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Yang L.,Kyoto University | Horibe T.,Kyoto University | Kohno M.,Kyoto University | Kohno M.,Kaigan Inc. | And 4 more authors.
Molecular Cancer Therapeutics | Year: 2012

Interleukin-4 receptor α (IL-4Rα) chain is highly expressed on the surface of various human solid tumors. We designed a novel hybrid peptide termed IL-4Rα-lytic peptide that targets the IL-4Rα chain. The IL-4Rα-lytic peptide contains a target moiety to bind to IL-4Rα and a cellular toxic lytic peptide that selectively kills cancer cells. The anticancer activity of the IL-4Rα-lytic peptide was evaluated in vitro and in vivo. It was found that the IL-4Rα-lytic peptide has cytotoxic activity in cancer cell lines expressing IL-4Rα, determined by quantitative real-time PCR. The IC 50 ratios of the lytic peptide to the IL-4Rα-lytic peptide correlated well with the expression levels of IL-4Rα on cancer cells (r = 0.80). In addition, IL-4Rα-lytic peptide administered either intratumoraly or intravenously significantly inhibited tumor growth in xenograft model of human pancreatic cancer (BXPC-3) in mice. These results indicate that the IL-4Rα-lytic peptide generated in this study has a potent and selective anticancer potential against IL-4Rα-positive solid cancers. ©2011 AACR.


PubMed | Japan Advanced Institute of Science and Technology, Kaigan Inc. and Vietnam National University, Hanoi
Type: Journal Article | Journal: The Journal of chemical physics | Year: 2015

We develop a method that combines data mining and first principles calculation to guide the designing of distorted cubane Mn(4+)Mn3(3+) single molecule magnets. The essential idea of the method is a process consisting of sparse regressions and cross-validation for analyzing calculated data of the materials. The method allows us to demonstrate that the exchange coupling between Mn(4+) and Mn(3+) ions can be predicted from the electronegativities of constituent ligands and the structural features of the molecule by a linear regression model with high accuracy. The relations between the structural features and magnetic properties of the materials are quantitatively and consistently evaluated and presented by a graph. We also discuss the properties of the materials and guide the material design basing on the obtained results.


Wakai T.,Japan Atomic Energy Agency | Inoue O.,Kaigan Inc. | Ando M.,Japan Atomic Energy Agency | Kobayashi S.,Japan Atomic Energy Agency
Nuclear Engineering and Design | Year: 2015

In Japan, the basic designing works for a demonstration plant of Japan Sodium cooled Fast Reactor (JSFR) are now conducted. JSFR is an advanced loop type reactor concept. To enhance the safety and the economic competitiveness, JSFR employs modified 9% chromium-1% molybdenum (Mod.9Cr-1Mo) steel as a material for coolant pipes and components, because the steel has both excellent high temperature strength and thermal properties. The steel has been standardized as a nuclear material in Japan Society of Mechanical Engineers (JSME) code in 2012. In JSFR pipes, demonstration of Leak Before Break (LBB) aspect is strongly expected because the safety assessment may be performed on the premise of leak rate where the LBB aspect is assured. Although the authors have already performed a series of thermal fatigue crack growth tests of austenitic stainless steel cylinders (Wakai et al., 2005), crack growth behavior in the structures made of Mod.9Cr-1Mo steel has not been investigated yet. Especially for the welded joints of Mod.9Cr-1Mo steel, "Type-IV" cracking may occur at heat affected zone (HAZ). Therefore, this study performed a series of thermal fatigue crack growth tests of thick wall cylinders made of Mod.9Cr-1Mo steel including welds, to obtain the crack growth data under cyclic thermal transients. The test results were compared to the analytical results obtained from JAEA's simplified methods (Wakai et al., 2005). © 2015.


