bluuebunny/crossref_metadata_2025 huggingface dataset:
Overview: Dealing with Crises
Authors: Chui Michael , Gai Prasanna
Published: August 2005

Presents an overview of Part 2 of the book—the management of financial crises. Sovereign bankruptcy and creditor coordination are at the center of this debate. The contractual and statutory approaches to crisis resolution, which lay stress on collective action clauses and formal structures for sovereign debt restructuring are introduced.
Risk Aversion, Background Risk, and the Pricing Kernel
Authors: Poon Ser-Huang , Stapleton Richard
Published: August 2005

‘Risk Aversion, background Risk, and the Pricing Kernel’ looks in more detail at utility functions and their effect on the shape of the pricing kernel. The authors discuss the meaning of risk aversion and, in particular, ‘relative risk aversion’ and show that if relative risk aversion is constant at different levels of wealth, then the pricing kernel exhibits constant elasticity. They then show that the introduction of ‘background risk’, that is, non-hedgeable risks, causes the pricing kernel to exhibit declining elasticity. This effect on the pricing kernel is particularly significant for the pricing of options.
Policies for promoting growth
Authors: Sapir André , Aghion Philippe , Bertola Giuseppe , Hellwig Martin , Pisani-Ferry Jean , Rosati Dariusz , Viñals José , Wallace Helen , Buti Marco , Nava Mario , Smith Peter M.
Published: August 2005

This chapter discusses policies for promoting economic growth in the European Union. These policies address two areas: measures to improve policies adopted in the past, and policies that go beyond the complementary policies that have been pursued to date. Some include promoting the entry of new players into the market, increasing investments in education and in research and development, and improving the macroeconomic policy framework of the Economic and Monetary Union.
The Contemporary Context
Authors: Brown David
Published: August 2005

The first part of the chapter considers non-ecclesial buildings, and uses work by a range of modern architects to argue that their potential role as mediators of the divine is in fact far more deeply entrenched than the alleged total secularity of modern culture might suggest. The second half of the chapter then explores ‘Church Architecture in Crisis’ and detects a failure of nerve that suggests the reduction of the building to the narrowly instrumental.
Widening the Perspective
Authors: Brown David
Published: August 2005

Although earlier chapters had occasional examples from a non-Christian context, here deeper presumptions are made explicit - that the generosity of God means that the divine is experienced through the material much more widely. Hindu temples and Muslim mosques are examined and sympathetic treatment is argued for both. The mediatorial character of gardens is conspicuous in Islam’s Paradise gardens and in Zen rock gardens. If modern sport might initially seem at the opposite extreme to the attitude evinced in the ancient Olympic Games, it is suggested otherwise by the exploration here of the use of sport as a religious metaphor in the modern cinema. The aim is not to suggest complete compatibility with Christianity in all such cases, but rather the importance of acknowledging that experience of God is to be found much more widely than any particular religion.
Building Europe's Parliament
Authors: Rittberger Berthold
Published: August 2005

Why have national governments of EU member states created and, over the past fifty years, successively endowed the European Parliament with supervisory, budgetary, and legislative powers? This book presents a three-staged argument to explain how the European Parliament acquired this power ‘trias’. First, it is argued that the construction of a supranational polity induces political elites in the member states to reflect on the implications posed by transfers of national sovereignty for domestic processes of democratic accountability and interest representation. It is shown empirically that there exists a strong correlation between national governments’ decisions to transfer sovereignty and political elites’ perception of a ‘democratic legitimacy deficit’ that triggers a search for institutional solutions for its remedy. In a second step, it is argued that political elites, first and foremost, domestic political parties, advance different proposals to alleviate the perceived ‘legitimacy deficit’. These proposals are derived from ‘legitimating beliefs’ that vary cross-nationally and across political parties. Consequently, the creation and empowerment of a supranational parliamentary institution plays a prominent but not exclusive role as potential remedy to the ‘democratic legitimacy deficit’. Third, the book illuminates the mechanisms through which ‘legitimating beliefs’ expressed by political elites and the behaviour of national governments who negotiate and decide on the creation and potential empowerment of the European Parliament are linked. What logic of action best captures national governments’ decisions to empower the European Parliament? The explanatory power of the theoretical argument will be explored by looking at three landmark cases in the European Parliament’s history: its creation as ‘Common Assembly’ of the ECSC Treaty and the concomitant acquisition of supervisory powers vis-à-vis the High Authority, the acquisition of budgetary powers (Treaty of Luxembourg of 1970) and of legislative powers (Single European Act signed in 1986). The developments ranging from the Maastricht Treaty to the adoption of the Treaty establishing a Constitution for Europe will also be analysed in the light of the theory.
1 The Empowerment of the European Parliament: Lessons from the New Institutionalism and Democratic Theory
Authors: Rittberger Berthold
Published: August 2005

Reviews the new institutionalist literature on institution-building and derives expectations based on rational choice and sociological institutionalism for explaining the empowerment of the European Parliament. Since concerns about ‘democratic legitimacy’ are cited frequently in the literature on European integration as ad hoc-explanations for the empowerment of the European Parliament, this chapter will also turn to work on the ‘democratic deficit’ and inquire whether this literature offers any cues to improve our understanding of the existence and empowerment of the European Parliament.
6 From Maastricht to the Constitutional Treaty: the Return of National Parliaments?
Authors: Rittberger Berthold
Published: August 2005

