bluuebunny/crossref_metadata_2025 huggingface dataset:
Living Standards in Liaoning, 1749–1909: Evidence from Demographic Outcomes
Authors: Lee James Z. , Campbell Cameron D.
Published: August 2005

To assess trends in the standard of living in Liaoning province in north-east China during the nineteenth century, the secular change in demographic rates and their sensitivity to economic conditions are examined. The findings show that marital fertility rose, child mortality fell and some men were able to marry much earlier. Fertility became less sensitive to grain prices, suggesting a decline in the vulnerability of rural populations to economic shocks. Based on these trends, the conclusion can be drawn that the standard of living in Liaoning rose during the nineteenth century. While these results may not be generalized to China as a whole, they do raise the possibility of variation between and within regions of China in trends in living standards during the nineteenth century.
Demographic Responses to Short-Term Economic Stress in Eighteenth- and Nineteenth-Century Rural Japan: Evidence from Two Northeastern Villages
Authors: Tsuya Noriko O. , Kurosu Satomi
Published: August 2005

Examines the patterns and trends of demographic responses to changes in living standards in two farming villages in north-eastern Japan from 1716 to 1870. Using the local population registers (ninbetsu-aratame-cho), we analyse the impacts of short-term economic stress measured by annual variations of rice prices on mortality, fertility, first marriage, and migration. The result shows that first marriage and out-migration are most responsive to short-term economic stress. Household resources and wealth also influence these individual demographic behaviours but the effects differ by sex, life stage, and type/reason of behaviour. Findings on temporal trends suggest improvements of female socio-demographic status during the late nineteenth century.
Virtual Footprint and PRODORIC: an integrative framework for regulon prediction in prokaryotes
Authors: Münch Richard , Hiller Karsten , Grote Andreas , Scheer Maurice , Klein Johannes , Schobert Max , Jahn Dieter
Published: August 2005

Summary: A new online framework for the accurate and integrative prediction of transcription factor binding sites (TFBSs) in prokaryotes was developed. The system consists of three interconnected modules: (1) The PRODORIC database as a comprehensive data source and extensive collection of TFBSs with corresponding position weight matrices. (2) The pattern matching tool Virtual Footprint for the prediction of genome based regulons and for the analysis of individual promoter regions. (3) The interactive genome browser GBPro for the visualization of TFBS search results in their genomic context and links to gene and regulator-specific information in PRODORIC. The aim of this service is to provide researchers a free and easy to use collection of interconnected tools in the field of molecular microbiology, infection and systems biology.

Availability:  

Contact:  d.jahn@tu-bs.de
WELFARE REFORM, EARNINGS, AND INCOMES: NEW EVIDENCE FROM THE SURVEY OF PROGRAM DYNAMICS
Authors: CONNOLLY LAURA S. , MARSTON CHRISTINE ENERSON
Published: August 2005

The authors ask how welfare reform has affected the earnings and incomes of welfare recipients using a detailed longitudinal data set, the recently released Survey of Program Dynamics (SPD). They find pre‐TANF waivers positively affected the earnings and incomes of both female high school graduates and nongraduates, but the effect is statistically significant only for nongraduates. In contrast, the effect of TANF policies is detrimental to nongraduates but improves economic outcomes for graduates. The findings indicate there are still families who are left behind by welfare programs. The results also warrant further use of longitudinal data sets such as the SPD. (JEL I38, H53)
INTEGRATION AND UTILIZATION OF PUBLIC EDUCATION RESOURCES IN REMOTE AND HOMOGENOUS AREAS: A CASE STUDY OF THE UPPER PENINSULA OF MICHIGAN
Authors: JEON YONGIL , SHIELDS MICHAEL P.
Published: August 2005

This article adopts the nonradial Russell measure in the context of data envelopment analysis to measure the relative efficiency of public education in the Upper Peninsula of Michigan, a geographically remote but homogenous region. The empirical analysis focuses on the effect of community characteristics on the schools efficiency by using school district–level data. Several different forms of model specifications in the stage of data envelopment analysis are executed to check the robustness of the findings by adopting extreme‐bound analysis and thick modeling approach. Interestingly, despite the homogeneity of the Upper Peninsula, wide differences in the efficiency of education are found. These differences are robust as to model specification, suggesting that efficiency studies might be a useful guide for policy makers. Community factors such as income and educational levels, obtained from the census data by school district, are introduced in the second stage because they will influence the efficiency of the schools and the technology by which schools help students learn. Median family income is the most important explanatory variable, whereas the median value of housing is insignificant. In addition, private school enrollments are unrelated to the efficiency of public education, contrary to what many advocates of private schools have contended. These findings help understand education efficiency, having policy implications for education‐oriented states such as Michigan. (JEL I2, N3, H52)
Molecular targeting therapy of cancer: drug resistance, apoptosis and survival signal
Authors: Tsuruo Takashi , Naito Mikihiko , Tomida Akihiro , Fujita Naoya , Mashima Tetsuo , Sakamoto Hiroshi , Haga Naomi
Published: August 2005

