Purpose: The RNA interference effect is an alternative to antisense DNA as an experimental method of downregulating a specific target protein. Although the RNA interference effect, which is mediated by small interfering RNA (siRNA) or micro-RNA, has potential application to human therapy, the hydrodynamic method usually used for rapid administration of oligonucleotides is unsuitable for use in humans. In this study, we have investigated the antitumor activity of a synthetic siRNA, B717, which is sequence specific for the human bcl-2 oncogene, complexed with a novel cationic liposome, LIC-101.Experimental Design: In a mouse model of liver metastasis, we administered B717/LIC-101 by bolus intravenous injection, adjusting the rate and volume of administration to what is feasible in human therapy. In a mouse model bearing prostate cancer in which the cells were inoculated under the skin, B717/LIC-101 was administered subcutaneously around the tumor.Results: The B717/LIC-101 complex inhibited the expression of bcl-2 protein and the growth of tumor cell lines in vitro in a sequence-specific manner in the concentration range of 3 to 100 nmol/L. Furthermore, the complex had a strong antitumor activity when administered intravenously in the mouse model of liver metastasis. B717 (siRNA) was shown to be delivered to tumor cells in the mouse liver, but only when complexed with LIC-101. The complex also inhibited tumor cell growth in the mouse model bearing prostate cancer.Conclusions: By combining siRNA with our cationic liposome, we overcame the difficulty of administering siRNA to animals in ways that can be applied in human therapy. Although our siRNA/liposome complex is not yet in clinical trials, it is expected to provide a novel siRNA therapy for cancer patients.

The forkhead box protein 3 (FOXP3) transcription factor is highly expressed in tumor cells as well as in regulatory T cells (Tregs). It plays a tumor-enhancing role in Tregs and suppresses carcinogenesis as a potent repressor of several oncogenes. The clinical prognostic value of FOXP3 expression has not yet been elucidated. In this study, immunohistochemistry was used to investigate the prognostic significance of FOXP3 expression in tumor cells and tumor-infiltrating lymphocytes (TILs) in breast cancer patients. Of the 100 tumor specimens obtained from primary invasive breast carcinoma, 63 and 57% were evaluated as FOXP3+ tumor cells and as being highly infiltrated by FOXP3+ lymphocytes, respectively. Although FOXP3 expression in tumor cells was of no prognostic significance, FOXP3+ lymphocytes were significantly associated with poor overall survival (OS) (n=98, log-rank test P=0.008). FOXP3 exhibited a heterogeneous subcellular localization in tumor cells (cytoplasm, 31%; nucleus, 26%; both, 6%) and, although cytoplasmic FOXP3 was associated with poor OS (P= 0.058), nuclear FOXP3 demonstrated a significant association with improved OS (P=0.016). Furthermore, when patients were grouped according to their expression of tumor cytoplasmic FOXP3 and lymphocyte FOXP3, there were notable differences in the Kaplan-Meier curves for OS (P<0.001), with a high infiltration of FOXP3+ lymphocytes accompanied by a cytoplasmic FOXP3+ tumor being the most detrimental phenotype. These findings indicated that FOXP3 expression in lymphocytes as well as in tumor cells may be a prognostic marker for breast cancer. FOXP3 in tumor cells may have distinct biological activities and prognostic values according to its localization, which may help establish appropriate cancer treatments.

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Our study is focused on the relationship between the structural coherence and intrinsic carrier transport in a regioregular poly(3-hexylthiophene-2,5-diyl) (P3HT) nanofiber, particularly in an isolated nanofiber, formed in various ratios of good and poor solvent mixtures. The P3HT nanofiber, which is formed in solvent mixtures, had a whisker structure with the length of several μm, the height decreased from 9 to 2 nm as estimated by scanning force microscope observation, and the structural coherent length along the longitudinal axis increased from 40 to 59Å as determined by x-ray-diffraction measurement, with increasing ratio of the good solvent. The I -V characteristics measured by the four-probe method showed that the activation energy of hopping conduction, which was considerably related with the structural disorder, decreased with increasing ratio of the good solvent. Moreover, the field-effect-transistor characteristics of the nanofiber showed that the carrier mobility increased with increasing ratio of the good solvent, and the nanofiber formed under the good-solvent-rich condition showed the mobility from 3.8 × 10 −2 to 5.6 × 10 −2 cm 2 V −1 s −1 . The tendency of the mobility to increase has been explained on the basis of the change in the structural coherent length and thermal activation energy, assuming the model that regarded the nanofiber as a one-dimensional array of electronically coherent regions and incoherent defects, and hence the relationship between the structural coherence and carrier transport has been clarified.