Analyses the developments from the Maastricht Treaty leading up to the approval of the Treaty establishing a Constitution for Europe. It is first shown that after adoption of the SEA, the role of national parliaments in EU decision-making has become an ever more salient item on the agenda of the member states. Asks whether this ‘trend’ towards empowering national parliaments follows the same logic as the empowerment of the European Parliament. Furthermore, the chapter explains why the empowerment of national parliaments still lags behind that of its EU-level counterpart, the European Parliament.
Grotius
Authors: Wight Martin
Published: August 2005

Grotius is acknowledged as the father of International Law. His thought is marked by richness and complexity. He was a reconciler and synthesizer, favoured ‘the middle way’ and advocated the reunion of Christendom. He believed not that war could be abolished but that its effects could be mitigated—his aim was to reduce suffering. He held that the existence of society reflected natural law, which is also to be found in the doctrine of prescription. Beyond natural law is the hierarchy of the moral life dependent ultimately upon individual moral responsibility.
Mazzini
Authors: Wight Martin
Published: August 2005

Mazzini was a nationalist, a revolutionary, and a romantic. Although an ex-Catholic, he was deeply sympathetic to religion. He saw progress as the law of God, and duty as what man owed to God. He was a democratic socialist who had contempt for power politics, as in the diplomatic manoeuvrings of Cavour. His brief dictatorship over Rome was based on high moral principles. He believed that God had allotted roles for the major European nations, seeing in this a special destiny for Italy and Rome.
The Dynamics of Losers' Consent: Persistence and Change in the Winner–Loser Gap
Authors: Anderson Christopher J. , Blais André , Bowler Shaun , Donovan Todd , Listhaug Ola
Published: August 2005

Traces the dynamics of losers’ and winners’ attitudes about the political system along three dimensions—before and after an election, over the course of electoral cycles, and over long periods of time. The results show that winning or losing, once it occurs, has immediate but also lasting effects. New electoral losers (old winners) become less content with the political system. Conversely, new winners (old losers) become significantly more positive about the political system. These effects persist over the course of an electoral cycle and beyond, as losers remain consistently less satisfied than winners between elections. Finally, we show that repeated losing serves to increasingly undermine losers’ attitudes towards the political system—while losing once does not immediately serve to undercut losers’ attitudes towards government, losing twice starts a process that leads to a gradual erosion of support for a system that consistently fails to make them winners.
How Political Institutions Shape Losers' Consent
Authors: Anderson Christopher J. , Blais André , Bowler Shaun , Donovan Todd , Listhaug Ola
Published: August 2005

The authors examine how formal political institutions mute or amplify the impact of losing on attitudes toward the political system. They can do so in one of several ways: by defining the rules of the process by which losers are produced in the first place, usually through the electoral system; by determining the substance of government policy, and how close policy is to the preferences of the losers; and, finally, by determining the boundaries of how power, once allocated, can be exercised by the winners, that is, the constraints on the ability of the winners to bring about policy change. We find that specific institutions, and not just combinations of institutions, help to shape the response of losers. Losers express less negative views about the political system than winners when electoral rules are more proportional, when the political system has a greater number of veto players, and when power is shared within the political system. We also show that federalism allows losers some say in the system, and therefore helps make losers more positive towards the system.
An Anatomy of Emotion
Authors: Pugmire David
Published: August 2005

Emotions can involve various levels of thought about the objects that attract them. They also involve (at least a disposition to) aroused feeling—affective response to perceived affective qualities. This registers in the fullest immediate way the value found in an emotion’s object. Indeed, certain values cannot be understood or acknowledged by creatures who lack the appropriate affective capacities. Because of the worth that emotions variously find and give, there are sorts of worth they themselves come to be given. This can rebound on emotional responses themselves, giving them or denying them, now at a third level, distinctive kinds of worth.
Profundity in Emotion
Authors: Pugmire David
Published: August 2005

Deep emotion is more than strongly felt emotion. It depends on the satisfaction of four conditions: real belief (the cognitive basis of the emotion must be robust); integration into a larger fabric of experiences and concerns; truth (the world must accord with what the emotion seeks to make of it); and strength of feeling. The truth requirement means that emotional depth is not just a psychological property of emotion. In certain cultural ambiences, emotional depth might become unattainable.
Cynicism and Safe Sentiment
Authors: Pugmire David
Published: August 2005

Cynicism, with its wariness of pleasant views, appeals as a prophylactic against sentimentality. It offers to forswear good feeling and live with bleak truth. Cynicism is one of five related attitudes. Less truthful than it seems, it is insistent and motivated, for it is driven by disdain and pride. As such, it manages to be at once emotionally constrictive and sentimental, after all.
Beginning of a Friendship
Authors: Small Robin
Published: August 2005

Presents the background to the formation of the friendship in 1876, by discussing Nietzsche’s early academic career and first important publications, The Birth of Tragedy and the Untimely Meditations. In Richard Wagner in Bayreuth, we can see Nietzsche uncomfortable with the standpoint of these works. A sympathy with natural science was always present in his thinking, but it was a growing dissatisfaction with the Wagnerian movement whose spokesman he had become that made him ready for a sharp change of direction, away from metaphysical romanticism towards a positivistic and scientific viewpoint, as well as the ‘cool’, self-disciplined style of writing that he found in Paul Rée’s work.
Nietzsche's New Direction
Authors: Small Robin
Published: August 2005