Recent progress in the development of molecular cancer therapeutics has revealed new types of antitumor drugs, such as Herceptin, Gleevec, and Iressa, as potent therapeutics for specific tumors. Our work has focused on molecular cancer therapeutics, mainly in the areas of drug resistance, apoptosis and apoptosis resistance, and survival‐signaling, which is related to drug resistance. In this review, we describe our research on molecular cancer therapeutics, including molecular mechanisms and therapeutic approaches. Resistance to chemotherapeutic drugs is a principal problem in the treatment of cancer. P‐Glycoprotein (P‐gp), encoded by the MDR1 gene, is a multidrug transporter and has a major role in multidrug resistance (MDR). Targeting of P‐gp by small‐molecular compounds and/or antibodies is an effective strategy to overcome MDR in cancer, especially hematologic malignancies. Several P‐gp inhibitors have been developed and are currently under clinical phased studies. In addition to the multi‐drug transporter proteins, cancer cells have several drug resistance mechanisms. Solid tumors are often placed under stress conditions, such as glucose starvation and hypoxia. These conditions result in topo II poison resistance that is due to proteasome‐mediated degradation of DNA topoisomerases. Proteasome inhibitors effectively prevent this stress‐induced drug resistance. Glyoxalase I, which is often elevated in drug‐ and apoptosis‐resistant cancers, offers another possibility for overcoming drug resistance. It plays a role in detoxification of methylglioxal, a side product of glycolysis, which is highly reactive with DNA and proteins. Inhibitors of glyoxalase I selectively kill drug‐resistant tumors that express glyoxalase I. Finally, the susceptibility of tumor cells to apoptosis induced by antitumor drugs appears to depend on the balance between pro‐apoptotic and survival (anti‐apoptotic) signals. PI3K‐Akt is an important survival signal pathway, that has been shown to be the target of various antitumor drugs, including UCN‐01 and geldanamycin, new anticancer drugs under clinical evaluation. Our present studies provide novel targets for future effective molecular cancer therapeutics. (Cancer Sci 2003; 94: 15–21)
Effects of phenyl N‐tert‐butyl nitrone and its derivatives on the early phase of hepatocarcinogenesis in rats fed a choline‐deficient, L‐amino acid‐defined diet
Authors: Nakae Dai , Kishida Hideki , Enami Tomonori , Konishi Yoichi , Hensley Kenneth L , Floyd Robert A. , Kotake Yashige
Published: August 2005

The present study examined the effects of various derivatives of a radical trapping agent, phenyl N‐tert‐butyl nitrone, on the early phase of hepatocarcinogenesis in male Wistar rats fed a cholinedeficient, L‐amino acid‐defined diet for 16 weeks. The derivatives used were 4‐hydroxyphenyl (a physiologically major metabolite), 3‐hydroxyphenyl, 2‐hydroxyphenyl and 2‐sulfoxyphenyl N‐tert‐butyl nitrone, and their effects were studied in a comparison with those of the parent compound, phenyl N‐tert‐butyl nitrone. The sizes of putatively preneoplastic, glutathione S‐transferase placental form‐positive lesions and the levels of extra‐nuclear oxidative injury of hepatocytes, using the formation of 2‐thiobarbituric acid‐reacting substances as a parameter, were decreased by all doses (0.009%, 0.045% and 0.090% in diet) of 4‐hydroxyphenyl N‐tert‐butyl nitrone and only by the highest dose of 3‐hydroxyphenyl N‐tert‐butyl nitrone and phenyl N‐tert‐butyl nitrone. While 4‐hydroxyphenyl N‐tert‐butyl nitrone, 3‐hydroxyphenyl N‐tert‐butyl nitrone and phenyl N‐tert‐butyl nitrone all enhanced and inhibited hepatocellular apoptosis in preneoplastic lesions and their surrounding tissue, respectively, only 4‐hydroxyphenyl N‐tert‐butyl nitrone additionally inhibited hepatocyte proliferation both in preneoplastic lesions and their surrounding tissue. 2‐Hydroxyphenyl or 2‐sulfoxyphenyl N‐tert‐butyl nitrone did not exert any of the above effects. These results suggest that the selective induction of apoptosis in preneoplastic hepatocyte populations plays a crucial role in the inhibition of hepatocarcinogenesis derived by phenyl N‐tert‐butyl nitrone and its effective derivatives. Further, the metabolic conversion to 4‐hydroxyphenyl N‐tert‐butyl nitrone may also be important for the inhibitory effects of phenyl N‐tert‐butyl nitrone on hepatocarcinogenesis. (Cancer Sci 2003; 94: 26–31)
Urokinase‐type plasminogen activator expression correlates with tumor angiogenesis and poor outcome in gastric cancer
Authors: Kaneko Takeshi , Konno Hiroyuki , Baba Megumi , Tanaka Tatsuo , Nakamura Satoshi
Published: August 2005

Urokinase plasminogen activating system (PA system) and vascular endothelial growth factor (VEGF) were recently suggested to contribute synergistically to tumor progression. To evaluate the roles of the PA system and VEGF in gastric cancer, the effects of the PA system and VEGF on tumor angiogenesis and the survival of patients with gastric cancer were investigated. Cancer tissues from 101 gastric cancer patients were assayed immunohistochemically for expression of urokinase‐type plasminogen activator (uPA), uPA receptor (uPAR), PA inhibitor‐1 (PAI‐1) and VEGF protein. The positive rates of uPA, uPAR, PAI‐1, VEGF expression were 22.8%, 32.7%, 36.6% and 26.7%, respectively. Positive staining was observed in tumor cells (uPA, uPAR, VEGF), or in both tumor cells and stromal cells (PAI‐1). The expressions of uPA, uPAR, PAI‐1 and VEGF were significantly correlated with the clinicopathological factors: uPA, depth of tumor invasion, differentiation, lymphatic and vascular invasion; uPAR, tumor size, depth, lymph node involvement, differentiation, vascular invasion; PAI‐1, tumor size, depth, lymph node involvement, differentiation, vascular invasion; VEGF, differentiation, vascular invasion. The microvessel density (MVD) assessed immunohistochemically was significantly higher in the patients with expression of uPA, uPAR or VEGF, and stepwise analysis identified uPA as an independent correlated factor with MVD. Furthermore, multivariate analysis demonstrated that depth of tumor invasion, lymph node involvement and uPA expression were independent prognostic factors. uPA is a key factor in the PA system, being associated with a poor outcome of gastric cancer, and contributing not only to invasive activity, but also to angiogenesis. (Cancer Sci 2003; 94: 43–49)
Chemosensitivity of peritoneal micrometastases as evaluated using a green fluorescence protein (GFP)‐tagged human gastric cancer cell line
Authors: Nakanishi Hayao , Mochizuki Yoshinari , Kodera Yasuhiro , Ito Seiji , Yamamura Yoshitaka , Ito Katsuki , Akiyama Seiji , Nakao Akimasa , Tatematsu Masae
Published: August 2005

