bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of B6RV2 Leukemia Growth by Immunization with Purified Unique Antigen
Authors: Uenaka Akiko , Nakayama Eiichi
Published: September 2010

Monoclonal antibody (mAb) NU7‐99 reacted with only B6RV2 cells, not with 28 other leukemia cell lines, fibroblasts or normal tissues. Biochemical analyses of the unique antigen on B6RV2 cells that reacted with NU7–99 mAb indicated its relationship to xenotropic murine leukemia virus gp70. The antigen that reacted with NU7‐99 mAb was extracted from the surface of B6RV2 cells with n‐butanol and purified by ion‐exchange chromatography and affinity chromatography. Growth of B6RV2 tumors in semi‐syngeneic mice was inhibited by immunization of the mice with a purified preparation of this unique antigen.
Suppression of Diethylnitrosamine‐initiated Preneoplastic Foci Development in the Rat Liver by Combined Administration of Four Antioxidants at Low Doses
Authors: Hasegawa Ryohei , Tiwawech Danai , Hirose Masao , Takaba Katsumi , Hoshiya Toru , Shirai Tomoyuki , Ito Nobuyuki
Published: September 2010

Potential synergism between 4 antioxidants acting at low doses on development of glutathione S‐transferase placental form (GST‐P)‐positive liver cell foci was examined in male rats initially given diethylnitrosamine (200 mg/kg, i.p.). Beginning 2 weeks after the initiation, rats received the antioxidants, individually or in combination, in the diet for 6 weeks. All rats were subjected to two‐thirds partial hepatectomy at week 3 and killed at week 8. The numbers and areas of GST‐P‐positive foci were significantly decreased by single treatment with butylated hydroxyanisole (BHA, 1%), tert‐butylhydroquinone (TBHQ, 1%) and catechol (0.8%), but not with sesamol (0.5%). Combined treatments (BHA+TBHQ, catechol + sesamol, or all 4 chemicals) at a quarter of the above dose levels resulted in decrease in numbers and areas of foci to levels less than the sums of individual inhibition data obtained with the one‐quarter levels. Although these combined effects were not statistically significant in the additive model, the results indicate possible synergistic suppression of carcinogenesis by low‐dose combined treatment with anti‐cancer agents and the usefulness of the present protocol for this type of analysis.
Impaired Long‐term T Cell Immunity to Epstein‐Barr Virus in Patients with Nasopharyngeal Carcinoma
Authors: Tamura Shinji , Yamazaki Atsushi , Kunimoto Masaru , Takemura Kiyoshi , Tabata Toshihide , Hinuma Yorio , Yoshie Osamu
Published: September 2010

The long‐term T cell immunity to Epstein‐Barr virus (EBV) is considered to play an important role in suppressing proliferation of EBV‐infected B cells and outgrowth of EBV‐associated tumors. It can be manifested and quantified by the EBV‐induced focus regression assay. In the present study, we examined the strength of T cell immunity to EBV in patients with nasopharyngeal carcinoma (NPC) and other cancers originating from the head and neck region. In contrast to patients with other types of cancers, including EBV‐negative NPC, patients with EBV‐positive NPC were found to have a profound impairment in the long‐term T cell immunity to EBV.
Inhibition of Human Immunodeficiency Virus‐1 Infection by Human Conglutinin‐like Protein: In vitro Studies
Authors: Ushijima Hiroshi , Schröder Heinz C. , Poznanovic Slobodan , Gasić Miroslav J. , Matthes Eckart , Müller Werner E. G.
Published: September 2010

The lectin‐like protein analogous to bovine conglutinin was purified from human serum. The carbohydrate‐binding ability of conglutinin‐like protein was inhibited by D‐mannose, N‐acetylglucosamine and L‐fucose as well as by mannan‐containing oligosaccharides. By applying a lectin‐based ELISA system it was demonstrated that conglutinin‐like protein binds to human immunodeficiency virus‐1 (HIV‐1) glycoprotein 120 (gpl20) via its carbohydrate binding site. In vitro experiments with T‐lymphoblastoid CEM cells revealed that conglutinin‐like protein abolishes infection by HIV‐1; a 50% cytoprotective concentration of 23.9 μg/ml was measured. These findings demonstrate that human conglutinin‐like protein binds to HIV‐gp120 and inhibits, under the described in vitro conditions, CEM cell infection.
Phenotypic and Genotypic Lineage Switch of a Lymphoma with Shared Chromosome Translocation and T‐Cell Receptor γ Gene Rearrangement
Authors: Yamamoto Kazuhito , Osada Hirotaka , Seto Masao , Ogura Michinori , Suzuki Hisamitsu , Utsumi Kazuhiko R. , Oyama Atsushi , Ariyoshi Yutaka , Nakamura Shigeo , Kurita Souji , Takahashi Toshitada , Ueda Ryuzo
Published: September 2010

