bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic models in patients with non‐small‐cell lung cancer using artificial neural networks in comparison with logistic regression
Authors: Hanai Taizo , Yatabe Yasushi , Nakayama Yusuke , Takahashi Takashi , Honda Hiroyuki , Mitsudomi Tetsuya , Kobayashi Takeshi
Published: August 2005

It is difficult to precisely predict the outcome of each individual patient with non‐small‐cell lung cancer (NSCLC) by using conventional statistical methods and ordinary clinico‐pathological variables. We applied artificial neural networks (ANN) for this purpose. We constructed a prognostic model for 125 NSCLC patients with 17 potential input variables, including 12 clinico‐pathological variables (age, sex, smoking index, tumor size, p factor, pT, pN, stage, histology) and 5 immunohistochemical variables (p27 percentage, p27 intensity, p53, cyclin D1, retinoblastoma (RB)), by using the parameter‐increasing method (PIM). Using the resultant ANN model, prediction was possible in 104 of 125 patients (83%, judgment ratio (JR)) and accuracy for prediction of survival at 5 years was 87%. On the other hand, JR and survival prediction accuracy in the logistic regression (LR) model were 37% and 78%, respectively. In addition, ANN outperformed LR for prediction of survival at 1 or 3 years. In these cases, PIM selected p27 intensity and cyclin D1 for the 3‐year survival model and p53 for the 1‐year survival model in addition to clinico‐pathological variables. Finally, even in an independent validation data set of 48 patients, who underwent surgery 10 years later, the present ANN model could predict outcome of patients at 5 years with the JR and accuracy of 81% and 77%, respectively. This study demonstrates that ANN is a potentially more useful tool than conventional statistical methods for predicting survival of patients with NSCLC and that inclusion of relevant molecular markers as input variables enhances its predictive ability. (Cancer Sci 2003; 94: 473–477)
Combined effects of prostaglandin E receptor subtype EP1 and subtype EP4 antagonists on intestinal tumorigenesis in adenomatous polyposis coli gene knockout mice
Authors: Kitamura Tomohiro , Itoh Masaki , Noda Tetsuo , Tani Kousuke , Kobayashi Michiyoshi , Maruyama Takayuki , Kobayashi Kaoru , Ohuchida Shuichi , Sugimura Takashi , Wakabayashi Keiji
Published: August 2005

Previous studies have shown that prostaglandin E2 (PGE2) is involved in intestinal carcinogenesis through its binding to the PGE2 receptor subtypes EP1 and EP4 and activation of downstream pathways. ONO‐8711 and ONO‐AE2–227, prostaglandin E receptor subtype EP1‐ and EP4‐selective antagonists, respectively, are known to suppress formation of intestinal polyps in adenomatous polyposis coli gene‐deficient mice. The present study was designed to investigate the combined effects of EP1 and EP4 antagonists on spontaneous polyp formation in APC1309 mice in order to determine the contribution of each receptor to intestinal tumorigenesis. APC1309 mice were treated with 400 ppm of ONO‐8711 alone, 400 ppm of ONO‐AE2–227 alone or both in combination in the diet for 6 weeks. The mean area of polyps found in the intestine, calculated as the longer diameter × the shorter diameter ×π, was reduced by 12%, 43% (P<0.01) and 56% (P<0.01) of the mean control value (8.8 mm2) in the ONO‐8711 alone, ONO‐AE2–227 alone and combination treatment groups, respectively, suggesting clear additive effects of the combination. The same additive tendency for suppression was also observed with respect to the numbers of polyps in the intestine. Polyp size reduction was more remarkable with the EP4 antagonist, while the number reduction was more pronounced with the EP1 antagonist. Our results indicate that EP1 and EP4 may have separate intrinsic roles and, to some extent, contribute to polyp formation independently. Thus, combination treatment has potential for the chemoprevention of colon carcinogenesis.
Intraperitoneal radioimmunotherapy in treating peritoneal carcinomatosis of colon cancer in mice compared with systemic radioimmunotherapy
Authors: Kinuya Seigo , Li Xiao‐Feng , Yokoyama Kunihiko , Mori Hirofumi , Shiba Kazuhiro , Watanabe Naoto , Shuke Noriyuki , Bunko Hisashi , Michigishi Takatoshi , Tonami Norihisa
Published: August 2005

Peritoneal spread is one of major causes of mortality in colorectal cancer patients. In the current investigation, the efficacy of radioimmunotherapy (RIT) with i.p. administration of an anti‐colorectal cancer IgG1,131I‐A7, was compared to that with i.v. administration in BALB/c female mice bearing peritoneal nodules of LS180 human colon cancer cells, at the same toxicity level. Distribution of either i.p. or i.v. administered 131I‐A7 and i.p. administered irrelevant 131I‐HPMS‐1 was assessed. Based on the results of toxicity determination at increments of 2 MBq and estimated dosimetry, an i.p. dose of 11 MBq and an i.v. dose of 9 MBq were chosen for treatment. Mice were monitored for long‐term survival: untreated mice (n=11), mice undergoing i.p. RIT with 131I‐A7 (n=11), mice undergoing i.v. RIT with 131I‐A7 (n=11) and mice undergoing non‐specific i.p. RIT with 131I‐HPMS‐1 (n=5). Intraperitoneal injection of 131I‐A7 produced faster and greater tumor accumulation than i.v. injection: 34.2±16.5% of the injected dose per g (% ID/ g) and 11.1±3.6% ID/g at 2 h, respectively (P<0.0001). Consequently, cumulative radioactivity in tumors was 1.73‐fold higher with i.p. injection. 131I‐HPMS‐1 did not show specific accumulation. Non‐specific RIT with 131I‐HPMS‐1 (mean survival, 26.0±2.5 days) did not affect the survival as compared to no treatment (26.7±1.9 days). Intravenous RIT with 131I‐A7 prolonged the survival of mice to 32.8±1.8 days (P<0.01). Intraperitoneal RIT with 131I‐A7 improved the survival more significantly and attained cure in 2 of 11 mice (P<0.05 vs. i.v. RIT). In conclusion, i.p. RIT is more beneficial in treating peritoneal carcinomatosis of colon cancer than i.v. RIT in a murine model.
Identification of human tumor antigens and its implications for diagnosis and treatment of cancer
Authors: Kawakami Yutaka , Fujita Tomonobu , Matsuzaki Yuriko , Sakurai Toshiharu , Tsukamoto Makoto , Toda Masahiro , Sumimoto Hidetoshi
Published: August 2005

