bluuebunny/crossref_metadata_2025 huggingface dataset:
On Not Three Gods: Gregory of Nyssa's Trinitarian Theology
Authors: Ayres Lewis
Published: August 2005

Against the background of the previous three chapters, this chapter offers a new reading of the fundamental structures of the Trinitarian theology of Gregory of Nyssa. Considers the argument of his Ad Ablabium, showing how it reveals a concern to express God’s unitary power rather than any early ‘social’ analogy for the Trinity. This concern is expressed in the context of the anthropological and epistemological dynamics discussed in Chs 11–13 and, alongside, an insistence on the irreducibility of the three persons.
Two Models of Belief
Authors: Christensen David
Published: August 2005

Ties the book's central question to a choice between a qualitative binary (all-or-nothing) conception of belief and a quantitative graded conception of belief (degrees of belief). The two conceptions invite different formal constraints. Argues that probabilistic coherence is best seen not as a new logic for graded belief, but as a way of applying standard logic to graded belief. Explores different ways of understanding the relation between binary and graded belief, concluding that the way one sees this relation has important implications for the questions of whether and how beliefs are subject to formal rationality constraints.
ARGUMENTS FOR DEDUCTIVE COGENCY
Authors: Christensen David
Published: August 2005

Examines and rejects several arguments claiming that the fundamental purposes of binary belief requires deductive cogency. The strongest such argument claims that if deductive cogency were not rationally required, deductive arguments would have no rational force. Develops and defends an alternative explanation of the epistemic importance of deductive arguments, rooted in a probabilistic coherence constraint on graded belief. Ends with a discussion of whether binary belief has any epistemic importance; argues that although our binary way of talking and thinking about belief may be very useful, it may not, in the end, capture any important aspect of rationality. Moreover, further development of extended Preface-type cases shows that the sort of binary belief that was subject to deductive cogency could not have the connections to central aspects of our practical reasoning, our assertions, and our emotions that seem to give belief its point.
Introduction
Authors: Chui Michael , Gai Prasanna
Published: August 2005

Reviews the modern debate on the international financial architecture. Reviews the financial crisis in Korea during 1997–98, which marked a watershed in the debate and encouraged policymakers to advocate debt standstills, collective action clauses, and statutory Sovereign Debt Restructuring Mechanisms (SDRM) as ways of tackling creditor coordination problems.
VALUATION OF CONTINGENT CLAIMS: EXTENSIONS
Authors: Poon Ser-Huang , Stapleton Richard
Published: August 2005

‘Valuation of Contingent Claims: Extensions’ extends the analysis in Ch. 3 to contingent claims on assets with non-lognormal distributions, for example, normal distributions, as in the Brennan (1979), and generalized lognormal distributions, as in the shifted lognormal case of Rubinstein (1983). Next, the authors consider the pricing of claims where risk-neutral valuation relationships do not exist. For this case, they discuss Heston (1993)'s extension to the case of ‘preference-parameter free valuation relationships’, where at least one preference parameter in the pricing kernel becomes irrelevant for the pricing of contingent claims. Then, they derive the related results in Franke, Stapleton, and Subrahmanyam (1999) who showed that if assets are lognormal, but the pricing kernel has declining elasticity, possibly due to background risk, then all options have higher prices than in the Black–Scholes world. Finally, they discuss the bounds on option prices in such economies.
FORWARD AND FUTURES PRICES OF CONTINGENT CLAIMS
Authors: Poon Ser-Huang , Stapleton Richard
Published: August 2005

‘Forward and Futures Prices of Contingent Claims’ applies the multi-period rational expectations model to analyse the pricing of forward and futures contracts and derives an expression for the difference between the prices of the two, which is commonly known as the convexity adjustment. These are illustrated using an example where the asset price, the pricing kernel and the bond prices are joint lognormal variables. The authors then consider the futures and forward prices of contingent claims, such as call options. Futures prices of options can be significantly different from the forward prices of the contingent claims, especially when the options are on interest-rate related assets such as bonds or swaps. Forward prices of long-term bond can be obtained by taking appropriate expected values of future spot pries under the risk-neutral measure.
Placement and Pilgrimage
Authors: Brown David
Published: August 2005

This chapter consists of three sections. The first considers feelings of alienation in modern cities and contrasts this with ancient approaches to home and city. Detailed consideration is given to attitudes in ancient Rome, and the history of religious influences on town planning over the centuries is also explored. The second section then looks at the question of symbolic geography, and in particular the medieval practice of placing Jerusalem at the centre of maps (never understood literally). The final section discusses pilgrimage, noting how even those religions initially hostile nonetheless eventually succumb (e.g. Buddhism, Sikhism). Two aspects are explored in some detail: the contrasting use of the maze or labyrinth to expound the nature and meaning of the journey; and some unusual features of pilgrimage in medieval Rome.
2 JUDGEMENT AND DESIRE
Authors: ODDIE GRAHAM
Published: August 2005

This chapter outlines two problems of knowledge which any cognitivist about value faces. One is the familiar problem of the motivational inertness of bare facts, and the knowledge of such facts. The other is the much less familiar problem of value data. The inertness problem can be approached through a puzzling asymmetry in value judgements, an asymmetry which can easily be explained by the internalist thesis that value judgements are special in being intrinsically or necessarily motivating. It is argued that there is a natural way for the cognitivist to explain the puzzling asymmetry, and it is one which simultaneously solves the problem of the missing data. The explanation appeals to two rather radical ideas. First, experiences of value are necessary, though not sufficient, for us to have knowledge of value. Second, desires are experiences of value. The conjunction of these two theses is referred to as the experience conjecture, and it is shown how it explains, inter alia, the puzzling asymmetry.
IRREDUCIBLE VALUE
Authors: ODDIE GRAHAM
Published: August 2005

