bluuebunny/crossref_metadata_2025 huggingface dataset:
MyLibrary: the library's response to the campus portal
Authors: McGeary Tim
Published: September 2005

Purpose

In August 2004, the Library Collections and Systems team at Lehigh University released MyLibrary @ Lehigh within the campus portal to the university community. The purpose of this article is to explain how what began as an integration strategy of the library's electronic resources into one complete stand‐alone application became the library's response to the fast‐growing campus portal.

Design/methodology/approach

Explains how MyLibrary@Lehigh was developed and implemented.

Findings

It became evident during its development and integration stages that MyLibrary@Lehigh would greatly enhance the success and usage of the campus portal. As a repository of all of the library's electronic resources, MyLibrary@Lehigh has become the one‐stop shop for the library within the campus‐wide, one‐stop shop of the campus portal.

Originality/value

MyLibrary has become a clear choice as an open‐source solution.
Subjective and objective evaluation of interactive and automatic query expansion
Authors: Shapira Bracha , Taieb‐Maimon Meirav , Nemeth Yael
Published: September 2005

Purpose

Query expansion and query limitation are two known techniques for assisting users to define efficient queries. The purpose of this article is to examine the effectiveness of the two methods.

Design/methodology/approach

The research entailed an objective and subjective evaluation of the effectiveness of automatic and interactive query expansion and of two query limit options. The evaluation included both lab simulations and large‐scale user studies. The objective aspects were evaluated in lab simulations with experts judging user performance. The subjective analysis was carried out by having the participants evaluate the quality of, and express their satisfaction with, the retrieval process and its results, thus employing perceived‐value analysis.

Findings

The main findings reveal a difference between the perceived and real values of these techniques. While users expressed their satisfaction with interactive query expansion and its performance, the real‐value analysis of their performance did not show any significant difference between the retrieval modes.

Originality/value

The article evaluates the objective and subjective effectiveness of automatic and interactive query expansion and two query limit options.
The web as a free source for scientific information: a comparison with fee‐based databases
Authors: Doldi Luisa M. , Bratengeyer Erwin
Published: September 2005

Purpose

The aim of this study was an evaluation of the web as a source of scientific bibliographic information.

Design/methodology/approach

In order to give this evaluation a quantitative dimension, a comparison with the information obtained from fee‐based bibliographic databases was performed. Based on a concrete search example in the field of plant production biotechnology, a comparative study of selected fee‐based bibliographic databases (CAB Abstracts and Biosis Preview) and a search of the web with selected search engines (Scirus and Google) was carried out. A comparison of the information retrieved through the databases and that retrieved through search engines was conducted with respect to the quantity and quality of retrieved documents, search time, the cost of information, retrieval strategies, the reliability of information and the demands on the skills of the searcher.

Findings

The surprising results of this comparison clearly indicate that the web, assuming a professional use of the medium, is not only a valuable source for scientific information, but also provides the scientific community with an instrument to make knowledge available and accessible for almost anyone.

Originality/value

This study shows that the web has reached a certain level of maturity in regard to scientific and qualitative content and can be considered a worthwhile source of scientific information.
Options for presenting search results
Authors: Jacsó Péter
Published: September 2005

Purpose

The purpose of this paper is to examine the growing importance of information available when searching for cited papers

Design/methodology/approach

Looks at the different formats available when searching for cited papers and how these formats can be manipulated to provide more relevant information.

Findings

Although progress has been made to provide user‐friendly citation information, it seems there are more features that might prove useful that have not as yet been implemented.

Originality/value

Provides an overview of various options available for searching for cited articles and any relevant information.
The pay‐per‐use revolution in the internet world
Authors: Kim Sangkyun
Published: September 2005

Purpose

The purpose of this article is to assess the spread of internet use and the pay‐per‐use system.

Design/methodology/approach

Presents the active debate with regard to “pay‐per‐use” for internet access, and pays particular consideration to the progress and propects of pay‐per‐use in Korea.

Findings

Although the trend is towards a pay‐per‐use system, the Korean Government has concerns about a pay‐per‐use system.

Originality/value

Indicates that transformation into pay‐per‐use will require a dramatic revolution and a change in the internet service indudustry.
Flooding induces a suite of adaptive plastic responses in the grass Paspalum dilatatum
Authors: Insausti P. , Grimoldi A. A. , Chaneton E. J. , Vasellati V.
Published: September 2005

We studied individual responses to flooding in the perennial grass Paspalum dilatatum, a widespread species in the Flooding Pampa of Argentina, using plants established in species‐diverse grassland microcosms.

Flooding effects were evaluated on root and leaf sheath anatomy and shoot morphological traits. Leaf water status and CO2 exchange rates were monitored in flooded and unflooded plants under changing, natural and controlled atmospheric conditions.

Root porosity and leaf sheath aerenchyma increased with flooding. Leaf extension rates and tiller height were also higher in flooded plants, which resulted in a large fraction of the shoot architecture emerging above the water surface. Flooding enhanced stomatal conductance, leaf water potential and net photosynthesis, especially under conditions leading to high air‐vapour pressure deficits. Therefore, flooded plants experienced fewer water deficits during periods of high atmospheric evaporative demand.

