bluuebunny/crossref_metadata_2025 huggingface dataset:
Beethoven's Operatic Plans
Authors: Anderson Emily
Published: January 2007

When I was invited two years ago to read a paper on some subject connected with the research work on which I was then engaged, I felt a certain hesitation about doing so. For I naturally assumed that in the case of Beethoven a good deal of ground must have already been covered by earlier contributors. But on looking up the records of the Royal Musical Association I discovered to my surprise that since 1874, the year of its foundation, only six papers had been read on subjects closely relating to Beethoven (and in one of these he shares the honours with Mozart). Six papers in 88 years! And, what is even more startling, not one has been read since 1927, the centenary of Beethoven's death, that is to say, for the last 35 years. I need hardly add that such an apparent lack of interest in the life and work of this composer prompted me to make some amends, however small, for an indignity amounting almost to lèse-majesté.
The English Consort Song, 1570–1625
Authors: Brett Philip
Published: January 2007

The Italian Madrigal style adopted by English composers towards the close of the sixteenth century seems, on the face of it, to have almost eclipsed the native forms of secular vocal music. But although the madrigal and the lute-song account for much of the finest music of the time, the traditional style continued to exist and to develop in the songs of a number of composers who were not wholly committed to the new forms. Since these composers include William Byrd and Orlando Gibbons, we can be sure that the artistic achievements of the style are not negligible and that an understanding of their true nature is vital to our grasp of the period.
Gottfried van Swieten Patron of Haydn and Mozart
Authors: Olleson Edward
Published: January 2007

The Picture of Gottfried van Swieten which is found in musical literature can scarcely be described as wholly favourable. It has long been recognised that his tastes in music influenced Mozart profoundly, but his close-fistedness has been blamed for contributing to the composer's poverty, and finally for giving Mozart only the cheapest possible funeral. In his dealings with Haydn, Swieten is acknowledged as the leader of that group of the nobility which sponsored the Creation and the Seasons, but this credit is more than balanced by criticism of his libretti to the two oratorios. At the best, it would seem, van Swieten's presence in Vienna was a mixed blessing.
Harps in the Baroque Era
Authors: Rimmer Joan
Published: January 2007

The nature of harping before the general use of the pedal harp makes research peculiarly frustrating. Apart from bagpiping—which is to this day so secret a skill that most virtuosi will never reveal the true details of their reed-making and playing—no instrumental technique remained so long a craft, without a written literature. As far as the baroque era is concerned, there is the additional problem that the word harp covered a number of harps with different forms, techniques and functions. This preamble is not, like that of the music-hall juggler, to make the act seem so difficult that the sympathy of the audience is assured at the start, but simply to warn you that the information I have been able to collect on the subject of harps between roughly 1600 and 1750 is drawn from somewhat disparate sources and is rather unevenly spread, both geographically and chronologically.
Satie's Rose Croix Music (1891–1895)
Authors: Gowers Patrick
Published: January 2007

It may seem strange to commemorate the centenary of Satie's birth by a discussion of his output from 1891 to 1895 rather than by an overall appreciation. But his accepted standing as a minor yet historically important composer has had a twofold result: on the one hand, little basic documentary research into his output has been undertaken; on the other, general appreciations of him have been written many times, largely by authors whose main concern is Debussy, Ravel, Les Six or recent French music as a whole. As you would expect, this literature tends to be accurate in outline but unreliable in detail. Therefore I have thought it best, rather than repeat the easily available broad facts of Satie's life and work, to concentrate on some topic which can be more thoroughly covered in the time. The Rose Croix music stands out as being conveniently self-contained, unusual, interesting and misunderstood.
Cavalli's Operas
Authors: Leppard Raymond
Published: January 2007

The root cause of Francesco Cavalli's importance in the history of opera lies, I believe, in the fact that he was the first composer to write almost exclusively for the professional public theatre. That he did so with outstanding success for twenty-seven years, enhancing the reputation and consolidating the supremacy of Venetian opera throughout Europe, is a testimony to the sheer quality of his music and theatrical ability which, of course, must count for more than anything else in a final assessment.
English String Concertos before 1800
Authors: Edwards Owain
Published: January 2007

During the early eighteenth century, and up to the 1760s, the mainstay of every English instrumental concert was the concerto. If one had dropped in on a private ‘musical evening’ at a Gentlemen's subscription concert, one would have been certain of hearing a number of concertos. But after this date, and especially towards the closing years of the century, they figured less often in concert programmes than they had done formerly. The changes brought about by the general acceptance in this country of the galant style were many, and perhaps the most enervating of them was the decline of the amateur music society in favour of the larger professional concert. When in the 1760s British composers joined the avant garde and imitated the lively style of John Christian Bach, they were effectively putting a stop to the amateur music-making which had flourished so vigorously during the previous half-century. Their new compositions were technically too demanding for most amateurs and, because they omitted to write easy ripieno parts for the less proficient of them, the result was not slow to follow. But although many players were distressed at not being able to tackle the new music, it appealed to a far wider audience than music in the ‘Ancient’ style had done—or had been able to, on account of its limited availability or accessibility to the general public. Music was ceasing to be the preserve of select groups in society. It continued to be heard in church and theatre, and now the public concert and the pleasure garden admitted persons of any social standing for the price of a ticket. By the last quarter of the eighteenth century music had become at least a topic of interest, if not importance, for the man in the street.
A Profile of Jan Václav Vořišek
Authors: Simpson Adrienne
Published: January 2007

