bluuebunny/crossref_metadata_2025 huggingface dataset:
Terahertz surface impedance of epitaxial MgB2 thin film
Authors: Jin B. B. , Kuzel P. , Kadlec F. , Dahm T. , Redwing J. M. , Pogrebnyakov A. V. , Xi X. X. , Klein N.
Published: August 2005

We report on terahertz (THz) surface impedance measurement of an epitaxial MgB2 thin film using time domain THz spectroscopy. We show that the surface resistance of the MgB2 film is much lower than that of YBa2Cu3O7−δ and copper in the THz range. A linear dependence of the surface reactance on frequency is observed, yielding a penetration depth of about 100nm at low temperatures. The measurements agree qualitatively with calculations based on impurity scattering in the Born limit. Our results clearly indicate that MgB2 thin films have a great potential for THz electronic applications.
Spatial ordering of quantum dots in microdisks
Authors: Xie Z. G. , Solomon G. S.
Published: August 2005

We demonstrate the spatial localization of optically active InAs quantum dots in the narrow whispering gallery mode region of a GaAs microdisk cavity. This is achieved through preferential In adatom surface diffusion on a partial cavity structure in a way that can be generalized to other optical cavities. In agreement with our model, and contrary to regrowth on mesa structures, we observe decreasing perimeter quantum dot densities with decreasing microdisk diameters. Photoluminescence measurements indicate optically-active single-quantum-dot emission.
Detection of Severe Human Metapneumovirus Infection by Real-Time Polymerase Chain Reaction and Histopathological Assessment
Authors: Sumino Kaharu C. , Agapov Eugene , Pierce Richard A. , Trulock Elbert P. , Pfeifer John D. , Ritter Jon H. , Gaudreault-Keener Monique , Storch Gregory A. , Holtzman Michael J.
Published: August 2005

BackgroundInfections with common respiratory tract viruses can cause high mortality, especially in immunocompromised hosts, but the impact of human metapneumovirus (hMPV) in this setting was previously unknown

MethodsWe evaluated consecutive bronchoalveolar lavage and bronchial wash fluid samples from 688 patients—72% were immunocompromised and were predominantly lung transplant recipients—for hMPV by use of quantitative real-time polymerase chain reaction (PCR), and positive results were correlated with clinical outcome and results of viral cultures, in situ hybridization, and lung histopathological assessment

ResultsSix cases of hMPV infection were identified, and they had a similar frequency and occurred in a similar age range as other paramyxoviral infections. Four of 6 infections occurred in immunocompromised patients. Infection was confirmed by in situ hybridization for the viral nucleocapsid gene. Histopathological assessment of lung tissue samples showed acute and organizing injury, and smudge cell formation was distinct from findings in infections with other paramyxoviruses. Each patient with high titers of hMPV exhibited a complicated clinical course requiring prolonged hospitalization

ConclusionsOur results provide in situ evidence of hMPV infection in humans and suggest that hMPV is a cause of clinically severe lower respiratory tract infection that can be detected during bronchoscopy by use of real-time PCR and routine histopathological assessment
Three Eyes for the Journey
Authors: Stewart Dianne M.
Published: August 2005

Studies of African-derived religious traditions have generally focused on their retention of African elements. This emphasis slights the ways in which communities in the African diaspora have created and formed new religious meaning. In this fieldwork-based study, this book shows that African people have been agents of their own religious, ritual, and theological formation. The book examines the African-derived and African-centered traditions in historical and contemporary Jamaica: Myal, Obeah, Native Baptist, Revival/Zion, Kumina, and Rastafari, drawing on them to forge a new womanist liberation theology for the Caribbean.
Divination
Authors: Stewart Dianne M.
Published: August 2005

This chapter begins with a discussion of Christian theology. It then describes the purpose of this study, which is to offer a new paradigm in Caribbean theology, which will reflect the prophetic insights and liberative traditions in the African-derived religions of the region, focusing on the island of Jamaica. Relevant comparisons are also made between Jamaica and other islands in the Caribbean. An overview of the chapters included in this volume is presented.
Epistemology and the Psychology of Human Judgment
Authors: Bishop Michael A , Trout J. D.
Published: August 2005

This book presents a new approach to epistemology (the theory of human knowledge and reasoning). Its approach aims to liberate epistemology from the scholastic debates of standard analytic epistemology, and treat it as a branch of the philosophy of science. The approach is novel in its use of cost-benefit analysis to guide people facing real reasoning problems and in its framework for resolving normative disputes in psychology. Based on empirical data, the book shows how people can improve their reasoning by relying on Statistical Prediction Rules (SPRs). It then develops and articulates the positive core of the book. The view presented — Strategic Reliabilism — claims that epistemic excellence consists in the efficient allocation of cognitive resources to reliable reasoning strategies, applied to significant problems. The last third of the book develops the implications of this view for standard analytic epistemology; for resolving normative disputes in psychology; and for offering practical, concrete advice on how this theory can improve real people's reasoning.
The Amazing Success of Statistical Prediction Rules
Authors: Bishop Michael A , Trout J. D.
Published: August 2005