A case of non‐Hodgkin's lymphoma showed a phenotypic and genotypic cell lineage switch twice during nine years of his clinical history; first, T‐cell type, pleomorphic small cell lymphoma developed, followed by B‐cell type, diffuse centroblastic/centrocytic lymphoma, and finally T‐zone lymphoma without follicles again developed, from which AST‐1 cultured cell line was established. Karyotype analysis demonstrated a shared abnormal chromosome, der(1)t(1;?)(p36;?), among the first relapsed B‐cell tumor, the second relapsed T‐cell tumor and AST‐1 cell line. Furthermore, T‐cell receptor (TCR) γ gene rearrangement bands of the same size were observed in the first relapsed B‐cell tumor and the second relapsed T‐cell tumor as well as AST‐1 cell line. These results suggested that both relapsed tumors of different cell lineages are derived from a common malignant clone, presumably a committed lymphoid stem cell. A unique translocation, t(2;14)(q37;q11.2), which may involve TCR δ/α gene complex, was observed in the second relapsed tumor and AST‐1 cells. To attempt to isolate the breakpoint of this translocation, the configuration of TCR δ/α gene complex was studied. The result showed that two rearrangements of TCR α gene detected with Jα probes were the products of the normal TCR rearrangement process, and were not involved in the translocation at this region. This patient, together with the AST‐1 cell line, provided us a unique opportunity to study the development and clonal evolution of malignant lymphoma.
Kinetic Analysis of Combination Effect of Navelbine (KW‐2307) with Cisplatin against Human Lung Adenocarcinoma PC‐12 Cells in Culture
Authors: Gomi Katsushige , Ohno Hiroe , Nomura Kayo , Okabe Masami , Kobayashi Kunihiko , Niitani Hisanobu
Published: September 2010

The combination effect of navelbine (NVB, KW‐2307), a newly synthesized vinca alkaloid, and cisplatin (CDDP) was compared with that of vindesine (VDS) and CDDP using human lung adenocarcinoma PC‐12 cells. The growth‐inhibitory activity of NVB or VDS was time‐dependent, whereas that of CDDP was AUC (area under the curve)‐dependent. When NVB or VDS was used in combination with CDDP simultaneously for 24 h, antagonism was observed in terms of growth‐inhibitory activity. However, additive combination effect was observed when NVB or VDS treatment was followed by CDDP treatment. On this treatment schedule, a synergistic combination effect was observed in terms of the cell‐killing activity assessed by colony formation assay. The growth‐inhibitory activity of NVB or VDS was detected 24 h after the treatment, whereas that of CDDP became significant 72 h after the treatment. NVB and VDS caused cell accumulation in G2M phase at 10 times their IC80 values, and cells with less than diploid DNA content were detected after 24 h at IC80. CDDP caused accumulation of cells in S phase, and the effect became detectable 16 h after the treatment. The DNA histogram of cells treated with NVB or VDS in combination with CDDP was a superposition of those of cells treated with each drug alone. Significant differences in the characteristics of anticellular activity were not detected between NVB and VDS, although NVB inhibited cell growth at a slightly lower concentration than VDS at the short exposure time of 1–8 h.
Mechanism of Synergistic Cytotoxic Effect between Tumor Necrosis Factor and Hyperthermia
Authors: Yamauchi Naofumi , Watanabe Naoki , Maeda Masahiro , Okamoto Tetsuro , Sasaki Hiroyoshi , Tsuji Naoki , Tsuji Yasushi , Umeno Hiroshi , Akiyama Shinichiro , Niitsu Yoshiro
Published: September 2010

We previously reported that recombinant human tumor necrosis factor (rhTNF) and hyperthermia had a synergistic effect against tumors, in vitro and in vivo. We have now investigated the mechanism of this synergy by measuring the lysosomal enzyme activity and hydroxyl radical production of L‐M cells treated with rhTNF and/or hyperthermia. A synergistic activation of lysosomal enzyme and the induction of hydroxyl radical production in L‐M cells treated with both rhTNF and hyperthermia was observed. A synergistic cytotoxic effect was observed when rhTNF and hyperthermia were combined, and was inhibited by the addition of a reactive oxygen scavenger, dimethyl sulfoxide or bipyridine. The results show that the augmenting effect of hyperthermia on lysosomal enzyme activation and induction of hydroxyl radical production by rhTNF plays an important role in the synergistic cytotoxic effect.
Strain Difference of Susceptibility to 4‐Nitroquinoline 1‐Oxide‐induced Tongue Carcinoma in Rats
Authors: Kitano Motoo , Hatano Hiromichi , Shisa Hayase
Published: September 2010

Strain difference of susceptibility to 4‐nitroquinoline 1‐oxide (4NQO)‐induced squamous cell carcinomas of the tongue among Dark‐Agouti, Long‐Evans, Sprague‐Dawley, ACI/Ms, Fischer 344, Donryu and Wistar/Furth rats was surveyed by evaluating the survival times, incidences and sizes of developed tumors as markers of susceptibility. Administration of 4NQO dissolved in drinking water induced squamous cell carcinomas in various sites of the upper digestive tract mucosa of all the experimental male and female rats of the seven strains. Regarding the mean survival times, Wistar/Furth rats survived much longer than any other strain of rats, and Dark‐Agouti showed the shortest survival. The incidence of large, mass‐type carcinomas of the tongue of Dark‐Agouti rats was higher than in any other strain of rats, while that of Wistar/Furth rats was the lowest. Subsequently the mitotic activity and bromodeoxyuridine incorporation in the tongue epithelium of Dark‐Agouti and Wistar/Furth rats were estimated after a short‐term administration of 4NQO. There was a pronounced difference between the two strains of rats, because the proliferative responses of the tongue epithelium of Dark‐Agouti rats to the 4NQO stimulation were much higher than those of Wistar/Furth rats. These results indicated that there are marked differences in the susceptibility to 4NQO‐induced tongue carcinoma among the seven strains of rats, and that Dark‐Agouti and Wistar/Furth rats could be useful as models of highly and poorly susceptible strains, respectively, for further genetic analysis.
Non‐transformed, but not ras/myc‐transformed, Serum‐free Mouse Embryo Cells Recover from Growth Suppression by Azatyrosine
Authors: Nomura Takahiro , Ryoyama Kazuo , Okada Gensaku , Matano Sadaya , Nakamura Shinobu , Kameyama Tadanori
Published: September 2010

