bluuebunny/crossref_metadata_2025 huggingface dataset:
DESIRES AS VALUE DATA
Authors: ODDIE GRAHAM
Published: August 2005

This chapter argues for the experience conjecture and addresses some of the fairly obvious objections to it. The realist thinks that the world enjoys a certain independence from experience which the idealist denies. She thinks that our experiences do not, all by themselves, determine the shape of reality. The value realist, likewise, thinks that value enjoys a certain independence from our experiences of value — our desires, if the experience conjecture is correct. And the value idealist denies this. Something about value idealism has proved perennially attractive. There is something compelling about the idea that value is, at least in part, the product of our experiences of value. The value idealist thinks that this is the essence of the relationship between value and desire — that desires, taken collectively, fully determine the shape of value.
VALUE AS REFINED DESIRE
Authors: ODDIE GRAHAM
Published: August 2005

This chapter develops a promising reduction of value to desire. The guiding principle is not the simple idea that the valuable is what we happen to desire in fact (that is, perhaps, a value analogue of Berkeleian idealism), but the more sophisticated and plausible idea that the valuable is what we would desire were we to refine our actual desires into a completely coherent set (a value analogue of phenomenalism). It is shown that the map of value which this refinement account delivers is surprisingly close to the realist's map over large stretches of the terrain — much closer than realists would have believed possible, or their antirealist rivals could have reasonably hoped for.
VALUE BEYOND DESIRE
Authors: ODDIE GRAHAM
Published: August 2005

This chapter examines what happens when certain pathologies of desire are systematically refined. The results suggest that there is a desire-independent value residue, one to which the pure idealist cannot appeal, but one which it seems necessary to invoke if desire-refinement is to converge on the good. That there is a value residue at the level of higher-order desires is pretty well undeniable. At the end of the chapter, the question is raised as to whether there is a value residue at the first-order level as well.
VALUE, JUDGEMENT, AND DESIRE: BRIDGING THE GAPS
Authors: ODDIE GRAHAM
Published: August 2005

This chapter presents a different and complementary take on the nature of realism and antirealism, one which has a clearer application to value when our journey is almost over than it would have here just as we embark. It argues that realism can be characterized as the affirmation of three important logical gaps. First, there is the gap between appearance and reality — the logical gap which constitutes the possibility of illusion or distortion. Second, there is the gap between reality and belief — the logical gap which constitutes the possibility of error. Third, there is the gap between appearance and belief — the logical gap which constitutes the possibility of incoherence between percept and concept. Various versions of antirealism try to close these gaps, thereby handily blocking the possibility of a certain kind of shortcoming.
2 Parliamentary Institutions in International Polities: What are the Conditions?
Authors: Rittberger Berthold
Published: August 2005

Develops a three-staged theory to explain why national governments have created and successively empowered the European Parliament. In a first step, it is argued that attempts by national governments to transfer sovereignty to the EU-level in order to improve the problem-solving capacity of their domestic polities threaten to undermine domestic channels of interest representation and accountability. These challenges are commonly perceived by political elites in the member states as a ‘democratic legitimacy deficit’. In a second step, it is argued that the proposals political elites in different member states advance to alleviate the ‘democratic legitimacy deficit’ vary across and even within member states. In the final step, the chapter inquires how the different concerns about the ‘democratic legitimacy deficit’ affect the interaction among national governments during Treaty amending intergovernmental conferences. For each stage in the development of the theory, the chapter develops a set of hypotheses and observable implications. The hypotheses are subjected to empirical scrutiny in the ensuing chapters.
Conclusion: No Integration Without Representation?1
Authors: Rittberger Berthold
Published: August 2005

The conclusion discusses the broader implications of the book’s findings for the ‘state’ of parliamentary democracy in the EU and the prospects for parliamentary democracy in other international organizations. Are concerns for democracy in international polities linked to the degree to which national governments transfer sovereignty to international organizations? Under what conditions can we expect parliamentary institutions to arise and develop outside the EU?
Machiavelli
Authors: Wight Martin
Published: August 2005

Machiavelli’s popular image is inadequate, for it ignores the idealism of his intense Italian patriotism. He starts with the ‘is’ rather than the ‘ought’ and rejects transcendentalism. He derives, although uncritically, his realism from historical examples found in Livy (The Discourses) as well as from contemporary politics (The Prince). He sees men as bad although their pursuit of power reflects their insecurity. One way to understand Machiavelli is through political irony, which fascinated him. He has a bias towards extremism and ruthlessness and lays emphasis upon virtù (political skill) and fortuna (luck). The political art is to move with the tide of history.
Winning Isn't Everything: Losers' Consent and Democratic Legitimacy
Authors: Anderson Christopher J. , Blais André , Bowler Shaun , Donovan Todd , Listhaug Ola
Published: August 2005

Provides an overview of the argument. Describes how elections produce unequal outcomes—for some to win, others have to lose. Also highlights the importance of losers’ consent for understanding political legitimacy. Losers’ consent is critical for democratic systems to function because losers are numerous; in part, it is important because of the incentives that losing creates. Also describes examples of graceful and sore losers in various countries around the world. Concludes by providing an alternative view of elections as institutional mechanisms that can enhance or diminish the legitimacy of political systems.
Political Legitimacy and the Winner–Loser Gap
Authors: Anderson Christopher J. , Blais André , Bowler Shaun , Donovan Todd , Listhaug Ola
Published: August 2005