This chapter discusses Statistical Prediction Rules (SPRs) and provides an explanation for their success. SPRs are simple, formal rules that have been shown to be typically more reliable, than the predictions of human experts on a wide variety of problems. Based on testable results, psychology can make normative recommendations about how we ought to reason. The branches of psychology that provide normative recommendations are dubbed as ‘Ameliorative Psychology’. Two central lessons of Ameliorative Psychology are that when it comes to social judgment, (a) proper unit weight models outperform humans in terms of reliability and (b) improper unit weight models often perform nearly as well as proper models and therefore better than humans. It is argued that the reason people resist this ‘practical conclusion’ is partly because the SPR results are noxious to our conception of ourselves as good reasoners. Further, they undermine our hope — so evident in the a priorism of so much contemporary epistemology — that we can be experts at recognizing good reasoning without massive empirical aid.
Strategic Reliabilism: Robust Reliability
Authors: Bishop Michael A , Trout J. D.
Published: August 2005

This chapter discusses Strategic Reliabilism. The epistemological theory underlying Ameliorative Psychology is a view called Strategic Reliabilism: Epistemic excellence involves the efficient allocation of cognitive resources to robustly reliable reasoning strategies applied to significant problems. Strategic Reliabilism gives a systematic voice and a theoretical foundation to the long-standing success of SPRs while at the same time avoiding the most serious objections to traditional process reliabilism.
Strategic Reliabilism: Epistemic Significance
Authors: Bishop Michael A , Trout J. D.
Published: August 2005

This chapter offers a framework for understanding significance that tolerates our incomplete knowledge of the conditions for human well-being. Topics discussed include the role of significance in Strategic Reliabilism, a reason-based approach to significance, and the potential unavailability of objective reasons. It is argued that a proper understanding of the notion of epistemic significance is a core problem for any epistemological theory that claims to be able to guide reason, and that any epistemological view that gives a central place to the notion of significance is bound to be deeply empirical.
Putting Epistemology into Practice: Normative Disputes in Psychology
Authors: Bishop Michael A , Trout J. D.
Published: August 2005

This chapter uses Strategic Reliabilism to resolve two debates about whether certain experimental findings demonstrate deep and systematic failures of human reasoning. It illustrates one of the main benefits of the current approach to epistemology: it can be used to adjudicate disputes that arise in psychology that are, at bottom, normative epistemological disputes about the nature of good reasoning.
Putting Epistemology into Practice: Positive Advice
Authors: Bishop Michael A , Trout J. D.
Published: August 2005

This chapter attempts to consolidate some of the lessons of Ameliorative Psychology with some handy heuristics and illustrative injunctions. It explores the empirical research that shows how to enhance the accuracy of diagnostic reasoning, reduce overconfidence, avoid the regression fallacy, improve policy assessments, and restrain the unbridled story-telling surrounding rare or unusual events. For problems tractable to voluntary reasoning strategies, the simple strategies recommended in the chapter can improve reasoning at low cost and high fidelity.
The Integrated Approach to Managing Defined Benefit Plans
Authors: Baker August , Logue Dennis E. , Rader Jack S.
Published: August 2005

This chapter examines the policy implications of managing a defined benefit (DB) plan as a separate entity or as an entity integrated into the sponsoring organization. It shows how the pension liability affects investment policy and how different views on the nature of the labor market lead to different investment policies. In general, the management of DB pension plans should be integrated with the management of the sponsoring organization since the two are closely entwined. However, this will depend on the best interests of plan beneficiaries.
Asset Allocation for Defined Benefit Plans
Authors: Baker August , Logue Dennis E. , Rader Jack S.
Published: August 2005

This chapter begins by defining the strategic asset allocation decision and discussing how the strategic asset allocation should be set. It introduces the factors that should be considered in setting the defined benefit (DB) strategic asset allocation. Theoretical arguments favoring allocations to stocks and bonds are considered, followed by empirical evidence that shows what pension funds actually do. Finally, the allocation of DB assets over time is discussed.
Contemporary Perceptions
Authors: Smil Vaclav
Published: August 2005

Most of the people who were alive during the Age of Synergy had only poor or uncertain understanding of the epochal nature of this new era but some scientists, engineers and historians perceived its revolutionary contributions with a remarkable accuracy and clarity. Most of these changes were welcome, but some, including the loss of artisanal labor, were regretted. And the gap between near-miraculous technical capabilities and dubious socio-economic arrangements that began to widen during that era of accelerated innovation shows no signs of closing.
In the Dreamtime
Authors: Tumminia Diana G.
Published: August 2005

This chapter explains the Unarian practice of dream analysis as a fact-finding process that constructs reality. Dreams are used for healing, contact with Space Brothers, viewing past lives, and solving problems of interpretation. The narrative accounts from members show the ways they use dreams in their sense-making process. The ethnographer recounts her dream about Space Brothers as part of the challenge of interpretation in fieldwork.
Death and Transition
Authors: Tumminia Diana G.
Published: August 2005

Ruth Norman, who played the role of Uriel the Archangel, illustrates the power of charisma in a spiritual group. The death of a leader can affect the transition of authority as illustrated by several examples (e.g., Theosophy, ISKCON, Spirit Fruit Company, among others). Max Weber’s theory of routinization of charisma indicates several possibilities for transition. The group coped with the death of Uriel and Antares through past-life therapy and channeling.
How Prophecy Endures
Authors: Tumminia Diana G.
Published: August 2005

