bluuebunny/crossref_metadata_2025 huggingface dataset:
The inhibition of aluminium corrosion in potassium hydroxide by “Congo Red” dye, and synergistic action with halide ions
Authors: Oguzie E.E. , Onuoha G.N. , Onuchukwu A.I.
Published: August 2005

Purpose

To investigate the inhibitive effect of Congo red dye (CR) for aluminium corrosion in strong alkaline solutions and evaluate the synergistic effect of halide ions on the inhibition efficiency.

Design/methodology/approach

Corrosion rates of aluminium test coupons were determined by gravimetric technique at 30 and 60°C. Inhibition efficiencies of the additives (0.01‐5.0 mM CR and 5.0 mM CR+0.5 mM halides) were evaluated by comparing corrosion rates of the test coupons in 2 M KOH solution in the absence and presence of the additives.

Findings

CR inhibited aluminium corrosion in 2 M KOH by physical adsorption of the dye molecules on the corroding metal surface. Maximum efficiency at 30 and 60°C was 31.72 and 19.32 per cent, respectively. Dye adsorption was enhanced in the presence of halides in the order KCl < KBr < KI, with KI increasing efficiency up to 48.63 and 41.70 per cent at 30 and 60°C, respectively.

Research limitations/implications

Further studies to involve variation of dye and halide concentrations for CR+halide systems to determine the best combination for optimum inhibition synergism.

Originality/value

This paper forms part of an extensive database on the inhibition characteristics of organic dyes for corrosion of different metals in various aggressive environments. This is to serve as a guide to possible applications in metal‐surface anodizing and as additives in surface coatings for service in different environments.
Robot cleans glass roof of Louvre pyramid
Authors: Kochan Anna
Published: August 2005

Purpose

Aims to describe the application of robotics to the cleaning of the glass roof of the 21 m high pyramid that stands in front of the Louvre in Paris.

Design/methodology/approach

Presents the design of the robot, its traction mechanism, cleaning system and operating mode.

Findings

Finds that a robot is capable of cleaning a glass roof at a great height and on a steep slope using only suction to adhere to the surface.

Originality/value

Introduces the concept of a robot in commercial use that cleans a steeply sloping glass roof.
Incorporating cannibalization models into demand forecasting
Authors: Ragharan Srinivasan Sundara , Ramakrishnan Sreeram , Grasman Scott E.
Published: August 2005

Purpose

Quantitative measures are not commonly available to identify and measure product cannibalization resulting from the introduction of new products, and existing forecasting methods such as ARIMA do not explicitly account for the phenomenon. This paper aims to present a methodology to build cannibalization effects into forecasting models as measured through product attributes. It follows on from a paper by the same authors in Vol. 23 No. 4

Design/methodology/approach

The contribution of product attributes to cannibalization is tested by a series of hypotheses, then integrated into the proposed cannibalization model. Results are compared with predictions from an ARIMA‐based model and actual historical sales data.

Findings

The proposed model improves on the fidelity of ARIMA‐based models, by between 16 and 42 percent.

Originality/value

Effective prediction of cannibalization losses will allow marketing planners to make better‐informed decisions with respect to new product introduction.
Building an open archive union catalog for digital archives
Authors: Yu Shien‐Chiang , Chen Hsueh‐hua , Chang Huai‐wen
Published: August 2005

Purpose

In January 2002, the National Science Council of Taiwan launched a National Digital Archives Program (NDAP) and has proceeded with the implementation of a system related to the open archives initiative (OAI) framework. This paper aims to introduce the protocol and the prototype system of the project.

Design/methodology/approach

A general review of the project.

Findings

The OAI interoperability framework has received much attention from scholars of library and information sciences. In Europe and North America, many academic organizations and universities have undertaken theoretical studies, system design, and implementation of the OAI framework. In January 2002, the National Science Council of Taiwan launched a NDAP, and the institutional project of the National Taiwan University is one of its institutional projects. Now, the project has proceeded with the implementation of a system related to the OAI framework.

Originality/value

Provides information of value to information professionals.
The development of digital libraries in China and the shaping of digital librarians
Authors: Zhou Qian
Published: August 2005

Purpose

Aims to focus on the need for appropriately trained librarians of the next‐generation, the “Digital Librarians”, with particular emphasis on China.

Design/methodology/approach

The paper first analyzes the definition and features of the digital library, and is followed by an introduction to digital libraries developing in China. Work modes and quality composition of digital librarians are then analyzed and discussed.

Findings

Digital libraries emerging in the information age represent an inevitable trend for library development. A digital library contains a vast amount of digital information resources in multiple media. It may provide readers with diversified information services using digital and network technologies. In addition to certain hardware and software availabilities, the evolving digital library requires appropriately trained librarians of the next‐generation, the “Digital Librarians”, which forms the theme of this paper.

Originality/value

Provides recommendations and measures on how China can develop further its digital librarians.
On numerical implementation of a coupled rate dependent damage‐plasticity constitutive model for concrete in application to high‐rate dynamics
Authors: Hervé Guillaume , Gatuingt Fabrice , Ibrahimbegović Adnan
Published: August 2005

Purpose

To provide an efficient and robust constitutive equations for concrete ion application to high rate dynamics.

Design/methodology/approach

Develops an explicit‐implicit integration scheme for a concrete model. This robust integration scheme ensures computational efficiency. Comparison between simulations of impact of equivalent aircraft engine projectiles and the tests carried out in Sandia laboratory also demonstrate its efficiency.

Findings

Shows that modeling transient high rate dynamic behavior of concrete is very important to take into account for design concrete structures in the cases of dynamic loading conditions, such as an impact on the structure.