Although political scientists have recognized the importance of election outcomes for how people feel about the democratic political process for some time, few have systematically examined the effect of elections and election outcomes on people’s attitudes about government. Examines the underpinnings of what we call the ‘winner–loser gap’ in democratic legitimacy from several perspectives. First, it discusses how social scientists have approached the study of political legitimacy over the years as well as the major findings that have emerged from their efforts. Second, it explains the underlying premises for the winner–loser gap in legitimacy beliefs gleaned from different corners of the social sciences. Finally, we develop a model of losers’ consent that forms the theoretical core of our empirical investigation. This model demonstrates how election outcomes and the sorting of voters into winners and losers affects legitimacy beliefs.
Sound Sentiments
Authors: Pugmire David
Published: August 2005

Drawing on recent work in the theory of emotion, this book concerns what is involved in the adequacy of emotions, which, it is argued, amounts to more than feeling good. The book analyses a series of ways in which emotions, and the emotional life, can be well-formed or not. Some of these amount to properties emotions can have (e.g. depth) which variously enhance or detract from them. Others are attitudes with characteristic emotional loadings and effects (e.g. cynicism and sophistication), and both are affected by culture. The study even of elusive lapses in the integrity of emotions matter, it is held, for their costs are themselves emotional.
Sophistication
Authors: Pugmire David
Published: August 2005

Sophistication can be a virtue. Cynics lay claim to it; it allows one to settle for and negotiate the reality of mixed emotions; moreover, the refusal to stereotype or simplify things in the attempt to see them for what they unobviously are, belongs to the truthfulness needed for sound emotion. However, it also tempts pride with superiority of insight. However, the idea that few things are what they seem makes trust in spontaneous emotional reactions difficult. Sophistitcation can become a posture of irony in which nothing is ever quite believed; and this is inimical to all but the most tentative emotion.
Retrospective
Authors: Pugmire David
Published: August 2005

Residual issues—emotions need a kind of simplicity, but this is compatible with subtlety. Generally, what is the point of scrutinising the losses of integrity to which emotions are various susceptible? Isn’t this over-sophisticated, and shouldn’t feeling good not be enough? The answer is no: the costs of emotion’s foibles are themselves emotional.
Nietzsche and Rée
Authors: Small Robin
Published: August 2005

This book is about the relationship of Friedrich Nietzsche (1844–1900) and Paul Rée (1849–1901). During a close friendship lasting for seven years, the two shared ideas and developed a new and original approach to philosophy and ethics. There followed a dramatic break, brought about in part by personal factors but also by a divergence in their directions as thinkers. For Nietzsche, the period of collaboration was a crucial stage in his development, and a springboard for his most characteristic and radical contributions to philosophy. Nietzsche gave the label ‘Réealism’ to the naturalistic philosophy presented in Rée’s work, which gave him the opportunity to break away from metaphysical romanticism and to refine his writing style by adopting a disciplined, aphoristic mode of expression. As an approach to moral psychology, ‘Réealism’ drew on the evolutionary theory of natural selection to explain the moral concepts of good, evil, conscience and justice. Nietzsche developed this project in his own way in a series of works starting with Human, All-Too-Human. Yet, he eventually came to criticise and reject ‘Réealism’ as inadequate to the task of a radical ‘revaluation of values’, and replaced the ‘historical approach’ with his own genealogy of morality.
Aspects of a Friendship
Authors: Small Robin
Published: August 2005

Discusses aspects of the personalities of Rée and Nietzsche arising from their different backgrounds and experiences. We have information from many sources about Nietzsche, but Rée’s character remains largely hidden. Even so, we can see how they complemented each other in many ways. Rée’s relation to his Jewish background is a hidden theme in his life and work. A section explores the significance of this aspect and its influence on Nietzsche’s changing attitudes towards the so-called ‘Jewish question’, and his rejection of contemporary anti-Semitism. Finally, the question of Nietzsche’s influence on Rée is discussed.
A Negative Answer
Authors: Olsson Erik J.
Published: August 2005

A sustained argument is given showing that more coherence does not imply a higher likelihood of truth even in fortunate circumstances (independence, individual credibility) and in a ceteris paribus sense. The argument makes critical use of an observation about the effect of prior on posterior probability. This point draws on a discussion of L. Jonathan Cohen. The chapter ends with an impossibility theorem to the effect that no coherence measure can be both useful and truth conducive. The conclusion is drawn that coherence is itself an incoherent notion.
Decision Theory
Authors: Bergin James
Published: August 2005

Deals with decision theory. The coverage includes decision making under risk and uncertainty. The theories of vonNeumann–Morgenstern and Savage are reviewed, along with recent developments in the field.
Preferences, Risk, and Stochastic Dominance
Authors: Bergin James
Published: August 2005

Focuses on preferences, attitude to risk and the ranking of risky returns. The state space model is discussed and related to risk aversion. First, second, and higher order stochastic dominance criteria are examined and related to the hazard function and the monotone likelihood ratio. Semi-deviation measures of risk are described.
Nash Equilibrium—Existence and Refinements
Authors: Bergin James
Published: August 2005

Existence of Nash equilibrium is considered. The major strategic form equilibrium refinements are examined. Classical ?xed point theorems used in establishing existence of equilibrium are reviewed.
Mechanism Design
Authors: Bergin James
Published: August 2005

Mechanism Design is introduced, The key classifications of complete and incomplete information are given and the revelation principle is described. Direct mechanisms and dominant strategy implementation are discussed. The Gibbard–Satterthwaite theorem and some positive results are given—for single peaked and quasi-linear preferences.
Information
Authors: Bergin James
Published: August 2005

Discusses models of information. Blackwells theorem in garbling and the value of information is proved. Monotonicity of decisions in signals is considered and related to supermodularity of the pay-off function and monotone likelihood ratio. Rational expectations equilibrium is discussed and existence of rational expectations equilibrium considered. Finally, equilibrium in abstract games of incomplete information is considered.
Signaling
Authors: Bergin James
Published: August 2005

