MB-231 cells. Our findings suggest that the synthetic lethal approach via PARP1 gene silencing holds promise for the treatment of patients with PTEN-null breast cancer.

Design of a Novel PEGylated Liposomal Vector for Systemic Delivery of siRNA to Solid Tumors.

A small interfering RNA (siRNA) delivery system using dioleylphosphate-diethylenetriamine conjugate (DOP-DETA)-based liposomes (DL) was assessed for systemic delivery of siRNA to tumors. DL carrying siRNA capable of inducing efficient gene silencing with low doses of siRNA were modified with polyethylene glycol (PEG-DL/siRNA) for systemic injection of siRNA. The biodistribution of DL and siRNA in the PEG-DL/siRNA was studied by using radiolabeled DL and fluorescence-labeled siRNA, respectively. DL in the PEG-DL/siRNA showed a high retention in the plasma, accumulation in the tumor, and low accumulation in the liver and spleen after intravenous injection. The in vivo effects of PEGylation were observed only when distearoylphosphatidylethanolamine (DSPE)-PEG but not distearoylglycerol (DSG)-PEG were used. This result suggests that the electrostatic interaction between lipid molecules on the surface of PEG-DL/siRNA was a critical determinant for the in vivo effect of PEGylation. When PEG-DL/siRNA (0.1 mg/kg siRNA) was intravenously injected into tumor-bearing mice, in vivo gene silencing was observed in subcutaneous tumors. These results indicate that PEG-DL/siRNA designed in this study is a promising formulation for systemic use of siRNA.

[Evaluation of change in the optimal image reconstruction phase in retrospective ECG-gated reconstruction].

The purpose of this study was to optimize the reconstruction phase in order to improve depiction of the coronary artery in the relative delay method of the retrospective electrocardiogram (ECG)-gated reconstruction technique using a multi-slice computed tomography (MSCT) scanner with four channels. The following items were evaluated; 1) image quality of the coronary arteriogram, 2) degree of difference between the standard phase corresponding to the diastasis period and the selected phase, which was determined in each case to obtain the best image, and 3) the factors causing the phase difference. The image quality in the selected phase was better than that in the standard phase. A positive correlation was observed between the degree of phase difference and the median value and standard deviation of the heart rate. The degradation of image quality was remarkable in cases showing a large degree of phase difference. A negative correlation was observed between image quality in the selected phase and the degree of phase difference. Individualizing the reconstruction phase is required to improve the image quality of coronary arteriograms with MSCT. It should be noted that the condition of a low and stable heart rate results in reduction in the degree of phase difference, which is useful for the acquisition of better images.

[Measurement of modulation transfer function in Z-axis for multi-slice spiral CT using the micro-disk method: comparison with the bead method and examination of geometric influence].

Many methods of measuring the section-sensitive profile (SSP) of computed tomography (CT) by the input of a delta function have been reported. In Japan, the bead method is used as a common measurement because of the high flexibility of the multi-purpose method. However, the intensity of the response of the bead method tends to decline, creating a relatively large error in the base of section-sensitive profiles. A problem is considered to be the accuracy of measurement in evaluating spatial resolution along the z-axis in multi-slice spiral/helical CT (MSCT). We therefore evaluated the modulation transfer function (MTF) by conducting research with the micro-disk method (100 micro m thickness and 1.0 mmphi diameter) and the bead method (1.0 mmphi diameter) for the same input width. Moreover, in the micro-disk method, we also examined alignment, circular region of interest (ROI), and the energy characteristic. Our comparison of MTFs obtained by the micro-disk method and the bead method showed that the former resulted in a higher value and lower standard deviation. The difference was significant at p<0.01. Measurement using the micro-disk method did not show significant differences in terms of alignment and ROIs. Moreover, the energy characteristic was not indicated. This research demonstrated that the accuracy of MTF measurement with the micro-disk method was greater than that with the bead method, and it was found that there was no influence on the actual measurement level of the geometric structure with the micro-disk method.