The Chemosensitivity of micrometastases in the peritoneal cavity to a 5‐fluorouracil derivative (TS‐1) was examined with a micrometastasis model featuring a human gastric cancer cell line tagged with the green fluorescence protein (GFP) gene in nude mice. Peritoneal metastases on the omentum and mesentery could be specifically visualized even when minute or dormant and also externally monitored noninvasively under illumination with blue light from 1 day after intraperitoneal (i.p.) injection of tumor cells. Metastatic deposits formed after i.p. injection of 2×106 tumor cells were significantly reduced by TS‐1 in a dose‐dependent manner (15–20 mg/kg), when it was orally administered from day 1 post‐injection for 4 weeks (early administration). No such inhibition was evident after injection of 1×107 tumor cells. When 2×106 tumor cells given injection, the ascites‐free period in TS‐1‐treated mice was significantly longer than in their untreated counterparts. Survival of TS‐1‐treated mice (5/15) was also significantly higher than the zero rate in controls (0/15), with 4 out of 5 surviving mice being free from peritoneal metastasis and the exception having only a few dormant metastases. In contrast, when TS‐1 was administered starting from day 7 post‐injection for 4 weeks (late administration), the survival and ascites‐free period of the TS‐1‐treated mice were not significantly influenced. The results indicate that the Chemosensitivity of peritoneal metastases to TS‐1 is dependent on the number of i.p. tumor cells and the timing of drug administration. Peritoneal micrometastases at an early stage are most susceptible and can be effectively eliminated by oral administration of an anti‐cancer agent, which leads to the longer survival and better quality of life (QOL) of the mice. (Cancer Sci 2003; 94: 112–118)
Estrogen sulfotransferase and sulfatase: Roles in the regulation of estrogen activity in human uterine endometrial carcinomas
Authors: Tanaka Kyoko , Kubushiro Kaneyuki , Iwamori Yuriko , Okairi Yuzuru , Kiguchi Kazushige , Ishiwata Isamu , Tsukazaki Katsumi , Nozawa Shiro , Iwamori Masao
Published: August 2005

The regulation of estrogen activity through the formation and cleavage of sulfoconjugates of estrogens is known to be related to the progression and metastasis of estrogen‐dependent breast carcinomas, but the involvement of sulfoconjugates in the steroid stimulation of endometrial functions and the progression of endometrial adenocarcinomas is not clearly understood yet. Estrogen sulfotransferase (EST) in the uterine endometria during the follicular phase was more active than during the luteal phase, but estrogen sulfate (ES) sulfatase exhibited lower activity during the follicular phase than during the luteal phase. However, ES sulfatase activities in cancerous tissues were lower than those in normal endometria and endometrial adenocarcinoma‐derived cells, among which the activity was exceedingly high in Ishikawa cells, suggesting that ES sulfatase in Ishikawa cells contributes to the estrogen‐dependent growth of these cells. EST activities higher than that in Ishikawa cells were found in only 3 of 24 cancerous tissues. Reverse transcriptase‐polymerase chain reaction (RT‐PCR) analysis of the EST and ES sulfatase genes in carcinoma‐derived cells demonstrated the extensive expression of both genes in Ishikawa cells. The isolated EST gene was transfected into Ishikawa cells with a mammalian expression vector to establish cell clones with enhanced EST activity, and the estrogen‐dependent cell growth of the resultant cell clones was found to be abolished, due to the enhanced sulfoconjugation of estrogen. Since ES sulfatase activity in cancerous tissues was significantly lower than that in Ishikawa cells, it might be not involved in the enhancement of estrogen activity associated with the pathogenesis of endometrial adenocarcinoma tissues.
DNA methylation of multiple genes in gastric carcinoma: Association with histological type and CpG island methylator phenotype
Authors: Oue Naohide , Oshimo Yasuhiro , Nakayama Hirofumi , Ito Reiko , Yoshida Kazuhiro , Matsusaki Keisuke , Yasui Wataru
Published: August 2005

Hypermethylation of CpG islands is associated with silencing of various tumor suppressor genes. Recent studies on colorectal and gastric cancer have identified a CpG island methylator phenotype (CIMP), which involves the targeting of multiple genes by promoter hypermethylation. For determination of association between DNA methylation pattern or histological type and CIMP status in gastric carcinoma, CpG islands in the promoters of hMLH1 and CDH1 genes, CpG islands overlapping exon 1 of MGMT and p16INK4a genes, and a non‐CpG island in exon 1 of the RAR‐β gene were studied. The presence of the CIMP was determined by monitoring five methylated in tumor (MINT) loci in 103 gastric carcinomas. Among the 103 gastric carcinomas, DNA hypermethylation was detected in the following frequencies: 14 (14%) for hMLH1, 26 (25%) for MGMT, 26 (25%) for p16INK4a, 54 (52%) for CDH1, and 53 (52%) for RAR‐β. Forty‐two (41%) of 103 gastric carcinomas were positive for the CIMP. CIMP and hypermethylation of p16INK4a gene were found more frequently in intestinal and diffuse‐adherent types than in diffuse‐scattered type (P=0.013 and 0.017, respectively). In contrast, hypermethylation of the CDH1 and RAR‐β genes was more common in the diffuse‐scattered type than in the other types (P=0.008 and 0.007, respectively). In intestinal‐ and diffuse‐adherent‐type gastric carcinomas, we found significant associations between the presence of the CIMP and hypermethylation of several genes: hMLH1 (P=0.006), p16INK4a (P=0.018), CDH1 (P=0.024), and RAR‐β (P=0.044). Our overall results suggest that in some intestinal‐ and diffuse‐adherent‐type gastric carcinomas, DNA hypermethylation affects non‐specific gene promoters concordantly, at least in part, whereas in diffuse‐scattered‐type gastric carcinoma, DNA hyper‐methylation affects specific genes such as CDH1 and RAR‐β.
The roles of hepatitis C virus proteins in modulation of cellular functions: A novel action mechanism of the HCV core protein on gene regulation by nuclear hormone receptors
Authors: Watashi Koichi , Shimotohno Kunitada
Published: August 2005