The anti‐proliferative effect of azatyrosine, a newly discovered antibiotic from Streptomyces, was examined in Balb/c‐originated serum‐free mouse embryo (SFME) cells and transformed ras/myc SFME cells which have activated human c‐Ha‐ras genes. Azatyrosine suppressed their growth in a concentration‐dependent manner. Growth suppression in both cells was detectable within 2 days after culture with 250 μg/ml azatyrosine. Non‐transformed SFME cells, however, regained rapid growth after 6 days even in the presence of azatyrosine, whereas ras/myc SFME cells did not recover from the suppression. Despite the growth inhibition of ras/myc SFME cells, expression of human ras in the cells was not inhibited by azatyrosine. Meanwhile, SFME cells have the ability to express glial fibrillary acidic protein (GFAP). This expression is induced by serum‐supplemented medium, though the serum inhibits the growth of SFME cells. Azatyrosine did not induce GFAP in ras/myc SFME cells, but inhibited growth. Furthermore, azatyrosine did not induce GFAP in SFME cells, and had no effect upon the expression of GFAP induced by serum in these cells. These results suggest that azatyrosine inhibited the growth of ras/myc SFME cells through a mechanism independent of those involved in growth inhibition and induction of GFAP expression by serum in SFME cells.
High Susceptibility to Lung Cancer Analyzed in Terms of Combined Genotypes of P450IA1 and Mu‐class Glutathione S‐Transferase Genes
Authors: Hayashi Shinichi , Watanabe Junko , Kawajiri Kaname
Published: September 2010

Lung cancer is closely associated with cigarette smoking. Aromatic hydrocarbons in smoke, including benzo[n]pyrene, first require metabolic activation by Phase I enzymes, cytochrome P450, to their ultimate forms, and these activated forms are then subjected to detoxification by Phase II enzymes, especially glutathione S‐transferases. Thus, genetically determined susceptibility to lung cancer may depend on the metabolic balance between Phase I and Phase II enzymes. In this study, we identified individuals genetically at high risk of lung cancer in terms of polymorphisms of the P450IA1 gene and GST1 gene. The relative risk of individuals with a combination of the genotypes of both a homozygous rare allele of the P450IA1 gene and the nulled GST1 gene was remarkably high at 5.8 for lung cancer and 9.1 for squamous cell carcinoma compared with other combinations of genotypes.
Production of Human Immunoglobulin G Reactive against Human Cancer in Tumor‐bearing Mice with Severe Combined Immunodeficiency Reconstituted with Human Splenic Tissues
Authors: Furukawa Toshiharu , Watanabe Masahiko , Kubota Tetsuro , Yamaguchi Hiroshi , Teramoto Tatsuo , Ishibiki Kyuya , Kitajima Masaki
Published: September 2010

Splenic tissues derived from patients with gastric cancer were implanted into mice with severe combined immunodeficiency (SCID) and then the mice were challenged with COLO‐20S, a human colon cancer cell line. Production of human immunoglobulin G (IgG) reactive against the COLO‐205 cells was detected by enzyme‐linked immunosorbent assay in sera from the reconstituted and tumor‐bearing SCID mice. The titers of the reactive IgG relative to total IgG in the sera of SCID mice began to increase from one week after implantation of the tumor cells, and became 10‐ to 100‐fold higher than that in the donor's serum by 3–4 weeks. This model using implantation of human cancer cells in SCID mice reconstituted with human splenic tissues would facilitate further studies of human cancer immunology.
Potentiation of 1‐(2‐Chloroethyl)‐3‐cyclohexyl‐1‐nitrosourea's Toxicity in vitro by Two New Bioreductive Agents
Authors: Papadopoulou Maria V. , Mainwaring Anne , Bloomer William D.
Published: September 2010

Two new bioreductive compounds, 9‐[3‐(2‐nitro‐1‐imidazolyl)propylamino]acridine hydrochloride (NLA‐1) and 9‐[2‐(2‐nitro‐1‐imidazolyl)ethylamino]acridine hydrochloride (NLA‐2), which behave as hypoxic cytotoxins and radiosensitizers, have been investigated for potentiation of 1‐(2‐chloroethyl)‐3‐cyclohexyl‐1‐nitrosourea's (CCNU) cytotoxic activity in vitro using V‐79 cells. The preincubation effect as well as conditions of coadministration of CCNU with each sensitizer have been examined. In this latter case, the median‐effect analysis was applied to evaluate whether the phenomenon was additive or synergistic. A clonogenic assay was used to score survival. Both bioreductive compounds, even at very low concentrations, significantly enhance the cytotoxic activity of CCNU under conditions of hypoxic preincubation. The enhancement of CCNU cytotoxicity is dependent upon preincubation time and the concentrations of both CCNU and the specific bioreductive agent. Coincubation of cells under hypoxia with CCNU and each bioreductive agent led to some potentiation, but only at lower survival levels. No chemosensitization was observed under aerobic conditions with either sensitizer.
Development of invasive follicular cell carcinomas in a rat thyroid carcinogenesis model: Biological impact of capsular inflammation and reduced cyclooxygenase‐2 expression
Authors: Imai Toshio , Hasumura Mai , Onose Jun‐ichi , Ueda Makoto , Takizawa Tamotsu , Cho Young‐Man , Hirose Masao
Published: September 2010