Human tumor antigens recognized by T cells have been identified by means of various molecular biological and immunological methods, including cDNA expression cloning with patients' T cells and antibodies, cDNA subtraction using RDA and PCR differential display, systematic gene analysis such as DNA sequencing, CGH, DNA chip/microarray and SAGE, in vitro T cell induction and immunization of HLA transgenic mice. The identification of human tumor antigens has led to a better understanding of the nature of tumor antigens, anti‐tumor immune responses in patients before and after immunotherapy, and tumor escape mechanisms. The information obtained from these researches has enabled us to develop and improve immunotherapy by attempting to overcome the identified problems, including intrinsically low immuno‐genicity of tumor antigens and several escape mechanisms, such as regulatory T cell induction. The existence of immunogenic unique antigens derived from genetic alterations in tumor cells, and the varied immunogenicity of shared tumor antigens among patients due to differing expression in tumor cells and immunore‐activity of patients, indicates that individualized immunotherapy should ideally be performed. The identified antigens will also be useful for development of diagnostic methods and molecular targeting therapy for cancer.
Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage
Authors: Yoshida Kiyotsugu , Miki Yoshio
Published: August 2005

BRCA1 (BReast‐CAncer susceptibility gene 1) and BRCA2 are tumor suppressor genes, the mutant phenotypes of which predispose to breast and ovarian cancers. Intensive research has shown that BRCA proteins are involved in a multitude of pivotal cellular processes. In particular, both genes contribute to DNA repair and transcriptional regulation in response to DNA damage. Recent studies suggest that BRCA proteins are required for maintenance of chromosomal stability, thereby protecting the genome from damage. New data also show that BRCAs transcriptionally regulate some genes involved in DNA repair, the cell cycle, and apo ptosis. Many of these functions are mediated by a large number of cellular proteins that interact with BRCAs. The functions of BRCA proteins are also linked to distinct and specific phosphory‐lation events; however, the extent to which phosphorylation‐acti‐vated molecular pathways contribute to tumor suppressor activity remains unclear. Finally, the reasons why mutations in BRCA genes lead to the development of breast and ovarian cancers are not clearly understood. Elucidation of the precise molecular functions of BRCAs is expected to improve our understanding of hereditary as well as sporadic mammary carcinogenesis.
Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and colorectal cancer: The Fukuoka Colorectal Cancer Study
Authors: Yin Guang , Kono Suminori , Toyomura Kengo , Hagiwara Tomoko , Nagano Jun , Mizoue Tetsuya , Mibu Ryuichi , Tanaka Masao , Kakeji Yoshihiro , Maehara Yoshihiko , Okamura Takeshi , Ikejiri Koji , Futami Kitaroh , Yasunami Yohichi , Maekawa Takafumi , Takenaka Kenji , Ichimiya Hitoshi , Imaizumi Nobutoshi
Published: August 2005

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating folate metabolism, which affects DNA synthesis and methylation. This study investigated the relation of MTHFR C677T and A1298C polymorphisms to colorectal cancer in a case‐control study in Fukuoka, Japan. The subjects comprised 685 incident cases of histologically confirmed colorectal adenocarcinomas and 778 community controls selected randomly in the study area. The genotype was determined by the PCR‐RFLP method using genomic DNA extracted from buffy coat. Alcohol use was ascertained by in‐person interview. Statistical adjustment was made for gender, age class, area, and alcohol use. The MTHFR 677TT genotype was associated with a statistically significant decrease in the risk with an adjusted odds ratio of 0.69 (95% confidence interval 0.51–0.93) compared with the 677CC and 677CT combined, and the decrease was most evident in individuals with no alcohol consumption. While the A1298C polymorphism showed no measurable association with the overall risk of colorectal cancer, the 1298CC genotype was associated with a statistically significant increase in the risk when alcohol consumption was high, and was also associated with an approximately 2‐fold increase in the risk of each of proximal and distal colon cancer. The findings add to evidence that individuals with the MTHFR 677TT genotype have a decreased risk of colorectal cancer in the absence of folate depletion, suggesting a protective role of folate by ensuring a sufficient thymidylate pool for DNA synthesis. Because very few individuals had the 1298CC genotype, the findings regarding the A1298C polymorphism need careful interpretation and confirmation in larger studies.
Ninth Japanese‐German Workshop on Molecular and Cellular Aspects of Carcinogenesis, Essen, Germany, 18–20 September, 2003
Authors: Miyazono Kohei , Ishikawa Fuyuki , Winterhager Elke , Deppert Wolfgang , Rajewsky Manfred F.
Published: August 2005