Hepatitis C virus (HCV) is one of the major causative agents inducing the development of hepatocellular carcinoma. The underlying mechanism of HCV pathogenesis, however, is largely unknown. Recent reports have implicated specific HCV proteins in persistent HCV infection, reduction of interferon sensitivity, and the modulation of cell proliferation, including alterations in apoptotic responses. However, the roles of these viral proteins remain controversial, because of conflicting results. Thus, it remains necessary to elucidate the precise molecular mechanisms through which the viral proteins influence cell growth and pathogenesis. In this review, after briefly describing what is known about the roles of the HCV proteins, in particular HCV core protein (core), in the modulation of cellular functions, we propose a novel molecular mechanism of the core in modulating gene expression via activation of nuclear hormone receptors.
Renal carcinogenesis: Genotype, phenotype and dramatype
Authors: Hino Okio , Kobayashi Toshiyuki , Momose Shuji , Kikuchi Yasushi , Adachi Hiroyuki , Okimoto Kazuo
Published: August 2005

Cancer is a heritable disorder of somatic cells. Environment and heredity are both important in the carcinogenic process. The Eker rat model of hereditary renal carcinoma (RC) is an example of a Mendelian dominantly inherited predisposition to a specific cancer in an experimental animal. Forty years after the discovery of the Eker rat in Oslo, we and Knudson's group independently identified a germline retrotransposon insertion in the rat homologue of the human tuberous sclerosis (TSC2) gene. To our knowledge, this was the first isolation of a Mendelian dominantly predisposing cancer gene in a naturally occurring animal model. Recently, we discovered a new hereditary renal carcinoma in the rat. This rat was named the “Ninon'’rat and its predisposing (Nihon) gene could be a novel renal tumor suppressor gene. This article will review the utility of these unique models for the study of problems in carcinogenesis; e.g., species‐specific differences in tumorigenesis, cell stage and tissue/cell‐type specific tumorigene‐sis, multistep carcinogenesis, modifier gene(s) in renal carcinogenesis, cancer prevention and the development of therapeutic treatments which can be translated to human patients, as well as how environmental factors interact with cancer susceptibility gene(s). (Cancer Sci 2003; 94: 142–147)
Histological characteristics of tumors in blood vessels play an important role in tumor progression of invasive ductal carcinoma of the breast
Authors: Hasebe Takahiro , Sasaki Satoshi , Imoto Shigeru , Ochiai Atsushi
Published: August 2005

Whether the characteristics of tumor cells in blood vessels play an important role in the tumor progression of invasive ductal carcinoma (IDC) of the breast is not known. The purpose of this study was to investigate the significance of the characteristics of tumor cells in blood vessels in relation to tumor progression in 247 IDC patients with blood vessel invasion, in comparison with well‐known histological parameters. Blood vessel tumor embolus dimensions were measured. Nuclear atypia, numbers of mitotic and apoptotic figures, and fibrosis grade of tumor cells in blood vessels were assessed. Cox proportional hazard multivariate analyses showed that >2 mitotic figures in blood vessel tumors significantly increased the hazard rates (HRs) of disease‐free survival (P=0.002) and initial distant organ metastasis‐free survival (IDOMS) in node‐negative IDCs (P=0.005), and the HRs of diseasefree survival (DFS,P=0.007) and IDOMS (P=0.015) in node‐positive IDCs. Apoptotic figures >2 in blood vessel tumor emboli significantly increased the HR of overall survival (P=0.007) in node‐positive IDCs. The present study showed the number of mitotic and apoptotic figures in tumor cells in the blood vessels to play a very important role in the tumor progression of IDCs. (Cancer Sci 2003; 94: 158–165)
Physical exercise reduces risk of breast cancer in Japanese women
Authors: Hirose Kaoru , Hamajima Nobuyuki , Takezaki Toshiro , Miura Shigeto , Tajima Kazuo
Published: August 2005

To evaluate the effects of physical exercise on breast cancer risk, a large‐scale case‐referent study of 2376 incident breast cancer cases and 18 977 non‐cancer referents was conducted using data from the hospital‐based epidemiologic research program at Aichi Cancer Center (HERPACC). To adjust appropriately for possible confounders, we examined the effects within subgroups of the study population. The multivariable‐adjusted odds ratio (OR) was 0.81 (95% confidence interval (CI): 0.69–0.94) for twice a week or more regular exercise. We observed a decreased risk of breast cancer for women who regularly exercised for health twice a week or more, irrespective of menopausal status, and were able to detect greater risk reductions within particular subgroups, including women who were parous, without a family history or non‐drinkers. Among premenopausal women, a particularly strong protective effect of physical exercise was observed (OR=0.57, 95%CI: 0.28–1.15) for those women whose body mass index (BMI) was high (BMI≥25). In contrast, risk reduction was found (OR=0.71, 95%CI: 0.50–1.01) among postmenopausal women whose BMI was medium (BMI: 22–25). Stratification of history of stomach cancer screening to adjust modifying effects of healthy consciousness allows a more precise assessment of the protective effect of exercise twice a week or more, independent of stomach cancer screening history. This study provides evidence that physical exercise, especially exercise twice a week or more, reduces the risk of breast cancer among Japanese women. (Cancer Sci 2003; 94: 193–199)
Anti‐cancer effect of genistein in oral squamous cell carcinoma with respect to angiogenesis and in vitro invasion
Authors: Myoung Hoon , Hong Sam‐Pyo , Yun Pil‐Young , Lee Jong‐Ho , Kim Myung‐Jin
Published: August 2005

