bluuebunny/crossref_metadata_2025 huggingface dataset:
On the Surjectivity of the Exponential Function of Solvable Lie Groups
Authors: Wüstner Michael
Published: May 2007

For a solvable Lie group G the surjectivity of the exponential function expG is equivalent to the connectedness of the near‐Cartan subgroups and to the connectedness of the centralizers in a Cartan subgroup of all nilpotent elements in its Lie algebra g. Furthermore, these conditions are satisfied if and only if for all elements g ϵ G there is an x ϵ g with g = expG x in which expG is regular.
The dual method of solving the linear programming problem
Authors: Lemke C. E.
Published: May 2007

Many problems in logistics are capable of being formulated as linear programming problems. For example, one such problem is the so‐called transportation problem, which is concerned with obtaining the best way (in the sense of least time, or of least expense, etc.) of shipping stipulated quantities of materials from m origins to n destinations. This paper develops a new computational method of solving general linear programming problems.
Some blotto games
Authors: Blackett D. W.
Published: May 2007

In many military “games” each “player” must allocate his forces to different “battlefields,” “fronts.” or “operations areas” before he has a clear picture of the deployment of the enemy. The following paper illustrates how each player should distribute his forces in certain interdiction games.
Optimal two‐ and three‐stage production schedules with setup times included
Authors: Johnson S. M.
Published: May 2007

Each of a collection of items are to be produced on two machines (or stages). Each machine can handle only one item at a time and each item must be processed through machine one and then through machine two. The setup time plus work time for each item for each machine is known. A simple decision rule is obtained in this paper for the optimal scheduling of the production so that the total elapsed time is a minimum. A three‐machine problem is also discussed and solved for a restricted case.
Professor to the rescue
Authors: Detzer Karl
Published: May 2007

Washington communities, when facing economic disaster, find expert help at state university.
Surveys, dust, action
Authors: Grant Daniel R. , Greene Lee S.
Published: May 2007

Court cites 1952 study in upholding Nashville annexation of 82,000 persons, 43 square miles.
Chaos or conquest?
Authors: Williams Harrison A.
Published: May 2007

Long‐range urban transportation program is urged to eliminate our chronic traffic jams.
The fight for beauty
Authors: Hamilton Andrew
Published: May 2007

Los Angeles citizens prove elimination of eyesores good business, contagious example.
The states' concern
Authors: Manvel Allen D.
Published: May 2007

Advisory Commission recommends actions which might help solve metropolitan area problems.
Breaking the barriers
Authors: Bergan Francis
Published: May 2007

Efficiency and economy demanding removal of legal bars to intergovernmental cooperation.
Freedom and federalism
Authors: Odegard Peter H.
Published: May 2007

Intergovernmental relations in America have assumed a new face and have a new orientation.
Wanted: Volunteers
Authors: Canham Erwin D.
Published: May 2007

Citizen action does not act as a substitute for government but as supporter, invigorator.
States must be strong
Authors: Carvel Elbert N.
Published: May 2007

Their capacity to identify, solve problems is termed vital to the future of the nation.
Temporal-callosal pathway diffusivity predicts phonological skills in children
Authors: Dougherty Robert F. , Ben-Shachar Michal , Deutsch Gayle K. , Hernandez Arvel , Fox Glenn R. , Wandell Brian A.
Published: May 2007

The development of skilled reading requires efficient communication between distributed brain regions. By using diffusion tensor imaging, we assessed the interhemispheric connections in a group of children with a wide range of reading abilities. We segmented the callosal fibers into regions based on their likely cortical projection zones, and we measured diffusion properties in these segmented regions. Phonological awareness (a key factor in reading acquisition) was positively correlated with diffusivity perpendicular to the main axis of the callosal fibers that connect the temporal lobes. These results could be explained by several physiological properties. For example, good readers may have fewer but larger axons connecting left and right temporal lobes, or their axon membranes in these regions may be more permeable than the membranes of poor readers. These measurements are consistent with previous work suggesting that good readers have reduced interhemispheric connectivity and are better at processing rapidly changing visual and auditory stimuli.
Intracellular targeting of telomeric retrotransposon Gag proteins of distantly related
Drosophila
species
Authors: Casacuberta Elena , Marín Fernando Azorín , Pardue Mary-Lou
Published: May 2007

The retrotransposons that maintain telomeres in
Drosophila melanogaster
have unique features that are shared across all
Drosophila
species but are not found in other retrotransposons. Comparative analysis of these features provides insight into their importance for telomere maintenance in
Drosophila
. Gag proteins encoded by

HeT-A
mel

and

TART
mel

are efficiently and cooperatively targeted to telomeres in interphase nuclei, a behavior that may facilitate telomere-specific transposition.
Drosophila virilis
, separated from
D. melanogaster
by 60 MY, has telomeres maintained by

HeT-A
vir

and

TART
vir

. The Gag proteins from

HeT-A
mel

and

HeT-A
vir

have only 16% amino acid identity, yet several of their functional features are conserved. Using transient transfection of cultured cells from both species, we show that the telomere association of

HeT-A
vir

Gag is indistinguishable from that of

HeT-A
mel

Gag. Deletion derivatives show that organization of localization signals within the two proteins is strikingly similar. Gag proteins of

TART
mel

and

TART
vir

are only 13% identical. In contrast to
HeT-A
, surprisingly,

TART
vir

Gag does not localize to the nucleus, although

TART
vir

is a major component of
D. virilis
telomeres, and localization signals in the protein have much the same organization as in

TART
mel

Gag. Thus, the mechanism of telomere targeting of

TART
vir

differs, at least in a minor way, from that of

TART
mel

. Our findings suggest that, despite dramatic rates of protein evolution, protein and cellular determinants that correctly localize these Gag proteins have been conserved throughout the 60 MY separating these species.
Detection of generic spaced motifs using submotif pattern mining
Authors: Wijaya Edward , Rajaraman Kanagasabai , Yiu Siu-Ming , Sung Wing-Kin
Published: May 2007

Motivation: Identification of motifs is one of the critical stages in studying the regulatory interactions of genes. Motifs can have complicated patterns. In particular, spaced motifs, an important class of motifs, consist of several short segments separated by spacers of different lengths. Locating spaced motifs is not trivial. Existing motif-finding algorithms are either designed for monad motifs (short contiguous patterns with some mismatches) or have assumptions on the spacer lengths or can only handle at most two segments. An effective motif finder for generic spaced motifs is highly desirable.