The signalling model is considered. The model is used to highlight the difference between various equilibrium refinements. The Spence signalling model is discussed and forward induction restrictions described.
Bargaining
Authors: Bergin James
Published: August 2005

Deals with bargaining. The discussion includes axiomatic and non-cooperative bargaining. Four axiomatic solutions are discussed: Egalitarian, Utilitarian, Nash and Kala–Smorodinsky. The connection between Nash bargaining and the alternating offers model is described.
Wages, Inequality, and Pre-Industrial Growth in Japan, 1727–1894
Authors: Saito Osamu
Published: August 2005

It is widely recognized that in Japan before the Meiji Restoration there occurred a gradual increase in output. Examines whether or not the trend in real wages diverged from that of per capita output growth, and concludes that traditional Japan did not exhibit a drastic divergence between wage change and output growth as experienced in early modern

Western Europe. Also explores briefly the factors accounting for the differences between the two pre-modern growth processes.
Maternal Mortality as an Indicator of the Standard of Living in Eighteenth- and Nineteenth-Century Slavonia
Authors: Hammel Eugene A. , Gullickson Aaron
Published: August 2005

This study of maternal mortality on the Croatian-Bosnian border in the eighteenth and nineteenth centuries shows that the chance of death in childbirth was sensitive to major changes in the social and economic system. Death was more likely when men were called to military duty, in military rather than civil parishes even in peacetime, and over time as wage labour increased and as economies of scale were lost as the joint household system decayed. The unifying factor in all of these influences is the withdrawal of male labour from family farming, placing greater burdens on pregnant and parturient women and on those other women who might nurture them.
The Standard of Living in Denmark in the Eighteenth and Early Nineteenth Centuries
Authors: Johansen Hans Chr.
Published: August 2005

Traditional measures of real wages cover only the standard of living of a small fraction of the Danish population in the eighteenth and early nineteenth centuries and due to constant wages over long periods the measures reflect primarily price changes. Mortality statistics can also be used to measure changes in the standard of living—both in the short and the long run until about 1840. Human stature of the Danish population shows relatively constant average heights from 1789 to the 1850s.
Contested Spaces: Forest Rights, Registration, and Social Conflict
Authors: Ho Peter
Published: August 2005

Assesses the forest property rights system with particular reference to forest registration and customary forest rights. It is argued that—different than in the case of cropland—the forest tenure system is far from socially acceptable and credible. This is expressed through improper forest management, forest degradation, and the loss of forest through illegal conversion to non-forestry land. In addition, the forest sector also features a relatively high incidence of social conflict over forest land. Forest disputes have been a particular problem since forest registration started in the early 1980s. To illustrate the problems in forestry, the chapter also includes a description of two cases that demonstrate the complexity involved in the recognition of customary and historical forest claims.
DOES IMPROVING SCHOOL QUALITY REDUCE THE PROBABILITY OF UNEMPLOYMENT?
Authors: EIDE ERIC R. , SHOWALTER MARK H.
Published: August 2005

The authors investigate the relationship between high school quality and the probability of extended unemployment among noncollege‐bound men during three periods: the first two years, two to four years, and seven to nine years after high school. They find that larger high schools and schools with lower pupil–teacher ratios tend to decrease the probability of being unemployed for noncollege‐bound men in the period shortly after high school graduation. However, no effect is found of high school quality on unemployment probabilities approximately a decade after high school completion. (JEL I21, J64)
HOW TO COMPLY WITH ENVIRONMENTAL REGULATIONS? THE ROLE OF INFORMATION
Authors: BOTELHO ANABELA , PINTO LÍGIA M. COSTA , RODRIGUES ISABEL
Published: August 2005

The effectiveness of environmental regulation can be viewed as conditioned by the action of two main agents: regulated firms and public agency. Using a questionnaire on the pulp and paper industry in Portugal, this article finds that firms' decision to comply with environmental regulations is strongly influenced by firms' information on its legal obligations; this effect is stronger for smaller firms. Moreover larger/younger firms are less likely to comply with environmental regulations than smaller/older firms. Regarding the public agency's behavior, the authors find that greater monitoring efforts are directed toward larger/younger firms and toward those firms most likely to cause higher pollution levels. (JEL K32, Q28)
Malignant rhabdoid tumor shows a unique neural differentiation as distinct from neuroblastoma
Authors: Higashino Katsumi , Narita Tsutomu , Taga Takashi , Ohta Shigeru , Takeuchi Yoshihiro
Published: August 2005

Malignant rhabdoid tumors (MRT) show a multiphenotypic diversity, including a neural phenotype. To elucidate the difference in neural characteristics between MRT and neuroblastoma, we examined the expression of synapsin I, neuron‐restrictive silencer factor (NRSF), neurofilament medium‐size (NF‐M) and chromogranin A (CGA) in five MRT cell lines (TM87–16, STM91–01, TTC549, TTC642 and YAM‐RTK1) and five neuroblastoma cell lines under differentiation‐induction with 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA). Our results showed TM87–16 and TTC642 cells, expressed synapsin I and NF‐M before TPA induction, had a neural phenotype. After differentiation‐induction, only TM87–16 cells expressed CGA. Among all neuroblastoma cells, expression of NF‐M and CGA was stable at a high level throughout TPA‐induced differentiation. In TM87–16 and TTC642 MRT cells, synapsin I mRNA promptly increased after TPA differentiation, with the peak level at 6 h, and thereafter, synapsin I mRNA rapidly decreased in a time‐dependent manner. The decreased expression of synapsin I correlated with an increased expression of NRSF during differentiation‐induction. In contrast, in some neuroblastoma cells, a significant up‐regulation of synapsin I was observed concurrently with a down‐regulation of NRSF. The inverse relationship between NRSF and synapsin I expression in TM87–16 and TTC642 MRT cells was opposite to that of neuroblastoma cells. Our results showed that the neural characteristics of these MRT cells are fairly distinct from those of neuroblastoma cells. These MRT cells appeared to have only limited capability for neural differentiation, and were still in an extremely early stage of neural differentiation. (Cancer Sci 2003; 94: 37–42)
Expression of constitutively activated EGFRvlll in non‐small cell lung cancer
Authors: Okamoto Isamu , Kenyon Lawrence C. , Emlet David R. , Mori Takeshi , Sasaki Ji‐ichiro , Hirosako Susumu , Ichikawa Yasuko , Kishi Hiroto , Godwin Andrew K. , Yoshioka Masakazu , Suga Moritaka , Matsumoto Mitsuhiro , Wong Albert J.
Published: August 2005