The Japanese‐German Workshops “Molecular and Cellular Aspects of Carcinogenesis”, held biennially since 1987, have been organized traditionally at the University of Essen Medical School and West German Cancer Center Essen in Germany. This 9th Workshop was held on September 18–20, 2003. It was generously supported by the Cancer Research Program of the Ministry of Education, Culture, Sports, Science and Technology and the International Cooperation Program for the 2nd Term Comprehensive 10‐Year Strategy for Cancer Control of the Ministry of Health, Labour and Welfare on the Japanese side, and by the Deutsche For‐schungsgemeinschaft (DFG) on the German side. Additional support from many other sponsors in Germany and Japan is gratefully acknowledged. The Workshop participants are listed at the end of this Report.
A prospective study of reproductive and menstrual factors and colon cancer risk in Japanese women: Findings from the JACC study
Authors: Tamakoshi Koji , Wakai Kenji , Kojima Masayo , Watanabe Yoshiyuki , Hayakawa Norihiko , Toyoshima Hideaki , Yatsuya Hiroshi , Kondo Takaaki , Tokudome Shinkan , Hashimoto Shuji , Suzuki Koji , Suzuki Sadao , Kawado Miyuki , Ozasa Kotaro , Ito Yoshinori , Tamakoshi Akiko ,   JACC Study Group
Published: August 2005

The effects of reproductive factors on the etiology of colon cancer in Asian populations remain unexplored. So we examined 38,420 Japanese women aged 40‐79 years who responded to a questionnaire on reproductive and other lifestyle factors from 1988 to 1990 in the Japan Collaborative Cohort Study for Evaluation of Cancer Risk. During an average 7.6 years of follow‐up, we documented 207 incident colon cancers. Multivariate analysis indicated that colon cancer risk was likely to be lower among pa‐rous women than among nulliparous. Women who had two abortions or more had a 72% higher risk of developing colon cancer [relative risk (RR) 1.72; 95% confidence interval (CI) 1.16‐2.55; trend P<0.01] compared with women who never had an abortion. The RR of colon cancer among postmenopausal women significantly decreased with increasing age at menarche (trend P=0.01). No apparent association between colon cancer and gravida, age at first birth, age at menopause, or duration of menstruation was seen. These prospective data support the hypothesis that female reproductive events modify colon cancer risk, and suggest that reproductive factors, particularly age at menarche and having an abortion, may be of importance in the etiology of colon cancer among Japanese women.
Promoter methylation status and expression of TMS1 gene in human epithelial ovarian cancer
Authors: Akahira Jun‐ichi , Sugihashi Youko , Ito Kiyoshi , Niikura Hitoshi , Okamura Kunihiro , Yaegashi Nobuo
Published: August 2005

Gene silencing associated with aberrant DNA methylation of promoter CpG islands is one mechanism through which tumor suppressor genes are inactivated in human cancers. TMS1 (target of methylation‐induced silencing) is a CpG island‐associated gene that functions in the regulation of apoptosis. In this study, we examined the DNA methylation status of the TMS1 promoter in ovarian cancer cell lines and tissues by methylation‐specific PCR (MSP) and its mRNA expression by reverse transcription and quantitative PCR. Aberrant methylation of TMS1 was present in 7/12 ovarian cancer cell lines and 8/20 primary ovarian cancer tissues. The median value of relative TMS1 gene expression in cancers with methylation (0.15) was significantly lower than that in cancers without methylation (13.9) (P<0.001). The expression of the TMS1 gene was relatively high (48.5) in the normal ovarian cDNA library. TMS1 gene expression was restored by treatment with the demethylating agent 5‐aza‐2′‐deoxycitidine in the OV90 cell line, which lacks the TMS1 transcript. Our results suggest that aberrant methylation of TMS1 may play a role in the pathogenesis of ovarian cancer. (Cancer Sci 2004; 95: 40–43)
Vaccination with autologous endothelium inhibits angiogenesis and metastasis of colon cancer through autoimmunity
Authors: Okaji Yurai , Tsuno Nelson Hirokazu , Kitayama Joji , Saito Shinsuke , Takahashi Tsuyoshi , Kawai Kazushige , Yazawa Kentaro , Asakage Masahiro , Hori Nobukazu , Watanabe Toshiaki , Shibata Yoichi , Takahashi Koki , Nagawa Hirokazu
Published: August 2005

Overcoming immune tolerance of tumor angiogenesis should be useful for adjuvant therapy of cancer. We hypothesized that vaccination with autologous endothelium would induce an autoimmune response targeting tumor angiogenesis. To test this concept, we immunized BALB/c mice with a vaccine of glutaraldehyde‐fixed murine hepatic sinusoidal endothelial cells (HSEs) in a lung metastasis model of Colon‐26 cancer. Vaccination with autologous HSEs induced both preventive and therapeutic anti‐tumor immunity that significantly inhibited the development of metastases. ELISA revealed an immunoglobulin response involving IgM and IgG subclasses. These antibodies had a strong affinity for antigens of both murine and human endothelium, and lyzed endothelial cells in the CDC assay. Flow‐cytometry and chromium‐release cytotoxicity assay revealed a specific CTL response against endothelial cells, which were lyzed in an effector: target ratio‐dependent manner. Neither antibodies nor CTLs reacted with Colon26. The effect of autologous HSEs was more pronounced than that of xenogeneic human umbilical vein endothelial cells (HU‐VECs), which were tested in the same experimental setting. Our results suggest that vaccination with autologous endothelium can overcome peripheral tolerance of self‐angiogenic antigens and therefore should be useful for adjuvant immunotherapy of cancer. (Cancer Sci 2004; 95: 85–90)
Adenovirus‐mediated p53AIP1 gene transfer as a new strategy for treatment of p53‐resistant tumors
Authors: Yoshida Koji , Monden Morito , Nakamura Yusuke , Arakawa Hirofumi
Published: August 2005