Results: This article proposes a novel approach for identifying spaced motifs with any number of spacers of different lengths. We introduce the notion of submotifs to capture the segments in the spaced motif and formulate the motif-finding problem as a frequent submotif mining problem. We provide an algorithm called SPACE to solve the problem. Based on experiments on real biological datasets, synthetic datasets and the motif assessment benchmarks by Tompa et al., we show that our algorithm performs better than existing tools for spaced motifs with improvements in both sensitivity and specificity and for monads, SPACE performs as good as other tools.

Availability: The source code is available upon request from the authors.

Contact:  ksung@comp.nus.edu.sg

Supplementary information: Supplementary data are available at Bioinformatics online.
BioDownloader: bioinformatics downloads and updates in a few clicks
Authors: Shapovalov Maxim V. , Canutescu Adrian A. , Dunbrack Roland L.
Published: May 2007

Summary: There are many ftp or http servers storing data required for biological research. While some download applications are available, there is no user-friendly download application with a graphical interface specifically designed and adapted to meet the requirements of bioinformatics. BioDownloader is a program for downloading and updating files from ftp and http servers. It is optimized to work robustly with large numbers of files. It allows the selective retrieval of only the required files (batch downloads, multiple file masks, ls-lR file parsing, recursive search, recent updates, etc.). BioDownloader has a built-in repository containing the settings for common bioinformatics file-synchronization needs, including the Protein Data Bank (PDB) and National Center for Biotechnology Information (NCBI) databases. It can post-process downloaded files, including archive extraction and file conversions.

Availability: The program can be installed from http://dunbrack.fccc.edu/BioDownloader. The software is freely available for both non-commercial and commercial users under the BSD license.

Contact: Roland.Dunbrack@fccc.edu
A Markov random field model for network-based analysis of genomic data
Authors: Wei Zhi , Li Hongzhe
Published: May 2007

Motivation: A central problem in genomic research is the identification of genes and pathways involved in diseases and other biological processes. The genes identified or the univariate test statistics are often linked to known biological pathways through gene set enrichment analysis in order to identify the pathways involved. However, most of the procedures for identifying differentially expressed (DE) genes do not utilize the known pathway information in the phase of identifying such genes. In this article, we develop a Markov random field (MRF)-based method for identifying genes and subnetworks that are related to diseases. Such a procedure models the dependency of the DE patterns of genes on the networks using a local discrete MRF model.

Results: Simulation studies indicated that the method is quite effective in identifying genes and subnetworks that are related to disease and has higher sensitivity and lower false discovery rates than the commonly used procedures that do not use the pathway structure information. Applications to two breast cancer microarray gene expression datasets identified several subnetworks on several of the KEGG transcriptional pathways that are related to breast cancer recurrence or survival due to breast cancer.

Conclusions: The proposed MRF-based model efficiently utilizes the known pathway structures in identifying the DE genes and the subnetworks that might be related to phenotype. As more biological networks are identified and documented in databases, the proposed method should find more applications in identifying the subnetworks that are related to diseases and other biological processes.

Contact:  hongzhe@mail.med.upenn.edu or hli@cceb.upenn.edu
Genomix: a method for combining gene-finders' predictions, which uses evolutionary conservation of sequence and intron–exon structure
Authors: Coghlan Avril , Durbin Richard
Published: May 2007

Motivation: Correct gene predictions are crucial for most analyses of genomes. However, in the absence of transcript data, gene prediction is still challenging. One way to improve gene-finding accuracy in such genomes is to combine the exons predicted by several gene-finders, so that gene-finders that make uncorrelated errors can correct each other.

Results: We present a method for combining gene-finders called Genomix. Genomix selects the predicted exons that are best conserved within and/or between species in terms of sequence and intron–exon structure, and combines them into a gene structure. Genomix was used to combine predictions from four gene-finders for Caenorhabditis elegans, by selecting the predicted exons that are best conserved with C.briggsae and C.remanei. On a set of ∼1500 confirmed C.elegans genes, Genomix increased the exon-level specificity by 10.1% and sensitivity by 2.7% compared to the best input gene-finder.

Availability: Scripts and Supplementary Material can be found at http://www.sanger.ac.uk/Software/analysis/genomix

Contact:  alc@sanger.ac.uk

Supplementary information: Supplementary data are available at Bioinformatics online.
Weighted rank aggregation of cluster validation measures: a Monte Carlo cross-entropy approach
Authors: Pihur Vasyl , Datta Susmita , Datta Somnath
Published: May 2007

Motivation: Biologists often employ clustering techniques in the explorative phase of microarray data analysis to discover relevant biological groupings. Given the availability of numerous clustering algorithms in the machine-learning literature, an user might want to select one that performs the best for his/her data set or application. While various validation measures have been proposed over the years to judge the quality of clusters produced by a given clustering algorithm including their biological relevance, unfortunately, a given clustering algorithm can perform poorly under one validation measure while outperforming many other algorithms under another validation measure. A manual synthesis of results from multiple validation measures is nearly impossible in practice, especially, when a large number of clustering algorithms are to be compared using several measures. An automated and objective way of reconciling the rankings is needed.