P. dilatatum showed tight regulation of water and carbon relations under severe soil‐oxygen deficiency, even in the presence of natural competitors. The suite of adaptive responses documented here might help to explain the observed increase in abundance of this species during extensive floods.
Mechanistic Insights into Chemopreventive Effects of Phenethyl Isothiocyanate in N‐Nitrosobis(2‐oxopropyl)amine‐treated Hamsters
Authors: Nishikawa Akiyoshi , Lee In‐Seon , Uneyama Chikako , Furukawa Fumio , Kim Hyoung‐Chin , Kasahara Ken‐ichiro , Huh Namho , Takahashi Michihito
Published: August 2005

The influence of phenethyl isothiocyanate (PEITC) on cell kinetics in the target organs of N‐nitroso‐bis(2‐oxopropyl)amine (BOP) tumorigenicity and on xenobiotic‐metabolizing enzymes was investigated in hamsters. Female 5‐week‐old Syrian hamsters were given a single s.c. dose of 0, 20 or 50 mg/ kg of BOP 2 h after receiving PEITC by gavage at a dose of 0, 100 or 250 μmol/animal (0, 16.3 or 40.8 mg/animal). Six and 22 h after the BOP administration, hamsters were killed and tissues were sampled. Proliferating cell nuclear antigen immunohistochemistry demonstrated significant reduction (P< 0.05–0.001) by PEITC of the labeling indices in the pancreatic acini and ducts, bronchioles, and renal tubules of the BOP‐treated animals in a dose‐dependent manner. In the lungs, the PEITC pre treat merit significantly (P< 0.001) reduced the 06‐methyldeoxyguanosine levels as compared to the BOP‐alone value. Immunoblot analysis of liver cytochrome P450 isoenzymes showed CYP 2B1 to be mainly involved in the metabolic activation of BOP. PEITC significantly (P<0.05) inhibited the induction of several isoenzymes, including CYP 2B1, while lowering the hepatic glutathione S‐transferase activity as well as glutathione levels, regardless of BOP administration. Our results thus suggest that PEITC exerts its chemopreventive activity against BOP initiation of carcinogenesis in hamsters by decreasing cell turnover and DNA methylation in the target organs, and by influencing hepatic xenobiotic‐metabolizing phase I enzymes, although the relationship, if any, of the latter with the former events remains to be investigated.
Prediction of Sensitivity to STI571 among Chronic Myeloid Leukemia Patients by Genome‐wide cDNA Microarray Analysis
Authors: Kaneta Yasuyuki , Kagami Yoshitoyo , Katagiri Toyomasa , Tsunoda Tatsuhiko , Jin‐nai Itsuro , Taguchi Hirokuni , Hirai Hisamaru , Ohnishi Kazunori , Ueda Takanori , Emi Nobuhiko , Tomida Akihiro , Tsuruo Takashi , Nakamura Yusuke , Ohno Ryuzo
Published: September 2005

One of the most critical issues to be solved in regard to cancer chemotherapy is the establishment of ways to predict the efficacy of anti‐cancer drugs for individual patients. To develop a prediction system based on expression of specific genes, we analyzed expression profiles of mononuclear cells from 18 chronic myeloid leukemia (CML) patients who were treated with the tyrosine kinase inhibitor STI571. cDNA microarrays representing 23 040 genes identified 79 genes that were expressed differentially between responders and non‐responders to STI571. On the basis of the expression patterns of 15 or 30 of these genes among the patients, we developed a “Prediction Score” system that could clearly separate the responder group from the non‐responder group. Verification of this system using four additional (“test”) cases succeeded in predicting the response of each of those four patients to the drug. These results provide the first evidence that gene‐expression profiles can predict sensitivity of CML cells to STI571, and may eventually lead to the achievement of “personalized therapy” for this disease.
Hypermethylation of the TSLC1 Gene Promoter in Primary Gastric Cancers and Gastric Cancer Cell Lines
Authors: Honda Teiichiro , Tamura Gen , Waki Takayoshi , Jin Zhe , Sato Kiyoshi , Motoyama Teiichi , Kawata Sumio , Kimura Wataru , Nishizuka Satoshi , Murakami Yoshinori
Published: September 2005

The TSLC1 (tumor suppressor in lung cancer–1) gene is a novel tumor suppressor gene on chromosomal region 11q23.2, and is frequently inactivated by concordant promoter hypermethylation and loss of heterozygosity (LOH) in non‐small cell lung cancer (NSCLC). Because LOH on 11q has also been observed frequently in other human neoplasms including gastric cancer, we investigated the promoter methylation status of TSLC1 in 10 gastric cancer cell lines and 97 primary gastric cancers, as well as the corresponding non‐cancerous gastric tissues, by bisulfite‐SSCP analysis followed by direct sequencing. Allelic status of the TSLC1 gene was also investigated in these cell lines and primary gastric cancers. The TSLC1 promoter was methylated in two gastric cancer cell lines, KATO‐III and ECC10, and in 15 out of 97 (16%) primary gastric cancers. It was not methylated in non‐cancerous gastric tissues, suggesting that this hypermethylation is a cancer‐specific alteration. KATO‐III and ECC10 cells retained two alleles of TSLC1, both of which showed hypermethylation, associated with complete loss of gene expression. Most of the primary gastric cancers with promoter methylation also retained heterozygosity at the TSLC1 locus on 11q23.2. These data indicate that bi‐allelic hypermethylation of the TSLC1 promoter and resulting gene silencing occur in a subset of primary gastric cancers.
The Mouse rasH2/BHT Model as an in vivo Rapid Assay for Lung Carcinogens
Authors: Umemura Takashi , Kodama Yukio , Hioki Kyoji , Nomura Tatsuji , Nishikawa Akiyoshi , Hirose Masao , Kurokawa Yuji
Published: September 2005