The epidermal growth factor receptor (EGFR) variant type III (variously called EGFRvlll, de2–7 EGFR or ΔGFR) has an in‐frame deletion of the extracellular domain and is found in numerous types of human tumors. Since EGFRvlll has been reported to be tumorspecific and has oncogenic potential, it is being investigated as a potential therapeutic target. Because the cell‐specific expression of EGFRvlll in lung has not been well documented, we examined the expression of EGFRvlll in 76 non‐small cell lung cancers (NSCLCs) and 10 non‐neoplastic lung tissues by immunohistochemistry using a new monoclonal antibody specific for this variant receptor. We found a higher incidence (30 of 76, 39%) of enhanced EGFRvlll expression in NSCLC than previously described. Interestingly, the presence of EGFRvlll was also observed in several normal tissue components of lung (e.g., normal bronchial epithelium). Given the high prevalence of EGFRvlll in NSCLC, a newly developed phospho‐specific (activated) EGFR antibody was employed for immunohistochemical analysis that permitted visualization of activated EGFR and/or EGFRvlll in tumors. This study presents evidence, for the first time, that EGFRvlll expressed in human tumors is phosphorylated and hence activated. Our results suggest that the sustained activation of EGFRvlll is implicated in the pathogenesis of NSCLC and thus EGFRvlll is a potential therapeutic target in this challenging disease. (Cancer Sci 2003; 94: 50–56)
Ethnic difference in serology of Helicobacter pylori CagA between Japanese and non‐Japanese Brazilians for non‐cardia gastric cancer
Authors: Tatemichi Masayuki , Hamada Gerson Shigeaki , Nishimoto Inês Nobuko , Kowalski Luiz Paulo , Iriya Kiyoshi , Rodrigues Joaquim Josê Gama , Tsugane Shoichiro
Published: August 2005

The usefulness of serology against CagA of Helicobacter pylori as a biomarker to identify high‐risk individuals for non‐cardia gastric cancer (ncGC) remains unclear among several ethnic populations with a high prevalence of cagA‐positive strains. We investigated ethnic differences of CagA serology in two sets of case‐control subjects, Japanese‐Brazilians (JB) and non‐Japanese Brazilians (NJB). We performed a cross‐sectional comparison of IgG antibody titers to CagA (CagA‐Ab) and the combination of CagA‐Ab with conventional surface antigen (Hp‐Ab) in 80 JB and 178 NJB ncGC patients and their controls (160 JB and 178 NJB). The level of CagA‐Ab titer in cancer cases was significantly higher in NJB than in JB. The strength of the association between CagA‐Ab seropositivity (+) (>10 U/ml) and ncGC was almost 2‐fold higher in NJB than in JB [odds ratio (OR) (95% confidence interval), 4.5 (2.6–7.8) and 2.1 (1.2–3.6), respectively]. However, in both JB and NJB, the OR was highest in CagA‐Ab(+) subjects with low titer (10–29 U/ml), and decreased inversely with elevating CagA‐Ab titer. In addition, the serological status of CagA‐Ab(+) and Hp‐Ab(‐) showed a similar close association with ncGC between JB and NJB [5.4 (1.9–15.3) and 5.4 (2.0–15.0), respectively]. These results suggest that although the roles of CagA in the carcinogenic process of ncGC might be different between JB and NJB, the CagA‐Ab could be a useful marker for ncGC, independently of ethnicity, particularly in high‐risk individuals with the serological status of CagA‐Ab(+) with low IgG titer or combined with Hp‐Ab(‐). (Cancer Sci 2003; 94: 64–69)
Hypermethylation of death‐associated protein (DAP) kinase CpG island is frequent not only in B‐cell but also in T‐ and natural killer (NK)/T‐cell malignancies
Authors: Nakatsuka Shin‐ichi , Takakuwa Tetsuya , Tomita Yasuhiko , Hoshida Yoshihiko , Nishiu Mieko , Yamaguchi Motoko , Nishii Kazuhiro , Yang Woo‐Ick , Aozasa Katsuyuki
Published: August 2005