Nietzsche learned from both the style and content of Rée’s work but used them in his own way. This chapter discusses Nietzsche’s understanding of the ‘historical approach to philosophy’, which he linked with both Hegel and Darwin. Much of the chapter is concerned with Nietzsche’s new style of writing, with particular attention to his uses of the aphoristic form, not just by itself but within broader contexts such as the short essays of Human, All-Too-Human and the dramatic discourses of Thus Spake Zarathustra. The advantages as well as the disadvantages of the aphorism are discussed.
From Altruism to Morality
Authors: Small Robin
Published: August 2005

Examines the moral psychology presented in The Origin of the Moral Sensations. Borrowing from British associationist psychology, Rée maintains that an original valuation of behaviour according to its utility has given rise to the moral sense that treats an action as ‘good’ or ‘bad’ in itself, apart from its beneficial or harmful consequences. Utilitarianism is here combined with a Darwinian and Lamarckian model of evolutionary change, although Rée disagrees with Darwin’s account of remorse as essentially a frustration of social instincts of sympathy and loyalty, suggesting that it fails to acknowledge the specificity of morality.
Nietzsche's Retreat from Réealism
Authors: Small Robin
Published: August 2005

Nietzsche’s allegiance to Rée’s theories was never complete—the moral psychology found in Human, All-Too-Human resembles Rée’s and yet shows differences in some important areas, such as its account of religious experience. A re-emergence of Nietzsche’s individuality and originality is identifiable in the further books that begin with Daybreak. His views on the origin of society were strongly influenced by Walter Bagehot, who asserted the materiality of social discipline and the importance of a ‘herd instinct’. This emphasis makes Nietzsche’s version of evolutionary thought far closer to Darwin’s than Rée’s theory had been.
End of a Friendship
Authors: Small Robin
Published: August 2005

Dramatic events during the autumn of 1882 resulted in the ending of Nietzsche and Rée’s friendship. Their meeting with the young Lou Salomé led to the formation of an unconventional ‘trinity’, with ambitious plans for a shared life of study and work. But the three-way relationship was made unstable by an unacknowledged rivalry between the two men for Lou’s loyalty, and the intrigues of Nietzsche’s conventional and possessive sister Elisabeth. The tense situation ended in painful estrangement, and a wounded Nietzsche retreated to the Italian Riviera, where he began a new kind of writing with Thus Spake Zarathustra.
Egoism Rehabilitated
Authors: Small Robin
Published: August 2005

In On the Genealogy of Morals (1887), Nietzsche criticizes the ideas of the ‘English psychologists’—in fact, the account of the moral sense he had earlier borrowed from Rée—and elaborates his own alternative. In many ways, this is the naturalistic approach taken further, not just explaining valuation but placing values themselves in question, and opening up the possibility of their re-valuation through a new conception of the life process. This chapter presents Nietzsche’s rehabilitation of egoism through his engagement with Herbert Spencer’s ethics, arguing that his hostility is largely due to an unacknowledged amount of common ground.
Against Coherence
Authors: Olsson Erik J.
Published: August 2005

According to the popular coherence theory of knowledge and justification, if a person's beliefs are coherent, they are also likely to be true. This book is the most extensive and detailed study of coherence and probability to date. The book takes the reader through much of the history of the subject, from early theorists like A. C. Ewing and C. I. Lewis to contemporary figures like Laurence BonJour and C. A. J. Coady. The arguments presented are general enough to cover coherence between any items of information, including those deriving from belief, memory, or testimony. It is argued that coherence does not play the positive role that it is generally ascribed in the process whereby beliefs are acquired. The opposite of coherence, incoherence, is nonetheless the driving force in the process whereby beliefs are retracted.
Other Coherence Theories
Authors: Olsson Erik J.
Published: August 2005

Other accounts of coherence are described and compared with the present theory. They include those of Nicholas Rescher, Donald Davidson, Keith Lehrer, and Paul Thagard, whereby the latter’s theory of explanatory coherence is seen to be most relevant. Closer examination reveals that there is little in Thagard’s argumentation suggesting that coherence is truth conducive, be it only in a weak ceteris paribus sense.
Auctions II: Dependent Values
Authors: Bergin James
Published: August 2005

Considers auctions with non-independent valuations. Equilibrium bidding behaviour in the first price, second price, and English auctions is characterized. Revenue comparisons are given, showing that the revenue equivalence theorem fails for the standard auctions when values are correlated. The linkage principle (price is positively ‘linked’ to information) is described. Finally, full surplus extraction is discussed at length.
Extensive Form Games
Authors: Bergin James
Published: August 2005

Introduces extensive form games. Informations structures—perfect, imperfect, and incomplete information are explained. Pure behavioural and mixed strategies are defined. Finally, perfect recall and the equivalence of mixed and behavioural strategies (in terms of end point distributions) is considered.
The Principal–Agent Problem
Authors: Bergin James
Published: August 2005

The principal-agent problem is considered. The full information case is taken as the benchmark and efficient risk allocation with a risk averse principal and risk averse agent is considered, again with full information. Turning to the incomplete information case, unobservable effort raises the key incentive problem. The first order approach is discussed at length and key conditions for sufficiency of the approach examined.
Evolution and Learning
Authors: Bergin James
Published: August 2005

