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Predecessor
Volume 133, Issue 3
Displaying 1-20 of 20 articles from this issue
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Symposium Reviews
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Fuminori Sakurai, Masuo Kondoh2013 Volume 133 Issue 3 Pages 289
Published: 2013
Released on J-STAGE: March 01, 2013
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Fuminori Sakurai, Toshiyoshi Fujiwara, Hiroyuki Mizuguchi2013 Volume 133 Issue 3 Pages 291-296
Published: March 01, 2013
Released on J-STAGE: March 01, 2013
JOURNAL FREE ACCESSAn easy and sensitive detection method for circulating tumor cells (CTC) is expected to be developed because CTC are a promising biomarker for early diagnosis of tumors and prognosis prediction of tumor patients. Our group has already developed a CTC detection method using a conditionally replicating adenovirus (Ad) which efficiently replicates and expresses GFP in telomerase-positive tumor cells. However, malignant tumor cells express much low levels of coxsackievirus and adenovirus receptor (CAR), leading to inefficient infection with a conventional conditionally replicating Ad. In addition, a tiny fraction of normal blood cells, including lymphocytes, express GFP following infection. To overcome these problems, we have developed a next-generation conditionally replicating Ad. The next-generation conditionally replicating Ad possesses the fiber protein derived from Ad serotype 35, leading to efficient infection in both CAR-positive and -negative tumor cells, because the fiber protein of Ad serotype 35 binds to CD46, which is expressed on almost all human cells. Furthermore, sequences complementary to blood cell-specific miRNA (miR-142-3p) were inserted into the 3′ untranslated region of the E1 gene and GFP gene, leading to the suppression of GFP expression in normal blood cells. In this symposium, we will not only introduce the importance of CTC as a biomarker and conventional CTC detection methods but also show our data of the novel CTC detection using the next-generation conditionally replicating Ad.
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Hisako Yamamura, Katsuhito Takahashi2013 Volume 133 Issue 3 Pages 297-303
Published: March 01, 2013
Released on J-STAGE: March 01, 2013
JOURNAL FREE ACCESSThe safety and anti-tumor effect of oncolytic virus have been reported in a clinical study conducted in Japan. We have engineered a novel multimutated tumor-specific oncolytic herpes virus, harboring a smooth muscle-specific calponin promoter. Since tumor cells present in a hypoxic environment are known to be resistant to chemotherapy and radiotherapy, we also engineered a novel oncolytic herpes virus targeting a specific tumor microenvironment, which harbors a gene encoding a fusion protein of oxygen-dependent degradation (ODD) domain of HIF1α and ICP4, a master viral transcription factor required for replication. The recombinant virus selectively replicates in and disrupts the target tumor cells, including human sarcoma and malignant mesothelioma cells which are unresponsive to chemotherapy and molecular targeted therapy. We confirmed significant anti-tumor effects of the novel viruses in vivo in an allogeneic experimental model of an undifferentiated pleomorphic sarcoma (malignant fibrous histiocytoma; MFH) spontaneously generated in immunocompetent Fischer rats. Our viruses, manufactured in the Master Virus Seed Stock in the Good Manufacturing Practice facility will become novel agents that enable tumor cells unresponsive to conventional treatment to be disrupted.
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Takeshi Yoshida, Masuo Kondoh, Hiroyuki Mizuguchi, Kiyohito Yagi2013 Volume 133 Issue 3 Pages 305-311
Published: March 01, 2013
Released on J-STAGE: March 01, 2013
JOURNAL FREE ACCESSHepatitis C virus (HCV) is a hepatotropic member of the Flaviviridae family and contains a 9.6 kb positive-sense RNA genome. Approximately 170-million people are infected with HCV worldwide. These people face increased risks of chronic hepatitis, cirrhosis and hepatocellular carcinoma compared with the general population. Transduction of the HCV genome into hepatocytes is essential for understanding the mode of action of HCV infection, and for preparing HCV, evaluating HCV replication, and screening anti-HCV drugs. Although electroporation of in vitro-synthesized HCV genome and transduction of plasmid vectors containing the HCV genome are widely used in HCV research, a more convenient system with higher transduction efficiency is needed. Among viral transduction systems, adenovirus (Ad) vector is one of the most efficient and convenient systems; Ad vector has been widely used in clinical gene therapies. Therefore, Ad vector is a promising system for the delivery of the HCV genome; however, an Ad vector expressing the HCV genome has never been developed. We here describe the preparation of an Ad vector expressing the HCV genome, and outline future directions of HCV research using this vector system.