Jan Vořišek is an oddly shadowy figure in musical history. Admirer and intimate of Beethoven, friend of Schubert—yet exponent of Bach fugues and continuo realisations for seventeenth- and eighteenth-century compositions; on the one hand a war-office clerk, on the other organist to the Imperial Court—his life is made up of such contrasts. He was born into the generation that saw the rise of Czech cultural nationalism, but took no part in it. Indeed, he is almost the last of the long line of emigré Czechs (the Stamitz family, the Bendas, Mysliviček, Vaňhal, Reicha and others) who practised with distinction the international musical style. He was a virtuoso pianist and a popular, even fashionable, figure in the salons of the Viennese musical dilettanti, yet he left some compositions of such excellence that one marvels that their revival has been so long delayed. The more one knows about his career, the further one seems to travel from Jan Voříšek as a person.
Measuring Issue Preferences: The Problem of Response Instability
Authors: Feldman Stanley
Published: January 2007

The problem of response instability in survey measures of policy positions has been studied for over 20 years without any apparent resolution. Two major interpretations remain: Philip Converse's nonattitudes model and a measurement error model. One reason why neither interpretation has as yet been rejected or well supported is that previous analyses have depended on three-wave panel data that do not contain sufficient information to assess the goodness-of-fit of the models and also provide unreliable estimates of the error variance for the issue questions. Using five-wave panel data, this article first re-estimates the measurement models for the issue positions to assess goodness-of-fit and then estimates models of response instability to help establish its determinants. Evidence consistent with both interpretations of response instability is found. It thus appears as if neither model can adequately deal with the empirical characteristics of opinion questions in panel data. In the conclusion, a third interpretation of the response instability problem is offered that better accounts for the empirical findings and is more consistent with our understanding of public opinion.
How the Cases You Choose Affect the Answers You Get: Selection Bias in Comparative Politics
Authors: Geddes Barbara
Published: January 2007

This article demonstrates how the selection of cases for study on the basis of outcomes on the dependent variable biases conclusions. It first lays out the logic of explanation and shows how it is violated when only cases that have achieved the outcome of interest are studied. It then examines three well-known and highly regarded studies in the field of comparative politics, comparing the conclusions reached in the original work with a test of the arguments on cases selected without regard for their position on the dependent variable. In each instance, conclusions based on the uncorrelated sample differ from the original conclusions.
Error Correction, Attitude Persistence, and Executive Rewards and Punishments: A Behavioral Theory of Presidential Approval
Authors: Ostrom Charles W. , Smith Renée M.
Published: January 2007

Beginning with Mueller's (1970) seminal work, researchers have wrestled with explanations of the movement of presidential approval over time. In his initial argument, Mueller states that

in tandem, the concepts underlying the coalition of minorities and rally round the flag variables predict that the president's popularity will continually decline over time and that international crises and similar events will explain short-term bumps and wiggles in this otherwise inexorable descent. (1970, 22)

From this basis, Mueller posits “… a general downward trend in each president's popularity” (1970, 19) that is linear and deterministic over the course of a term. Others later moved away from arguments of linearity (e.g., Stimson 1976) and from the coalition of minorities concept (e.g., Kemell 1978), but these early characterizations of approval's time path, perpetuated in the “myth of the inexorable descent,” remain to this day.
Dynamic Change, Specification Uncertainty, and Bayesian Vector Autoregression Analysis
Authors: Williams John T.
Published: January 2007

The analysis of time-series data is fraught with problems of specification uncertainty and dynamic instability. Vector autoregression (VAR) is one attempt to overcome specification problems in time-series analysis, but this methodology has been criticized for being unparsimonious and potentially unstable through time.1This article describes an important extension of VAR, one using Bayesian methods and allowing for time-varying parameters. These extensions improve VAR, making analysis less vulnerable to these criticisms. These VAR methods, developed by Doan, Litterman, and Sims (1984), provide a reasonable method for dealing with general time variation when theory does not provide useful a priori specification restrictions.
Attitudes, No Opinions, and Guesses
Authors: Jackson John E.
Published: January 2007

This article presents a statistical model of the survey response that includes both a measure of the respondent's likely true attitude and a measure of the probability that the respondent is uncertain about her or his attitude and is “guessing” at a response. This latter possibility introduces systematic measurement error that may bias efforts to get unbiased estimates of attitudes. The model and the likely consequences of guessing are illustrated with questions about Vietnam policy taken from the 1968, 1970, and 1972 National Election Studies (NES) surveys. The article ends with a discussion of the limitations and fragility of the model.
Nasopharyngeal Carriage of Respiratory Pathogens in Children Undergoing Pressure Equalization Tube Placement in the Era of Pneumococcal Protein Conjugate Vaccine Use
Authors: Jacobs Michael R. , Good Caryn E. , Sellner Tom , Bajaksouzian Saralee , Windau Anne , Anon Jack B.
Published: January 2007

Objective: To define carriage of bacterial respiratory pathogens in children undergoing pressure equalization tube placement.

Study Design: Nasopharyngeal cultures were performed during tube placement. Antibiotic susceptibilities and serotypes of pneumococci were determined.