The discussion revisits the criticisms of Leon Festinger’s cognitive dissonance theory by indicating alternative explanations of disconfirmed prophecy and adherence to irrational beliefs. Subsequent empirical research on actual prophecies show Festinger’s original perspective to be flawed. Charismatic organizations that give rise to prophecy provide whole lifeworlds of activity and meaning that go beyond a single prediction. Groups, like Unarius, with repeated prophetic failure develop coping mechanisms and specific methods of interpretation that explain away the reality disjuncture connected with such disappointments. One Unarian method is to account for the non-arrival of the Space Brothers in terms of past lives.
Unobserved Heterogeneity
Authors: Arellano Manuel
Published: August 2005

Unobserved heterogeneity is one instance in where correlation between observables and unobservables may be expected. This has been a pervasive problem in cross-sectional analysis. A major motivation for using panel data has been the ability to control from the possibly correlated, time-invariant heterogeneity without observing it. This chapter analyses fixed effects models, heteroskedasticity and serial correlation, likelihood approaches, and nonlinear models with additive effects.
Models with Both Strictly Exogenous and Lagged Dependent Variables
Authors: Arellano Manuel
Published: August 2005

Regression models with strictly exogenous regressors and individual effects are extended to include lags of the dependent variable as additional exploratory variables allowing for serial correlation of unknown form. The model is applied to the analysis of cigarette addiction. It discusses GMM estimation and maximum likelihood estimators.
Introduction
Authors: Rebick Marcus
Published: August 2005

Sets the stage for the analysis in the rest of the book. There is a review of Japan’s long recession, and the thesis is put forward that rising labour costs due to yen appreciation, the downturn of the 1990s, and changes in corporate governance that have made firms more sensitive to profits have all pushed firms to look for ways of lowering their labour costs through greater use of atypical forms of labour. Also discusses the difficulty in finding a single point at which the labour economy may have seen a structural break.
Changes to the Employment and Treatment of Regular Employees
Authors: Rebick Marcus
Published: August 2005

Examines changes that have been taking place in the treatment of regular full-time workers in Japan. Among the developments examined are the introduction of performance-related pay, flattening of the age-earnings profile, specialist training, and shorter working hours. Looks at trends in labour mobility and concludes that long-term employment is still the rule for the majority of these employees.
Industrial Relations
Authors: Rebick Marcus
Published: August 2005

Examines recent developments in industrial relations in Japan. The decline in union density is analysed and found to be due to a mixture of causes including sectoral shifts in employment and the failure of unions to organise new workplaces. The weakened role of the Shunto in the early 2000s and the increase in civil litigation and court-mediated dispute resolution are symptoms of the declining role of unions. Japanese labour relations are becoming more individualised.
Middle-Aged and Older Workers
Authors: Rebick Marcus
Published: August 2005

Focuses on the labour market for older workers. Japan has one of the highest rates of participation for workers over the age of 60 and explains why this is so. This explanation brings in a discussion of the mandatory retirement system in Japan and the pension system, both public and private. The labour market for middle-aged workers is also briefly touched on.
Conclusions and Prospects
Authors: Rebick Marcus
Published: August 2005

The concluding chapter reviews the portrait of the employment system of the preceding chapters. Argues that Japan’s firms need to become more flexible with hiring mid-career employees. The labour market needs to allow for greater labour mobility without undermining the strong features of the system.
The Diversity of Modern Capitalism
Authors: Amable Bruno
Published: August 2005

Capitalist economies have developed with a fair amount of diversity among themselves, which should have resulted in dramatic differences in levels of development. The fact that these differences are for the most part not noticeable may indicate that capitalism is based on such robust mechanisms that it accommodates varied institutional environments. In other words, institutional differences would be akin to national folklore, with few if any consequences for economic dynamics. If institutional specificities did have an effect, competition among nations would sooner or later lead to the adoption of international ‘best practices’. This book challenges these views on several counts. There are some elements of truth in the statement that differences in macroeconomic policy mix could explain in part the differences in economic performance. But this does not amount to saying that institutional specificities do not matter in explaining important differences in the basic economic mechanisms of the different countries. There is a considerable amount of theoretical and historical work that insists on the central role of institutions in economic dynamics.
Institutions, Complementarity, and Hierarchy
Authors: Amable Bruno
Published: August 2005

This chapter provides the theoretical background for the book. It proposes a theory of institutions as political equilibriums, and presents the concepts of institutional complementarity and hierarchy. It shows how institutions influence the economic equilibrium, and that these are political-economy choices. An economy is characterized by a set of complementary institutional forms resting on specific political equilibria defining the hierarchy among institutions.
Whither Continental European Capitalism?
Authors: Amable Bruno
Published: August 2005

This chapter examines the main transformations that have taken place in the Continental European model of capitalism, in connection with the opposition between the main ideological and political currents. It analyses the opposition between a project of regulated capitalism, which corresponds to a renewal of the Continental model, and a neo-liberal project, which aims at transforming the EU countries into market-based economies. It is argued that the Third Way was one political strategy compatible with the neo-liberal project, and that its relative failure can be explained with the help of our theory of the diversity of capitalism.
Sovereign Debt Workouts
Authors: Chui Michael , Gai Prasanna
Published: August 2005