Death‐associated protein (DAP) kinase is a pro‐apoptotic serine/threonine kinase with a death domain, which is involved in apoptosis induced by interferon‐γ, tumor necrosis factor‐α, and Fas ligand. Down‐regulation of DAP kinase gene expression by hypermethylation of its promoter region might result in resistance to apoptotic cell death, and could provide a basis for tumor development. In the present study, we employed methylation‐specific polymerase chain reaction to examine the methylation status of CpG islands in the DAP kinase gene in 19 cases of T‐cell malignancies (including eight adult T‐cell leukemia/lymphoma), 24 of natural killer (NK)/T‐cell, and 34 of B‐cell. Frequency of methylation was significantly higher in B‐cell (27 of 34, 79.4%) than in T‐cell malignancies (nine of 19, 47.4%) (P<0.05). Fifteen of 24 (62.5%) NK/T‐cell lymphomas showed DNA methylation. One B‐cell lymphoma cell line with DNA methylation was resistant to apoptotic stimuli, and treatment of the cells with a demethylating agent restored apoptotic cell death. These findings suggested that suppression of DAP kinase expression by DNA methylation might play a substantial role in the development of not only B‐cell, but also T‐ and NK/T‐cell lymphomas. (Cancer Sci 2003; 94: 87–91)
Role of AML1/Runx1 in the pathogenesis of hematological malignancies
Authors: Kurokawa Mineo , Hirai Hisamaru
Published: August 2005

AML1/Runx1, originally identified as a gene located at the breakpoint of the t(8;21) translocation, encodes one of the two subunits forming a heterodimeric transcription factor. AML1 contains a highly evolutionally conserved domain called the Runt domain, responsible for both DNA binding and heterodimerization with the partner protein, CBFβ. AML1 is widely expressed in all hematopoietic lineages, and regulates the expression of a variety of hematopoietic genes. Numerous studies have shown that AML is a critical regulator of hematopoietic development. In addition, AML1 and CBFβ are frequent targets for chromosomal translocation in human leukemia. Translocations lead to the generation of fusion proteins, which play a causative role for the development of leukemia, primarily by inhibiting AML1 function. Point mutations that impair AML1 function are also associated with familial and sporadic leukemias. Loss of AML1 function is thus implicated in a number of leukemias through multiple pathogenic mechanisms. However, AML1‐related translocations or haploinsufficiency of AML1 are not immediately leukemogenic in animal models, suggesting that additional genetic events are required for the development of full‐blown leukemia.
Critical role of the Th1/Tc1 circuit for the generation of tumor‐specific CTL during tumor eradication in vivo by Th1‐cell therapy
Authors: Chamoto Kenji , Kosaka Akemi , Tsuji Takemasa , Matsuzaki Junko , Sato Takeshi , Takeshima Tsuguhide , Iwakabe Kenji , Togashi Yuji , Koda Toshiaki , Nishimura Takashi
Published: August 2005

Th1 and Th2 cells obtained from OVA‐specific T cell receptor transgenic mice completely eradicated the tumor mass when transferred into mice bearing A20‐OVA tumor cells expressing OVA as a model tumor antigen. To elucidate the role of Tc1 or Tc2 cells during tumor eradication by Th1‐ or Th2‐cell therapy, spleen cells obtained from mice cured of tumor by the therapy were restimulated with the model tumor antigen (OVA) for 4 days. Spleen cells obtained from mice cured by Th1‐cell therapy produced high levels of IFN‐γ, while spleen cells from mice cured by Th2‐cell therapy produced high levels of IL‐4. Intracellular staining analysis demonstrated that a high frequency of IFN‐γ‐producing Tc1 cells was induced in mice given Th1‐cell therapy. In contrast, IL‐4‐producing Tc2 cells were mainly induced in mice after Th2‐cell therapy. Moreover, Tc1, but not Tc2, exhibited a tumor‐specific cytotoxicity against A20‐OVA but not against CMS‐7 fibrosarcoma. Thus, immunological memory essential for CTL generation was induced by the Th1/Tc1 circuit, but not by the Th2/Tc2 circuit. We also demonstrated that Th1‐cell therapy is greatly augmented by combination therapy with cyclophosphamide treatment. This finding indicated that adoptive chemoimmuno‐therapy using Th1 cells should be applicable as a novel tool to enhance the Th1/Tc1 circuit, which is beneficial for inducing tumor eradication in vivo.
Expression of pericyte, mesangium and muscle markers in malignant rhabdoid tumor cell lines: Differentiation‐induction using 5‐azacytidine
Authors: Kato Hirofumi , Ohta Shigeru , Koshida Shigeki , Narita Tsutomu , Taga Takashi , Takeuchi Yoshihiro , Sugita Kanji
Published: August 2005

Malignant rhabdoid tumor (MRT) has been considered to have multiphenotypic diversity characteristics. Some MRTs exhibit a neural phenotype. However, it is still unclear whether MRT cells can display a skeletal muscle, smooth muscle or smooth muscle‐like cell phenotype, like those of pericytes and mesangial cells. To determine if MRTs exhibit skeletal muscle cell or smooth muscle‐like cell phenotypes, six MRT cell lines (TM87‐16, STM91‐01, TTC549, TTC642, YAM‐RTK1 and TTC1240) were examined for markers of skeletal muscle (MyoD, myogenin, myf‐5, myf‐6, acetylcholine receptor‐α, ‐β and ‐γ), smooth muscle (α‐smooth muscle actin, SM‐1 and SM22), and smooth muscle‐like cells, such as pericytes (angiopoietin‐1 and ‐2) and mesangial cells (megsin), using conventional RT‐PCR, semi‐quantitative PCR, western blotting and immunocytochemistry before and after differentiation‐induction with 5‐azacytidine. α‐Smooth muscle actin and SM22 were detected in all six MRT cell lines, while MyoD and myf‐5, crucial markers for skeletal myogenic determination, were not. The TM87‐16 cell line expressed SM‐1 and angiopoietin‐1. TTC1240 also expressed angiopoietin‐1. Interestingly, STM91‐01 expressed megsin, a novel marker for mesangial cells, in addition to angiopoietin‐1. Our results indicated that some MRTs exhibited smooth muscle and/or smooth muscle‐like cell phenotypes and some renal MRTs might be of mesangial origin. Recently, smooth muscle and also smooth muscle‐like cells have been considered to be of neuroectodermal origin. MRT can thus considered to belong to the category of primitive neuroectodermal tumors (PNETs) in the broad sense.
Combination effect of AC‐7700, a novel combretastatin A‐4 derivative, and cisplatin against murine and human tumors in vivo
Authors: Morinaga Yoshihiro , Suga Yasuyo , Ehara Sumiko , Harada Katsuhiro , Nihei Yukio , Suzuki Manabu
Published: August 2005

