bluuebunny/crossref_metadata_2025 huggingface dataset:
Si wafer bonded of a-Si∕a-SiNx distributed Bragg reflectors for 1.55-μm-wavelength vertical cavity surface emitting lasers
Authors: Levallois C. , Le Corre A. , Loualiche S. , Dehaese O. , Folliot H. , Paranthoen C. , Thoumyre F. , Labbé C.
Published: August 2005

Amorphous silicon (a-Si) and amorphous silicon nitride (a-SiNx) layers deposited by magnetron sputtering have been analyzed in order to determine their optical and surface properties. A large value of ∼1.9 of index difference is found between these materials. Distributed Bragg reflectors (DBRs) based on these dielectric material quarter wave layers have been studied by optical measurements and confronted to theoretical calculations based on the transfer matrix method. A good agreement has been obtained between the experimental and expected reflectivities. A maximum reflectivity of 99.5% at 1.55μm and a large spectral bandwidth of 800nm are reached with only four and a half periods of a-Si∕a-SiNx. No variation of the DBR reflectivity has been observed with the time nor when annealed above 240°C and stored during few months. This result allows us to use this DBR in a metallic bonding process to realize a vertical cavity surface emitting laser (VCSEL) with two dielectric a-Si∕a-SiNx DBRs. This bonding method using AuIn2 as the bonding medium and Si substrate can be performed at a low temperature of 240°C without damaging the optical properties of the microcavity. The active region used for this VCSEL is based on lattice-matched InGaAs∕InGaAsP quantum wells and a laser emission has been obtained at room temperature on an optically pumped device.
From micro- to nanotransport properties in Pr2O3-based thin layers
Authors: Fiorenza P. , Lo Nigro R. , Raineri V. , Lombardo S. , Toro R. G. , Malandrino G. , Fragalà I. L.
Published: August 2005

In this paper, the conduction mechanisms in Si/SiO2/PrxSiyOz/Pr2O3/Au metal-insulator-semiconductor capacitors have been investigated. The dielectric stack has been produced by metal-organic chemical-vapor deposition. Nanoscopic and microscopic capacitance properties have been correlated. The capacitance-voltage (C-V) characteristics of 25-μm-radius metal-oxide-semiconductor capacitors have been evaluated and compared to the measurements performed by scanning capacitance microscopy (SCM). The study of the SCM images allows us to confirm the value of interface state density (Dit≈1012cm−2eV−1) obtained by C-V investigation excluding any defect or grain-boundary contribution in the capacitance phenomena. The conduction mechanisms have been investigated by current-density–voltage (J-V) measurements performed at different temperatures (from 100 to 200 °C). At low electric fields, a slight dependence of J-V characteristics in function of both temperature and electric field has been observed, while a relatively strong dependence at high fields has been found. Hill’s diagram indicated that at high electric fields the conduction follows the Poole-Frenkel mechanism. Finally, Hill’s diagram points out that the traps contributing to the conduction phenomena are approximately at the midgap value.
The charge trapping effect of metal-ferroelectric (PbZr0.53Ti0.47O3)-insulator (HfO2)-silicon capacitors
Authors: Juan Pi-chun , Hu Yu-ping , Chiu Fu-chien , Lee Joseph Ya-min
Published: August 2005

Metal-ferroelectric-insulator-semiconductor (MFIS) capacitors with a Pb(Zr0.53,Ti0.47)O3 ferroelectric layer and a hafnium oxide insulator layer have been fabricated and characterized. The size of the capacitance-voltage memory windows was investigated. The memory window first increases to a saturated value of 0.7V with the sweep voltage and then decreases due to charge injection. The oxide trapped charges in the ferroelectric∕insulator layers are studied by a voltage stress method. The flatband voltage (VFB) is measured before and after the voltage stress. The ΔVFB is 0.59V at a negative stress voltage pulse of −5V for 30s. The ΔVFB under positive voltage stress was much less and was 0.06V at a stress voltage of +5V for 5min. The energy-band diagram of the MFIS structure at inversion and accumulation modes are plotted and the VFB shift can be explained by the trapping or detrapping of charges. The current-density versus stress time (J-t) characteristics were also measured. The result is consistent with the charge trapping model.
Ionic conduction in 70-MeV C5+-ion-irradiated poly(vinylidenefluoride-co-hexafluoropropylene)-based gel polymer electrolytes
Authors: Saikia D. , Kumar A. , Singh F. , Avasthi D. K. , Mishra N. C.
Published: August 2005

In an attempt to increase the Li+-ion diffusivity, poly(vinylidenefluoride-co-hexafluoropropylene)-(propylene carbonate+diethyl carbonate)-lithium perchlorate gel polymer electrolyte system has been irradiated with 70-MeV C5+-ion beam of nine different fluences. Swift heavy-ion irradiation shows enhancement in ionic conductivity at lower fluences and decrease in ionic conductivity at higher fluences with respect to unirradiated gel polymer electrolyte films. Maximum room-temperature (303K) ionic conductivity is found to be 2×10−2S∕cm after irradiation with a fluence of 1011ions∕cm2. This interesting result could be attributed to the fact that for a particular ion beam with a given energy, a higher fluence provides critical activation energy for cross linking and crystallization to occur, which results in the decrease in ionic conductivity. X-ray-diffraction results show decrease in the degree of crystallinity upon ion irradiation at low fluences (⩽1011ions∕cm2) and increase in crystallinity at higher fluences (>1011ions∕cm2). Analysis of Fourier-transform infrared spectroscopy results suggests the bond breaking at a fluence of 5×109ions∕cm2 and cross linking at a fluence of 1012ions∕cm2 and corroborate conductivity and x-ray-diffraction results. Scanning electron micrographs exhibit increased porosity of the polymer electrolyte after ion irradiation.
Subwavelength imaging with opaque nonlinear left-handed lenses
Authors: Zharov Alexander A. , Zharova Nina A. , Shadrivov Ilya V. , Kivshar Yuri S.
Published: August 2005