Explains how policymakers must trade the ex-post costs of creditor coordination failure, which can help discipline sovereign debtors, against the ex-ante costs of debtor moral hazard. The threat of a liquidity crisis—a creditor run—is shown to be a powerful, albeit blunt, disciplining force in international capital markets, and the chapter explores the circumstances under which official intervention by the IMF can substitute for this discipline. The efficacy of collective action clauses as a means of ameliorating creditor coordination problems is also given a formal treatment.
Next Steps in the Debate
Authors: Chui Michael , Gai Prasanna
Published: August 2005

Provides a brief summary of the international financial architecture debate and suggest possible future directions for research.
Overview
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 begins with a brief description of the three facets of the European economic system: the single market and complementary microeconomic policies, macroeconomic policies in the monetary union, and the EU budget. An overview of the chapters included in this volume is then presented. These cover European Union policies, growth, stability, cohesion, economic trade-offs, economic governance, sustainability, enlargement, and policy recommendations.
Economic performance: Growth, stability, and cohesion
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 presents an in-depth analysis of the European Union’s economic performance in terms of growth, macroeconomic stability, and cohesion. The discussion on growth focuses on long-term economic performance, the reasons behind Europe’s slow growth, educational attainment and expenditure, new entry and product markets, innovation, finance, and labour markets. Macroeconomic stability covers the importance of stability, good practices vs. good luck in achieving stability, macroeconomic policies in the EU, and the European Monetary Union. Under cohesion, the theoretical motivation and effects of European redistribution policies are reviewed, including the evolution of regional and interpersonal inequality in last decades.
The Winner–Loser Gap: Contours and Boundaries
Authors: Anderson Christopher J. , Blais André , Bowler Shaun , Donovan Todd , Listhaug Ola
Published: August 2005

Investigates the gap in winners’ and losers’ attitudes with regard to different kinds of attitudes about the political system across established and newly emerging democracies. The results show that being in the political majority generally translates into more positive attitudes toward government, while losers have more negative attitudes toward the political system. We find that there usually is a gap in winners’ and losers’ sense of whether elections are fair, their evaluations of the performance of the political system, as well as feelings about whether government is responsive. Moreover, losing elections appears to diminish people’s support for democratic principles overall, and losers exhibit a heightened propensity to engage in political protest.
Winning and Losing in Old and New Democracies
Authors: Anderson Christopher J. , Blais André , Bowler Shaun , Donovan Todd , Listhaug Ola
Published: August 2005

Examines the dimensions of losers’ consent in old and new democracies. We expect that losing has stronger negative effects in new democracies relative to mature democracies since losers have not yet learned to lose in countries where democratic governance is of recent vintage. The results show that, with few exceptions, political losers have lower support levels than winners across all dimensions of political support, including beliefs in core principles of democracy. Moreover, we find that the winner–loser gap is more prominent in newly democratized and democratizing states. The data also indicate that the supporters of the old communist parties exhibit significantly lower levels of support for the democratic system than voters for other parties, and in particular, if they are not in power.
Sentiment and Sentimentality
Authors: Pugmire David
Published: August 2005

Sentimentality, the most easily recognizable of emotional vices, is often charged with subordinating truth to desired emotional effect. Yet there can be good reasons for doing that. Where there is fault, it lies in allowing the real importance of the object to be subordinated to its emotive utility to the agent. Sentimental concern is narcissistic: it is not with the actual significance of an object but with the emotional impact of that on oneself. In thus being indifferent to the object in its own right, the sentimental attitude is actually cynical.
Sketching the Rise of Real Inequality in Early Modern Europe
Authors: Hoffman Philip T. , Jacks David S. , Levin Patricia A. , Lindert Peter H.
Published: August 2005

The concept of real, as opposed to nominal or conventional, income inequality reveals pronounced inequality movements, because relative prices happened to move very differently for the poor and the rich before 1914. Between 1500 and 1790 to 1815, the prices of staple foods rose much more than the prices of what the rich consumed. This greatly magnified the rise in real-income inequality. The opposite happened between 1815 and 1914. Looking at life expectancy, rather than at annual income or consumption, we again find a widening of inequality in the eighteenth century, at least within the countries of Western Europe.
Economic Growth, Human Capital Formation and Consumption in Western Europe Before 1800
Authors: Reis Jaime
Published: August 2005

Argues that during the early modern period in Europe living standards gradually rose not only because probate inventories reveal that people were acquiring more and better quality durable goods. They were also increasingly allocating resources to the acquisition of the skills of literacy. Partly, this human capital served to enhance their productivity and earning ability, but it also served for pleasure, edification and gaining status and to this extent it should be considered as a consumer durable too. A quantitative exercise tries to show that if this is factored into the more traditional ‘material consumption’ approach, it can lead to a significant reconsideration of the standard of living debate, in particular, as regards the eighteenth century.
Institutions in Transition
Authors: Ho Peter
Published: August 2005