Originality/value

Proposes an original integration scheme for a coupled rate dependent damage plasticity model. Also provides a detailed consideration of the numerical stability of this kind of scheme for rate‐dependent damage model.
A Large Germline Deletion of the MEN1 Gene in a Family with Multiple Endocrine Neoplasia Type 1
Authors: Kishi Mari , Tsukada Toshihiko , Shimizu Satoko , Futami Hitoyasu , Ito Yukio , Kanbe Masako , Obara Takao , Yamaguchi Ken
Published: August 2005

Multiple endocrine neoplasia type 1 (MEN1) is a familial cancer syndrome inherited as an autosomal dominant trait. Various heterozygous germline mutations of the responsible gene, MEN1, have been identified within its exons in many, but not all, affected individuals. We here demonstrate, by DNA polymorphism analysis and gene dosage analysis with polymerase chain reaction (PCR), a large heterozygous germline MEN1 deletion in a kindred with MEN1, in whom no mutation could be detected in the PCR‐amplified exons. The deletion spanned an at least 7 kb region containing the entire MEN1 gene. These findings indicate that a large germline deletion of the MEN1 gene, which escapes detection in PCR‐based sequence analysis, should be considered as a potential cause of MEN1.
Geographic Clustering Patterns in Mortality from Biliary Tract Cancer in Japan
Authors: Kodama Kuniko , Nakadaira Hiroto , Endoh Kazuo , Yamamoto Masaharu
Published: August 2005

We calculated the standardized mortality ratios (SMRs) of biliary tract cancer (BTC) in Japan from 1981 to 1990 and statistically analyzed the results according to 333 Secondary Areas of Medical Care, as well as sex and subsite [gallbladder cancer (GBC) and extrahepatic bile duct cancer (BDC)], in order to examine geographic clustering patterns of BTC. In GBC in both sexes, the Secondary Areas of Medical Care with high SMRs were clustered in the eastern part of Japan. In BDC in both sexes, the Areas with high SMRs were clustered between the northern and eastern parts of Japan. In comparison with GBC, this clustering favored the northern part of Japan. In males, the clustering pattern in mortality from BTC was mainly due to the occurrence of BDC. In females, the clustering pattern in mortality from BTC reflected that of GBC. The clustering of BTC, especially GBC, seems to be related to the distribution of plains, basins, and rivers.
Infrequent Mutations in the PTEN/MMAC1 Gene among Primary Breast Cancers
Authors: Ueda Kazuki , Nishijima Misae , Inui Hiroki , Watatani Masahiro , Yayoi Eiji , Okamura Jun , Yasutomi Masayuki , Nakamura Yusuke , Miyoshi Yasuo
Published: August 2005

Recently PTEN/MMAC1, a candidate tumor suppressor gene, was isolated from chromosome 10q23‐24 and somatic mutations of this gene were detected in several malignancies including brain, prostate, and breast tumors. To investigate further the potential role of this gene in mammary carcinogenesis, we examined 69 primary breast cancers for mutations in PTEN/MMAC1 by means of polymerase chain reaction single‐strand conformation polymorphism and sequencing analysis. We detected only one somatic missense mutation, a change from T to C at codon 59 (TCA to CCA) resulting in substitution of Pro for Ser in the predicted protein. This site is located outside of phosphatase or phosphate‐acceptor motifs, but this codon encodes a residue that is conserved in homologous proteins, tensin and auxilin and is likely to be crucial for normal function of PTEN/MMAC1. Among the 69 tumors examined, three low‐frequency polymorphisms were found as well, one in the non‐coding region of exon 1 and one each in introns 2 and 7. Our results suggested that mutation of the PTEN/MMAC1 gene is not a major factor in the development of most primary breast cancers.
Inhibitory Effect of Tomato Juice on Rat Urinary Bladder Carcinogenesis after N‐Butyl‐N‐(4‐hydroxybutyl)nitrosamine Initiation
Authors: Okajima Eijiro , Tsutsumi Masahiro , Ozono Seiichiro , Akai Hiroyuki , Denda Ayumi , Nishino Hoyoku , Oshima Syunji , Sakamoto Hideki , Konishi Yoichi
Published: August 2005

The effects of tomato juice on urinary bladder carcinogenesis were studied in male Fischer 344 rats initiated with N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine (BBN) in rats. The animals (6 weeks old) were given 0.05% BBN in their drinking water for 8 weeks, followed by diluted tomato juice for 12 weeks, and killed at 20 weeks after the beginning of the experiment. Lycopene concentrations in the livers of rats given tomato juice were elevated. Histopathological analysis of urinary bladder lesions revealed the numbers, but not incidences, of urinary bladder transitional cell carcinomas (TCCs) to be decreased in the group given tomato juice. No influence on the incidence of simple and nodullopapillary hyperplasias, invasion or differentiation of TCC was noted. These results indicate that tomato juice, presumably the contained lycopene and other anti‐oxidants in combination, exerts an inhibitory effect on the development of TCCs in the rat urinary bladder.
Alteration of p53 Clonality Accompanying Colorectal Cancer Progression
Authors: Kuwabara Akifumi , Watanabe Hidenobu , Ajioka Yoichi , Yasuda Kazuhiro , Saito Hidetoshi , Matsuda Keiji , Kijima Hiroshi , Hatakeyama Katuyoshi
Published: August 2005

The aim of this study was to clarify whether or not the status of gene alteration is heterogeneous in intramucosal carcinoma and homogeneous within invasive carcinoma. We selected 10 colorectal carcinoma cases (1 mucosal, 5 submucosal and 4 advanced carcinomas including 2 cases with lymph node metastasis) and analyzed the p53 gene sequence. Six colorectal cancers in this study showed heterogeneity in p53 mutations in cells from the intramucosal part. In the invasive part of a carcinoma, p53 mutation status was homogeneous intratumorally in all cases. These data indicate that, in regard to p53 gene alterations, colorectal cancers can be composed of various subclones when limited to the mucosa, but clonal selection occurs when one of these subclones commences invasion to the submucosa, generating a monoclonal invasive carcinoma.
Preliminary Study of Percutaneous Alcohol Injection into the Lung
Authors: Suzuki Kenji , Moriyama Noriyuki , Yokose Tomoyuki , Nakaya Yoshihiro , Ishihara Toshihiro , Niho Seiji , Nagai Kanji , Esumi Hiroyasu
Published: August 2005