We have demonstrated the utility of a 9–week in vivo two‐stage assay for lung cancer initiating agents, using transgenic mice carrying the human prototype c‐Ha‐ras gene (rasH2 mice) and butylhydroxytoluene (BHT) as a potent lung promoter (rasH2/BHT model). In the present study, to ascertain appropriate conditions for BHT administration in this model, the effects of exposure on proliferation of alveolar type II cells in male rasH2 mice were examined. Additionally, use of BHT was validated for promotion of urethane (UR) carcinogenesis in male and female rasH2 mice. In a time‐course study of a single intragastric administration of BHT at a dose of 400 mg/kg, increased bromodeoxyuridine‐labeling index (LI) reached a maximum 3 days after treatment and was still observed after 7 days. In a dose‐response study, effects were dose‐dependent, the dose of 400 mg/kg causing eight‐fold elevation as compared to the control. With repeated administration, whereas the LI was increased dramatically at first, effects gradually diminished with further exposure, and finally six BHT treatments failed to induce cell proliferation. In a two‐stage model using UR as the initiator, although up to five consecutive doses of BHT were able to exert continued enhancing effects in terms of adenoma yield, no increment was evident with further treatments. The data overall indicate that a rasH2/BHT model with five weekly administrations of BHT at a dose of 400 mg/kg is most efficacious.
Colorectal Cancers with both p16 and p14 Methylation Show Invasive Characteristics
Authors: Hibi Kenji , Nakayama Hiroshi , Koike Masahiko , Kasai Yasushi , Ito Katsuki , Akiyama Seiji , Nakao Akimasa
Published: September 2005

Recent studies indicated that p16 and p14 inactivation owing to promoter methylation was important for colorectal tumorigenesis. In this study, we examined the methylation status of these genes in 86 primary colorectal cancers using methylation‐specific PCR (MSP) and correlated the results with the clinicopathological features of the patients. Aberrant promoter methylation of p16 and p14 genes was detected in 43 of 86 (50%) and 25 of 86 (29%) colorectal cancers, respectively. Next, we examined the correlation of methylation status with the clinicopathological features. We found a significant difference in maximal tumor size (P=0.022) when patients with both p16 and p14 methylation were compared to other patients. On the other hand, there was no significant difference in other factors, such as the extent of tumor and Dukes stage. These results suggested that colorectal cancer with both p16 and p14 methylation has the same invasiveness at a smaller size compared to that of the cancer with neither p16 nor p14 methylation. Inactivation of both p16 and p14 genes may result in a malignant change in colorectal cancer cells, leading to advanced cancers with a smaller size than those with p16 or p14 activity.
Down‐regulation of drs mRNA in Colorectal Neoplasms
Authors: Mukaisho Ken‐ichi , Suo Masashi , Shimakage Misuzu , Kushima Ryoji , Inoue Hirokazu , Hattori Takanori
Published: September 2005

The drs gene was originally isolated as a transformation suppressor gene against the v‐src oncogene. Expression of drs mRNA is down‐regulated by retroviral oncogenes such as v‐src and v‐K‐ras in the rat cell line F2408. Expression of drs mRNA is also markedly reduced in a variety of human cancer cell lines, including those of carcinomas of the colon, bladder, and ovary, suggesting that down‐regulation of drs mRNA is correlated with the development of human cancers. To clarify the correlation between down‐regulation of the drs gene and malignant tumor formation in human colorectal neoplasms, we examined expression of drs mRNA in a variety of colon cancer tissues by in situ hybridization. A total of 53 morphologically distinct neoplastic specimens were divided into the following five groups according to morphology: low and high grade adenoma in 7 and 12 cases, respectively (groups A, B), protruded‐type carcinoma in 16 (group C), superficial‐type carcinoma with an adenomatous component in 10 (group D) or superficial‐type carcinomas without any adenomatous component in 8 (group E). Expression of drs mRNA was detected in normal mucosa, low‐grade adenoma and most superficial‐type carcinomas without any adenomatous component. On the other hand, the rate of drs mRNA expression was significantly lower in protruded‐type adenocarcinoma and superficial‐type carcinoma with an adenomatous component. Our results indicate that down‐regulation of drs mRNA is closely correlated with carcinomas which arise from adenomatous polyps in the course of the adenoma‐carcinoma sequence, but that most carcinomas arising de novo are independent of the tumor suppressor function of the drs gene.
Microarray Analysis of Gene‐expression Profiles in Diffuse Large B‐cell Lymphoma: Identification of Genes Related to Disease Progression
Authors: Nishiu Mieko , Yanagawa Rempei , Nakatsuka Shin‐ichi , Yao Masayuki , Tsunoda Tatsuhiko , Nakamura Yusuke , Aozasa Katsuyuki
Published: September 2005

To identify genes that are associated with progression of malignant lymphoma, the expression profiles of 18 432 genes were analyzed in diffuse large B‐cell lymphomas at early (stages I and II, 6 cases) and advanced stages (stages III and IV, 9 cases) by means of cDNA microarrays. By comparing expression profiles between localized and advanced lymphomas, a number of genes that were differentially expressed were identified: 48 genes with increased expression and 30 genes with reduced expression in advanced‐stage diffuse large B‐cell lymphomas. Increased expression of MPHOSPH1, RUVBL1, CHN2, PSA and CDC10 genes, and reduced expression of COL1A2, COL4A1, FBLN5, CLECSF6, MIC2, CAV1 and S100A10 genes in the advanced lymphoma group were confirmed by semi‐quantitative reverse transcription‐PCR. RUVBL1 and PSA expression was further confirmed by real‐tune quantitative PCR, whose results paralleled the microarray data. The highly expressed genes encode proteins that promote cell proliferation and the genes with reduced expression encode adhesion proteins and target protein for cytotoxic T‐lymphocytes. These findings suggested that analysis with cDNA microarrays is a useful approach for identifying genes related to tumor progression and their products could be potential tumor markers or disease‐specific targets for anti‐tumor therapy.
Molecular Cytogenetic Characterization of Drug‐resistant Leukemia Cell Lines by Comparative Genomic Hybridization and Fluorescence in situ Hybridization
Authors: Shimizu Hajime , Fukuda Takeaki , Ghazizadeh Mohammad , Nagashima Mikio , Kawanami Oichi , Suzuki Toshimitsu
Published: September 2005