Studying institutional change regardless of whether it is focused on transitional or developing economies, may prove most fruitful when focused on its structuring of the means of production—land, labour, and capital. This book does exactly that: it singles out land as an object of study and places it in the context of one of the world’s largest and most populous countries undergoing institutional reform, the People’s Republic of China. The book argues that private property protected by law, the principle of ‘getting-the-prices-right’, and the emergence of effectively functioning markets can not be imposed, but are the outcome of a society’s historical development and institutional fabric. In other words, the creation of institutions that are trusted and perceived as ‘credible’ in the eyes of social actors hinges in part on choice and timing in relation to the constellation of socio-economic and political parameters. It is demonstrated that disregarding these might result in the establishment of ‘empty institutions’ that have little effect on social actors’ actions, and can even cause rising inequality, bad land stewardship, and social conflict. The book concludes that the key to understanding China’s successes in rural reforms lies in the state’s hands-off approach and upholding an intentional institutional ambiguity that allowed for local, credible institutions to arise.
The zebrafish gene map defines ancestral vertebrate chromosomes
Authors: Woods Ian G. , Wilson Catherine , Friedlander Brian , Chang Patricia , Reyes Daengnoy K. , Nix Rebecca , Kelly Peter D. , Chu Felicia , Postlethwait John H. , Talbot William S.
Published: August 2005

Genetic screens in zebrafish (Danio rerio) have identified mutations that define the roles of hundreds of essential vertebrate genes. Genetic maps can link mutant phenotype with gene sequence by providing candidate genes for mutations and polymorphic genetic markers useful in positional cloning projects. Here we report a zebrafish genetic map comprising 4073 polymorphic markers, with more than twice the number of coding sequences localized in previously reported zebrafish genetic maps. We use this map in comparative studies to identify numerous regions of synteny conserved among the genomes of zebrafish, Tetraodon, and human. In addition, we use our map to analyze gene duplication in the zebrafish and Tetraodon genomes. Current evidence suggests that a whole-genome duplication occurred in the teleost lineage after it split from the tetrapod lineage, and that only a subset of the duplicates have been retained in modern teleost genomes. It has been proposed that differential retention of duplicate genes may have facilitated the isolation of nascent species formed during the vast radiation of teleosts. We find that different duplicated genes have been retained in zebrafish and Tetraodon, although similar numbers of duplicates remain in both genomes. Finally, we use comparative mapping data to address the proposal that the common ancestor of vertebrates had a genome consisting of 12 chromosomes. In a three-way comparison between the genomes of zebrafish, Tetraodon, and human, our analysis delineates the gene content for 11 of these 12 proposed ancestral chromosomes.
Global and non‐random CpG‐island methylation in gastric carcinoma associated with Epstein‐Barr virus
Authors: Chong Ja‐Mun , Sakuma Kazuya , Sudo Makoto , Ushiku Tetsuo , Uozaki Hiroshi , Shibahara Junji , Nagai Hideo , Funata Nobuaki , Taniguchi Hirokazu , Aburatani Hiroyuki , Fukayama Masashi
Published: August 2005

DNA hypermethylation may play a primary role in the genesis of Epstein‐Barr virus (EBV)‐associated gastric carcinoma (GC) (EB‐VaGC). Methylation‐specific PCR targeting CpG‐islands demonstrated markedly increased methylation of specific genes, such as p14, p15 and p16 genes, in EBVaGC in vivo. A high frequency of methylation was observed in an EBVaGC strain of severe combined immunodeficiency mice, and the expression of methylated genes in the strain was apparently lower than the expression of the unmethylated genes in EBV‐negative GC strains. Although over‐expression of DNA methyltransferases (DNMTs) is known to be associated with some human cancers, real‐time PCR demonstrated that DNMTs expression was suppressed in EBVaGC. The DNA methylation of specific genes, independently of DNMTs expression, may be important in the development of EBVaGC. (Cancer Sci 2003; 94: 76–80)
Ubiquitin‐immunoreactive degradation products of cytokeratin 8/18 correlate with aggressive breast cancer
Authors: Iwaya Keiichi , Ogawa Hitoshi , Mukai Yasuo , Iwamatsu Akihiro , Mukai Kiyoshi
Published: August 2005

Decreased amounts of cytokeratin (CK) 8/18 in the cytoplasm of breast cancer cells correlate with a poor prognosis. Although such decreases have been attributed to suppressed gene expression, accelerated protein degradation may also be responsible. In order to investigate whether selective degradation via the ubiquitin (Ub)‐dependent proteasome pathway occurs in breast cancer, one‐ and two‐dimensional (1‐D and 2‐D) immunoblot analysis was performed on cancerous and normal breast tissue from 50 breast cancer patients using the anti‐Ub monoclonal antibodies (mAbs) KM691 and KM690. On 1‐D gel electrophoresis, one broad band or two bands were detected at about 43 kDa; these were detected only in cancer tissue. Immunoreactive bands at 43 kDa were significantly associated with aggressive morphology (P=0.011), nuclear p53 accumulation (P=0.015) and overexpression of Her2/neu protein (P=0.012). On 2‐D gel electrophoresis, these bands were fractionated into a group of several spots that formed a staircase pattern at 40–45 kDa. Partial amino acid sequencing analysis demonstrated that these Ub‐immunoreactive spots corresponded to CK8 and CK18; however, since they did not have an amino‐terminal domain, and were located at lower molecular weight positions than intact CK8 and CK18 on the 2‐D gel, they were regarded as degradation products. CK18 degradation was confirmed by confocal microscopy as loss of the frame‐like network that forms the luminal structure. These results indicate that CK 8/18 degradation products are detected specifically in breast cancer and may determine its aggressiveness.
Murine leukemia RL1 and sarcoma Meth A antigens recognized by cytotoxic T lymphocytes (CTL)
Authors: Uenaka Akiko , Nakayama Eiichi
Published: August 2005

