bluuebunny/crossref_metadata_2025 huggingface dataset:
A Public Choice Analysis of the Evolution of Tort Law:
Authors: Harris William T.
Published: July 2006

Abstract. Economic analysis has generally concluded that most loss shifting under current standards of personal injury liability is allocatively non‐Pareto optimal. The economic and legal arguments that support this conclusion are reviewed and an explanation is offered of why our legal system has evolved over time into an inefficient institution. It is argued that state sponsored lotteries and current personal injury liability laws have enough In common to be similarly viewed as a system of income redistribution demanded by the citizenry and supplied by the public sector.
Structural Re‐Adjustment in Nigeria:Diagnosis of a Severe Dutch Disease Syndrome
Authors: Ezeala‐Harrison Fidel
Published: July 2006

Abstract.Nigeriahas adopted a program of structural adjustmenteconomic reformssince 1986 in an effort to retrace steps towardeconomic stability.This Nigerianeconomic recoveryeffort based onstructural adjustmentis an attempt to cure a classic although extreme symptom of the “Dutch disease,” but despite this determined effort, success may be threatened by two fundamental economic errors that contributed to the problem in the first place.
The Globalization of Privacy
Authors: Regan PriscllaM.
Published: July 2006

Abstract. The Council of Europe is currently considering a directive that would harmonize data protection laws throughout the European Community. If approved, this directive would affect exchanges of personal information between European countries and the United States. This article argues that the proposed Data Protection Directive will lead to a strengthening of American privacy laws. This will occur not as a simple reaction to a perceived economic threat, but because a number of social, economic and political changes in the privacy environment in the United States converge at this time. The European Directive presents an opportunity for policy change to occur, but will not be the cause of the change.
The Practice of Buddhist Economics?
Authors: Zadek Simon
Published: July 2006

Abstract. The guidance provided by Buddhism about forms of economy is examined, focusing on individual and social aspects of Buddhist practice, rather than a literal readings of the canonical texts. The case of the village‐level development organization in Sri Lanka, Sarvodaya Shramadana, illustrates issues concerning Buddhist approaches to organization at the micro level. The impact of the Buddhist institution of the laity supporting monks on economic growth is considered, and the role of material welfare in a Buddhist conception of development. This examination of Buddhism suggests that its practice reveals insights into approaches to economy.
Agency in Health Care: Lessons for Economists from Sociologists
Authors: Ryan Mandy
Published: July 2006

Abstract. What economists can learn from sociologists with regard to the economic theory of agency in health care is considered. Whilst the concept of agency has become widely accepted in health economics, its application to the doctor‐patient relationship remains somewhat limited. Research is needed on the nature of the patient's and doctor's utility functions before an efficient outcome in health care can be achieved. Economists have much to learn from sociologists concerning the nature of patient's and doctor's utility functions. Only when economists take account of this literature will moves towards an efficient outcome in health care be achieved.
Crime and Unemployment Among Youths in the United States, 1958‐1990
Authors: Britt Chester L.
Published: July 2006

Abstract. Unemployment and arrest time series data for persons aged 16 to 19 years in the United States from 1958 to 1990 show crime among youth to be associated with both the current level of youth unemployment and the annual change in the rate of youth unemployment. For violent offenses (homicide, rape and aggravated assault), as well as for property offenses (robbery, burglary and larceny), higher rates of youth unemployment are negatively associated with annual changes in the arrest rates of youth. Conversely, the lagged effect of youth unemployment is limited to property offenses, where annual changes in youth unemployment are positively related to annual changes in the arrest rates of youth for robbery, burglary and larceny, but negatively related to changes in the auto theft arrest rate.
Hospital Mergers and Antitrust: Some Economic and Legal Issues
Authors: Whitesell Sarah E. , Whitesell Wiilliam E.
Published: July 2006

AbstractThe article traces the development of the market for hospital services through evolutionary stages to the present emphasis on merger and consolidation. Examination of the traditional principles of antitrust analysis suggests they are sufficiently flexible to warrant their application in evaluating the competitive impact of hospital mergers.
An Analysis of Causal Flow Between Social Development and Economic Growth:
Authors: Mazumdar Krishna
Published: July 2006

Abstract.

This is an attempt to examine whether there is any causal relation between social development and economic growth. Social development in this context is measured by a social development index, which is a weighted composite index formed with eight social indicators of life representing various spheres of social life. Economic growth is indicated by Per Capita Real Gross Domestic Product (PCRGDP), The causality test offered by Granger has been performed for the entire sample as well as for three income groups: high, middle and low. The study also tests causality between PCRGDP and the eight social indicators of life.
Henry George's Ingenious Tax
Authors: Backhaus G. Jürgen
Published: July 2006

Abstract. Henry George (1839–1897) has left an intellectual legacy which is shrouded under a cloak of controversy. “Professional economists who focused attention on the single‐tax proposal and condemned Henry George's teaching, root and branch, were hardly just to him.” (Schumpeter 1954, p. 865). This essay tries to do justice to Henry George from the point of view of economic theory and relevant economic practical questions in 1997. The single tax proposal is looked at from the point of view of constitutional economics, and the wider applicability of Henry George's basic notions is emphasized.
Social Networks and Economic Sociology
Authors: Davern Michael
Published: July 2006