Results: Sixty‐nine Streptococcus pneumoniae, 72 Haemophilus influenzae (41% β‐lactamase positive), and 39 Moraxella catarrhalis (all β‐lactamase positive) were isolated from 201 children. Overall, 42% of pneumococci were nonsusceptible to penicillin, and 34.8% were resistant to macrolides. In relation to the pneumococcal conjugate vaccine, 17.4% were vaccine, 31.9% vaccine‐related, and 50.7% nonvaccine serotypes.

Conclusion: Twenty‐five percent of children colonized with pneumococci carried antibiotic resistant nonvaccine serotypes rarely detected before the introduction of pneumococcal conjugate vaccine, including serotype 19A isolates (7%) resistant to all oral agents tested and type 35B isolates (12%) nonsusceptible to penicillin and cefuroxime.

Significance: Pneumococcal colonization suggests replacement of vaccine serotypes with vaccine related and nonvaccine serotypes, many of which are resistant to common oral antimicrobials.
Political‐Economic Values and the Relationship Between Socioeconomic Status and Self‐Esteem
Authors: Malka Ariel , Miller Dale T.
Published: January 2007

ABSTRACT
Values concerning the distribution of wealth are an important aspect of identity for many Americans, and such values may therefore influence how Americans experience their own socioeconomic status (SES). Based on this proposition, the present research examines political‐economic values as a moderator of the relationship between SES and self‐esteem. Results supported the hypothesis that there is a stronger relationship between SES and self‐esteem among individuals who report relatively inegalitarian values than among individuals who report relatively egalitarian values. This result was replicated using both objective and subjective measures of SES. Implications of the present findings for the study of values and well‐being, psychological conflict, and the influence of economic factors on self‐esteem are discussed.
Numerical Simulation of Operational-Shock in Small Form Factor Hard Disk Drives
Authors: Bhargava P. , Bogy D. B.
Published: January 2007

As nontraditional applications of hard disk drives emerge, their mechanical robustness during the operating state is of greater concern. Over the past few years, there has been an increasing application of small form factor (1in. and smaller) hard disk drives in portable consumer appliances and gadgets. A procedure for simulating the operational shock response of a disk-suspension-slider air bearing system is proposed in this paper. A coupled structural-fluid model is presented which can be used to obtain the dynamic response of the slider-suspension-disk system. A commercial program, ANSYS, is used for the finite element models of the suspension and the disk, while the CML dynamic air bearing code is used to concurrently solve the air bearing equations of the system. We obtain not only the responses of the structural components, but also the responses of the air bearing slider. The procedure is convenient for practical application as well as being highly accurate, since it implicitly solves the structural and air bearing problems simultaneously. It is used to simulate the shock response of a 1in. drive. The air bearing has different responses for upward and downward shocks (which are referred to as positive and negative shocks, respectively). For negative shocks, slider-disk contacts are observed to occur when a strong shock is applied, however, the air bearing does not collapse. For positive shocks, we observe a collapse of the air bearing when the shock is sufficiently strong, which is followed by severe contacts between the slider and the disk due to the “head-slap” phenomenon.
Experimental Investigation of the Influence of Supply Temperature and Supply Pressure on the Performance of a Two-Axial Groove Hydrodynamic Journal Bearing
Authors: Brito F. P. , Miranda A. S. , Bouyer J. , Fillon M.
Published: January 2007

An experimental study of the influence of oil supply temperature and supply pressure on the performance of a 100mm plain journal bearing with two axial grooves located at ±90deg to the load line was carried out. The hydrodynamic pressure at the mid-plane of the bearing, temperature profiles at the oil-bush and oil-shaft interfaces, bush torque, oil flow rate, and the position of the shaft were measured for variable operating conditions. Shaft rotational speed ranged from 1000 to 4000rpm and two different values of applied load were tested (2 and 10kN). The supply temperature ranged from 35 to 50°C, whereas the oil supply pressure range was 70 to 210kPa. Bearing performance is strongly dependent on the supply conditions. It was found that the existence of the downstream groove significantly affects the temperature profile at the oil-bush interface except for the low load, low feeding pressure cases, where the cooling effect of the upstream groove is significant. Feeding temperature has a strong effect on the minimum film thickness. The increase in maximum temperature is significantly lower than the corresponding increase in supply temperature. Increases in supply pressure lead to a significant rise in oil flow rate but have little effect on the maximum temperature and power-loss, except in the case of the lightly loaded bearing. Shaft temperature was found to be close to the bearing maximum temperature for low applied loads, being significantly smaller than this value for high loads. The mean shaft temperature is only significantly higher than the outlet temperature at high shaft speeds.
Neoadjuvant Therapy with Paclitaxel followed by 5-Fluorouracil, Epirubicin, and Cyclophosphamide Chemotherapy and Concurrent Trastuzumab in Human Epidermal Growth Factor Receptor 2–Positive Operable Breast Cancer: An Update of the Initial Randomized Study Population and Data of Additional Patients Treated with the Same Regimen
Authors: Buzdar Aman U. , Valero Vicente , Ibrahim Nuhad K. , Francis Deborah , Broglio Kristine R. , Theriault Richard L. , Pusztai Lajos , Green Marjorie C. , Singletary Sonja E. , Hunt Kelly K. , Sahin Aysegul A. , Esteva Francisco , Symmans William F. , Ewer Michael S. , Buchholz Thomas A. , Hortobagyi Gabriel N.
Published: January 2007

Purpose: Findings from our previously published phase III randomized trial showed a high pathologic complete remission (CR) rate in patients with human epidermal growth factor receptor 2–positive breast cancer after the concurrent administration of trastuzumab and paclitaxel, followed by concurrent trastuzumab and 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) preoperative chemotherapy. The safety and efficacy data of initial population were updated, with inclusion of additional experience with the same therapy.