Resistance to chemotherapeutic drugs is one of the major difficulties encountered during cancer chemotherapy. To detect genomic aberrations underlying the acquired drug resistance, we examined three cultured human myelomonocytic leukemia cell sublines each resistant to adriamycin (ADR), 1‐β–1‐d‐arabinofuranosylcytosine (ara‐C), or vincristine (VCR), using comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), RT‐PCR, and western blot techniques. Chromosomes 7, 10 and 16 most conspicuously showed frequent aberrations among the resistant sublines as compared to the parental KY–821 cell line. In ADR‐resistant cells, gains at 7q21, 16p12, 16p13.1–13.3, 16q11.1–q12.1, and losses at 7p22–pter, 7q36–qter, 10p12, 10p11.2–pter, 10q21–q25, 10q26–qter were notable. In ara‐C‐resistant cells, no remarkable gain or loss on chromosome 7, but losses at 10p14–pter, 10q26–qter and 16p11.2–p11.3 were observed. In VCR‐resistant cells, gain at 7q21 and losses at 10p11–p13, 10p15 and 16p11.2–p13.3 were found. FISH identified amplified signals for the MDR–1 gene located at 7q21.1 in ADR‐and VCR‐but not ara‐C‐resistant cells, and for the MRP–1 gene located at 16pl3.1 in ADR‐resistant cells. These findings were validated at the mRNA and protein levels. Overlapping of the amplified MRP–1 gene with MDR–1 gene may play a critical part in the acquisition of resistance to ADR. Resistance to ara‐C excluded MDR–1 gene involvement and highlighted other key genes such as MXR gene. Several other genes putatively involved in the development of drug resistance might lie in other aberrated chromosomal regions.
Sequential Involvement of Two Distinct CD4+ Regulatory T Cells during the Course of Transplantable Tumor Growth and Protection from 3–Methylcholanthrene‐induced Tumorigenesis by CD25–depletion
Authors: Tawara Isao , Take Yutaka , Uenaka Akiko , Noguchi Yuji , Nakayama Eiichi
Published: September 2005

The involvement of two phenotypically different regulatory T cells in different stages of tumor growth was investigated. Treatment of BALB/c mice with anti‐CD25 monoclonal antibody (mAb) (PC61), but not anti‐CD4 mAb (GK1.5) before RL male 1 or Meth A inoculation caused tumor rejection. On the other hand, treatment of BALB/c mice with anti‐CD4 mAb (GK1.5) but not anti‐CD25 mAb (PC61) on day 6 after inoculation of the same tumors caused rejection. The findings suggest that CD4+CD25+ T cells downregulated the rejection response in the early stage of tumor growth. On the other hand, putative CD4+CD25− T cells downregulated the tumor rejection response in the late stage. Both CD4+CD25+ and putative CD4+CD25‐T cells appeared to inhibit the efficient generation of cytotoxic T lymphocytes (CTL). The present study also demonstrated that the treatment of BALB/c mice with anti‐CD25 mAb (PC61) at 4 or 6 weeks after 3–methylcholanthrene (3–MC) inoculation retarded tumor occurrence and prolonged survival.
Natural Antigenic Peptides from Squamous Cell Carcinoma Recognized by Autologous HLA‐DR8–restricted CD4+ T Cells
Authors: Kondo Hiroaki , Sahara Hiroeki , Miyazaki Akihiro , Nabeta Yuki , Hirohashi Yoshihiko , Kanaseki Takayuki , Yamaguchi Akira , Yamada Naoyuki , Hirayama Kazuo , Suzuki Manabu , Hamuro Junji , Torigoe Toshihiko , Takahashi Nobuaki , Kohama Gen‐iku , Ikeda Hideyuki , Sato Noriyuki
Published: September 2005

A large number of human tumor antigens recognized by CD8+ cytotoxic T lymphocytes (CTL) have been identified. Some of them have been employed in clinical trials and have achieved some objective responses. However, little is known about those that are recognized by CD4+ T cells, except for a very few that were identified from melanomas. Previously, we reported that an oral squamous cell carcinoma (SCC) cell line, OSC–20, was effectively lysed by HLA‐DRB1·08032 (HLA‐DRS)‐restricted autologous CD4+ T cell line, TcOSC–20. In this study, we performed two steps of chromatographic purification of the tumor cell lysate in combination with mass spectrometry. We found one reverse‐phase high‐performance liquid chromatography (RP‐HPLC) fraction that was effectively recognized by the T cells. We analyzed the fraction by nano‐liquid chromatography/electrospray ionization ion trap mass spectrometry (LC/MS/MS) and found six representative ions. We could determine the primary amino acid sequence of each of the six ions. Three of them contained a potential HLA‐DR8 binding motif, and TcOSC–20 showed a rather strong cytotoxic response to one of the synthetic pep tides, namely, amino acid residues 321–336 of human a‐enolase. Thus, several gene products of squamous cancer cells are endogenously processed and may be presented on HLA class II molecules, so that they could constitute target molecules for autologous CD4+ T cells.
Dendritic Cell Appearance and Differentiation during Early and Late Stages of Rat Stomach Carcinogenesis
Authors: Takeuchi Motoi , Yamamoto Masami , Tatematsu Masae , Miki Kazumasa , Sakaki Yoshiyuki , Furihata Chie
Published: September 2005