This chapter presents a promising way of defending the determination of value by nature, while resisting reduction. Recent developments in both property theory and value theory help clarify a thesis about the relation between irreducibility and multiple realizability which has not been as clearly articulated as it can be. This in turn will help to establish and illustrate the possibility of supervenience without reduction.
Kant
Authors: Wight Martin
Published: August 2005

Kant was the greatest of modern philosophers. He held that we have knowledge of the phenomenal world alone; of the realm of the noumenal we have only moral experience. But he had moral passion in his notion of the categorical imperative, or goodwill dedicated to duty. Kant’s revolutionism is seen in the idea of the homogeneity of states—a federation of ‘republics’; or alternatively in cosmopolitanism— a world of individuals and peoples rather than of governments and states. Kant’s belief in the harmony of interests underlies his doctrine of progress. There are categories of Kantians, although Kant himself was both comprehensive and universal as a philosopher.
The Work of Emotion
Authors: Pugmire David
Published: August 2005

Emotion, especially as expressed, has social impact. Can emotions, then, be seen as manipulative devices, strategic stances? They are sometimes used in this way, and some philosophers have proposed understanding emotion instrumentally. This is unsatisfactory, however, at both the practical and the theoretical levels. Manipulative emotive responses could only work if they were not believed to be manipulative; so if we were all doing it, it would not work (without collective self-deception). Targeted emotion would also lack depth. And anyway, emotions are too unlike actions to remain well-formed when used strategically.
The Case for a Human Right to an Adequate Environment
Authors: Hayward Tim
Published: August 2005

Argues that a right to an adequate environment is a genuine human right. After indicating the scope of the right, it defends this proposition against sceptical counterarguments. Clarifies how the question of its genuineness includes both moral and legal considerations. Regarding the moral case, it shows that the right to an adequate environment meets each test of genuineness that can reasonably be proposed. Regarding the status of the right in international law, it suggests there is sufficient evidence to claim that the right is in the process of emergence internationally, and that its further consolidation can reasonably be expected.
Environmental Rights as Democratic Rights
Authors: Hayward Tim
Published: August 2005

Constitutionalising a right makes it immune to the possibility of (routine) democratic revision. So, constitutional rights that set certain substantive values beyond the reach of routine political revision have the effect of pre-empting decisions that might otherwise be arrived at through democratic procedures. To the extent that environmental rights can be taken to embody substantive value commitments, they would appear to be vulnerable to the criticism that the constitutional entrenchment of them is undemocratic. Certain procedural rights, however, are necessary for the very functioning of democracy as such. Can procedural environmental rights be justified on this ground? And what about the substantive right to an adequate environment? Argues that both kinds of environmental rights, in common with some existing and far less controversial rights, can in fact be justified on the very grounds that democracy itself is justified.
C. I. Lewis's Radical Justification of Memory
Authors: Olsson Erik J.
Published: August 2005

C. I. Lewis’s coherence (congruence) justification of memory is examined with respect to how well it can accommodate the troublesome facts uncovered in Ch. 2. Lewis draws on a presumed parallel between memory and testimony. Various ways for how to model witness scenarios are discussed. Distinctions are made between different kinds of witness reliability. A connection is established with Bayesian networks. Lewis is seen to underestimate the effect of the credibility of individual reports on the overall likelihood of truth.
Strategic Form Games
Authors: Bergin James
Published: August 2005

Discusses games in strategic form. Models of behaviour are described. Nash and correlated equilibrium are considered.
Equilibrium in Extensive Form Games
Authors: Bergin James
Published: August 2005

Equilibrium in extensive form games is considered. Covers Nash equilibrium, perfect equilibrium, sequential equilibrium, and perfect Bayesian equilibrium. The classic chain store paradox example is discussed to illustrate.
Common Knowledge
Authors: Bergin James
Published: August 2005

Introduces common knowledge is introduced. The definition of common knowledge is given. Convergence of beliefs under iterative announcement is discussed, and the implications of common knowledge of an aggregate statistic described. In a game theoretic framework, it is show how lack of common knowledge can lead to cooperative equilibrium in a finitely repeated prisoners’ dilemma game. Finally, a no-trade theorem is given.
The Burden of Grandeur: Physical and Economic Well-Being of the Russian Population in the Eighteenth Century
Authors: Mironov Boris
Published: August 2005

From 1700-1704 to 1795-1799 the average stature of Russian recruits decreased from 164.7 to 159.5 cm. It means that the eighteenth century is noted for the fall in the biological status of the Russian population. The decrease occurred against the background of a considerable economic growth and was caused not by economic depression but by the rise in taxes and obligations. Increase in payments to the state was linked with the wars Russia waged for outlets to the Baltic and Black seas, and for the status of a great power, and with reforms carried out by the supreme power catching up with the West European countries.
Short-Term Demographic Changes in Relation to Economic Fluctuations: The Case of Tuscany During the Pre-Transitional Period
Authors: Breschi Marco , Fornasin Alessio , Gonano Giovanna
Published: August 2005

Focuses on the short-term relations between prices of consumer goods and demographic time series. The area considered is the Grand Duchy of Tuscany from 1823 to 1854. The research identifies the different demographic outcomes in specific social groups in presence of price fluctuations.
Individuals and Communities Facing Economic Stress: A Comparison of Two Rural Areas in Nineteenth-Century Belgium
Authors: Oris Michel , Neven Muriel , Alter George
Published: August 2005