The in vivo combination effect of AC‐7700, a novel combretastatin A‐4 derivative, and cisplatin (CDDP) was examined. The combination of AC‐7700 and CDDP increased antitumor activity against murine colon 26 tumor in mice and cured the mice. This combination effect was found over wide dosage ranges of AC‐7700 (20–80 mg/kg) and CDDP (2.5–5 mg/kg). Moreover, this combination augmented antitumor activity against murine S180 and M109 tumors, and human LX‐1 and LS180 tumor xenografts in mice. The effect was the strongest when AC‐7700 and CDDP were administered simultaneously. To study this combination effect we measured the concentrations of CDDP in tumors, plasma and kidneys of the mice with colon 26 tumor. In the combination with AC‐7700, the concentration of CDDP in the tumors increased from 0.5 to 96 h after administration, but did not change or decrease in plasma or kidneys. Against human LS180 xenografts in mice, the combination similarly increased the concentration of CDDP in the tumors. These results suggest that AC‐7700 may specifically augment the accumulation of CDDP in tumors, and thus has the potential to be useful in combination chemotherapy with CDDP. (Cancer Sci 2003; 94: 200–204)
Overexpression of the Wilms' tumor gene WT1 in human bone and soft‐tissue sarcomas
Authors: Ueda Takafumi , Oji Yusuke , Naka Norifumi , Nakano Yoko , Takahashi Eigo , Koga Satoko , Asada Momotaro , Ikeba Ai , Nakatsuka Shin‐ichi , Abeno Sakie , Hosen Naoki , Tomita Yasuhiko , Aozasa Katsuyuki , Tamai Noriyuki , Myoui Akira , Yoshikawa Hideki , Sugiyama Haruo
Published: August 2005

The expression levels of the Wilms' tumor gene WT1 were examined in 36 cases of various types of human bone and soft‐tissue sarcomas using quantitative real‐time reverse transcription‐poly‐merase chain reaction (RT‐PCR). They included 12 malignant fibrous histiocytomas (MFH), 3 malignant peripheral nerve sheath tumors (MPNST), 6 synovial sarcomas (SyS), 4 myxoid liposarco‐mas (MyLS), one angiosarcoma (ACS), one clear cell sarcoma (CCS), and 9 osteosarcomas (OS). Eleven (92%) of 12 MFH, 2 (67%) of 3 MPNST, all (100%) of 6 SyS, 2 (50%) of 4 MyLS, one ACS, one CCS, and 5 (56%) of 9 OS cases overexpressed WT1 in the range of 1.4×10‐3‐3.9×10‐1 levels (WT1 expression level in K562 leukemic cells was defined as 1.0). Thus, 28 (78%) out of 36 various types of human bone and soft‐tissue sarcomas overexpressed the WT1 gene. Immunohistochemical analysis showed positive staining for WT1 protein in all of 4 cases (one case each of MFH, MyLS, ACS and OS) with WT1 gene Overexpression detected by RT‐PCR analysis, demonstrating clearly that WT1 was expressed at the protein level in various types of human bone and soft‐tissue sarcomas. The direct sequencing analysis of the WT1 genomic DNA showed no mutations in any of 10 exons of the WT1 gene in 8 different sarcoma samples (3 MFH, one SyS, one MyLS, one ACS, and 2 OS). The present study demonstrates that various types of human bone and soft‐tissue sarcomas frequently overexpress the wild‐type WT1 gene, suggesting an important role of the wild‐type WT1 gene in tumorigenesis of various types of human bone and soft‐tissue sarcomas. (Cancer Sci 2003; 94: 271–276)
Urinary bladder lesions induced by persistent chronic low‐dose ionizing radiation
Authors: Romanenko Alina , Morimura Keiichirou , Wanibuchi Hideki , Wei Min , Zaparin Wadim , Vinnichenko Wladimir , Kinoshita Anna , Vozianov Alexander , Fukushima Shoji
Published: August 2005

The incidence of urinary bladder cancer in the Ukraine increased from 26.2 to 43.3 per 100 000 population between 1986 and 2001 after the Chernobyl accident. The present study was conducted to evaluate the development of radiation‐dependent lesions in the urinary bladders of people living in cesium 137 (137Cs) radio‐contaminated areas of the Ukraine. Bladder urothelial biopsies from 159 male and 5 female patients were subjected to histological examination and immunohistochemical study of p38 mitogen‐acti‐vated protein kinase (MAPK), as well as the p50 and p65 subunits of nuclear factor kappa B (NF‐kB). A pattern of chronic proliferative atypical cystitis accompanied with large areas of sclerosis of connective tissue in the lamina propria was commonly observed in all cases. Interestingly, these lesions were associated with a dramatic increase in the incidences of dysplasia/carcinoma in situ, and, moreover, small urothelial carcinomas were incidentally detected. We defined the overall condition as “Chernobyl cystitis.'’Greatly elevated levels of p38, p65 and p50 expression in the urothelium were evident and the patients showed increased 137Cs in urine. The data support conclusions from our previous studies of a critical role for increased oxidative stress in generation of urinary bladder urothelial lesions in individuals chronically exposed to low‐dose 137Cs radiation. Alterations in the p38 MARK cascade and accumulation of NF‐kB subunits could be crucial early molecular events in the pathogenesis of Chernobyl cystitis. (Cancer Sci 2003; 94: 328–333)
PPARγ ligand‐induced apoptosis through a p53‐dependent mechanism in human gastric cancer cells
Authors: Nagamine Miho , Okumura Toshikatsu , Tanno Satoshi , Sawamukai Mitsuko , Motomura Wataru , Takahashi Nobuhiko , Kongo Yutaka
Published: August 2005