Studies evolution and learning. The discussion includes fictitious play and replicator dynamics, and stochastic stability is considered at length. Following this, some detailed discussion of stochastic stability is given, including the computation of invariant distributions and minimum cost trees. Blackwell approachability is used to define strategies that minimize regret across all actions. This is then connected to correlated equilibrium. Calibrated forecasts are defined, and a connection to correlated equilibria also noted. Provides a brief discussion of Bayesian learning and the key role of the martingale convergence theorem.
Farm Labour Productivity in Jiangnan, 1620–1850
Authors: Li Bozhong
Published: August 2005

Contrary to the conventional view, labour productivity on farms in Jiangnan, the Yangzi Delta in East China, did not deteriorate or stagnate but instead improved between 1620 and 1850. Changes in the factors of major production of farming and in the peasant economy both contributed to the improvement and this development resulted in a rising standard of living of peasants. Neither an old, misleading Malthusian conception nor conventional wisdom on the standard of living, therefore, squares with what we know of Jiangnan history.
Health and Nutrition in the Pre-Industrial Era: Insights from a Millennium of Average Heights in Northern Europe
Authors: Steckel Richard H.
Published: August 2005

Gives perspective to the debate over living standards during industrialization by examining health and nutrition over the past 1200 years using stature either recorded on military records or inferred from skeletal remains. From an average of 173.4 cm in the early Middle Ages, the heights of men fell approximately 6.4 cm, reaching a minimum sometime in the seventeenth or eighteenth century, and recovery to levels of a millennium earlier was not attained until the 1920s. The decline that began in the late Middle Ages may be linked with a cooler and more variable climate; growing inequality; urbanization; fluctuations in population size that impinged on nutritional status; the global spread of diseases associated with European expansion and colonization; and wars over state building or religion. The upturn well underway by the nineteenth century was associated initially with dietary improvements and later with reduced exposure to disease related to public health measures and better housing.
New Evidence on the Standard of Living in Sweden During the Eighteenth and Nineteenth Centuries: Long-Term Development of the Demographic Response to Short-Term Economic Stress
Authors: Bengtsson Tommy , Dribe Martin
Published: August 2005

Presents a new view of the standard of living development in Sweden during the agricultural revolution, using evidence on the ability to overcome short-term economic stress. The results corroborate previous findings, based on a variety of indicators, that standard of living in Sweden increased for most people after the mid-nineteenth century, but also support a more negative view of the immediate effects of the agricultural transformation in the beginning of the nineteenth century on the landless groups in society.
Why the Village Has No Power: Land Ownership Disputes and Customary Tenure
Authors: Ho Peter
Published: August 2005

Starts with a historical analysis of China’s land property structure and its weaknesses. It is argued that the former production team exercised no real power over land, even though it enjoyed formal land ownership. Instead, control over land ownership resided with the commune and the local state. This has resulted in frequent illegal land expropriation, the neglect of customary rights, and the failure to register land. Through an analysis of a unique set of court cases it is shown how this historical background is the source for many land disputes between the state and the collective.
Prognostic significance of UDP‐N‐acetyl‐α‐D‐galactosamine:polypeptide N‐acetylgalactosaminyltransferase‐3 (GalNAc‐T3) expression in patients with gastric carcinoma
Authors: Onitsuka Koji , Shibao Kazunori , Nakayama Yoshifumi , Minagawa Noritaka , Hirata Keiji , Izumi Hiroto , Matsuo Ken‐ichi , Nagata Naoki , Kitazato Kenji , Kohno Kimitoshi , Itoh Hideaki
Published: August 2005

Aberrant glycosylation occurs during development of gastric carcinomas. The initiation of mucin‐type O‐glycosylation is regulated by GalNAc‐T3 (UDP‐N‐acetylgalactosamine:polypeptide N‐acetyl‐galactosaminyltransferase‐3). However, the clinical significance of GalNAc‐T3 expression in human gastric carcinoma has not yet been demonstrated. In the present study, we investigated the relationship between immunohistochemical GalNAc‐T3 expression and various clinicopathologic factors, including prognosis, in 117 gastric carcinoma patients. Of 117 gastric carcinomas examined, 59 (50.4%) showed strong expression of GalNAc‐T3. Strong expression was detected in 38 of 59 (64.4%) differentiated type and in 21 of 58 (36.2%) undifferentiated gastric carcinomas, indicating that the expression of GalNAc‐T3 correlated significantly with tumor differentiation (P=0.0023, x2 test). Overall 5‐year survival rate in patients with strong GalNAc‐T3 expression (71.0%) was significantly better than that of patients with weak expression (49.3%) (P=0.0197, log‐rank test). Multivariate analysis identified GalNAc‐T3 expression as an independent prognostic factor (P=0.0158, Cox proportional hazards model). Our data suggest that GalNAc‐T3 expression may be a useful marker for prognosis and differentiation of gastric carcinomas. (Cancer Sci 2003; 94: 32–36)
Expression of the coxsackievirus and adenovirus receptor in musculoskeletal tumors and mesenchymal tissues: efficacy of adenoviral gene therapy for osteosarcoma
Authors: Kawashima Hiroyuki , Ogose Akira , Yoshizawa Tatsuya , Kuwano Ryozo , Hotta Yuko , Hotta Tetsuo , Hatano Hiroshi , Kawashima Hiroyuki , Endo Naoto
Published: August 2005