In the early nineteenth century, eastern Belgium was the first region on the European continent to follow the British example of industrialization based on textiles, coal, and iron. Rural areas were faced with old problems and new opportunities. On the one hand, they faced intensified population pressure due to population growth and the decline of proto-industrial production. On the other hand, new industrial jobs in growing cities beckoned rural workers. Examines the range of demographic responses to economic stress in this transitional period through an analysis of two very different rural societies. The correlations between prices and demographic behaviours in the early nineteenth century mostly disappeared after 1850. Rural people were able to shift from a ‘defensive logic’, which families used to protect themselves against hard times, to positive choices intended to take advantage of new opportunities.
Governing China's Grasslands: The Creation of Empty Institutions
Authors: Ho Peter
Published: August 2005

Offers a detailed institutional analysis of national grassland policy. It is demonstrated that one of the main reasons for the failure of national grassland policy and the pasture lease system is the fact that both do not suit the current socio-economic parameters. In other words, they are ‘empty institutions’. The ‘empty institution’ incorporates rules that have not yet been widely accepted in society, yet in such way that these can have no real impact on the behaviour of social actors. An ‘empty institution’ generally arises from a compromise over sensitive political issues. In this case, national grassland policy reflects a political compromise over the core of grassland property rights: the distinction between state and collective property.
Origin and evolution of new exons in rodents
Authors: Wang Wen , Zheng Hongkun , Yang Shuang , Yu Haijing , Li Jun , Jiang Huifeng , Su Jianning , Yang Lei , Zhang Jianguo , McDermott Jason , Samudrala Ram , Wang Jian , Yang Huanming , Yu Jun , Kristiansen Karsten , Wong Gane Ka-Shu , Wang Jun
Published: August 2005

Gene number difference among organisms demonstrates that new gene origination is a fundamental biological process in evolution. Exon shuffling has been universally observed in the formation of new genes. Yet to be learned are the ways new exons originate and evolve, and how often new exons appear. To address these questions, we identified 2695 newly evolved exons in the mouse and rat by comparing the expressed sequences of 12,419 orthologous genes between human and mouse, using 743,856 pig ESTs as the outgroup. The new exon origination rate is about 2.71 × 10-3 per gene per million years. These new exons have markedly accelerated rates both of nonsynonymous substitutions and of insertions/deletions (indels). A much higher proportion of new exons have Ka/Ks ratios >1 (where Ka is the nonsynonymous substitution rate and Ks is the synonymous substitution rate) than do the old exons shared by human and mouse, implying a role of positive selection in the rapid evolution. The majority of these new exons have sequences unique in the genome, suggesting that most new exons might originate through “exonization” of intronic sequences. Most of the new exons appear to be alternative exons that are expressed at low levels.
Effect of seed passage through birds and lizards on emergence rate of mediterranean species: differences between natural and controlled conditions
Authors: RODRÍGUEZ‐PÉREZ J. , RIERA N. , TRAVESET A.
Published: August 2005

The ingestion of fruits by vertebrate frugivores produces great variation on seed germination responses which depend on (1) the frugivorous species; (2) several factors intrinsic to the plant species; and (3) the conditions under which germination tests are conducted. Most studies on this topic have used only one or a few disperser species, and have been performed under controlled conditions.

The main goals of this study were to determine (1) the effect that birds (Turdus merula) and lizards (Podarcis pityusensis) have on seed emergence patterns of a group of common mediterranean plants; and (2) whether such patterns differ between field and common garden conditions. Over 2 years we compared seed emergence times with those of controls (pulp‐removed seeds).

Emergence patterns were inconsistent for most plant species when comparing field vs. common‐garden conditions. In some cases results were even contradictory: for instance lizards accelerated the emergence time of Rubus seeds in the field, but delayed it in the experimental garden; likewise Rubia seeds ingested by Blackbirds emerged more slowly than controls in the field, but faster than those in the garden. The two frugivorous species had also inconsistent effects on the same plant species.

Significant changes in seed weight after passage through the animals’ digestive tracts were observed in most species. However, seed weight did not explain differences in seed emergence patterns between ingested and non‐ingested seeds.

This study demonstrates the great heterogeneity in seed‐emergence responses of the different plant species to ingestion by different types of frugivore, and to the different experimental conditions. Thus, caution is needed when making generalizations from studies that aim to evaluate the influence of frugivores on seed dispersal quality.
Down‐regulation of cyclooxygenase‐2 expression but up‐regulation of cyclooxygenase‐1 in renal carcinomas of the Eker (TSC2 gene mutant) rat model
Authors: Okamoto Toshihiro , Hara Atsuko , Hino Okio
Published: August 2005

Although it is generally accepted that cyclooxygenase (Cox)‐ 2 is overexpressed in carcinomas, few studies have examined Cox‐2 expression in renal carcinoma (RC). The Eker rat RC is an example of a Mendelian dominantly inherited carcinoma, and in the present study, expression of Cox‐2 in the Eker rat RC was examined. Reverse transcription polymerase chain reaction indicated constitutive expression of Cox‐2 mRNA in the normal control kidney and non‐tumor part of Eker rat kidney. Unexpectedly, expression of Cox‐2 mRNA was down‐regulated in four Eker RCs from two Eker rats, and in the cell line Lk9ds. Immunohistochemical analysis failed to reveal Cox‐2 protein staining in Eker RCs. As a control to Cox‐2 expression, Cox‐1 expression was examined. Interestingly, in contrast to the down‐regulated Cox‐2 expression, Cox‐1 mRNA expression was induced in these four Eker RCs and cell lines. Cox‐2 and Cox‐1 expression were further examined in six additional Eker RCs. In total, Cox‐2 mRNA expression was down‐regulated in eight out of ten Eker RCs and cell lines, while Cox‐1 mRNA expression was up‐regulated in nine out of ten Eker RCs and cell lines. (Cancer Sci 2003; 94: 22–25)
Evodiamine, a constituent of Evodiae Fructus, induces anti‐proliferating effects in tumor cells
Authors: Fei Xiao Fang , Wang Ben Xiang , Li Tei Jin , Tashiro Shin‐ichi , Minami Mutsuhiko , Xing De Jun , Ikejima Takashi
Published: August 2005