Ueyama H.,Kyoto University | Horibe T.,Kyoto University | Nakajima O.,Kyoto University | Ohara K.,Kyoto University | And 3 more authors.
Biochemical and Biophysical Research Communications | Year: 2011

We previously reported that novel targeted " hybrid peptide" in which epidermal growth factor receptor (EGFR) binding peptide was conjugated with lytic-type peptide had selective cytotoxic activity to EGFR expressing cancer cells. In this study, we have generated a novel type hybrid peptide, semaphorin 3A lytic (Sema3A-lytic), which is composed of two functional amino acid domains: a sequence derived from Sema3A that binds to neuropilin-1 (NRP1) and a cytotoxic lytic peptide. We found that this hybrid peptide had cytotoxic activity against NRP1-positive pancreatic cancer cell lines such as BxPC-3 and Panc-1, whereas the peptide did not affect the viability of normal cells in vitro. It was also found by affinity analysis that Sema3A peptide binds to NRP1, and two arginines (372R and 377R) in Sema3A peptide are involved in the interaction with NRP1 protein. In addition, confocal microscopy analysis revealed that Sema3A-lytic peptide could not penetrate normal cells regardless of the presence of NRP1 mRNA, suggesting that the ability of Sema3A-lytic peptide to concentrate adjacent to the cell membrane by binding to NRP1 with the target-binding moiety contributes to its selective cytotoxic activity. These results indicate that Sema3A-lytic hybrid peptide would be a possible anti-cancer agent for treatment of human pancreatic cancer. © 2011 Elsevier Inc.


Horibe T.,Kyoto University | Kawamoto M.,Kyoto University | Kohno M.,Kyoto University | Kohno M.,Kaigan Inc. | Kawakami K.,Kyoto University
Journal of Bioscience and Bioengineering | Year: 2012

We previously reported that Antp-TPR hybrid peptide inhibited the interaction of Hsp90 with TPR2A and had selective cytotoxic activity discriminating between normal and cancer cells to induce cancer cell death. In this study, we investigated the cytotoxic activity of Antp-TPR peptide toward acute myeloid leukemia (AML) cells. It was demonstrated that Antp-TPR peptide induced AML cell death in cell lines such as U937, K562, THP-1, and HL-60 via activation of caspases 3 and 7, and disruption of mitochondrial membrane potential. Conversely, Antp-TPR peptide did not reduce the viability of normal cells including peripheral blood mononuclear cells (PBMCs), although both geldanamycin and 17-AAG, small-molecule inhibitors of Hsp90, mediated cytotoxicity to these normal cells at low concentrations. In addition, mutation analysis of TPR peptide demonstrated that the highly conserved amino acids Lys and Arg were critical to the cytotoxic activity. These results indicated that Antp-TPR hybrid peptide would provide potent and selective therapeutic options in the treatment of AML. © 2012 The Society for Biotechnology, Japan.


Tada N.,Kyoto University | Horibe T.,Kyoto University | Haramoto M.,Kyoto University | Ohara K.,Kyoto University | And 3 more authors.
Biochemical and Biophysical Research Communications | Year: 2011

We previously reported that novel targeted " hybrid peptide" in which epidermal growth factor receptor (EGFR) binding peptide was conjugated with lytic-type peptide had selective cytotoxic activity to EGFR expressing cancer cell lines, and in vivo analysis revealed that this EGFR-lytic peptide displayed significant antitumor activity in a xenograft model of human breast cancer which was resistant to tyrosine kinase inhibitor drugs. As an attempt to improve the selective anticancer activity of EGFR-lytic peptide, we modified the EGFR-binding peptide through introducing the mutation of amino acid according to biophysical analysis by biomolecular interaction and circular dichroism (CD) spectra. When cytotoxic activity of EGFR-lytic or EGFR(2R)-lytic hybrid peptides was investigated in various human cancer and normal cell lines, it was demonstrated that EGFR(2R)-lytic, in which second histidine (H) of EGFR-binding peptide was replaced to arginine (R) had 1.2-1.9-fold higher cytotoxic activity than that of original EGFR-lytic peptide. In vivo analysis also revealed that this modified peptide displayed significant antitumor activity at as low as 1. mg/kg dosage. These results suggest that mutated arginine on EGFR-lytic peptide produces higher binding ability to EGFR on cancer cells, and thereby the improved anticancer activity. © 2011 Elsevier Inc.