Abstract The social network metaphor is widely used by sociologists to study socioeconomic behavior and processes The use of social networks generally takes place within the ranks of sociology However, a more complete social science would result by combining work being done on social networks within sociology with mainline economic theory The insights from such a research agenda will help us better understand socioeconomic behavior With this in mind, the main objective of this paper is to demonstrate the utility of the network metaphor to economists This objective will be accomplished through developing four basic components of social networks, and using them to navigate through the existing literature in economic sociology Furthermore, topics for future research in which social networks can provide contributions to the explanation of socioeconomic behavior are explored as well
Education and Intergenerational Mobility in Occupations
Authors: Checchi Daniele
Published: July 2006

AbstractThe problem of measuring the intergenerational transmission of inequality and its implications for social welfare is studied. A possible decomposition of relevant factors–namely, educational attainments and other factors–is proposed and applied to three individual data sets regarding Germany, Italy, and the United States. The main result is that educational attainment is responsible for almost half of observed immobility The possibility that increasing equality of opportunity in entering the educational system may result in less inequality in income distribution is considered.
Regulation, Unionization, and Racial Wage Discrimination: An Analysis of the Trucking Industry
Authors: Agesa Jacqueline , Brown Anita
Published: July 2006

Abstract. This article tests the hypothesis that increased product market competition of deregulation decreased employer and union wage discrimination in the motor carrier industry. Specifically, in each regulatory period, we estimate the portion of the industry racial wage differential that is due to racial differences: in driver attributes, returns to attributes, and unionization. Our findings suggest that enhanced product market competition directly reduces wage discrimination and may have a smaller indirect effect of further reducing racial wage disparities in industries with racially exclusive unions. These findings support the use of competition to reduce wage discrimination as opposed to government intervention.
Debt as the Basis of Currency
Authors: Skaggs Neil T.
Published: July 2006

Abstract Even more than most nineteenth‐century economists, Henry Dunning Macleod recognized the importance of trust in a properly functioning monetary system. Macleod developed a credit theory of money in which he argued that money originated as a debt claim against society. The value of money depends on the willingness of economic agents to accept it, no matter what material the money is made of. Macleod applied this theory to the evaluation of other systems in which money is not based on debt, showing the dangerous consequences that could arise from pursuing other theories of money creation to their logical conclusions.
Between Wicksell and Hayek
Authors: Bellofiore Riccardo
Published: July 2006

AbstractMises’Theoryis grounded on the “ultra‐Wicksellian” idea that the pure credit system represents the working of a modern monetary economy, and that forcing banks to raise the rate of money interest does not need to operate through some bindingbank‐liquidityconstraint. It is the rise in the relative price of consumption goods against production goods that accounts for the end of inflation. According to Mises, it is in the power of the banks to resist this readjustment; in this event, the only end to hyperinflation comes from the breaking of the monetary system. Hayek develops the second side of Mises’argument, the capital‐allocation effect, while the first side, the ultra‐Wicksellian picture of the monetary economy, is either weakened or taken for granted. Wicksell's 1914 reaction to Mises’book is recalled. Some criticism of Mises’readjustment mechanism from a Keynesian‐Schumpeterian point of view is offered in the concluding remarks.
Ontology With Human subjects Testing:
Authors: Smith Barry , Mark David
Published: July 2006

Abstract The paper presents a framework for the formulation and testing of ontological theories embodied in human cognition, concentrating primarily on the domain of geographic categories. Evidence for and against alternative theories of cognitive categories, for example on the part of E. Rosch and her associates, has been hitherto hased primarily on studies of categorization of entities of table‐top space (pets, tools, fruits). We hypothesize that the structure of our categories does not remain constant as we move from categories of abjects at manipulable scales to geographic categories suchas nation, mountain, river. Mre precisely: Geographic objects are not merely located in space, they are tied intrinsically to space in such a way that they inherit from space many of its structural (mercological, topological, geometrical) properties. Categorization in the geographic world is often size‐or scale‐dependent (consider:pond, lake, sea, ocean), and to a much greater extent than in the world of table‐top space, the realization that a thing or type of thing exists at all in the geographic world may have individual or culturalvariability. Geographic objects are in very many cases the products of delineation within a continuum, and the boundaries of such objects are themselves highly salient phenomena for purposes of categorization. A battery of experiments is described to test these hypotheses and to serve as bases for more detailed ontological theorizing.
The Russian Crisis:
Authors: Boettke Peter J.
Published: July 2006

ABSTRACTSince 1992, the rhetoric of Russian economic reformers has been one of full‐speed ahead to a free‐market economy. The reality, however, has diverged significantly from this rhetoric at both a broad “rules of the game” level and specific “policy within rules” level. The resulting ambiguity of the economic environment and the lingering effects of the previous system which is supposed to be reformed has led to a continued deterioration of the Russian economy. This paper offers a modified defense of “shock therapy” as a path to a cure for Russia's economic malaise, as opposed to the cure itself.
Max Weber as an Economist and as a Sociologist
Authors: Swedberg Richard
Published: July 2006