Study Design: The initial randomized study population of 42 patients were randomly assigned to either four cycles of paclitaxel followed by four cycles of FEC or to the same chemotherapy with simultaneous weekly trastuzumab for 24 weeks. All data were updated through November 2005.

Results: Pretreatment characteristics of the initial patients and of the second cohort were similar. In the second cohort, pathologic CR rate was 54.5% (95% confidence interval, 32.2-75.6%) and the pathologic CR rate among all patients treated with chemotherapy plus trastuzumab was 60% (95% confidence interval, 44.3-74.3%). Three patients in the chemotherapy only group have recurred, and one has died. There has been no recurrences in the patients randomized to chemotherapy plus trastuzumab, and the estimated disease-free survival at 1 and 3 years was 100% (P = 0.041). In additional cohort treated with chemotherapy and trastuzumab at the median follow-up of 16.3 months, no patients had recurred. No new safety concerns were observed in this study.

Conclusion: Our expanded cardiac safety data and the updated efficacy data showed that the natural history of this subset of breast cancer patients can be substantially modified by this treatment approach.
Expression of the Hypoxia Marker Carbonic Anhydrase 9 Is Associated with Anaplastic Phenotypes in Meningiomas
Authors: Yoo Heon , Baia Gilson S. , Smith Justin S. , McDermott Michael W. , Bollen Andrew W. , VandenBerg Scott R. , Lamborn Kathleen R. , Lal Anita
Published: January 2007

Purpose: Hypoxia in the tumor microenvironment triggers a variety of genetic and adaptive responses that regulate tumor growth. Tumor hypoxia is often associated with more malignant phenotypes, resistance to therapy, and poor survival. The purpose of this study was to evaluate the prevalence of hypoxia in meningiomas using the endogenous hypoxia marker carbonic anhydrase 9 (CA9) and to relate the expression of CA9 to tumor vascularity, histopathologic grade, and clinical variables, such as recurrent tumor status.

Experimental Design: Expression of CA9 and CD34, an endothelial cell marker, was examined in serial paraffin-embedded sections by immunohistochemistry in 25 grade 1, 17 grade 2, and 20 grade 3 meningiomas. Areas of immunoreactivity were semiquantitatively scored and correlated to clinical variables using Statistical Analysis System statistical software.

Results: Approximately 50% (29 of 62) of all meningiomas contained regions of hypoxia as judged by expression of CA9, and this expression was significantly associated with higher-grade histology (P = 0.001). In contrast, vascularity, as assessed by the percentage of vascular hotspots, was inversely associated with tumor grade (P = 0.023) and was not associated with CA9 expression. Among lower-grade meningiomas, CA9 expression tended to be more common in recurrent tumors.

Conclusions: Tumor hypoxia is an endogenous feature of meningiomas, and therapeutic regimens should include strategies to target the subpopulation of hypoxic as well as the normoxic cells within the tumor. Hypoxia in meningiomas is associated with an aggressive phenotype. Further studies to define the contribution of hypoxia to meningioma pathophysiology are warranted.
Alum with Interleukin-12 Augments Immunity to a Melanoma Peptide Vaccine: Correlation with Time to Relapse in Patients with Resected High-Risk Disease
Authors: Hamid Omid , Solomon Jolie C. , Scotland Ronald , Garcia Marile , Sian Shirley , Ye Wei , Groshen Susan L. , Weber Jeff S.
Published: January 2007

Purpose: We attempted to augment immunity to melanoma antigens using interleukin-12 (IL-12) with aluminum hydroxide (alum) for sustained release or granulocyte macrophage colony-stimulating factor (GM-CSF) added to a multipeptide vaccine.

Experimental Design: Sixty patients with high-risk resected melanoma were randomized to receive melanoma peptides gp100209-217 (210M), MART-126-35 (27L), and tyrosinase368-376 (370D) with adjuvant Montanide ISA 51 and either IL-12 at 30 ng/kg with alum (group A), IL-12 at 100 ng/kg with alum (group B), or IL-12 at 30 ng/kg with 250 μg GM-CSF (group C).

Results: Three patients had stage IIC (5%), 50 had stage III (83%), and 7 had stage IV (12%) melanoma. Most toxicities were grade 1/2 and resolved rapidly. Significant toxicity included grade 3 colitis and visual changes and grade 3 headache resolving after stopping IL-12 but continuing peptide vaccine. A higher rate of post-vaccine 6-month immune response to gp100 and MART-1 was observed in group A (15 of 19) or B (19 of 20) that received IL-12 plus alum versus group C with IL-12/GM-CSF (4 of 21; P < 0.001). Post-vaccine enzyme-linked immunospot response rates to peptide analogues in group B were higher than group A (P = 0.031 for gp100 and P = 0.010 for MART-1); both were higher than group C (P < 0.001 for gp100 and P < 0.026 for MART-1). With a median of 24 months of follow-up, 23 patients have relapsed. Post-vaccine immune response to MART-1 was associated with relapse-free survival (P = 0.012).