Dendritic cell appearance and differentiation during early and late stages of rat stomach carcinogenesis were studied in the pyloric mucosa. Young male rats were given drinking water with or without N‐methyl‐N′‐nitro‐N‐nitrosoguanidine (MNNG; 100 nig/liter) for 14 days. Use of competitive RT‐PCR and northern blotting showed that MNNG exposure induced 3‐to 4–fold greater expression of the genes for integrin β7 and integrin αE2 (identical with antigen OX–62, a dendritic cell marker), as well as three cytokines, IL–4, GM‐CSF and TNFα, in the stomach pyloric mucosa of resistant Buffalo rats compared to sensitive ACI rats. These genes were minimally expressed in control animals. The results confirm the appearance of dendritic cells in the target pyloric mucosa and suggest the possibility that dendritic cell differentiation and maturation are induced by various cytokines, at least in Buffalo rats. Competitive RT‐PCR showed expression of integrin αE2 and β7, MHC class II‐associated invariant chain (Ii), MHC class II, B7–1, CD28, GM‐CSF and TNFα genes in all 12 examined stomach adenocarcinomas and adenomas induced in male Lewis and WKY rats with 30 weeks' MNNG exposure, suggesting the presence of dendritic cells in tumors. OX–62 staining and western blotting for OX–62 also confirmed the presence of dendritic cells in tumors. However, the population of dendritic cells in tumors was less than that in the pyloric mucosa after 14 days' MNNG exposure. The present results suggest that immune defense involving dendritic cells is marshaled from the very early initiation stage during rat stomach cancer development, but is downgraded in developed tumors.
Calponin h1 Suppresses Tumor Growth of Src‐induced Transformed 3Y1 Cells in Association with a Decrease in Angiogenesis
Authors: Kaneko Miwako , Takeoka Michiko , Oguchi Misae , Koganehira Yoko , Murata Hiroshi , Ehara Takashi , Tozuka Minoru , Saida Toshiaki , Taniguchi Shun'ichiro
Published: September 2005

Calponin h1 (CNhl) is a basic actin‐binding protein that is abundantly expressed in smooth muscle cells and involved in smooth muscle contraction by inhibiting actomyosin MgATPase. In recent studies, CNhl was noted to suppress cell proliferation and tumorigenicity in leiomyosarcoma and tumor growth in fibrosarcoma cell lines. To further investigate the function of CNhl as a tumor suppressor, we transfected the human CNhl gene into a v‐src‐transformed rat fibroblast cell line SR–3Y1. The volume of the tumors derived from one randomly selected CNh1‐transfectant (C1) in nude mice was reduced to 34.1% of that from a randomly selected vector transfectant (VI). A similar tendency was observed in another independent pair (C2, V2). Pathological analysis showed a significant decrease in the number of mitotic cells in the CNh1‐transfectants. Further, a marked reduction in the number of vessels in the CNhl‐transfectant was observed. DNA synthesis under conditions without serum was significantly reduced in the CNhl‐transfectant (C1) compared with the control transfectant (VI), while no significant difference was seen in the cellular growth in the presence of 10% serum. A slight but significant reduction in in vitro cellular motility in the CNhl‐transfectant was also observed. While the suppression of growth potential and cell motility by CNhl transfer was significant but partial, a marked reduction in vascular endothelial growth factor (VEGF) mRNA and the secretion of VEGF protein was observed in the CNhl‐transfectant. These results suggest that CNhl plays a role as tumor suppressor in SR–3Y1 mainly by decreasing VEGF expression and angiogenesis in vivo and partially through reducing cellular proliferative potential and cell motility.
β‐Hydroxyisovalerylshikonin Is a Novel and Potent Inhibitor of Protein Tyrosine Kinases
Authors: Hashimoto Sachiko , Xu Ying , Masuda Yutaka , Aiuchi Toshihiro , Nakajo Shigeo , Uehara Yoshimasa , Shibuya Masabumi , Yamori Takao , Nakaya Kazuyasu
Published: September 2005

β‐Hydroxyisovalerylshikonin (β‐HIVS), a compound isolated from Lithospermium radix, most efficiently induced cell‐death in two lines of lung cancer cells, namely, NCI‐H522 and DMS114, whereas shikonin was effective against a wide variety of tumor cell lines. During our studies of the mechanism of action of β‐HIVS on tumor cells, we found that this compound inhibited protein tyrosine kinase (PTK) activity. The tyrosine kinase activities of a receptor for EGF (EGFR) and v‐Src were strongly inhibited and that of KDR/Flk–1 was weakly inhibited by β‐HIVS. The inhibition by β‐HIVS of the activities of EGFR and v‐Src was much stronger than that by shikonin. The IC50values of β‐HIVS for EGFR and v‐Src were approximately 0.7 μM and 1 μM, respectively. Moreover, the inhibition of v‐Src by β‐HIVS was non‐competitive with respect to ATP. These results strongly suggest that the action of β‐HIVS, as well as that of shikonin, involves the inhibition of PTK, and they also suggest the possibility of producing a novel group of PTK inhibitors based on shikonin as the parent compound.
Clinical significance of serum NM23‐H1 protein in neuroblastoma
Authors: Okabe‐Kado Junko , Kasukabe Takashi , Honma Yoshio , Hanada Ryoji , Nakagawara Akira , Kaneko Yasuhiko
Published: September 2005