Although percutaneous ethanol injection is widely used to treat hepatic tumors, this technique has not been applied to lung tumors. We performed a preliminary experiment with percutaneous ethanol injection into the rabbit lung, and evaluated the local and systemic effects of absolute ethanol injection on pulmonary structures in order to assess the feasibility and safety of this technique as a local treatment for human lung tumors. Percutaneous injection of absolute ethanol into the rabbit lung was performed under CT guidance. The volume of ethanol injected ranged from 0.6 to 1.0 ml (approximately 0.2–0.5 ml/kg). Follow‐up CT scans were performed 1, 2, 7 and 30 days after the injection. The animals were killed at intervals (range: 3 h–30 days), and the lung was examined histologically. The ethanol was well tolerated and did not induce significant systemic side‐effects. All doses induced necrosis in the injected lung, but none was lethal. Although ethanol spilling into the thoracic cavity induced effusion and pleuritis, these reactions were manageable. Alcohol injection produced an area of necrosis surrounded by pulmonary edema associated with polymorphonuclear cells invasion within 24 h; moreover, granulation change, epithelial regeneration, and alveolar septal fibrosis had appeared by one week. The necrosis was sometimes multifocal, probably due to transbronchial spread of the injected ethanol. In conclusion, the feasibility and safety of absolute ethanol injection were confirmed. Neither severe systemic side effects nor lethal extensive necrosis were observed with injected ethanol; however, an unexpected side effect, multifocal necrosis, was seen. The latter reaction suggests that careful observation and care would be essential after alcohol injection into the lung.
The PTEN, BAX, and IGFIIR Genes Are Mutated in Endometrial Atypical Hyperplasia
Authors: Yoshinaga Kousuke , Sasano Hironobu , Furukawa Toru , Yamakawa Hiromitsu , Yuki Michihiro , Sato Shinji , Yajima Akira , Horii Akira
Published: August 2005

To pursue the pathogenesis of endometrial carcinogenesis, we investigated microsatellite instability, mutations in the PTEN, TGFβRII, IGFIIR, and BAX genes, and LOHs on 10q in 18 putative endometrial premalignant lesions (11 endometrial atypical hyperplasias (ATHs), 2 complex hyperplasias, and 5 simple hyperplasias) as well as 8 endometrial cancers (ECs). In the ATH cases, MSIs as well as LOHs at 10q were observed at frequencies similar to those in ECs. Mutations in PTEN, BAX, and IGFIIR were observed only in ATHs and ECs. These results suggest that (1) PTEN, BAX, and IGFIIR are already mutated in ATHs, and (2) ATH is one of the precursor lesions which could lead to EC.
Expression of CD44 Variants and Its Association with Survival in Pancreatic Cancer
Authors: Gotoda Takuji , Matsumura Yasuhiro , Kondo Hitoshi , Saitoh Daizo , Shimada Yasuhiro , Kosuge Tomoo , Kanai Yae , Kakizoe Tadao
Published: August 2005

Since the CD44 variant 6(v6) molecule has been noted as a marker for tumor metastasis and prognosis in several tumors, we examined whether or not v6 is a useful marker for evaluating the prognosis of pancreatic cancer patients. In addition, we attempted to assess the clinicopathological implications for pancreatic cancer of the variant 2 (v2) isoform using a recently developed monoclonal antibody against a v2 epitope. The expression of CD44 variants was evaluated immunohistochemically in paraffin‐embedded pancreatic cancer tissues from 42 patients who were confirmed surgically and histologically to have received curative resection. An indirect immunoperoxidase method was used with monoclonal antibodies against epitopes of the standard (CD44s) portion, v6 and v2. Protein expression data were evaluated statistically for any correlations with the length of survival or with histological parameters. The expression of CD44v6 and v2 was observed only in tumor cells, if at all. On the other hand, expression of total CD44 (including CD44v, as well as CD44s) was observed in both tumors and adjacent normal sites. Tumor tissue from 21 (50%) and 16 (38%) patients showed positive immunoreactivity with mAb 2F10 (anti‐CD44v6) and mAb M23.6.1 (anti‐CD44v2), respectively. The expression of CD44v6 and v2 was correlated with decreased overall survival (P=0.0160 and P=0.0125, respectively). A significant correlation was obtained between CD44v2 peptide expression and vessel invasion (P=0.026). These results suggest that CD44v2 and CD44v6 may be useful markers for poor prognosis in curatively resected primary pancreatic cancer.
Different Effects of FK317 on Multidrug‐resistant Tumor in vivo and in vitro
Authors: Naoe Yoshinori , Inami Masamichi , Takagaki Shoji , Matsumoto Sanae , Kawamura Ikuo , Nishigaki Fusako , Tsujimoto Susumu , Manda Toshitaka , Shimomura Kyoichi
Published: August 2005