The p53AIP1 gene, which we recently identified as a novel p53‐target, mediates p53‐dependent apoptosis. We evaluated the effects of adenovirus‐mediated introduction of p53AIP1 (Ad‐p53AIP1) on 30 human cancer‐cell lines in vitro, and two cell lines in vivo, in comparison with the effects of p53 (Ad‐p53). In 20 of the 30 cell lines, p53AIP1‐induced apoptosis was observed, and in 12 of these p53AIP1‐sensitive cancer cell lines, the apoptotic effects of p53AIP1 were greater than those of p53 itself. Cancers with wild‐type p53, which were thought to be p53‐resistant, were likely to be sensitive to p53AIP1‐induced apoptosis. p53‐re‐sistant cancers such as LS174T (p53+/+) and A549 (p53+/+), in which no increase of p53AIP1 mRNA expression was observed when Ad‐p53 was introduced, were killed effectively by Ad‐p53AIP1. Furthermore, co‐introduction of p53 and p53AIP1 had a synergistic effect on the induction of apoptosis, regardless of p53 status. Finally, adenovirus‐mediated introduction of p53AIP1 suppressed tumor growth in vivo. These results suggested that p53AIP1 gene transfer might become a new strategy for the treatment of p53‐resistant cancers. (Cancer Sci 2004; 95: 91–97)
Oncogenic role of NALP7 in testicular seminomas
Authors: Okada Koichi , Hirota Eiji , Mizutani Yoichi , Fujioka Tomoaki , Shuin Taro , Miki Tsuneharu , Nakamura Yusuke , Katagiri Toyomasa
Published: August 2005

To isolate novel molecular targets for treatment of testicular germ cell tumor (TGCT), we performed genome‐wide expression profile analysis of testicular seminomas using a cDNA microarray. We here report identification of NACHT, leucine‐rich repeat and PYD containing 7 (NALP7), that was significantly transactivated in testicular seminomas. Subsequent semi‐quantitative RT‐PCR and northern blot analyses confirmed an approximately 3.3‐kb transcript that was expressed exclusively in testis, although the expression level of this gene in normal testis was much lower than in tumor cells, suggesting an important role of this gene in germ‐cell proliferation. Immunohistochemical analysis using anti‐NALP7 polyclonal antibody detected the endogenous NALP7 protein in the cytoplasm of embryonal carcinoma cells and testicular seminoma tissues. Transfection of small interfering RNA (siRNA) for NALP7 significantly reduced the NALP7 expression and resulted in growth suppression of testicular germ‐cell tumors. These findings imply that NALP7 may play a crucial role in cell proliferation, as well as testicular tumorigenesis, and it appears to be a promising candidate for development of targeted therapy for TGCTs.
Herpes simplex virus‐induced, death receptor‐dependent apoptosis and regression of transplanted human cancers
Authors: Kamiyama Hironaga , Kurosaki Kunikazu , Kurimoto Masanori , Katagiri Toyomasa , Nakamura Yusuke , Kurokawa Masahiko , Sato Hitoshi , Endo Shunro , Shiraki Kimiyasu
Published: August 2005

Inoculation of a live attenuated herpes simplex virus (HSV) vector, bH1, into human U87MG glioblastoma cells transplanted into athymic nude mice induced complete regression of tumors. The infected cells underwent histochemically confirmed apoptosis without lymphocyte infiltration after expressing CD30, CD30 ligand (CD30L), tumor necrosis factor (TNF)‐a, TNF receptor 1 (TNF‐R1), FAS, and FAS ligand (FAS‐L) with activation of caspases 3 and 8. Induction of the transcripts of these receptors and ligands in inoculated tumors was confirmed by quantitative RT‐PCR. To examine the specificity of apoptosis in the transplanted tumor, we inoculated bH1 into transplanted human lung, breast, gastric, and colon cancer tumors, and similar tumor regression with apoptosis was observed in all tumors. We analyzed the roles of expression of CD30, CD30L, TNF‐a, TNF‐R1, FAS, and FAS‐L in the tumors, and found that HSV‐induced apoptosis was suppressed by the respective antibodies. These findings indicate that the CD30/CD30L, TNF‐a/TNF‐R1, and FAS/FAS‐L interactions resulted in apoptosis and tumor regression in immunocompromised mice. In addition to the death receptor‐dependent apoptosis induced by HSV, the expressed ligands and receptors might enhance the susceptibility of tumor cells to cell‐mediated cyto‐toxicity and augment the activation of tumor‐killing lymphocytes in immunocompetent models.
Detection of a smaller, 32‐kDa 8‐oxoguanine DNA glycosylase 1 in 3′‐methyl‐4‐dimethylamino‐azobenzene‐treated mouse liver
Authors: Hirano Takeshi , Kudo Hideaki , Doi Yoshiaki , Nishino Tomoko , Fujimoto Sunao , Tsurudome Yosuke , Ootsuyama Yuko , Kasai Hiroshi
Published: August 2005

We previously reported that 3′‐methyl‐4‐dimethylaminoazobenzene (3′‐MeDAB) increased the 8‐hydroxyguanine (8‐OH‐Gua) content in nuclear DNA and the base excision repair activity in mouse liver. However, to understand the mechanism of 3′‐MeDAB carcinogenesis, a further investigation of the 8‐OH‐Gua repair systems was necessary. In this report, we examined the expression of the repair enzyme, 8‐oxoguanine DNA glycosylase 1 (OGG1), in 3′‐MeDAB‐treated mouse liver. We prepared four kinds of anti‐peptide polyclonal antibodies raised against mouse OGG1 (mOGG1). The sequences used as epitopes were designed from positions located close to the N‐terminus, the nuclear localization signal (NLS), and the regions containing Lys249 and Asp267, which are involved in the catalytic mechanisms of mOGG1 (glycosylase and lyase, respectively). Immunoblotting, using all four antibodies, revealed a 32‐kDa protein (mOGG1‐32) in addition to the 38‐kDa mOGG1 in the 3′‐MeDAB‐treated mouse liver. Moreover, immunostaining with mOGG1 antibody yielded strong, positive signals in the 3′‐MeDAB‐treated mouse liver nuclei. However, we could not detect any difference in the Ogg1 mRNA expression pattern. Although the function of mOGG1‐32 remains unclear, these findings suggest that 3′‐MeDAB may alter the function of the DNA repair protein, and this action may be related to 3′‐MeDAB carcinogenesis.
Tumor formation is correlated with expression of β‐catenin‐accumulated crypts in azoxymethane‐induced colon carcinogenesis in mice
Authors: Hata Kazuya , Yamada Yasuhiro , Kuno Toshiya , Hirose Yoshinobu , Hara Akira , Qiang Sheng Hong , Mori Hideki
Published: August 2005