Results: Using a Monte Carlo cross-entropy algorithm, we successfully combine the ranks of a set of clustering algorithms under consideration via a weighted aggregation that optimizes a distance criterion. The proposed weighted rank aggregation allows for a far more objective and automated assessment of clustering results than a simple visual inspection. We illustrate our procedure using one simulated as well as three real gene expression data sets from various platforms where we rank a total of eleven clustering algorithms using a combined examination of 10 different validation measures. The aggregate rankings were found for a given number of clusters k and also for an entire range of k.

Availability: R code for all validation measures and rank aggregation is available from the authors upon request.

Contact: somnath.datta@louisville.edu

Supplementary information: Supplementary information are available at http://www.somnathdatta.org/Supp/RankCluster/supp.htm.
Incorporating prior knowledge of predictors into penalized classifiers with multiple penalty terms
Authors: Tai Feng , Pan Wei
Published: May 2007

Motivation: In the context of sample (e.g. tumor) classifications with microarray gene expression data, many methods have been proposed. However, almost all the methods ignore existing biological knowledge and treat all the genes equally a priori. On the other hand, because some genes have been identified by previous studies to have biological functions or to be involved in pathways related to the outcome (e.g. cancer), incorporating this type of prior knowledge into a classifier can potentially improve both the predictive performance and interpretability of the resulting model.

Results: We propose a simple and general framework to incorporate such prior knowledge into building a penalized classifier. As two concrete examples, we apply the idea to two penalized classifiers, nearest shrunken centroids (also called PAM) and penalized partial least squares (PPLS). Instead of treating all the genes equally a priori as in standard penalized methods, we group the genes according to their functional associations based on existing biological knowledge or data, and adopt group-specific penalty terms and penalization parameters. Simulated and real data examples demonstrate that, if prior knowledge on gene grouping is indeed informative, our new methods perform better than the two standard penalized methods, yielding higher predictive accuracy and screening out more irrelevant genes.

Contact:  weip@biostat.umn.edu
Improving the efficacy of trastuzumab in breast cancer
Authors: Suzuki Eiji , Toi Masakazu
Published: May 2007

Although overexpression of human epidermal growth factor receptor 2 (HER2) protein, amplification of the gene or both are associated with poor prognosis in breast cancer, trastuzumab has clearly provided clinical benefits in metastatic breast cancer, adjuvant treatment settings and primary systemic therapy. However, even in those HER2 overexpressors, the majority of patients who achieve an initial response generally acquire resistance within 1 year. Therefore, it is critical to elucidate the mechanism of resistance and to search for better combination treatments with chemotherapeutic agents or other novel modalities. Here, we discuss both clinical and preclinical data regarding these issues. (Cancer Sci 2007; 98: 767–771)
Restoration of RUNX3 enhances transforming growth factor‐β‐dependent p21 expression in a biliary tract cancer cell line
Authors: Hasegawa Kazunori , Yazumi Shujiro , Wada Manabu , Sakurai Toshiharu , Kida Masaya , Yamauchi Junichi , Hisatsune Hiroshi , Tada Shinsuke , Ida Hiroshi , Nakase Yuenn , Sakakura Chohei , Hagiwara Akeo , Chiba Tsutomu
Published: May 2007

RUNX3 is a candidate tumor suppressor gene localized in 1p36, a region commonly inactivated by deletion and methylation in various human tumors. To elucidate the role of RUNX3 in transforming growth factor (TGF)‐β signaling in biliary tract cancer, we transfected Mz‐ChA‐2 cells, which do not express RUNX3 but have intact TGF‐β type II receptor and SMAD4 genes, with the RUNX3 expression plasmid pcDNA3.1/RUNX3 or with the vector pcDNA3.1 as a control. Four Mz‐ChA‐2/RUNX3 clones and one control clone were obtained. Although TGF‐β1 only slightly inhibited growth of the control cells, growth inhibition and TGF‐β‐dependent G1 arrest were significantly enhanced in the RUNX3‐transfected clones. None of the clones, however, exhibited apoptosis. The slightly increased TGF‐β1‐induced p21 expression in the control clone was strongly enhanced in the RUNX3‐transfected clones, and was accompanied by augmented decreases in the expression of cyclins D1 and E. When RUNX3 small interfering RNA was added, TGF‐β‐dependent induction of p21 was reduced in the RUNX3‐transfected clones. Xenografts of the clones in nude mice demonstrated that tumorigenicity was significantly decreased in the RUNX3‐transfected clones in inverse proportion to the expression levels of RUNX3. Based on these results, RUNX3 is involved in TGF‐β‐induced expression of p21 and the resulting induction of TGF‐β‐dependent G1 arrest. (Cancer Sci 2007; 98: 838–843)
Association of maternal fat and alcohol intake with maternal and umbilical hormone levels and birth weight
Authors: Nagata Chisato , Iwasa Shinichi , Shiraki Makoto , Sahashi Yukari , Shimizu Hiroyuki
Published: May 2007