FK317, a novel substituted dihydrobenzoxazine, was examined for antitumor effects on multidrug‐resistant (MDR) tumor cells in vitro and in vivo. In nude mice, FK317 markedly inhibited the growth of s.c. implanted KB‐V1 vinblastine (VLB)‐resistant human epidermal carcinoma KB cells, as well as the parent cells (KB‐3‐1). However, KB‐V1 showed much greater resistance to FK317 than to VLB and adriamycin (ADM) in the in vitro study. This resistance was reversed by the addition of verapamil, whereby intracellular accumulation of FK317 in the KB‐V1 cells was also decreased. After incubation of FK317 in human and mouse blood, it was shown to be rapidly metabolized to a monodeacetylated form, and slowly metabolized further to a dideacetylated form. With the removal of the acetyl groups from FK317, resistance indexes in KB‐V1 and SBC‐3/ADM, ADM‐resistant human lung carcinoma, decreased. In addition, photolabeling of P‐glycoprotein with [3H]azidopine in KB‐V1 plasma membrane was completely inhibited by FK317, but not by the deacetylated metabolites. These results indicate that FK317 is metabolized to deacetylated forms, which do not bind to P‐glycoprotein and are incorporated into MDR cells, causing cytotoxic effects.
Tumor‐selective Distribution of an Active Metabolite of the 9‐Aminoanthracycline Amrubicin
Authors: Noguchi Toshihiro , Ichii Shinji , Morisada Shinya , Yamaoka Takashi , Yanagi Yoshikazu
Published: August 2005

It has been reported that the 9‐aminoanthracycline amrubicin shows good efficacy in human tumor xenograft models. We studied the disposition and metabolism of amrubicin in mice, in comparison with those of doxorubicin. Amrubicinol, a 13‐hydroxy metabolite of amrubicin, which is 10 to 100 times more cytotoxic than amrubicin, was detected as a major metabolite in blood and tissues, and aglycones of amrubicin were also detected. A pharmacokinetic study revealed that amrubicin had a smaller distribution volume and a shorter half‐life than doxorubicin. In several normal tissues, the levels of amrubicin and amrubicinol were lower than those of doxorubicin. In contrast, the tumor levels of amrubicinol in the mice treated with amrubicin were higher than those of doxorubicin in the mice treated with that drug, in tumors that are sensitive to amrubicin. These results suggest that the potent therapeutic activity of amrubicin is caused by the selective distribution of its highly active metabolite, amrubicinol, in tumors.
Cytotoxicity of Amrubicin, a Novel 9‐Aminoanthracycline, and Its Active Metabolite Amrubicinol on Human Tumor Cells
Authors: Yamaoka Takashi , Hanada Mituharu , Ichii Shinji , Morisada Shinya , Noguchi Toshihiro , Yanagi Yoshikazu
Published: August 2005

Amrubicin, a completely synthetic 9‐aminoanthracycline derivative, was previously shown to have potent antitumor activities against various human tumor xenografts. In this study, the in vitro activities of amrubicin and its major metabolite, amrubicinol, were examined using 17 human tumor cell lines. Amrubicinol was 5 to 54 times more potent than amrubicin, and as potent as doxorubicin, in inhibiting the growth of the cells following 3‐day continuous drug exposure. Amrubicinol closely resembled doxorubicin in its profile of activities on the 17 human tumor cell lines. Cells were incubated with the drugs for 1 h, and the intracellular drug concentration and cell growth inhibition after 3 days were determined. Amrubicinol attained similar intracellular concentrations at lower medium concentrations compared to amrubicin, and the intracellular concentration of amrubicinol necessary to produce 50% cell growth inhibition was 3 to 8 times lower than that of amrubicin in 4 cell lines tested. Amrubicinol has a higher activity level inside the cells than does amrubicin. When cells were incubated with amrubicin for 5 h, a substantial amount of amrubicinol, more than 9% of that of amrubicin, was found in cells in 4 of the 8 cell lines tested. Amrubicinol may contribute to the in vitro growth‐inhibitory effect of amrubicin on these cells. The results suggest that amrubicinol plays an important role in the in vivo antitumor effect of amrubicin as an active metabolite.
Elevation of Cytoplasmic Cytochrome c in Radiation‐induced Apoptosis
Authors: Kurihara Miki , Kurihara Hiroaki , Tsukuda Mamoru
Published: August 2005

The signal transduction pathway involved in radiation‐induced apoptosis remains unclear, especially as regards the site at which the primary effect of radiation occurs. In this study, we demonstrate that cytochrome c may be released from mitochondria into the cytosol after irradiation, but that direct irradiation of isolated mitochondria induces no elevation of cytochrome c release. These observations suggest that cytochrome c and mitochondria may be involved in the radiation‐induced apoptotic pathway, but mitochondria might not be a target of radiation, and that a signal transduction pathway from an unknown target might exist upstream of mitochondria during radiation‐induced apoptosis.
Helicobacter pylori Risk Associated with Sibship Size and Family History of Gastric Diseases in Japanese Adults
Authors: Kikuchi Shogo , Kurosawa Michiko , Sakiyama Tsuguo
Published: August 2005

Helicobacter pylori is thought to be a cause of gastric cancer. Risk factors of H. pylori positivity were investigated among 4,361 public service workers in Japan. Sera and information on family history and lifestyle were collected, and H. pylori antibody was measured using the sera. Sex‐ and age‐adjusted odds ratios of factors expected to influence H. pylori seropositivity were calculated. The factors with a significant influence were included in a logistic regression model and the final model was obtained by backward elimination. Sibship size (4 and more vs. 1), smoking habit (current vs. never), and paternal and siblings' histories of gastric diseases showed significant relationships to H. pylori seropositivity, with odds ratios (95% confidence intervals) of 1.5 (1.0–2.1), 0.8 (0.7–0.9), 1.5 (1.3–1.8) and 1.7 (1.1–2.6) respectively. However, spouse's history was not related. In the final model, sibship size and paternal history remained as positive factors, and smoking as a negative one. Contradictory results on the relationship between H. pylori status and smoking among recent studies indicate the existence of hidden confounding factors. It is suggested that infection from family members in childhood considerably affects the H. pylori status of Japanese adults, whereas infection between adults is rare.
Modulation of Dihydroxy‐di‐n‐propylnitrosamine‐induced Liver Lesion Development in Opisthorchis‐infected Syrian Hamsters by Praziquantel Treatment in Association with Butylated Hydroxyanisole or Dehydroepiandrosterone Administration
Authors: Moore Malcolm A. , Thamavit Witaya , Tiwawech Danai , Ito Nobuyuki , Tsuda Hiroyuki
Published: August 2005