We consider a slab of a composite left-handed metamaterial with quadratic nonlinear response and discuss the properties of opaque nonlinear left-handed lens. We find the conditions when this left-handed flat lens can create, with a subwavelength resolution, an image of the second-harmonic field of the source being opaque for the fundamental frequency.
Defending God
Authors: Crenshaw James L.
Published: August 2005

The existence of evil has given rise to perplexed questioning of divine justice from the beginning of recorded history. The present volume examines early responses to the problem of theodicy in Mesopotamia, Egypt, and Syria-Palestine as a way of assessing modern approaches to existential and religious crises. Through close readings of many texts in the Hebrew Bible and comparison with treatments in extrabiblical literature, it explores the richly diverse legacy of those who have influenced the West in so many ways. That legacy ranges from denying that a problem exists—the atheistic answer—to positing a vulnerable deity who assumes full responsibility for evil and its eradication. Between those two poles are responses that attempt to spread the blame, assuming a multiplicity of deities, a single rival deity (the personification of all evil), or a solitary deity who is somehow constrained, either by limited power and knowledge or by a split personality that struggles to balance the conflicting demands of justice and mercy. Analogies from parenting, jurisprudence, and the cult offer responses of discipline, retribution, and substitutionary atonement, respectively. Two final responses acquiesce to injustice in the present life, anticipating rectification beyond the grave or acknowledging human ignorance in the face of divine mystery. The limitation articulated by the last response requires that even the effort to provide a theodicy be questioned, especially given the fact that mortals have already received from the deity the greatest gift of all: life. Still, the search for answers is bound to continue, for it is only in challenging belief that theological discourse retains its integrity.
Introduction
Authors: Bishop Michael A , Trout J. D.
Published: August 2005

This introductory chapter presents an overview of the subsequent chapters in this book which will discuss topics such as epistemological theory, Statistical Prediction Rules, Strategic Reliabilism, and Standard Analytic Epistemology.
A New Civilization
Authors: Smil Vaclav
Published: August 2005

Pre-WWI technical advances have created economies and societies whose abundance of material possessions, rates of energy consumption, and overall tempo of life were entirely unprecedented. Both the fundamental infrastructures of modern life and countless everyday actions rest on enduring artifacts and ubiquitous innovations of the Age of Synergy. Mechanization of virtually all productive tasks led to mass production and both were made possible by steadily rising combustion of fossil fuels and generation of electricity. They brought new economic arrangements (including powerful multinational companies) as well as new forms of leisure.
Scholarship and Christian Faith
Authors: Jacobsen Douglas , Jacobsen Rhonda Hustedt , Marty Martin E.
Published: August 2005

The book examines the various ways Christian scholars incorporate faith into their academic endeavors. Literature in this area has frequently assumed a Reformed and evangelical style that links Christianity and academic study under the rubric of “the integration of faith and learning.” In contrast, Scholarship and Christian Faith argues that there are many different ways that faith and scholarship can interact with each other. Catholic, Lutheran, Episcopal, Wesleyan, Anabaptist, and Pentecostal alternatives are discussed. “Living the questions” of learning and faith is suggested as an approach that allows Christians (and, by analogy, persons of other faiths) to be constructively involved in the academy. The work of Ernest L. Boyer is used as an example. Scholarship and Christian Faith also discusses the role that scholarship can play in personal faith and in the life of the church. Finally, this book explores the idea of scholarship itself, drawing distinctions between analytic, strategic and empathic forms of scholarship. Four essays by other scholars embody and elucidate the themes of the book, including hope, hospitality, the relationship of science and religion, and the imbrication of learning and faith. A prologue (by Rodney Sawatsky) and an epilogue (by Kim Phipps) relate the discussion more explicitly to church-related higher education.
Civic Virtue and Science in Prerevolutionary Europe
Authors: Moore John C.
Published: August 2005

In prerevolutionary Europe, science in the broad sense of organized knowledge (scientia) played a crucial role in the emergence of democracy and civic virtue. Medieval thinkers drew on Cicero, Aristotle, Roman law, the Christian tradition, and their own experiences to create systems of thought and institutions necessary for that emergence. Science in the modern sense of the exact physical sciences, however, made only limited and indirect contributions to that development.
Evolutionary Biology and the Question of Trust
Authors: Ruse Michael
Published: August 2005

This chapter argues that the phenomenon of fraud and dishonesty in science is more akin to a perversion than a straight sin. Examples from the history of evolutionary biology are used to show how scientists employ supposed examples of fraud to discredit their opponents. Examples are drawn from the history of evolutionary biology involving Darwin, the Piltdown hoax, Edward O. Wilson, and Stephen Jay Gould.
Defending the Radical Center
Authors: Parsons Keith
Published: August 2005