Abstract In this article I first give a picture of Weber as an economist, mainly by focussing on a text which he distributed to his students when he taught economics in the 1890s. From this text it is, for example, clear that Weber was positive to the use of marginal utility theory in theoretical economics, but also felt that this approach was insufficient, by itself, to analyze empirical phenomena. I then outline Weber's work in economic sociology, relying primarily on Economy and Society and its central Chapter 2 (“Sociological Categories of Economic Action”). The differences between the approaches of economic theory and economic sociology, as seen by Weber, are summarized, and an account is given of some of Weber's most suggestive concepts in economic sociology. In the concluding section the question is raised as to when the analyst, according to Weber, should use economic sociology rather than economic theory, and vice versa. Weber's ideas about a broad economic science–what he termed Sozialökonomik or social economics–are also presented.
The Changing Relationship Between Economic Sociology and Institutional Economics
Authors: Velthuis By Olav
Published: July 2006

Abstract In his early work. Talcott Parsons severely criticized Old Institutional Economists like Thorstein Veblen and Clarence Ayres. Parsons’main objection was that institutional economics had a misconceived view on the scope of economics: institutions, being the embodiment of values, were the proper subject of sociology rather than economics. By arguing for a clear‐cut division of labor between economics and sociology. Parsons legitimated the divide between the two disciplines that came into being in the years to follow. Recently however, the relationship between economic‐sociology and institutional economics has changed dramatically. New Economic Sociology (advocated by scholars like Mark Granovetter and Richard Swedberig) rejects the division of labor proposed by Parsons. By‐providing substitutes rather than just complements to economics, it tries to counter economic imperialism. This creates significant similarities between New Economic Sociology, Old Institutional Economics and the recent return of institutionalism in economic theory. However, the quest for a division of labor between economics and sociology remains unfinished.
Ethnic Solidarity and Black Business
Authors: Silverman Robert Mark
Published: July 2006

Abstract This paper examines the development of a separate economic niche for black entrepreneurs in Chicago's ethnic beauty aids industry. It argues that this economic niche developed in response to advantages black entrepreneurs had in mobilizing ethnic resources in the black community. The paper's findings lend support to general theoretical arguments stating that ethnicity, race, and other symbols for identity function as low‐cost screening devices for evaluating the likelihood that trading partners will honor economic contracts, particularly in a market setting where formal market mechanisms are not fully developed. The findings are based on a series of in‐person interviews with Korean, Jewish and black distributors of ethnic beauty aids in Chicago. Although this paper focuses on a single market niche, its conclusions indicate that greater attention needs to be paid to the effects of social, political, economic and structural factors on minority business development.
The common −318C/T polymorphism in the promoter region of CTLA4 gene is associated with reduced risk of ophthalmopathy in Chinese Graves’ patients
Authors: Han S. Z. , Zhang S. H. , Li R. , Zhang W. Y. , Li Y.
Published: July 2006

Studies in the past have clearly established that CTLA4 is a susceptible gene for Graves’ disease (GD). However, association studies between CTLA4 and the risk of developing Graves’ ophthalmopathy (GO) in GD patients have shown conflicting results. In this study, associations of five CTLA4 single nucleotide polymorphisms (−1722A/G, −1661A/G, −318C/T, +49G/A, CT60) with GD risk and GO susceptibility in GD patients were investigated in a Chinese population. Our results showed that either +49A/G or CT60 polymorphism was associated with GD susceptibility in the Chinese population. Significant differences in the distribution of the genotypes or alleles evaluated between GD patients with and without clinically evident GO were only found for −318C/T polymorphism (P = 0.03). Multiple logistic regressions revealed that the −318T allele was negatively associated with GO under both additive and dominant genetic models (adjusted OR = 0.56, 95%CI 0.35–0.89, P = 0.014; adjusted OR = 0.51, 95%CI 0.30–0.84, P = 0.009, respectively). Stratification analysis according to gender demonstrated different scenarios concerning the role of the −318T allele in GO risk: a significant protective role for GO was only confirmed in male but not in female GD patients. Haplotype analyses showed that only the haplotypes containing the −318T allele played a protective role in GO. In conclusion, results from this study suggested that the −318T allele might play a protective role in GO susceptibility for GD patients at least in the Chinese population. However, extended analyses with larger sample size should be carried out in patients from different ethnic origins to further verify this association.
Environmental Governance
Authors: Lemos Maria Carmen , Agrawal Arun
Published: July 2006

▪ Abstract  This chapter reviews the literature relevant to environmental governance in four domains of scholarship: globalization, decentralization, market and individual incentives-based governance, and cross-scale governance. It argues that in view of the complexity and multiscalar character of many of the most pressing environmental problems, conventional debates focused on pure modes of governance–where state or market actors play the leading role–fall short of the capacity needed to address them. The review highlights emerging hybrid modes of governance across the state-market-community divisions: comanagement, public-private partnerships and social-private partnerships. It examines the significant promise they hold for coupled social and natural systems to recover from environmental degradation and change and explores some of the critical problems to which hybrid forms of environmental governance are also subject.
Searches for Astrophysical and Cosmological Axions
Authors: Asztalos Stephen J. , Rosenberg Leslie J , van Bibber Karl , Sikivie Pierre , Zioutas Konstantin
Published: July 2006