The effects of praziquantel coupled with dehydroepiandrosterone (DHEA) or butylated hydroxyanisole (BHA) administration 16 weeks subsequent to dihydroxy‐di‐n‐propylnitrosamine (DHPN) treatment and infection with Opisthorchis viverrini (OV) on lesion development in the liver of Syrian hamsters were investigated. Animals were given 80 OV metacercariae and then two i.p. injections of DHPN (500 mg/kg body weight) 4 and 5 weeks thereafter. At week 16, groups received praziquantel (250 mg/kg, i.g.) and were placed on normal diet or diet supplemented with BHA (1%) or DHEA (0.6%) until they were killed at week 24. Histopathological assessment revealed that, whereas antihelminthic treatment alone resulted in a clear reduction in hepatocellular lesion development, effects on cholangiocellular lesions were equivocal. BHA and DHEA, in contrast, were both associated with a significant reduction in frequency of cholangiofibrosis and cholangiocellular carcinoma. The former chemical, however, increased the numbers of liver nodules while the hormone brought about a decrease as well as a shift in the phenotype of the lesions. The results thus indicate that although cholangiocellular lesion development may, unlike generation of hepatocellular nodules, be to a certain extent independent of the continued presence of parasite, it can be influenced by exogenous treatments.
Inhibition of Early‐phase Exogenous and Endogenous Liver Carcinogenesis in Transgenic Rats Harboring a Rat Glutathione S‐Transferase Placental Form Gene
Authors: Nakae Dai , Denda Ayumi , Kobayashi Yozo , Akai Hiroyuki , Kishida Hideki , Tsujiuchi Toshifumi , Konishi Yoichi , Suzuki Toshiya , Muramatsu Masami
Published: August 2005

Hepatocarcinogenesis initiated with N‐nitrosodiethylamine (DEN) and that initiated by feeding of a choline‐deficient, l‐amino acid‐defined (CDAA) diet were compared in transgenic male Wistar rats harboring a rat glutathione S‐transferase placental form (GST‐P) gene (GST‐P‐Tg rats) and non‐transgenic (N‐Tg) rats. Eight‐week‐old GST‐P‐Tg and N‐Tg rats were administered DEN intraperitoneally at 100 mg/kg body weight, subjected to a selection procedure with 2‐acetylaminofluorene and CCl4, and killed at the end of weeks 5 and 12. Other groups were fed the CDAA diet for 12 weeks and killed. Five weeks after the DEN treatment, numbers and sizes of γ‐glutamyltransferase (GGT)‐ or GST‐P‐positive lesions and 8‐hydroxyguanine (8‐OHG) levels in the livers were significantly less in GST‐P‐Tg rats than in N‐Tg rats. The lesion numbers were unchanged between the ends of weeks 5 and 12 in GST‐P‐Tg rats, but decreased in N‐Tg rats. The lesion sizes were increased in GST‐P‐Tg rats, but unchanged in N‐Tg rats. While the proliferating cell nuclear antigen labeling indices (PCNA L.I.) in and surrounding the lesions were decreased, more prominently in GST‐P‐Tg rats than in N‐Tg rats, the 8‐OHG levels were also decreased but similarly in both cases. After 12 weeks on the CDAA diet, the lesion incidences, numbers and sizes, 8‐OHG levels, PCNA L.I. in and surrounding the lesions, and liver injury were significantly less in GST‐P‐Tg rats than in N‐Tg rats. These results indicate that insertion of a rat GST‐P transgene alters the early phase of exogenous and endogenous rat hepatocarcinogenesis, presumably due to enhanced detoxification by GST‐P expressed both transiently during the initiation and chronically in the altered hepatocyte populations.
A Novel Mutant from Apoptosis‐resistant Colon Cancer HT‐29 Cells Showing Hyper‐apoptotic Response to Hypoxia, Low Glucose and Cisplatin
Authors: Suzuki Hiroyuki , Tomida Akihiro , Tsuruo Takashi
Published: August 2005

Solid tumors usually have regions of hypoxia and glucose deprivation. Human colon carcinoma HT‐29 cells show an apoptosis‐resistant phenotype in response to microenvironmental stresses. In this study, we isolated a novel mutant of HT‐29, designated as HA511, that showed a high apoptotic response to hypoxia, glucose deprivation and treatment with the chemical stressors tunicamycin and glucosamine. The mutant HA511 cells exhibited nuclear condensation and fragmentation and activation of CPP32 (caspase‐3) protease under the stress conditions, while the parental HT‐29 cells did not. We found that apoptosis occurred in HA511 cells after prolonged cell cycle arrest at the G1 phase, while in the parental cells a progression to S phase occurred after the G1 arrest. Upon exposure to an anti‐Fas antibody, HA511 cells underwent apoptosis, whereas the parental cells proliferated without substantial cell death. Furthermore, HA511 cells were preferentially hypersensitive to cisplatin. We found no alteration in expression of GRP78, anti‐apoptotic protein Bcl‐XL, or p53, of which the gene was mutated in HT‐29 cells. The mutant HA511 cells could provide useful information on the mechanism of apoptosis of solid tumors.
High Rate of Induction of Human Autologous Cytotoxic T Lymphocytes against Renal Carcinoma Cells Cultured with an Interleukin Cocktail
Authors: Liu Shu Qin , Kawai Koji , Shiraiwa Hiroshi , Hayashi Hitoshi , Akaza Hideyuki , Hashizaki Kazuko , Shiba Reiko , Saijo Kaoru , Ohno Tadao
Published: August 2005