Because science claims to offer objective knowledge that transcends sectarian bias, it stands in a “middle” position between extremist ideologies of both the left and the right. Contrary to the claims of feminist philosophers such as Sandra Harding, traditional ideals of scientific objectivity do not require rejection or radical revision. Contrary to the claims of neo-creationists Phillip Johnson and Alvin Plantinga, scientific objectivity is not compromised by its commitment to naturalism. By eschewing ideological bias in favor of broadly shared standards of objectivity, science provides an example of how diverse societies can pursue common aims.
Faith in Reading
Authors: Nord David Paul
Published: August 2005

In the years after 1815, a few visionary entrepreneurs decided the time was right to launch true mass media in America. They believed it was possible through new technology, national organization, and the grace of God to place the same printed message into the hands of every man, woman, and child in America. Though these entrepreneurs were savvy businessmen, their publishing enterprises were not commercial businesses. They were nonprofit religious organizations, including the American Bible Society, American Tract Society, and American Sunday School Union. Faith in Reading tells the story of the noncommercial origins of mass media in America. The theme is how religious publishers learned to work against the flow of ordinary commerce. Religious publishing societies believed that reading was too important to be left to the “market revolution”; they sought to foil the market through the “visible hand” of organization. Though religious publishers worked against the market, they employed modern printing technologies and business methods, and were remarkably successful, churning out millions of Bibles, tracts, religious books, and periodicals. At the same time, they tried to teach people to read those books in the most traditional way. Their aim was to use new mass media to encourage old reading habits. This book examines both publishers and readers. It is about how religious publishing societies imagined their readers. It is also about reader response — how ordinary readers received and read religious books and tracts in early 19th century America.
Being a Good Student
Authors: Tumminia Diana G.
Published: August 2005

The status of a student depends on participation in the narrative production, specifically the retelling of past lives and recovered memories. Several examples are given. The ethnographer’s experience of the phenomenological lifeworld of Unarius takes shape as she participates in a past-life readings and momentary glimpses of member experience. The ethnographer explains the problems of fieldwork in the context of the balance between immersion and objectivity. Because of this issue, she restrains herself from contributing to the narrative.
The Ethics of Animal Experimentation
Authors: Yarri Donna
Published: August 2005

The ethical treatment of animals is one of serious academic interest today. Specifically, both the practice of animal experimentation and ethical concerns about it have a long history, going virtually back to the ancient Greek period and continuing to the present day. With new breakthroughs in science and technology, it is likely that this practice will be with us for a long time to come. Thus, this book provides an interdisciplinary approach to the topic by utilizing the insights of cognitive ethology, philosophy, science, and Christian theology in order to present a benign approach to the ethical treatment of experimental animals. The reality and existence of animal minds, animal pain, and animal suffering provide the foundation for animal rights, and subsequently, for more positive treatment. Concrete suggestions are offered with regard to more humane animal legislation, improved animal husbandry conditions, as well as concrete guidelines that offset the burdens to animals against the benefits to humans. The ultimate result is a more humane practice in experimentation, modeled somewhat on the practice of pet keeping, in which experimental animals are viewed not only as having instrumental value but intrinsic value as well.
Introduction
Authors: Yarri Donna
Published: August 2005

The ethical treatment of animals in general, and in particular the issue of animal experimentation, continues to be a disputed moral issue. This chapter surveys the history of the use of animals in experimentation, beginning with the ancient Greek period and going through the contemporary era. It presents the history of experimentation as well the eventual opposition to it on the part of some. The chapter concludes by laying out how the book will proceed, which addresses the following topics: animal legislation, animal minds, animal sentience, animal rights, Christian theology and its perspective on animals, and the burdens and benefits of animal experimentation.
Animal Pain
Authors: Yarri Donna
Published: August 2005

The issue of animal sentience, particularly animal pain and suffering, is probably the most significant one in animal experimentation. Many experimental procedures cause significant harm for laboratory animals. After arguing for the reality of the harm caused to animals, this chapter offers specific suggestions on how to minimize this harm, which need to be more widely utilized. These include alternatives to the use of animals (particularly the 3Rs), refining current animal legislation, rigorous application of both pain scales and the use of drugs, improved animal husbandry conditions, and humane euthanasia, when it is necessary.
Render to Caesar
Authors: Bryan Christopher
Published: August 2005

Several recent studies have raised postcolonial issues in relation to the biblical texts. Render to Caesar aims to address that conversation and to offer some critique. Chapter 1 discusses Israel’s traditions about empire and its attitudes toward international superpowers as it experienced them from the Egyptians to the Greeks. Chapter 2 considers the same question during the period from the Maccabees to the War with Rome and its aftermath. Against this background, chapter 3 examines what we may know or surmise of the teaching and ministry of Jesus and considers its likely significance vis-à-vis Rome and Roman imperium. Chapter 4 does the same with the passion narratives. Chapters 5 and 6 turn to other early Christian witnesses, namely Paul, Luke-Acts, 1 Peter, and the Book of Revelation. Chapter 7 reflects on appropriate and possibly inappropriate relationships between the study of first- century Israel and Rome, and contemporary postcolonial insights. A concluding “unscientific postscript” reflects on the possible significance of this for our own understanding of empire and “superpower status,” then and now.
Truth, Language, and History
Authors: Davidson Donald
Published: August 2005