We have previously reported that thyroid capsular inflammation induced by sulfadimethoxine (SDM), a goitrogen, might play a role in development of invasive follicular cell adenocarcinomas in rats initiated with N‐bis(2‐hydroxypropyl)nitrosamine (DHPN). The present study was designed to examine the role of cyclooxygenase (COX)‐2, widely known to be up‐regulated in inflammatory states, during chemically induced rat thyroid carcinogenesis. Male F344 rats received a subcutaneous DHPN (2800 mg/kg) injection, and 1 week later were allowed free access to drinking water containing antithyroidal propylthiouracil (PTU, 0.003%) or SDM (0.1%) for 4 or 10 weeks. Control groups receiving goitrogen alone and no treatment were also included. At week 4, diffuse follicular cell hyperplasia was induced in all PTU‐ and SDM‐treated groups, along with fibrous capsular thickening and capsular thickening with inflammation, respectively. Additionally, multiple focal follicular cell hyperplasias and adenomas were observed in the DHPN + PTU and DHPN + SDM cases. At week 10, adenocarcinomas invasive to the capsule and restricted to the capsular adjacent region, were frequent in the DHPN + SDM group, but not observed in the animals given DHPN + PTU. Western blots and immunohistochemistry revealed constitutive COX‐2 expression in non‐neoplastic follicular cells of the control and all of the PTU‐ and SDM‐treated rats. However, COX‐2 reactivity was significantly reduced or negative in the preneoplastic/neoplastic lesions in the DHPN‐treated groups. In fibrous or inflamed thickened capsules, only a few component cells with inflammatory elements were positive for COX‐2, and there was no significant difference in this regard between the PTU and SDM treatments. The present results suggest that capsular inflammation could play a role in development of invasive carcinomas, but COX‐2 expression does not make a major contribution. (Cancer Sci 2005; 96: 31–38)
Primary malignant lymphoma of the brain: Frequent abnormalities and inactivation of p14 tumor suppressor gene
Authors: Zhang Shu‐Jing , Endo Sumio , Saito Takafumi , Kouno Mitsuo , Kuroiwa Toshihiko , Washiyama Kazuo , Kumanishi Toshiro
Published: September 2010

Ten primary central nervous system lymphomas (PCNSL, brain lymphomas) were examined for p14 gene exon 1β deletion, mutation and methylation by Southern blot analysis, nucleotide analysis of polymerase chain reaction clones and Southern blot‐based methylation assay. In Southern blot analysis, from the signal densities of the hybridized bands and their similarities to those of exons 2 and 3 in our previous quantitative study, we found that exon 1β was homozygously deleted in four cases, hemizygously deleted in five cases and not deleted in one case. Thus, the same deletion patterns covered the entire p14 gene for all cases except for one case, which suggested the hemizygous deletion of exons 1β and 2 and homozygous deletion of exon 3. In addition, although exon 1β mutation is rare in various tumors, we detected a missense mutation (L50R) in one case with a hemizygous deletion. Methylation of the 5′CpG island of the p14 gene was not suggested for any case without homozygous deletion. Our observation of frequent p14 gene abnormalities (90%) and inactivation (40–60%) was in striking contrast to the same pathological subtype of systemic lymphoma in which p14 gene abnormalities and inactivation were infrequent, suggesting a difference in carcinogenesis between PCNSL and systemic lymphoma. (Cancer Sci 2005; 96: 38 –41)
Possible enhancing effects of atrazine on growth of 7,12‐dimethylbenz(a) anthracene‐induced mammary tumors in ovariectomized Sprague–Dawley rats
Authors: Ueda Makoto , Imai Toshio , Takizawa Tamotsu , Onodera Hiroshi , Mitsumori Kunitoshi , Matsui Takane , Hirose Masao
Published: September 2010

Atrazine, one of the most commonly used herbicides in the world, has been reported to have endocrine disrupting effects in vivo. In the present experiment, influence of dietary atrazine on the late promotion/progression stage of mammary carcinogenesis in ovariectomized female Sprague–Dawley rats was examined after a single intragastric administration of 7,12‐dimethylbenz(a)anthracene (DMBA). When the incidence of palpable mammary tumors reached about 50%, the animals were subjected to ovariectomy and divided into tumor bearing [DMBA‐Tumor(+)] and non‐tumor bearing [DMBA‐Tumor(–)] groups, with subgroups of each fed a soybean‐free diet containing 0, 5, 50, or 500 p.p.m. atrazine for 34 weeks. At the completion of the study, the tumor volume in the 50 and 500 p.p.m. treatment Tumor(+) subgroups was greater than in the 0 p.p.m. control case. In the DMBA‐Tumor(–) group, higher incidences and volumes of the mammary tumors, with or without statistical significance (P < 0.05), were observed in the 50 and 500 p.p.m. subgroups. Atrazine treatment tended to increase proportion of estrogen receptor α‐positive tumors and stimulated cell proliferation in the DMBA‐Tumor(+) group, but with no clear effects on serum hormone levels. The present study indicates that atrazine has a potential for enhancing the growth of mammary tumors, partly through increasing cell proliferation in the promotion/progression stage in female rats under ovarian hormone‐free conditions. (Cancer Sci 2005; 96: 19 –25)
Impact of menstrual and reproductive factors on breast cancer risk in Japan: Results of the JACC study
Authors: Tamakoshi Koji , Yatsuya Hiroshi , Wakai Kenji , Suzuki Sadao , Nishio Kazuko , Lin Yingsong , Niwa Yoshimitsu , Kondo Takaaki , Yamamoto Akio , Tokudome Shinkan , Toyoshima Hideaki , Tamakoshi Akiko ,   for the JACC Study Group
Published: September 2010