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Shigefumi Okamoto2013 Volume 133 Issue 3 Pages 313-321
Published: March 01, 2013
Released on J-STAGE: March 01, 2013
JOURNAL FREE ACCESSEndemic infection by seasonal influenza virus usually occurs every winter season. Inside the host, human influenza viruses frequently undergo various point mutations at antigenic regions, in response to antibody pressure. Furthermore, the influenza virus has undergone frequent antigenic shifts for at least 100 years, some of which have caused influenza pandemics. In Japan, intramuscular immunization with influenza split-virion vaccines has been used to prevent seasonal influenza virus infections. Unfortunately, the efficacy of the current influenza vaccine immunization method is limited, even against viruses belonging to the same clade. Furthermore, the current vaccines are not expected to be protective against antigenically shifted viruses. Therefore, new approaches to vaccine development are needed to protect human populations against a potential pandemic virus. We are studying novel influenza vaccine designs to resolve the above weaknesses of the current influenza vaccines. I will describe our vaccine studies, “Cross-protection by mucosal immunization,” and, “Preparation of seed virus strains to produce vaccines for possible pandemic influenza,” in this symposium.
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Hiroyuki Oshiumi, Misako Matsumoto, Tsukasa Seya2013 Volume 133 Issue 3 Pages 323-328
Published: March 01, 2013
Released on J-STAGE: March 01, 2013
JOURNAL FREE ACCESSRetinoic acid-inducible gene-I(RIG-I) is a cytoplasmic RNA helicase and a viral RNA sensor. RIG-I recognizes 5′ triphosphate double-stranded RNA (dsRNA) and activates the IPS-1 adaptor molecule. The association of IPS-1 with RIG-I causes the formation of the prion-like structure of IPS-1. This structure is essential for activation of the signaling required for the induction of type I interferon (IFN), which possesses strong antiviral activity. Recent studies have revealed the novel factors involved in the RIG-I-dependent pathway. DDX3 and DDX60 RNA helicases associate with RIG-I and promote its binding to viral RNA. Riplet and TRIM25 ubiquitin ligase deliver Lys63-linked polyubiquitin moiety to RIG-I and result in signal activation. Several pathogenic viruses have evolved excellent systems to suppress type I IFN production. For example, NS3-4A of hepatitis C virus (HCV) cleaves IPS-1, which is the adaptor molecule of RIG-I, while the HCV core protein abrogates DDX3 function to suppress RIG-I-dependent IPS-1 activation, and the NS-1 of flu inhibits TRIM25 function to suppress RIG-I activation.
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Seiichi Furuta2013 Volume 133 Issue 3 Pages 329-330
Published: March 01, 2013
Released on J-STAGE: March 01, 2013
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Kenji Hazama2013 Volume 133 Issue 3 Pages 331-336
Published: March 01, 2013
Released on J-STAGE: March 01, 2013
JOURNAL FREE ACCESSThe percentage of the population over age 65 in Japan was greater than 23% in 2010. Therefore, Japan is the world's first “super-aged society”, and our country needs a new regional health care system. Our medical systems face many challenges, such as this increase in elderly population with chronic diseases, maintenance of universal health insurance and free access to hospitals, and expensive health care costs. It is not easy to change the current health care system without a sufficient number of doctors. On the other hand, Japan's curriculum in pharmaceutical education has been expanded to six years to establish a new profession of pharmacist. Rapid progress in the market of pharmacies in accepting prescriptions since 1974 has caused pharmacists to primarily act as “technicians”. But this is not the best way to solve the serious problems of Japanese medical systems. I want to present the image of a next-generation pharmacist (Pharmacist 3.0), to be involved in the idea of collaborative drug therapy management (CDTM) in this article. The total optimization of our medical supply system with all medical and pharmaceutical specialists is necessary in Japan.
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Yoshiko Miyazaki2013 Volume 133 Issue 3 Pages 337-341
Published: March 01, 2013
Released on J-STAGE: March 01, 2013
JOURNAL FREE ACCESSIn the future, home medical care will become increasingly significant. The Heisei 24 annual budget request included 2,000,000,000 yen for “the base pharmacy service which provides home medical care,” more is anticipated, and greater expectations are attached to activity in the area of the pharmacist. However, as to the actual setting of this care, home medical care provided by pharmacists is still lacking. The community-based pharmacist is pursued and supported by the pharmaceutical business, and deals with issues of patient compatibility. Therefore, in the current pharmacy model, concern with home patients is not adequate. Also, as regards home medical care, the problem is not only with the community-based pharmacist. For medicine prescribed in a hospital to a patient for home medical care, it is a hospital-based pharmacist that serves as a bridge. However, hospital-based pharmacists are constantly tasked with multiple in-hospital business functions, so in this present situation, the pharmacist's concern with home care is minimal. There should be cooperation between pharmacists concerned with treatment at home, discussion of how to introduce ideas based on cooperative medicine in the area, and so on, as regards the actual state of the conference. This would lead to the realization that “medical treatment without a break in care” would involve patients leaving the hospital, and assuring continued medical/pharmaceutical oversight, with a medical exchange as an example.