This book features a collection of essays by Donald Davidson that explore the relations between language and the world, speaker intention and linguistic meaning, language and mind, mind and body, mind and world, and mind and other minds. Davidson’s underlying thesis is that we are acquainted directly with the world, that thought emerges through interpersonal communication in a shared material world, and that language depends on communication. He also finds interconnections between his views and those of major philosophers of the past.
The Social Aspect of Language
Authors: Davidson Donald
Published: August 2005

This essay clarifies the Davidson’s claim that “There is no such thing as language, not if a language is anything like what many philosophers and linguists have supposed”. It agrees with Dummett that a theory of meaning requires the Wittgensteinian distinction between using words correctly and merely thinking one is, between following a rule and believing one is following a rule; and that a grasp of this distinction requires social interaction. Communication is successful if the speaker is taken to mean what he wants to be taken to mean. What is needed is not a set of shared rules but that speaker and listener be able to correlate the speaker’s responses with the occurrence of a shared stimulus in their common world.
Panel Data Econometrics
Authors: Arellano Manuel
Published: August 2005

This book reviews some of the main topics in panel data econometrics. It analyses econometric models with non-exogenous explanatory variables, and the problem of distinguishing between dynamic responses and unobserved heterogeneity in panel data models. The book is divided into three parts. Part I deals with static models. Part II discusses pure time series models. Part III considers dynamic conditional models.
The Japanese Employment System
Authors: Rebick Marcus
Published: August 2005

Reviews the stylised features of Japan’s employment system as it existed prior to the mid-1980s. The features described include employment protection, the complex compensation system, enterprise unionism, severe gender discrimination, intensive and internal training of core employees, employee involvement and consultation by management, marked wage differentials according to firm size, and mandatory retirement systems.
Rising Unemployment and Inequality
Authors: Rebick Marcus
Published: August 2005

Begins by examining the definition of the unemployment rate in Japan and shows the ways in which the rate may differ from the ILO standard definition. Looks at the phenomenon of labour hoarding and lower labour force participation and their relation to unemployment. The causes of the recent surge in unemployment are examined. Concludes that despite some increase in involuntary separations, it is the slowdown in hiring that is generating most of the unemployment. This implies that job guarantees have not been eroded that much by the long recession. The last part of the chapter looks at recent trends in income distribution in Japan, and the possibility that income inequality will grow in the future.
Introduction
Authors: Amable Bruno
Published: August 2005

This introductory chapter begins with an analysis of the economic performance and models of capitalism in Europe, Japan, and the USA. It discusses the difficulties of comparative institutional analysis, institutions as the expression of political compromise, five models of capitalism, empirical investigation of the diversity of capitalism, and institutional change and political strategies in Europe. An overview of the chapters in this volume is presented.
Open Issues
Authors: Chui Michael , Gai Prasanna
Published: August 2005

Explores the circumstances under which the imposition of statutory debt restructuring mechanisms and/or debt standstills can trigger a ‘rush for the exits’ by creditors. Given the possibility of such creditor pre-emption, it also examines how the IMF and the official sector can galvanize private sector involvement by providing ‘catalytic finance’. Concludes with an empirical assessment of the extent of debtor moral hazard—the main reason cited against the adoption of a statutory approach to crisis management.
An Agenda for a Growing Europe
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 book presents the report on the European economic system, which was submitted to the President of the European Commission in July 2003. The report is divided into three parts. The first contains an assessment of the economic performance in terms of growth, stability, and cohesion. The second explores the challenges facing the European Union. The third presents a series of policy recommendations for the future.
A conceptual framework
Authors: Sapir André , Aghion Philippe , Bertola Giuseppe , Hellwig Martin , Pisani-Ferry Jean , Rosati Dariusz , Viñals José , Wallace Helen , Buti Marco , Nava Mario , Smith Peter M.
Published: August 2005

This chapter discusses the conceptual framework for this report. This report seeks to determine whether and how economic policy in the EU has achieved its objective. It then examines how the policy-making framework can be adapted in response to globalisation and enlargement, against the backdrop of an aging population.
Is the European model sustainable?
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

The sustainability of the European model has become more uncertain. Low growth rates and high unemployment rates have strained public finances, which is incompatible with the fiscal rectitude required by a growing Trends in demography, technology, and globalisation; and the inability to establish a new social contract have prevented Europe from preserving the unprecedented growth achieved during the trente glorieuses — the thirty years between 1945 and 1975. These trends are expected to increase the demands for social protection, further threatening the sustainability of the European model.
Individual Differences in Losers' Consent
Authors: Anderson Christopher J. , Blais André , Bowler Shaun , Donovan Todd , Listhaug Ola
Published: August 2005

While winning and losing are experienced by individuals and create a lens through which citizens view politics, in this chapter we examine whether individuals’ political predispositions, measured by partisanship and ideology, matter for how they view the system. We find that voters’ political predispositions heighten the effect of winning and losing, though they do not affect levels of winners’ and losers’ consent in all circumstances. In those cases where we find evidence of mediating effects, they point to such predispositions acting as amplifiers, rather than as buffers for the winner-–loser effect. Winners who are strongly attached to their political party express more positive appraisals of the political system’s performance than other winners. With regard to ideological extremism, we find that ideologues are particularly prone to view the system through the lens of winning and losing.
Comparing Losers' Assessments of Electoral Democracy
Authors: Anderson Christopher J. , Blais André , Bowler Shaun , Donovan Todd , Listhaug Ola
Published: August 2005