Conclusions: IL-12 with alum augmented an immune response to melanoma antigens compared with IL-12 with GM-CSF. Immune response was associated with time to relapse.
Expression of Cellular FLICE Inhibitory Protein, Caspase-8, and Protease Inhibitor-9 in Ewing Sarcoma and Implications for Susceptibility to Cytotoxic Pathways
Authors: de Hooge Alfons S.K. , Berghuis Dagmar , Santos Susy Justo , Mooiman Esther , Romeo Salvatore , Kummer J. Alain , Egeler R. Maarten , van Tol Maarten J.D. , Melief Cornelis J.M. , Hogendoorn Pancras C.W. , Lankester Arjan C.
Published: January 2007

Purpose: Ewing sarcoma is a common pediatric bone tumor with an unfavorable prognosis for metastatic or recurrent disease. Cellular immunotherapy may provide new treatment options and depends on the cytolytic death receptor and perforin/granzyme pathways. Expression of death receptor pathway inhibitor cellular FLICE inhibitory protein (cFLIP), initiator caspase-8, and granzyme B inhibitor protease inhibitor-9 (PI-9) have been reported to determine susceptibility to cell- and chemotherapy-mediated killing in several tumor types. Here, we have studied their in vitro and in vivo expression in Ewing sarcoma and the implications for susceptibility to cytotoxicity.

Experimental Design: Ewing sarcoma cell lines (n = 8) were tested for cFLIP, PI-9, and caspase-8 expression. Functional significance was tested by anti-Fas antibody (death receptor pathway) or natural killer cell (perforin/granzyme pathway) treatment. Immunohistochemistry was done on 28 sections from 18 patients. In half of the cases, sequential material, including metastases, was available.

Results: Although all tested Ewing sarcoma cell lines expressed cFLIP, resistance to CD95/Fas–mediated apoptosis was only observed in two cell lines lacking caspase-8 expression. PI-9 was expressed at low levels in four of eight Ewing sarcoma cell lines, but positive cell lines remained susceptible to perforin/granzyme–mediated killing. In primary Ewing sarcoma, including metastases, cFLIP was abundantly expressed in 18 of 18 patients. Caspase-8 was expressed in all patients but showed more intertumoral and intratumoral variation in both intensity and heterogeneity of staining. PI-9, in contrast, was undetectable.

Conclusions: The expression patterns of cFLIP, caspase-8, and the absence of PI-9 provide a rationale to preferentially exploit the perforin/granzyme pathway in cytotoxic therapies against Ewing sarcoma.
Inactivation of SMAD4 Tumor Suppressor Gene During Gastric Carcinoma Progression
Authors: Wang Li-Hui , Kim Seok-Hyung , Lee Jung Hyun , Choi Yoon-La , Kim Young Chul , Park Tae Sung , Hong Yun-Chul , Wu Chun-Fu , Shin Young Kee
Published: January 2007

Purpose: Mothers against decapentaplegic homologue 4 (SMAD4) is a tumor suppressor gene associated with gastrointestinal carcinogenesis. The aim of the present study is to more precisely characterize its role in the development and progression of human gastric carcinoma.

Experimental Design: The expression of SMAD4 was investigated in 283 gastric adenocarcinomas and related lesions, as well as in 9 gastric carcinoma cell lines. We also analyzed the methylation status of SMAD4 gene by using methylation-specific PCR, examined loss of heterozygosity (LOH) of this gene locus by using a vicinal marker, and detected exon mutation of SMAD4 through exon-by-exon amplification. Moreover, we assessed whether MG132, a proteasome inhibitor, affected the SMAD4 protein level.

Results: We found loss of SMAD4 protein expression in the cytoplasm (36 of 114, 32%) and in the nucleus (46 of 114, 40%) of gastric cancer cells. The loss of nuclear SMAD4 expression in primary tumors correlated significantly with poor survival, and was an independent prognostic marker in multivariate analysis. We also found a substantial decrease in SMAD4 expression at both the RNA and protein level in several human gastric carcinoma cell lines. In addition, we found that LOH (20 of 70, 29%) and promoter hypermethylation (4 of 73, 5%) were associated with the loss of SMAD4 expression. SMAD4 protein levels were also affected in certain gastric carcinoma cell lines following incubation with MG132.

Conclusion: Taken together, our results indicate that the loss of SMAD4, especially loss of nuclear SMAD4 expression, is involved in gastric cancer progression. The loss of SMAD4 in gastric carcinomas was due to several mechanisms, including LOH, hypermethylation, and proteasome degradation.
High Human Papillomavirus Oncogene mRNA Expression and Not Viral DNA Load Is Associated with Poor Prognosis in Cervical Cancer Patients
Authors: de Boer Marjon A. , Jordanova Ekaterina S. , Kenter Gemma G. , Peters Alexander A. , Corver Willem E. , Trimbos J. Baptist , Fleuren Gert Jan
Published: January 2007

Purpose: Cervical cancer is now known to be caused by infection with an oncogenic type of the human papillomavirus (HPV). However, little is known about the continued role of HPV once cancer has been established. Here, we describe the quantitative relation between HPV DNA copy number and mRNA expression of the viral oncogenes (E6 and E7) and the prognostic value of both measures in cervical cancer patients.