We found that evodiamine, a major alkaloidal component of Evodiae Fructus (Goshuyu in Japan), inhibited proliferation of several tumor cell lines, but had less effect on human peripheral blood mononuclear cells (PBMC). We used human cervical cancer cells, HeLa, as a model to elucidate the molecular mechanisms of evodiamine‐induced tumor cell death. The results showed that evodiamine induced oligonucleosomal fragmentation of DNA in HeLa cells and increased the activity of caspase‐3, but not that of caspase‐1, in vitro. Both evodiamine‐induced DNA fragmentation and caspase‐3 activity were effectively inhibited by a caspase‐3 inhibitor, z‐DEVD‐fmk (z‐Asp‐Glu‐Val‐Asp‐fmk). In addition, evodiamine increased the expression of the apoptosis inducer Bax, but decreased the expression of the apoptosis suppressor Bcl‐2 in mitochondria. Taken together, our data indicated that evodiamine alters the balance of Bcl‐2 and Bax gene expression and induces apoptosis through the caspase pathway in HeLa cells. (Cancer Sci 2003; 94: 92–98)
Usefulness of combined treatment with mild temperature hyperthermia and/or tirapazamine in the treatment of solid tumors: its independence of p53 status
Authors: Masunaga Shin‐ichiro , Ono Koji , Takahashi Akihisa , Ohnishi Ken , Ohnishi Takeo , Suzuki Minoru , Nagata Kenji , Kinashi Yuko , Nagasawa Hideko , Uto Yoshihiro , Hori Hitoshi
Published: August 2005

Human head and neck squamous cell carcinoma cells transfected with mutant TP53 (SAS/mp53) or with neo vector as a control (SAS/neo) were inoculated subcutaneously into both hind legs of Balb/cA nude mice. Mice bearing the tumors received 5′‐bromo‐2′‐deoxyuridine (BrdU) continuously to label all proliferating (P) cells in the tumors. The mice then received tirapazamine (TPZ) with or without mild temperature hyperthermia (40°C, 60 min) (MTH), γ‐ray irradiation with or without MTH and/or TPZ, cisplatin (CDDP) with or without MTH and/or TPZ, or paclitaxel (TXL) with or without MTH and/or TPZ. After each treatment, the tumors were excised, minced and trypsinized. The tumor cell suspensions thus obtained were incubated with a cytokinesis blocker (cytochalasin‐B), and the micronucleus (MN) frequency in cells without BrdU labeling (i.e., quiescent (Q) cells) was determined by using immunofluorescence staining for BrdU. Meanwhile, 6 h after γ‐ray irradiation or 24 h after other cytotoxic treatments, tumor cell suspensions obtained in the same manner were used for determining the frequency of apoptosis in Q cells. The MN frequency and apoptosis frequency in total (P+Q) tumor cells were determined from the tumors that were not pretreated with BrdU. On the whole, γ‐ray irradiation and CDDP injection induced a higher frequency of apoptosis and lower frequency of MN in SAS/neo cells than SAS/mp53 cells. There were no apparent differences in the induced frequency of apoptosis and MN between SAS/neo and SAS/mp53 cells after TPZ or TXL treatment. MTH sensitized cells to TPZ‐inducing cytotoxicity more markedly in SAS/mp53 and Q cells than in SAS/neo cells and total cells, respectively. In y‐ray irradiation and CDDP treatment, the enhancement in combination with MTH and/or TPZ was more remarkable in SAS/mp53 cells and Q cells than in SAS/neo and total tumor cells, respectively. Also in the case of TXL treatment, the combination with MTH and/or TPZ induced a slightly greater enhancement effect in SAS/mp53 cells and Q cells. In view of the difficulty in controlling mutated p53 status tumors and intratumor Q cells, combination treatment with MTH and/or TPZ as a cooperative modality in cancer therapy is considered to have potential for controlling solid tumors as a whole. (Cancer Sci 2003; 94: 125–133)
Pre‐B lymphomas in SL/Kh mice: A multifactorial disease model
Authors: Hiai Hiroshi , Tsuruyama Tatsuaki , Yamada Yoshihiro
Published: August 2005

The pre‐B lymphoma in the inbred mouse strain SL/Kh is an excellent multifactorial disease model. The endogenous murine leukemia virus provirus Emv11, genetically acquired from an AKR progenitor, is the pathogenetic agent that reintegrates to dysregulate several host genes, i.e., Stat5a, Evi3, c‐Myc, N‐Myc, Stat5b, and others. Constitutive activation of Stat5a either by provirus integration or by transfection of the active mutant Stat5a cDNA transforms pre‐B cells in bone marrow. Genetically determined expansion of early B cells and a dominant SL/Kh MHC allele predispose the animals to succumb to pre‐B lymphomas. A number of other host genetic and epigenetic factors that determine the types of lymphomas, susceptibility to lymphomas, and length of the latent period are discussed.
Multiple fuzzy neural network system for outcome prediction and classification of 220 lymphoma patients on the basis of molecular profiling
Authors: Ando Tatsuya , Suguro Miyuki , Kobayashi Takeshi , Seto Masao , Honda Hiroyuki
Published: August 2005

