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Search Results: 1 - 10 of 2257 matches for " Koji Kawakami "
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Clinical Research in Japan: ways to Alleviate Unnecessary Regulatory Burdens - DOI: 10.3395/reciis.v1i1.44en
Koji Kawakami,Hiroko Yamane
RECIIS : Electronic Journal of Communication, Information & Innovation in Health , 2007,
Abstract: For drug discovery and development today, synergy between pure science, clinical research, and the organization of clinical trials is essential. In Japan, there is a delay in the institutional response to this need. This paper identifies one of the bottlenecks in the Japanese regulatory process. Clinical research undertaken by university researchers and medical doctors are not integrated into the Japanese drug approval procedure. Therefore, their efforts and research data are wasted in the inherently unpredictable nature of long and costly biomedical research. Collaborative efforts between companies and researchers/medical doctors should be encouraged through institutional incentives, by integrating university and medical clinical research ab initio into regulatory process. In order to achieve this, it would be necessary to promote commercial exchange of database information and short-term employment of researchers in those projects leading to regulatory approval.
Biased Safety Reporting in Blinded Randomized Clinical Trials: Meta-Analysis of Angiotensin Receptor Blocker Trials
Nobuyoshi Takabayashi, Hisashi Urushihara, Koji Kawakami
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0075027
Abstract: Background Cough is listed as an adverse drug reaction (ADR) on the labels of angiotensin receptor blockers (ARB). However, a causal association with cough has also been reported for angiotensin converting enzyme inhibitors (ACEI), which have frequently been used as comparator drugs in the registration clinical trials of ARBs. This prompted us to examine the possible influence of using comparator drugs with well-known ADRs on the safety reporting of investigational drugs in blinded randomized clinical trials. Methods and Findings The double-blinded, randomized clinical trials with comparator drugs were identified in the Japanese dossiers for the new drug applications of ARBs. The risk ratios (RR) of reporting cough and headache in ARB arms were calculated for each ARB by comparing trials using ACEIs and trials using non-ACEIs, were then combined with a meta-analysis. 23 trials with a total of 6643 patients were identified, consisting 6 trials using an ACEI comparator including 819 ARB patients and 17 trials using a non-ACEI comparator including 5824 ARB patients. The combined RR of cough reporting was significantly elevated (20.77; 95% confidence interval [CI], 7.47 to 57.76), indicating more frequent reporting of cough in clinical trials using an ACEI comparator. In contrast, the combined RR of headache, a negative control, was insignificant (1.45; 95% CI, 0.34 to 6.22). Conclusion The use of comparators with well-known ADRs in blinded randomized trials produces potential bias in the reporting frequency of ADRs for investigational drugs. The selection of appropriate comparator drugs should be critical in unbiased safety assessment in double-blinded, randomized clinical trials and thus have relevance in reviewing the safety results from a regulatory point of view.
Patterns and Trends in Diagnostic Tests Used for Detection of Colorectal Cancer after Screening with the Immunochemical Fecal Occult Blood Test in Japan  [PDF]
Junta Yamamichi, Kahori Seto, Shiro Hinotsu, Koichi Nagata, Yasutoshi Kobayashi, Hisashi Urushihara, Koji Kawakami
Open Journal of Clinical Diagnostics (OJCD) , 2015, DOI: 10.4236/ojcd.2015.53018
Abstract: According to the guidelines by the Japanese government, optical colonoscopy is the most strongly recommended diagnostic test after screening with the immunochemical fecal occult blood test (iFOBT), followed by double-contrast barium enema (BE) or sigmoidoscopy. Our study was to assess patterns and trends of colorectal cancer (CRC) diagnostic testing within 2 years after iFOBT. We analyzed both iFOBT results and claims data provided by employee health insurance societies in Japan from 2005 to 2010. 25,596 enrollees underwent iFOBT screening. The positive rate was 5.1%. 32.3% of those positive underwent diagnostic tests and 1.0% (12 patients) were confirmed as having cancer. The most common test was optical colonoscopy (77.2% of total tests), followed by BE (16.2%). From 2006 to 2009, the rate of optical colonoscopy for females increased from 55% to 82% and that of BE declined from 36% to 12%, while no significant changes were seen for males. Only one-third of those who tested positive underwent diagnostic test in the 2 years following screening iFOBT. As official guidelines for diagnostic testing of CRC recommend, optical colonoscopy is now the most commonly used diagnostic test after positive iFOBT result for enrollees in employee health insurance societies in Japan.