We have recently demonstrated that the PPARγ ligand troglitazone induced cell growth arrest and evoked apoptosis in a gastric cancer cell line, MKN–45. Since in general, p53 plays an important role in the induction of apoptosis and growth inhibition, we tried to clarify whether or not p53 mediates troglitazone‐induced apoptosis and growth arrest in gastric cancer cells. Troglitazone increased the number of apoptoic cells in MKN‐28, MKN‐45 and MKN‐74, but not in KATO‐III cells. The troglitazone‐induced apo‐ptotic change was significantly reduced by coincubation with bisphenol A digycidyl ether (BADGE), a synthetic PPARy antagonist, in MKN‐74 cells, suggesting that PPARγ mediates the apo‐ptotic effect of troglitazone. Since KATO‐III lacks the p53 gene, we speculated that p53 might be implicated in the PPARγ ligand‐induced apoptosis. Western blot analysis revealed that p53 expression was increased by troglitazone in a time‐dependent manner in MKN‐74 cells, further suggesting that p53 may mediate the ap‐optotic process induced by troglitazone. We next established a dominant‐negative p53 mutant by stable transfection of p53 mutant into MKN‐74 cells. In the dominant‐negative p53 mutant cells, troglitazone failed to induce apoptosis, strongly supporting the hypothesis that p53 indeed mediates the process of the troglitazone‐induced apoptosis. In the dominant‐negative p53 mutant cells, troglitazone significantly induced cell growth arrest and increased expression of p27Kip1 protein, which is thought to be the key molecule to evoke growth arrest, suggesting that p53 is not involved in the growth inhibition by troglitazone. All these results suggest that p53 mediates the PPARy ligand‐induced apoptosis, but not the cell growth inhibition. (Cancer Sci 2003; 94: 338–343)
Down‐regulation of SKP2 induces apoptosis in lung‐cancer cells
Authors: Yokoi Sana , Yasui Kohichiroh , Lizasa Toshihiko , Takahashi Takashi , Fujisawa Takehiko , Inazawa Johji
Published: August 2005

S‐Phase kinase associated protein 2 (SKP2), an F‐box protein constituting the substrate‐recognition subunit of the SCFSKP2 ubiquitin ligase complex, targets cell‐cycle regulators, such as the cyclin‐de‐pendent kinase inhibitor p27KIP1, for ubiquitin‐mediated degradation. Our earlier studies indicated frequent amplification and over‐expression of the SKP2 gene in primary small‐cell lung cancers (SCLCs) and cell lines derived from this type of tumor, and showed that down‐regulation of SKP2 expression by means of an antisense oligonucleotide inhibited the growth of SCLC cells in culture (Yokoi et al. Am J Pathol, 161, 207‐216, 2002). The anti‐sense effect was confirmed in two cell lines of non‐small cell lung cancer (NSCLC) that also exhibited over‐expression of the gene. In the work reported here, we examined the mechanism(s) responsible for antisense‐mediated growth inhibition of SCLC‐ and NSCLC‐derived cultures. SKP2‐antisense treatment not only suppressed DNA synthesis, as determined by [3H]thymidine incorporation, but also induced spontaneous apoptosis characterized by an increase in the sub‐G1 population, fragmentation of nuclei, and activation of caspase‐3. Our results suggest that since down‐regulation of SKP2 appears to induce apoptosis in lung‐cancer cells directly, targeting this molecule could represent a promising new therapeutic approach for this type of cancer, and possibly other tumors that over‐express SKP2. (Cancer Sci 2003; 94: 344–349)
Promoter methylation status of DAP‐kinase and RUNX3 genes in neoplastic and non‐neoplastic gastric epithelia
Authors: Waki Takayoshi , Tamura Gen , Sato Makoto , Terashima Masanori , Nishizuka Satoshi , Motoyama Teiichi
Published: August 2005

Silencing of tumor suppressor and tumor‐related genes by hyper‐methylation at promoter CpG islands is frequently found in human tumors, including gastric cancer. Promoter methylation is not restricted to cancer cells, and is also present in non‐neoplastic cells as an age‐related tissue‐specific phenomenon. To clarify the physiological consequence of DAP‐kinase and RUNX3 age‐related methylation in gastric epithelia, we investigated the promoter methylation status of these genes in both neoplastic and non‐neoplastic gastric epithelia obtained at autopsy and surgery, as well as in 10 gastric cancer cell lines. Methylation of DAP‐kinase and RUNX3 was detected in 10% (1/10) and 70% (7/10) of the cell lines, respectively, and was almost concordant with their expression status. Among autopsy samples, methylation of these genes was not seen in non‐neoplastic gastric epithelia from persons who were aged 22 years and below (0%; 0/4). DAP‐kinase was methylated in 87% (13/15) of non‐neoplastic gastric epithelia of persons who were aged 45 years or older, while RUNX3 methylation in non‐neoplastic gastric epithelia was restricted to individuals who were aged 77 years or older. Among samples obtained from patients with stomach cancer, methylation was observed in both the neoplastic and the corresponding non‐neoplastic gastric epithelia; 43% (40/93) and 73% (68/93) for DAP‐kinase, and 45% (42/93) and 8% (7/93) for RUNX3, respectively. Frequencies of DAP‐kinase and RUNX3 methylation differed significantly in non‐neoplastic gastric epithelia (P<0.01), although those in gastric cancers were almost the same. RUNX3 methylation is mostly cancer‐specific, except for very old individuals, and therefore may be a possible molecular diagnostic marker and malignancy predictor. (Cancer Sci 2003; 94: 360–364)
Food/nutrient intake and risk of atrophic gastritis among the Helicobacter pylori‐infected population of northeastern Japan
Authors: Montani Ai , Sasazuki Shizuka , Inoue Manami , Higuchi Kazuhide , Arakawa Tetsuo , Tsugane Shoichiro
Published: August 2005