We have previously reported that NM23 genes are overexpressed in various hematological malignancies and that serum NM23‐H1 protein levels are useful for predicting patient outcomes. In this study we assessed the clinical implications of serum NM23‐H1 protein on neuroblastoma. We examined serum NM23‐H1 protein levels in 217 patients with neuroblastoma, including 131 found by mass‐screening and 86 found clinically by an enzyme‐linked immunosorbent assay, and determined the association between levels of this protein, and known prognostic factors or the clinical outcome. The serum NM23‐H1 protein level was higher in neuroblastoma patients than in control children (P < 0.0001). Patients with MYCN amplification had higher serum NM23‐H1 levels than those with a single copy of MYCN. Overall survival was assessed in the 86 patients found clinically, and was found to be worse in patients with higher serum MN23‐H1 levels (≥ 250 ng/mL) than in those with lower levels (< 250 ng/mL; P = 0.034). The higher level of NM23‐H1 was correlated with a worse outcome in patients with a single MYCN copy, or in those younger than 12 months of age. Serum NM23‐H1 protein levels may contribute to predictions of clinical outcome in patients with neuroblastoma. (Cancer Sci 2005; 96: 653 – 660)
Array‐based comparative genomic hybridization analysis of high‐grade neuroendocrine tumors of the lung
Authors: Peng Wei‐Xia , Shibata Tatsuhiro , Katoh Hiroto , Kokubu Akiko , Matsuno Yoshihiro , Asamura Hisao , Tsuchiya Ryosuke , Kanai Yae , Hosoda Fumie , Sakiyama Tokuki , Ohki Misao , Imoto Issei , Inazawa Johji , Hirohashi Setsuo
Published: September 2005

We examined a large number of primary high‐grade neuroendocrine tumors of the lung (10 small cell lung carcinomas and 31 large cell neuroendocrine carcinomas) by using array‐based comparative genomic hybridization using microarrays spotted with 800 bacterial artificial chromosome clones containing tumor‐related genes from throughout the human genome. We identified the genome‐wide copy number alteration profiles of these tumors, including recurrent amplifications located at 2q21.2, 3q21–27, 3q26, 3q27–29, 5p14.2, 5p13, 7q21.1, 8q21, and 8q24 and homozygous deletions at 1p36, 4p16, 4p16.3, 9p21.3, 9p21, 19p13.3, and 20q13. Our results revealed that small cell lung carcinomas and large cell neuroendocrine carcinomas have multiple characteristic chromosomal alterations in common, but that distinctive alterations also exist between the two subtypes. Moreover, we found that the two subtypes undergo different processes of accumulating these genetic alterations during tumor development. By comparing the genetic profiles with the clinicopathological features, we discovered many chromosomal loci whose alterations were significantly associated with clinical stage and patient prognosis. These results will be valuable for evaluating clinical status, including patient prognosis, and for identifying novel molecular targets for effective therapies. (Cancer Sci 2005; 96: 661 – 667)
DNA vaccination of HSP105 leads to tumor rejection of colorectal cancer and melanoma in mice through activation of both CD4+ T cells and CD8+ T cells
Authors: Miyazaki Masafumi , Nakatsura Tetsuya , Yokomine Kazunori , Senju Satoru , Monji Mikio , Hosaka Seiji , Komori Hiroyuki , Yoshitake Yoshihiro , Motomura Yutaka , Minohara Motozumi , Kubo Tatsuko , Ishihara Keiichi , Hatayama Takumi , Ogawa Michio , Nishimura Yasuharu
Published: September 2005

We report that HSP105, identified by serological identification of antigens by recombinant expression cloning (SEREX), is overexpressed in a variety of human cancers, including colorectal, pancreatic, thyroid, esophageal, and breast carcinoma, but is not expressed in normal tissues except for the testis. The amino acid sequences and expression patterns of HSP105 are very similar in humans and mice. In this study, we set up a preclinical study to investigate the usefulness of a DNA vaccine producing mouse HSP105 whole protein for cancer immunotherapy in vivo using BALB/c and C57BL/6 mice, Colon26, a syngeneic endogenously HSP105‐expressing colorectal cancer cell line, and B16.F10, a melanoma cell line. The DNA vaccine was used to stimulate HSP105‐specific T‐cell responses. Fifty percent of mice immunized with the HSP105 DNA vaccine completely suppressed the growth of subcutaneous Colon26 or B16.F10 cells accompanied by massive infiltration of both CD4+ T cells and CD8+ T cells into tumors. In cell transfer or depletion experiments we proved that both CD4+ T cells and CD8+ T cells induced by these vaccines play critical roles in the activation of antitumor immunity. Evidence of autoimmune reactions was not present in surviving mice that had rejected tumor cell challenges. We found that HSP105 was highly immunogenic in mice and that the HSP105 DNA vaccination induced antitumor immunity without causing autoimmunity. Therefore, HSP105 is an ideal tumor antigen that could be useful for immunotherapy or the prevention of various human tumors that overexpress HSP105, including colorectal cancer and melanoma. (Cancer Sci 2005; 96: 695 – 705)
Influence of hospital procedure volume on uterine cancer survival in Osaka, Japan
Authors: Ioka Akiko , Tsukuma Hideaki , Ajiki Wakiko , Oshima Akira
Published: September 2005

Recent publications suggest that the relationships between hospital procedure volume and cancer survival may be different according to characteristics of the cancer such as primary site, extent of disease, and the year of diagnosis. The associations between hospital procedure volume and survival for uterine cancer, however, have never been studied in Japan. Data from the Osaka Cancer Registry were used to investigate this issue. Hospitals were ranked according to the number of operations for uterine cancer performed per year (high, medium, low, very low) in a diagnosis year period (1975–1981, 1982–1989 and 1990–1997). Survival analysis was carried out for the reported 7213 patients who lived in Osaka Prefecture (excluding Osaka City) diagnosed in 1975–1997, or patients who lived in Osaka City diagnosed in 1993–1997, because active follow‐up data on vital status 5 years after diagnosis were available. The relative 5‐year survival was higher with increased hospital procedure volume after 1982 (49.8, 68.6, 70.9, and 75.9%, respectively, in 1982–1989; 45.7, 62.7, 71.4, and 77.6%, respectively, in 1990–1997), and only survival in high‐volume hospitals increased in the period 1975–1997. After adjustment for age, subsite, extent of disease and surgery by using the Cox regression model, patients receiving care in very low, low, or medium‐volume hospitals were found to have a higher risk of death than patients receiving care in high‐volume hospitals. Similar findings were obtained when the analysis was conducted separately for patients with cancer of the cervix and those with cancer of the corpus uteri. Although some limitations exist in this study, our results suggest that uterine cancer survival might be superior in high‐volume hospitals in Osaka, Japan. (Cancer Sci 2005; 96: 689 – 694)
Overexpressed Skp2 within 5p amplification detected by array‐based comparative genomic hybridization is associated with poor prognosis of glioblastomas
Authors: Saigusa Kuniyasu , Hashimoto Naoya , Tsuda Hitoshi , Yokoi Sana , Maruno Motohiko , Yoshimine Toshiki , Aoyagi Masaru , Ohno Kikuo , Imoto Issei , Inazawa Johji
Published: September 2005