Oral squamous cell carcinoma (OSCC) is one of the most common head and neck cancers. OSCC generally has a poor prognosis due to its tendency towards local invasion and subsequent metastasis, which is mediated by multiple proteolytic enzymes and angiogenesis. The purpose of this study was to evaluate the anti‐cancer effects of genistein, a soybean product known to be an effective natural anti‐angiogenic agent with respect to tumor growth, angiogenesis and in vitro invasion in an OSCC model. Northern blot analysis for vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and matrix metallo‐proteinase‐2 (MMP‐2), in vitro invasion assay and gelatin zymog‐raphy were carried out for HSC‐3 cells treated with genistein (27.3 μg/ml). In the animal experiment, genistein (0.5 mg/kg) was injected into tumor (HSC‐3)‐bearing mice (male balb/c/nu). The tumor growth rate and metastasis to lymph node or lung were compared and the microvessel density (CD31) was subsequently analyzed by immunohistochemistry. The genistein‐treated group showed a down‐regulation in VEGF mRNA expression, but not in bFGF and MMP‐2 mRNA expression. Genistein reduced in vitro invasion through the artificial basement membrane and gelatin zymography also showed a reduced gelatinolytic activity in the genistein‐treated group. In the genistein‐treated mice, a significantly lower CD31 immunoreactivity was found. However, the tumor growth and metastatic behavior in the experimental group and the control group were similar and there were no significant differences. These results suggest the possible use of genistein as an anti‐cancer agent in oral squamous cell carcinoma. However, it appears from the present study that anti‐angiogenic therapy consisting of a single application of genistein may not provide a satisfactory treatment for OSCC. As a result, further research is recommended to confirm that genistein may be employed as an adjunct treatment modality for OSCC. (Cancer Sci 2003; 94: 215–220)
Possible chemoresistance‐related genes for gastric cancer detected by cDNA microarray
Authors: Suganuma Kazuhiro , Kubota Tetsuro , Saikawa Yoshiro , Abe Sadanori , Otani Yoshihide , Furukawa Toshiharu , Kumai Koichiro , Hasegawa Hirotoshi , Watanabe Masahiko , Kitajima Masaki , Nakayama Hironobu , Okabe Hisafumi
Published: August 2005

To identify chemoresistance‐related genes of gastric cancer, we utilized cDNA microarray technology. Thirty‐five gastric cancer specimens surgically resected at our institute between 1998 and 1999 were studied for quantification of expression of 6300 genes by means of oligonucleotide microarray methods, and the results were evaluated in comparison with the chemoresistance of the specimens, which was determined by MTT (tetrazolium‐based 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) assay. Inhibition rates (IR) were determined for cisplatin (DDP), 5‐fluorouracil (5‐FU), mitomycin C or doxorubicin. IR of 60% or more was regarded as sensitive to each agent, and IR of less than 40% was defined as resistant. Clustering was successfully completed for DDP, resulting in selection of 23 candidates as DDP‐resistance‐related genes, including vascular permeability factor, 2 membrane transporting subunits, and retinoblastoma‐binding protein‐1. In addition, further selection of DDP‐resistance‐related genes was performed according to these criteria: 1) Expression of the gene can be detected in more than 70% of resistant tumors. 2) Expression can be detected in less than 30% of sensitive tumors. 3) Expression in tumors is more than twice that of normal mucosa in more than 50% of specimens. Then, metallothionein‐IG and heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF) were identified as candidate DDP‐resistance‐related genes. When known DDP‐resistance‐related genes were analyzed according to the MTT assay result, families of glutathione‐S‐transferase and cydooxygenase‐2 genes were also evaluated as resistance‐related genes. For 5‐FU resistance, dihydropyrimidine dehydrogenase and HB‐EGF‐like growth factor genes were also suggested to be resistance‐related genes. The present study demonstrated that oligonucleotide microarrays can provide information regarding chemoresistance factors in cancer. (Cancer Sci 2003; 94: 355–359)
Increased expansion of Vα24+ T cells derived from G‐CSF‐mobilized peripheral blood stem cells as compared to peripheral blood mononuclear cells following α‐galactosylceramide stimulation
Authors: Asada‐Mikami Rumiko , Heike Yuji , Harada Yukie , Kanai Sachiyo , Ikarashi Yoshinori , Kato Kazunori , Shirakawa Kazuo , Takaue Yoichi , Abe Tatsuo , Wakasugi Hiro
Published: August 2005

In the present study, unpurified peripheral blood mononuclear cells (PBMCs) from various sources, including steady‐state blood (normal donors) and granulocyte colony‐stimulating factor (G‐CSF)‐mobilized blood (cancer patients and normal donors) (G‐PBSC), were cultured in RPMI‐1640 in the presence of IL‐2 and α‐galactosylceramide (α‐GalCer) to expand Vα24+ T cells, and their expansion kinetics were compared. G‐CSF‐mobilized cells showed markedly higher expansion potential (350‐fold expansion of Vα24+ T cells, regardless of whether the cells were from cancer patients or normal donors) than steady‐state cells (15‐fold expansion, compared to the initial inoculums) (n=5, P<0.01). We also confirmed that the CD14‐ fraction of G‐PBSCs contained a large number of precursors of Vα24+ T cells, compared to PBSCs, as well as a large number of CD14+ cells, which assist Vα24+ T cell proliferation. Our simple and practical procedure, which eliminates complicated cell manipulation (including cell purification), produces efficient expansion of Vα24+ T cells when G‐CSF‐mobilized blood cells are cultured with α‐GalCer. (Cancer Sci 2003; 94: 383–388)
DJ‐927, a novel oral taxane, overcomes P‐glycoprotein‐mediated multidrug resistance in vitro and in vivo
Authors: Shionoya Motoko , Jimbo Takeshi , Kitagawa Mayumi , Soga Tsunehiko , Tohgo Akiko
Published: August 2005