A high rate of induction (9 of 10 cases) of human autologous cytotoxic T lymphocytes (CTL) was achieved in vitro from peripheral blood mononuclear cells of renal carcinoma patients by applying an interleukin (IL)‐cocktail consisting of IL‐1, ‐2, ‐4, and ‐6. The CTL specifically lysed their own target carcinoma cells within 24 h but did not kill neighboring autologous normal kidney cells or allogeneic renal cancer cell lines. In the case of TUHR4TKB, for which autologous CTL were not induced, no expression of MHC class‐I molecules was observed on the surface of these carcinoma cells, although they were sensitive to autologous natural killer cells. The results imply that adoptive immunotherapy for metastasized renal carcinoma will be feasible with autologous CTL in combination with natural killer cells.
Inhibitory Effects of a Cyclosporin Derivative, SDZ PSC 833, on Transport of Doxorubicin and Vinblastine via Human P‐Glycoprotein
Authors: Kusunoki Nobuya , Takara Kohji , Tanigawara Yusuke , Yamauchi Aiko , Ueda Kazumitsu , Komada Fusao , Ku Yonson , Kuroda Yoshikazu , Saitoh Yohichi , Okumura Katsuhiko
Published: August 2005

The inhibitory effects of SDZ PSC 833 (PSC833), a non‐immunosuppressive cyclosporin derivative, on the P‐glycoprotein (P‐gp)‐mediated transport of doxorubicin and vinblastine were compared with those of cyclosporin A (Cs‐A). The transcellular transport of the anticancer drugs and PSC833 across a monolayer of LLC‐GA5‐COL150 cells, which overexpress human P‐gp, was measured. Both PSC833 and Cs‐A inhibited P‐gp‐mediated transport of doxorubicin and vinblastine in a concentration‐dependent manner and increased the intracellular accumulation of doxorubicin and vinblastine in LLC‐GA5‐COL150 cells. The values of the 50%‐inhibitory concentration (IC50) of PSC833 and Cs‐A for doxorubicin transport were 0.29 and 3.66 μM, respectively, and those for vinblastine transport were 1.06 and 5.10 μM, respectively. The IC50 of PSC833 for doxorubicin transport was about 4‐fold less than that for vinblastine transport, suggesting that the combination of PSC833 and doxorubicin might be effective. PSC833 itself was not transported by P‐gp and had higher lipophilicity than Cs‐A. These results indicated that the inhibitory effect of PSC833 on P‐gp‐mediated transport was 5‐ to 10‐fold more potent than that of Cs‐A, and this higher inhibitory effect of PSC833 may be related to the absence of PSC833 transport by P‐gp and to the higher lipophilicity of PSC833.
Expression of MRP and cMOAT in Childhood Neuroblastomas and Malignant Liver Tumors and Its Relevance to Clinical Behavior
Authors: Matsunaga Tadashi , Shirasawa Hiroshi , Hishiki Tomoro , Enomoto Hideki , Kouchi Katsunori , Ohtsuka Yasuhiro , Iwai Jun , Yoshida Hideo , Tanabe Masahiro , Kobayashi Susumu , Asano Takehide , Etoh Takao , Nishi Yoshisuke , Ohnuma Naomi
Published: August 2005

Advanced neuroblastoma and malignant liver tumor are representative childhood cancers for which combined chemotherapy including cisplatin and doxorubicin is routinely performed. The prognosis of patients with tumors which develop multiple drug resistance (MDR) is unfavorable. To elucidate the role of multidrug resistance‐associated protein (MRP) and canalicular multispecific organic anion transporter (cMOAT) in the clinical behavior of the tumors, we examined 42 neuroblastomas and 10 malignant liver tumors for the expressions of MRP and cMOAT by quantitative RNA‐polymerase chain reaction (PCR). The amplification and expression of N‐myc oncogene in the neuroblastomas were also investigated. We found a close association between MRP and N‐myc expression in each neuroblastoma sample but no significant relationship between MRP expression and the patients' outcome. The forced expression of N‐myc failed to enhance the expression of MRP in N‐myc transfected neuroblastoma cell lines. cMOAT was rarely expressed in the neuroblastomas, but was frequently expressed in the malignant liver tumors. The expression of MRP and cMOAT in the childhood liver tumors was more common and higher, especially in advanced cases with a poor outcome, than that observed in normal liver or in 9 hepatocellular carcinomas from adult patients. The enhanced expression of these genes might be characteristic of childhood malignant liver tumors and related to their clinical chemoresistance.
Effects of Sex Steroids and Growth Factors on Invasive Activity and 5′‐Deoxy‐5‐fluorouridine Sensitivity in Ovarian Adenocarcinoma OMC‐3 Cells
Authors: Ueda Masatsugu , Fujii Hideji , Yoshizawa Keiko , Kumagai Koji , Ueki Ken , Terai Yoshito , Yanagihara Tomoko , Ueki Minoru
Published: August 2005

Effects of sex steroids (estradiol‐17β, E2; progesterone, Prog) and growth factors (epidermal growth factor, EGF; transforming growth factor‐α, TGF‐α) on invasive activity and 5′‐deoxy‐5‐fluorouridine (5′‐dFUrd) sensitivity of ovarian adenocarcinoma OMC‐3 cells were investigated. Tumor cell migration along a gradient of substratum‐bound fibronectin and invasion into reconstituted basement membrane were inhibited by 10 μM Prog, but stimulated by 0.1–10 nM EGF and TGF‐α in a concentration‐dependent manner. E2 did not have any effect on tumor cell migration or invasion. The zymography of tumor conditioned medium showed that the treatment of OMC‐3 cells with EGF and TGF‐α resulted in increases of type IV collagenase, stromelysin and urokinase‐type plasminogen activator (uPA). EGF and TGF‐α up‐regulated thymidine phosphorylase (dThdPase) expression of tumor cells and consequently enhanced the antiproliferative action of 5′‐dFUrd, which is converted to 5‐fluorouracil by dThdPase. E2 and Prog did not have significant effects on the expression of proteolytic enzymes and dThdPase, or on the 5′‐dFUrd sensitivity of tumor cells. The inhibitory effect of Prog on tumor cell invasion may depend on its inhibitory action on the motility of tumor cells. These results suggest that EGF and TGF‐α simultaneously up‐regulate the potential of ovarian adenocarcinoma cells to invade extracellular matrices and their dThdPase expression, both of which are associated with the specific action of 5′‐dFUrd selectively to kill tumor cells with high invasive and metastatic potential.
A Proposal for a New Histological Classification Scheme for Predicting Short‐term Tumor Recurrence and Death in Patients with Invasive Ductal Carcinoma of the Breast
Authors: Hasebe Takahiro , Imoto Shigeru , Sasaki Satoshi , Mukai Kiyoshi
Published: August 2005