A fuzzy neural network (FNN) using gene expression profile data can select combinations of genes from thousands of genes, and is applicable to predict outcome for cancer patients after chemotherapy. However, wide clinical heterogeneity reduces the accuracy of prediction. To overcome this problem, we have proposed an FNN system based on majoritarian decision using multiple noninferior models. We used transcriptional profiling data, which were obtained from “Lymphochip” DNA microarrays (http://llmpp.nih.gov/DLBCL), reported by Rosenwald (N Engl J Med 2002; 346: 1937–47). When the data were analyzed by our FNN system, accuracy (73.4%) of outcome prediction using only 1 FNN model with 4 genes was higher than that (68.5%) of the Cox model using 17 genes. Higher accuracy (91%) was obtained when an FNN system with 9 noninferior models, consisting of 35 independent genes, was used. The genes selected by the system included genes that are informative in the prognosis of Diffuse large B‐cell lymphoma (DLBCL), such as genes showing an expression pattern similar to that of CD10 and BCL‐6 or similar to that of IRF‐4 and BCL‐4. We classified 220 DLBCL patients into 5 groups using the prediction results of 9 FNN models. These groups may correspond to DLBCL subtypes. In group A containing half of the 220 patients, patients with poor outcome were found to satisfy 2 rules, i.e., high expression of MAX dimerization with high expression of unknown A (LC_26146), or high expression of MAX dimerization with low expression of unknown B (LC_33144). The present paper is the first to describe the multiple noninferior FNN modeling system. This system is a powerful tool for predicting outcome and classifying patients, and is applicable to other heterogeneous diseases.
Enhancement of urinary bladder carcinogenesis by combined treatment with benzyl isothiocyanate and N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine in rats after initiation
Authors: Okazaki Kazushi , Umemura Takashi , Imazawa Takayoshi , Nishikawa Akiyoshi , Masegi Toshiaki , Hirose Masao
Published: August 2005

Previously we reported that benzyl isothiocyanate (BITC) strongly enhanced rat urinary bladder carcinogenesis after initiation with N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine (BBN), while potently inhibiting BBN‐induction of lesions when given simultaneously with the carcinogen. In the present experiment, the effects of simultaneous treatment with BITC and low‐dose BBN on the postinitiation period of rat urinary bladder carcinogenesis were examined. After treatment with 500 ppm BBN for 4 weeks for initiation, groups of 20, 6‐week‐old, F344 male rats were given 25 ppm BBN alone, basal diet alone, or 100 or 1000 ppm BITC in the diet together with or without 25 ppm BBN in their drinking water for 36 weeks and then killed for autopsy. Further groups consisting of 10 rats each were similarly given BITC or the basal diet together with or without 25 ppm BBN, without initiation treatment. In the initiated groups receiving subsequent BBN exposure, papillary and nodular hyperplasia, dysplasia and carcinoma incidences were significantly increased, and they were further increased by the combined treatment with 100 and 1000 ppm BITC in a dosedependent manner. In the non‐initiation groups, carcinomas were only observed in a single rat in each of the BBN‐treated control and BBN/BITC 100 ppm treatment groups. The results indicate that simultaneous treatment with BITC and a low dose of BBN does not inhibit, but rather enhances rat urinary bladder carcinogenesis after appropriate initiation, and further suggest that BITC may be a human risk factor, at least in high‐risk populations.
Establishment and characterization of mouse mammary carcinoma cell lines expressing RET with a multiple endocrine neoplasia 2A mutation
Authors: Kawai Kumi , Jijiwa Mayumi , Shimono Yohei , Kurokawa Kei , Murakumo Yoshiki , Ichihara Masatoshi , Takahashi Masahide
Published: August 2005

We recently generated transgenic mice expressing the RET protooncogene with a multiple endocrine neoplasia type 2A mutation (RET‐MEN2A). Mammary tumors with frequent lung metastasis were developed in 22% of female transgenic mice in a stochastic fashion. In the current study, we established two cell lines (named MKK‐f and MKK‐s) from mammary tumors developed in RET‐MEN2A transgenic mice. MKK‐f and MKK‐s were derived from well‐differentiated ductal carcinoma and sarcomatous spindle cell carcinoma, respectively. MKK‐f cells show epithelial‐like morphology with a doubling time of 19 h, and MKK‐s cells show spindle‐shaped morphology with a doubling time of 15 h. When inoculated in immunodeficient mice, both cell lines were tumorigenic, metastasized to the lung and displayed histological features similar to those of the primary tumors. They maintained a high level of RET expression and activation of signaling molecules downstream of RET. Consistent with the histological phenotype, expression of E‐cadherin was almost undetectable in MKK‐s cells, whereas its expression was very high in MKK‐f cells. When the difference of gene expression between the two cell lines was analyzed using cDNA microarrays including approximately 900 genes/ESTs, a total of 21 up‐ or down‐regulated (>2.0‐fold) genes were identified. Differentially regulated genes included thymosin β‐10, fibroblast growth factor receptor 4, aldo‐keto reductase and caspase 6 genes, which are known to be associated with tumor development and progression. These results may reflect the profiles of the transcriptional changes associated with dedifferentiation or progression of mammary carcinomas developed in genetically engineered mice.
Upregulation of FLIPSby Akt, a possible inhibition mechanism of TRAIL‐induced apoptosis in human gastric cancers
Authors: Nam Seon Young , Jung Gyung‐Ah , Hur Gwong‐Cheung , Chung Hee‐Yong , Kim Woo Ho , Seol Dai‐Wu , Lee Byung Lan
Published: August 2005

Tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) is a potent inducer of apoptosis in some, but not all cancer cells. To assess the regulation of TRAIL‐resistance in the human gastric cancer cells, we examined TRAIL sensitivity, TRAIL receptor expression, and intracellular signaling events induced by TRAIL. All the gastric cancer cell lines tested were susceptible to TRAIL to some extent except for SNU‐216 cell line, which was completely resistant. TRAIL receptor expression was not related to the TRAIL‐sensitivity. Of the cell lines tested, SNU‐216 showed the highest level of constitutively active Akt and the short form of FLICE inhibitory protein (FLIPS). Treatment with the phosphatidylinositol 3‐kinase (PI3K) inhibitor LY294002 or with the protein synthesis inhibitor cycloheximide induced a suppression of constitutive Akt activation in SNU‐216 cells and a concomitant decrease in the expression of FLIPS. The reduction of Akt activity by LY294002 affected the transcriptional level of FLIPS, but not the mRNA stability. As a result, LY294002 or cycloheximide significantly enhanced TRAIL‐induced apoptosis. Moreover, the overexpression of constitutively active Akt in the TRAIL‐sensitive cell line, SNU‐668, rendered the cell line resistant to TRAIL. In addition, infection of the same cell line with retrovirus expressing FLIPScompletely inhibited TRAIL‐induced apoptosis by blocking the activation of caspase‐8. Therefore, our results suggest that Akt activity promotes human gastric cancer cell survival against TRAIL‐induced apoptosis via upregulation of FLIPS, and that the cytotoxic effect of TRAIL can be enhanced by modulating the Akt/FLIPSpathway in human gastric cancers.
Thymic lymphomas in Wistar rats exposed to N‐methyl‐N‐nitrosourea (MNU)
Authors: Franchi Carla Adriene da Silva , Bacchi Maura Moscardi , Padovani Carlos Roberto , de Camargo João Lauro Viana
Published: August 2005

The Brazilian Agency for the Environment (IBAMA) recently adopted an alternative medium‐term multiple‐organ assay system with the Wistar rat strain for detection of the carcinogenic potential of pesticides. Originally, this initiation‐promotion protocol was established in Japan with the isogenic Fischer 344 male rat. Among the initiating agents used in that assay, N‐methyl‐N‐nitrosourea (MNU) rapidly induces malignant lymphoma and leukemia and early mortality of rats from different strains. This study was developed to evaluate whether the outbred Wistar rats are also similarly susceptible to MNU. Particularly, it aimed to evaluate the dose‐response relationship and to register the MNU‐induced pre‐neoplasia and neoplasia that may develop in the lympho‐hematopoietic system (LHS) of the Wistar rat within a medium‐term period. Four groups of male Wistar rats were treated during 2 weeks with vehicle or with MNU (80, 160 or 240 mg/kg body weight, i.p.). After sacrifice at the 12th and 20th weeks, the thymus, spleen, bone marrow, cervical and mesenteric lymph nodes and liver were collected for analysis. At the 20th week, LHS malignant tumors and benign vascular tumors occurred only in the high‐ and intermediate‐dose MNU‐treated animals. Four animals treated with 240 mg/kg developed diffuse thymic lymphomas; two others, treated respectively with 240 mg/kg and 160 mg/kg, developed spleen hemangiomas. The present observations indicate that the Wistar strain is as susceptible as other strains to the early development of MNU‐induced LHS (pre)neoplasia. Therefore, this strain seems suitable to be used as test system in bioassay protocols that adopt MNU as an initiating agent for carcinogenesis. (Cancer Sci 2003; 94: 240–243)
Enhanced sensitivity to cis‐diamminedichloro‐platinum(II) of a human carcinoma cell line with mutated p53 gene by cyclin‐dependent kinase inhibitor p21WAF1 expression
Authors: Satou Mamoru , Aizawa Syu , Hayakari Makoto , Ookawa Keizou , Tsuchida Shigeki
Published: August 2005

p53‐mediated induction of p21WAF1, a cyclin‐dependent protein kinase inhibitor, is known to protect cancer cells from the cytotoxic effects of anti‐cancer drugs or γ‐irradiation. Since the p53 gene is frequently inactivated in cancer cells, we examined whether p21WAF1 expression may alter the sensitivity of cancer cells with mutated p53 gene to anti‐cancer drugs. Cells of a colon cancer cell line DLD‐1 were transfected with p21WAF1 expression vector controlled by a tetracycline‐repressable promoter and transfec‐tants were cloned (Dp21–1). p21WAF1 expression induced by removal of tetracycline from culture media repressed cell proliferation and resulted in altered cell shape, suggesting induction of differentiation. Dp21–1 cells with p21WAF1 expression were more sensitive to cis‐diamminedichloroplatinum(II) (CDDP) (IC50 value, 10 μM) than those without p21WAF1 expression (IC50, 22 μM). Sensitivity to doxorubicin was not different between Dp21–1 cells with and without p21WAF1 expression. DNA ladder formation was observed in Dp21–1 cells treated with CDDP, indicating that the enhanced sensitivity to CDDP involves apoptosis. Sodium dodecyl sulfate‐polyacrylamide gel electrophoresis of cytosolic protein revealed that subunit protein bands with Mr 55 kDa and 44 kDa were markedly increased in cells with p21WAF1 expression. By im‐munoblotting, these proteins were identified as c‐Jun N‐terminal kinase (JNK) 2 and p38 mitogen‐activated protein kinase (MAPK) 8, respectively, both of which are believed to be involved in apoptosis induction by CDDP. These results suggest that p21WAF1 may enhance the sensitivity of colon cancer cells with mutated p53 gene to CDDP, possibly through the JNK and p38 MAPK pathways. (Cancer Sci 2003; 94: 286–291)
Detection of p16 promoter hypermethylation in serum of gastric cancer patients
Authors: Kanyama Yasuaki , Hibi Kenji , Nakayama Hiroshi , Kodera Yasuhiro , Ito Katsuki , Akiyama Seiji , Nakao Akimasa
Published: August 2005