DJ‐927 is a novel taxane, which was selected for high solubility, non‐neurotoxicity, oral bioavailability, and potent antitumor activity. In this study, we compared the in vitro and in vivo efficacy of DJ‐927 with those of paclitaxel and docetaxel. DJ‐927 exhibited stronger cytotoxicity than paclitaxel and docetaxel in various tumor cell lines, especially against P‐glycoprotein (P‐gp)‐expressing cells. The cytotoxicity of DJ‐927, unlike those of other taxanes, was not affected by the P‐gp expression level in tumor cells, or by the co‐presence of a P‐gp modulator. When intracellular accumulation of the three compounds was compared, intracellular amounts of DJ‐927 were much higher than those of paclitaxel or docetaxel, particularly in P‐gp‐positive cells. In vivo, DJ‐927 showed potent antitumor effects against two human solid tumors in male BALB/c‐nu/nu mice, and yielded significant life‐prolongation in a murine liver metastasis model with male C57BL/6 mice, in which neither paclitaxel nor docetaxel was effective. The results demonstrate the superior efficacy of orally administered DJ‐927 over intravenously administered paclitaxel or docetaxel against P‐gp‐expressing tumors, probably due to higher intracellular accumulation. A phase I clinical trials of DJ‐927 is currently ongoing in the US. (Cancer Sci 2003; 94: 459–466)
Chemosensitivity of human pancreatic carcinoma cells is enhanced by IkBα super‐repressor
Authors: Sato Toshiyuki , Odagiri Hiroki , Ikenaga Shojiro‐Kazunori , Maruyama Masateru , Sasaki Mutsuo
Published: August 2005

Pancreatic cancer has an unfavorable prognosis; surgery and chemotherapy at present have only limited value. To improve the prognosis of pancreatic cancer, effective non‐surgical therapy is necessary. NF‐kB is reported to be related to resistance to apopto‐sis, but its role in Chemosensitivity remains controversial. We examined the effects on Chemosensitivity of inhibition by induction of the super‐repressor IkBα in pancreatic cancer cell lines, BxPC‐3, Capan‐1 and Panc‐1. IkBα protein was transduced by infection of adenovirus vector AxCAhlkBδN. Sensitivity to VP‐16 and doxorubicin was increased significantly by IkBα induction in all three pancreatic cell lines. To investigate molecular events during IkBα induction, we examined the changes in expression of drug‐resistance‐related genes by real‐time RT‐PCR and those in apoptosis‐related genes by cDNA microarray. There was no common change of gene expression before and after IkBα induction among the three pancreatic cancer cell lines, except for mdm2. Further examination of other genes is necessary for a better understanding of the molecular mechanisms of enhancement of Chemosensitivity through IkBα induction. However, we have confirmed that IkBα induction leads to an increase of Chemosensitivity of pancreatic cancer. Many problems remain before clinical application of this adenoviral system will be feasible, but our results may ultimately lead to an improved therapy of pancreatic cancer. (Cancer Sci 2003; 94: 467–472)
Alterations of the c‐kit gene in testicular germ cell tumors
Authors: Sakuma Yuji , Sakurai Shinji , Oguni Sachiko , Hironaka Mitsugu , Salto Ken
Published: August 2005

Expression and gain‐of‐function mutation of the c‐kit gene, that encodes a receptor tyrosine kinase (KIT), have been reported in mast cell tumors and gastrointestinal stromal tumors (GISTs). Among human testicular germ cell tumors (GCTs), seminomas and seminoma components of mixed GCTs have also been shown to express KIT, but only one study has found the c‐kit gene mutation at exon 17 in seminoma. To elucidate the frequency and location of the c‐kit gene mutation of testicular GCTs, we analyzed the whole coding region of the c‐kit complementary DNA along with 4 mutational hot spots (exons 9, 11, 13 and 17) of the c‐kit genomic DNA by polymerase chain reaction and direct sequencing. Somatic mutations were found in 4 pure seminomas of 34 testicular GCTs (11.8%). One mutation was found in exon 11 (W557R) and the others were observed in exon 17 (D816H and D816V). These types of mutations were reported in GISTs (W557R), seminoma (D816H) and mastocytosis (D816V) and were considered to be gain‐of‐function mutations, although there were no differences of any clinicopathological factors or outcome between patients with and without mutations. Additionally, we also demonstrated coexpression of Gly‐Asn‐Asn‐Lys510–513 (GNNK)+ and GNNK‐ isoforms of the c‐kit gene with dominance of the GNNK‐ transcript in all testicular GCTs. The mutations and/or preferential expression of GNNK‐ isoform of the c‐kit gene might play an important role in the development of testicular GCTs, and these tumors may also be targets for STI571, which is a promising drug for advanced and metastatic GISTs.
Connexin26‐mediated gap junctional communication reverses the malignant phenotype of MCF‐7 breast cancer cells
Authors: Momiyama Megumi , Omori Yasufumi , Ishizaki Yasuko , Nishikawa Yuji , Tokairin Takuo , Ogawa Junichi , Enomoto Katsuhiko
Published: August 2005