We have reported that β‐catenin‐accumulated crypts (BCAC) are independent of aberrant crypt foci (ACF) in the colonic mucosa of rats exposed to colorectal carcinogens, and we suggested that they may be premalignant lesions. In the present study, we performed a comparative study on the formation of the two types of early‐appearing lesions (BCAC and ACF), and tumors of the colon in two mouse strains with different susceptibility to azoxymethane (AOM). SWR/J mice are known to be relatively susceptible to AOM, whereas AKR/J mice are reported to be virtually resistant. Both AKR/J and SWR/J mice, 6 weeks old, received subcutaneous injections of AOM (15 mg/kg body weight) once a week for 3 weeks, and were sacrificed at 16 and 41 weeks of age. Colons of the animals sacrificed at 16 and 41 weeks of age were processed to examine expression of the early‐appearing lesions and neoplasms. Although AKR/J mice had a lower incidence of colonic tumors than SWR/J mice did, AKR/J mice showed a similar frequency of ACF to that in SWR/J mice. In both strains, ACF were detected at high frequency in the proximal colon, whereas tumors developed mainly in the distal colon. Importantly, the incidence of BCAC in SWR/J mice was significantly higher than that in AKR/J mice, and the highest frequency was observed in the distal segments of the colon. These results support the idea that BCAC are a reliable surrogate endpoint for colon carcinogenesis in mice.
Genetic link between p53 and genes required for formation of the zonula adherens junction
Authors: Yamaguchi Masamitsu , Hirose Fumiko , Inoue Yoshihiro H. , Ohno Katsuhito , Yoshida Hideki , Hayashi Yuko , Deak Peter , Matsukage Akio
Published: August 2005

Ectopic expression of human p53 in Drosophila eye imaginal disc cells induces apoptosis and results in a rough eye phenotype in the adult flies. We have screened Drosophila stocks to identify mutations that enhance or suppress the p53‐induced rough eye phenotype. One of the dominant enhancers of the p53‐induced rough eye phenotype corresponds to a loss‐of‐function mutation of the crumbs gene, which is essential for the biogenesis of the zonula adherens junction and the establishment of apical polarity in epithelial cells. Enhancement of p53‐induced apoptosis in the eye imaginal discs by a half‐reduction of the crumbs gene dose was confirmed by a TUNEL method. Furthermore, mutations of genes for Shotgun (Drosophila E‐cadherin) and Armadillo (Drosophilaβ‐catenin), the two main components of the adherens junction, also strongly enhanced the p53‐induced rough eye phenotype. These results suggest that human p53 senses subtle abnormality at the adherens junction or in signals derived from the junction, and consequently induces apoptosis to remove abnormal cells from tissue. Thus p53 likely plays a role as a guardian of the tissue not only by sensing the damaged DNA, but also by sensing signals from the adherens junction.
Prediction of prognosis of estrogen receptor‐positive breast cancer with combination of selected estrogen‐regulated genes
Authors: Yoshida Nobuyuki , Omoto Yoko , Inoue Akio , Eguchi Hidetaka , Kobayashi Yasuhito , Kurosumi Masafumi , Saji Shigehira , Suemasu Kimito , Okazaki Tomoki , Nakachi Kei , Fujita Toshiro , Hayashi Shin‐ichi
Published: August 2005

Estrogen receptor (ER)‐positive breast cancer is a distinct subpopulation of breast cancer exhibiting a high response rate to endocrine therapy. However, not all ER‐positive patients respond to the therapy, and a subgrouping of ER‐positive patients based on the physiology of estrogen signaling is expected to be useful for predicting the prognosis. This study has revealed that selected estrogen‐regulated genes (ERGs) are useful in identification of a poor‐prognosis population among ER‐positive breast cancer patients. First, the expression levels of 11 ERGs, selected based on our earlier microarray study in cultured cells, were analyzed by means of real‐time reverse transcription‐PCR in 14 ER‐positive human breast cancer tissues. The patients were clearly divided into two groups in cluster analysis. Then, we examined the expression levels of two representative ERGs, histone deacetylase 6 (HDAC6) and insulin‐like growth factor binding protein 4 (IGFBP‐4), In 62 ER‐positive patients with immunohistochemistry to assess the impact of ERG expression on prognosis (median follow‐up 4409 days). Positive HDAC6 staining was significantly correlated with a lower disease‐free survival rate. Moreover, when the expression level of HDAC6 was assessed in combination with IGFBP‐4 expression in the nucleus, the poor‐prognosis patients were more accurately identified. This study has identified new candidate ERGs for prediction of prognosis, and we suggest that combined assessment of the expression levels of these ERGs will contribute to the clinically useful stratification of ER‐positive breast cancer patients.
Identification of a novel fusion gene in a pre‐B acute lymphoblastic leukemia with t(1;19)(q23;p13)
Authors: Yuki Yasuhiro , Imoto Issei , Imaizumi Masue , Hibi Shigeyoshi , Kaneko Yasuhiko , Amagasa Teruo , Inazawa Johji
Published: August 2005