Examines losers’ evaluations of electoral democracy. The data show that more losers are satisfied with the functioning of democracy than dissatisfied, an overwhelming majority believes that the most recent election was fair, and more losers say that parties care what ordinary people think than the opposite. We also find that losers’ evaluations of satisfaction and fairness are lower but evaluations of responsiveness higher in non-established democracies. We also find that losers evaluate all three aspects of electoral democracy more positively in countries with more proportional electoral systems. Moreover, our results indicate that losers in more developed countries are more satisfied with democracy but less positive in their assessments of the fairness of the most recent election. The analyses further indicate that supporters of losing parties that have never been in government are the most critical of representative democracy, while supporters of the major losing party that formed the government at the time of the election feel most positive.
Losing and Support for Institutional Change
Authors: Anderson Christopher J. , Blais André , Bowler Shaun , Donovan Todd , Listhaug Ola
Published: August 2005

Examines the question of whether electoral losers will try to change the rules of the game or will stop participating in politics altogether. Expectations of future loss are likely to have an important impact when citizens are asked to consider replacing the current status quo institutions with another set. Examining proposed and enacted institutional reforms in a variety of areas and countries, we find that losers by and large are more likely to support changes in institutional practices. The findings help to demonstrate that losing is an important part of the motor that drives institutional change. While losing does not presage a disaster or an abrupt end to democratic practices, it does seem to be one of the first steps in the direction of change and reform. One of the difficulties facing the design of democratic institutions is to have institutions that make losers, but not permanent losers, and to allow current losers some reasonable chance of winning in future periods.
Real Wages in Europe and Asia: A First Look at the Long-Term Patterns
Authors: Allen Robert C.
Published: August 2005

In the seventeenth and eighteenth centuries, wage rates in Japan, India, and China were lower than their counterparts in Europe when the wages are compared at the exchange rates implied by the silver contents of coins. The cost of living was also lower in Asia than in Europe. The purchasing power of Asian wages was similar to that of wages in France, Italy, and Germany but less than the purchasing power of wages in the leading economies—England and the Netherlands. Real wage comparisons contradict the opinions of Smith, Malthus, and Marx that Europe was more prosperous than Asia before the industrial revolution.
Comparative genomics of Gossypium and Arabidopsis: Unraveling the consequences of both ancient and recent polyploidy
Authors: Rong Junkang , Bowers John E. , Schulze Stefan R. , Waghmare Vijay N. , Rogers Carl J. , Pierce Gary J. , Zhang Hua , Estill James C. , Paterson Andrew H.
Published: August 2005

Both ancient and recent polyploidy, together with post-polyploidization loss of many duplicated gene copies, complicates angiosperm comparative genomics. To explore an approach by which these challenges might be mitigated, genetic maps of extant diploid and tetraploid cottons (Gossypium spp.) were used to infer the approximate order of 3016 loci along the chromosomes of their hypothetical common ancestor. The inferred Gossypium gene order corresponded more closely than the original maps did to a similarly inferred ancestral gene order predating an independent paleopolyploidization (α) in Arabidopsis. At least 59% of the cotton map and 53% of the Arabidopsis transcriptome showed correspondence in multilocus gene arrangements based on one or both of two software packages (CrimeStatII, FISH). Genomic regions in which chromosome structural rearrangement has been rapid (obscuring gene order correspondence) have also been subject to greater divergence of individual gene sequences. About 26%-44% of corresponding regions involved multiple Arabidopsis or cotton chromosomes, in some cases consistent with known, more ancient, duplications. The genomic distributions of multiple-locus probes provided early insight into the consequences for chromosome structure of an ancient large-scale duplication in cotton. Inferences that mitigate the consequences of ancient duplications improve leveraging of genomic information for model organisms in the study of more complex genomes.
A medium‐term rat liver bioassay for rapid in vivo detection of carcinogenic potential of chemicals
Authors: Lto Nobuyuki , Tamano Seiko , Shirai Tomoyuki
Published: August 2005

A reliable medium‐term bioassay system for rapid detection of carcinogenic potential of chemicals in the human environment has been developed. The 8‐week‐protocol consists of 2 stages; male F344 rats are given a single intraperitoneal injection of diethylnitrosamine (200 mg/kg) for initiation of liver carcinogenesis, followed by a 6‐week test chemical treatment starting 2 weeks thereafter. Test chemicals are usually given in the diet or the drinking water and in the 2nd week of test chemical treatment, all rats are subjected to two‐thirds partial hepatectomy in order to induce regenerative cell replication. The end‐point marker is the glutathione S‐transferase placental form (GST‐P)‐positive hepatic focus, the numbers and sizes of which are analyzed using an image‐analyzer and expressed as values per unit liver section (1 cm2). When the yield of GST‐P‐positive foci is significantly enhanced (P<0.05) over the control value, a chemical is judged to possess carcinogenic or promotion potential for the liver. Among 313 chemicals already tested in this system in our laboratory, 30/31 (97%) mutagenic hepatocarcinogens and 29/33 (88%) non‐mutagenic hepatocarcinogens gave positive results. Ten out of 43 (23%) agents known to be carcinogenic in organs other than the liver were also positive. It is particularly important that only one of 48 non‐carcinogens gave a very weak positive result, so that the system has a very low false‐positivity rate. It is now well documented that the assay system is highly effective for detecting hepatocarcinogens, bridging the gap between traditional long‐term carcinogenicity tests and short‐term screening assays. At the Fourth International Conference on Harmonization, our medium‐term liver bioassay based on an initiation and promotion protocol was recommended in the guidelines as an acceptable alternative to the long‐term rodent carcinogenicity test. (Cancer Sci 2003; 94: 3–8)
Serum carotenoids and mortality from lung cancer: a case‐control study nested in the Japan Collaborative Cohort (JACC) Study
Authors: Ito Yoshinori , Wakai Kenji , Suzuki Koji , Tamakoshi Akiko , Seki Nao , Ando Masahiko , Nishino Yoshikazu , Kondo Takaaki , Watanabe Yoshiyuki , Ozasa Kotaro , Ohno Yoshiyuki ,   JACC Study Group
Published: August 2005