The incidence of breast cancer among Japanese women, a traditionally low‐risk population, has increased substantially. To evaluate the association of reproductive factors with breast cancer risk, we examined 38 159 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. During an average 7.6 years of follow‐up, we documented 151 incidents of breast cancers. Cox proportional hazards modeling was employed to estimate relative risks (RR) and 95% confidence intervals (CI). There was a significant decline in the risk of breast cancer with increasing parity among parous women (trend P = 0.01). Women with four or more parities had a 69% lower risk than uniparous women, a reduced risk was also evident among menopausal women. Breast cancer risk tended to rise with increasing age at first delivery (trend P = 0.05), the association being very apparent among menopausal women (trend P = 0.02). Compared to the women who had their first delivery before age 25, those who delayed this event until after age 34 had an RR of 2.12 (95% CI: 0.72–6.21) and 3.33 (1.07–10.3) among the overall subjects and the menopausal, respectively. There was no apparent association of breast cancer risk with age at menarche or menopause. Our study concerning reproductive risk factors suggests that breast cancer in Japan is similar to that in Western countries, and that reproductive factors, particularly the number of parity and age at first delivery, might be important in the etiology of breast cancer among Japanese women. (Cancer Sci 2005; 96: 57–63)
Inhibition of peroxisome proliferator‐activated receptor γ activity suppresses pancreatic cancer cell motility
Authors: Nakajima Atsushi , Tomimoto Ayako , Fujita Koji , Sugiyama Michiko , Takahashi Hirokazu , Ikeda Ikuko , Hosono Kunihiro , Endo Hiroki , Yoneda Kyoko , Iida Hiroshi , Inamori Masahiko , Kubota Kensuke , Saito Satoru , Nakajima Noriko , Wada Koichiro , Nagashima Yoji , Nakagama Hitoshi
Published: September 2010

Peroxisome proliferator‐activated receptor γ (PPARγ) is a ligand‐activated transcription factor that has been implicated in the carcinogenesis and progression of various solid tumors, including pancreatic carcinomas. We aimed to clarify the role of this receptor in pancreatic cell motility in vitro and in metastasis in vivo. Cell motility was examined by assaying transwell migration and wound filling in Capan‐1 and Panc‐1 pancreatic cancer cells, with or without the PPARγ‐specific inhibitor T0070907. A severe combined immunodeficiency xenograft metastasis model was used to examine the in vivo effect of PPARγ inhibition on pancreatic cancer metastasis. In both transwell‐migration and wound‐filling assays, inhibition of PPARγ activity suppressed pancreatic cell motility without affecting in vitro cell proliferation. Inhibition of PPARγ also suppressed liver metastasis in vivo in metastatic mice. In PPARγ‐inhibited cells, p120 catenin accumulation was induced predominantly in cell membranes, and the Ras‐homologous GTPases Rac1 and Cdc42 were inactive. Inhibition of PPARγ in pancreatic cancer cells decreased cell motility by altering p120ctn localization and by suppressing the activity of the Ras‐homologous GTPases Rac1 and Cdc42. Based on these findings, PPARγ could function as a novel target for the therapeutic control of cancer cell invasion or metastasis. (Cancer Sci 2008; 99: 1892–1900)
Cancer stem cells and chemoradiation resistance
Authors: Ishii Hideshi , Iwatsuki Masaaki , Ieta Keisuke , Ohta Daisuke , Haraguchi Naotsugu , Mimori Koshi , Mori Masaki
Published: September 2010

Cancer is a disease of genetic and epigenetic alterations, which are emphasized as the central mechanisms of tumor progression in the multistepwise model. Discovery of rare subpopulations of cancer stem cells (CSCs) has created a new focus in cancer research. The heterogeneity of tumors can be explained with the help of CSCs supported by antiapoptotic signaling. CSCs mimic normal adult stem cells by demonstrating resistance to toxic injuries and chemoradiation therapy. Moreover, they might be responsible for tumor relapse following apparent beneficial treatments. Compared with hematopoietic malignancies, conventional therapy regimes in solid tumors have improved the overall survival marginally, illustrating the profound impact of treatment resistance. This implies that the present therapies, which follow total elimination of rapidly dividing and differentiated tumor cells, need to be modified to target CSCs that repopulate the tumor. In this review article, we report on recent findings regarding the involvement of CSCs in chemoradiation resistance and provide new insights into their therapeutic implications in cancer. (Cancer Sci 2008; 99: 1871–1877)
Cross‐sectional analysis of germline BRCA1 and BRCA2 mutations in Japanese patients suspected to have hereditary breast/ovarian cancer
Authors: Sugano Kokichi , Nakamura Seigo , Ando Jiro , Takayama Shin , Kamata Hiroyuki , Sekiguchi Isao , Ubukata Megumi , Kodama Tetsuro , Arai Masami , Kasumi Fujio , Hirai Yasuo , Ikeda Tadashi , Jinno Hiromitsu , Kitajima Masaki , Aoki Daisuke , Hirasawa Akira , Takeda Yuko , Yazaki Kumiko , Fukutomi Takashi , Kinoshita Takayuki , Tsunematsu Ryuichiro , Yoshida Teruhiko , Izumi Masako , Umezawa Shino , Yagata Hiroshi , Komatsu Hiroko , Arimori Naoko , Matoba Noriko , Gondo Nobuhisa , Yokoyama Shiro , Miki Yoshio
Published: September 2010