Recombinant adenovirus is used as a competent vector in a wide spectrum of cancer gene therapies. Adenovirus infection depends on coxsackievirus and adenovirus receptor (CAR)‐mediated virus attachment to the cell surface. However, the expression levels of CAR and the efficiency of adenoviral gene transduction in musculoskeletal tumors have not been systematically investigated. To study the feasibility of gene therapy in musculoskeletal tumors, the expression levels of CAR and the antiproliferative effect of an adenovirally transduced wild‐type p53 tumor suppressor gene were examined in 15 distinct musculoskeletal tumor cell lines, 19 tumor tissue samples, and the corresponding pathologically unremarkable mesenchymal tissues. The expression levels of the CAR gene were significantly higher in six of seven osteosarcoma cell lines and two of five osteosarcoma tissue samples than in the other cell lines, musculoskeletal tumors, and mesenchymal tissues. CAR expression levels were closely correlated with adenoviral gene transduction efficiency and the antiproliferative effect of a transduced adenoviral p53 gene in the tested cell lines. In addition, an immunocytochemical study confirmed that transfected green fluorescent protein (GFP) borne by Ad‐CAG‐GFP was expressed at the cell surface of CAR‐positive cells. These results indicate that CAR expression is a critical determinant of transduction efficiency in adenovirus‐based gene therapy. Most osteosarcomas appeared to express high levels of CAR, and thus adenovirus‐mediated p53 gene therapy is likely to be suitable for the treatment of such tumors. (Cancer Sci 2003; 94: 70–75)
Lack of correlation between expression of human mammaglobin mRNA in peripheral blood and known prognostic factors for breast cancer patients
Authors: Lin Yung‐Chang , Chen Shin‐Chie , Hsueh Swei , Lo Yung‐Feng , Chow‐Wu Ye‐Hwei , Liaw I‐Chin , Cheng An‐Joy
Published: August 2005

Human mammaglobin (hMAM) mRNA is considered to be a promising candidate for a sensitive molecular marker for breast cancer. In this study, we attempted to relate the presence of hMAM mRNA in the peripheral blood with certain established clinico‐pathological features of breast cancer in order to validate its clinical utility. A total of 139 subjects including 79 with localized cancer, 33 with metastatic disease, and a control group of 27 individuals were studied. hMAM mRNA expression was assessed by reverse transcriptase polymerase chain reaction on cells from peripheral blood. The expression of hMAM mRNA was found in 0 of the 27 control subjects, 1 of the 8 stage 0 (12.5%) patients, 4 of the 16 stage I (25%) patients, 13 of the 40 stage II (32.5%) patients, 5 of the 15 stage III (33.3%) patients, and 18 of the 33 (54%) cases of metastatic disease. There was a statistically significant (P=0.045) difference in frequency between patients with localized disease (29%) and those with metastatic disease. Although trends of increasing frequency of hMAM mRNA expression existed in patients with unfavorable prognostic factors, including primary tumor size, T stage, N stage, overall stage, presence of angiolymphatic permeation, negative estrogen receptor, high S‐phase fraction (>7%), and aneuploid DNA index, none of the differences was significant. In conclusion, the clinical utility of hMAM mRNA may not be in screening or staging of breast cancer, but in following patients after surgery to detect recurrence. Further evaluation of hMAM mRNA in combination with other molecular markers to follow post‐operative breast cancer patient is warranted. (Cancer Sci 2003; 94: 99–102)
Characterization of cell death induced by ethacrynic acid in a human colon cancer cell line DLD‐1 and suppression by N‐acetyl‐l‐cysteine
Authors: Aizawa Shu , Ookawa Keizou , Kudo Toshihiro , Asano Junpei , Hayakari Makoto , Tsuchida Shigeki
Published: August 2005

Since ethacrynic acid (EA), an SH modifier as well as glutathione S‐transferase (GST) inhibitor, has been suggested to induce apoptosis in some cell lines, its effects on a human colon cancer cell line DLD‐1 were examined. EA enhanced cell proliferation at 20–40 μM, while it caused cell death at 60–100 μM. Caspase inhibitors did not block cell death and DNA ladder formation was not detected. Poly(ADP‐ribose) polymerase, however, was cleaved into an 82‐kDa fragment, different from an 85‐kDa fragment that is specific for apoptosisis. The 82‐kDa fragment was not recognized by antibody against PARP fragment cleaved by caspase 3. N‐Acetyl‐l‐cysteine (NAC) completely inhibited EA‐induced cell death, but 3(2)‐t‐butyl‐4‐hydroxyanisole or pyrrolidinedithiocarbamate ammonium salt did not. Glutathione (GSH) levels were dose‐dependently increased in cells treated with EA and this increase was hardly affected by NAC addition. Mitogen‐activated protein kinase (MAPK) kinase (MEK) 1, extracellular signal‐regulated kinase (ERK) 1 and GST P1‐1 were increased in cells treated with 25–75 μM EA, while c‐Jun N‐terminal kinase (JNK) 1 and p38 MAPK were markedly decreased by 100 μM EA. NAC repressed EA‐induced alterations in these MAPKs and GST P1‐1. p38 MAPK inhibitors, SB203580 and FR167653, dose‐dependently enhanced EA‐induced cell death. An MEK inhibitor, U0126, did not affect EA‐induced cell death. These studies revealed that EA induced cell death concomitantly with a novel PARP fragmentation, but without DNA fragmentation. p38 MAPK was suggested to play an inhibitory role in EA‐induced cell death.
Hepatoma‐derived growth factor induces tumorigenesis in vivo through both direct angiogenic activity and induction of vascular endothelial growth factor
Authors: Okuda Yorihide , Nakamura Hideji , Yoshida Kenya , Enomoto Hirayuki , Uyama Hirokazu , Hirotani Tomonori , Funamoto Masanobu , Ito Hiroaki , Everett Allen D , Hada Toshikazu , Kawase Ichiro
Published: August 2005