To investigate whether high serum levels of carotenoids, tocopherols, and folic acid decrease risk of lung cancer in Japanese, we conducted a case‐control study nested in the Japan Collaborative Cohort (JACC) Study. A total of 39 140 subjects provided serum samples at baseline between 1988 and 1990. We identified 147 cases (113 males and 34 females) of death from lung cancer during an 8‐year follow‐up. Of the subjects who survived to the end of this follow‐up, 311 controls (237 males and 74 females) were selected, matched to each case of lung cancer death for gender, age and participating institution. We measured serum levels of antioxidants in cases of lung cancer death and controls. Odds ratios (ORs) for lung cancer death were estimated using conditional logistic models. The risk of lung cancer death for the highest quartile of serum α‐carotene, β‐carotene, lycopene, β‐cryptoxanthin, and canthaxanthin was significantly or marginally significantly lower than for the lowest quartile: the ORs, adjusted for smoking and other covariates, were 0.35 (95% confidence interval (Cl), 0.14–0.88), 0.21 (0.08–0.58), 0.46 (0.21–1.04), 0.44 (0.17–1.16) and 0.37 (0.15–0.91), respectively. The ORs for the highest serum levels of zeaxanthin/lutein and folic acid tended to be low, but the differences were not statistically significant. Serum total cholesterol was also inversely related to risk of lung cancer death: the OR for the highest vs. the lowest quartile was 0.39 (95% Cl, 0.19–0.79). Higher serum levels of carotenoids such as α‐ and β‐carotenes may play a role in preventing death from lung cancer among Japanese. (Cancer Sci 2003; 94: 57–63)
Effects of carvedilol on MDR1 ‐mediated multidrug resistance: comparison with verapamil
Authors: Kakumoto Mikio , Sakaeda Toshiyuki , Takara Kohji , Nakamura Tsutomu , Kita Tomoko , Yagami Tatsurou , Kobayashi Hironao , Okamura Noboru , Okumura Katsuhiko
Published: August 2005

The reversing effects of carvedilol and other β‐adrenoceptor antagonists on multidrug resistance (MDR) were assessed in HeLa cells and the MDR1‐overexpressing derivative Hvr100–6 cells, established by stepwise increases of vinblastine concentration in the culture medium. The inhibitory effects on the transcellular transport and intracellular accumulation of [3H]vinblastine and [3H]daunorubicin were also assessed using LLC‐GA5‐COL150 cell monolayers, established by transfection of human MDR1 cDNA into porcine kidney epithelial LLC‐PK, cells. The cytotoxic effects of vinblastine, paclitaxel, doxorubicin and daunorubicin in Hvr100–6 were reversed 1.4‐ to 7.1‐fold by carvedilol at the realistic clinical concentration of 1 μM, whereas other β‐adrenoceptor antagonists had weaker or no such effects. Transport experiments using LLC‐GA5‐COL150 cell monolayers demonstrated that this effect of carvedilol was due to the inhibition of MDR1‐mediated transport of vinblastine, paclitaxel, doxorubicin and daunorubicin. These MDR1‐mediated reversing effects of carvedilol were similar to those of 1 μM verapamil, suggesting that carvedilol could be a candidate modulator of MDR in clinical use. Since other β‐adrenoceptor antagonists had no inhibitory effect on transport, the effects of carvedilol were not related to β‐adrenoceptors and might have been due to antioxidant activity. (Cancer Sci 2003; 94: 81–86)
A novel carbazole topoisomerase II poison, ER‐37328: potent tumoricidal activity against human solid tumors in vitro and in vivo
Authors: Nakamura Katsuji , Uenaka Toshimitsu , Nagasu Takeshi , Sugumi Hiroyuki , Yamaguchi Atsumi , Kotake Yoshihiko , Okada Toshimi , Kamata Junichi , Niijima Jun , Taniguchi Tomoyoshi , Koyanagi Nozomu , Yoshino Hiroshi , Kitoh Kyosuke , Yoshimatsu Kentaro
Published: August 2005