High levels of estrogen during pregnancy have been hypothesized to increase the risk of breast cancer in offspring. Some studies have reported a positive association of estrogen level during pregnancy with fetal size, which has been linked to the subsequent risk of breast cancer in offspring. We examined whether maternal diet, including fat and alcohol intake, was associated with hormone levels during pregnancy, as well as with birth weight. The concentrations of estradiol, estriol, and testosterone were measured in the maternal serum and umbilical cord blood of 189 women during pregnancy and at delivery. Intakes of fat, alcohol, and other nutrients were assessed by 5‐day diet records at approximately the 29th week of pregnancy before blood sampling. Intake of polyunsaturated fatty acids was moderately but significantly positively correlated with the umbilical cord estriol level (r = 0.17, P = 0.03) after controlling for covariates. The positive association between intake of polyunsaturated fatty acids and birth weight was of borderline significance (r = 0.14, P = 0.06). Intake of long‐chain n‐3 fatty acids was significantly inversely correlated with the umbilical cord estradiol and testosterone levels (r = –0.18, P = 0.02 and r = –0.24, P = 0.002, respectively). Alcohol intake was significantly positively correlated with the maternal estradiol level in the 29th week of pregnancy (r = 0.19, P = 0.01), but was unrelated to birth weight. Estrogen level during pregnancy may be regulated by dietary polyunsaturated fatty acids and mediate their effects on fetal growth. (Cancer Sci 2007; 98: 869–873)
von Willebrand factor type D domain mutant of SVS‐1/SUSD2, vWDm, induces apoptosis in HeLa cells
Authors: Sugahara Tetsuo , Yamashita Yzumi , Shinomi Masahito , Isobe Yumiko , Yamanoha Banri , Iseki Hiroyoshi , Takeda Akihiko , Okazaki Yasushi , Kawai Kenji , Suemizu Hiroshi , Andoh Toshiwo
Published: May 2007

SVS‐1/SUSD2 is a novel gene, which inhibits growth and reverses tumorigenic phenotypes of cancer cells in vitro. Here we report identification of a mutant of SVS‐1, designated SVS‐1‐vWDm, in which conserved amino acids GLLG at positions 591–594 in von Willebrand factor type D (vWD) domain are replaced by AAAA. As observed by laser confocal microscope, intracellular localization of the mutant protein has changed such that both the N‐terminus and the C‐terminus of SVS‐1‐vWDm were localized in the inner surface of the plasma membrane, whereas the N‐terminus of SVS‐1 was localized in the outer surface of the plasma membrane. Additionally, SVS‐1‐vWDm was processed much less efficiently and in a slightly different manner. In in vitro studies, adenovirus‐mediated transduction of the SVS‐1‐vWDmgene induced growth suppression of HeLa cells in a dose‐dependent manner, as the wild‐type gene and inhibition of anchorage‐independent growth. Of great interest is the finding that the mutant protein, vWDm, but not the wild‐type one induced apoptosis, as observed by nuclear as well as DNA fragmentation. Activation of caspase‐3 and ‐9, but not caspase‐8 or ‐12, was also demonstrated in vWDm‐expressing cells. An inhibition of Akt phosphorylation, a major survival signaling component, also occurred in vWDm‐expressing HeLa cells. Together these data suggest that vWDm induces apoptosis by inactivation of survival signaling component Akt and activation of caspase cascade (mitochondrial pathway) in HeLa cells. We propose SVS‐1‐vWDmas an alternative gene for use in developing new therapeutic strategies for the treatment of cancer. (Cancer Sci 2007; 98: 909–915)
Fully human antibody exhibits pan‐human leukocyte antigen‐DR recognition and high in vitro/vivo efficacy against human leukocyte antigen‐DR‐positive lymphomas
Authors: Tawara Tomonori , Hasegawa Kazumasa , Sugiura Yusuke , Tahara Tomoyuki , Ishida Isao , Kataoka Shiro
Published: May 2007

HD8, a fully human monoclonal antibody specific for human leukocyte antigen‐DR (HLA‐DR), was generated by using the transchromosome mouse that bears the human immunoglobulin genes. HD8 could bind to all 13 tested HLA‐DR‐positive cell lines and 35 B‐cells from healthy donors. Epitope mapping revealed that while the antibody recognizes the most polymorphic region of the HLA‐DRB chain, its critical epitope residues are conserved in the major alleles. Indeed, HD8 could recognize 99.2% of HLA‐DRB alleles. Since its essential epitope residues are also largely conserved in HLA‐DP and HLA‐DQ, HD8 could recognize 100% and 66% of the HLA‐DP and HLA‐DQ alleles tested, respectively. HD8 exerted strong antibody‐dependent cellular cytotoxicity and complement‐dependent cytotoxicity in vitro, and significantly extended the life span of immunocompromised mice inoculated with non‐Hodgkin lymphoma cell lines. The HD8 antibody may be highly useful in HLA‐DR‐targeted immunotherapy as it is likely to evoke similarly strong responses in individuals carrying different HLA‐DR alleles. (Cancer Sci 2007; 98: 921–928)
Carcinogenicity of dimethylarsinic acid in Ogg1‐deficient mice
Authors: Kinoshita Anna , Wanibuchi Hideki , Morimura Keiichirou , Wei Min , Nakae Dai , Arai Tsuyoshi , Minowa Osamu , Noda Tetsuo , Nishimura Susumu , Fukushima Shoji
Published: May 2007