The prevalence of BRCA1/2 germline mutations in Japanese patients suspected to have hereditary breast/ovarian cancer was examined by a multi‐institutional study, aiming at the clinical application of total sequencing analysis and validation of assay sensitivity in Japanese people using a cross‐sectional approach based on genetic factors estimated from personal and family histories. One hundred and thirty‐five subjects were referred to the genetic counseling clinics and enrolled in the study. Full sequencing analysis of the BRCA1/2 gene showed 28 types of deleterious mutations in 36 subjects (26.7%), including 13 types of BRCA1 mutations in 17 subjects (12.6%) and 15 types of BRCA2 mutations in 19 subjects (14.1%). Subjects were classified into five groups and 22 subgroups according to their personal and family history of breast and/or ovarian cancer, and the prevalence of deleterious mutations was compared with previously reported data in non‐Ashkenazi individuals. Statistical analysis using the Mantel‐Haenszel test for groups I through IV revealed that the prevalence of Japanese subjects was significantly higher than that of non‐Ashkenazi individuals (P = 0.005, odds ratio 1.87, 95% confidence interval 1.22–2.88). Family history of the probands suffering from breast cancer indicated risk factors for the presence of deleterious mutations of BRCA1/2 as follows: (1) families with breast cancer before age 40 within second degree relatives (P = 0.0265, odds ratio 2.833, 95% confidence interval 1.165–7.136) and (2) families with bilateral breast cancer and/or ovarian cancer within second degree relatives (P = 0.0151, odds ratio 2.88, 95% confidence interval 1.25–6.64). (Cancer Sci 2008; 99: 1967–1976)
Optimal amount of monocyte chemoattractant protein‐1 enhances antitumor effects of suicide gene therapy against hepatocellular carcinoma by M1 macrophage activation
Authors: Tsuchiyama Tomoya , Nakamoto Yasunari , Sakai Yoshio , Mukaida Naofumi , Kaneko Shuichi
Published: September 2010

Suicide gene therapy combined with chemokines provides significant antitumor efficacy. Coexpression of suicide gene and monocyte chemoattractant protein‐1 (MCP‐1) increases antitumor effects in murine models of hepatocellular carcinoma (HCC) and colon cancer. However, it is unclear whether the doses administered achieved the maximum antitumor effects. We evaluated antitumor effects of various amounts of recombinant adenovirus vector (rAd) expressing MCP‐1 in the presence of a suicide gene in a murine model of HCC. HCC cells were transplanted subcutaneously into BALB/c nude mice, and transduced with a fixed amount of Ad‐tk harboring the suicide gene, HSV‐tk, and various doses of Ad‐MCP1 harboring MCP‐1 (ratios of 1:1, 0.1:1, and 0.01:1 relative to Ad‐tk). Growth of primary tumors was suppressed when treated with Ad‐tk plus Ad‐MCP1 (1:1 and 1:0.1) as compared with Ad‐tk alone. The antitumor effects against tumor rechallenge tended to be high in the Ad‐tk plus Ad‐MCP1 group (1:0.1). The effects were dependent on production of Th1 type‐cytokines. Delivery of an optimal amount of rAd expressing MCP‐1 enhanced the antitumor effects of suicide gene therapy against HCC by M1 macrophage activation, suggesting that this is a plausible form of cancer gene therapy to prevent HCC progression and recurrence. (Cancer Sci 2008; 99: 2075–2082)
A UK‐based cost–utility analysis of radiofrequency ablation or oesophagectomy for the management of high‐grade dysplasia in Barrett’s oesophagus
Authors: Boger P. C. , Turner D. , Roderick P. , Patel P.
Published: September 2010

Aliment Pharmacol Ther2010;32:1332–1342

Background In the UK, oesophagectomy is the current recommendation for patients with persistent high‐grade dysplasia in Barrett’s oesophagus. Radiofrequency ablation is an alternative new technology with promising early trial results.

Aim To undertake a cost–utility analysis comparing these two strategies.

Methods We constructed a Markov model to simulate the natural history of a cohort of patients with high‐grade dysplasia in Barrett’s oesophagus undergoing one of two treatment options: (i) oesophagectomy or (ii) radiofrequency ablation followed by endoscopic surveillance with oesophagectomy for high‐grade dysplasia recurrence or persistence.

Results In the base case analysis, radiofrequency ablation dominated as it generated 0.4 extra quality of life years at a cost saving of £1902. For oesophagectomy to be the most cost‐effective option, it required a radiofrequency ablation treatment failure rate (high‐grade dysplasia persistence or progression to cancer) of >44%, or an annual risk of high‐grade dysplasia recurrence or progression to cancer in the ablated oesophagus of >15% per annum. There was an 85% probability that radiofrequency ablation remained cost‐effective at the NICE willingness to pay threshold range of £20 000–30 000.

Conclusion Radiofrequency ablation is likely to be a cost‐effective option for high‐grade dysplasia in Barrett’s oesophagus in the UK.
ORIGINAL ARTICLE: A survey of the management of needlestick injuries from incapacitated patients in intensive care units*
Authors: Burrows L. A. , Padkin A.
Published: September 2010

The Human Tissue Act 2004 and Mental Capacity Act 2005 resulted in a change in the management of needlestick injuries sustained from incapacitated patients. It appears unlawful to test for blood‐borne viruses without a patient’s consent for the sole benefit of the healthcare worker. This survey of intensive care units within England, Wales and Northern Ireland investigated how needlestick injuries from incapacitated patients had been managed within the previous year. Of the 225 intensive care units surveyed, 99 (44%) responded. Sixty‐two (62.6%) reported a needlestick injury to a healthcare worker from an incapacitated patient. Thirty‐six (64.3%) patients were tested for blood‐borne viruses without consent. Sixteen (25.8%) patients tested positive for blood‐borne viruses. Only 19 (30.6%) healthcare workers took post‐exposure prophylaxis following the injury. These results show that needlestick injuries from incapacitated patients are common and that the majority of patients were tested for blood‐borne viruses without consent.
Along‐strike variations in foreland basin evolution: possible evidence for continental collision along an irregular margin
Authors: Lash GARY G.
Published: September 2010