Hepatoma‐derived growth factor (HDGF) is highly expressed in tumor cells, and stimulates their proliferation. In the present study, we investigated the role of HDGF in tumorigenesis and elucidated the mechanism of action. Stable transfectants of NIH3T3 cells overexpressing HDGF did not show significant anchorage‐independent growth in soft agar assay. However, these stable transfectants overexpressing HDGF generated sarcomatous tumors in nude mice. These tumors were red‐colored macroscopically, and histologically showed a rich vascularity. Immunohistochemical analysis using CD31 antibody showed new vessel formation. Recombinant HDGF stimulated proliferation of human umbilical vein endothelial cells in a dose‐dependent manner, and stimulated tubule formation. Furthermore, vascular endothelial growth factor (VEGF) was detected immunohistochemically in the tumor tissues. Transient expression of HDGF induced both VEGF gene and protein expression as demonstrated by a reporter assay using VEGF gene promoter. The administration of anti‐VEGF neutralizing antibody significantly suppressed, but did not block, the tumor growth of HDGF‐overexpressing cells in nude mice. Thus, these findings suggested that HDGF‐induced tumor formation in vivo involves induction of VEGF as well as direct angiogenic activity.
Lack of effect of human c‐Ha‐ras proto‐oncogene overexpression on prostate carcinogenesis in probasin/SV40 T antigen transgenic rats
Authors: Hokaiwado Naomi , Asamoto Makoto , Cho Young‐Man , Tsuda Hiroyuki , Shirai Tomoyuki
Published: August 2005

We have previously reported that transgenic (Tg) rats bearing the SV40 T antigen under probasin promoter control (PB/SV40T) develop prostate carcinomas at 100% incidence, showing their prostate carcinoma growth to be completely androgen‐dependent. Transgenic rats carrying three copies of the human c‐Ha‐ras proto‐oncogene (Hras128) are also highly susceptible to carcinogen induction of multiple mammary carcinomas, in this case estrogen‐independent, since ovariectomy does not affect mammary tumor formation. A relationship between ras/mitogen‐activated protein kinase signaling and androgen responsiveness of prostate cancer cells has been reported. Therefore it is of interest to investigate whether expression of human c‐Ha‐ras affects the androgen‐dependence of prostate carcinomas developing in the PB/SV40T Tg rat. For this purpose, we established double transgenic (rasTag) rats bearing both PB/SV40T and Hras128. In prostate tissues of the rasTag rats, expression of both human c‐Ha‐ras and SV40T was confirmed, but the prostate tumor incidence and growth were not significantly affected. Castration at 15 weeks of age induced complete tumor involution in the rasTag rats. These results indicate that the human c‐Ha‐ras proto‐oncogene product does not influence the androgen‐dependence of prostate carcinogenesis due to the probasin‐mediated SV40 T antigen, despite the estrogen‐independence of mammary carcinogenesis in Hras128 rats.
β‐Catenin mutations and nuclear accumulation during progression of rat stomach adenocarcinomas
Authors: Tsukamoto Tetsuya , Yamamoto Masami , Ogasawara Naotaka , Ushijima Toshikazu , Nomoto Tomoko , Fujita Hirofumi , Matsushima Taijiro , Nozaki Koji , Cao Xueyuan , Tatematsu Masae
Published: August 2005

Aberrant Wnt/β‐catenin signaling caused by mutations in exon 3 of the β‐catenin gene has been identified in a number of human malignancies, including stomach cancer. However, studies of mutation frequency have yielded conflicting results, and timing during progression remains largely unknown. In this study, we utilized an animal model to address this question. A total of 20 ACI male rats were treated with N‐methyl‐N′‐nitro‐N‐nitrosoguanidine (MNNG) in the drinking water and 22 induced differentiated adenocarcinomas were histopathologically and immunohistochemically evaluated for β‐catenin localization. Fourteen tumors (63.6%) that showed homogeneous low‐grade morphology, preserving cell polarity, were found to harbor β‐catenin protein on the cell membranes (M). Eight tumors exhibited regions of high‐grade morphology among areas with low‐grade morphology, and they were characterized by denser cell growth and loss of cell polarity. Among these 8 tumors, 4 (18.2%) showed cytoplasmic localization (C) of β‐catenin in small regions. The remaining 4 tumors (18.2%) contained more dysplastic regions that displayed nuclear (N) β‐catenin staining. Analysis of DNA obtained by microdissection demonstrated that all of 4 regions with C staining and 20 with M staining, as well as 17 samples of surrounding normal mucosa (S) had wild‐type β‐catenin. In contrast all of 3 regions with N staining featured mutations (3 of 3=100%; N vs. C, P<0.05; N vs. M and N vs. S, P<0.001, Fisher's exact test) in exon 3, at glycine 34, threonine 41, and serine 45, which affected phosphorylation sites. In conclusion, β‐catenin mutations appear to be associated with the late progression stage of adenocarcinoma development in rat stomach carcinogenesis, in contrast to the case of colorectal cancers, in which mutations appear to occur in the early stages.
Redifferentiation and ZO‐1 reexpression in liver‐metastasized colorectal cancer: Possible association with epidermal growth factor receptor‐induced tyrosine phosphorylation of ZO‐1
Authors: Kaihara Tsukasa , Kawamata Hitoshi , Imura Johji , Fujii Shigehiko , Kitajima Kazuaki , Omotehara Fumie , Maeda Naomi , Nakamura Tetsuya , Fujimori Takahiro
Published: August 2005