Peptide elution and expression cloning methods have been used to identify T cell‐recognized antigens for which no molecular information is available. We identified a unique tumor antigen peptide pRL1a, IPGLPLSL that is recognized by CTL on BALB/c RL1 leukemia by peptide elution. The sequence of the peptide corresponded to the normally untranslated 5’region of akt. Cytotoxicity was generated in BALB/c spleen cells by in vivo and in vitro sensitization with pRL1a peptide in the form of multiple antigen peptide (MAP), but not the original form. pRL1a MAP immunization had a significant growth‐inhibitory effect. pRL1a MAP was mostly internalized into the endosomal compartment of antigen‐presenting cells, leaked to the cytosol, and degraded, and the pRL1a peptide produced was presented through the MHC class I pathway. In vivo depletion of CD4 T cells from tumor‐inoculated BALB/c mice caused RL1 regression. Overexpression of the RLakt molecule seemed to induce CD4 immunoregulatory cells, which resulted in progressive RL1 growth in BALB/c mice. In vivo administration of anti‐CD25 mAb (PC61) caused regression of RL1, suggesting that CD4+CD25+ immunoregulatory cells were involved in the tumor growth. Recently, we improved the sensitivity and the efficacy of T cell antigen cloning from cDNA expression libraries by using large‐ and small‐scale ELISPOT assays. Using the IFN‐γ ELISPOT method, we obtained a cDNA clone S35 of 937 bp recognized by AT‐1 CTL on BALB/c Meth A sarcoma. S35 was a part of the retinoic acid‐regulated nuclear matrix‐associated protein (ramp). AT‐1 CTL recognized the peptide LGAE‐AIFRL, which was derived from a newly created open reading frame due to the exon 14 extension.
Roles of luteinizing hormone/chorionic gonadotropin receptor in anchorage‐dependent and ‐independent growth in human ovarian surface epithelial cell lines
Authors: Tashiro Hironori , Katabuchi Hidetaka , Begum Monjura , Li Xiaoguang , Nitta Makoto , Ohtake Hideyuki , Okamura Hitoshi
Published: August 2005

Epithelial ovarian carcinomas are thought to arise from cells of ovarian surface epithelium (OSE) covering the free surface of the human ovary. Two immortalized human cell lines, OSE2a (non‐tumorigenic) and OSE2b‐2 (tumorigenic), were previously established from normal OSE cells of a reproductive‐age patient. In the present study, we found that expression of luteinizing hormone (LH)/chorionic gonadotropin (CG) receptor (LH/CGR) is present in OSE2a cells and absent in OSE2b‐2 cells. In OSE2a cells, a low concentration (103 mlU/ml) of CG enhanced anchorage‐dependent growth via up‐regulation of insulin‐like growth factor‐1 (IGF1), whereas a high concentration (105 mlU/ml) of CG induced anchorage‐independent growth and down‐regulation of IGF1 expression. To investigate involvement of other genes in LH/CGR‐related tumorigenicity, we compared cDNA expression arrays of OSE2a and OSE2b‐2 cells, and found that the following genes had lower expression in OSE2b‐2 than in OSE2a: integrin β1, intercellular adhesion molecule‐1 (ICAM1), and Waf1/Cip1. Subsequent semiquantitative reverse transcription polymerase chain reaction using OSE2a cells showed that expression of integrin β1 was down‐regulated by a high concentration (105 mlU/ml) of CG. These results suggest that LH/CGR affects anchorage‐dependent and ‐independent growth by mediating up‐ and down‐regulation of IGF1 and integrin β1. Repetitive and excessive activation of LH/CGR may cause genetic alteration of its signal transduction pathway, resulting in stimulation of growth of OSE cells, initiation of ovarian carcinogenesis, and cancer progression.
A novel inflammation‐related mouse colon carcinogenesis model induced by azoxymethane and dextran sodium sulfate
Authors: Tanaka Takuji , Kohno Hiroyuki , Suzuki Rikako , Yamada Yasuhiro , Sugie Shigeyuki , Mori Hideki
Published: August 2005

To develop an efficient animal model for colitis‐related carcinogenesis, male Crj: CD‐1 (ICR) mice were given a single intraperitoneal administration (10 mg/kg body weight) of a genotoxic colonic carcinogen, azoxymethane (AOM), and a 1‐week oral exposure (2% in drinking water) to a non‐genotoxic carcinogen, dextran sodium sulfate (DSS), under various protocols. At week 20, colonic neoplasms (adenocarcinomas, 100% incidence with 5.60±2.42 multiplicity; and adenomas, 38% incidence with 0.20±0.40 multiplicity) with dysplastic lesions developed in mice treated with AOM followed by DSS. Protocols in which AOM was given during or after DSS administration induced a few tubular adenomas or no tumors in the colon. Immunohistochemical investigation of such dysplasias and neoplasms revealed that all lesions were positive for β‐catenin, cyclooxygenase‐2 and inducible nitric oxide synthase, but did not show p53 immunoreactivity. The results indicate that 1‐week administration of 2% DSS after initiation with a low dose of AOM exerts a powerful tumor‐promoting activity in colon carcinogenesis in male ICR mice, and may provide a novel mouse model for investigating colitis‐related colon carcinogenesis and for identifying xenobiotics with modifying effects.
Regulation of TGF‐β signaling and its roles in progression of tumors
Authors: Miyazono Kohei , Suzuki Hiroyuki , Imamura Takeshi
Published: August 2005