Oxidative stress to DNA is recognized as a mechanism underlying carcinogenic effects of some environmental agents. Here, we hypothesized that dimethylarsinic acid (DMAV), an organic metabolite of inorganic arsenic in humans, might exert carcinogenic potential in a mouse line carrying a mutant Mmh allele of the Mmh/OGG1 gene encoding the enzyme 8‐hydroxyguanine DNA glycosylase 1 (OGG1). Ogg1 mutant and wild type mice were treated with DMAV in their drinking water at a dose of 200 p.p.m. for up to 72 weeks. All DMAV‐treated Ogg1−/–animals developed tumors, with a tendency for lower total incidences in the Ogg1+/+ cases. Lung tumors in particular were induced as compared to the lack in non‐carcinogen controls and were significantly more frequent in the homozygotes. At week 4, the levels of DNA 8‐OH‐dG and cell proliferation were significantly elevated in the lungs of non‐treated Ogg1−/– as compared to Ogg1+/+ mice and were strongly enhanced by DMAV treatment. Marked induction of Pola1, Cyp7b1, Ndfua3, Mmp13 and other genes specific to cell proliferation, cell signaling and xenobiotic metabolism in the lungs of DMAV‐treated Ogg1−/– mice was found. Electron microscopic examination revealed the growth of microvilli, with increased numbers of mitochondria only in lungs and lung tumors of DMAV‐exposed Ogg1−/– mice. Therefore, we strongly suggest that DMAV exerts carcinogenicity in the lungs of Ogg1−/– mutant mice, with a possible role for persistent accumulation of DNA oxidative adducts. (Cancer Sci 2007; 98: 803–814)
DNA topoisomerase inhibitor, etoposide, enhances GC‐box‐dependent promoter activity via Sp1 phosphorylation
Authors: Niina Ichiro , Uchiumi Takeshi , Izumi Hiroto , Torigoe Takayuki , Wakasugi Tetsuro , Igarashi Tomonori , Miyamoto Naoya , Onitsuka Takamitsu , Shiota Masaki , Okayasu Ryuichi , Chijiiwa Kazuo , Kohno Kimitoshi
Published: May 2007

Modification of transcription factors by anticancer agents plays an important role in both apoptotic and survival signaling. Here we report that both DNA topoisomerase I and II inhibitors such as SN‐38 and etoposide, but not cisplatin, 5‐fluorouracil or actinomycin D, can induce phosphorylation of the transcription factor Sp1. Furthermore, DNA topoisomerase inhibitors were shown to transactivate GC‐box‐dependent promoters such as the SV40 and vascular endothelial growth factor promoters. The phosphorylated form of Sp1 was detectable within 30 min of etoposide treatment and was greatly diminished by the presence of the PI3K inhibitor wortmannin and by DNA‐dependent protein kinase (DNA‐PK) knockdown. We also confirmed that the phosphorylated form of DNA‐PK was increased by treatment with both etoposide and SN‐38. Taken together, these findings demonstrate a novel genomic response to anticancer agents that induce Sp1 phosphorylation, and might contribute to tumor progression and drug resistance. (Cancer Sci 2007; 98: 858–863)
Helicobacter pylori infection‐negative gastric cancer in Japanese hospital patients: Incidence and pathological characteristics
Authors: Kato Shunji , Matsukura Norio , Tsukada Katsuya , Matsuda Noriko , Mizoshita Tsutomu , Tsukamoto Tetsuya , Tatematsu Masae , Sugisaki Yuichi , Naito Zenya , Tajiri Takashi
Published: May 2007

We used Helicobacter pylori sero‐positivity and mucosal atrophy as detected by the serum pepsinogen method to identify H. pylori infection‐negative gastric cancer patients with or without atrophy. One hundred and six of 748 (14.2%) primary gastric cancer patients were infection‐negative by a serum antibody detection system. Further, 121 (16.2%) of the 748 were negative for gastric mucosal atrophy by the pepsinogen method, of whom 15/748 (2.0%) were H. pylori‐negative by pepsinogen I level (>70 ng/mL) and pepsinogen I/II ratio (>3.0). Twenty‐seven of 782 (3.6%) gastric cancer patients were H. pylori‐negative by antibodies and severe atrophy as determined by pepsinogen I level (<30 ng/mL) and pepsinogen I/II ratio (<2.0). H. pylori‐negative gastric cancer patients with severe atrophy likely had a previous infection. These results indicate that the actual number of H. pylori‐negative patients is 2.0% at minimum and 10.6% (14.2% minus 3.6%) at maximum in the general Japanese population. Five of 15 (33%) cases displaying neither anti‐H. pylori antibodies nor atrophy were intestinal‐type and 10 (67%) were diffuse‐type adenocarcinomas. Thirteen surgical patients with primary gastric cancer displaying neither antibodies nor mucosal atrophy were further analyzed for pathological and phenotypic characteristics. The mucin phenotype was divided into four gastric, five gastric and intestinal, two intestinal and two null types, independent of histological classification. Intestinal phenotype elements were detected by Cdx2 immunohistochemical methods in nine of 13 (70%) cases examined. We conclude that a small fraction of gastric cancer patients displayed multifactorial carcinogenesis without H. pylori infection, indicating that gastric cancer risk still exists in the absence of H. pylori infection, at an incidence of 2.0% at minimum and 10.6% at maximum in the general Japanese population. (Cancer Sci 2007; 98: 790–794)
Gene expression profiling of epidermal growth factor receptor/KRAS pathway activation in lung adenocarcinoma
Authors: Shibata Tatsuhiro , Hanada Satoko , Kokubu Akiko , Matsuno Yoshihiro , Asamura Hisao , Ohta Tsutomu , Sakamoto Michiie , Hirohashi Setsuo
Published: May 2007

We examined the genome‐wide expression profiles of 86 primary lung adenocarcinomas and compared them with the mutation status of the four key molecules (EGFR, ERBB2, KRAS and BRAF) in the EGFR/KRAS/BRAF pathway. Unsupervised classification revealed two subtypes (the bronchial type and the alveolar type) of lung adenocarcinoma. Mutually exclusive somatic mutations of the epidermal growth factor receptor (EGFR) gene (36/86, 41.8%), K‐ras gene (11/86, 12.8%) and BRAF gene (1/86, 1.1%) were detected. KRAS mutations were observed significantly frequently in bronchial‐type tumors, whereas the frequencies of EGFR mutations were similar in both the alveolar and bronchial types. Twenty‐seven genes showed increased expression in EGFR‐mutated tumors and these included molecules that function in the EGFR/KRAS/BRAF pathway (EGFR, AKT1 and BCR). In particular, expression of BCR, which is required for EGFR protein degradation, was induced by EGF stimulation, suggesting a negative feedback loop in lung cancer. A subgroup of the alveolar type tumors showed significantly better prognosis than other tumors. Integrated analysis of genetic and gene expression profiling aimed to delineate inherent oncogenic pathways in cancer will be valuable not only for the understanding of molecular pathogenesis, but also for discovering novel biomarkers and predicting clinical outcome. (Cancer Sci 2007; 98: 985–991)
Changes in the invasive and metastatic capacities of HT‐29/M3 cells induced by the expression of fucosyltransferase 1
Authors: Mejías‐Luque Raquel , López‐Ferrer Anna , Garrido Marta , Fabra Àngels , De Bolós Carme
Published: May 2007