Experimental Design: We studied the number of viral DNA copies and the level of HPV E6/E7 mRNA expression in 75 HPV 16–positive or HPV 18–positive International Federation of Gynecology and Obstetrics stage Ib and IIa cervical cancer patients. Measurements were done with quantitative PCR. DNA copy number analysis was done on pure tumor cell samples enriched with flow sorting. mRNA expression data were compensated for the percentage of tumor cells included.

Results: The number of viral DNA copies was not predictive of survival in cervical cancer patients. In contrast, high HPV E6/E7 mRNA expression was strongly related to an unfavorable prognosis (P = 0.006). In a multivariate Cox model for overall survival, including all known prognostic variables and stratified for HPV type, the level of E6/E7 mRNA expression was an independent prognostic indicator, second only to lymph node status. No correlation was observed between DNA copy number and the level of HPV E6/E7 mRNA expression, which reflects that not all DNA copies are equally transcriptionally active.

Conclusions: Cervical cancer patients with high HPV E6/E7 oncogene mRNA expression have a worse survival independently from established prognostic factors.
The Effects of Histone Deacetylase Inhibitors on the Induction of Differentiation in Chondrosarcoma Cells
Authors: Sakimura Riku , Tanaka Kazuhiro , Yamamoto Syunsaku , Matsunobu Tomoya , Li Xu , Hanada Masuo , Okada Takamitsu , Nakamura Tomoyuki , Li Yang , Iwamoto Yukihide
Published: January 2007

Purpose: Histologically, chondrosarcomas represent the degree of chondrogenic differentiation, which is associated with the prognosis of the disease. Histone acetylation and deacetylation play key roles in the regulation of chondrocytic differentiation. Here, we describe the antitumor effects of histone deacetylase (HDAC) inhibitors as differentiating reagents on chondrosarcomas.

Experimental Design: We examined the effects of a HDAC inhibitor, depsipeptide, on the growth of chondrosarcoma cell lines. We also investigated the modulation of the expression levels of extracellular matrix genes and the induction of phenotypic change in chondrosarcoma cells treated with depsipeptide. Finally, we examined the antitumor effect of depsipeptide on chondrosarcoma in vivo.

Results: Depsipeptide inhibited the growth of chondrosarcoma cells by inducing cell cycle arrest and/or apoptosis. HDAC inhibitors increased the expression of the α1 chain of type II collagen (COL2A1) gene due to the enhanced histone acetylation in the promoter and enhancer. Depsipeptide also up-regulated the expressions of aggrecan and the α2 chain of type XI collagen (COL11A2) mRNA in a dose-dependent manner. Moreover, long-term treatment with a low dose of depsipeptide resulted in the induction of differentiation into hypertrophic phenotype, as shown by the increment of the α1 chain of type X collagen (COL10A1) expression in chondrosarcoma cells. In vivo studies and histologic analyses confirmed that depsipeptide significantly inhibited tumor growth and induced differentiation into the hypertrophic and mineralized state in chondrosarcoma cells.

Conclusions: These results strongly suggest that HDAC inhibitors may be promising reagents for use as a differentiating chemotherapy against chondrosarcomas.
Therapeutic Synergy of Human Papillomavirus E7 Subunit Vaccines plus Cisplatin in an Animal Tumor Model: Causal Involvement of Increased Sensitivity of Cisplatin-Treated Tumors to CTL-Mediated Killing in Therapeutic Synergy
Authors: Bae Sung Hwa , Park Young-Ja , Park Jae-Bok , Choi Youn Seok , Kim Mi Suk , Sin Jeong-Im
Published: January 2007

Purpose: The goal of this study was to investigate the therapeutic potentials of combining chemotherapy with human papillomavirus (HPV) E7 subunit vaccines in an animal tumor model and to determine the underlying therapeutic mechanisms.

Experimental Design: Animals bearing HPV E6/E7–expressing tumors were treated intratumorally with a selected cytotoxic drug, cisplatin, twice at 1-week interval and s.c. with E7 subunit vaccines thrice at 1-week interval. Tumor chemoimmunoresponse was measured by tumor size. Ag-specific CTL activities and tumor histology were checked in mice under treatments. Apoptosis, in vivo T-cell subset depletion, adoptive CTL transfer, and tumor regression were used to determine the mechanisms for antitumor therapeutic effects.

Results: Combined therapy using cisplatin plus E7 subunit vaccines improved cure and recurrence rates of tumors and long-term antitumor immunity dramatically more than single therapy alone. In particular, both components of E7 subunit vaccines were required for induction of Ag-specific CTL as well as therapeutic synergy when combined with cisplatin. This therapeutic synergy was abrogated by depletion of CD8+ T cells in vivo and was concomitant with histologic changes (such as heavy infiltration of lymphocytes and reduced tumor cell density). Finally, the increased sensitivity of cisplatin-treated tumors to CTL-mediated killing was found to be responsible for therapeutic synergy.