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Tsutomu Bandoh2013 Volume 133 Issue 3 Pages 343-348
Published: March 01, 2013
Released on J-STAGE: March 01, 2013
JOURNAL FREE ACCESSAs we enter more and more into a super-aging society, the requirement for home healthcare will increase. Pharmacists must work along with doctors and nurses in the field of home healthcare. Within the 6-year pharmacy curriculum, we must educate students as medicinal professionals who will join a medical team to serve the community. The Good Practice (GP) program, which has been supported by the Ministry of Education, Culture, Sports, Science & Technology, continues to be offered in our university. As a part of this program, students learn home healthcare in the community in cooperation with Yubari Medical Center. In addition, our students (pharmacy) can study community medicine together with students from Tenshi College (nursing and nutrition) in an optional class made available in Yubari during their summer vacation. According to the results of our survey after these programs, students have achieved a deep recognition of the importance of community medicine and cooperation with other medical staff in contributing to community home healthcare. We carry out these programs under agreements of collaboration with Yubari Medical Center and Tenshi College. We will talk today about training for pharmaceutical care in the community and the effect of training through this class on pharmacy education.
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Hiroshi Abe, Shin Mizukami2013 Volume 133 Issue 3 Pages 349
Published: March 01, 2013
Released on J-STAGE: March 01, 2013
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Shin Mizukami2013 Volume 133 Issue 3 Pages 351-354
Published: March 01, 2013
Released on J-STAGE: March 01, 2013
JOURNAL FREE ACCESSVisualization of biomolecules in living bodies has attracted increasing attention in recent years. Magnetic resonance imaging (MRI) is a noninvasive technique that yields high-resolution structural information of deep anatomical regions; therefore, it has promising applications in the development of probes to visualize biological functions. By using stimuli-responsive polymers, we developed 1H MRI probes to measure the pH of aqueous solutions. The longitudinal relaxivity of P-Gd, a conjugate of n-octylamine-modified poly(SM-EVE) with Gd3+ complexes, increased as the pH of the solution decreased from neutral to acidic. Fluorometric investigation confirmed that the side chains of P-Gd were more rotationally restricted in acidic pH than in neutral pH conditions. In order to improve the magnitude of relaxivity, we developed novel probes C10-Gd and C30-Gd on the basis of cross-linked polymer nanoparticles. The relaxivities of these probes were measured, and the values showed that these nanoparticle-based probes also possessed pH-responsive molecular switches. In addition, their relaxivities were much larger than those of non-cross-linked probes. These nanoparticle-based MRI probes would be useful for the diagnosis of various diseases such as cancer and inflammatory diseases.
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Kohei Soga2013 Volume 133 Issue 3 Pages 355-367
Published: March 01, 2013
Released on J-STAGE: March 01, 2013
JOURNAL FREE ACCESSFluorescence bioimaging is an inevitable method for biological, medical and pharmaceutical sciences to visualize substances in biological objects in a highly sensitive, multicolor and dynamic way. Recently, elongation of the fluorescence wavelength is a trend used in this imaging to suppress scattering, which limits the imaging depth to within several millimeters. It has been known that the so-called “biological window” with low loss for a biological tissue has been known to lie in the near-infrared (NIR) wavelength range between 1000 and 1700 nm. The use of fluorescence in the over-1000-nm (OTN) NIR can deepen the observation to several centimeters. The use of imaging devices based on semiconductor silicon has limited the wavelength of the fluorescence bioimaging to less than 1000 nm. However, the appearance of InGaAs CCD on the market, to allow for imaging of the OTN-NIR light, is now changing the situation. On the other hand, rare-earth doped ceramic nanophosphors (RED-CNP) can emit efficient fluorescence in the OTN-NIR wavelength range. The author's group has applied the RED-CNP to OTN-NIR fluorescence bioimaging by hybridizing the RED-CNP with various polymers or molecules. The present paper will review the development of the materials and systems for this OTN-NIR fluorescence bioimaging, together with some applications of the imaging method for biological research and a medical surgery.