Tubular gland structures of colorectal cancer (CRC) have been demonstrated to undergo dedifferentiation at the primary site, and then the gland structures are re‐formed in the liver me‐tastases. In this study, we examined the degree of differentiation of the gland structure of 48 cases of CRCs (24 cases with synchronous liver metastasis, 24 cases without metastasis) by the modified Gleason grading system. We also investigated the role of ZO‐1, one of the tight junction proteins, in the morphological changes, i.e., dedifferentiation and redifferentiation, of CRCs at the primary site and liver metastases. Liver‐metastasized CRCs (2.47±0.37) showed a lower score in the modified Gleason grading system than the corresponding primary tumors (3.28±0.36) did, i.e., the tumor cells had undergone redifferentiation at liver metastases. ZO‐1 was expressed at the apical cell borders of normal colorectal epithelium, the luminal side of which has tubular gland structures. In comparison with this normal epithelium, the ZO‐1 expression level was frequently reduced in primary CRC with liver metastasis (20.8%) and ZO‐1 was reexpressed in liver metastasized cancers (79.2%). Furthermore, it was demonstrated by an immunoprecipitation‐western blotting analysis on 5 cases of CRC with liver metastasis that ZO‐1 bound to epidermal growth factor receptor (EGFR) irrespective of the phosphorylation status of EGFR, and that EGFR associated ZO‐1 was highly ty‐rosine‐phosphorylated only in the primary CRC, but was dephos‐phorylated in the liver‐metastasized cancers. Our observations suggest that tyrosine phosphorylation of ZO‐1 leads to down‐regulation of the function of ZO‐1 and dedifferentiation of the glands in CRCs, and these phenomena contribute to liver metastases, and redifferentiation of the glands occurs in the liver metastases. (Cancer Sci 2003; 94: 166–172)
Tumor formation by genetic mutations in the components of the Wnt signaling pathway
Authors: Kikuchi Akira
Published: August 2005

The genetics of development and cancer have converged in the identification of intra‐ and extra‐cellular signaling pathways that are aberrantly regulated in cancer, and are also central to embryonic patterning. The Wnt signaling pathway has provided an outstanding example of this. The genes for β‐catenin, ARC, and Axin in the Wnt signaling pathway are often mutated in human cancers. In all such cases, the common denominator is the activation of gene transcription by β‐catenin. The resulting gene expression profile should provide a significant clue to the developmental mechanisms of cancers carrying defects in the Wnt signaling pathway. In this review, the functions of β‐catenin, APC and Axin, and the alterations of the three genes in human cancers are described. (Cancer Sci 2003; 94: 225–229)
Colon cancer cells with high invasive potential are susceptible to induction of apoptosis by a selective COX‐2 inhibitor
Authors: Chen Wei‐Shone , Liu Jin‐Hwang , Wei Sung‐Jen , Liu Jacqueline Ming , Hong Chi‐Yuan , Yang Wen K.
Published: August 2005

Cyclooxygenase‐2 (COX‐2) expression has been shown to correlate with the invasiveness of colon cancer cells. To further investigate this positive correlation and its possible therapeutic implications, a selective COX‐2 inhibitor, etodolac, was tested on three variants of HT‐29 colon cancer cell lines, HT‐29/lnv1, HT‐29/ Inv2 and HT‐29/lnv3, with graded increases of in vitro Matrigel invasive potential and COX‐2 expression levels. HT‐29 variants with higher invasive potential were found to be more sensitive to etodolac by in vitro growth inhibition assays, the estimated LD50 being 0.5 mM for highly invasive HT‐29/lnv2 and HT‐29/lnv3 cells, 0.6 mM for slightly less invasive HT‐29/lnv1, and 1.8 mM for the parental HT‐29. Treatment of the highly invasive HT‐29/lnv2 and Inv3 variants with as little as 0.1 mM etodolac in the growth medium produced signs of apoptosis, as detected by DNA fragmentation and TUNEL (terminal deoxynucleotidyl transferase dUTP‐biotin nick end labeling) assay. In vivo experiments in SCID mice showed that etolodac inhibited the growth of subcutaneous tumors induced by HT‐29/lnv3 cells significantly more than those by the parental HT‐29 cells. These results suggest that COX‐2 inhibitors have a potential role in prevention of tumor invasion in colon cancer patients. (Cancer Sci 2003; 94: 253–258)
Glypican‐3 is overexpressed in human hepatocellular carcinoma
Authors: Sung Young Kwan , Hwang Sun Young , Park Mi Kyung , Farooq Mohammad , Han In Sook , Bae Han Ik , Kim Jung‐Chul , Kim Moonkyu
Published: August 2005

To identify candidate genes that could be used as diagnostic and therapeutic targets for hepatocellular carcinoma (HCC), we searched for the genes that are overexpressed in HCC by combining representational difference analysis and microarray. Genes such as glypican‐3 (GPC3), insulin‐like growth factor 2, long‐chain fatty‐acid‐coenzyme A ligase 4, farnesyl diphosphate synthase were frequently identified in our screening. Northern blot analysis with these four genes confirmed their overexpression in HCC. Among them we found that GPC3 transcript is upregulated in six out of seven cases of HCC. Immunoblot and immunohistochemical staining using polyclonal anti‐GPC3 antibodies further confirmed that GPC3 protein is indeed increased in HCC tumor samples. We also found that GPC3 is secreted into culture media from cell lines derived from HCC. We conclude that GPC3 is a good molecular marker for HCC. (Cancer Sci 2003; 94: 259–262)
Gastrointestinal stromal tumors (GIST): A model for molecule‐based diagnosis and treatment of solid tumors
Authors: Kitamura Yukihiko , Hirota Seiichi , Nishida Toshirou
Published: August 2005