▪ Abstract  The axion, a favored dark matter candidate, is expected to have a very small mass and extraordinarily weak couplings. Although it has eluded discovery or exclusion for three decades, it remains the most compelling solution to the strong-CP problem. Axions may be detected by their resonant conversion to RF photons in a microwave cavity permeated by a magnetic field. Experiments have already set significant limits on the axion's mass and photon coupling; progress in photon detection schemes at or below the standard quantum limit will soon enable definitive searches. Similarly, axions produced in the solar burning core may be detectable by their conversion to X rays in a magnetic helioscope. Significant improvements in both mass range and sensitivity of the axion helioscope will likewise be forthcoming in the next few years.
Sequential Activation of Muscle Synergies During Locomotion in the Intact Cat as Revealed by Cluster Analysis and Direct Decomposition
Authors: Krouchev Nedialko , Kalaska John F. , Drew Trevor
Published: July 2006

During goal-directed locomotion, descending signals from supraspinal structures act through spinal interneuron pathways to effect modifications of muscle activity that are appropriate to the task requirements. Recent studies using decomposition methods suggest that this control might be facilitated by activating synergies organized at the level of the spinal cord. However, it is difficult to directly relate these mathematically defined synergies to the patterns of electromyographic activity observed in the original recordings. To address this issue, we have used a novel cluster analysis to make a detailed study of the organization of the synergistic patterns of muscle activity observed in the fore- and hindlimb during treadmill locomotion. The results show that the activity of a large number of forelimb muscles (26 bursts of activity from 18 muscles) can be grouped into 11 clusters on the basis of synchronous co-activation. Nine (9/11) of these clusters defined muscle activity during the swing phase of locomotion; these clusters were distributed in a sequential manner and were related to discrete behavioral events. A comparison with the synergies identified by linear decomposition methods showed some striking similarities between the synergies identified by the different methods. In the hindlimb, a simpler organization was observed, and a sequential activation of muscles similar to that observed in the forelimb during swing was less clear. We suggest that this organization of synergistic muscles provides a means by which descending signals could provide the detailed control of different muscle groups that is necessary for the flexible control of multi-articular movements.
Expression of ΔNp73 and TAp73α Independently Associated with Radiosensitivities and Prognoses in Cervical Squamous Cell Carcinoma
Authors: Liu Stephanie Si , Chan Kelvin Yuen-Kwong , Cheung Annie Nga-Yin , Liao Xiao-Yun , Leung Tsin-Wah , Ngan Hextan Yuen-Sheung
Published: July 2006

Purpose: The p73 gene produces different protein isoforms using alternative promoters and splicing, which have different biological characteristics. This study was to investigate the expression patterns of two distinct p73 isoforms (ΔNp73 and TAp73α) in cervical squamous cell carcinomas (SCC) and the relationship between their expressions and prognostic significance in cervical SCC patients.

Experimental Design: We investigated the protein expressions of ΔNp73 and TAp73α in 117 cervical SCC and 113 normal cervical tissues using immunohistochemistry. The expression levels were analyzed with clinical variables and patients' survival.

Results: ΔNp73and TAp73α were significantly overexpressed in cervical SCC compared with those in normal cervical epithelium (P < 0.001). However, their expressions were inversely correlated (P < 0.001, R = −0.368) and associated with differential tumor radiosensitivity. Overexpression of ΔNp73 was significantly found in SCC resistant to irradiation (P < 0.001), whereas increase of TAp73α expression was observed in the majority of SCC sensitive to irradiation (P < 0.001). Multivariate and survival analyses indicated that the expressions of ΔNp73 and TAp73α were independently associated with prognosis: ΔNp73 was associated with recurrence of the disease [P = 0.001; odds ratio (OR), 4.857] and an adverse outcome (P = 0.012; OR, 4.676), whereas TAp73α predicted a better survival of cervical SCC patients (P = 0.018; OR, 0.065).

Conclusions: The p73 gene might be an important determinant of cellular response to irradiation. The expressions of the two main isoforms (ΔNp73 and TAp73α) might be potential markers for predicting the prognosis and sensitivity to radiotherapy in patients with cervical SCC.
Orotate Phosphoribosyltransferase Gene Polymorphism Predicts Toxicity in Patients Treated with Bolus 5-Fluorouracil Regimen
Authors: Ichikawa Wataru , Takahashi Takehiro , Suto Kenichi , Sasaki Yasutsuna , Hirayama Renzo
Published: July 2006

Purpose: We investigated whether the determination of orotate phosphoribosyltransferase (OPRT) and thymidylate synthase (TYMS) polymorphisms could predict the toxicity of 5-fluorouracil (5-FU) in colorectal cancer patients.

Experimental Design: The determination of OPRT and TYMS genotypes were done in genomic DNA extracted from blood by PCR amplification in 69 patients treated with bolus 5-FU as adjuvant chemotherapy. Associations between these polymorphisms and toxicity were evaluated retrospectively.

Results: The Ala allele in OPRT Gly213Ala polymorphism and the two tandem repeats (2R) in TYMS promoter polymorphism were associated with grade 3 to 4 neutropenia and diarrhea. The multivariate logistic regression models revealed that only TYMS promoter polymorphism had an independent value to predict grade 3 to 4 neutropenia [odds ratio, 19.2 for patients with the 2R allele compared with patients with homozygous with the three repeat (3R) alleles], whereas both OPRT and TYMS promoter polymorphisms were independent predictive factors for grade 3 to 4 diarrhea (odds ratio, 13.3 for patients with the Ala allele compared with patients in the Gly/Gly genotype and 11.1 for patients with the 2R allele compared with patients in the 3R/3R genotype). A significant difference was observed in the time to onset of severe toxicity, defined as grade 4 neutropenia and/or grade 3 to 4 gastrointestinal toxicities according to OPRT and TYMS promoter polymorphisms.