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Takuro Niidome2013 Volume 133 Issue 3 Pages 369-372
Published: March 01, 2013
Released on J-STAGE: March 01, 2013
JOURNAL FREE ACCESSGold nanorods have absorption bands in the near-infrared region; in this spectral range, light penetrates deeply into tissues. The absorbed light energy is converted into heat by gold nanorods. This is the so-called photothermal effect. Gold nanorods are therefore expected to act not only as thermal converters for photothermal therapy, but also as controllers for drug-release systems responding to irradiation with near-infrared light. To achieve a controlled-release system that could be triggered by light irradiation, the gold nanorods were modified with double-stranded DNA (dsDNA). When the dsDNA-modified gold nanorods were irradiated with near-infrared light, single-stranded DNA (ssDNA) was released from the gold nanorods because of the photothermal effect. The release of ssDNA was also observed in tumors grown on mice after near-infrared light irradiation. We also proposed a different controlled-release system responding to near-infrared light. Gold nanorods were modified with polyethylene glycol (PEG) through Diels-Alder cycloadducts. When the gold nanorods were irradiated with near-infrared light, the PEG chains were released from the gold nanorods because of the retro Diels-Alder reaction induced by the photothermal effect. Such controlled-release systems triggered by near-infrared light irradiation will be expanded for gold nanorod drug delivery system applications.
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Hiroshi Abe2013 Volume 133 Issue 3 Pages 373-378
Published: March 01, 2013
Released on J-STAGE: March 01, 2013
JOURNAL FREE ACCESSRNA interference (RNAi) is a potent and highly specific gene-silencing phenomenon which is initiated or triggered by double-stranded RNAs (dsRNAs). Shortly after the development of RNAi, small interfering RNAs (siRNAs) that are 21 nucleotides in length with a 3′ nucleotide overhang were shown to be very effective in mammalian cells. Much effort has been dedicated to the application of siRNAs, both as biological tools and as therapeutic agents. Currently, synthetic siRNA would be the method of choice for clinical purposes. However, natural RNA strands are quickly degraded in biological fluids. Chemically synthesized unnatural nucleotides have been developed and introduced into the siRNA strand. For example, modification of the ribose moiety with a 2′-deoxy, 2′-O-methyl, or 2′-fluoro group, or modification of the phosphate backbone have been examined. Although these modifications improve the stability of siRNA in serum, they often cause a decrease in RNAi activity. There is also concern that unnatural RNA derivatives are toxic in the human body. A method to stabilize nontoxic natural RNA strands should be very useful for applications in RNAi technology. We came up with an idea that nano-structural design stabilizes natural RNA. We tested several new designs such as dumbbell RNA, double stranded circular RNA, or branched RNA in biological stability and RNA interference activity. Consequently, dumbbell or branched design offered prolonged RNAi effect due to high biological stability.
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Tatsuhiro Ishida, Hiroshi Kiwada2013 Volume 133 Issue 3 Pages 379-386
Published: March 01, 2013
Released on J-STAGE: March 01, 2013
JOURNAL FREE ACCESSEfficient systemic siRNA delivery to cells in the target tissue is a current critical challenge in the drug delivery field. Several studies have demonstrated that nanoparticles such as polyethylene glycol (PEG)-coated siRNA-lipoplexes may enhance the systemic delivery of siRNA to tumor. However, the disordered tumor microenvironment still poses a potential impediment with respect to the efficient delivery of PEG-coated siRNA-lipoplexes. We recently showed that metronomic S-1 dosing (daily oral administration) enhanced the accumulation of PEG-coated liposome containing anticancer drug in solid tumor tissue and thereby increased therapeutic efficacy in tumor-bearing mouse model. To extend this work, we tried to investigate the effect of metronomic S-1 dosing on the intratumoral accumulation of PEG-coated siRNA-lipoplex and, thereby, their therapeutic efficacy in solid tumor-bearing mouse model. Results showed that metronomic S-1 dosing improved systemic delivery of intravenously injected PEG-coated siRNA-lipoplexes into solid tumor tissue. In addition, the combined therapy of S-1 and PEG-coated siRNA-lipoplexes showed potent tumor growth suppressive effect. Our proposed strategy may pose a promising therapeutic one to conquer cancer progression with siRNA.
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Takaki Koide2013 Volume 133 Issue 3 Pages 387-392
Published: March 01, 2013
Released on J-STAGE: March 01, 2013
JOURNAL FREE ACCESSCollagen family proteins are the predominant components of extracellular matrices existing in all multicellular animals. They provide mechanical strength to tissues, and maintain structural integrity of organs. Also, collagens regulate various biological events, including cell attachment, migration, tissue regeneration and animal development. The specific functions of collagens are generally elicited by interactions of collagen-binding molecules (membrane receptors, soluble factors and other matrix components) with certain amino acid sequences displayed on the collagen triple helices. To date, numbers of functional sequences have been identified from the triple helical domains. Collagen is also acknowledged as one of useful biomaterials in regenerative medicine and tissue engineering. In this review, I summarize challenges made for the development of safer and highly-functional collagen surrogates by means of self-assembly of synthetic collagen-like peptides. I also describe other possible applications of collagen-like peptides in drug delivery focusing on the particular biophysical properties of the triple helical structure.