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the human gastrointestinal (GI) tract. The c‐kit receptor tyrosine kinase (KIT) is expressed by practically all GISTs, and gain‐of‐function mutations of KIT are present in most GISTs. Interstitial cells of Cajal (ICC) are the pacemaker of the peristaltic movement of the GI tract. Since signals through KIT are essential for development of ICC and since multiple GISTs develop from the hyperplastic lesion of ICCs in familial GIST patients with germ‐line mutations of KIT, GISTs are considered to originate from ICC. Imatinib mesylate, which was developed for treatment of chronic myeloid leukemia (CML), was found to be useful for treatment of GISTs. Imatinib mesylate inhibits BCR‐ABL fused tyrosine kinase that causes CML. Imatinib mesylate also inhibits the mutated KIT observed in most GISTs, and this explains the effectiveness of Imatinib mesylate on GISTs. GISTs appear to serve as a model for molecule‐based diagnosis and treatment of solid tumors. (Cancer Sci 2003; 94: 315–320)
Synergistic interaction between excess caffeine and deficient iodine on the promotion of thyroid carcinogenesis in rats pretreated with N‐bis(2‐hydroxypropyl)nitrosamine
Authors: Son Hwa‐Young , Nishikawa Akiyoshi , Kanki Keita , Okazaki Kazushi , Kitamura Yasuki , Lee Kyong‐Youl , Umemura Takashi , Hirose Masao
Published: August 2005

The combined effects of caffeine (1,3,7‐trimethylxanthine) with iodine deficiency (ID) were examined in a rat two‐stage thyroid carcinogenesis model using N‐bis(2‐hydroxypropyl)nitrosamine (DHPN). Male F344 rats were divided into 6 groups each consisting of 10 animals, and received a single s.c. injection of 2800 mg/ kg DHPN. From 1 week after the DHPN initiation, the rats were respectively fed a basal diet in which the protein was exchanged for 20% gluten, containing 1500 ppm caffeine+ID, 300 ppm caffeine+ID, 60 ppm caffeine+ID, 1500 ppm caffeine or ID or a basal diet alone for 12 weeks. Relative thyroid weights were significantly (P<0.05) increased due to the development of prolifera‐tive lesions induced by the ID diet as compared to the DHPN‐alone group value, which was enhanced by caffeine, albeit without statistical significance. Relative pituitary weights were significantly (P<0.05) increased with 300 or 1500 ppm caffeine+ID as compared to the DHPN‐alone group value. Serum thyroid stimulating hormone (TSH) levels were slightly increased by ID, an effect which was further enhanced by 300 or 1500 ppm caffeine. Serum thyroxine (T4) levels were slightly increased by caffeine or ID alone, but decreased by caffeine with ID. Histopathologically, thyroid follicular carcinomas were found only in the 1500 ppm caffeine+ID group, although thyroid follicular adenomas were detected in all the ID‐treated groups. The multiplicity of focal thyroid follicular hyperplasias was significantly (P<0.05) increased by 1500 ppm caffeine. These results indicate that caffeine may synergistically promote thyroid carcinogenesis with ID partially through a pituitary‐dependent pathway in rats, implying the possible implication of routine caffeine intake in the promotion of thyroid carcinogenesis. (Cancer Sci 2003; 94: 334–337)
The effect of 5‐year vitamin C supplementation on serum pepsinogen level and Helicobacter pylori infection
Authors: Sasazuki Shizuka , Sasaki Satoshi , Tsubono Yoshitaka , Okubo Shunji , Hayashi Masato , Kakizoe Tadao , Tsugane Shoichiro
Published: August 2005

We conducted a population‐based, double‐blind, randomized controlled trial to examine the effect of vitamin C supplementation on serum pepsinogen (PG) level, Helicobacter pylori (H. pylori) infection, and cytotoxin‐associated gene A (Cag A) status. Subjects aged 40 to 69 years living in one village in Akita prefecture, a high‐risk area for gastric cancer in Japan, were recruited through annual health check‐up programs. Among 635 subjects diagnosed as having chronic gastritis on the basis of serum PG levels, after excluding ineligible cases, 439 subjects were assigned to one of four groups using a 2×2 factorial design (0 or 15 mg/day β‐carotene and 50 or 500 mg/day vitamin C). However, based on the results from two β‐carotene trials in the United States, we discontinued β‐carotene (vitamin C supplementation was continued). Finally, 120 subjects in the low‐dose group (vitamin C 50 mg), and 124 subjects in the high‐dose group (vitamin C 500 mg) completed the 5‐year supplementation. The difference in the change of PGI/II ratio between baseline and after 5‐year follow up was statistically significant between the intervention groups among those who completed the supplementation: ‐0.25 for the low‐dose group and ‐0.13 for the high‐dose group (P=0.046). To conclude, vitamin C supplementation may protect against progression of gastric mucosal atrophy. (Cancer Sci 2003; 94: 378–382)