Tumor recurrence rate (TRR) and mortality rate (MR) of invasive ductal carcinoma (IDC) of the breast in short‐term follow‐up are relatively low. Nevertheless, it is extremely important to identify patients at risk of early recurrence or death after surgery. The aim of this study was to establish a new histological prognostic classification scheme for IDC in order accurately to predict the short‐term outcome. The following histological parameters were analyzed in 201 IDCs: 1) tumor size, 2) structural atypia, 3) nuclear atypia, 4) number of mitotic figures, 5) fibrotic focus (FF), 6) vascular invasion, 7) tumor necrosis, 8) skin invasion, 9) muscle invasion, 10) nodal status and 11) extramammary fat invasion. Multivariate analysis showed that nuclear atypia, presence of FF, and the invasive length of fat invasion (ILFI) were the most important histological parameters correlated with TRR or MR of IDCs. Accordingly, a new histological classification based on nuclear atypia, FF and ILFI (Nucleus‐Fibrotic focus‐Fat invasion, NFF) was devised. Comparative studies were performed with the following existing prognostic classifications: 1) histological grade, 2) modified Scarff‐Bloom‐Richardson histological grade, 3) prognostic index and 4) pathological TNM (pTNM) stage classifications. Patient grouping defined by NFF classification significantly correlated with tumor recurrence or death of IDCs in all cases, cases at stages I and II, those without lymph node metastasis and those who were estrogen receptor (ER)‐positive after adjustment for the other four classifications, using multivariate analysis. NFF classification appeared superior to existing prognostic classifications for the accurate prediction of the short‐term outcome for patients with IDCs in low risk groups.
Enhancing Effects of Quinacrine on Development of Hepatopancreatic Lesions in N‐Nitrosobis(2‐oxopropyl)amine‐initiated Hamsters
Authors: Furukawa Fumio , Nishikawa Akiyoshi , Imazawa Takayoshi , Kasahara Ken‐ichiro , Takahashi Michihito
Published: August 2005

The modifying effects of quinacrine administration during the post‐initiation phase of carcinogenesis were investigated in hamsters treated with N‐nitrosobis(2‐oxopropyl)amine (BOP). Female Syrian hamsters were given three weekly s.c. injections of BOP at a dose of 10 mg/kg and then 300 or 100 ppm quinacrine in their diet for 37 weeks. Additional groups of animals received the BOP injection alone, or only the 300 ppm quinacrine treatment as BOP‐negative controls. At week 40 of the experiment, all surviving animals were killed and development of proliferative lesions was assessed histopathologically. The multiplicity of pancreatic adenocarcinomas and dysplastic lesions per hamster was significantly higher (P<0.01 and P<0.05) in the BOP/Q100 group (1.92 and 1.78) than in the BOP‐alone group (1.07 and 0.79). The incidence of hepatocellular adenomas plus carcinomas was also significantly elevated (P<0.05) in the BOP/Q300 and BOP/Q100 groups. In contrast, the multiplicity of lung adenomas plus adenocarcinomas was significantly decreased (P<0.05) by the Q300 treatment. Neither the incidence nor the multiplicity of renal cell tumors (adenomas and carcinomas) or nephroblastomas significantly differed between the BOP‐treated groups. Electron microscopic examination revealed an abundance of myeloid lamellar bodies filling the cytoplasm of hepatocytes and pancreatic ductular and acinar cells, and epithelial cells of the gallbladder in the quinacrine‐treated animals, the degree being dose‐dependent. Our results indicate that quinacrine enhances pancreatic and hepatic carcinogenesis in hamsters induced by BOP.
Transgenic Mouse Expressing a Full‐length Hepatitis C Virus cDNA
Authors: Matsuda Jun‐ichi , Suzuki Misao , Nozaki Chikateru , Shinya Noriko , Tashiro Kayo , Mizuno Kyousuke , Uchinuno Youichi , Yamamura Ken‐ichi
Published: August 2005

Hepatitis C virus (HCV), a major causative agent of post transfusion non‐A, non‐B hepatitis (NANBH), can only infect humans and chimpanzees. We produced nine transgenic mouse lines carrying a full‐length HCV cDNA with the human serum amyloid P component (hSAP) promoter that can direct liver‐specific expression. In one of these lines HCV mRNA and HCV core protein were detected in the liver of the transgenic mouse, although the levels of expression were very low. In addition, HCV‐related antibody was detected in the serum.
Homotypic Adhesion through Carcinoembryonic Antigen Plays a Role in Hepatic Metastasis Development
Authors: Yoshioka Toshiaki , Masuko Takashi , Kotanagi Hitoshi , Aizawa Osamu , Saito Yuri , Nakazato Hiroshi , Koyama Kenji , Hashimoto Yoshiyuki
Published: August 2005