We have discovered a novel topoisomerase II (topo II) poison, ER‐37328 (12,13‐dihydro‐5‐[2‐(dimethylamino)ethyl]‐4H‐benzo[c]py‐rimido[5,6,1‐jk]carbazole‐4,6,10(5H, 11H)‐trione hydrochloride), which shows potent tumor regression activity against Colon 38 cancer inoculated s.c. Here, we describe studies on the cell‐killing activity against a panel of human cancer cell lines and the antitumor activity of ER‐37328 against human tumor xenografts. In a cell‐killing assay involving 1‐h drug treatment, ER‐37328 showed more potent cell‐killing activity (50% lethal concentrations (LC50s) ranging from 2.9 to 20 μM) than etoposide (LC50s>60 μM) against a panel of human cancer cell lines. ER‐37328 induced double‐stranded DNA cleavage, an indicator of topo II‐DNA cleavable complex formation, within 1 h in MX‐1 cells, and the extent of cleavage showed a bell‐shaped relationship to drug concentration, with the maximum at 2.5 μM. After removal of the drug (2.5 μM) at 1 h, incubation was continued in drug‐free medium, and the amount of cleaved DNA decreased. However, at 10 μM, which is close to the LC50 against MX‐1 cells, DNA cleavage was not detected immediately after 1‐h treatment, but appeared and increased after drug removal. This result may explain the potent cell‐killing activity of ER37328 in the 1‐h treatment. In vivo, ER‐37328 showed potent tumor regression activity against MX‐1 and NS‐3 tumors. Moreover, ER‐37328 had a different antitumor spectrum from irinotecan or cisplatin against human tumor xenografts. In conclusion, ER‐37328 is a promising topo II poison with strong cell killing activity in vitro and tumor regression activity in vivo, and is a candidate for the clinical treatment of malignant solid tumors. (Cancer Sci 2003; 94: 119–124)
Development of consensus fluorogenically labeled probes of the immunoglobulin heavy‐chain gene for detecting minimal residual disease in B‐cell non‐Hodgkin lymphomas
Authors: Uchiyama Michihiro , Maesawa Chihaya , Yashima Akiko , Tarusawa Mitsu , Satoh Takashi , Ishida Yoji , Ito Shigeki , Murai Kazunori , Enomoto Sanae , Utsugisawa Taiju , Motoyoshi Kazuo , Masuda Tomoyuki
Published: August 2005

We have examined 72 patients with B‐cell non‐Hodgkin lymphoma (B‐NHL) in order to search for consensus sequences of the immunoglobulin heavy chain (IgH) gene, and developed consensus fluorogenically labeled probes for use in an allele‐specific oligonucleotide (ASO) real‐time quantitative polymerase chain reaction (RQ‐PCR) assay of minimal residual disease (MRD). We detected a clonal IgH variable region (VH) sequence in 51 (70.8%) of the 72 B‐NHLs, the most frequent VH gene usages being VH3 and VH4 (45/51, 88.2%). It was possible to design three consensus fluorogenic probes for the VH3 gene and one for the VH4 gene avoiding these hypermutations. Our sequencing results suggested that consensus fluorogenic probes would be best based on the 5′‐side of the framework region 3 (FR3) because the frequency of somatic hypermutations was significantly lower in the regions on which the probes were based than in the remaining parts of FR3 (P<0.05). Nineteen (54.3%) of 35 B‐NHLs with the VH3 gene and 5 (50%) of 10 with the VH4 gene had sequences identical to at least one of these probes. We found that probes containing one base substitution were still applicable for a MRD study, whereas those containing two or more were not. Therefore, our four probes were applicable for 37 (82.2%) of the 45 patients with VH3 or VH4. This limited number of probes makes a large‐scale study of MRD in B‐NHL more feasible.
Up‐regulation of DNA‐dependent protein kinase correlates with radiation resistance in oral squamous cell carcinoma
Authors: Shintani Satoru , Mihara Mariko , Li Chunnan , Nakahara Yuuji , Hino Satoshi , Nakashiro Koh‐ichi , Hamakawa Hiroyuki
Published: August 2005

DNA‐PK is a nuclear protein with serine/threonine kinase activity and forms a complex consisting of the DNA‐PKcs and a heterodimer of Ku70 and Ku80 proteins. Recent laboratory experiments have demonstrated that the DNA‐PK complex formation is one of the major pathways by which mammalian cells respond to DNA double‐strand breaks induced by ionizing radiation. In this study, we evaluated the relationship between expression levels of DNA‐PKcs, Ku70 and Ku80 proteins and radiation sensitivity in oral squamous cell carcinoma (OSCC) cell lines and in OSCC patients treated with preoperative radiation therapy. The OSCC cell lines greatly differed in their response to irradiation, as assessed by a standard colony formation assay. However, the expression levels of the DNA‐PK complex proteins were all similar, and there was no association between the magnitude of their expression and the tumor radiation sensitivity. Expression of DNA‐PK complex proteins increased after radiation treatment, and the increased values correlated with the tumor radiation resistance. Expression of DNA‐PKcs and Ku70 after irradiation was increased in the surviving cells of OSCC tissues irradiated preoperatively. These results suggest that up‐regulation of DNA‐PK complex protein, especially DNA‐PKcs, after radiation treatment correlates to radiation resistance. DNA‐PKcs might be a molecular target for a novel radiation sensitization therapy of OSCC.
Dose‐dependent suppression of hyperlipidemia and intestinal polyp formation in Min mice by pioglitazone, a PPARγ ligand
Authors: Niho Naoko , Takahashi Mami , Shoji Yutaka , Takeuchi Yoshito , Matsubara Satoshi , Sugimura Takashi , Wakabayashi Keiji
Published: August 2005