Conclusions: E7 subunit vaccines plus cisplatin mediate antitumor therapeutic synergy through the increased sensitivity of cisplatin-treated tumors to CTL-mediated killing. Moreover, E7-based therapeutic vaccines have the potential to improve chemotherapy in patients with cervical cancer.
The −20 and −217 Promoter Variants Dominate Differential Angiotensinogen Haplotype Regulation in Angiotensinogen-Expressing Cells
Authors: Dickson Matthew E. , Zimmerman M. Bridget , Rahmouni Kamal , Sigmund Curt D.
Published: January 2007

A number of naturally occurring polymorphisms exist in the human angiotensinogen locus, some of which have been associated with essential hypertension, preeclampsia, and other medical disorders. However, to date there has been no comprehensive determination of the significance of specific haplotypes in relation to the regulation of angiotensinogen expression. We cloned the promoters extending from −1219 to +125 bp from 11 ethnically diverse individuals to acquire a representative cross-section of known haplotype diversity. Eight nonredundant haplotypes were identified, fused to luciferase, and studied for their effect on transcriptional regulation in human astrocyte, proximal tubule, and hepatocyte cell lines endogenously expressing angiotensinogen and in a mouse adipocyte cell line. The studies were carried out under baseline conditions, in the presence of the angiotensinogen enhancer, and in response to hormonal stimulation by dexamethasone, β-estradiol, or testosterone. A statistical model was then constructed to assess the significance of individual polymorphisms. The polymorphisms with the greatest effect on transcription in these cell lines were located at −20 and −217. There were modest haplotype-specific effects of the angiotensinogen enhancer and no haplotype-specific effects of β-estradiol, dexamethasone, or testosterone treatment. We conclude the following: (1) the −20 and −217 polymorphisms have the largest influence on angiotensinogen transcription, (2) other polymorphisms have a much smaller impact on angiotensinogen transcription, and (3) the transcriptional influence of the promoter polymorphisms may act cell specifically. Therefore, our data support a hypothesis that polymorphisms in the angiotensinogen promoter may act cell specifically to differentially regulate the level of angiotensinogen transcription in angiotensin-producing tissues.
Early Outcomes of Tricuspid Valve Replacement in Young Children
Authors: Bartlett Heather L. , Atkins Dianne L. , Burns Trudy L. , Engelkes Kelly J. , Powell Sarah J. , Hills Christine B. , Moller James H.
Published: January 2007

Background—

Early outcomes after tricuspid valve replacement in young children are ill defined. The experience of the Pediatric Cardiac Care Consortium (45 centers, 1984 to 2002) was reviewed to evaluate the results of tricuspid valve replacement in children <6 years of age.

Methods and Results—

Ninety-seven patients who underwent initial tricuspid valve replacement are included in the present analysis. The most frequent cardiac diagnoses were Ebstein’s anomaly (40%), pulmonary atresia (11%), and tetralogy of Fallot (8%). Age at tricuspid valve replacement was 2.9±1.7 years (mean±SD). Mean patient weight was 12.7±6.1 kg. The major outcome was survival to discharge. Associations among age, diagnosis, valve type/size, and outcome were evaluated through the use of χ

2

analysis and logistic regression model fitting approaches. Hospital mortality was 26% and was very high (64%) in patients <1 year of age. A large size-to-weight ratio was the strongest predictor of mortality based on multivariable analysis (
P
<0.001). Mortality was 54% for patients with a size-to-weight ratio >2.5. Other complications included heart block requiring a pacemaker (13%) and thrombosis (5%). Pacemaker implantation was associated with the use of a mechanical valve (23% versus 6% bioprosthetic valve;
P
=0.01)

Conclusions—

Tricuspid valve replacement in young children is associated with high mortality, especially in infants <1 year of age. Surgical options other than tricuspid valve replacement such as transplantation may need to be considered in infants.
Reflections on tourist satisfaction research: Past, present and future
Authors: Bowen David , Clarke Jackie
Published: January 2007

An overview is provided of some key considerations in the now considerable literature that exists on consumer and tourist satisfaction. Special emphasis is placed on the distinctiveness or otherwise of the three concepts of satisfaction, quality and value; the supposed components of satisfaction and related theoretical paradigms; the particular characteristics of tourism that provide the context for the development of satisfaction; and, finally, the felt need for innovation with regard to research methodologies and new research methods. The overall objective is to raise issues and to indicate answers — or at least provide some signposts — that will be of use to practitioners and academics alike as they seek better to understand tourist satisfaction.
Mythologies of a theme park: An icon of modern family life
Authors: Johns Nick , Gyimóthy Szilvia
Published: January 2007

This study took the view that visitors perceive theme parks in terms of hedonic experience rather than simply as commercial service offerings, and respond to emotional content rather than to the utility of tourism service provision. The study took place at Legoland, at Billund in Denmark. The views of 35 customers were solicited through indepth interviews and these were analysed in two diferent ways in order to investigate customer perceptions and satisfaction. Grounded theory was employed to identify basic concepts that cropped up in the interview transcripts, and a linguistic analysis of ‘mythologies’ underlying visitors' discourse was also used, providing important reference points to visitors' choice, expectation, perception and evaluation of the theme park. The two techniques were in broad agreement that the park catered well for children's needs, but left adults with a feeling that they were ‘babysitting’. The paper suggests various ways in which Legoland might address this disparity.
Gene-Expression and Immunohistochemical Study of Specific T-Cell Subsets and Accessory Cell Types in the Transformation and Prognosis of Follicular Lymphoma
Authors: Glas Annuska M. , Knoops Laurent , Delahaye Leonie , Kersten Marie José , Kibbelaar Robby E. , Wessels Lodewyk A. , van Laar Ryan , van Krieken J. Han J.M. , Baars Joke W. , Raemaekers John , Kluin Philip M. , van ’t Veer Laura J. , de Jong Daphne
Published: January 2007

Purpose

Despite the generally favorable clinical course in follicular lymphoma (FL), a minority of patients have a poor prognosis—with death within 3 years of diagnosis—most often due to transformation to aggressive disease.