Designed hybrid TPR peptide targeting Hsp90 as a novel anticancer agent
Tomohisa Horibe, Masayuki Kohno, Mari Haramoto, Koji Ohara, Koji Kawakami
Journal of Translational Medicine , 2011, DOI: 10.1186/1479-5876-9-8
Abstract: We focused on the interaction of Hsp90 with its cofactor protein p60/Hop, and engineered a cell-permeable peptidomimetic, termed "hybrid Antp-TPR peptide", modeled on the binding interface between the molecular chaperone Hsp90 and the TPR2A domain of Hop.It was demonstrated that this designed hybrid Antp-TPR peptide inhibited the interaction of Hsp90 with the TPR2A domain, inducing cell death of breast, pancreatic, renal, lung, prostate, and gastric cancer cell lines in vitro. In contrast, Antp-TPR peptide did not affect the viability of normal cells. Moreover, analysis in vivo revealed that Antp-TPR peptide displayed a significant antitumor activity in a xenograft model of human pancreatic cancer in mice.These results indicate that Antp-TPR peptide would provide a potent and selective anticancer therapy to cancer patients.Heat-shock protein 90 (Hsp90) is a molecular chaperone [1] that participates in the quality control of protein folding. The mechanism of action of Hsp90 includes sequential ATPase cycles and the stepwise recruitment of cochaperones, including Hsp70, CDC37, p60/Hsp-organizing protein (Hop), and p23 [2,3]. In particular, Hsp90 and Hsp70 interact with numerous cofactors containing so-called tetratricopeptide repeat (TPR) domains. TPR domains are composed of loosely conserved 34-amino acid sequence motifs that are repeated between one and 16 times per domain. Originally identified in components of the anaphase-promoting complex [4,5], TPR domains are now known to mediate specific protein interactions in numerous cellular contexts [6-8]. Moreover, apart from serving mere anchoring functions, TPR domains of the chaperone cofactors Hip and p60/Hop also are able to regulate the ATPase activities of Hsp70 and Hsp90, respectively [9,10]. Each 34-amino acid motif forms a pair of antiparallel α-helices. These motifs are arranged in a tandem array into a superhelical structure that encloses a central groove. The TPR-domain-containing cofactors of the Hsp70/Hsp
A novel transferrin receptor-targeted hybrid peptide disintegrates cancer cell membrane to induce rapid killing of cancer cells
Megumi Kawamoto, Tomohisa Horibe, Masayuki Kohno, Koji Kawakami
BMC Cancer , 2011, DOI: 10.1186/1471-2407-11-359
Abstract: 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.The TfR-lytic hybrid peptide showed cytotoxic activity in 12 cancer cell lines, with IC50 values as low as 4.0-9.3 μM. Normal cells were less sensitive to this molecule, with IC50 values > 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.TfR-lytic peptide might provide a potent and selective anticancer therapy for patients.The transferrin receptor (TfR) is a cell-membrane-associated glycoprotein involved in the cellular uptake of iron and the regulation of cell growth [1]. Iron is a required cofactor of heme and nonheme proteins involved in a variety of cellular processes including metabolism and DNA synthesis [2,3]. Therefore, various studies have shown elevated levels of TfR expression on cancer cells when compared with their normal counterparts [4-13]. Bladder-transitional cell carcinomas, breast cancer, glioma, lung adenocarcinoma, chronic lymphocytic leukemia, and non-Hodgkin's lymphoma also showed increased TfR expression that correlated with tumor grade and stage or prognosi