The most common nonrandom translocation found among childhood pre‐B acute lymphoblastic leukemias (ALL) is t(1;19)(q23;p13), which frequently results in fusion of E2A with PBX1. However, rare cases of childhood ALL and various other hematological diseases with t(1;19) lack the E2A‐PBX1 fusion. Analyzing a cell line with pre‐B‐cell phenotype, TS‐2, that carries t(1;19)(q23;p13) but lacks the E2A‐PBX1 fusion, we successfully cloned the breakpoints, which fell within introns of MEF2D and DAZAP1. Both chimeric transcripts, MEF2D‐DAZAP1 and DAZAP1‐MEF2D, whose sequences indicated in‐frame fusions between MEF2D and DAZAP1, were expressed in TS‐2 cells and in bone‐marrow cells of the patient from whom the TS‐2 was established. MEF2D‐DAZAP1 and DAZAP1‐MEF2D proteins were both located in the nucleus, and MEF2D‐DAZAP1 was able to form dimers with MEF2D and HDAC4. In addition, exogenous expression of MEF2D‐DAZAP1 and DAZAP1‐MEF2D promoted the growth of HeLa cells. Given the frequency of t(1;19) without the E2A‐PBX1 fusion in hematological malignancies, we suggest that MEF2D/DAZAP1 rearrangements might be involved in the pathogenesis of those diseases.
Potential for drug interactions involving cytochrome P450 in patients attending palliative day care centres: a multicentre audit
Authors: Wilcock A. , Thomas J. , Frisby J. , Webster M. , Keeley V. , Finn G. , Fossey K. , Wee B. , Beale J. , Lennard M. S.
Published: August 2005

Aim

To determine the potential for drug interactions involving cytochrome P450 (CYP) in patients receiving palliative day care.

Methods

Drugs used by patients attending four specialist palliative day care centres were reviewed to identify combinations that could result in a pharmacokinetic interaction via any of the five main human forms of CYP.

Results

Of 160 patients, 145 (91%) were prescribed at least one drug that was a substrate, inhibitor or inducer of one of the five main CYP isoforms. Twenty‐four drug combinations, involving 34 patients, could have given rise to a clinically important interaction.

Conclusions

Prescribers should be aware that in this group of patients, one in five are at risk of a clinically important CYP‐mediated drug interaction.
Pollination of two species of Ferocactus: interactions between cactus‐specialist bees and their host plants
Authors: MCINTOSH M. E.
Published: August 2005

Resolving the controversy over the prevalence of generalization in plant–pollinator interactions requires field studies characterizing the pollination effectiveness of all a plant's floral visitors. Herein, the pollination effectiveness of all visitors to two species of barrel cactus (Ferocactus) was quantified.

Flowers of both species were pollinated almost exclusively by cactus‐specialist bees: 99% (F. cylindraceus (Engelm.) Orcutt) and 94% (F. wislizeni (Engelm.) Britt. and Rose) of all seeds produced in this study resulted from cactus bee visits.

For F. cylindraceus, the cactus‐specialist Diadasia rinconis was the most abundant visitor. For F. wislizeni, three cactus‐specialists (including D. rinconis) plus generalists in the family Halictidae (which did not act as pollinators) each accounted for a quarter of all visits.

Diadasia rinconis visits to F. wislizeni flowers were more effective (per‐visit) than visits by the other two cactus‐specialists.

Pollen‐collecting and nectar‐collecting visits were equally effective. Nectar‐collecting visits were the most abundant.

Apart from the non‐pollinating halictids, floral visitors surprisingly did not include commonly co‐occurring generalist bees.

These data suggest that, just as apparently specialized flowers may be visited by a diverse assemblage of generalists, so apparently generalized flowers may be visited predominantly by specialists, and that these specialists may perform virtually all of the pollination.
Importance of changing CO2, temperature, precipitation, and ozone on carbon and water cycles of an upland‐oak forest: incorporating experimental results into model simulations
Authors: Hanson Paul J. , Wullschleger Stan D. , Norby Richard J. , Tschaplinski Timothy J. , Gunderson Carla A.
Published: August 2005

Observed responses of upland‐oak vegetation of the eastern deciduous hardwood forest to changing CO2, temperature, precipitation and tropospheric ozone (O3) were derived from field studies and interpreted with a stand‐level model for an 11‐year range of environmental variation upon which scenarios of future environmental change were imposed. Scenarios for the year 2100 included elevated [CO2] and [O3] (+385 ppm and +20 ppb, respectively), warming (+4°C), and increased winter precipitation (+20% November–March). Simulations were run with and without adjustments for experimentally observed physiological and biomass adjustments.

Initial simplistic model runs for single‐factor changes in CO2 and temperature predicted substantial increases (+191% or 508 g C m−2 yr−1) or decreases (−206% or −549 g C m−2 yr−1), respectively, in mean annual net ecosystem carbon exchange (NEEa≈266±23 g C m−2 yr−1 from 1993 to 2003). Conversely, single‐factor changes in precipitation or O3 had comparatively small effects on NEEa (0% and −35%, respectively). The combined influence of all four environmental changes yielded a 29% reduction in mean annual NEEa. These results suggested that future CO2‐induced enhancements of gross photosynthesis would be largely offset by temperature‐induced increases in respiration, exacerbation of water deficits, and O3‐induced reductions in photosynthesis. However, when experimentally observed physiological adjustments were included in the simulations (e.g. acclimation of leaf respiration to warming), the combined influence of the year 2100 scenario resulted in a 20% increase in NEEa not a decrease. Consistent with the annual model's predictions, simulations with a forest succession model run for gradually changing conditions from 2000 to 2100 indicated an 11% increase in stand wood biomass in the future compared with current conditions.