Abstract The evolution of a passive margin to a foreland basin is generally assumed to entail early load‐induced up warping of the stable continental platform followed by foreland subsidence. This relatively straightforward elastic response of the continental platform, however, may be complicated if the colliding passive margin is irregular in outline. In a tectonic scenario in which an irregular margin is migrating toward a trench (A‐subduction), those areas of the margin which project seaward, the continental promontories, would be the first to ‘feel’ the approaching thrust terrane by flexing upward and eroding to form shelf unconformities. Those parts of the continental margin that are convex to the craton, the continental re‐entrants, however, would remain subsiding depocentres unaffected by load‐induced uplift at the promontories. Careful analysis of the geographic distribution of shelf unconformities in orogenic belts, then, may help to reveal the pre‐deformation morphology of the passive continental margin. An example of this may be found in the early phases of Ordovician foreland basin development in the central Appalachian orogen. Here, the shelf unconformities are most pronounced (greatest erosional relief) at the inferred Virginia and New York continental promontories. An adjacent inferred continental re‐entrant, the Pennsylvania re‐entrant, is characterized by an uninterrupted Ordovician sequence suggesting that the area of the proto‐North American platform, represented by this segment of the orogen, remained a depocentre during uplift in adjacent areas of the continental margin.
A comparative study of neotectonic basins across the Hellenic arc: the Messiniakos, Argolikos, Saronikos and Southern Evoikos Gulfs
Authors: Papanikolaou D. , Lykousis V. , Chronis G. , Pavlakis P.
Published: September 2010

Abstract Detailed single‐channel continuous seismic reflection profiling data from four gulfs as well as onshore neotectonic investigations have allowed the study of the neotectonic structure of the Hellenic arc along a complete transverse section from its external area in the trench to the internal back‐arc area.

Messiniakos Gulf is an asymmetric NW‐SE structure with considerable tilt towards the NE. It is the direct continuation of the continental slope from the trench to the island arc (Peloponnesus, Crete, Dodekannese). Argolikos Gulf is an almost symmetric NW‐SE graben occupying the northern edge of the Cretan back‐arc basin. Saronikos Gulf is a multi‐complex structure of a NW‐SE graben in the SW (Epidaurus Basin) and alternation of E‐W horsts and grabens in the North. Its neotectonic evolution is characterized by the Plio‐Quaternary volcanic arc activity. Southern Evoikos Gulf is a relatively shallow neotectonic graben in the back‐arc area at the northern prolongation of the Cycladic Platform.

Each of the above neotectonic basins has its own characteristics which are probably due to their geodynamic position in the Hellenic arc. In general, there is a decrease in the neotectonic deformation, the sediment thickness and the sedimentation rates from SW to NE, going from the periphery to the core of the arc.
The Corinth‐Patras rift as the initial stage of continental fragmentation behind an active island arc (Greece)
Authors: Doutsos THEODOR , Kontopoulos NIKOLAOS , Poulimenos GEORGIOS
Published: September 2010

AbstractDuring the migration of the back arc extension from central to western Greece the Corinth and Patras grabens are being formed. Orthogonal opening of these graben zones is accomplished by WNW listric normal faults and NNE transfer faults which produce an along‐axis fragmentation. The listric faults show an increase in the dip of the fault plane westwards as well as a decrease in the maximum extension rate from 50% to the east in the Corinth graben, to 10% to the west in the Patras graben. Similarly, towards the west, Plio‐Quaternary deposits become thinner whereas Pliocene sediments thin‐out indicating a westward rift propagation.

As the back arc extension migrates westwards it is interacting or is being superimposed above another orthogonal fault system consisting of NNW and ENE normal faults. These faults have been formed during general uplift behind the orogenic front which has been migrating from western Greece to the Ionian islands. The ENE‐trending Rio graben which belongs to his orthogonal system connects the Patras graben to the Corinth graben and has subsequently been active as a transfer fault between them.

Plio‐Quaternary geodynamic processes in central continental Greece are quite similar to those earlier processes observed in the central Aegean region which reflect the initial stage of continental break‐up behind a migrating orogenic front.
Estimating the slip rates of normal faults in the Great Basin, USA
Authors: DePolo C. M. , Anderson J. G.
Published: September 2010

A reconnaissance slip‐rate‐estimation technique is needed for hundreds of uncharacterized normal faults in the Great Basin. We use the occurrence and/or absence of primary tectonic geomorphology, alluvial fault scarps and fault facets, to distinguished between categories of faults that have differences of orders of magnitudes in slip rate. Normal faults that lack alluvial fault scarps and fault facets (Type 3) have vertical slip rates on the order of 0.001 m kyr−1. Faults with alluvial fault scarps but that lack active fault facets (Type 2) have vertical slip rates on the order of 0.01 m kyr−1. Faults with active fault facets with a minimum height of 30 m (Type 1) are the most important faults in the Great Basin with respect to seismic hazard, tectonic deformation, and basin development and deposition. These faults generally have vertical slip rates of 0.1 m kyr−1 and faster. For better precision we have developed a relationship between vertical slip rate and maximum basal facet height: Log10 Sv=0.00248H−0.938 where Sv is vertical slip rate in m kyr−1 and H is maximum basal facet height in metres. The standard deviation of this relationship is 0.239, which corresponds to plus or minus a multiplicative factor of 1.7 in vertical slip rate.