Kawamoto M.,Kyoto University | Horibe T.,Kyoto University | Kohno M.,Kyoto University | Kohno M.,Kaigan Inc. | Kawakami K.,Kyoto University
BMC Cancer | Year: 2011

Background: Transferrin receptor (TfR) is a cell membrane-associated glycoprotein involved in the cellular uptake of iron and the regulation of cell growth. Recent studies have shown the elevated expression levels of TfR on cancer cells compared with normal cells. The elevated expression levels of this receptor in malignancies, which is the accessible extracellular protein, can be a fascinating target for the treatment of cancer. We have recently designed novel type of immunotoxin, termed "hybrid peptide", which is chemically synthesized and is composed of target-binding peptide and lytic peptide containing cationic-rich amino acids components that disintegrates the cell membrane for the cancer cell killing. The lytic peptide is newly designed to induce rapid killing of cancer cells due to conformational change. In this study, we designed TfR binding peptide connected with this novel lytic peptide and assessed the cytotoxic activity in vitro and in vivo.Methods: In vitro: We assessed the cytotoxicity of TfR-lytic hybrid peptide for 12 cancer and 2 normal cell lines. The specificity for TfR is demonstrated by competitive assay using TfR antibody and siRNA. In addition, we performed analysis of confocal fluorescence microscopy and apoptosis assay by Annexin-V binding, caspase activity, and JC-1 staining to assess the change in mitochondria membrane potential. In vivo: TfR-lytic was administered intravenously in an athymic mice model with MDA-MB-231 cells. After three weeks tumor sections were histologically analyzed.Results: The TfR-lytic hybrid peptide showed cytotoxic activity in 12 cancer cell lines, with IC50values as low as 4.0-9.3 μM. Normal cells were less sensitive to this molecule, with IC50values > 50 μM. Competition assay using TfR antibody and knockdown of this receptor by siRNA confirmed the specificity of the TfR-lytic hybrid peptide. In addition, it was revealed that this molecule can disintegrate the cell membrane of T47D cancer cells just in 10 min, to effectively kill these cells and induce approximately 80% apoptotic cell death but not in normal cells. The intravenous administration of TfR-lytic peptide in the athymic mice model significantly inhibited tumor progression.Conclusions: TfR-lytic peptide might provide a potent and selective anticancer therapy for patients. © 2011 Kawamoto et al; licensee BioMed Central Ltd.


Matsumoto K.,Chuo University | Honda M.,Chuo University | Ito Y.,Kaigan Inc. | Shirai D.,Chuo University
International Journal of Refrigeration | Year: 2014

Frosting to a cooling solid surface is often unavoidable and is severe problems. Thus, in order to control the frosting, it is necessary to clarify the mechanism of frosting, both scientifically and technologically. Furthermore, when investigating this mechanism, knowing how frost crystals start to form and grow is very important, therefore, frosting from generation to primary growth stage must be clarified. Since frost crystals dimensions are very small in their generation and primary growth stage, it is essential to conduct these investigations at the micro scale level. In this study, using a scanning probe microscope (SPM), frost crystals dimensions/distribution and scraping force of frost crystals, were measured under fixed surface temperatures, comparing influence of humidity with that of surface temperature via a method proposed by one of the authors. Then, correlations among the above frost crystals dimensions/distribution and scraping force were clarified, comparing with influence of cooling solid surface temperature. © 2013 Elsevier Ltd and IIR. All rights reserved.


Matsumoto K.,Chuo University | Ito Y.,Kaigan Inc. | Hayashi K.,Chuo University | Murahashi K.,Chuo University | And 2 more authors.
International Journal of Refrigeration | Year: 2013

Since frosting to a cooling solid surface has caused many serious accidents accompanied by economic losses, it is necessary to clarify the mechanism of frosting to the cooling solid surface both scientifically and technologically. Thus, at first clarification of frosting from generation to primary stage of growth is very important. And considering the size of frost crystals until the primary stage, it is essential to investigate frost crystals in nano/micro scale field. In this paper, using a scanning probe microscope (SPM), frost crystals dimensions/distribution and scraping force of frost crystals were measured based on the method proposed by one of authors, under a fixed humidity varying cooling solid surface temperatures. And then, the correlations among frost crystals dimensions/distribution and scraping force were clarified. © 2012 Elsevier Ltd and IIR. All rights reserved.


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