We established a cell line with high metastatic potential to the liver (LS‐LM4) after four successive repetitions of splenic injection of liver‐metastatic cells in SCID mice. This cell line strongly expressed CEA and showed increased homotypic adhesion as compared with the parent cell line (LS174T). To examine the role of CEA in the increased homotypic adhesion, LS‐LM4 cells were treated with anti‐CEA antibody and subjected to an in vitro adhesion and aggregation assay. Further, to study the role of CEA in the hepatic metastasis of cells with high metastatic potential, LS‐LM4 cells were treated with anti‐CEA antibody, and the inhibition of hepatic metastasis after splenic injection in vivo was examined. There was a 62% decrease in the homotypic adhesion of anti‐CEA antibody‐treated (100 μg/ml) LS‐LM4 cells under a Ca2+‐free condition as compared with the control (P<0.01). Anti‐CEA antibody (100 μg/ml) inhibited cell aggregation under a Ca2+‐free condition (P<0.05). Treatment with anti‐E‐cadherin antibody (60 μ/ml) plus anti‐CEA antibody (100 μg/ml) inhibited cell aggregation more potently than anti‐E‐cadherin antibody treatment alone in the presence of Ca2+. In vivo, there was a 75% decrease in the number of hepatic metastatic nodules in the G125 anti‐CEA antibody‐treated group as compared with the control group (P<0.01). Similarly, there was a 40% decrease in the diameter of metastatic nodules and there was a 90% decrease in total tumor volume of hepatic metastasis in the G125 anti‐CEA antibody‐treated group as compared with the control (P<0.01). These results suggest that increased metastatic potential to the liver is at least partly due to increased homotypic binding mediated by CEA.
Anthropometric and Other Risk Factors for Ovarian Cancer in a Case‐Control Study
Authors: Mori Mitsuru , Nishida Takashi , Sugiyama Toru , Komai Kan , Yakushiji Michiaki , Fukuda Koichi , Tanaka Toshimitsu , Yokoyama Masatoshi , Sugimori Hajime
Published: August 2005

Because it has been suggested that an environmental factor may play a role in the etiology of ovarian cancer, a case‐control study was conducted to assess some environmental and other risk factors for ovarian cancer from 1994 to 1996 in northern Kyushu, Japan. We analyzed the data of 89 cases with epithelial ovarian cancer and 323 controls without any cancer or ovarian disorder. After controlling for the effect of potential confounders, the odds ratios of ovarian cancer across increasing quartiles of the heaviest body weight were 1.00, 1.15, 1.71, 2.29 (P=0.008, test for trend). Significantly increased risks were noted for a history of diabetes mellitus (P<0.05), and for a family history of ovarian cancer (P<0.05). Significantly decreased trends for risk were obtained for the number of pregnancies (P<0.01) and the number of live births (P<0.001). This study provides additional support for an association between obesity and the risk of ovarian cancer. This relationship may at least partly explain the recent increase in the incidence of ovarian cancer in Japan, although possible contributions of other factors can not be ruled out.
p53 Gene Mutation and Loss of Heterozygosity of Chromosome 11 in Methylcholanthrene‐induced Mouse Sarcomas
Authors: Shimokado Kiyoshi , Watanabe Hiroshi , Sumii Masaharu , Miyagawa Kiyoshi , Kamiya Kenji , Dohi Kiyohiko , Niwa Ohtsura
Published: August 2005

Mutations of the p53 tumor suppressor gene are the most prevalent genetic alteration observed in a wide variety of human cancers. In this study we examined 63 methylcholanthrene (MCA)‐induced sarcomas from C57BL/6N×C3H/HeN F1 (BCF1) or C3H/HeN×C57BL/6N F1 (CBF1) mice for p53 gene mutations and loss of heterozygosity (LOH) of chromosome 11. Mutation analysis was done on exons 5 to 8 of the p53 gene by polymerase chain reaction‐single strand conformation polymorphism analysis. This identified 53 potential mutations in 45 sarcomas. Mutations were further confirmed by direct sequencing of the region. Forty‐nine of the 53 cases (94%) were missense mutations, while the rest included two nonsense mutations, one silent mutation and one insertional mutation. Spectra of base substitutions were: 25 cases (47%) of G:C→T:A transversion, 13 cases (25%) of G:C→A:T transition (CpG site 15%), 13 cases (24%) of G:C→C:G transversion, a case (2%) of A:T→T:A transversion and a case (2%) of insertion. In addition, analysis of 5 polymorphic markers of mouse chromosome 11 revealed LOH in ten cases (22%) among those carrying p53 mutations. In nine of these 10 cases, the loss involved all 5 markers. In addition, the loss was biased toward the C57BL allele (9 cases). The present study establishes the pattern of mutation of the p53 gene in MCA‐induced mouse sarcomas.
Loss of pS2 Protein Expression Is an Early Event of Intestinal‐type Gastric Cancer
Authors: Wu Ming‐Shiang , Shun Chia‐Tung , Wang Hsiu‐Po , Lee Wei‐Jei , Wang Teh‐Hong , Lin Jaw‐Town
Published: August 2005

To investigate the prevalence of pS2 expression in gastric cancer with respect to tumor histopathology, intestinal metaplasia and Helicobacter pylori (H. pylori) infection, pathologic specimens of 91 patients with gastric cancer were immunostained for pS2. Such immunoreactivity was correlated with the status of H. pylori infection, tumor staging, histology, subtyping, and associated intestinal metaplasia. Positive pS2 staining was seen throughout all non‐neoplastic epithelia, and in all 9 patients with the complete type of intestinal metaplasia. In contrast, 21 of 45 incomplete type of intestinal metaplasia had negative pS2 staining (P<0.001), and 54 out of 91 tumors (59.3%) showed loss of pS2 expression in the cancer tissues proper. There was no correlation of pS2 expression with age, gender, depth of invasion, duodenal involvement, lymph node metastasis, venous invasion or H. pylori infection. Negative pS2 staining was significantly higher in the intestinal (74.5%) and Borrmann type I, II, III (64.2%) tumors than the diffuse (43.2%, P<0.005) and Borrmann type IV (20%, P<0.05) tumors. Our results indicate that loss of pS2 expression may occur as an early event in the malignant transformation process of intestinal‐type tumors.