To better understand the pathogenesis of glioblastoma multiforme (GBM) and to increase the accuracy of predicting outcomes for patients with this disease, we performed genome‐wide screening for DNA copy‐number aberrations in 22 glioma‐derived cell lines using a custom‐made comparative genomic hybridization‐array. Copy‐number gains were frequently detected at 3q, 7p, 7q, 20q, Xp and Xq, and losses at 4q, 9p, 10p, 10q, 11q, 13q, 14q, 18q, and 22q. Among several non‐random chromosomal aberrations, the gain/amplification of DNA at 5p, which has never been reported before in GBM, was detected with a relatively high ratio (log2 ratio = 0.41–1.19) in four cell lines. Amplification and subsequent overexpression of SKP2, a possible target of amplification within 5p, were detected in four of the 22 cell lines. We also investigated the expression of the gene product in primary GBM by immunohistochemistry, which revealed increased levels of Skp2 in 11 of the 35 tumors examined (31.4%). Heightened expression of Skp2 was associated with shorter overall survival (P = 0.001, logrank test), especially in patients younger than 65 years. These results suggest that overexpression of Skp2 through gene amplification may contribute to the pathogenesis of GBM, and that overabundance of the protein might be a useful prognostic tool in patients with this disease.(Cancer Sci 2005; 96: 676 – 683)
Establishment of an immortalized cell line from a precancerous lesion of lung adenocarcinoma, and genes highly expressed in the early stages of lung adenocarcinoma development
Authors: Shimada Aki , Kano Junko , Ishiyama Tadashi , Okubo Chigusa , Iijima Tatsuo , Morishita Yukio , Minami Yuko , Inadome Yukinori , Shu Yujian , Sugita Shintaro , Takeuchi Tomoyo , Noguchi Masayuki
Published: September 2005

Atypical adenomatous hyperplasia (AAH) is classified as a precancerous lesion of lung adenocarcinoma. We established an immortalized AAH cell line (PL16T) and a human non‐neoplastic bronchial epithelial cell line (PL16B) from the same patient by transfection with the gene for SV40 large T antigen. The expression profile of PL16T was compared with that of PL16B by the suppression subtractive hybridization method. From 704 selectively hybridized clones, we finally selected 25 fragments of mRNA that showed transcription levels more than three times higher in PL16T than in PL16B. Thirteen (52%) and eight (32%) of them encoded tumor‐associated calcium signal transducer 2 (TACSTD2) and S100 calcium binding protein A2 (S100A2), respectively. The high transcription of TACSTD2 and S100A2 in PL16T was confirmed by in situ hybridization. In normal lung tissue, both TACSTD2 and S100A2 were expressed at very low levels, but seven and five of 14 AAH were positive for TACSTD2 and S100A2, respectively. The frequency of TACSTD2 positivity was increased in 16 of 22 bronchioloalveolar carcinomas (BAC) and adenocarcinoma with mixed subtype with BAC component (mixed BAC). Positivity for S100A2 occurred in four of 22 BAC and mixed BAC. The abnormal transcription of TACSTD2 and S100A2 are thought to be unique molecular markers of the preinvasive stage of lung adenocarcinoma.(Cancer Sci 2005; 96: 668 – 675)
Airway management before, during and after extubation: a survey of practice in the United Kingdom and Ireland
Authors: Rassam S. , SandbyThomas M. , Vaughan R. S. , Hall J. E.
Published: September 2005

Complications at extubation remain an important risk factor in anaesthesia. A postal survey was conducted on extubation practice amongst consultant anaesthetists in the United Kingdom and Ireland. The use of short acting drugs encourages anaesthetists to extubate the trachea at lighter levels of anaesthesia. The results show that oxygen (100%) is not routinely administered either before extubation or en route to the recovery area. A trend towards a head up or sitting position at extubation is emerging. However, further research into the use of these positions is required. Airway related complications at extubation are relatively frequent but are usually dealt with by simple basic measures. The role of drugs such as propofol in decreasing the incidence of these complications needs further evaluation. Some of these results give concern for patient safety and for training. The importance of teaching and adherence to continued oxygenation until complete recovery is strongly emphasised. Nerve stimulators should be used continually as standard monitoring throughout the anaesthetic period when muscle‐relaxing drugs are part of the anaesthetic technique.
Variation in end‐of‐life decision making between critical care consultants*
Authors: Poulton B. , Ridley S. , Mackenzie‐Ross R. , Rizvi S.
Published: September 2005

Considerable variation in end‐of‐life decision making is reported between intensive care units in the United Kingdom, possibly because of differences in casemix. Senior medical staff within any one unit should, however, be consistent in such decision making. We reviewed the medical records for a 4‐year period to establish if there was consistency in our own unit. This revealed considerable variation in the apparent willingness of consultants to make end‐of‐life decisions, emphasising the subjective nature of these decisions. Personality typing (Myers‐Briggs Type Indicator) of consultants revealed that those who had made more than the expected number of decisions had scores towards the judging end of the judging/perceiving domain.
Modelling the impact of an influenza pandemic on critical care services in England
Authors: Menon D. K. , Taylor B. L. , Ridley S. A. ,   on behalf of the Intensive Care Society, UK
Published: September 2005