Transforming growth factor‐β (TGF‐β) is a potent growth inhibitor of most types of cells; therefore, perturbations of TGF‐β signaling are believed to result in progression of various tumors. On the other hand, TGF‐β has been shown to act as an oncogenic cyto‐kine through induction of extracellular matrices, angiogenesis, and immune suppression. A wide variety of effects of TGF‐p are mediated by physical interaction of signal transducer Smad proteins with various transcription factors. Among these, Runx3 plays a pivotal role in prevention of gastric cancer. TGF‐β signaling is regulated by various mechanisms in the cytoplasm and nucleus. Inhibitory Smads (l‐Smads) repress TGF‐β signaling mainly by interacting with activated TGF‐β receptors. Smad ubiquitin regulatory factors (Smurfs) play important roles in facilitating the inhibitory signals induced by l‐Smads. In addition, the transcrip‐tional co‐repressors c‐Ski and SnoN interact with Smads, and repress transcription induced by TGF‐β. Abnormalities of these regulators of TGF‐β signaling may thus participate in the progression of various tumors. (Cancer Sci 2003; 94: 230–234)
Soluble Fas in malignant pleural effusion and its expression in lung cancer cells
Authors: Mitani Kayo , Nishioka Yasuhiko , Yamabe Kazue , Ogawa Hirohisa , Miki Toyokazu , Yanagawa Hiroaki , Sone Saburo
Published: August 2005

Soluble Fas (sFas) has the ability to block Fas‐mediated apoptosis, suggesting that sFas at tumor sites might inhibit tumor cell‐killing by immune effector cells. We examined the sFas level in pleural effusion associated with lung cancer. The level of sFas in malignant pleural effusion was significantly higher than those in transudate and tuberculous pleural effusion. There was no significant difference in the sFas concentration among various histological types of lung cancer. The cytotoxicity mediated by anti‐Fas agonistic antibody against Jurkat cells was inhibited by the addition of malignant pleural effusion, being inversely correlated with the sFas concentration. When Fas expression was examined using flow cytometry, eight of ten (80%) lung cancer cell lines expressed cell surface Fas. On the other hand, sFas protein and mRNA were detected in six of ten (60%) lung cancer cell lines, but there was no correlation between Fas and sFas expression. Furthermore, although the expressions of Fas and sFas were clearly detected in tumor cells derived from malignant effusion, the sFas expression was down‐regulated in an in vitro culture. These results suggest that sFas in malignant pleural effusion is at least in part produced by lung cancer cells, and might play a role in local immunosuppression by tumor cells. (Cancer Sci 2003; 94: 302–307)
hCDC4b, a regulator of cyclin E, as a direct transcriptional target of p53
Authors: Kimura Takashi , Gotoh Mitsukazu , Nakamura Yusuke , Arakawa Hirofumi
Published: August 2005

To identify p53‐target genes we have been using a cDNA‐microar‐ray system to assess gene expression in a p53‐mutated glioblas‐toma cell line (U373MG) after adenovirus‐mediated transfer of wild‐type p53 into the p53‐deficient cells. In the work reported here, expression of hCDC4b, which encodes one of the four sub‐units of the SCF (ubiquitin ligase) complex responsible for degradation of cyclin E, was dramatically up‐regulated by infection with Ad‐p53. An electrophoretic mobility‐shift assay and a chro‐matin immunoprecipitation assay indicated that a potential p53‐binding site (p53BS) present in exon 1b of the hCDC4 gene was able to bind to p53, and a reporter assay confirmed that this p53BS had p53‐dependent transcriptional activity. Expression of endogenous hCDC4b, but not the alternative transcript of this gene, hCDC4a, was induced in a p53‐dependent manner in response to genotoxic stresses caused by UV irradiation and adria‐mycin treatment, suggesting that each transcript has a different functional role. These results suggest that hCDC4b is a previously unrecognized transcriptional target of the p53 protein, and that by negatively regulating cyclin E through induction of hCDC4b, p53 might stop cell‐cycle progression at GO‐G1. This would represent a novel mechanism for p53‐dependent control of the cell cycle, in addition to the well‐known p21WAF1 machinery. (Cancer Sci 2003; 94: 431–436)
Amplification, up‐regulation and over‐expression of DVL‐1, the human counterpart of the Drosophila disheveled gene, in primary breast cancers
Authors: Nagahata Takemitsu , Shimada Takashi , Harada Akima , Nagai Hisaki , Onda Masamitsu , Yokoyama Shiro , Shiba Tadayoshi , Jin Enjing , Kawanami Oichi , Emi Mitsuru
Published: August 2005