In our previous study, a peroxisome proliferator‐activated receptor γ (PPARγ) agonist, pioglitazone, suppressed both hyperlipidemia and intestinal polyp formation in Apc1309 mice at doses of 100 and 200 ppm in the diet. In contrast, it has been reported that doses of 1500 or 2000 ppm of another PPARγ agonist, troglitazone, enhanced colon polyp development in Min mice. In the present study, we therefore investigated the effects of a wide range of pioglitazone doses on both hyperlipidemia and intestinal polyp formation in Min mice. Serum triglycerides and very low density lipoprotein (VLDL) cholesterol in the basal diet group were elevated to levels 13–15 times higher than those in the wild‐type counterparts at 20 weeks of age. They were reduced dose‐dependently by treatment with 100, 200, 400 and 1600 ppm pioglitazone from 6–20 weeks of age with suppression to almost the wild‐type level at the highest dose. Moreover, up‐regulation of the liver mRNA levels for lipoprotein lipase (LPL) was evident in the pioglitazone‐treated animals. Dose‐dependent reduction of intestinal polyps was observed in Min mice given 100–1600 ppm for 14 weeks, total numbers being decreased to 63–9% of the control value. A suppressive effect of pioglitazone on colon polyp formation was also found. The PPARγ agonist, pioglitazone, may thus be a promising candidate chemopreventive agent for colon cancer.
Different expression patterns of KIT, EGFR, and HER‐2 (c‐erbB‐2) oncoproteins between epithelial and mesenchymal components in uterine carcinosarcoma
Authors: Sawada Morio , Tsuda Hitoshi , Kimura Mikihiko , Okamoto Sanshiro , Kita Tsunekazu , Kasamatsu Takahiro , Yamada Takuro , Kikuchi Yoshihiro , Honjo Hideo , Matsubara Osamu
Published: August 2005

Uterine carcinosarcoma histologically comprises the components of epithelial and mesenchymal malignancies, and is known to be clinically highly aggressive. To reveal the significance of the expression of tyrosine‐kinase‐receptor‐type oncoproteins in this tumor type, the incidence and distribution of the KIT, EGFR, and HER‐2 (c‐erbB‐2) oncoproteins were immunohistochemically examined in 16 surgically resected cases. For 6 cases, the EGFR and HER‐2 amplifications were also examined by fluorescence in situ hybridization (FISH). In the epithelial component, overexpressions of KIT, EGFR, and HER‐2 were detected in 4 (25%), 5 (31%), and 9 (56%) cases, respectively, whereas these overexpressions in the mesenchymal component were detected in 6 (38%), 8 (50%), and 1 (6%) cases, respectively. KIT and EGFR were co‐overexpressed in the mesenchymal component of 4 cases and in the epithelial component of 2 cases. However, HER‐2 overexpression was mostly detected in the epithelial component only, and tended to occur independently of KIT and/or EGFR overexpression. By FISH, one of the 4 cases with HER‐2 overexpression showed low‐level gene amplification. In two cases with EGFR overexpression, the gain of EGFR alleles and/or polyploidization of chromosome 7 had occurred. The expression patterns of KIT, EGFR, and HER‐2 differed between the epithelial and mesenchymal components, and the regulation of their expression appeared important in the acquisition of mesenchymal metaplasia in uterine carcinosarcoma. Structural and/or numerical alterations of chromosomes might be in part involved in EGFR and/or HER‐2 overexpression in this tumor type.
CD4+ T cells in cancer stroma, not CD8+ T cells in cancer cell nests, are associated with favorable prognosis in human non‐small cell lung cancers
Authors: Wakabayashi Osamu , Yamazaki Koichi , Oizumi Satoshi , Hommura Fumihiro , Kinoshita Ichiro , Ogura Shigeaki , Dosaka‐Akita Hirotoshi , Nishimura Masaharu
Published: August 2005

We investigated intratumoral tumor‐infiltrating lymphocytes (TILs), including CD4+ and CD8+ T cells, in non‐small cell lung cancers (NSCLCs) and their relationships with clinicopathological variables and post‐operative survival. Tumor specimens from 178 NSCLCs were consecutively obtained by surgery at the Hokkaido University Medical Hospital between 1976 and 1994. CD8+ T cells, CD4+ T cells and Ki‐67/CD8+ T cells were visualized immunohistochemically, and counted within cancer cell nests and in cancer stroma. CD8+ T cells and CD4+ T cells were observed at higher frequencies within cancer cell nests in moderately and poorly differentiated tumors compared with well differentiated tumors (P<0.01), and in tumors with high Ki‐67 expression compared with low Ki‐67 expression (P<0.01), that showed severe cellular atypia and a higher growth rate. Patients with higher numbers of CD8+ T cells within cancer cell nests showed significantly shorter survival times compared to those with lower numbers of CD8+ T cells within cancer cell nests (5‐year survival rates, 47% and 60%, respectively; P=0.03). Moreover, patients with higher labeling index of Ki‐67/CD8+ T cells showed significantly shorter survival than those with lower labeling index of Ki‐67/CD8+ T cells within cancer cell nests (5‐year survival rates, 41% and 69%, respectively; P=0.02), and the labeling index of Ki‐67/CD8+ T cells within cancer cell nests was found to be a significant and independent unfavorable prognostic factor by multivariate analysis (P=0.01). On the other hand, higher numbers of CD4+ T cells in cancer stroma, but not within cancer cell nests, were correlated with longer survival times in patients with NSCLC (5‐year survival rates, 64% and 43%, respectively; P=0.04). CD4+ T cells in cancer stroma might reflect immune responses against cancer cells, while CD8+ T cells do not appear to work as effectors in tumor tissues of NSCLC. Moreover, the higher labeling index of Ki‐67/CD8+ T cells within cancer cell nests is a strong indicator of unfavorable clinical outcome.