For the early detection of tumor‐related aberrant DNA in the serum of patients, we examined promoter hypermethylation of the p16 gene using methylation‐specific PCR (MSP) in paired tumor and serum samples of 60 gastric cancer patients. Aberrant p16 methylation was found in 23 of 60 (38%) primary gastric cancers, but in none of the corresponding gastric mucosae. Of these 23 patients, 6 (26%) exhibited the same alteration in their serum DNA. As a control, we screened for aberrant methylation in the serum DNA of 37 patients with gastric cancers whose corresponding tumor DNA had no methylation in the p16 promoter. We also screened for methylation in the serum DNA of 16 non‐cancer individuals. No methylation was found in serum DNA of these control groups. Our results suggest that p16 methylation would be a good marker for the detection of tumor DNA in the serum of primary gastric cancer patients. (Cancer Sci 2003; 94: 418–420)
Molecular mechanisms of angiogenesis in non‐small cell lung cancer, and therapeutics targeting related molecules
Authors: Yano Seiji , Nishioka Yasuhiko , Goto Hisatsugu , Sone Saburo
Published: August 2005

Angiogenesis, neovascularization from pre‐existing vasculature, is necessary to supply oxygen and nutrition for tumor growth in both primary and distant organs. It consists of sprouting and non‐sprouting (the enlargement, splitting, and fusion of pre‐existing vessels) processes, and both can occur concurrently. Growth of solid tumors, including non‐small cell lung cancer (NSCLC), is usually dependent on angiogenesis, which is regulated by complex mechanisms involving various angiogenesis‐related molecules. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), one of the most potent angiogenic molecules, regulates both angiogenesis and vascular permeability, and hence promotes tumor progression and development of malignant pleural effusions in NSCLC. Signals via epidermal growth factor receptor (EGFR) promote not only the tumor cell cycle, but also the process of angiogenesis. Therefore, these molecules are potential targets for anti‐tumor vasculature therapy. Many agents targeting tumor vasculature have been developed, and several compounds have shown anti‐tumor potential in pre‐clinical studies. Their efficacy against NSCLC is currently being evaluated in clinical trials.
Associations between cigarette smoking and the risk of four leading cancers in Miyagi Prefecture, Japan: A multi‐site case‐control study
Authors: Minami Yuko , Tateno Hiroo
Published: August 2005

Although cigarette smoking is a well‐known risk factor of lung cancer, associations of cigarette smoking with the risk of other sites have not been fully elucidated in Japan. To simultaneously evaluate the associations of cigarette smoking with the risks of cancers of the stomach, lung, colon, and rectum, which have been the leading cancer sites in recent years in Miyagi Prefecture, Japan, we conducted a hospital‐based case‐control study. Study subjects consisted of 614 stomach, 515 lung, 324 colon, and 164 rectal cancer cases and 2444 hospital controls admitted to a single hospital in Miyagi Prefecture from 1997 to 2001. Information on smoking habit and other lifestyle factors was collected using a self‐administered questionnaire. Distributions of referral base among cases and controls were also investigated. For each site, odds ratios (ORs) and 95% confidence intervals (95% Cls) for smoking habit were estimated with adjustment for age, year of survey, history of alcohol drinking, family history of index cancer, and occupational history, respectively, using an unconditional logistic regression model. Cigarette smoking (ever vs. never) was associated with an increased risk of stomach (OR=1.62; 95% Cl 1.20–2.19) and lung (OR=3.82; 95% Cl 2.49–5.86) cancer among males and lung cancer among females (OR=2.02; 95% Cl 1.28–3.18). For female stomach cancer, the association with cigarette smoking was uncertain (OR=0.65, P=0.1533). For rectal cancer, a significant increased risk was observed in both‐sex‐combined analysis. There was no association between cigarette smoking and the risk of colon cancer. Detailed analysis showed that the association of cigarette smoking with cancer risk might be modified by the patient referral pattern, i.e., screened or not screened. The present results indicate that the association of cigarette smoking with cancer risk may differ among sites and sexes. In terms of the population attributable risk, a large proportion of leading cancers in males appears to be related to cigarette smoking.
The role of circulating IL‐8 and VEGF protein in the progression of gastric cancer
Authors: Konno Hiroyuki , Ohta Manabu , Baba Megumi , Suzuki Shohachi , Nakamura Satosi
Published: August 2005