Conclusion: OPRT Gly213Ala polymorphism seems to be a useful marker for predicting toxicity to bolus 5-FU chemotherapy. Prospective translational treatment trials including larger number of patients are needed to confirm our results.
Immune Escape Associated with Functional Defects in Antigen-Processing Machinery in Head and Neck Cancer
Authors: Ferris Robert L. , Whiteside Theresa L. , Ferrone Soldano
Published: July 2006

Recent revival of interest in the role of immune surveillance in the pathogenesis and control of malignant diseases has focused attention on escape mechanisms used by tumor cells to evade immune recognition. Defects in the host's tumor antigen–specific immune responses and abnormalities in tumor cell expression of HLA class I molecules and tumor antigen are known to contribute to tumor progression. However, the mechanism(s) responsible for the lack of tumor cell recognition by functional HLA class I antigen–restricted, tumor antigen–specific CTLs despite expression of the restricting HLA class I allele and targeted tumor antigen by tumor cells remain(s) unexplained. In squamous cell carcinomas of the head and neck (SCCHN), this type of tumor escape is a rule rather than the exception. Here, we discuss evidence pointing to functional defects in the antigen-processing machinery as one mechanism underlying resistance of SCCHN cells to recognition and lysis by HLA class I antigen–restricted, tumor antigen–specific CTL. In addition, based on the restoration by IFN-γ of SCCHN cell sensitivity to recognition by these CTL, we suggest strategies that may improve the clinical course of the disease by enhancing susceptibility of malignant cells to immune recognition.
Accurate Prediction of BRCA1 and BRCA2 Heterozygous Genotype Using Expression Profiling after Induced DNA Damage
Authors: Kote-Jarai Zsofia , Matthews Lucy , Osorio Ana , Shanley Susan , Giddings Ian , Moreews Francois , Locke Imogen , Evans D. Gareth , Eccles Diana ,   The Carrier Clinic Collaborators, Williams Richard D. , Girolami Mark , Campbell Colin , Eeles Ros
Published: July 2006

Purpose: In this study, the differential gene expression changes following radiation-induced DNA damage in healthy cells from BRCA1/BRCA1 mutation carriers have been compared with controls using high-density microarray technology. We aimed to establish if BRCA1/BRCA2 mutation carriers could be distinguished from noncarriers based on expression profiling of normal cells.

Experimental Design: Short-term primary fibroblast cultures were established from skin biopsies from 10 BRCA1 and 10 BRCA2 mutation carriers and 10 controls, all of whom had previously had breast cancer. The cells were subjected to 15 Gy ionizing irradiation to induce DNA damage. RNA was extracted from all cell cultures, preirradiation and at 1 hour postirradiation. For expression profiling, 15 K spotted cDNA microarrays manufactured by the Cancer Research UK DNA Microarray Facility were used. Statistical feature selection was used with a support vector machine (SVM) classifier to determine the best feature set for predicting BRCA1 or BRCA2 heterozygous genotype. To investigate prediction accuracy, a nonprobabilistic classifier (SVM) and a probabilistic Gaussian process classifier were used.

Results: In the task of distinguishing BRCA1 and BRCA2 mutation carriers from noncarriers and from each other following radiation-induced DNA damage, the SVM achieved 90%, and the Gaussian process classifier achieved 100% accuracy. This effect could not be achieved without irradiation. In addition, the SVM identified a set of BRCA genotype predictor genes.

Conclusions: We conclude that after irradiation-induced DNA damage, BRCA1 and BRCA2 mutation carrier cells have a distinctive expression phenotype, and this may have a future role in predicting genotypes, with application to clinical detection and classification of mutations.
Phase I Trial of Doxorubicin-Containing Low Temperature Sensitive Liposomes in Spontaneous Canine Tumors
Authors: Hauck Marlene L. , LaRue Susan M. , Petros William P. , Poulson Jean M. , Yu Daohai , Spasojevic Ivan , Pruitt Amy F. , Klein Allison , Case Beth , Thrall Donald E. , Needham David , Dewhirst Mark W.
Published: July 2006

Purpose: To determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic characteristics of doxorubicin encapsulated in a low temperature sensitive liposome (LTSL) when given concurrently with local hyperthermia to canine solid tumors.

Experimental Design: Privately owned dogs with solid tumors (carcinomas or sarcomas) were treated. The tumors did not involve bone and were located at sites amenable to local hyperthermia. LTSL-doxorubicin was given (0.7-1.0 mg/kg i.v.) over 30 minutes during local tumor hyperthermia in a standard phase I dose escalation study. Three treatments, given 3 weeks apart, were scheduled. Toxicity was monitored for an additional month. Pharmacokinetics were evaluated during the first treatment cycle.

Results: Twenty-one patients were enrolled: 18 with sarcomas and 3 with carcinomas. Grade 4 neutropenia and acute death secondary to liver failure, possibly drug related, were the dose-limiting toxicities. The maximum tolerated dose was 0.93 mg/kg. Other toxicities, with the possible exception of renal damage, were consistent with those observed following free doxorubicin administration. Of the 20 dogs that received ≥2 doses of LTSL-doxorubicin, 12 had stable disease, and 6 had a partial response to treatment. Pharmacokinetic variables were more similar to those of free doxorubicin than the marketed liposomal product. Tumor drug concentrations at a dose of 1.0 mg/kg averaged 9.12 ± 6.17 ng/mg tissue.