A growing body of evidence indicates that the gap junction (GJ) plays a pivotal role in tumor suppression by exerting cell‐cell communication. It has, however, been reported that expression of connexin26 (Cx26) protein is induced in human ductal carcinomas of the breast and that its amount increases in proportion to the grade of malignancy. We thus examined the effects of over‐expressed Cx26 on growth characteristics in GJ‐deficient human MCF‐7 breast cancer cells that maintain the phenotype of early‐stage cancers. MCF‐7 cells were transfected with Cx26 cDNA, and several clones of stable transformants exhibiting a high level of cell‐cell communication were established. When they were examined in terms of various growth characteristics in vitro, the proliferation rate and the saturation density were drastically reduced in Cx26‐transfected clones compared with the mock‐transfectant. The anchorage‐independent growth capacity was also decreased by 50–75% after transfection of Cx26. Furthermore, the cell migration toward growth factors and cell invasion into Matrigel in a Boyden chamber were suppressed to 5–10% and 20–60%, respectively, of the control in Cx26‐transfected clones. When implanted into the mammary fat pads of nude mice in the presence of an excess of 17β‐estradiol, Cx26‐transfected clones tended to show slower tumor growth than the mock‐transfectant, although the difference was not statistically significant. Our results strongly suggest that the induction of Cx26 protein observed in human breast cancers, reported previously, may not be very relevant to the development of breast cancers, and that Cx26 can function as a tumor suppressor in breast cancer cells.
Overexpression of the Wilms' tumor gene WT1 in head and neck squamous cell carcinoma
Authors: Oji Yusuke , Inohara Hidenori , Nakazawa Mitsuhiro , Nakano Yoko , Akahani Shiro , Nakatsuka Shin‐ichi , Koga Satoko , Ikeba Ai , Abeno Sakie , Honjo Yuichiro , Yamamoto Yoshifumi , Iwai Soichi , Yoshida Kaori , Oka Yoshihiro , Ogawa Hiroyasu , Yoshida Jun‐ichi , Aozasa Katsuyuki , Kubo Takeshi , Sugiyama Haruo
Published: August 2005

The expression levels of the Wilms' tumor gene WT1 were examined in 56 cases of head and neck squamous cell carcinoma (HNSCC) using quantitative real‐time reverse transcriptase‐polymerase chain reaction (RT‐PCR). They included 4 cases of floor of mouth, 9 of gingiva, 25 of tongue, 10 of oropharynx, 3 of hypopharynx, and 5 larynx squamous cell carcinoma (SCC). All (100%) of 4 cases of floor of mouth, 5 (56%) of 9 gingiva, 17 (68%) of 25 tongue, 8 (80%) of 10 oropharynx, all (100%) of 3 hypopharynx, and all (100%) of 5 larynx SCC overexpressed the WT1 gene in the range of 3.07×10−4‐8.60×10−1 levels (the WT1 expression level in K562 leukemie cells was defined as 1.0). Thus, 42 (75%) out of 56 cases of HNSCC overexpressed the WT1 gene. The high expression level of the WT1 gene significantly correlated with poor histological tumor differentiation and high tumor stage of HNSCC. Immunohistochemical analysis confirmed the expression of WT1 protein in 6 cases (one floor of mouth, 2 tongue, 2 oropharynx, and one larynx SCC) with Overexpression of the WT1 gene. The direct sequencing analysis of the WT1 genomic DNA showed no mutations in any of 10 exons of the WT1 gene in 5 different HNSCC. These findings suggest an important role of the wild‐type WT1 gene in the tumorigenesis of HNSCC.
Preoperative serum midkine concentration is a prognostic marker for esophageal squamous cell carcinoma
Authors: Shimada Hideaki , Nabeya Yoshihiro , Tagawa Masatoshi , Okazumi Shin‐ichi , Matsubara Hisahiro , Kadomatsu Kenji , Muramatsu Takashi , Ikematsu Shinya , Sakuma Sadatoshi , Ochiai Takenori
Published: August 2005

High preoperative serum midkine concentration is associated with poor survival in patients with esophageal cancer, even after radical surgery, and thus may have prognostic value. Midkine (MK), a heparin‐binding growth factor, is expressed in numerous cancer tissues, and serum MK (S‐MK) concentrations are increased in patients with various neoplasms. The aim of this study is to evaluate the clinical significance of S‐MK in patients with esophageal squamous cell cancer (SCC). S‐MK was measured by enzyme‐linked immunosorbent assay in 135 healthy controls, 16 patients with benign esophageal disease, and 93 patients with primary esophageal SCC before surgery. The serum concentrations of carcinoembryonic antigen (CEA), SCC antigen (SCC‐Ag), and cytokeratin 19 fragment (CYFRA21–1) were also evaluated. All patients with esophageal SCC underwent radical esophagec‐tomy. Tumor MK expression was assessed by immunohistochemistry in 14 fresh tumor specimens. To determine whether S‐MK is of value as a prognostic factor, the authors conducted a survival analysis using Cox's proportional hazards model. S‐MK values in patients with esophageal SCC were significantly higher than those in healthy controls (417±342 pg/ml vs. 154±76 pg/ml, P<0.001). Using 300 pg/ml as the cut‐off value (representing the mean +2 standard deviations of the S‐MK of healthy controls), 61% of patients with esophageal SCC were classified as positive. MK expression by the tumor was significantly associated with high level of S‐MK. High S‐MK (≥300 pg/ml) was associated with tumor size, immunoreactivity and poor survival. Multivariate analysis indicated that S‐MK was an independent prognostic factor. S‐MK may be a useful tumor marker for esophageal SCC. Increased preoperative S‐MK in patients with esophageal SCC is associated with poor survival.
Nectins and nectin‐like molecules: Roles in cell adhesion, migration, and polarization
Authors: Takai Yoshimi , Irie Kenji , Shimizu Kazuya , Sakisaka Toshiaki , Ikeda Wataru
Published: August 2005