Lewis antigens are terminal fucosylated oligosaccharides synthesized by the sequential action of several glycosyltransferases. The fucosyltransferases are the enzymes responsible for the addition of terminal fucose to precursor oligosaccharides attached to proteins or lipids. These oligosaccharides, defined as cell surface markers, have been implicated in different types of intercellular interactions and in adhesion and invasion processes. Transfection of HT‐29/M3 colon cancer cells with the full length of human fucosyltransferase (FUT1), induces the synthesis of H type 2 and Lewis y antigens, associated with a decrease of sialyl‐Lewis x. The capacity to develop primary tumors when cells were injected intrasplenically was similar in parental and FUT1‐transfected cells, but the capacity to colonize the liver after spleen removal was significantly reduced in M3/FUT1 transfected cells. These results indicate that the expression of FUT1 induces changes in the metastatic capacity of HT‐29/M3 colon cancer cells, as a consequence of the altered expression pattern of type 2 Lewis antigens. Also, an association between MUC5AC expression and the degree of gland differentiation in both primary splenic tumors and hepatic metastases was detected. (Cancer Sci 2007; 98: 1000–1005)
RNA interference‐mediated signal transducers and activators of transcription 3 gene silencing inhibits invasion and metastasis of human pancreatic cancer cells
Authors: Qiu Zhengjun , Huang Chen , Sun Jing , Qiu Wei , Zhang Jufeng , Li Huiming , Jiang Tao , Huang Kejian , Cao Jun
Published: May 2007

Signal transducers and activators of transcription‐3 (STAT3), a central cytoplasmic transcription factor, is frequently overexpressed and constitutively activated by tyrosine during malignant transformation. The overexpression and phosphorylation of STAT3 in pancreatic cancer has been described only recently, but the roles and mechanism still remain unclear. In this study, we elucidate the significance of the STAT3 signaling pathway in metastatic potentials of pancreatic cancer. We stably silence the expression of the STAT3 and p‐STAT3 by using RNA interference (RNAi) in the pancreatic cancer cell line SW1990, and then reduce its invasion capacity in vitro and metastasis capacity in vivo compared to parental cells or cells tansfected with a control vector. Furthermore, silencing SW1990 cells with the STAT3 gene by RNAi also led to a decrease of matrix metalloproteinases‐2 (MMP‐2) and vascular endothelial growth factor (VEGF) at the mRNA and protein level. Collectively, these studies suggest that activation of the STAT3 signaling pathway plays an important role in the progression of pancreatic cancer, and that silence of the STAT3 gene with RNAi may be a useful anti‐invasive therapeutic option in pancreatic cancer. (Cancer Sci 2007; 98: 1099–1106)
Adiponectin inhibits the growth and peritoneal metastasis of gastric cancer through its specific membrane receptors AdipoR1 and AdipoR2
Authors: Ishikawa Makoto , Kitayama Joji , Yamauchi Toshimasa , Kadowaki Takashi , Maki Toshiyuki , Miyato Hideyo , Yamashita Hiroharu , Nagawa Hirokazu
Published: May 2007

Adiponectin, a circulating peptide hormone produced in adipose tissue, has been shown to be reduced in the plasma of patients with cancer, suggesting that this adipokine may be mechanically involved in the pathogenesis of adiposity‐related carcinogenesis. In this study, we examined the expression of adiponectin receptors (AdipoR1 and AdipoR2) and assessed the function of adiponectin in gastric cancer. All of the six gastric cancer cell lines significantly expressed mRNA and protein of both receptors with variable levels. Addition of 30 µg/mL adiponectin potently induced apoptosis and inhibited the proliferation of AZ521 and HCG27. Down‐regulation of either AdipoR1 or AdipoR2 by specific siRNA significantly suppressed the growth inhibitory effects of adiponectin in both cell lines. Moreover, a local injection of adiponectin markedly inhibited the growth of AZ521 inoculated subcutaneously in nude mice. Similarly, the continuous intraperitoneal infusion of adiponectin effectively suppressed the development of peritoneal metastasis of AZ521. Adiponectin negatively regulates the progression of gastric cancer cells possibly through both AdipoR1 and AdipoR2. Although adiponectin was already reported to have antiangiogenic effects, our results suggest that the antitumor effect of adiponectin was, at least partially, dependent on the direct effects on tumor cells. (Cancer Sci 2007; 98: 1120–1127)
Correlation between liver metastasis of the colocalization of actin‐related protein 2 and 3 complex and WAVE2 in colorectal carcinoma
Authors: Iwaya Keiichi , Oikawa Kosuke , Semba Seitaro , Tsuchiya Benio , Mukai Yasuo , Otsubo Toshiya , Nagao Toshitaka , Izumi Miki , Kuroda Masahiko , Domoto Hideharu , Mukai Kiyoshi
Published: May 2007