Conclusion: LTSL-doxorubicin offers a novel approach to improving drug delivery to solid tumors. It was well tolerated and resulted in favorable response profiles in these patients. Additional evaluation in human patients is warranted.
Clinical Significance of Aminopeptidase N in Non–Small Cell Lung Cancer
Authors: Tokuhara Takahiro , Hattori Noboru , Ishida Hisao , Hirai Tatsuya , Higashiyama Masahiko , Kodama Ken , Miyake Masayuki
Published: July 2006

Purpose: The aim of our study is to investigate the mechanism of metastasis, to detect novel metastasis-associated molecules, and to evaluate the molecules from the point of view of clinical application. A monoclonal antibody MH8-11, which we established, recognizes a glycoprotein that is identical to aminopeptidase N (APN/CD13). APN/CD13 degrades the extracellular matrix, while it is also involved in cell motility and improves angiogenesis.

Experimental Design: We investigated the expression of APN/CD13 in 194 cases of non–small cell lung cancer (NSCLC) by immunohistochemical analyses and reverse transcription-PCR assay to determine the significance of this prognostic factor; 95 tumors were stage I, 36 were stage II, 39 were stage IIIA, and 24 were stage IIIB. Moreover, we investigated that the relationship between the expression of APN/CD13 and angiogenesis and prognosis for patients with NSCLC.

Results: We found a correlation between the expression of APN/CD13 and angiogenesis (r = 0.659; P < 0.0001). In the 194 patients with NSCLC, we found 68 patients to be APN/CD13+ and 126 patients to be APN/CD13−. The 5-year survival rate in patients with APN/CD13+ tumors was significantly lower than in those whose tumors had negative APN/CD13 (48.3% versus 67.1%; P = 0.0001).

Conclusion: Our data suggest the expression of APN/CD13 for patients with NSCLC to be associated with a poor prognosis and angiogenesis. This is the first study to show the relationship between the expression of APN/CD13 and the prognosis of patients with NSCLC. The inhibition of APN/CD13 may be an effective new molecular target therapy for patients with NSCLC.
Calcitonin Gene-Related Peptide and Substance P Regulate the Intestinal Radiation Response
Authors: Wang Junru , Qiu Xiaohua , Kulkarni Ashwini , Hauer-Jensen Martin
Published: July 2006

Purpose: Intestinal toxicity is important in the therapeutic use of radiation as well as in nontherapeutic radiation exposure scenarios. Enteric sensory nerves are critical for mucosal homeostasis and for an appropriate response to injury. This study assessed the role of the two major neuropeptides released by sensory nerves, calcitonin gene-related peptide (CGRP) and substance P, in the intestinal radiation response.

Experimental Design: Male rats received full-length CGRP, CGRP antagonist (CGRP8-37), a modified substance P peptide (GR73632), a small-molecule substance P receptor antagonist (neurokinin-1 receptor antagonist, SR140333), or vehicle for 2 weeks after localized X irradiation of a 4-cm loop of small bowel. Structural, cellular, and molecular aspects of the intestinal radiation response were assessed.

Results: Intestinal CGRP and substance P transcript levels increased after irradiation. Multivariate analysis showed that CGRP and SR140333 ameliorated and CGRP8-37 and GR73632 exacerbated intestinal radiation injury. Univariate analysis revealed increased radiation injury score, bowel wall thickening, and collagen III deposition after treatment with CGRP8-37, whereas SR140333 ameliorated radiation injury score, loss of mucosal surface area, collagen III deposition, and mucosal inflammation.

Conclusions: The two major neuropeptides released by sensory neurons, CGRP and substance P, are overexpressed after irradiation and have opposing effects during development of intestinal radiation injury. Systematic studies to assess CGRP agonists and/or neurokinin-1 receptor blockers as protectors against intestinal toxicity during radiation therapy and after nontherapeutic radiation exposure are warranted.
Reversal of temporal and spatial heterogeneities in tumor perfusion identifies the tumor vascular tone as a tunable variable to improve drug delivery
Authors: Martinive Philippe , De Wever Julie , Bouzin Caroline , Baudelet Christine , Sonveaux Pierre , Grégoire Vincent , Gallez Bernard , Feron Olivier
Published: July 2006