These criteria were used to estimate vertical slip rates for major normal faults in Nevada, USA. Based on the rates and orientations of these faults, seven Quaternary tectonic subprovinces are distinguished. The fastest faults (≥0.5 m kyr−1) are generally located in the Walker Lane belt, perhaps because of higher extension rates created by the addition of strike‐slip tectonics. Earthquake occurrence rates based on the faults in Nevada and their estimated slip rates are about a factor of two lower than historical earthquake rates.
The structural and sedimentological evolution of early synrift successions: the Middle Jurassic Tarbert Formation, North Sea
Authors: Davies S. J , Dawers N. H. , McLeod A. E. , Underhill J. R.
Published: September 2010

This study addresses the complex relationship between an evolving fault population and patterns of synrift sedimentation during the earliest stages of extension. We have used 3D seismic and well data to examine the early synrift Tarbert Formation from the Middle–Late Jurassic northern North Sea rift basin. The Tarbert Formation is of variable thickness across the study area, and thickness variations define a number of 1‐ to 5‐km‐wide depocentres bounded by normal faults. Seismic reflections diverge towards the bounding faults indicating that the faults were active contemporaneous with the deposition of the formation. Many of these faults became inactive during later Heather Formation times. The preservation of the Tarbert Formation in both footwall and hangingwall locations demonstrates that, during the earliest synrift, the rate of deposition balanced the rate of tectonic subsidence. Local space generated by hangingwall subsidence was superimposed upon accommodation generated due to a regional rise in relative sea‐level. In basal Tarbert Formation times, transgression across the prerift coastal plain produced lagoons and bays, which became increasingly marine. During continued transgression, barrier islands moved landward across the drowned bays. In the southern part of our study area, shallow marine sediments are erosionally truncated by fluvial deposition. These fluvial systems were constrained by fault growth monoclines, and flowed parallel to the main faults. We illustrate that stratal architecture and facies distribution of early sedimentation is strongly influenced by the active short‐lived faults. Local depocentres adjacent to fault displacement maxima focused channel stacking and allowed the aggradation of thick shoreface successions. These depocentres formed early in the rift phase are not necessarily related to Late Jurassic – Early Cretaceous depocentres developed along the major linked normal fault systems.
Miocene–Recent tectonic and climatic controls on sediment supply and sequence stratigraphy: Canterbury basin, New Zealand
Authors: Lu Hongbo , Fulthorpe Craig S. , Mann Paul , Kominz Michelle A.
Published: September 2010

The well‐constrained seismic stratigraphy of the offshore Canterbury basin provides the opportunity to investigate long‐term changes in sediment supply related to the formation of a transpressive plate boundary (Alpine Fault). Reconstructions of the relative motion of the Australian and Pacific plates reveal divergence in the central Southern Alps prior to ∼20.1 Ma (chron 6o), followed by increasing average rates of convergence, with a marked increase after ∼6 Ma (late Miocene). A strike–slip component existed prior to 33.5 Ma (chron 13o) and perhaps as early as Eocene (45 Ma). However, rapid strike–slip motion (>30 mm yr−1) began at ∼20.1 Ma (chron 6o). Since ∼20.1 Ma there has been no significant change in the strike–slip component of relative plate motion.

Sedimentation rates are calculated from individual sequence volumes that are then summed to represent sequence groups covering the same time periods as the tectonic reconstructions. Rates are relatively high (>22 mm yr−1), from 15 to ∼11.5 Ma (sequence group 1). Rates decrease to a minimum (<15 mm yr−1) during the ∼11.5–6 Ma interval (sequence group 2), followed by increased rates during the periods of ∼6–2.6 Ma (21 mm yr−1; group 3) and 2.6–0 Ma (∼25 mm yr−1; group 4). Good agreement between sedimentation and tectonic convergence rates in sequence groups 2–4 indicates that tectonism has been the dominant control on sediment supply to the Canterbury basin since ∼11.5 Ma. In particular, high sedimentation rates of 21 and ∼25 mm yr−1 in groups 3 and 4, respectively, may reflect increased plate convergence and uplift at the Southern Alps at ∼6 Ma. The early‐middle Miocene (∼15–11.5 Ma) high sedimentation rate (22 mm yr−1) correlates with low convergence rates (∼2 mm yr−1) and is mainly a response to global climatic and eustatic forcing.
Lithospheric bulge in the West Taiwan Basin
Authors: Tensi J. , Mouthereau F. , Lacombe O.
Published: September 2010

We use well data to investigate the timing and the origin of the lithospheric bulge in the West Taiwan Basin. The possibility that the subsidence patterns observed since Middle‐Upper Miocene are simply related to the flexural response of the Chinese continental margin to loading is examined by the reconstructions of the West Taiwan Basin evolution using two‐dimensional geometric and numerical flexural modelling of a purely elastic plate. Reconstructions of the forebulge and basin evolution since Middle Miocene are finally discussed in terms of plate strength and geological context. The results are finally placed in the framework of the geodynamic setting of the Philippines Sea Plate/Eurasia convergence in order to provide new insights on the early stage of the Taiwan arc‐continent collision. Modelling suggests that the initiation of the flexure in the West Taiwan Basin occurred at ca. 12.5–8.6 Ma. A good fit is obtained for Te of 10–20 km, consistent with earlier studies. During 5–6 m year−1 the growth of the bulge was static and associated with increasing plate curvature. Then, at 3–4 Ma the bulge migrated forelandward within the West Taiwan Basin in relation to the migration of the load and the increase in plate curvature. The passage of the forebulge into an inherited weaker portion of the Chinese margin produced an increase in plate curvature and renewed extension, leading to enhancement of the bulge uplift and to its localization for a prolonged period of time. Taking into account the age of the flexure initiation and plate convergence rates, we infer that the load might not be related to the arc‐continent collision. We conclude that a Middle Miocene obduction, already proposed by some authors, may explain the deflection of the Chinese margin at that time. It is not before 3–4 Ma that the bulge and the load propagated forelandward in association with the development of the Taiwan arc‐continent collision.