Patients and Methods

In this study, we analyzed the potential of predicting early transformation on the basis of gene expression and immunologic parameters in FL biopsy samples taken at diagnosis.

Results

At the gene-expression level, FL is a highly uniform disease at the time of diagnosis, precluding the detection of sufficiently validated prognostic gene-expression profiles suitable for a clinical setting. Combinations of differentially expressed genes indicate that immunologic mechanisms play a differential role in the risk of early transformation. Using immunohistochemistry for specific cell populations, the spatial distribution to neoplastic follicles and the activation of CD4–positive T-helper cells (P = .002) and specifically T-helper 1 (P = .004) were shown to be highly discriminatory to predict early transformation. A role for functional modulation of follicular dendritic cells could also be supported (P = .04). Other cell populations, including CD68-positive macrophages and regulatory T cells, were not differentially present.

Conclusion

These results support the identification of FL as an immunologically functional disease in which an interaction of the tumor cells and the functional composition of the microenvironment determines the clinical behavior.
Five Years of Letrozole Compared With Tamoxifen As Initial Adjuvant Therapy for Postmenopausal Women With Endocrine-Responsive Early Breast Cancer: Update of Study BIG 1-98
Authors: Coates Alan S. , Keshaviah Aparna , Thürlimann Beat , Mouridsen Henning , Mauriac Louis , Forbes John F. , Paridaens Robert , Castiglione-Gertsch Monica , Gelber Richard D. , Colleoni Marco , Láng István , Del Mastro Lucia , Smith Ian , Chirgwin Jacquie , Nogaret Jean-Marie , Pienkowski Tadeusz , Wardley Andrew , Jakobsen Erik H. , Price Karen N. , Goldhirsch Aron
Published: January 2007

Purpose

Previous analyses of the Breast International Group (BIG) 1-98 four-arm study compared initial therapy with letrozole or tamoxifen including patients randomly assigned to sequential treatment whose information was censored at the time of therapy change. Because this presentation may unduly reflect early events, the present analysis is limited to patients randomly assigned to the continuous therapy arms and includes protocol-defined updated results.

Patients and Methods

Four thousand nine hundred twenty-two of the 8,028 postmenopausal women with receptor-positive early breast cancer randomly assigned (double-blind) to the BIG 1-98 trial were assigned to 5 years of continuous adjuvant therapy with either letrozole or tamoxifen; the remainder of women were assigned to receive the agents in sequence. Disease-free survival (DFS) was the primary end point.

Results

At a median follow-up time of 51 months, we observed 352 DFS events among 2,463 women receiving letrozole and 418 events among 2,459 women receiving tamoxifen. This reflected an 18% reduction in the risk of an event (hazard ratio, 0.82; 95% CI, 0.71 to 0.95; P = .007). No predefined subsets showed differential benefit. Adverse events were similar to previous reports. Patients on tamoxifen experienced more thromboembolic events, endometrial pathology, hot flashes, night sweats, and vaginal bleeding. Patients on letrozole experienced more bone fractures, arthralgia, low-grade hypercholesterolemia, and cardiovascular events other than ischemia and cardiac failure.

Conclusion

The present updated analysis, which was limited to patients on monotherapy arms in BIG 1-98, yields results similar to those from the previous primary analysis but more directly comparable with results from other trials of continuous therapy using a single endocrine agent.
Association between Blood Pressure and Serum Thyroid-Stimulating Hormone Concentration within the Reference Range: A Population-Based Study
Authors: Åsvold Bjørn O. , Bjøro Trine , Nilsen Tom I. L. , Vatten Lars J.
Published: January 2007

Context: The association between thyroid function and blood pressure is insufficiently studied.

Objective: The objective of the investigation was to study the association between TSH within the reference range and blood pressure.

Design and Setting: This was a cross-sectional, population-based study.

Subjects: A total of 30,728 individuals without previously known thyroid disease were studied.

Main Outcome Measures: The main outcome measures were mean systolic and diastolic blood pressure and pulse pressure and odds ratio for hypertension (>140/90 mm Hg or current or previous use of antihypertensive medication), according to categories of TSH.

Results: Within the reference range of TSH (0.50–3.5 mU/liter), there was a linear increase in blood pressure with increasing TSH. The average increase in systolic blood pressure was 2.0 mm Hg [95% confidence interval (CI) 1.4–2.6 mm Hg] per milliunit per liter increase in TSH among men, and 1.8 mm Hg (95% CI 1.4–2.3 mm Hg) in women. The corresponding increase in diastolic blood pressure was 1.6 mm Hg (95% CI 1.2–2.0 mm Hg) in men and 1.1 mm Hg (95% CI 0.8–1.3 mm Hg) in women. Comparing TSH of 3.0–3.5 mU/liter (upper part of the reference) with TSH of 0.50–0.99 mU/liter (lower part of the reference), the odds ratio for hypertension was 1.98 (95% CI 1.56–2.53) in men and 1.23 (95% CI 1.04–1.46) in women.

Conclusion: Within the reference range of TSH, we found a linear positive association between TSH and systolic and diastolic blood pressure that may have long-term implications for cardiovascular health.