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Review
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Tsutomu Takahashi2013 Volume 133 Issue 3 Pages 393-396
Published: March 01, 2013
Released on J-STAGE: March 01, 2013
JOURNAL FREE ACCESSAdriamycin is an anthracycline antibiotic that is widely used in the treatment of various cancers. However, the efficacy of adriamycin-based chemotherapy is compromised by the development of adverse effects and the emergence of adriamycin-resistant cancer cells. In a search for novel mechanisms of resistance to adriamycin, we searched for genes that are related to adriamycin resistance using the budding yeast Saccharomyces cerevisiae and identified several genes (Akl1, Bsd2, Ssl2 and Erg13, etc.). We investigated the role of Akl1, a member of Ark/Prk kinase family, in adriamycin resistance and found that Akl1 might reduce adriamycin toxicity by inhibition of the internalization step in endocytosis via phosphorylation of component of endocytic complex. Furthermore, defects in vesicle trafficking from endoplasmic reticulum (ER) to vacuole reduced the degree of the adriamycin resistance induced by Akl1-overexpression, suggesting that inhibition of internalization step in endocytosis facilitates transport of protein from ER to vacuole, and decreases adriamycin toxicity.
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Regular Article
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Kumiko Noda, Toshinori Yokoyama, Yasushi Akiyama, Koji Tadano2013 Volume 133 Issue 3 Pages 397-404
Published: 2013
Released on J-STAGE: March 01, 2013
Advance online publication: December 04, 2012JOURNAL FREE ACCESSThis report describes a modified method for the quantitative determination of unbound micafungin (MCFG) in human plasma that is unrelated to chemical methods currently in use, and the relationship between the concentration of unbound and total MCFG in plasma of the patients. The mobile phase consisted of 50 mM phosphate buffer:tetrahydrofuran (65:35, v/v). Samples were fractionated on a C-18 column. The fluorescence detection wavelengths of excitation and emission were set at 273 nm and 464 nm, respectively. The retention times of MCFG and 1-hydroxy-2-naphtoeic acid (internal standard: IS) were 10.5 min and 7.3 min, respectively. For each concentration of MCFG/IS, the peak height ratio on a 5-point calibration curve was linear from 0.004 to 0.08 μg/mL (r=0.999, p<0.001). In addition, the concentrations of unbound and total MCFG were measured in the plasma of 11 patients treated with MCFG for fungal infection. In total, 99 samples were collected. The concentration of unbound and total MCFG in plasma correlated with one another (r=0.896, p<0.001). These concentrations were not affected by serum albumin, total bilirubin, blood urea nitrogen, or creatinine clearance. There were small differences of [fu (unbound MCFG/total MCFG)×100%] in the every term after start of treatment of MCFG. Further, there was no difference in the unbound and total concentration of MCFG in plasma between the effective group and the ascertained effectiveness group. The concentration of MCFG in plasma could be used as an indicator of clinical effect as a substitute for the concentration of unbound MCFG in plasma.
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Note
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Shunji Nagata, Aya Jin-nai, Ken-ichi Hirai, Mikako Baba, Kousuke Higas ...2013 Volume 133 Issue 3 Pages 405-410
Published: March 01, 2013
Released on J-STAGE: March 01, 2013
Advance online publication: December 21, 2012JOURNAL FREE ACCESSThe dissolution profiles of paliperidone from INVEGA® 3-mg tablets, osmotic-controlled release tablets, were evaluated by using the reciprocating cylinder method (RC method). We used 4 different compositions of the dissolution fluids, by considering the environment of the tablet in the gastrointestinal tract. After a lag time of 2 to 4 h, paliperidone was approximately dissolved to 24 h by zero-order release. The dissolution characteristics of paliperidone were not affected by the kind of the test medium, pH, and surfactant. In addition, the dissolution of the tablets was evaluated using the paddle method in distilled water, Japanese Pharmacopeia (JP) 1st test fluid, and JP 2nd test fluid. The dissolution profiles of paliperidone obtained using the RC method and the paddle method were very similar. Further, the dispersion of the percentage of the dissolved paliperidone obtained using the RC method and the paddle method was small.
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