Directed movement of normal cells occurs when actin‐related protein 2 and 3 complex (Arp2/3 complex) triggers the actin polymerization that forms lamellipodia immediately after binding to WAVE2. In order to determine whether the same mechanism correlates with liver metastasis from colorectal cancer, paired mirror sections of 154 cancer specimens (29 cases with liver metastasis and 125 cases without liver metastasis in which T factor, gender, primary tumor site, and age at operation were matched) were examined immunohistochemically for the localization of Arp2 and WAVE2. Expression of both Arp2 and WAVE2 was detected in the same cancer cells in 55 (35.7%) of the 154 cases, but not detected in the normal colonic epithelial cells. Univariate analysis showed that the colocalization was significantly predictive of liver metastasis (risk ratio [RR] 8.760. Likewise, histological grade (RR 2.46), lymphatic invasion (RR 9.95), and tumor budding (RR 4.00) were significant predictors. Among these, colocalization and lymphatic invasion were shown to be independent risk factors by multivariate analysis. Another 59 colorectal specimens were examined for mRNA expression of Arp2 by real time polymerase chain reaction. High mRNA levels of Arp2, that in situ hybridization revealed to be expressed by the cancer cells, were significantly associated with liver metastasis. However, its effect was absorbed by the influence of risk of the colocalization that is closely related to high expression of Arp2. These results indicate that the colocalization of Arp2 and WAVE2 is an independent risk factor for liver metastasis of colorectal carcinoma. (Cancer Sci 2007; 98: 992–999)
Prognostic implications of the nuclear localization of Y‐box‐binding protein‐1 and CXCR4 expression in ovarian cancer: Their correlation with activated Akt, LRP/MVP and P‐glycoprotein expression
Authors: Oda Yoshinao , Ohishi Yoshihiro , Basaki Yuji , Kobayashi Hiroaki , Hirakawa Toshio , Wake Norio , Ono Mayumi , Nishio Kazuto , Kuwano Michihiko , Tsuneyoshi Masazumi
Published: May 2007

The nuclear localization of Y‐box‐binding protein‐1 (YB‐1) is known to be a poor prognostic factor in several human malignancies, including ovarian carcinoma. Following on from our basic study dealing with microarray analyses of YB‐1‐associated gene expression in ovarian cancer cells, we examined whether nuclear localization of YB‐1 is associated with the expression of CXCR4, a vault protein named lung resistance‐related vault protein (LRP/MVP), phosphorylated Akt (p‐Akt) or P‐glycoprotein (P‐gp) in human ovarian carcinoma. Fifty‐three surgically resected ovarian carcinomas treated with paclitaxel and carboplatin were examined immunohistochemically for nuclear YB‐1 expression and intrinsic expression of p‐Akt, P‐gp, LRP/MVP and CXCR4. Nuclear expression of YB‐1 demonstrated significant correlation with p‐Akt, P‐gp and LRP expression, but no relationship with CXCR4 expression. By multivariate analysis, only YB‐1 nuclear expression and CXCR4 expression were independent prognostic factors with regard to overall survival. These results indicate that YB‐1 nuclear expression and CXCR4 expression are important prognostic factors in ovarian carcinoma. (Cancer Sci 2007; 98: 1020–1026)
c‐Met activation in lung adenocarcinoma tissues: An immunohistochemical analysis
Authors: Nakamura Yu , Niki Toshiro , Goto Akiteru , Morikawa Teppei , Miyazawa Keiji , Nakajima Jun , Fukayama Masashi
Published: May 2007

c‐Met is often overexpressed in non‐small cell lung cancer, but it remains unsolved whether its overexpression leads to its activation. We used an antibody specific to phospho‐c‐Met (Tyr1235) to investigate c‐Met activation immunohistochemically in 130 surgically resected lung adenocarcinomas. The expression of c‐Met and hepatocyte growth factor (HGF) was also investigated. Phospho‐c‐Met was positive in 21.5% (28/130) of cases. c‐Met was positive in 74.6% of cases (97/130) and was expressed at high levels in 36.1% of cases (47/130). HGF was expressed at high levels in 31.5% of cases (41/130). Phospho‐c‐Met was correlated with high levels of HGF (P =0.0010) and high levels c‐Met expression (P = 0.0303), but it was also found to be positive in 12 cases with little to no HGF expression. Phospho‐c‐Met expression was significantly associated with tumor differentiation (P = 0.0023) and papillary histology (P = 0.0011), but not with pathological stage, lymph node metastasis or survival. High levels of c‐Met and HGF were also associated with papillary histology (P = 0.0056 and P = 0.0396, respectively), but not with tumor differentiation. Phospho‐c‐Met was correlated with phospho‐Akt (P = 0.0381), but not with phospho‐Erk or phospho‐Stat3. Phospho‐Akt expression was marginally correlated with the expression of phospho‐epidermal growth factor receptor (EGFR) (P = 0.0533) and, importantly, it was strongly correlated with the expression of either phospho‐c‐Met or phospho‐EGFR (P = 0.0013). The data suggest that in lung adenocarcinoma tissue, c‐Met activation may take place either ligand‐dependently or ligand‐independently via c‐Met overexpression. c‐Met activation may play special roles in the papillary subtype and in well differentiated lung adenocarcinomas. (Cancer Sci 2007; 98: 1006–1013)
Occludin‐mediated premature senescence is a fail‐safe mechanism against tumorigenesis in breast carcinoma cells
Authors: Osanai Makoto , Murata Masaki , Nishikiori Nami , Chiba Hideki , Kojima Takashi , Sawada Norimasa
Published: May 2007