Although Helicobacter pylori (H. pylori) infection is considered a key risk factor for atrophic gastritis, along with other environmental factors, it is still unclear which factor is involved in the development of atrophic gastritis among H. pylori‐infected subjects. In the present cross‐sectional study, therefore, we analyzed various dietary factors in relation to the presence of atrophic gastritis among H. pylori‐infected subjects who participated in a health check‐up program in a town in northeastern Japan. One thousand and seventy‐one subjects (362 males and 709 females) who provided both self‐administered validated food frequency questionnaires and blood samples were the basis for the study, and all of them were serologically positive for H. pylori immunoglobulin G (IgG) antibody. Among them, 663 (223 males and 440 females) were diagnosed as having atrophic gastritis on the basis of serum pepsinogen levels. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated based on tertile categories of subjects without atrophic gastritis, using logistic regression analysis. Among females, high consumptions of rice (OR=1.6, 95% CI: 1.1–2.3), cod roe (OR=1.5, 95% CI: 1.0–2.2) and cuttlefish (OR=1.5, 95% CI: 1.0–2.3) were associated with a moderately increased risk of atrophic gastritis after adjustment for age (P for trend=0.02 for these items). Among males, high consumptions of rice and miso soup showed a tendency toward an increased risk (P for trend=0.12 and 0.13, respectively). Vegetables and fruits showed no association among either males or females. From these results, it is suggested that the dietary habits of consumers of traditional Japanese foods may play a role in the development of atrophic gastritis after H. pylori infection. (Cancer Sci 2003; 94: 372–377)
Fatty acid‐CoA ligase 4 is overexpressed in human hepatocellular carcinoma
Authors: Sung Young Kwan , Hwang Sun Young , Park Mi Kyung , Bae Han Ik , Kim Woo Ho , Kim Jung‐Chul , Kim Moonkyu
Published: August 2005

Fatty acid‐CoA ligase 4 (FACL4) is a central enzyme controlling the unesterified arachidonic acid (AA) level in cells. It has been shown that FACL4 blocks apoptosis and promotes colon carcinogenesis by lowering the cellular level of unesterified AA. Consistent with this, FACL4 is upregulated in colon adenocarcinoma. The status of FACL4 in other tumors including hepatocellular carcinoma (HCC) is not known. Here, we report that FACL4 is overexpressed in human HCC compared with adjacent normal liver tissues. FACL4 mRNA and protein were overexpressed in 5 out of 12 (41.7%) and 3 out of 8 (37.5%) cases of HCC, respectively. Immunohistochemical staining showed strong fine granular intracytoplasmic staining in tumor cells, whereas we observed occasional weak staining in normal liver tissues surrounding the tumors. We found that 14 out of 37 (37.8%) HCC expressed moderate to strong FACL4 immunostaining. Both normal adult and fetal liver tissues showed very weak to no detectable staining, whereas 3 out of 10 (30%) cirrhotic livers expressed weak staining. In addition, we found that 4 out of 8 (50%) human hepatoma cell lines expressed high levels of FACL4 by northern blot analysis. Our results show that FACL4 is a new molecular marker for HCC and suggest that the FACL4 pathway may be involved in liver carcinogenesis. (Cancer Sci 2003; 94: 421–424)
Different frequencies of Streptococcus anginosus infection in oral cancer and esophageal cancer
Authors: Morita Eiko , Narikiyo Michihiro , Yano Akira , Nishimura Eisaku , Igaki Hiroyasu , Sasaki Hiroki , Terada Masaaki , Hanada Nobuhiro , Kawabe Ryoichi
Published: August 2005

Multiple cancers frequently occur in the upper aerodigestive tract. The high incidence rate of multiple carcinomas in this region is often explained in terms of involvement of the same underlying risk factors. It has been reported that the oral bacterium Streptococcus anginosus (S. anginosus) is associated with esophageal, gastric, and pharyngeal cancer tissues. In this study, a highly specific quantification method for S. anginosus DNA using real‐time PCR was established. We employed this assay to determine whether S. anginosus is also associated with oral cancer tissues. This precise quantification method revealed different degrees of infection with S. anginosus in esophageal cancer and oral cancer. We assayed 10 ng of genomic DNA from cancer tissues, and found that eight of 18 samples (44%) from the esophagus contained a detectable level (>10 fg) of S. anginosus DNA, whereas this was the case for only five of 38 samples (13%) of oral cancer. The quantity of S. anginosus DNA in the esophageal cancer tissues was significantly higher than in oral cancer. The maximum amount of S. anginosus DNA was approximately ten times higher in esophageal than in oral cancer tissues. In addition, none of the five different oral cancer sites (floor of the mouth, mandibular gingival, maxillary gingival, buccal mucosal, and tongue) showed significant signs of S. anginosus infection. On the other hand, most non‐cancerous tissues of the esophagus and tongue showed an undetectable level of S. anginosus. These results suggest that S. anginosus is associated with esophageal cancer, but is not closely related with oral cancer.