These model‐based analyses identify critical areas of uncertainty for multivariate predictions of future ecosystem response, and underscore the importance of long term field experiments for the evaluation of acclimation and growth under complex environmental scenarios.
Potential decoupling of trends in distribution area and population size of species with climate change
Authors: Shoo Luke P. , Williams Stephen E. , Hero Jean‐Marc
Published: August 2005

Global climates are changing rapidly and biological responses are becoming increasingly apparent. Here, we use empirical abundance patterns across an altitudinal gradient and predicted altitudinal range shifts to estimate change in total population size relative to distribution area in response to climate warming. Adopting this approach we predict that, for nine out of 12 species of regionally endemic birds, total population size will decline more rapidly than distribution area with increasing temperature. Two species showed comparable loss and one species exhibited a slower decline in population size with change in distribution area. Population size change relative to distribution area was greatest for those species that occurred at highest density in the middle of the gradient. The disproportional loss in population size reported here suggests that extinction risk associated with climate change can be more severe than that expected from decline in distribution area alone. Therefore, if we are to make accurate predictions of the impacts of climate change on the conservation status of individual species, it is crucial that we consider the spatial patterns of abundance within the distribution and not just the overall range of the species.
A test of Brown's principle in the intertidal limpet Collisella scabra (Gould, 1846)
Authors: Gilman Sarah
Published: August 2005

Aim  Brown's principle predicts that a species will peak in density near its range centre, and decline gradually towards the margins of its geographical distribution. The decline is assumed to reflect a decrease in individual performance near range margins. I test this abundance–performance hypothesis by comparing patterns in density and size across the northern half of the geographical distribution of the marine patellogastropod Collisella scabra (Gould, 1846).

Location  Collisella scabra is a high intertidal patellogastropod species distributed along the Pacific coast of North America from Cape Mendocino (CA, USA) to southern Baja California (Mexico). I surveyed 11 research sites spanning c. 36–44° N.

Methods  In each of the 11 research sites I surveyed four distinct microhabitats, and compared spatial patterns in density and in the size of solitary limpets.

Results  Both density and size were highly variable across the species range. Density peaked near the northern range margin, and showed greater variance at small spatial scales (< 10 km) than at large scales (> 100 km). In contrast, large size occurred uniformly across the survey area, and size was strongly associated with microhabitat.

Main conclusion  Collisella scabra does not show spatial patterns of density or performance that are consistent with Brown's principle. The underlying assumptions of Brown's principle may conflict with specific characteristics of C. scabra's life history and/or patterns of environmental variation across its range. Because such conflicts may be common in a large number of marine and terrestrial species, the generality of Brown's principle is questioned.
Zoogeography of the shallow‐water holothuroids of the western Indian Ocean
Authors: Samyn Yves , Tallon Irena
Published: August 2005

Aim  To analyse the zoogeography of the shallow‐water holothuroids of the western Indian Ocean (WIO). Based on this analysis we ask to what extent differences in species’ ability to disperse across potential barriers provide an explanation for holothuroid zoogeography.

Location  Shallow‐waters (50 m isobaths) of the WIO, extending from Suez to Cape Town and from the coastline of East Africa upward to 65° E.

Methods  Data for the analysis were obtained from Samyn's (2003) monograph on the shallow‐water sea cucumbers of the WIO. A species presence/absence matrix with a resolution of 1° latitude/longitude was constructed. These cells were assigned to eight coarser operational geographical units, which were delimited on the basis of published faunistic and geological borders. The analytical zoogeographical methods employed were cluster analysis on several β‐diversity coefficients and parsimony analyses of endemicity. The influence of life‐history strategies on the distribution pattern was analysed through examination of latitudinal and longitudinal gradients, and by plotting cumulative curves for species number against range size.

Results  The shallow‐water holothuroid fauna of the WIO can be split into several biogeographical units. To the north, we found evidence that the northern Red Sea holothuroid fauna differs from that of the southern Red Sea. The latter has closest affinity with south‐east Arabia and the Persian Gulf, and thus the biogeographical barrier of Bab‐el‐Mandab nowadays seems to be of minor importance. The cold upwelling at the east coast of Somalia forms an effective barrier for holothuroids and especially those with lecitothrophic (short‐lived) larvae. Even though the circumtropical biogeographical pattern is not well resolved, important taxonomic turnovers suggest that it is composed of several distinct subprovinces. Taxonomic turnover is at least partially dictated by the dispersion capacity of the different orders.

Main conclusions  This study concludes that the WIO is best split into at least three biogeographical realms: (1) the Red Sea and associated Arab Basin, (2) the asymmetrical circumtropical region stretching from the horn of Africa to southern Mozambique, and (3) southern Africa. Conspicuous differences in dispersal abilities of the three dominant orders are identified. The biogeography of the WIO is best explained by: (1) species’ dispersion ability, (2) the prevalent current patterns, and (3) to a lesser, geographically limited extent, recent geological history. As a serendipitous discovery, we found that Rapoport's rule does not hold in the WIO.
Metformin improves endothelial function in patients with metabolic syndrome
Authors: VITALE C. , MERCURO G. , CORNOLDI A. , FINI M. , VOLTERRANI M. , ROSANO G. M. C.
Published: August 2005

Background.  Metabolic Syndrome (MS) is associated with impaired endothelial function and increased cardiovascular risk. Insulin resistance is a key feature of MS and plays an important role in the pathogenesis of endothelial dysfunction. Aim of the present study was to evaluate the effect of metformin on endothelial function and insulin resistance, assessed by the homeostasis model (HOMA‐IR, homeostasis model assessment‐insulin resistance), in patients with MS.

Methods.  Sixty‐five subjects (37 men and 28 women, mean age 54 ± 6 years) with MS were allocated to receive metformin 500 mg twice daily (n = 32) or placebo (n = 33) for 3 months. Before and after treatment we assessed endothelial function, using flow‐mediated dilatation of the brachial artery, and HOMA‐IR.