We have previously demonstrated that epigenetic silencing of occludin, a tight junction‐associated membrane protein, results in the acquisition of apoptotic resistance to various apoptogenic stimuli, causally contributing to the enhanced tumorigenicity of cancer cells. However, it remains to be examined whether occludin expression in transformed cells has an alternative impact that is important for cancer progression. Here we show that forced expression of occludin induces anoikis and promotes oxidative stress‐induced premature senescence in breast carcinoma cells, which is accompanied by upregulation of negative cell cycle regulators such as p16INK4A, p21Waf1/Cip1 and p27Kip1 but not p53. The senescent phenotype is reversed by specific inhibition of mitogen‐activated protein kinase. Endogenous reexpression of occludin mediated by a synergistic effect with a demethylator and histone deacetylase inhibitor or retinoids that stimulate retinoic acid receptor α is also sufficient for provoking the senescent phenotype. In addition, tumors that developed from occludin‐expressing cells in mice showed a feature of cellular senescence that has not been described as a consequence of occludin signaling. These findings suggest that the loss of occludin expression is at least partially involved in the senescence‐escape program during mammary tumorigenesis. (Cancer Sci 2007; 98: 1027–1034)
Association of KLK5 overexpression with invasiveness of urinary bladder carcinoma cells
Authors: Shinoda Yasuo , Kozaki Ken‐ichi , Imoto Issei , Obara Wataru , Tsuda Hitoshi , Mizutani Yoichi , Shuin Taro , Fujioka Tomoaki , Miki Tsuneharu , Inazawa Johji
Published: May 2007

Array‐based comparative genomic hybridization (array‐CGH) has powerful potential for high‐throughput identification of genetic aberrations in cell genomes. We identified high‐level amplification of kallikrein (KLK) genes, which are mapped to 19q13.3 and belong to the serine protease family, in the course of a program to screen a panel of urinary bladder carcinoma cell lines for genomic copy number aberrations using our in‐house CGH‐array. Expression levels of KLK5, ‐6, ‐8 and ‐9 were significantly increased in three cell lines with copy number gains of these KLK genes. Knockdown of these KLK transcripts by specific small interfering RNA significantly inhibited the invasion of a bladder carcinoma cell line through Matrigel in vitro. Reverse transcription–polymerase chain reaction analysis of 42 primary bladder tumor samples showed that increased expression of KLK5 was frequently observed in invasive tumors (pT2–pT4) (14.3%, 6/42) compared with superficial tumors (pTa, pT1) (0%, 0/42; P = 0.0052), and expression levels of KLK5, ‐6, ‐8 and ‐9 mRNA were higher in invasive tumors than in superficial tumors (P < 0.0001, P = 0.0043, P = 0.0790 and P = 0.0037, respectively). These observations indicate that KLK5, ‐6, ‐8 and ‐9 may be the most likely targets of the 19q13.3 amplification, and may play a crucial role in promoting cancer‐cell invasion in bladder tumor. (Cancer Sci 2007; 98: 1078–1086)
Immunological evaluation of personalized peptide vaccination in combination with a 5‐fluorouracil derivative (TS‐1) for advanced gastric or colorectal carcinoma patients
Authors: Sato Yuji , Fujiwara Toshiyoshi , Mine Takashi , Shomura Hiroki , Homma Shigenori , Maeda Yoshiaki , Tokunaga Naoyuki , Ikeda Yoshihiro , Ishihara Yuki , Yamada Akira , Tanaka Noriaki , Itoh Kyogo , Harada Mamoru , Todo Satoru
Published: May 2007

The aim of the present study was to investigate the safety and immunological responses of personalized peptide vaccination in combination with oral administration of a 5‐fluorouracil derivative (TS‐1) in advanced gastric or colorectal carcinoma patients. Eleven patients (four with gastric cancer and seven with colorectal cancer) who failed to improve by prior TS‐1‐based chemotherapies were enrolled in this study. Peptides to be administered to patients were determined based on the presence of peptide‐specific cytotoxic T lymphocyte (CTL) precursors in peripheral blood mononuclear cells and peptide‐specific IgG in the plasma of cancer patients. Patients were vaccinated with peptides (a maximum of four) biweekly in combination with or without three different doses of TS‐1 (20, 40 and 80 mg/m2/day). Although grade 3 toxicity, including anemia (one patient) and neutropenia (one patient) were observed, the combination therapy was generally well tolerated. An increase in peptide‐specific IgG after the sixth vaccination was observed in the vast majority of patients irrespective of the dose of TS‐1 used. In contrast, an increase in peptide‐specific interferon‐γ production by CTL was most evident in patients who were administered the highest dose of TS‐1. Furthermore, in the patients who received 80 mg/m2/day TS‐1, CTL‐mediated cytotoxicity against cancer cells was maintained at the prevaccination level. These results indicate that administration of the standard dose (80 mg/m2/day) of TS‐1 in combination with a personalized peptide vaccination does not necessarily impede immunological responses in cancer patients, and could actually maintain or augment them. (Cancer Sci 2007; 98: 1113–1119)
Genetic relationships between feral cattle from Chirikof Island, Alaska and other breeds
Authors: MacNeil M. D. , Cronin M. A. , Blackburn H. D. , Richards C. M. , Lockwood D. R. , Alexander L. J.
Published: May 2007

The origin of cattle on Chirikof Island, off the coast of Alaska, is not well documented. We assessed genetic differentiation of cattle isolated on Chirikof Island from several breeds commonly used for commercial production in North America including breeds popularly believed to have contributed to the Chirikof Island population. A set of 34 microsatellite loci was used to genotype Angus, Charolais, Hereford, Highland, Limousin, Red Angus, Salers, Shorthorn, Simmental, Tarentaise and Texas Longhorn cattle sampled from North America and the Chirikof Island population. Resulting FST statistics for these loci ranged from 0.06 to 0.22 and on average, 14% of total genetic variation was between breeds. Whether population structure was modelled as a bifurcating tree or genetic network, Chirikof Island cattle appeared to be unique and strongly differentiated relative to the other breeds that were sampled. Bayesian clustering for multiple‐locus assignment to genetic groups indicated low levels of admixture in the Chirikof Island population. Thus, the Chirikof Island population may be a novel genetic resource of some importance for conservation and industry.