Both vascular endothelial growth factor (VEGF) and interleukin 8 (IL‐8) play an important role in the progression of gastric cancer (GC). In this study, we investigated whether circulating levels of VEGF or IL‐8 in drainage veins of GC patients were correlated with any clinicopathological factors. Thirty‐seven patients with primary GC who underwent gastrectomy at our department between 1999 and 2002 were analyzed. Blood samples were drawn from a peripheral vein just before surgery and from a drainage vein immediately after laparotomy. Plasma VEGF levels were significantly higher than those in 10 healthy controls. There was no correlation between VEGF levels in drainage veins and any clinicopathological variable, whereas there was a significant relationship in the case of VEGF levels in peripheral veins; the levels were higher in patients with venous invasion. We found a significant relationship between IL‐8 levels in drainage veins and both tumor size and lymph node metastasis, whereas no significant relationship between IL‐8 levels in peripheral veins and any variable was found. There was no correlation between VEGF and IL‐8 levels in drainage veins. Large tumors, deeply invasive tumors, lymph node involvement, venous invasion and high IL‐8 levels in drainage veins were all significantly associated with shorter disease‐free survival, although multivariate analysis revealed that lymph node involvement was the only independent prognostic factor. In conclusion, the measurement of IL‐8 levels in drainage veins of GC patients may reflect production mainly by the primary lesion and is valuable as an indicator of risk for recurrent disease.
Effect of 5‐fluorouracil and epidermal growth factor on cell growth and dihydropyrimidine dehydrogenase regulation in human uterine cervical carcinoma SKG‐IIIb cells
Authors: Kashima Naomi , Ueda Masatsugu , Kanazawa Junji
Published: August 2005

We previously demonstrated that epidermal growth factor (EGF) induces a decrease in dihydropyrimidine dehydrogenase (DPD), which is the first and rate‐limiting enzyme in the catabolism of 5‐fluorouracil (5‐FU), in EGF receptor (EGFR)‐positive human SKG‐IIIb uterine cervical carcinoma cells, and thereby increased the sensitivity of the cells to 5‐FU. In the present study, we examined the individual and combined effects of 5‐FU and EGF on growth and DPD activity in SKG‐IIIb cells, and also investigated the mode of regulation of DPD activity. The cells showed sensitivity to 5‐FU, and growth was stimulated by EGF. When the agents were used in combination, the sensitivity of SKG‐IIIb cells to 5‐FU was increased roughly sixfold at maximum, as judged in terms of the 50% growth‐inhibitory concentration. We then examined the effects of 5‐FU and EGF on DPD. Either agent inhibited DPD activity and protein expression in a concentration‐dependent manner. Expression of DPD mRNA was concentration‐dependently inhibited by treatment with 5‐FU and by EGF at a concentration that strongly stimulated cell growth. Further, combination treatment inhibited DPD activity, as well as DPD protein and mRNA expression, more strongly than did treatment with 5‐FU or EGF alone. These results suggest that inhibition of DPD activity by EGF or 5‐FU is regulated at least at the level of protein expression and that regulation via mRNA is also involved. The above findings indicate that 5‐FU and EGF act synergistically in suppressing DPD activity and that the use of 5‐FU against tumors in which EGF plays an important role would maximize the potential of 5‐FU as an anticancer drug.
Activation of c‐Met (hepatocyte growth factor receptor) in human gastric cancer tissue
Authors: Inoue Takao , Kataoka Hiroaki , Goto Kouichiro , Nagaike Koki , Igami Ko , Naka Daiji , Kitamura Naomi , Miyazawa Keiji
Published: August 2005

c‐Met is a high‐affinity receptor for hepatocyte growth factor (HGF) and plays a crucial role in embryonic development, as well as in the process of tissue repair. Overexpression and amplification of c‐Met are often observed in various cancer tissues, especially in gastric carcinoma. It has, however, been unclear whether the overexpression leads to activation of the c‐Met receptor. To address this point, we prepared an antibody (anti‐phospho‐Met) which specifically recognizes c‐Met that is phosphorylated at Y1235, a major phosphorylation site of c‐Met. Normal as well as cancerous gastric tissue was positive for anti‐total‐Met staining, whereas only cancerous tissue was strongly positive for anti‐phospho‐Met staining; cells near the basal layer were moderately positive, and the proliferative zone in normal tissue was only weakly positive. Among cancerous tissues from seven patients examined in the present study, those from six patients were strongly positive for phospho‐Met staining. These results indicate that c‐Met is actually activated in gastric carcinoma tissue, and may trigger proliferation/anti‐apoptotic signals.
Frequent promoter methylation and gene silencing of CDH13 in pancreatic cancer
Authors: Sakai Mitsuru , Hibi Kenji , Koshikawa Katsumi , Inoue Soichiro , Takeda Shin , Kaneko Tetsuya , Nakao Akimasa
Published: August 2005

It has recently been reported that CDH13 expression is silenced by aberrant methylation of the promoter region in several cancers. We examined the methylation status of the CDH13 gene in pancreatic cancer using methylation‐specific PCR (MSP), and detected aberrant methylation of CDH13 in all 6 pancreatic cancer cell lines examined. To confirm the status of the CDH13 gene in relation to the methylation pattern, we next examined CDH13 expression in these cell lines using reverse transcription (RT)‐PCR. As expected, no CDH13 expression was detected in any of the 6 pancreatic cancer cell lines. Moreover, 5‐aza‐2′‐deoxycytidine (5‐aza‐dC) treatment of CDH13‐methylated cell lines led to restoration of CDH13 expression. Among primary pancreatic cancers, 19 of 33 (58%) cases exhibited CDH13 methylation, while no cases exhibited it in corresponding normal pancreatic tissues. CDH13 methylation was detected even in relatively early pancreatic cancers, such as stage II cancers and cancers less than 2 cm in diameter. Our results suggest that the aberrant methylation of CDH13 occurs frequently in pancreatic cancer, even at a relatively early stage.