Wnt proteins form a family of highly conserved, secreted signaling molecules that regulate cell‐to‐cell interactions during embryogenesis. Wnt genes and Wnt signaling are also implicated in cancer. It has been shown that Wnt proteins bind to receptors of the frizzled family on the cell surface. Through several cytoplasmic relay components including DVL‐1, the human counterpart of the Drosophila disheveled gene, the signal is transduced to β‐catenin, which then enters the nucleus and forms a complex with T‐cell factor (TCP) to activate transcription of Wnt target genes. We describe here the amplification of DVL‐1 in 13 of 24 primary breast cancers examined, and increased expression of this gene in 11 of those tumors in comparison to corresponding non‐cancerous breast tissues. Immunohistochemical staining demonstrated that DVL‐1 protein was prominent in the cytoplasm of cancer cells, but not in normal epithelial cells of the mammary duct or in myoepithelial cells. These data indicate that amplification and increased expression of the DVL‐1 gene may play some role in human breast carcinogenesis through derangement of the Wnt signaling pathway.
Distinct mechanisms of site‐specific oxidative DNA damage by doxorubicin in the presence of copper(II) and NADPH‐cytochrome P450 reductase
Authors: Mizutani Hideki , Oikawa Shinji , Hiraku Yusuke , Murata Mariko , Kojima Michio , Kawanishi Shosuke
Published: August 2005

The anticancer mechanism of doxorubicin (DOX), an anthracycline antibiotic, is believed to involve DNA damage through topoi‐somerase II inhibition and free radical generation. The free radical generation may also participate in genotoxicity, as well as car‐diotoxicity, in normal human cells. The present study showed that DOX generates 8‐oxo‐7,8‐dihydro‐2′‐deoxyguanosine (8‐oxo‐dG), an indicator of oxidative DNA damage, in HL‐60 cells, but not in H2O2‐resistant HP100 cells, suggesting the involvement of H2O2 in cellular DNA damage. Since DOX has both p‐quinone and p‐hydroquinone residues, free radical generation can be initiated by either reduction or oxidation of DOX. To clarify whether the oxidized or reduced form is more important for DOX‐induced H2O2 generation, we investigated the site‐specific DNA damage induced by DOX in the presence of Cu(II), in comparison with that in the presence of cytochrome P450 reductase, using 32P‐labeled DNA fragments. DOX caused DNA damage in the presence of Cu(II) or cytochrome P450 reductase. The degree of Cu(II)‐mediated DNA damage, including 8‐oxodG formation, was much greater than that of cytochrome P450 reductase‐mediated DNA damage. DOX plus Cu(II) caused DNA damage specifically at guanine, thymine and cytosine residues, particularly at 5′‐GG‐3′, 5′‐GT‐3’and 5′‐TG‐3’sequences. Scavenger experiments suggested the involvement of reactive species generated from H2O2 and Cu(I). When cytochrome P450 reductase and NADPH were used instead of Cu(II), every nucleotide was uniformly damaged, suggesting the participation of *OH. We conclude that DOX may induce carcinostatic and genotoxic effects through oxidation of its p‐hydroquinone moiety by metal ion rather than through p‐quinone reduction by cytochrome P450 reductase.
DNA hypermethylation and histone hypoacetylation of the HLTF gene are associated with reduced expression in gastric carcinoma
Authors: Hamai Yoichi , Oue Naohide , Mitani Yoshitsugu , Nakayama Hirofumi , Ito Reiko , Matsusaki Keisuke , Yoshida Kazuhiro , Toge Tetsuya , Yasui Wataru
Published: August 2005

The SWI/SNF proteins are ATP‐dependent chromatin remodeling enzymes that have been implicated in the regulation of gene expression. Recent studies have shown that members of the SWI/ SNF superfamily can function as tumor suppressor genes. DNA methylation and transcriptional inactivation of the HLTF gene, which is a homologue to the SWI/SNF genes, have been observed in colon cancer. In the present study, we studied the DNA methylation status of the HLTF gene by methylation‐specific PCR in 50 gastric carcinoma tissues, and seven gastric carcinoma cell lines and compared the methylation status with the levels of HLTF mRNA expression. DNA methylation of the HLTF gene was found in 25 (50%) of 50 gastric carcinomas, and levels of HLTF mRNA were associated with methylation status of HLTF (P=0.027; Mann‐Whitney U test). No correlations were found between HLTF mRNA levels and DNA methylation and T grade, N grade, tumor stage, or histological type. In corresponding non‐neoplastic mucosae, DNA methylation of the HLTF gene was found in 1 (7%) of 15 samples. The methylated allele was not detected in any of 10 normal gastric mucosae from 10 healthy volunteers. Among seven gastric carcinoma cell lines, the KATO‐III cell line showed loss of HLTF mRNA expression associated with DNA methylation. This loss was rectified by treatment with both Aza‐2′‐deoxycytidine, a demethylating agent, and trichostatin A, a histone deacetylase inhibitor. Chromatin immunoprecipitation assay revealed that the acetylation levels of histones H3 and H4 in the 5’CpG island of the HLTF gene were inversely associated with DNA methylation status. These results suggest that transcriptional inactivation of HLTF by aberrant DNA methylation and histone deacetylation may be involved in stomach carcinogenesis through down‐regulation of HLTF expression.