Molecular mechanism of cytotoxicity induced by Hsp90-targeted Antp-TPR hybrid peptide in glioblastoma cells
Horibe Tomohisa,Torisawa Aya,Kohno Masayuki,Kawakami Koji
Molecular Cancer , 2012, DOI: 10.1186/1476-4598-11-59
Abstract: Background Heat-shock protein 90 (Hsp90) is vital to cell survival under conditions of stress, and binds client proteins to assist in protein stabilization, translocation of polypeptides across cell membranes, and recovery of proteins from aggregates. Therefore, Hsp90 has emerged as an important target for the treatment of cancer. We previously reported that novel Antp-TPR hybrid peptide, which can inhibit the interaction of Hsp90 with the TPR2A domain of Hop, induces selective cytotoxic activity to discriminate between normal and cancer cells both in vitro and in vivo. Results In this study, we investigated the functional cancer-cell killing mechanism of Antp-TPR hybrid peptide in glioblastoma (GB) cell lines. It was demonstrated that Antp-TPR peptide induced effective cytotoxic activity in GB cells through the loss of Hsp90 client proteins such as p53, Akt, CDK4, and cRaf. Antp-TPR also did not induce the up-regulation of Hsp70 and Hsp90 proteins, although a small-molecule inhibitor of Hsp90, 17-AAG, induced the up-regulation of these proteins. It was also found that Antp-TPR peptide increased the endoplasmic reticulum unfolded protein response, and the cytotoxic activity of this hybrid peptide to GB cells in the endoplasmic reticulum stress condition. Conclusion These results show that targeting of Hsp90 by Antp-TPR could be an attractive approach to selective cancer-cell killing because no other Hsp90-targeted compounds show selective cytotoxic activity. Antp-TPR might provide potent and selective therapeutic options for the treatment of cancer.
Targeted Anticancer Immunotoxins and Cytotoxic Agents with Direct Killing Moieties
Koji Kawakami,Oumi Nakajima,Ryuichi Morishita,Ryozo Nagai
The Scientific World Journal , 2006, DOI: 10.1100/tsw.2006.162
An RSA Encryption Hardware Algorithm using a Single DSP Block and a Single Block RAM on the FPGA
Song Bo,Kensuke Kawakami,Koji Nakano,Yasuaki Ito
International Journal of Networking and Computing , 2011,
Abstract: The main contribution of this paper is to present an efficient hardware algorithm for RSA encryption/decryption based on Montgomery multiplication. Modern FPGAs have a number of embedded DSP blocks (DSP48E1) and embedded memory blocks (BRAM). Our hardware algorithm supporting 2048-bit RSA encryption/decryption is designed to be implemented using one DSP48E1, one BRAM and few logic blocks (slices) in the Xilinx Virtex-6 family FPGA. The implementation results showed that our RSA module for 2048-bit RSA encryption/decryption runs in 277.26ms. Quite surprisingly, the multiplier in DSP48E1 used to compute Montgomery multiplication works in more than 97% clock cycles over all clock cycles. Hence, our implementation is close to optimal in the sense that it has only less than 3% overhead in multiplication and no further improvement is possible as long as Montgomery multiplication based algorithm is used. Also, since our circuit uses only one DSP48E1 block and one Block RAM, we can implement a number of RSA modules in an FPGA that can work in parallel to attain high throughput RSA encryption/decryption.