Maturation of tumor vasculature involves the recruitment of pericytes that protect the endothelial tubes from a variety of stresses, including antiangiogenic drugs. Mural cells also provide mature tumor blood vessels with the ability to either relax or contract in response to substances present in the tumor microenvironment. The observed cyclic alterations in tumor blood flow and the associated deficit in chemotherapeutic drug delivery could in part arise from this vasomodulatory influence. To test this hypothesis, we focused on endothelin-1 (ET-1), which, besides its autocrine effects on tumor cell growth, is a powerful vasoconstrictor. We first document that an ETA receptor antagonist induced relaxation of microdissected tumor arterioles and selectively and quantitatively increased tumor blood flow in experimental tumor models. We then combined dye staining of functional vessels, fluorescent microsphere-based mapping, and magnetic resonance imaging to identify heterogeneities in tumor blood flow and to examine the reversibility of such phenomena. Data from all these techniques concurred to show that administration of an ETA receptor antagonist could reduce the extent of underperfused tumor areas, proving the key role of vessel tone variations in tumor blood flow heterogeneity. We also provide evidence that ETA antagonist administration could, despite an increase in tumor interstitial fluid pressure, improve access of cyclophosphamide to the tumor compartment and significantly influence tumor growth. In conclusion, tumor endogenous ET-1 production participates largely in the temporal and spatial variations in tumor blood flow. ETA antagonist administration may wipe out such heterogeneities, thus representing an adjuvant strategy that could improve the delivery of conventional chemotherapy to tumors. [Mol Cancer Ther 2006;5(6):1620–7]
Potent cytotoxicity of an auristatin-containing antibody-drug conjugate targeting melanoma cells expressing melanotransferrin/p97
Authors: Smith Leia M. , Nesterova Albina , Alley Stephen C. , Torgov Michael Y. , Carter Paul J.
Published: July 2006

Identifying factors that determine the sensitivity or resistance of cancer cells to cytotoxicity by antibody-drug conjugates is essential in the development of such conjugates for therapy. Here the monoclonal antibody L49 is used to target melanotransferrin, a glycosylphosphatidylinositol-anchored glycoprotein first identified as p97, a cell-surface marker in melanomas. L49 was conjugated via a proteolytically cleavable valine-citrulline linker to the antimitotic drug, monomethylauristatin F (vcMMAF). Effective drug release from L49-vcMMAF likely requires cellular proteases most commonly located in endosomes and lysosomes. Melanoma cell lines with the highest surface p97 expression (80,000–280,000 sites per cell) were sensitive to L49-vcMMAF whereas most other cancer cell lines with lower p97 expression were resistant, as were normal cells with low copy numbers (≤20,000 sites per cell). Cell line sensitivity to L49-vcMMAF was found by immunofluorescence microscopy to correlate with intracellular fate of the conjugate. Specifically, L49-vcMMAF colocalized with the lysosomal marker CD107a within sensitive cell lines such as SK-MEL-5 and A2058. In contrast, in resistant cells expressing lower p97 levels (H3677; 72,000 sites per cell), L49-vcMMAF colocalized with caveolin-1, a protein prominent in caveolae, but not with CD107a. Thus, for antibody-drug conjugates targeting p97, antigen level and trafficking to the lysosomes are important factors for achieving robust in vitro cytotoxicity against cancer cells. Immunohistochemical analysis with L49 revealed that 62% of metastatic melanoma tumors had strong staining for p97. Overexpression of p97 in melanoma as compared with normal tissue, in conjunction with the greater sensitivity of tumor cells to L49-vcMMAF, supports further evaluation of antibody-drug conjugates for targeting p97-overexpressing tumors. [Mol Cancer Ther 2006;5(6):1474–82]
B cell translocation gene 1 contributes to antisense Bcl-2-mediated apoptosis in breast cancer cells
Authors: Nahta Rita , Yuan Linda X.H. , Fiterman Derek J. , Zhang Li , Symmans W. Fraser , Ueno Naoto T. , Esteva Francisco J.
Published: July 2006

The antiapoptotic protein Bcl-2 is overexpressed in a majority of breast cancers, and is associated with a diminished apoptotic response and resistance to various antitumor agents. Bcl-2 inhibition is currently being explored as a possible strategy for sensitizing breast cancer cells to standard chemotherapeutic agents. Antisense Bcl-2 oligonucleotides represent one method for blocking the antiapoptotic effects of Bcl-2. In this study, we show that antisense Bcl-2 efficiently blocks Bcl-2 expression, resulting in the apoptosis of breast cancer cells. Antisense Bcl-2-mediated cytotoxicity was associated with the induction of the B cell translocation gene 1 (BTG1). Importantly, knockdown of BTG1 reduced antisense Bcl-2-mediated cytotoxicity in breast cancer cells. Furthermore, BTG1 expression seems to be negatively regulated by Bcl-2, and exogenous expression of BTG1 induced apoptosis. These results suggest that BTG1 is a Bcl-2-regulated mediator of apoptosis in breast cancer cells, and that its induction contributes to antisense Bcl-2-mediated cytotoxic effects. [Mol Cancer Ther 2006;5(6):1593–601]
Integrin-Linked Kinase, a Hypoxia-Responsive Molecule, Controls Postnatal Vasculogenesis by Recruitment of Endothelial Progenitor Cells to Ischemic Tissue
Authors: Lee Seung-Pyo , Youn Seock-Won , Cho Hyun-Jai , Li Lian , Kim Tae-Youn , Yook Hyung-Seon , Chung Jae-Woong , Hur Jin , Yoon Chang-Hwan , Park Kyung-Woo , Oh Byung-Hee , Park Young-Bae , Kim Hyo-Soo
Published: July 2006

Background—

Recruitment and adhesion of endothelial progenitor cells (EPCs) to hypoxic endothelial cells (ECs) is essential for vasculogenesis in ischemic tissue; little is known, however, about the key signals or intracellular signaling pathways involved in orchestrating the expression of adhesion molecules by ECs in response to hypoxia and how this is related to the recruitment of EPCs to the ischemic tissue. Here, we report that endogenous integrin-linked kinase (ILK) is a novel molecule that responds to hypoxia in ECs that regulates the expression of stromal cell–derived factor-1 (SDF-1) and intercellular adhesion molecule-1 (ICAM-1) through nuclear factor-κB and hypoxia-inducible factor-1α and induces recruitment of EPCs to ischemic areas.