The UK Influenza Pandemic Contingency Plan does not consider the impact of a pandemic on critical care services. We modelled the demand for critical care beds in England with software developed by the Centers for Disease Control (Flusurge 1.0), using a range of attack rates and pandemic durations. Using inputs that have been employed in UK Department of Health scenarios (25% attack rate and 8‐week pandemic duration) resulted in a demand for ventilatory support that exceeded 200% of present capacity. Demand remained unsustainably high even when more favourable scenarios were considered. Current critical care bed capacity in England would be unable to cope with the increased demand provided by an influenza pandemic. Appropriate contingency planning is essential.
Screening for thrombophilia in high‐risk situations: a meta‐analysis and cost‐effectiveness analysis
Authors: Wu Olivia , Robertson Lindsay , Twaddle Sara , Lowe Gordon , Clark Peter , Walker Isobel , Brenkel Ivan , Greaves Mike , Langhorne Peter , Regan Lesley , Greer Ian ,   The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study
Published: September 2005

Laboratory testing for the identification of heritable thrombophilia in high‐risk patient groups have become common practice; however, indiscriminate testing of all patients is unjustified. The objective of this study was to evaluate the cost‐effectiveness of universal and selective history‐based thrombophilia screening relative to no screening, from the perspective of the UK National Health Service, in women prior to prescribing combined oral contraceptives and hormone replacement therapy, women during pregnancy and patients prior to major orthopaedic surgery. A decision analysis model was developed, and data from meta‐analysis, the literature and two Delphi studies were incorporated in the model. Incremental cost‐effectiveness ratios (ICERs) for screening compared with no screening was calculated for each patient group. Of all the patient groups evaluated, universal screening of women prior to prescribing hormone replacement therapy was the most cost‐effective (ICER £6824). In contrast, universal screening of women prior to prescribing combined oral contraceptives was the least cost‐effective strategy (ICER £202 402). Selective thrombophilia screening based on previous personal and/or family history of venous thromboembolism was more cost‐effective than universal screening in all the patient groups evaluated.
Cannabis use in sickle cell disease: a questionnaire study
Authors: Howard Jo , Anie Kofi A. , Holdcroft Anita , Korn Simon , Davies Sally C.
Published: September 2005

Cannabinoids are increasingly being considered for the management of various painful conditions, and could be considered as an option for treating acute pain in sickle cell disease (SCD). The objective of this study was to determine the extent of use of cannabis in the community for pain and other symptom relief, and its side effects during self‐administration in patients with SCD. Patients attending Central Middlesex Hospital in London were invited to complete a structured self‐administered anonymous questionnaire. Eighty‐six young adults with HbSS, HbSC and HbSβthalassaemia disease (median age 30 years) participated in the study. Results showed that 31 (36%) had used cannabis in the previous 12 months to relieve symptoms associated with SCD. The main route in all but two patients was by smoking. The main reasons for use were to reduce pain in 52%, and to induce relaxation or relieve anxiety and depression in 39%. Symptoms related to sedation and mood effects were reported in 77% of patients. The majority of patients (58%) expressed their willingness to participate in studies of cannabis as a medicine. We conclude that research in the use of cannabinoids for pain relief in SCD would be both important and acceptable to adult patients.
Response to bortezomib is associated to osteoblastic activation in patients with multiple myeloma
Authors: Zangari Maurizio , Esseltine Dixie , Lee Choon‐Kee , Barlogie Bart , Elice Francesca , Burns Michael J. , Kang Seung‐Hee , Yaccoby Shmuel , Najarian Kevin , Richardson Paul , Sonneveld Peter , Tricot Guido
Published: September 2005

The prompt response to bortezomib observed in a 63‐year‐old woman with multiple myeloma was associated with a significant increase in alkaline phosphatase (ALP). After similar elevations were noted in patients responding to bortezomib, thalidomide, dexamethasone combination, ALP levels were analysed in two large bortezomib trials. A statistically significant elevation of ALP from baseline was observed in responding patients (complete and partial responders) within three cycles of therapy. The rise in ALP after bortezomib in three patients was explained by a parallel increase in bone‐specific ALP and parathyroid hormone, suggesting that response to bortezomib in myeloma is closely associated with osteoblastic activation.
Clinical correlates of steady‐state oxyhaemoglobin desaturation in children who have sickle cell disease
Authors: Quinn Charles T. , Ahmad Naveed
Published: September 2005

Individuals with sickle cell disease (SCD) may have oxyhaemoglobin desaturation during the steady‐state, the causes of which are incompletely known. We studied a cohort of 585 children who have sickle cell anaemia (SS), sickle β0‐thalassaemia (Sβ0), sickle‐haemoglobin C disease (SC), or sickle β+‐thalassaemia (Sβ+) to determine the relationships between steady‐state oxyhaemoglobin saturation (SpO2) and SCD genotype, age, gender, steady‐state haemoglobin (Hb) and reticulocyte count, and rate of acute chest syndrome (ACS). The SS/Sβ0 group (n = 390) had lower mean SpO2 than the SC/Sβ+ group (n = 195) (96·3% vs. 98·7%, P < 0·001). Among SS/Sβ0 subjects, a decrease in steady‐state SpO2 correlated with a decrease in Hb, an increase in reticulocytes, older age and male gender. These correlations were not found in the SC/Sβ+ group. Prior ACS did not correlate with steady‐state SpO2. A multivariate model explained 45% of the variability in SpO2, but only 5% of the variation in SpO2 was explained by Hb. We conclude that steady‐state desaturation is common in individuals with SCD, but it appears to be unrelated to prior episodes of ACS and largely unexplained by chronic anaemia.