Oseltamivir Prescription and Regulatory Actions Vis-à-Vis Abnormal Behavior Risk in Japan: Drug Utilization Study Using a Nationwide Pharmacy Database
Hisashi Urushihara, Yuko Doi, Masaru Arai, Toshiyuki Matsunaga, Yosuke Fujii, Naoko Iino, Takashi Kawamura, Koji Kawakami
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0028483
Abstract: Background In March 2007, a regulatory advisory was issued in Japan to restrict oseltamivir use in children aged 10-19 years because of safety concerns over abnormal behavior. The effectiveness and validity of regulatory risk minimization actions remain to be reviewed, despite their significant public health implications. To assess the impact of the regulatory actions on prescribing practices and safety reporting. Methodoloy/Prinicpal Findings In this retrospective review of a nationwide pharmacy database, we analyzed 100,344 dispensation records for oseltamivir and zanamivir for the period from November 2006 to March 2009. The time trend in dispensations for these antiviral agents was presented before and after the regulatory actions, contrasted with intensity of media coverage and the numbers of spontaneous adverse reaction reports with regard to antivirals. The 2007 regulatory actions, together with its intense media coverage, reduced oseltamivir dispensation in targeted patients in fiscal year 2008 to 20.4% of that in fiscal year 2006, although influenza activities were comparable between these fiscal years. In contrast, zanamivir dispensation increased approximately nine-fold across all age groups. The number of abnormal behavior reports associated with oseltamivir in children aged 10-19 years decreased from fiscal year 2006 to 2008 (24 to 9 cases); this decline was offset by the increased number of reports of abnormal behavior in children under age 10 (12 to 28 cases). The number of reports associated with zanamivir increased in proportion to increased dispensation of this drug (11 to 114 cases). Conclusions/Significance The 2007 actions effectively reduced oseltamivir prescriptions and the number of reports of abnormal behavior in the targeted group. The observed increase in abnormal behavior reports in oseltamivir patients under age 10 and in zanamivir patients suggests that these patient groups may also be at risk, calling into question the validity of the current discrimination by age and agent (translation is available in Japanese: Appendix S1).
Targeting Interleukin-4 Receptor Alpha by Hybrid Peptide for Novel Biliary Tract Cancer Therapy
Kahori Seto,Junichi Shoda,Tomohisa Horibe,Eiji Warabi,Masayuki Kohno,Toru Yanagawa,Hiroki Bukawa,Yasuni Nakanuma,Koji Kawakami
International Journal of Hepatology , 2014, DOI: 10.1155/2014/584650
Abstract: It is known that the interleukin-4 receptor α (IL-4Rα) is highly expressed on the surface of various human solid tumors. We previously designed novel IL-4Rα-lytic hybrid peptide composed of binding peptide to IL-4Rα and cell-lytic peptide and reported that the designed IL-4Rα-lytic hybrid peptide exhibited cytotoxic and antitumor activity both in vitro and in vivo against the human pancreatic cancer cells expressing IL-4Rα. Here, we evaluated the antitumor activity of the IL-4Rα-lytic hybrid peptide as a novel molecular targeted therapy for human biliary tract cancer (BTC). The IL-4Rα-lytic hybrid peptide showed cytotoxic activity in six BTC cell lines with a concentration that killed 50% of all cells (IC50) as low as 5?μM. We also showed that IL-4Rα-lytic hybrid peptide in combination with gemcitabine exhibited synergistic cytotoxic activity in vitro. In addition, intravenous administration of IL-4Rα-lytic hybrid peptide significantly inhibited tumor growth in a xenograft model of human BTC in vivo. Taken together, these results indicated that the IL-4Rα-lytic hybrid peptide is a potent agent that might provide a novel therapy for patients with BTC. 1. Introduction Biliary tract cancer such as gallbladder cancer and extrahepatic bile duct cancer as well as intrahepatic bile duct cancer (one of the primary liver cancers) is likely to undergo metastasis to the peritoneum (peritoneal dissemination) or the liver at early stages and is often resistant to conventional chemotherapy and radiotherapy. These cancers have been thus viewed as intractable cancers unlikely to be cured completely. In Japan, the incidence of biliary tract cancer and intrahepatic bile duct cancer is about 10 out of every 100,000 people [1]. As for intrahepatic bile duct cancer, both the incidence and death rate have been rising in Japan in recent years, resembling the trend observed in western countries [2, 3]. In Japan, gemcitabine and S-1 have recently begun to be used for anticancer chemotherapy, and these drugs are expected to prolong the survival period of patients as compared to existing anticancer drugs [4]. However, because of frequent adverse events of the hematological system arising from these drugs and because of compromised hepatic function often noted in patients with intrahepatic bile duct cancer due to accompanying liver cirrhosis and in those with extrahepatic bile duct cancer or gallbladder cancer due to accompanying obstructive cholestasis, treatment with these drugs has to be discontinued or stopped. To improve the outcome of treatment of these cancers, it is very
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