Methods and Results—

Under hypoxia, both the endogenous amount and kinase activity of ILK were time-dependently upregulated in ECs, which was associated with increased ICAM-1 and SDF-1. This upregulation of ILK was mediated by stabilization of ILK by heat shock protein 90. ILK overexpression in normoxic ECs resulted in ICAM-1 and SDF-1 upregulation through dual control by nuclear factor-κB and hypoxia-inducible factor-1α. Blockade of ILK in hypoxic ECs significantly abrogated the expression of both molecules, which led to decreased EPC incorporation into ECs. A hindlimb ischemia model showed that ILK blockade significantly reduced EPC homing to ischemic limb and consequently led to poor neovascularization. Overexpression of ILK in the Matrigel plug significantly improved neovascularization in vivo, whereas the blockade of ILK resulted in the opposite effect.

Conclusions—

Endogenous ILK is a novel and physiological upstream responder of numerous intracellular molecules involved in hypoxic stress in ECs and may control the recruitment of EPCs to ischemic tissue.
Effect of Amiodarone and Sotalol on Ventricular Defibrillation Threshold
Authors: Hohnloser Stefan H. , Dorian Paul , Roberts Robin , Gent Michael , Israel Carsten W. , Fain Eric , Champagne Jean , Connolly Stuart J.
Published: July 2006

Background—

Many patients with implanted cardioverter defibrillators (ICDs) receive adjunctive antiarrhythmic drug therapy, most commonly amiodarone or sotalol. The effects of these drugs on defibrillation energy requirements have not been previously assessed in a randomized controlled trial.

Methods and Results—

The Optimal Pharmacological Therapy in Cardioverter Defibrillator Patients (OPTIC) trial was a randomized clinical trial evaluating the efficacy of amiodarone plus β-blocker and sotalol versus β-blocker alone for reduction of ICD shocks. Within OPTIC, a prospectively designed substudy evaluated the effects of the 3 treatment arms on defibrillation energy requirements. Defibrillation thresholds (DFTs) were measured (binary step-down protocol) at baseline and again after 8 to 12 weeks of therapy in 94 patients, of whom 29 were randomized to receive β-blocker therapy (control group), 35 to amiodarone plus β-blocker, and 30 to sotalol. In the control group, the mean DFT decreased from 8.77±5.15 J at baseline to 7.13±3.43 J (
P
=0.027); in the amiodarone group, DFT increased from 8.53±4.29 to 9.82±5.84 J (
P
=0.091). In the sotalol group, DFT decreased from 8.09±4.81 to 7.20±5.30 J (
P
=0.21). DFT changes in the β-blocker and the amiodarone group were significantly different (
P
=0.006). In all patients, adequate safety margins for defibrillation were maintained. No clinical variable predicted baseline DFT or changes in DFT on therapy.

Conclusion—

Although amiodarone increased DFT, the effect size with modern ICD systems is very small. Therefore, DFT reassessment after the institution of antiarrhythmic drug therapy with amiodarone or sotalol is not routinely required.
Healthy Lifestyle Factors in the Primary Prevention of Coronary Heart Disease Among Men
Authors: Chiuve Stephanie E. , McCullough Marjorie L. , Sacks Frank M. , Rimm Eric B.
Published: July 2006

Background—

Healthy lifestyle choices such as eating a prudent diet, exercising regularly, managing weight, and not smoking may substantially reduce coronary heart disease (CHD) risk by improving lipids, blood pressure, and other risk factors. The burden of CHD that could be avoided through adherence to these modifiable lifestyle factors has not been assessed among middle-aged and older US men, specifically men taking medications for hypertension or hypercholesterolemia.

Methods and Results—

We prospectively monitored 42 847 men in the Health Professionals Follow-up Study, 40 to 75 years of age and free of disease in 1986. Lifestyle factors were updated through self-reported questionnaires. Low risk was defined as (1) absence of smoking, (2) body mass index <25 kg/m
2
, (3) moderate-to-vigorous activity ≥30 min/d, (4) moderate alcohol consumption (5 to 30 g/d), and (5) the top 40% of the distribution for a healthy diet score. Over 16 years, we documented 2183 incident cases of CHD (nonfatal myocardial infarction and fatal CHD). In multivariate-adjusted Cox proportional hazards models, men who were at low risk for 5 lifestyle factors had a lower risk of CHD (relative risk: 0.13; 95% confidence interval [CI]: 0.09, 0.19) compared with men who were at low risk for no lifestyle factors. Sixty-two percent (95% CI: 49%, 74%) of coronary events in this cohort may have been prevented with better adherence to these 5 healthy lifestyle practices. Among men taking medication for hypertension or hypercholesterolemia, 57% (95% CI: 32%, 79%) of all coronary events may have been prevented with a low-risk lifestyle. Compared with men who did not make lifestyle changes during follow-up, those who adopted ≥2 additional low-risk lifestyle factors had a 27% (95% CI: 7%, 43%) lower risk of CHD.

Conclusions—

A majority of CHD events among US men may be preventable through adherence to healthy lifestyle practices, even among those taking medications for hypertension or hypercholesterolemia.