Nectins are a family of Ca2+‐independent immunoglobulin‐like cell‐cell adhesion molecules consisting of four members, which homophilically and heterophilically trans‐interact and cause cell‐cell adhesion. Nectin‐based cell‐cell adhesion is involved in the formation of cadherin‐based adherens junctions in epithelial cells and fibroblasts. The nectin‐based cell‐cell adhesion induces activation of Cdc42 and Rac small G proteins, which eventually regulate the formation of adherens junctions through reorganization of the actin cytoskeleton, gene expression through activation of a mitogen‐activated protein kinase cascade, and cell polarization through cell polarity proteins. Five nectin‐like molecules (necls), which have domain structures similar to those of nectins, have recently been identified and appear to play different roles from those of nectins. One of them, named necl‐5, which does not homophilically trans‐interact, but heterophilically trans‐interacts with nectin‐3, regulates cell migration and adhesion. In this article, the roles and modes of action of nectins and necls in cell adhesion, migration, and polarization are reviewed.
The D4Mit12 locus on mouse chromosome 4 provides susceptibility to both γ‐ray‐induced and N‐methyl‐N‐nitrosourea‐induced thymic lymphomas
Authors: Sato Hiroki , Tamura Yasushi , Ochiai Yukie , Kodama Yasumitsu , Hatakeyama Katsuyoshi , Niwa Ohtsura , Kominami Ryo
Published: August 2005

Low‐penetrance genes control different susceptibilities to γ‐ray‐induced thymic lymphomas in mouse strains. Our previous genetic analyses with backcross mice between BALB/c and MSM strains and congenic lines localized one such gene near the D4Mit12 locus on chromosome 4. N‐Methyl‐N‐nitrosourea (MNU) is a guanine base‐alkylating agent and differs from γ‐radiation in its mechanism of mutagenic action. Accordingly, in this study, we examined whether or not the locus also provides susceptibility to MNU‐induced thymic lymphomas using 84 offsprings derived from congenic mice for D4Mit12. Association analysis provided a suggestive linkage at D4Mit12 (P=0.0075) and the linkage was sustained by the peak of likelihood ratio statistical values being at the same position as that for the γ‐ray‐induced lymphomas. The results strongly suggest that the BALB/c allele near D4Mit12 is associated with susceptibility to lymphomas induced by two carcinogenic agents having different mechanisms of mutagenic action.
Repeated hepatocyte injury promotes hepatic tumorigenesis in hepatitis C virus transgenic mice
Authors: Kato Takanobu , Miyamoto Michiko , Date Tomoko , Yasui Kotaro , Taya Choji , Yonekawa Hiromichi , Ohue Chiharu , Yagi Shintaro , Seki Ekihiro , Hirano Tadamichi , Fujimoto Jiro , Shirai Tomoyuki , Wakita Takaji
Published: August 2005

Although hepatitis C virus (HCV) is a well‐known causative agent of hepatocellular carcinoma (HCC), the mechanism by which HCV induces HCC remains obscure. To elucidate the role of HCV in hepatocarcinogenesis, a model of hepatocyte injury was established using HCV core transgenic mice, which were developed using C57BL/6 mice transfected with the HCV core gene under control of the serum amyloid P component promoter. After 18–24 months, neither steatosis nor hepatic tumors were found in transgenic mice. The extent of hepatocyte injury and tumorigenesis were then examined in transgenic mice following repeated administration of carbon tetrachloride (CCl4) using various protocols (20%, 1/week; 10%, 2/week and 20%, 2/week). Serum alanine aminotransferase (ALT) levels did not differ among HCV core transgenic mice and non‐transgenic littermates; however, after 40 weeks, hepatic adenomas preferentially developed in transgenic mice receiving 20% CCl4 once weekly. Moreover, HCC was observed in transgenic mice receiving 2 weekly injections of a 20% solution of CCl4, and was not observed in the non‐transgenic control mice. In conclusion, the HCV core protein did not promote hepatic steatosis or tumor development in the absence of hepatotoxicity. However, the HCV core protein promoted adenoma and HCC development in transgenic mice following repeated CCl4 administration. These results suggest that hepatotoxicity resulting in an increased rate of hepatocyte regeneration enhances hepatocarcinogenesis in HCV‐infected livers. Furthermore, this experimental mouse model provides a valuable method with which to investigate hepatocarcinogenesis.
Long‐term follow‐up of patients with unresectable locally advanced non‐small cell lung cancer treated with chemoradiotherapy: A retrospective analysis of the data from the Japan Clinical Oncology Group trials (JCOG0003A)
Authors: Ohe Yuichiro , Ishizuka Naoki , Tamura Tomohide , Sekine Ikuo , Nishiwaki Yutaka , Saijo Nagahiro ,   for the Japan Clinical Oncology Group
Published: August 2005

To clarify the long‐term survival data and factors that are correlated with survival outcome of unresectable locally advanced non‐small cell lung cancer (NSCLC) following chemoradiotherapy, we analyzed patients who entered the Japan Clinical Oncology Group (JCOG) clinical trials for unresectable locally advanced NSCLC. Between October 1989 and August 1997, 240 patients (male 207, female 33; PS (performance status) 0 58, PS 1 172, PS 2 9, unknown 1; stage IIB 2, IIIA 62, IIIB 175, unknown 1) entered the 6 trials. All patients received chemotherapy and radiotherapy. The associations between survival outcome and treatment‐related factors were analyzed using Cox regression analysis. Median survival times and 5‐year survival rates in the trials were 11.9–19.7 months and 0–17.6%, respectively. Median survival time was 16.1 months and the 5‐ and 7‐year survival rates of all 240 patients were 14.4% and 12.0%, respectively. No deaths were observed 7 years after initiation of the treatment or later. For stage IIIA and IIIB patients, the 5‐year survival rates were 16.3% and 13.4%, respectively. Node status and age were significantly associated with survival, but no factors of the treatment were associated with survival of patients with unresectable locally advanced NSCLC. The present retrospective analysis showed that approximately 12% of patients with unresectable locally advanced NSCLC could be cured by various chemoradiotherapy regimens.