Results.  Patients who received metformin demonstrated statistically significant improvement in endothelium‐dependent vasodilation compared with those treated with placebo (from 7.4 ± 2.1% to 12.4 ± 1.9% vs. 7.3 ± 2.5% to 6.9 ± 2.7%, P = 0.0016, metformin vs. placebo respectively), without significant effect on endothelium‐independent response to sublingual glyceryl trinitrate (P =0.32). Metformin improved insulin resistance compared with placebo group (HOMA‐IR from 3.39 to 2.5 vs. 3.42 to 3.37; 26% reduction in HOMA‐IR, P = 0.01). An association between the improvement in insulin resistance and the improvement in endothelial function (r = −0.58, P = 0.0016) was found.

Conclusion.  Metformin improves both endothelial function and insulin resistance in patients with MS. These findings support the central role of insulin resistance in the development of endothelial dysfunction and the role of metformin for the treatment of patients with MS.
Organization of supercoil domains and their reorganization by transcription
Authors: Deng Shuang , Stein Richard A. , Higgins N. Patrick
Published: August 2005

During a normal cell cycle, chromosomes are exposed to many biochemical reactions that require specific types of DNA movement. Separation forces move replicated chromosomes into separate sister cell compartments during cell division, and the contemporaneous acts of DNA replication, RNA transcription and cotranscriptional translation of membrane proteins cause specific regions of DNA to twist, writhe and expand or contract. Recent experiments indicate that a dynamic and stochastic mechanism creates supercoil DNA domains soon after DNA replication. Domain structure is subsequently reorganized by RNA transcription. Examples of transcription‐dependent chromosome remodelling are also emerging from eukaryotic cell systems.
The influence of maternal age on very preterm birth of twins: differential effects by parity
Authors: Branum Amy M. , Schoendorf Kenneth C.
Published: August 2005

For singleton births, parity can modify the effect of maternal age on birth outcomes such as low birthweight and preterm birth; however, it is unknown whether this relationship exists for twin births. As the rate of twin births increases among older women, it is important to understand how parity may influence the relationship between maternal age and adverse birth outcomes. The NCHS Matched Multiple Birth Data Set, which contains all twin births in the USA from 1995 to 1998, was analysed. Parity was grouped into two levels (primiparous – no prior live births, and multiparous – at least one prior live birth), and maternal age was divided into the following groups: 20–24, 25–29, 30–34, 35–39, and 40 years or more. Very preterm birth was defined as births occurring before 33 weeks. Logistic regression was used to obtain odds ratios (OR) to estimate the risk of very preterm birth, and to determine the relationships between parity, maternal age, and very preterm birth. Among primiparae, women 40 years and older had a reduced risk of very preterm birth compared with women of 25–29 years (OR 0.74 [95% CI = 0.66, 0.84]). Among multiparae, women 40 years and older had the same risk of very preterm birth compared with women of 25–29 years (OR 1.00 [95% CI = 0.90, 1.12]). However, stratification by education revealed that the age gradient was limited to women with > 12 years education among primiparae.

The effect of maternal age on very preterm birth of twins differs according to parity. To some extent, that effect is further modified by education. Therefore, future analyses of maternal age and twin birth outcomes should account for measures of obstetric history and other factors, which may influence these results.
Haemocytes of larval Malacosoma disstria (Lepidoptera: Lasiocampidae) and factors affecting their adhesion to glass slides
Authors: Giannoulis Paschalis , Brooks Cory L. , Gulii Vladislav , Dunphy Gary B.
Published: August 2005

Abstract.  Although haemocytes of the forest pest lepidopteran, Malacosoma disstria (L.) have been studied, the physico‐chemical factors and signalling components affecting their non‐self activities have not been examined. Both the ameboid and stellate forms of plasmatocytes and the granular cells from fifth‐instar larvae adhere best to glass slides with phosphate‐buffered saline (PBS), with maximum granular cell binding within a pH range of 6.0–7.0 and plasmatocyte binding at pH 6.0. The divalent cations, calcium and magnesium, do not affect granular cell attachment. However, calcium in Galleria‐anticoagulant and PBS and, to a lesser extent, magnesium in the anticoagulant, increase plasmatocyte‐glass contact. Based upon the use of selective type I protein kinase A inhibitor (Rp‐8‐Br‐cAMPS) and activator (Sp‐8‐Br‐cAMPS), active protein kinase A inhibits the adhesion of both haemocyte types. Similarly, protein kinase C inhibited by Gö 6976 enhances haemocyte adhesion whereas the enzyme activator, phorbol‐myristate‐acetate, impairs attachment.
An analysis of uterine activity in spontaneous labour using a microcomputer
Authors: FAIRLIE F. M. , PHILLIPS G. F. , ANDREWS B. J. , CALDER A. A.
Published: August 2005

Summary. A microcomputer was used to analyse uterine activity during spontaneous labour in 30 nulliparous and 30 parous patients. The intrauterine mean active pressure (MAP) in the nulliparous group was 1·51 kPa (SD 0·45) in the first stage and 2·71 kPa (SD 0·77) in the second stage. For the parous group, the MAP in the first stage was 1·22 kPa (SD 0·37) and in the second stage was 2·92 kPa (SD 0·98). A significant parity difference in MAP and contraction frequency was observed in the first stage but not in the second stage. Epidural analgesia did not appear to influence uterine activity in the first stage but was associated with a lower MAP, contraction frequency and intensity in the second stage. During the first stage, MAP increased by 21% in nulliparas and by 39% in multiparas. The rise in MAP was mainly due to an increase in contraction frequency.
Fetal heart rate monitoring by telephone. I. Development of an integrated system in Cardiff
Authors: DAWSON ANDREW J. , MIDDLEMISS CHARLETTE , JONES EILEEN M. , GOUGH NIGEL A. J.
Published: August 2005

Summary. We report the development of a practical dedicated system for domiciliary fetal monitoring integrated in a scheme for its rational application. From experience of 1120 domiciliary recordings in 74 women (64 with high‐risk pregnancies), we suggest that domiciliary monitoring applied within a structured clinical context should be as safe as monitoring in hospital.